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Still Standing Up to Cancer

FitSugar — Sun, 14 Sep 2008 03:30:00 -0700

Just over a week ago, all three major networks simultaneously broadcast Stand Up to Cancer. The organization has raised $100 million since its inception and the funds will go directly to funding research programs to fight this deadly disease. Documentary film maker Errol Morris made this three minute video that captures surprising and surprisingly moving moments about how cancer has affected people's lives.

Maybe Lance Armstrong's return to bike racing will help raise even more funds for cancer research, but you can still donate to the cause at the Stand Up to Cancer website. Having friends and family that have succumbed to this disease, I can't watch this clip without crying. How about you? If you feel up to it, please share how cancer has affected your life.

Stand Up to Cancer With the Stars

FitSugar — Fri, 05 Sep 2008 12:00:00 -0700

Most likely, cancer has affected everybody in one way or another, which is why it's so important that we bind together to find a cure. But it's not just your own efforts to stay healthy that will keep cancer out of your life. You should also think about the greater cause.

Tonight be sure to check out the Stand Up to Cancer telethon. This one-hour, commercial-free event will be broadcast on NBC, ABC, and CBS simultaneously to raise funds for the fight against cancer. Celebs such as Jennifer Aniston, Fergie, Jack Black, Jennifer Garner, Miley Cyrus, America Ferrera, and many more will be on hand to give their support, so it's bound to be just as entertaining as it is a good cause. If you're not going to be around for the event or even if you are, you can still donate now online.

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Christina Applegate Stands Up to Breast Cancer

FitSugar — Tue, 05 Aug 2008 03:30:00 -0700

Who would have thought that the ditsy and carefree character Kelly Bundy in the hit TV show Married . . . With Children would ever receive such shocking news. The actress, Christina Applegate, known also for her roles in Don’t Tell Mom the Babysitter’s Dead and Anchorman: The Legend of Ron Burgundy, is undergoing treatment for breast cancer. Thankfully, it was caught early enough through an MRI her doctor ordered, so the cancer isn't life-threatening and a full recovery is expected.

Christina is appearing on a one-hour TV special called “Stand Up To Cancer” to talk about her experience with breast cancer. It's airing on Sept. 5 to help raise funds for cancer research, and to increase awareness about this disease. Hopefully they'll talk about the importance of early detection and how necessary it is to have a doctor check you out if breast cancer is in your family, or if you've felt something you're concerned about.

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Breast cancer

FitSugar — Wed, 08 Oct 2008 17:34:59 -0700

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approvals

In September 2007, Evista (raloxifene) was approved for prevention of breast cancer in postmenopausal women with osteoporosis, and postmenopausal women at high risk for invasive breast cancer. Raloxifene and tamoxifen are the only two drugs approved for breast cancer prevention in high-risk women.
In March 2007, lapatinib (Tykerb) was approved in combination with capecitabine (Xeloda) for treatment of advanced HER2-positive breast cancer.
In November 2006, trastuzumab (Herceptin) was approved for treatment of early-stage HER2-positive breast cancer. Trastuzumab is also approved for advanced HER2-positive breast cancer.

Screening

The American College of Physicians’ 2007 guidelines recommend that women with a low risk for breast cancer talk to their doctor before starting to have mammogram screening at age 40. Other associations, including the American Cancer Society, continue to recommend annual mammograms for women age 40 and older.
Women at high risk for breast cancer should have an MRI scan along with their annual mammogram, according to 2007 guidelines from the American Cancer Society.
For women who have been diagnosed with cancer in one breast, an MRI can help detect tumors in the other breast, indicates a 2007 study in the New England Journal of Medicine.

Post-Treatment Guidelines

The American Society of Clinical Oncology (ASCO)’s 2006 post-treatment guidelines recommend regular physical exams, breast self-exam, mammograms, and genetic counseling. Know how to recognize the signs of breast cancer recurrence. ASCO does not recommend blood and imaging tests for routine recurrence screening.

Hormone Replacement Therapy (HRT) and Breast Cancer Risk

Fewer women are using HRT, which may explain why new cases of breast cancer among postmenopausal women have declined, suggests a recent New England Journal of Medicine study.

Aromatase Inhibitors

Drug treatment with aromatase inhibitors is improving survival in women with hormone-sensitive advanced breast cancer, suggest recent studies. Switching from tamoxifen to an aromatase inhibitor may help improve the odds for survival.

Introduction

Breast cancers are potentially life-threatening malignancies that develop in one or both breasts. The structure of the female breast is important in understanding this cancer:

The interior of the female breast consists mostly of fatty and fibrous connective tissues.
It is divided into about 20 sections called lobes.
Each lobe is further subdivided into a collection of lobules, structures that contain small milk-producing glands.
These glands secrete milk into a complex system of tiny ducts. The ducts carry the milk through the breast and converge in a collecting chamber located just below the nipple.
Breast cancer is either noninvasive (referred to as in situ, confined to the site of origin) or invasive (spreading).

The female breast is either of two mammary glands (organs of milk secretion) on the chest.

Noninvasive breast cancers include:

Ductal carcinoma in situ (also called intraductal carcinoma or DCIS). DCIS consist of cancer cells in the lining of the duct. DCIS is a non-invasive, early cancer, but if left untreated, it may sometimes progress to an invasive, infiltrating ductal breast cancer.
Lobular carcinoma in situ, or LCIS. Although noninvasive, lobular carcinoma in situ is a marker for an increased risk of invasive cancer in both breasts. (Some experts prefer to call this condition lobular neoplasia rather than refer to it as a cancer.) According to a 2001 report, for patients with LCIS the risk for developing invasive cancer in the same breast is about 18% -- and 14% in the other breast -- after 20 years. These invasive cancers can be either lobular or ductal.

At the time of diagnosis of these early cancers (DCIS and LCIS), there is no evidence of invasion.

Invasive cancer occurs when cancer cells spread beyond the basement membrane, which covers the underlying connective tissue in the breast. This tissue is rich in blood vessels and lymphatic channels that are capable of carrying cancer cells beyond the breast. Invasive breast cancers include the following:

Infiltrating ductal carcinoma. This is invasive breast cancer that penetrates the wall of a duct. It comprises between 70 - 80% of all breast cancer cases.
Infiltrating lobular carcinoma. This invasive cancer has spread through the wall of a lobule. It accounts for 10 - 15% of all breast cancers. It may sometimes appear in both breasts, sometimes in several separate locations.

Click the icon to see an image of the breast.

There are other less common breast cancers that are not discussed in this report.

Risk Factors

About 12 - 13% of women develop breast cancer in their lifetime. Experts estimate that about 178,480 women will be newly diagnosed with invasive breast cancer in the United States in 2007. Another 2,030 men will be diagnosed with breast cancer during the year. Although breast cancer in men is rare, the incidence has been increasing, and men are diagnosed at a later stage than women. An estimated 40,460 women and 450 men will die from breast cancer in 2007. The earlier breast cancer is diagnosed, the earlier the opportunity for treatment. According to the American Cancer Society, over 2 million women who have been treated for breast cancer are alive today.

Age is a major identifiable risk factor. More than 80% of breast cancer cases occur in women over age 50, and especially in women over age 65. The odds by age are as follows:

From ages 30 - 39, a woman’s chance for being diagnosed with breast cancer is 1 in 233
Ages 40 - 49, the odds are 1 in 69
Ages 50 - 59, the odds are 1 in 38
Ages 60 - 69, the odds are 1 in 27
Ages 70 - 79, the odds are 1 in 11
After age 80, the odds are 1 in 8

Breast cancer is more prevalent among Jewish women of Eastern European (Ashkenazi) descent. Meanwhile, African-American women tend to get breast cancer at an earlier age than Caucasians. Although African-American women have lower overall rates of breast cancer, they represent the highest proportion of women who are diagnosed with the disease before age 45. Comparative studies of breast cancer rates among sub-Saharan Africans suggest a genetic component, as African women are diagnosed most frequently between ages 35 - 45.

The mortality rate in African-Americans is twice that of Caucasians, although it is declining. Social and economic factors make it less likely that African-American women will be screened, so they are more likely to be diagnosed at a later stage. They are also less likely to have access to effective treatments. However, there also appears to be a biological basis for African-American women’s poorer prognosis. According to research presented at the 2007 Breast Cancer Symposium, African-American women are more likely to have estrogen receptor-negative tumors, a type of breast cancer that is more difficult to treat.

An estimated 10% of all women with breast cancer have a very strong family history of the disease. Inherited forms of breast cancer often appear in young women under the age of 50. In such families, some members may also be at higher risk for ovarian cancer. These mutations can be inherited from either a mother or father.

Prior to menopause, a mass on the ovary that is smaller than 2 centimeters is probably a follicle cyst that will go away on its own. However, if the growth is larger and doesn't go away over the course of a few menstrual cycles, then it may need to be removed.

BRCA Genes. Inherited mutations in genes known as BRCA1 or BRCA2 are responsible for 30 - 50% of hereditary breast cancers, ovarian cancers, or both in families with a history of these cancers. According to some studies, the risk each gene carries is:

Between 25 - 35% of BRCA1 carriers develop breast cancer by age 70.
Between 35 - 50% of BRCA2 carriers develop the disease. BRCA2 genes also increase the lifetime risk of breast cancer in men.

These mutations are present in only about 0.5% of the overall population. However, certain ethnic groups -- such as Jewish women of Eastern European (Ashkenazi) descent -- have a higher prevalence (2.5%) of BRCA gene mutations. BRCA gene mutations are also seen in some African-American and Hispanic women.

Screening Guidelines for BRCA Genes. In 2005, the U.S. Preventive Services Task Force (USPSTF) released updated guidelines for BRCA testing. While women at high risk should be tested, the USPSTF does not recommend routine genetic counseling or testing for BRCA genes in low-risk women (no family history of BRCA 1 or 2 genetic mutations).

ESR Genes. Genetic variations in estrogen receptor genes (ESRs) may increase the risk for some women but offer protection to others. Mutations in the ESR1 and ESR2 genes may be associated with breast cancer susceptibility for Ashkenazi women over age 50 years.

Other Genetic Factors. Mutations in the tumor suppressor gene p53 are more common in the breast cancer tumors of African-American women than in Caucasian women. Researchers have also identified other defective genes that contribute to breast cancer, such as NOEY2 (which is inherited from the father), CHEK2, and ATM, a mutant gene for the rare disorder ataxia-telangiectasia. (The disease itself is rare, but 1% of the population carries a single copy -- enough to increase the risk for breast cancer.) Cowden's syndrome is an inherited disorder caused by a defective PTEN gene that is associated with a higher risk of breast cancer.

Not all genetic mutations are inherited. In 2007, scientists announced they had located a genetic mutation found in as many as 30 - 40% of breast cancers. The IKBKE mutation appears to occur during the course of a women’s lifetime. It causes overproduction of a kinase protein (IKK-epsilon) that fuels cell growth and tumor development. By identifying this genetic mutation, scientists hope they can develop drugs that will target and block IKK-epsilon production.

Because growth of breast tissue is highly sensitive to estrogens, the more estrogen a woman is exposed to over her lifetime, the higher her risk for breast cancer.

Duration of Estrogen Exposure. Early age at menarche (first menstrual period) or later age at menopause may slightly increase a women’s risk for breast cancer.

Pregnancy. Women who have never had children or who had their first child after age 30 may have a slightly increased breast cancer risk. Having children at an early age, and having multiple pregnancies, reduces breast cancer risk.

Although a few studies have suggested a slightly increased risk for breast cancer in women who have had abortions, the weight of evidence does not support an association between abortion and breast cancer. A large-scale 2007 study found that neither induced abortions nor spontaneous abortions (miscarriages) increases breast cancer risk. However, interrupting a pregnancy does reduce the protective features of a full-term pregnancy.

Studies have been mixed on whether breast-feeding decreases breast cancer risk. Breast-feeding reduces a woman’s total number of menstrual cycles, and thereby estrogen exposure, which may account for its possible protective effects. Some studies suggest that the longer a woman breast-feeds, the lower her risk.

Oral Contraception. Studies have been conflicting about whether estrogen in oral contraception increases the chances for breast cancer. Some studies have found no evidence that oral contraceptive use increases the risk for breast cancer, even in women who have taken birth control pills for 15 years or more or had taken them at young ages. In contrast, other studies have reported a slightly higher risk in women who are current or recent users and in women who take them for more than 4 years before a first full-term pregnancy.

Hormone Replacement Therapy. Many studies have reported a higher risk for breast cancer in postmenopausal women who take hormone replacement therapy (HRT) that contains both estrogen and progestin. A combination of estrogen and testosterone also increases breast cancer risk. A 2005 study suggested that HRT with no or low progestin is safer than standard estrogen-progestin combination therapy.

Several 2006 studies of women who had a hysterectomy indicated that estrogen alone does not increase overall breast cancer risk when the drug is used for 7 years or less. However, women who take estrogen for 10 - 15 years or more do have an increased risk, especially women who are already at higher risk for breast cancer. In addition, HRT increases breast cancer density, making mammograms more difficult to read. This can cause cancer to be diagnosed at a later stage. Women who take estrogen HRT should be aware that they need frequent mammogram screenings.

As further evidence of the association between HRT and breast cancer, a 2007 New England Journal of Medicine study noted that breast cancer rates have fallen as HRT use has declined. The decline in rates occurred among women over the age of 50 and was particularly associated with cancers that were estrogen receptor-positive. This type of cancer requires estrogen for growth. Experts think that postmenopausal women’s discontinuation of estrogen-containing HRT may explain the decrease in rates of new cases of estrogen receptor-positive cancer.

A 2007 position statement from the North American Menopause Society recommends that women who are at risk for breast cancer should avoid hormone therapy and try other options to manage menopausal symptoms such as hot flashes. At this time, most experts recommend that women use HRT only for short-term relief of menopausal symptoms. [See In-Depth Report #40: Menopause.]

Infertility and Infertility Treatments. There has been concern that infertility treatments using the drug clomiphene may increase the risk for breast cancer. A reassuring 2006 study indicated that ovulation induction with clomiphene does not increase breast cancer risk, and may actually decrease it. (Clomphine is related to tamoxifen, a drug that is used for breast cancer prevention in high-risk women.) The study also suggested that women who are infertile because of ovulatory dysfunction have a 25% lower risk for breast cancer than fertile women.

Abnormalities or Breast Conditions Suggesting a Higher Risk. Certain factors and breast conditions may increase the risk for breast cancer:

Dense breast tissue is associated with a higher risk for breast cancer. Studies suggest that women with highly dense tissue have 2 - 6 times the risk of women with the least dense tissue. Genetic factors play a large role in breast density. Hormone replacement therapy also increases breast density. In addition, dense breasts make mammograms more difficult to read, which increases the likelihood of missing early signs of cancer.
Benign proliferative breast disease, or unusual cell growth known as atypical hyperplasia, is a significant risk factor for breast cancer.

Some common benign breast abnormalities that pose few or no risks include the following:

Cysts. These mostly occur in women in their middle-to-late reproductive years and can be eliminated simply by aspirating fluid from them.

Click the icon to see an image of cysts in the breast.

Fibroadenoma. These are solid benign lumps that occur in women ages 15 - 30.
Breast abscesses during breast-feeding.

Click the icon to see an image of a breast abscess.

Nipple discharge. Discharge from the nipple is worrisome to patients, but is unlikely to be a sign of cancer. Unexplained discharge still warrants evaluation, however.

Click the icon to see an image of nipple discharge.

Mastalgia. This is breast pain that occurs in association with, or independently from, the menstrual cycle. About 8 - 10% of women experience moderate-to-severe breast pain associated with their menstrual cycle. In general, breast pain does not need assessment unless it is severe and prolonged.

The following physical characteristics have been associated with increased risk:

Obesity increases the risk for all types of estrogen receptor-positive breast cancers. Women who gain weight after menopause are most at risk. (On a positive note, losing weight after menopause decreases breast cancer risk.) In postmenopausal women, estrogen is produced in fat tissue. High amounts of fatty tissue increase levels of estrogen in the body, leading to faster growth of estrogen-sensitive cancers.
Estrogen is involved in building bone mass. Therefore, women with heavy, dense bones are likely to have higher estrogen levels and to be at greater risk for breast cancer.
Some studies have found a greater risk for breast cancer in taller women, possibly due to the higher estrogen levels associated with greater bone growth. In one study, regardless of their actual height, women who reached their full height at age 13 or younger had a higher risk than those who attained maximum height at age 18, reflecting higher estrogen levels at an earlier age.

Exposure to Estrogen-like Industrial Chemicals. Chemicals with estrogen-like effects, called xenoestrogens, have been under suspicion for years. There has been particular concern with pesticides containing organochlorines (DDT and its metabolites, such as dieldrin) and pyrethroids (permethrin), but at this time evidence of any causal association is very weak.

Exposure to Diethylstilbestrol. Women who took diethylstilbestrol (DES) to prevent miscarriage have a slightly increased risk for breast cancer. Recent studies also suggest a slightly increased risk for their daughters (commonly called "DES daughters"), who were exposed to the drug when their mothers took it during pregnancy.

Radiation Exposure. Heavy exposure to radiation is a significant risk factor for breast cancer. Girls who received high-dose radiation therapy face an increased risk for breast cancer in adulthood. Low-dose radiation exposure before age 20 may increase the risk for women with BRCA genetic mutations.

Researchers theorize that viruses may be involved in some types of breast cancers. A study of breast cancer samples taken from Tunisian women in North Africa found similarities with a virus known to cause breast cancer in mice. The samples were compared with those taken from women living in other global regions. The researchers suggested that a human breast cancer virus may be more prevalent in specific parts of the world.

Prevention and Lifestyle Factors

Evidence indicates that regular exercise, particularly vigorous exercise, may offer some modest protection against breast cancer. Exercise can help reduce body fat, which in turn lowers levels of cancer-promoting hormones such as estrogen. In fact, a 2006 study suggested that physical activity may help women reduce the risk for developing estrogen receptor-positive tumors.

Exercise can also help women who have been diagnosed with breast cancer. Studies indicate that both aerobic and weight training exercises benefit the body and the mind, and improve quality of life for breast cancer survivors. Even moderate exercise can help improve survival. A 2005 study in the Journal of the American Medical Association reported survival benefits for women diagnosed with breast cancer who walked 3 – 5 hours per week at an average pace. The American Cancer Society recommends engaging in 45 - 60 minutes of physical activity at least 5 days a week. A recent study indicated that diet and exercise can reduce the risk of breast cancer recurrence.

Physical activity contributes to health by reducing the heart rate, decreasing the risk for cardiovascular disease, and reducing the amount of bone loss that is associated with age and osteoporosis. Physical activity also helps the body use calories more efficiently, thereby helping in weight loss and maintenance. It can increase basal metabolic rate, reduces appetite, and helps in the reduction of body fat.

Despite much research on the association between diet and breast cancer, there is still little consensus. The best advice is to eat a well-balanced diet and avoid focusing on one "cancer-fighting" food. The American Cancer Society’s dietary guidelines for cancer prevention recommend that people:

Choose foods and amounts that promote a healthy weight.
Eat 5 or more servings of fruits and vegetables each day.
Choose whole grains instead of refined grain products.
Limit consumption of processed and red meat.
Women should limit alcohol consumption to 1 drink per day (women at high risk for breast cancer should consider not drinking alcohol at all).

For breast cancer survivors, the American Cancer Society recommends diets that include lots of fruits and vegetables, low amounts of saturated fat (from meat and high-fat dairy products), moderation in soy foods, and moderate or no alcohol consumption.

Here are results from recent studies evaluating diet and breast cancer, for preventing both the development of cancer and its recurrence:

Fats. Research is still mixed on the role that fats, and which specific types of fats, play in breast cancer risk and prevention. Several studies have indicated that red meat, which is high in saturated fat, may increase breast cancer risk when eaten in large quantities on a daily basis. (Red meat is also high in iron, which in itself may increase breast cancer risk.) According to results from the 2006 Women’s Health Initiative study of dietary fat and breast cancer, experts cannot yet definitely say that a low-fat diet will help prevent breast cancer. However, the study suggested that women who normally eat a very high-fat diet may benefit by reducing their fat intake. In the study, the low-fat diet reduced blood estrogen levels by 15%. The low-fat diet also appeared to reduce the risk for developing progesterone receptor-negative tumors.

Fruits and Vegetables. Fruits and vegetables are important sources of antioxidants, which may help protect against the tissue damage linked to increased cancer risk. Antioxidants include vitamin C, vitamin E, and carotenoids such as beta-carotene and lycopene. Richly colored fruits and vegetables -- not supplements -- are the best sources for these nutrients. These fiber-rich foods are an essential part of a healthy diet. However, it is not clear whether fruits and vegetables can specifically prevent breast cancer development or recurrence. According to a 2007 study of women with early-stage breast cancer, a low-fat diet very high in vegetables, fruit, and fiber does not work any better in preventing breast cancer recurrence than the standard 5 servings a day of fruits and vegetables. (However, a combination of diet and exercise may help.)

Calcium and Vitamin D. Eating lots of foods rich in calcium and vitamin D (such as yogurt and milk) may modestly reduce the risk of breast cancer for premenopausal -- but not postmenopausal -- women, according to a 2007 study. Low-fat or non-fat dairy products are a healthier choice than high-fat ones.

Click the icon to see an image of vitamin D sources.

Soy. Soy is an excellent low-fat protein alternative to meat. Soy contains phytoestrogens, which are estrogen-like plant chemicals. In particular, soy contains a type of phytoestrogen called isoflavones. Because many soy foods (such as tofu) are eaten in Asian countries where women tend to have a lower incidence of breast cancer, research has focused on whether soy may have a protective effect. To date, the evidence does not indicate that soy foods or supplements can reduce breast cancer risk. In addition, some studies suggest that high intakes of soy may actually increase the risk of estrogen-responsive cancers such as breast cancer. Some animal studies have suggested that the isoflavone compound genistein may reduce the protective properties of tamoxifen, a drug used to prevent breast cancer in high-risk women. The American Cancer Society recommends that women with breast cancer eat only moderate amounts of soy foods and avoid taking dietary supplements that contain high amounts of isoflavones.

Click the icon to see an image of phytochemicals.

Lifestyle Factors. Premenopausal women at higher risk, usually because of family history, should take as many preventive measures as possible, starting at an early age. The following lifestyle choices may be beneficial:

Exercising and eating healthily is the first essential rule.
High-risk premenopausal women may choose alternatives to oral contraceptives and, if feasible, consider having children early in their life.
High-risk postmenopausal women may want to forego hormone replacement therapy.
Any woman at high risk for breast cancer should consider avoiding alcohol or drinking it very sparingly.

In spite of some rumors published in the popular press, antiperspirants or use of deodorants after shaving have not been linked with any higher risk for breast cancer.

Tamoxifen and Raloxifene. Drugs known as selective estrogen-receptor modulators (SERMs) act like estrogen in some tissues but behave like estrogen blockers (anti-estrogens) in others. Two SERMs -- tamoxifen (Nolvadex) and raloxifene (Evista) -- are approved for breast cancer prevention for high-risk women. Tamoxifen and raloxifene are not recommended as prevention for women at low risk for breast cancer or its recurrence. Women at high risk for breast cancer should discuss with their doctors the risks and benefits of SERMs.

Tamoxifen (Nolvadex) is the most studied of these drugs. It is currently used to treat breast cancer and was the first drug approved for prevention. Evidence strongly suggests that it halves the risk for estrogen receptor-positive cancers in high-risk women, including those with BRCA2 mutations (although possibly not BRCA1). It also helps prevent recurrence in women who have been treated for breast cancers. However, it has no protective effects against estrogen receptor-negative (hormone-insensitive) cancers.

Tamoxifen can increase the risk for uterine (endometrial) cancers. It can also increase the risk for blood clots, strokes, and endometriosis. Less serious side effects include hot flashes and vaginal discharge.

Raloxifene (Evista) was approved in 2007 for prevention of breast cancer in postmenopausal women with osteoporosis and postmenopausal women at high risk for invasive breast cancer. Raloxifene was previously approved for prevention and treatment of osteoporosis in postmenopausal women. One of raloxifene’s main benefits is that it has a lower risk than tamoxifen of causing uterine cancer. However, raloxifene also has some serious risks.

According to the prescribing information from the Food and Drug Administration (FDA), raloxifene can increase the risk of blood clots. Women with a history of blood clots in the legs, lungs, or eyes should not take this medicine. Although studies indicate raloxifene does not increase the risk of stroke, it can increase the risk of dying from a stroke. Women with a history of stroke or current risk factors for stroke should discuss with their doctors whether raloxifene is an appropriate choice. Less serious side effects of raloxifene include hot flashes, leg cramps, swelling of the legs and feet, flu-like symptoms, joint pain, and sweating. Raloxifene can cause birth defects and is approved only for postmenopausal women. It should not be taken with the cholesterol-lowering drug cholestyramine (Questran) or with estrogens.

The FDA based its approval of raloxifene on results from several major studies. The comparison trial Study of Tamoxifen and Raloxifene (STAR), published in 2006 in the Journal of the American Medical Association, indicated that raloxifene works as well as tamoxifen in reducing the risk of invasive breast cancer, and has a lower risk of causing blood clots. However, the Raloxifene Use for the Heart (RUTH) trial, published in 2006 in the New England Journal of Medicine, suggested that raloxifene carries its own risks for blood clots and fatal strokes and may not be a safe choice for women at high risk of heart disease.

Investigational Drugs for Breast Cancer Prevention.

Aromatase inhibitors. Aromatase inhibitors such as anastrazole (Armidex), letrozole (Femara), and exemestane (Aromasin) are effective treatments for hormone-receptor positive breast cancer. Like tamoxifen, they are also being investigated for protection in high-risk women. However, these drugs may decrease bone mineral density and cognitive function, and increase the risk for falls.
Retinoids. Analogues of vitamin A called retinoids are being studied for protection against breast cancer. One retinoid, fenretinide, appears to offer some protection against a second breast cancer in previously diagnosed, premenopausal women (but not in postmenopausal women). It can cause birth defects and should not be used during pregnancy.

Symptoms

Breast cancers in their early stages are usually painless. Often the first symptom is the discovery of a hard lump. Fifty percent of such masses are found in the upper outer quarter of the breast. The lump may make the affected breast appear elevated or asymmetric. The nipple may be retracted or scaly. Sometimes the skin of the breast is dimpled like the skin of an orange. In some cases there is a bloody or clear discharge from the nipple. Many cancers, however, produce no symptoms and cannot be felt on examination. They can be detected only with a mammogram.

Monthly breast self-exams should always include: visual inspection (with and without a mirror) to note any changes in contour or texture, and manual inspection in standing and reclining positions to note any unusual lumps or thicknesses.

Diagnosis

Breast Examination by a Health Professional. Early detection of breast cancer significantly reduces the risk of death. Women ages 20 - 49 should have a physical examination by a health professional every 1 - 2 years. Those over age 50 should be examined annually. A breast exam by a health professional can find 10 - 25% of breast cancers that are missed by mammograms. Between 6 - 46% of the lumps detected by examination are malignant. (The yield is lowest in younger women and highest in older women.)

Self-Examinations. Woman have been encouraged to perform a self-examination each month, but well-conducted studies in 2002 reported no difference in mortality rates between women who were intensively instructed in self-examination and those who were not. This does not mean women should stop attempting self-examinations, but they should not replace the annual examination done by a health professional, which evidence suggests is beneficial.

1. Pick a time of the month that is easy to remember and perform self-examination at that time each month. The breast has normal patterns of thickness and lumpiness that change within a monthly period, and a consistently scheduled examination will help differentiate between what is normal from abnormal.

2. Stand in front of a mirror. Breasts should be basically the same size (one may be slightly larger than the other). Check for changes or redness in the nipple area. Look for changes in the appearance of the skin. With hands on the hips, push the pelvis forward and pull the shoulders back and observe the breasts for irregularities. Repeat the observation with hands behind the head. Move each arm and shoulder forward.

3. Lie down on the back with a rolled towel under one shoulder. Apply lotion or bath oil over the breast area.

The finger action should be as follows: Using the 2nd, 3rd, and 4th finger pads (not tips) held together, make dime-sized circles. Press lightly first to feel the breast area, then press harder using a circular motion.

Using this motion, start from the collarbone and move downward to underneath the breast. Shift the fingers slightly over, slightly overlapping the previously checked region, and work upward back to the collarbone. Repeat this up-and-down examination until the entire breast area has been examined. Be sure to cover the entire area from the collarbone to the bottom of the breast area and from the middle of the chest to the armpits. Move the towel under the other shoulder and repeat the procedure.

Examine the nipple area, by gently lifting and squeezing it and checking for discharge.

4. Repeat step 3 in an upright position. (The shower is the best place for this, using plenty of soap.)

Note: A lump can be any size or shape and can move around or remain fixed. Of special concern are specific or unusual lumps that appear to be different from the normal varying thicknesses in the breast.

Click the icon to see an image of a breast self-exam.

Current Recommendations for Screening. Mammograms are very effective low-radiation screening methods for breast cancer. At this time, the U.S. Preventive Services Task Force recommends screening mammograms, with or without breast examination, every 1 - 2 years for all women over age 40.

Guidelines from the American College of Physicians (ACP), however, debate whether women with a low risk for breast cancer should begin mammogram screening at age 40. The 2007 guidelines, instead, recommend that women in their 40s ask their doctor when they should begin having the test. In contrast, the American Cancer Society and the U.S. National Cancer Institute continue to endorse annual screening for women age 40 and older.

The ACP's guidelines have created controversy within the medical community. Supporters of the guidelines believe that these new recommendations reflect some of the risks involved in screening younger women. These risks include radiation exposure and unnecessary biopsies. Mammographies in younger women produce a relatively high rate of false-positive results (when the test falsely indicates breast cancer). Scientists are working on new technologies to improve mammography's accuracy, but more work is needed. For example, a 2007 New England Journal of Medicine study reported that computer-aided detection software, which is used to help radiologists interpret mammograms, may instead make readings less accurate.

Opponents of the ACP guidelines argue that mammograms help catch tumors while they are in their earliest and most treatable stages, and that the most deadly types of breast cancer tend to occur in women in their 40s.

In addition, according to a review in the American Cancer Society's journal, mammography rates have declined since 2000. In fact, while many experts believe that the recent decline in new cases of breast cancer is partially due to reduced use of hormone replacement therapy, other experts are concerned that fewer cases of breast cancer are being detected because fewer mammographies are being performed.

After age 50, all guidelines recommend annual screenings. The older a women gets, the greater her risk for developing breast cancer. (Women over age 65 account for most new cases of breast cancer.) Women with risk factors for breast cancer, including a close family member with the disease, should consider having annual mammograms starting 10 years earlier than the age at which the relative was diagnosed.

Click the icon to see an image of a mammogram.

Magnetic Resonance Imaging and Ultrasound. Magnetic resonance imaging (MRI) and ultrasound techniques can detect very small tumors (less than half an inch). However, they are expensive and time-consuming procedures. Nevertheless, some doctors believe they are important in identifying small tumors missed on mammography in women who are receiving lumpectomy or breast-conserving surgeries. Such findings would allow the surgeons to remove the optimal amount of abnormal tissue. Ultrasound may also be particularly important for women with dense breast tissue who show signs of breast cancer.

In a report published in 2007, the American Cancer Society recommended that high-risk women have an MRI of their breast with their annual mammogram, including those who have:

A BRCA1 or BRCA2 mutation
A first-degree relative (parent, sibling, child) with a BRCA1 or BRCA2 mutation, even if they have yet to be tested themselves
A lifetime risk of breast cancer that has been scored at 20 - 25% or greater
Had radiation to the chest between ages 10 - 30
Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome, or may have one of these genetic syndromes based on a history in a first-degree relative

For women who have had cancer diagnosed in one breast, MRIs can also be very helpful for detecting hidden tumors in the other breast. A landmark 2007 study in the New England Journal of Medicine reported that MRI scans of women who were diagnosed with cancer in one breast detected over 90% of cancers in the other breast that had been previously missed by mammography or clinical breast exam. Currently, few women who are diagnosed with cancer in one breast are offered an MRI of the other breast. Some experts advocate MRIs for all women newly diagnosed with breast cancer; others oppose this view. MRI scans may be most useful for younger women with breast cancer who have dense breast tissue that may obscure tumors from mammography readings. MRIs are less likely to be helpful for older women with early tumors in one breast and clear mammography readings in the other.

It is very important that women have MRIs at qualified centers that perform many of these procedures each year. MRI is a complicated procedure and requires special equipment and experienced radiologists. MRI facilities should also be able to offer biopsies when suspicious findings are detected.

Scintimammography. In scintimammography, a radioactive chemical is injected into the circulatory system, which is then selectively taken up by the tumor and revealed on mammograms. This method is very accurate in detecting the presence or absence of breast cancer, and some doctors hope that it might eventually reduce the number of unnecessary invasive biopsies. It is used for women who have had abnormal mammograms or for women who have dense breast tissue. It is not used for regular screening or as an alternative to mammography.

A definitive diagnosis of breast cancer can be made only by a biopsy (a microscopic examination of a tissue sample of the suspicious area).

When a lump can be felt and is suspicious for cancer on mammography, an excisional biopsy may be recommended. This biopsy is a surgical procedure for removing the suspicious tissue and typically requires general anesthetic.

Click the icon to see an image of breast biopsy.

A core biopsy involves a small incision and the insertion of a spring-loaded hollow needle that removes several samples. The patient only requires local anesthetic.
A wire localization biopsy may be performed if mammography detects abnormalities but there is no lump. With this procedure, using mammography as a guide, the doctor inserts a small wire hook through a hollow needle and into the suspicious tissue. The needle is withdrawn, and the hook is used by the surgeon to locate and remove the lesion. The patient may receive local or general anesthetic.
A new vacuum-assisted device may be useful for some biopsies. This uses a single probe through which a vacuum is used to draw out tissue. It allows several samples to be taken without having to remove and re-insert the probe.

Final analysis of the breast tissue may take several days.

If breast cancer has been determined, the next diagnostic step is to find out how far it has spread. To do this, the doctor performs a procedure called an axillary lymphadenectomy, which partially or completely removes the lymph nodes in the armpit beside the affected breast (called axillary lymph nodes). It may require a hospital stay of 1 - 2 days.

Click the icon to see an image of the axillary lymph nodes.

Once the lymph nodes are removed, they are analyzed to determine whether subsequent treatment needs to be more or less aggressive:

If no cancer is found in the lymph nodes, the condition is referred to as node negative breast cancer. The chances are good that the cancer has not spread and is still local.
If cancer cells are present in the lymph nodes, the cancer is called node positive. Their presence increases the possibility that the cancer has spread microscopically to other areas of the body. In such cases, however, it is still not known if the cancer has metastasized beyond the lymph nodes or, if so, to what extent. The doctor may perform further tests to see if the cancer has spread to the bone (bone scan), lungs (x-ray or CT scan) or brain (MRI or CT scan).

Side effects of the procedure include increased risk for infection and pain, swelling in the arm from fluid build-up, and impaired sensation and restricted movement in the affected arm. Patients might ask their doctor about the availability of physical therapy or upper-body exercises after treatment. In two studies, such programs resulted in quicker recovery and no fluid build-up in the arm.

A technique known as a sentinel node biopsy is a less invasive alternative to axillary lymph node dissection. This procedure can help determine if cancer has spread beyond the nodes. If the doctor finds no evidence of cancer, the patient may not need to have a complete axillary lymphadenectomy.

Click the icon to see an image of a sentinel node biopsy.

Sentinel node biopsy involves:

The procedure uses an injection of a tiny amount of a tracer, either a radioactively-labeled substance (radioisotope) or a blue dye, into the tumor site.
The tracer or dye then flows through the lymphatic system into the sentinel node. This is the first lymph node to which any cancer would spread.
The sentinel lymph node and possibly one or two others are then removed.
If they do not show any signs of cancer, it is highly likely that the remaining lymph nodes will be cancer free, making further surgery unnecessary.

Patients who have a sentinel node biopsy tend to have better arm function and a shorter hospital stay than those who have an axillary node biopsy. The American Society of Clinical Oncology's 2005 guidelines recommend sentinel node biopsy instead of axillary lymph node dissection for women with early stage breast cancer who do not have nodes that can be felt during a physical exam. It is still not known if the sentinel node biopsy has any survival advantages compared to standard lymph node removal procedures.

Women often have to wait several days for results of sentinel node biopsies to learn whether they will require another surgery to remove additional lymph nodes. In 2007, the Food and Drug Administration approved the GeneSearch BLN Assay to help speed sentinel node biopsy testing. This molecular-based lab test can detect within 40 minutes whether cancer has spread to nearby lymph nodes. Because the test delivers rapid results while the patient is still on the operating table, it may help spare women the discomforts of a second surgical procedure and help them get treatment earlier.

Prognosis

In the U.S., about 40,460 women will die from breast cancer this year, making it the second most lethal cancer in women. (Lung cancer is the leading cancer killer in women.) The good news is that early detection and new treatments have improved survival rates. The 5-year survival rate for women diagnosed with cancer is 80%. About 88% of women diagnosed with breast cancer will survive at least 10 years. Unfortunately, women in lower social and economic groups still have significantly lower survival rates than women in higher groups.

Several factors are used to determine successful treatment and the possibility for a cure. They include:

The location of the tumor and how far it has spread
Whether the tumor is hormone receptor-positive or -negative
Genetic factors
Tumor size and shape
Rate of cell division
Biologic markers

The good news is that women are living longer with breast cancer, and at this time more than 2 million American women are survivors. Due to better treatment options, from 1990 - 2003, breast cancer mortality rates declined by 24%. However, survivors must live with the uncertainties of possible recurrent cancer and some risk for complications from the treatment itself.

Recurrences of cancer usually develop within 5 years of treatment. However, 25% of recurrences and half of new cancers in the opposite breast occur after 5 years. One study suggested that the risk factors for a first breast cancer do not necessarily place a woman at any higher risk for recurrence. (Women with a first cancer, however, do have a higher risk for a new cancer in the opposite breast. The outlook for such new cancers is independent from those of the first one.)

The location of the tumor is a major factor in outlook:

If the cancer is ductal carcinoma in situ (DCIS) or has not spread to the lymph nodes (is node-negative), the 5-year survival rates with treatment are up to 98%. However, cancer recurs in 9 - 30% of women with node-negative cancers. Recurrence is a potentially life-threatening problem, even if the disease relapses locally in the same breast. In one study of DCIS patients with locally invasive recurrence, 8-year mortality rates were only 12%.
If the lymph nodes contain cancer cells (are node positive) then survival rates fall. If the tumor is larger than 5 cm or there is widespread involvement in the lymph nodes, the cancer is sometimes referred to as locally advanced. In such cases, the survival rate drops to about 75% and below.
If the cancer has spread (metastasized) to other sites (most often the lung, liver, and bone), the average survival time is about 2 years (with some patients living for many years). New drug therapies, particularly aromatase inhibitors, have helped prolong survival for women with metastatic cancer.

The location of the tumor within the breast is an important predictor. Tumors that develop toward the outside of the breast tend to be less serious than those that occur more toward the middle of the breast.

Breast cancer cells may contain receptors, or binding sites, for the hormones estrogen and progesterone. Cells containing these binding sites are known as hormone receptor-positive cells. If cells lack these connectors, they are called hormone receptor-negative cells. About 75% of breast cancers are estrogen receptor-positive (ER-positive, or ER+). About 65% of ER-positive breast cancers are also progesterone receptor-positive (PR-positive, or PR+). Cells that have receptors for one of these hormones, or both of them, are considered hormone receptor-positive.

Hormone receptor-positive cancer is also called "hormone sensitive" because it responds to hormone therapy such as tamoxifen or aromatose inhibitors. Hormone receptor-negative tumors are referred to as "hormone insensitive" or "hormone resistant."

Women have a better prognosis if their tumors are hormone receptor-positive because these cells grow more slowly than receptor-negative cells. In addition, women with hormone receptor-positive cancer have more treatment options. (Hormone receptor-negative tumors can be treated only with chemotherapy.) A 2007 study in the Journal of Clinical Oncology indicated that recent declines in breast cancer mortality rates have been most significant among women with estrogen receptor-positive tumors, due in part to the widespread use of post-surgical tamoxifen therapy.

Determining a "genetic signature" for a tumor may prove to be a very powerful predictor of the aggressive nature of a breast cancer. Researchers have focused on 70 genes whose activity patterns may help make such predictions. In 2007, the Food and Drug Administration approved MammaPrint, a DNA microarray diagnostic test that profiles these 70 genes. The molecular test may help predict how likely it is that breast cancer will recur within 5 - 10 years. However, the accuracy of the test depends on a woman’s risk. It is more accurate when predicting a low risk for recurrence than a high risk.

The relevance of the inherited BRCA1 or BRCA2 mutations to survival is controversial. Some studies have suggested that these mutations offer a survival advantage. Others suggest that they make no difference or even worsen prognosis. Women with these genetic mutations do have a greater risk for a new cancer to develop. Patients with BRCA1 mutations tend to develop tumors that are hormone receptor negative, which can behave more aggressively.

Researchers are investigating numerous substances in tumor cells that may indicate whether or not a cancer is likely to spread. Such chemical markers may help doctors determine treatments, and some may even prove to be targets for future drugs. The following are only a few of the more well-researched markers.

HER2. The American Cancer Society recommends that all women newly diagnosed with breast cancer get a biopsy test for a growth-promoting protein called HER2/neu. HER2-positive cancer usually occurs in younger women and is more quickly-growing and aggressive than other types of breast cancer. The HER2 marker is present in about 20% of cases of invasive breast cancer. Two types of tests are used to detect HER2:

Immunohistochemistry (IHC)
Fluorescence in-situ hybridization (FISH)

Some doctors think that FISH is a more accurate test than IHC. According to 2006 HER2 testing guidelines from the American Society of Clinical Oncology and the College of American Pathologists, either test may be used as long as it is performed by an accredited laboratory. Tests that are not clearly positive or negative should be repeated. Treatment with trastuzumab (Herceptin) or lapatinib (Tykerb) may help women who test positive for HER2.

Angiogenesis Factors. Angiogenesis is the growth of new blood vessels. High levels of angiogenesis factors indicate that the tumor is developing its own supply of blood vessels, which enable the tumor to send colonies of cancer cells into the bloodstream and spread to other parts of the body. Specific angiogenesis factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), may turn out to be important markers for determining treatment and prognosis. The monoclonal antibody bevacizumab (Avastin) targets VEGF. The drug is showing promise in clinical trials for prolonging progression-free survival in women with metastatic breast cancer.

Others. Many other markers are being investigated, including p53, cathepsin-D, protein c-erbB-2, bcl-2, Ki-67, telomerase, thymidylate synthase, CA 15-3, and carcinogenic embryonic antigen (CEA). The American Society of Clinical Oncology (ASCO) cautions, however, that the value of many of these factors has not yet been confirmed.

Tumor Size and Shape. Large tumors pose a higher risk than small tumors. Undifferentiated tumors, which have indistinct margins, are more dangerous than those with well-defined margins.

Rate of Cell Division. The more rapidly a tumor grows, the more dangerous it is. Several tests measure aspects of cancer cell division and may eventually prove to predict the disease. For example, the mitotic index (MI) is a measurement of the rate at which cells divide. The higher the MI, the more aggressive the cancer. Another test measures cells at a certain phase of their division.

Recent evidence has not supported early reports of survival benefits for women with metastatic breast cancer who engage in support groups. However, some studies have suggested that psychotherapy, group support, or both may relieve pain and reduce stress, particularly in women who are suffering emotionally.

Stress has been ruled out as a risk factor either for breast cancer itself or for its recurrence.

Treatment

The three major treatments of breast cancer are surgery, radiation, and drug therapy. No one treatment fits every patient, and combination therapy is usually required. The choice is determined by many factors, including the age of the patient, menopausal status, the kind of cancer (ductal vs. lobular), its stage, and whether or not the tumor contains hormone-receptors.

Breast cancer treatments are defined as local or systemic:

Local Treatment. Surgery and radiation are considered local therapies because they directly treat the tumor, breast, lymph nodes, or other specific regions. Surgery is usually the standard initial treatment.
Systemic Treatment. Drug treatment is called systemic therapy, because it affects the whole body.

Any or all of these therapies may be used separately or, most often, in different combinations. For example, radiation alone or with chemotherapy or hormone therapy may be beneficial before surgery, if the tumor is large or not easily removed at prevention. Surgery followed by radiation and hormone therapy is usually recommended for women with early-stage, hormone-sensitive cancer. There are numerous clinical trials investigating new treatments and treatment combinations. Patients, especially those with advanced stages of cancer, may wish to consider enrolling in a clinical trial.

Treatment strategies depend in part on the stage of the cancer.

Stage 0 (Carcinoma in Situ). Stage 0 breast cancer is considered non-invasive (‘in situ"), meaning that the cancer is still confined within breast ducts or lobules and has not yet spread to surrounding tissues. Stage 0 cancer is classified as either:

Ductal carcinoma in situ (DCIS). These are cancer cells in the lining of a duct that have not invaded the surrounding breast tissue.
Lobular carcinoma in situ (LCIS). These are cancer cells in the lobules of the breast. LCIS rarely develops into invasive breast cancer, but having it in one breast increases the risk of developing cancer in the other breast.

Treatment options for DCIS include:

Breast-conserving surgery and radiation therapy (followed by hormone therapy for women with hormone-sensitive cancer)
Total mastectomy (followed by hormone therapy for women with hormone-sensitive cancer)
Breast-conserving surgery without radiation therapy

Treatment options for LCIS include:

Regular exams and mammograms to monitor any potential changes (observation treatment)
Hormone therapy to prevent development of breast cancer (for women with hormone-sensitive cancer)
Mastectomy of both breasts was previously used as treatment, but is now rarely recommended

Stage I and II (Early-Stage Invasive). In stage I cancer, cancer cells have not spread beyond the breast, and the tumor is no more than 2 cm (about 3/4 of an inch) across.

Stage II cancer is classified as either stage IIA or stage IIb.

In stage IIA cancer the tumor is either:

No more than 2 centimeters and has spread to the underarm lymph nodes (axillary lymph nodes)
Between 2 - 5 centimeters and has not spread to the underarm lymph nodes

Treatment options for stage I and stage II breast cancer may include:

Breast-conserving surgery (such as lumpectomy) followed by radiation therapy
Modified radical mastectomy with or without breast reconstruction
Post-surgical therapy (adjuvant therapy), including radiation of lymph nodes, chemotherapy, or hormone therapy
Trastuzumab (Herceptin) given along with or following adjuvant chemotherapy for women with HER2-positive cancer

Stage III (Locally Advanced). Stage III breast cancer is classified into several sub-categories: Stage IIIA, stage IIIB, and stage IIIC (operable or inoperable).

In stage IIIA breast cancer, the tumor is usually confined to the underarm lymph nodes. Treatment options for stage IIIA breast cancer are the same as those for stages I and II.

In stage IIIB breast cancer, the tumor has spread to either:

Tissues near the breast (including the skin or chest wall)
Lymph nodes within the breast or under the arm

Stage IIIB treatment options may include:

Chemotherapy, and possibly hormone therapy (sometimes in combination with chemotherapy)
Chemotherapy followed by surgery (breast-conserving surgery or total mastectomy) with lymph node dissection followed by radiation therapy and possibly more chemotherapy or hormone therapy
Clinical trials

Stage IIIC breast cancer is classified as either operable or inoperable.

In operable stage IIIC, the cancer may be found in:

10 or more of the underarm lymph nodes
Lymph nodes beneath the collarbone and near the neck on the same side of the body as the affected breast
Lymph nodes within the breast as well as underarm lymph nodes

Treatment options for operable stage III breast cancer are the same as those for stage I and II breast cancers.

In inoperable stage III breast cancer, the cancer has spread to lymph nodes above the collarbone and near the neck on the same side of the body as the affected breast. Treatment options are the same as those for stage IIIB.

Stage IV (Advanced Cancer). In stage IV, the cancer has spread (metastasized) from the breast to other parts of the body. In about 75% of cases, the cancer has spread to the bone. The cancer at this stage is considered to be chronic and incurable, and the usefulness of treatments is limited. The goals of treatment for stage IV cancer are to stabilize the disease and slow its progression, as well as to reduce pain and discomfort.

Treatment options for stage IV cancer include:

Surgery or radiation for any localized tumors in the breast. A 2006 study indicated that surgical removal of the primary tumor immediately after metastatic cancer diagnosis can dramatically improve survival.
Chemotherapy, hormone therapy, or both. Targeted therapy with trastuzumab (Herceptin) or lapatinib (Tykerb) should be considered for women with HER2-positive cancer.
Cancer that has spread to the brain may require radiation and high-dose steroids.
Cancer that has spread to the bone may be helped by radiation or bisphosphonate drugs. Such treatments can relieve pain and help prevent bone fractures.
Clinical trials of new drugs or drug combinations, or experimental treatments such as high-dose chemotherapy with stem cell transplant.

In 2006, the American Society of Clinical Oncology (ASCO) released updated guidelines on follow-up care for patients who have been treated for breast cancer. ASCO recommends:

Visit your doctor every 3 - 6 months for the first 3 years after your first cancer treatment, every 6 - 12 months during the fourth and fifth year, and once a year thereafter.
Have a mammogram 1 year after the mammogram that diagnosed your cancer (but no earlier than 6 months after radiation therapy), and every 6 - 12 months thereafter.
Perform a breast self-exam every month (however, this is no substitute for a mammogram).
See your gynecologist regularly (women taking tamoxifen should be sure to report any vaginal bleeding).
A year after diagnosis, you can either continue to see your oncologist or transfer your care to your primary care physician.
If you are on hormone therapy, discuss with your oncologist how often to schedule follow-up visits for re-evaluation of your treatment.

ASCO does not recommend the use of laboratory blood tests (complete blood counts, carcinoembryonic antigen) or imaging tests (bone scans, chest x-rays, liver ultrasound, FDG-PET scan, CT scan) for routine breast cancer follow-up.

Genetic counseling may be helpful if you have:

Ashkenazi Jewish heritage
Personal or family history of ovarian cancer
Personal or family history of cancer in both breasts
Any first-degree female relative (mother, sister, daughter) diagnosed with breast cancer before age 50
Two or more first-degree or second-degree (grandparent, aunt, uncle) diagnosed with breast cancer
History of breast cancer in a male relative

Pregnancy after Breast Cancer Treatment. There are no definite recommendations on how long a woman should wait to become pregnant after breast cancer treatment. Because of the connection between estrogen levels and breast cancer cell growth, some experts recommend delaying pregnancy until 2 years after treatment in order to reduce the risk of cancer recurrence and improve odds for survival. However, a 2007 study indicated that conceiving 6 months after treatment does not negatively affect survival. Discuss with your doctor your risk for recurrence, and when it may be safe to attempt pregnancy.

Recurrent breast cancer is considered to be an advanced cancer. In such cases, the disease has come back in spite of the initial treatment. Most recurrences appear within the first 2 - 3 years after treatment, but breast cancer can recur many years later. Treatment options are based on the stage at which the cancer reappears, whether or not the tumor is hormone responsive, and the age of the patient. Between 10 - 20% of recurring cancers are local. Most recurrent cancers are metastatic. All patients with recurring cancer are candidates for clinical trials.

Because most breast cancer recurrences are discovered by patients in between doctor visits, it is important to notify your doctor if you experience any of the following symptoms. These symptoms may be signs of breast cancer recurrence:

New lumps in the breast
Bone pain
Chest pain
Abdominal pain
Shortness of breath or difficulty breathing
Persistent headaches or coughing
Rash on breast
Nipple discharge

Surgery

Surgery forms a part of nearly every patient's treatment for breast cancer. The initial surgical intervention is often a lumpectomy, the removal of the tumor itself. In the past, mastectomy (the removal of the breast) was the standard treatment for nearly all breast cancers. Now, many patients with early-stage cancers can choose breast-conserving treatment, or lumpectomy followed by radiation, with or without chemotherapy.

For invasive breast cancer, studies indicate that lumpectomy or partial mastectomy combined with radiation therapy works as well as a modified radical mastectomy.

Breast-conserving procedures are now appropriate and as successful as mastectomy in most women with early stage breast cancer. All women should discuss these options fully with their doctor. Recurrence rates with conservative surgery are highest in women under age 45. Some women choose mastectomy over breast-conserving treatment even if the latter is appropriate because it gives them a greater sense of security and allows them to avoid radiation therapy.

Lumpectomy. Lumpectomy is the removal of the tumor, often along with lymph nodes in the armpit. It serves as an opportunity for biopsy, a diagnostic tool, and a primary treatment for small local breast tumors. If invasive cancer is found, the doctor will decide to proceed with breast radiation therapy, to remove additional tissue (should the margins of the specimen show signs of cancer), or to perform a mastectomy. Lumpectomy followed by radiation therapy is appropriate and as effective as mastectomy in most women with Stage I or II breast cancers.

Click the icon to see an illustrated series detailing breast lump removal surgery.

Breast-Conserving Surgery (Quadrantectomy). Breast-conserving surgery (sometimes referred to as quadrantectomy) removes the cancer and a large area of breast tissue, occasionally including some of the lining over the chest muscles. It is less invasive than a full mastectomy, but the cosmetic results are less satisfactory than with a lumpectomy. Excellent studies have found that breast-conserving surgeries plus postoperative radiotherapy offer the same survival rates as radical mastectomy in women with early breast cancer. A new technology called partial breast radiation (MammoSite), approved by the Food and Drug Administration in 2002, confines radiation to the tumor site rather than delivering it to the whole breast, and reduces treatment time from 5 weeks to 5 days in women who undergo breast conserving surgery.

Surgery to remove the breast (mastectomy) is important for women with operable breast cancer who are not candidates for breast conserving surgeries. There are different variations on the procedure:

A total mastectomy involves removal of the whole breast and sometimes lymph nodes under the armpit.
A radical mastectomy removes the breast, chest muscles, all of the lymph nodes under the arm, and some additional fat and skin. (A modified radical mastectomy removes the entire breast and armpit lymph nodes, with the underlying chest wall muscle.) A 25-year study supported other research that observed no survival advantages from radical mastectomy compared to the less invasive mastectomies for the great majority of patients. It is rarely used anymore except when cancer is very advanced.

Click the icon to see an illustrated series detailing mastectomy surgery.

Complications and Side Effects of Surgery. Short-term pain and tenderness occur in the area of the procedure, and pain relievers may be necessary.

The most frequent complication of extensive lymph node removal is edema, or swelling, of the arm, which is usually mild and rarely painful but does increase the risk for infection. The likelihood of edema can be lessened by removing only some of the lymph nodes instead of all of them.

Infrequent complications include poor wound healing, bleeding, or a reaction to the anesthesia.

After mastectomy and lymph node removal, women may experience numbness, tingling, and difficulty in extending the arm fully. These effects can last for months or years afterward.

After a mastectomy, some women choose a breast prosthesis or opt for breast reconstruction, which can be performed during the mastectomy itself, if desired. Several studies have indicated that women who take advantage of cosmetic surgery after breast cancer have a better sense of well-being and a higher quality of life than women who do not choose reconstructive surgery. The breast is reshaped using a saline implant or, for a more cosmetic result, a muscle flap is taken from elsewhere in the body. Muscle flap procedures are more complicated, however, and blood transfusions may be required. (It should be noted that implants, including silicone implants, do not appear to put a woman at risk for breast cancer recurrence.) If the nipple is removed, it is rebuilt from other body tissues and color is applied using tattoo techniques. It is nearly impossible to rebuild a breast that is identical to its partner, and additional operations may be necessary to achieve a desirable effect.

Click the icon to see an illustrated series detailing breast reconstruction surgery.

Numerous studies are investigating minimally invasive techniques that use lasers, deep-freezing of cancer cells (cryosurgery), high-intensity ultrasound, and other experimental approaches to kill cancer cells and reduce severe complications of surgery. Radiofrequency ablation, for example, is an approach that uses an electrode inserted into the tumor. It emits radio waves that produce enough heat to destroy cancer cells. Early trials are promising. These procedures, however, are not considered standard at the present time.

Radiation

Radiation therapy uses high-energy x-rays to kill cancer cells or to shrink the size of a tumor in the breast or surrounding tissue. It is used for several weeks following lumpectomy or partial mastectomy, and sometimes after full mastectomy. Radiation therapy can help reduce the chance of breast cancer recurrence in the breast and chest wall. Radiation is also important in advanced stages of cancer for relief of symptoms and to slow progression. Research shows that radiation therapy is helpful for women of all ages, including those over age 65.

Radiation is generally administered in the following ways:

External Beam Radiation. This type of radiation is administered 4 - 6 weeks after surgery and delivered externally by an x-ray machine that targets radiation to the whole breast. It may be delivered to the chest wall in high-risk patients (large tumors, close surgical margins, or lymph node involvement). The treatment is generally given daily (except for weekends) for about 6 weeks. A follow-up boost of radiation therapy in patients with lumpectomies appears to reduce the risk for recurrence.

Brachytherapy. Less commonly, radiation is delivered in implants (called brachytherapy). Implants are most often used as a radiation boost after whole breast radiation. Studies suggest they improve survival in patients at high risk for local recurrence. Some evidence suggests that implants alone can reduce treatment time and may be as effective as external beam radiation in some patients with early stage breast cancer. A new technology for breast brachytherapy (MammoSite) was approved in 2002. The technique provides 5-year local tumor control rates similar to those of whole-breast radiation for selected patients, with much shorter treatment time and good cosmetic results.

Investigators are also testing other approaches to radiation treatment. One uses a combination of neutrons and protons (mixed-beam) or proton beams rather than the standard photon radiation therapy. Intensity-modulated radiation therapy is a promising technique that delivers different doses to multiple target areas using images of specific regions. Such an approach may improve the coverage of breast cancers while reducing the toxic effects to the heart and lungs.

Side effects of radiation include:

Fatigue is very common and increases with subsequent treatments, but most women are able to continue with normal activities. Exercise may be helpful.
Nausea and lack of appetite may develop and worsen as treatment progresses.
Skin changes and burns can occur on the breast skin. Using a cream that contains a corticosteroid, such as mometasone furoate (MMF), may be helpful. After repeated sessions, the skin may become moist and "weepy." Exposing the treated skin to air as much as possible helps healing. (Washing the affected skin with soap and water does not seem to be harmful and in one study was associated with a lower risk for this side effect.)
Uncommonly, the breast may change color, size, or become permanently firm.
Rarely, the nearest arm may swell and develop impaired mobility or even paralysis.

Future complications include:

Radiation to the left breast may increase the long-term risk for developing heart disease and heart attacks.
There is a very small risk (less than 1%) of lung irritation and scarring.
Some studies have reported a higher risk for future cancer in the opposite breast in younger women who have been given radiation to the chest wall.
Radiation therapy can increase the risk of developing other cancers, such as soft tissue malignancies known as sarcomas.

Current advanced imaging techniques use precise radiation that reduces exposure. These newer techniques are likely to reduce the risks for heart disease and other serious complications.

Medications

The most important advances in the cure of breast cancer have come through the use of drug therapy, also called systemic therapy. Surgery and radiation therapy are effective for treating tumors confined to the breast but not for cancer cells that have spread or are at risk of spreading. In such cases, drug therapy is needed.

Drug treatments for breast cancer include:

Chemotherapy. Chemotherapy drugs are "cytotoxic" (cell-killing) drugs. They are given orally or by injection. They work systemically by killing cancer cells throughout the body. (Unfortunately, they also kill normal cells, which accounts for many of their side effects.) Chemotherapy is always used for advanced breast cancer, but may also be used to treat types of early-stage breast cancer.
Hormone Therapy. The goal of hormone therapy is to prevent estrogen from stimulating breast cancer cells. It is recommended for women whose breast cancers are hormone-receptor positive (either estrogen or progesterone), regardless of the size of the tumor and whether or not it has spread to the lymph nodes. Like chemotherapy, hormone therapy works systemically.
Targeted Therapy. Newer biologic drugs target specific proteins involved in cancer. Because they do not work as systemically as chemotherapy or hormone therapy drugs, they tend to cause fewer widespread side effects. Currently, the monoclonal antibody trastuzumab (Herceptin) and the kinase inhibitor lapatinib (Tykerb) are the two targeted therapies approved for breast cancer. These drugs target the HER2/neu protein and are used to treat HER2-positive breast cancers. Bevacizumab (Avastatin) is a monoclonal antibody that targets vascular endothelial growth factor (VEGF), a protein involved in tumor blood vessel formation (angiogenesis). It is being studied in clinical trials for treatment of metastatic breast cancer.

Drug therapy may be used as:

Primary therapy for patients for whom surgery or radiation therapy is not appropriate.
Neoadjuvant therapy (before surgery or radiation) to shrink tumors to a size that can be treated with local therapy.
Adjuvant therapy (following surgery or radiation) to reduce the risk of cancer recurrence.

For metastatic cancer, drugs are used not to cure but to improve quality of life and prolong survival.

Chemotherapy

Chemotherapy needs to be tailored to the type of cancer involved. Women require different treatments depending on whether the tumor is node-negative or -positive, hormone receptor-positive or -negative, or HER2-positive or -negative. Different treatment approaches are also used for early-stage cancer and advanced cancer.

A 2006 study in the Journal of the American Medical Association indicated that women with hormone receptor-negative cancers respond better to chemotherapy than women with hormone receptor-positive cancer. However, some women with hormone receptor-positive cancer do benefit from chemotherapy, as well as from hormone therapy.

Adjuvant chemotherapy is administered following surgery and before radiation therapy. A 2007 study in the Journal of Clinical Oncology suggested that women with early-stage breast cancer can safely wait for up to 12 weeks after surgery before beginning chemotherapy. However, delaying chemotherapy until more than 12 weeks after surgery significantly increases the risk for breast cancer recurrence and can reduce the odds for survival by as much as 60%.

Many different types of chemotherapy drugs are used to treat breast cancer. Common types of chemotherapy drug classes include:

Anthracyclines include doxorubicin (Adriamycin) and epirubicin (Ellence). Anthracycline-based combination regimens are often used to treat early-stage breast cancer, as well as advanced cancer.
Taxanes include paclitaxel (Taxol) and docetaxel (Taxotere). Two 2003 studies suggested that taxane-based therapy is particularly helpful for node-positive breast cancer. A newer formulation of paclitaxel (Abraxane) is used as a secondary treatment for advanced breast cancer.
Platinum-based drugs include oxaliplatin (Eloxatin) and carboplatin (Paraplatin). These drugs may be used in combination regiments for advanced cancer or for cancers associated with BRCA genes.

Some of the abbreviations used for chemotherapy drug combinations (regimens) refer to drug classes rather than drug names. For example, regimens that contain an anthracycline drug (such as doxorubicin) use the letter "A," and regimens that contain a taxane drug (such as docetaxel) use the letter "T." Cyclophosphamide (Cytoxan), fluorouracil (5-FU), and methotrexate (MTX) are standard cancer drugs used in many breast cancer chemotherapy regimens.

Chemotherapy regimens usually consist of 4 - 6 cycles of treatment given over 3 - 6 months. Common chemotherapy regimens for early-stage breast cancer include:

AC (Doxorubicin and cyclophosphamide)
AC followed by T (Doxorubicin and cylophosphamide followed by paclitaxel)
CAF (Cyclophosphamide, doxorubicin, and 5-FU)
CMF (Cyclophosphamide, methotrexate, and 5-FU)
TAC (Docetaxel, doxorubicin, and cyclophosphamide)

Trastuzumab (Herceptin). Trastuzumab is a monoclonal antibody that targets the HER2 protein on cancer cells. HER2-positive cancers account for 15 - 25% of early-stage breast cancer and are associated with more aggressive disease. Younger women tend to be most affected. In November 2006, the Food and Drug Administration approved trastuzumab for treatment of HER2-positive, early-stage breast cancer (cancer confined to the breasts or lymph nodes that has been surgically removed). Trastuzumab is given along with other chemotherapy drugs following lumpectomy or mastectomy. Research indicates that trastuzumab can help prevent cancer recurrence and death among women with early-stage breast cancer, but it increases the risk of heart problems. Trastuzumab can cause heart failure. Women who have heart failure or weak heart muscle (cardiomyopathy) should not use this drug. Women who take trastuzumab need to have regular heart monitoring, especially if they have already have heart problems.

Patients who develop metastatic disease (cancer that spreads throughout the body) are generally not curable. New advances in drug therapies, however, can help shrink tumors, prolong survival, and improve quality of life.

Chemotherapy regimens for advanced cancer may use a single drug or a combination of drugs. Many chemotherapy regimens used for early-stage breast cancer are also used for advanced breast cancer. Some specific combinations for advanced cancer include:

Gemcitabine and paclitaxel. In 2004, the Food and Drug Administration approved the antimetabolite drug gemcitabine (Gemzar) for use in combination with paclitaxel (Taxol) as a first-line treatment option for women with metastatic breast cancer.
Capecitabine (Xeloda) and docetaxel (Taxotere). Capecitabine is an oral drug that is chemically related to 5-FU. It is also being studied in combination with many other drugs.

Numerous chemotherapy drugs and drug combinations are being tested in clinical trials. Patients with advanced breast cancer may also receive other types of drug treatments. Bisphosphonate drugs, such as zoledronic acid (Zometa) and pamidronate (Aredia), are important supportive drugs for preventing fractures and reducing pain in people whose cancer has spread to the bones.

Two targeted therapy drugs are approved for the treatment of HER2-positive advanced breast cancer

Trastuzumab (Herceptin) was approved in 1998 for treatment of metastatic breast cancer. It is used in adjuvant chemotherapy, along with drugs such as paclitaxel.
Lapatinib (Tykerb) was approved in March 2007 for patients who have not been helped by other cancer drugs, including an anthracycline, a taxane, or trastuzumab. Lapatinib is used in combination with capecitabine (Xeloda). Research suggests it may have fewer risks for heart problems than trastuzumab.

Promising new treatments for advanced breast cancer include:

Ixabepilone (BMS-247550). Ixabepilone is the first of a new class of cancer drugs called epothilones. It is showing encouraging results when combined with capecitabine, according to research presented at the 2007 annual meeting of the American Society of Clinical Oncology.
Bevacizumab (Avastin). Bevacizumab is a targeted therapy anti-angiogenesis drug approved for treatment of colorectal and lung cancers. It is being studied in combination with various chemotherapy drugs for treatment of advanced cancer.

Side effects occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment.

Common side effects include:

Nausea and vomiting. Drugs known as serotonin antagonists, especially ondansetron (Zofran), can relieve these side effects. In one study, a combination of dexamethasone (a corticosteroid) with ondansetron taken within 24 hours of chemotherapy achieved either a major or complete reduction in nausea and vomiting. Aprepitant (Emend), a new drug for preventing chemotherapy-caused nausea and vomiting, was approved in 2006.
Diarrhea
Temporary hair loss
Weight loss
Fatigue
Depression

Serious short- and long-term complications can also occur and may vary depending on the specific drugs used. They include the following:

Anemia. The erythropoietins epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp) stimulate red blood cell production and can help reduce or prevent anemia, resulting in significant improvement in quality of life. Aranesp persists longer in the blood than epoetin alfa and may therefore require fewer injections.
Increased chance for infection from severe reduction in white blood cells (neutropenia). The addition of a drug called granulocyte colony-stimulating factor (filgrastim and lenograstim) is very helpful in reducing the risk for severe infection.
Liver and kidney damage.
Abnormal blood clotting (thrombocytopenia).
Allergic reaction, particularly to platinum-based drugs.
Menstrual abnormalities and infertility. Premature menopause occurs in about 30% of women, particularly in those over 40. A natural hormone medication called a gonadotropin-releasing hormone analogue, which puts women in a temporary pre-pubescent state during chemotherapy, may preserve fertility in some women. Women may also wish to consider embryo cryopreservation -- the harvesting of eggs, followed by in vitro fertilization and freezing of embryos for later use. The American Society of Clinical Oncology recommends that women being treated for cancer see a reproductive specialist to discuss all available fertility preservation options.
Sexual dysfunction.
Rarely, secondary cancers such as leukemia.
A quarter to a third of women report problems in concentration, motor function, and memory, which can be long-term. In one study, women were having these symptoms 2 years after treatment, although by 4 years they had resolved.
Heart problems. Trastuzumab (Herceptin) may increase the risk for heart failure, particularly in women with pre-existing risk factors. Cumulative doses of anthracyclines (doxorubicin, epirubicin) can also damage heart muscles over time and increase the risk for heart failure.
Taxanes can cause a drop in white blood cells and possible problems in the heart and central nervous system. Allergic reactions can occur, more often in taxol than taxotere. Taking a steroid before taxane administration can help prevent such reactions. Taxane therapy may also cause severe joint and muscle pain in some patients, relievable with corticosteroids.

High-dose chemotherapy along with peripheral-blood stem cell rescue or bone marrow transplantation procedures have been used for cancer that has metastasized and, in some cases, for earlier stages of breast cancer in high-risk patients. The objective of this treatment is to be able to give patients very high toxic doses of cell-killing drugs.

Transplantation procedures are based on stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments can harm these growing cells as well as cancer cells.

Despite the initial enthusiasm over the use of high-dose therapy for treatment of high risk breast cancer, this approach can no longer be generally recommended and should not be used outside of a clinical trial setting. The results of several randomized studies have failed to show a convincing advantage for the use of high-dose therapy. Nevertheless, some experts believe this approach can still be useful in selected patients, and studies continue. In general, however, transplantation has a limited role in breast cancer management, and its use should be restricted to clinical trials.

Hormone Therapy

Hormone therapy works by blocking estrogen that causes cell proliferation. It is used only for patients with hormone receptor-positive tumors. Different types of hormone therapy work in different ways by:

Blocking estrogen receptors in cancer cells (Tamoxifen)
Suppressing estrogen production in the body (Aromatase inhibitors)
Destroying ovaries, which produce estrogen (Ovarian ablation)

Tamoxifen was the first widely used hormonal therapy drug, but it has been replaced by aromatase inhibitors for some women. Aromatase inhibitors are used only to treat postmenopausal women. Tamoxifen is mainly used as adjuvant therapy for premenopausal women with hormone-sensitive breast cancer.

Tamoxifen (Nolvadex) has been the standard hormonal drug used for breast cancer. It belongs to a class of compounds called selective estrogen receptor modulators (SERMs). SERMs chemically resemble estrogen and trick the breast cancer cells into accepting it in place of estrogen. Unlike estrogen, however, they do not stimulate breast cancer cell growth. Because SERMs block estrogen’s effects on cancer cells, they are sometimes referred to as "anti-estrogen" drugs.

Tamoxifen is used for all cancer stages in women of all ages with hormone receptor-positive cancers. In addition, it is used to prevent breast cancer in high-risk women. Another SERM drug, toremifene (Fareston), is an option for women with advanced cancer, but this drug is rarely used in the United States. A third drug, fulvestrant (Faslodex), works in a similar anti-estrogen way to tamoxifen but belongs to a different drug class. Fulvestrant is approved only for postmenopausal women with hormone-sensitive advanced breast cancer in which tamoxifen or aromatase inhibitors no longer work.

To prevent cancer recurrence, women should take tamoxifen for 5 years following surgery and radiation. Tamoxifen is an effective cancer treatment, but it can cause unpleasant side effects and has small (less than 1%) but serious risks for blood clots and uterine (endometrial) cancer. Immediately report any signs of vaginal bleeding to the doctor, as this may be a symptom of uterine cancer.

Less serious, but discomforting, side effects include hot flashes and mood swings. According to a 2007 study, nearly 25% of women stop taking tamoxifen within 1 year because of these symptoms. By 3.5 years, over 33% stop treatment. Taking tamoxifen for fewer than 5 years, however, increases the risk for cancer recurrence and death. Talk with your doctor about antidepressants or other therapies that may help you cope with tamoxifen’s side effects.

Many doctors now recommend that postmenopausal women switch to an aromatase inhibitor after 2 - 3 years of tamoxifen therapy. Several 2007 studies indicated that switching from tamoxifen to an aromatase inhibitor significantly improves survival rates and reduces the risk of death from breast cancer as well as other causes.

Endometrial cancer is a cancerous growth of the endometrium (lining of the uterus). It is the most common uterine cancer.

Aromatase inhibitors block aromatase, an enzyme that is a major source of estrogen in many major body tissues, including the breast, muscle, liver, and fat. Aromatase inhibitors work differently than tamoxifen. Tamoxifen interferes with tumors’ ability to use estrogen by blocking their estrogen receptors. Aromatase inhibitors reduce the overall amount of estrogen in the body.

Because these drugs cannot stop the ovaries of premenopausal women from producing estrogen, they are recommended only for postmenopausal women.

There are currently three aromatase inhibitors approved for treating early-stage, hormone receptor-positive breast cancer in postmenopausal women:

Anastrazole (Armidex) for treatment after surgery
Exemestane (Aromasin) for women who have taken tamoxifen for 2 - 3 years
Letrozole (Femara) for treatment after surgery or for women who have completed 5 years of tamoxifen therapy

All of these drugs are also approved for women with advanced (metastatic) hormone-sensitive breast cancer. Studies indicate that the introduction of aromatase inhibitors has helped greatly in prolonging survival for women with advanced cancer.

Compared to tamoxifen, aromatase inhibitors are less likely to cause blood clots and uterine cancer. However, these drugs are more likely to cause osteoporosis, which can lead to bone loss and fractures. In general, recent studies indicate that aromatase inhibitors are better than tamoxifen in improving survival and reducing the risk of cancer recurrence. Unfortunately, like tamoxifen, they can cause hot flashes, as well as joint pain.

Ovarian ablation literally shuts down estrogen production from the ovaries. Medications can accomplish ovarian ablation. Destroying the ovaries with surgery or radiation can also shut down estrogen production. (Osteoporosis is one serious side effect of this approach, but several therapies are available to help prevent bone loss.)

Chemical Ovarian Ablation. Drug treatment (non-chemotherapy drugs) to block ovarian production of estrogen is called chemical ovarian ablation. It is often reversible. The primary drugs used are luteinizing hormone-releasing hormone (LHRH) agonists, such as goserelin (Zoladex). (They are also sometimes called GnRH agonists). These drugs block the release of the reproductive hormones LH-RH, therefore stopping ovulation and estrogen production.

Studies suggest that women with estrogen-positive early stage cancer who take goserelin have similar survival rates to those who take standard chemotherapy. They also experience fewer serious side effects. A major analysis of four trials using LHRH agonists plus tamoxifen suggested that this combination should be the standard for patients with advanced breast cancers that are hormone-receptor positive, although this is an area of controversy. (Chemotherapy is still more effective in women with estrogen-negative tumors.)

Ovariectomy. Ovariectomy, the removal of the ovaries, has modestly improved breast cancer survival rates in some premenopausal women whose tumors are hormone receptor-positive. In these women, combining this procedure with tamoxifen may improve results beyond those of standard chemotherapies. Ovariectomy does not benefit women after menopause, and its advantages can be blunted in women who have received adjuvant chemotherapy. The procedure causes sterility and can have a major negative emotional impact on younger patients.

Resources

www.cancer.gov -- National Cancer Institute
www.cancer.org -- American Cancer Society
www.asco.org -- American Society of Clinical Oncology
www.oncolink.org -- Oncolink
www.womenshealth.gov -- National Women's Health Information Center
www.nccn.org -- National Comprehensive Cancer Network
www.plwc.org -- People Living With Cancer
www.cancer.gov/clinicaltrials -- Find clinical trials
www.breastcancer.org -- Find clinical trials

References

Bardia A, Hartmann LC, Vachon CM, Vierkant RA, Wang AH, Olson JE, et al. Recreational physical activity and risk of postmenopausal breast cancer based on hormone receptor status. Arch Intern Med. 2006 Dec 11-25;166(22):2478-83.

Barron TI, Connolly R, Bennett K, Feely J, Kennedy MJ. Early discontinuation of tamoxifen: a lesson for oncologists. Cancer. 2007 Mar 1;109(5):832-9.

Boccardo F, Rubagotti A, Aldrighetti D, Buzzi F, Cruciani G, Farris A, et al. Switching to an aromatase inhibitor provides mortality benefit in early breast carcinoma: pooled analysis of 2 consecutive trials. Cancer. 2007 Mar 15;109(6):1060-7.

Boehm JS, Zhao JJ, Yao J, Kim SY, Firestein R, Dunn IF, et al. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell. 2007 Jun 15;129(6):1065-79.

Boyd NF, Guo H, Martin LJ, Sun L, Stone J, Fishell E, et al. Mammographic density and the risk and detection of breast cancer. N Engl J Med. 2007 Jan 18;356(3):227-36.

Breen N, A Cronin K, Meissner HI, Taplin SH, Tangka FK, Tiro JA, et al. Reported drop in mammography : is this cause for concern? Cancer. 2007 Jun 15;109(12):2405-9.

Chia SK, Speers CH, D'Yachkova Y, Kang A, Malfair-Taylor S, Barnett J, et al. The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. Cancer. 2007 Jul 23;110(5):973-979 [Epub ahead of print]

Cho E, Chen WY, Hunter DJ, Stampfer MJ, Colditz GA, Hankinson SE, et al. Red meat intake and risk of breast cancer among premenopausal women. Arch Intern Med. 2006 Nov 13;166(20):2253-9.

Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007 Feb 17;369(9561):559-70.

Fenton JJ, Taplin SH, Carney PA, Abraham L, Sickles EA, D'Orsi C, et al. Influence of computer-aided detection on performance of screening mammography. N Engl J Med. 2007 Apr 5;356(14):1399-409.

Geiger AM, Thwin SS, Lash TL, Buist DS, Prout MN, Wei F, et al. Recurrences and second primary breast cancers in older women with initial early-stage disease. Cancer. 2007 Mar 1;109(5):966-74.

Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28;355(26):2733-43.

Ives A, Saunders C, Bulsara M, Semmens J. Pregnancy after breast cancer: population based study. BMJ. 2007 Jan 27;334(7586):194. Epub 2006 Dec 8.

Jatoi I, Chen BE, Anderson WF, Rosenberg PS. Breast cancer mortality trends in the United States according to estrogen receptor status and age at diagnosis. J Clin Oncol. 2007 May 1;25(13):1683-90. Epub 2007 Apr 2.

Kahlenborn C, Modugno F, Potter DM, Severs WB. Oral contraceptive use as a risk factor for premenopausal breast cancer: a meta-analysis. Mayo Clin Proc. 2006 Oct;81(10):1290-302.

Kerlikowske K, Miglioretti DL, Buist DS, Walker R, Carney PA; National Cancer Institute-Sponsored Breast Cancer Surveillance Consortium. Declines in invasive breast cancer and use of postmenopausal hormone therapy in a screening mammography population. J Natl Cancer Inst. 2007 Sep 5;99(17):1335-9. Epub 2007 Aug 14.

Khatcheressian JL, Wolff AC, Smith TJ, Grunfeld E, Muss HB, Vogel VG, et al.American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. J Clin Oncol. 2006 Nov 1;24(31):5091-7. Epub 2006 Oct 10.

Lehman CD, Gatsonis C, Kuhl CK, Hendrick RE, Pisano ED, Hanna L, et al. MRI evaluation of the contralateral breast in women with recently diagnosed breast cancer. N Engl J Med. 2007 Mar 29;356(13):1295-303. Epub 2007 Mar 28.

Lin J, Manson JE, Lee IM, Cook NR, Buring JE, Zhang SM. Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med. 2007 May 28;167(10):1050-9.

Lohrisch C, Paltiel C, Gelmon K, Speers C, Taylor S, Barnett J, et al. Impact on survival of time from definitive surgery to initiation of adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol. 2006 Oct 20;24(30):4888-94. Epub 2006 Oct 2.

Michels KB, Xue F, Colditz GA, Willett WC. Induced and spontaneous abortion and incidence of breast cancer among young women: a prospective cohort study. Arch Intern Med. 2007 Apr 23;167(:814-20.

Moss SM, Cuckle H, Evans A, Johns L, Waller M, Bobrow L. Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years' follow-up: a randomised controlled trial. Lancet. 2006 Dec 9;368(9552):2053-60.

North American Menopause Society. Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of The North American Menopause Society. Menopause. 2007 Mar-Apr;14(2):168-82.

Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007 Aug 10;25(23):3407-14. Epub 2007 Jul 2.

Pierce JP, Natarajan L, Caan BJ, Parker BA, Greenberg ER, Flatt SW, et al. Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer: the Women's Healthy Eating and Living (WHEL) randomized trial. JAMA. 2007 Jul 18;298(3):289-98.

Qaseem A, Snow V, Sherif K, Aronson M, Weiss KB, Owens DK; Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Screening mammography for women 40 to 49 years of age: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2007 Apr 3;146(7):511-5.

Ravdin PM, Cronin KA, Howlader N, Berg CD, Chlebowski RT, Feuer EJ, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. 2007 Apr 19;356(16):1670-4.

Saslow D, Boetes C, Burke W, Harms S, Leach MO, Lehman CD, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007 Mar-Apr;57(2):75-89.

Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007 Jan 6;369(9555):29-36.

Terry KL, Willett WC, Rich-Edwards JW, Michels KB. A prospective study of infertility due to ovulatory disorders, ovulation induction, and incidence of breast cancer. Arch Intern Med. 2006 Dec 11-25;166(22):2484-9.

Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007 Jan 1;25(1):118-45. Epub 2006 Dec 11.

Review Date:
1/26/2008
Reviewed By:
A.D.A.M. Editorial Team: David Zieve, MD, MHA, Greg Juhn, MTPW, David R. Eltz, Kelli A. Stacy, ELS. Previously reviewed by Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital (11/01/07).

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adam.com

Non-small cell lung cancer

FitSugar — Wed, 08 Oct 2008 17:35:06 -0700

In This Report

Highlights
Introduction
Causes
Symptoms
Risk Factors
Lifestyle Changes
Diagnostic Tests
Staging Systems
Surgical Procedures
Radiation Treatments
Treatment Options by Stages...
Chemotherapy Treatments
Investigative Agents
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Research News:

About 3,000 nonsmokers die each year of lung cancer resulting from exposure to secondhand smoke, according to a 2006 Surgeon General report.
Advexin, a genetic therapy that contains the p53 tumor-suppressor gene, is showing promise. A 2006 study in Japan found that out of 13 patients with advanced NSCLC receiving Advexin, 10 had stabilized. Advexin is in Phase II clinical trials for NSCLC.
Studies are finding that NSCLC tumors in people who never smoked have a much higher rate of epithelial growth-factor receptor (EGFR) mutations. EGFR helps new blood vessels grow to feed tumors. This discovery may help tailor future treatments to specific patient populations. It also helps explain why some newer treatments seem effective mostly in patients who never smoked.

Treatment News:

Video-assisted thoracic surgery (VATS) is a new, less-invasive surgical technique that uses a thin tube containing a miniature camera and surgical instruments. Though the procedure is not appropriate in all cases, it offers significant advantages, especially in older or frail patients, in the treatment of early stage non-small cell lung cancer (NSCLC).
Bevacizumab, a monoclonal antibody, was approved in October 2006 as a first-line treatment (in combination with carboplatin and paclitaxel) for inoperable, locally advanced, metastatic, or recurrent non-squamous, non-small cell lung cancer.
Gefitinib (Iressa), a drug that targets EGFR, proved disappointing in final clinical trials. However, erlotinib (Tarceva), a drug that targets a different part of the EGFR molecule, has shown benefits. Erlotinib is now approved as a second-line chemotherapy to treat patients with locally advanced or metastatic NSCLC after a previous course of chemotherapy failed.

Introduction

Although lung cancer accounts for only 13% of all cancers, it is among the most lethal, accounting for over 28% of all cancer deaths. It is more deadly than colon, breast, and prostate cancers combined. An estimated 160,390 people will die from lung cancer in 2007. Death rates have been declining in men over the past decade, and they have now stabilized in women.

The lungs are two spongy organs surrounded by a thin moist membrane called the pleura. Each lung is composed of smooth, shiny lobes: the right lung has three lobes, and the left has two. About 90% of the lung is filled with air; only 10% is solid tissue.

Air is carried from the trachea (the windpipe) into the lung through flexible airways called bronchi.
Like the branches of a tree, the bronchi in turn divide into over a million smaller airways called bronchioles.
The bronchioles lead to grape-like clusters of microscopic sacs called alveoli.
In each adult lung, there are about 300 million of these tiny alveoli. A thin membrane makes up the alveoli sacs. Oxygen and carbon dioxide pass through this membrane to and from capillaries.
Capillaries, the smallest of our blood vessels, carry blood throughout the body.

The major features of the lungs include the bronchi, the bronchioles, and the alveoli. The alveoli are the microscopic blood vessel-lined sacks in which oxygen and carbon dioxide gas are exchanged.

Lung cancer develops when genetic mutations (changes) occur in a normal cell within the lung. As a result, the cell becomes abnormal in shape and behavior, and reproduces endlessly. The abnormal cells form a tumor that, if not surgically removed, invades neighboring blood vessels and lymph nodes and spreads to nearby sites. Eventually, the cancer can spread (metastasize) to locations throughout the body.

The two major categories of lung cancer are small cell lung cancer and non-small cell lung cancer. Most lung cancers are non-small cell cancer, the subject of this report. Less common cancers of the lung are known as carcinoids, cylindromas, and certain sarcomas (cancer in soft tissues).

Some experts believe all primary lung cancers come from a single common malignant (cancerous) stem cell that, as it copies itself, can develop into any one of these cancer types in different individuals.

In addition, cancers in the lung may have spread from other primary sites, such as the breast, thyroid, or colon. In these cases, doctors name the cancer after its original location; for example, "breast cancer with lung metastases."

Non-small cell lung cancers are categorized into three types: squamous cell carcinoma (also called epidermoid carcinoma), adenocarcinoma, and large cell carcinoma. These separate types are grouped together because, in early stages before the cancers have spread, they all can be treated surgically.

Squamous Cell Carcinoma. Squamous cells are formed from reserve cells, which are round cells that replace injured or damaged cells in the lining (the epithelium) of the bronchi, the major airways. Tumors formed from squamous cells are usually found in the center of the lung, either in a major lobe or in one of the main airway branches. They may grow to large sizes and form cavities in the lungs.

Click the icon to see an image of squamous cell carcinoma.

When squamous cell cancer metastasizes, it may travel to the bone, adrenal glands, liver, small intestine, and brain.

Squamous cell carcinoma is nearly always caused by smoking and used to be the most common cancer. It still makes up 25 - 40% of all lung cancers.

Adenocarcinoma. Adenocarcinomas usually arise from the mucus-producing cells in the lung. About two-thirds of adenocarcinomas develop in the outer regions of the lung, while one-third develop in the center of the lung. In 1965, 12% of lung cancers were adenocarcinomas. They are now estimated to account for 30 - 50% of all lung cancers and are the most common lung cancers in many countries. They are also the most common lung cancers in women. In fact, a 2000 European study showed that nearly 34% of the women with lung cancer under investigation had adenocarcinoma, compared to 26.4% who had squamous cell carcinoma, and 22.3% with small cell lung cancer. Adenocarcinoma is also increasing dramatically in men. Until recently, adenocarcinoma was only weakly linked to smoking. Experts now suggest, however, that the dramatic increase in recent decades in this lung cancer type may be due to low-tar, filtered cigarettes. People who smoke them draw tiny particles deeper into the lungs, thereby possibly increasing the risk for adenocarcinoma.

The course of this cancer varies widely. Most often, it develops slowly and causes few or no symptoms until it is far advanced. In some cases, however, it can be extremely aggressive and rapidly fatal. In 50% of cases in which this cancer spreads, it spreads only to the brain. Other common locations it spreads to include the other lung, the liver, the adrenal glands, and bone.

Click the icon to see an image of adenocarcinoma.

Bronchoalveolar Lung Cancer. Bronchoalveolar lung cancer is actually a subtype of adenocarcinoma. It develops as a layer of column-like cells on the lung and spreads through the airways, causing great volumes of sputum. This cancer also is increasing in incidence.

Large Cell Carcinoma. Large cell carcinoma, which makes up about 10 - 20% of lung cancers, includes cancers that cannot be identified under the microscope as squamous cell cancers or adenocarcinomas.

Click the icon to see an image of large cell carcinoma.

Small cell lung cancer may, like squamous cells, be derived from reserve cells or other cells in the epithelium. It causes 15 - 25% of all lung cancers; without chemotherapy, it is very aggressive and usually rapidly fatal. It requires a different treatment approach from non-small cell lung cancer, so it is not discussed in this report.

Click the icon to see an image of small cell carcinoma.

Causes

Cigarette Smoke. Smoking causes 87% of lung cancer deaths, accounting for 30% of all cancer deaths. Cigarettes, nicotine, or both may contribute to lung cancer in one or more of the following ways:

In general, chronic exposure to nicotine may cause an acceleration of coronary artery disease, peptic ulcer disease, reproductive disturbances, esophageal reflux, hypertension, fetal illnesses and death, and delayed wound healing.

The smoke is the most dangerous component of the cigarette. Chemicals formed during smoking trigger genetic mutations that lead to cancer. When people inhale cigarette smoke, they bring into their lungs tar that includes over 4,000 chemicals, some of which are carcinogenic (cancer-causing). Other inhaled chemicals in cigarette smoke that may increase the risk for cancer include cyanide, benzene, formaldehyde, methanol (wood alcohol), acetylene (the fuel used in torches), and ammonia. Smoke also contains nitrogen oxide and carbon monoxide, both of which are harmful gases.
Nicotine itself may be a hazard. A 2000 laboratory study suggested that the human body might be converting inhaled nicotine into a chemical called aminoketone, which has been linked to the formation of tobacco-related lung cancer. A 2001 study reported that nicotine triggered new blood vessel growth, which could, in theory, promote growth of any existing tumors. A study published in 2005 found that nicotine was responsible for disabling a gene that induces the death of cancer cells in lung tumors. Whether or not these studies apply to long-term use of nicotine replacement products (such as patches), or to cigarette smoking, is still unclear. The studies should certainly not discourage people from using nicotine replacement methods for quitting. However, these studies may indicate that people should not use these devices on a long-term basis.

Radon. Radon is a gas produced naturally by the breakdown of uranium. It is often present in the soil and in water and can seep into any dwelling. Radon may be responsible for between 10% and 14% of lung cancer deaths, making it, after smoking, the second leading cause of this cancer.

Other Contributors. Toxic particles leading to precancerous changes in the lung are also found in marijuana. In one study, 53.8% of cigarette smokers, 66.7% of marijuana smokers, and all of those subjects who smoked both substances showed evidence of precancerous changes in the lungs.

There is considerable debate over the lung cancer risk posed by depleted uranium used in military weapons (such as in the Gulf and Balkan conflicts). A 2001 study estimated that it would cause an additional 8 deaths from lung cancer out of every 10,000 people or soldiers who were highly exposed to this substance. The study was based on a mathematical model, however, and the issue is not settled.

Other lung carcinogens include asbestos, arsenic, certain petrochemicals (materials made from crude oil or natural gas), and other airborne (carried through the air) byproducts of various mining and manufacturing processes.

Click the icon to see an image of the tobacco plant.

Genetic mutations that cause cancer generally occur in two types of genes:

Tumor-suppressor genes, which prevent cells from endlessly copying themselves
Proto-oncogenes, which encourage cells to keep making copies of themselves [when a proto-oncogene changes (becomes mutated), it is then called an oncogene]

Damage to either type of gene can cause a mutation that results in an uncontrolled division of cells. This uncontrolled division forms tumors.

It is unlikely that a single specific abnormality causes all lung cancer. It probably takes a variety of mutations to start the devastating chain of events leading to cancer. The following mutations are among those under investigation:

BPDE-caused mutations: The chemical BPDE, a byproduct of tobacco smoke, is involved with a number of genetic mutations, including those to an oncogene called K-ras and to three tumor-suppressor genes known as p53, PPP2R1B, and p16. When normal, the tumor-suppressor genes are involved in cell repair and healthy copying of the cell. When they are damaged or blocked, out of control cell production can occur, leading to cancer. About 10% of the population may carry a gene that protects against lung cancer, by reducing levels of BPDE.
Chemotherapy resistance genes: Tumors that contain the p53 mutation may also be more resistant to chemotherapy.
Rb Mutations: Another important contributor to lung cancer is a genetically defective protein called retinoblastoma (Rb), which is associated with very aggressive tumors. Low levels of the normal Rb gene may sometimes predict aggressive cancer, especially in patients with small cell lung cancer.
Mutations to the FHIT gene: Another potentially important mutation may be an abnormality in the FHIT gene. This mutation causes the cells lining the lung to become more vulnerable to the effects of tobacco smoke and other carcinogens.

Symptoms

Lung cancer is unlikely to produce symptoms until the disease is advanced. When symptoms develop, they may result from the lung tumor itself, from its effects on tissues outside the lung, or from the spread of malignant cells to other organs.

Early symptoms may include the following:

Frequent bouts of pneumonia, or pneumonia that does not clear up in a normal period of time
Coughing (particularly coughing up blood)
Weight loss
Fever
Shortness of breath
Chest pain

Later-stage symptoms include the following:

Shortness of breath: This common symptom is the result of cancer that has spread in the lung and the pleura, the membrane covering the lung.
Superior vena cava syndrome: In some cases, tumor growth or spreading of the cancer presses against the superior vena cava, a large vein that returns blood from the upper part of the body to the heart. When this happens, a condition called superior vena cava syndrome may occur, leading to obvious swelling in the arms and face.
Trouble swallowing: The esophagus is the pipe that takes food from the mouth to the stomach. The cancer may spread to or press against the esophagus, interfering with swallowing and nutrition.
Hoarseness: Cancer can damage the nerves that control the voice box, causing hoarseness.
Pancoast syndrome: Damage to the brachial plexus, a group of nerves branching from the neck, can cause pain, weakness, or numbness in the arm or hand (Pancoast syndrome).
Bronchoalveolar lung cancer may produce very large amounts of mucus.
Hypercalcemia: Some lung cancers produce substances that remove calcium from bone and release it into the bloodstream, causing a condition called hypercalcemia. Patients with this disorder can experience nausea, vomiting, constipation, weakness, and fatigue.

Other lung cancers (usually small cell cancer) cause the body to retain water, lowering the blood's sodium levels. This condition, called hyponatremia, can produce confusion, weakness, and even seizures.

Risk Factors

Before cigarettes became popular in the beginning of the 20th century, lung cancer was rare. In 2007, lung cancer is expected to strike up to 213,380 Americans, and about 160,390 are expected to die from it.The disease usually occurs in people over 50 years old. Men have a significantly greater incidence of lung cancer compared to women. On the encouraging side, the rate of lung cancer in men has been declining significantly over the past decade. While lung cancer rates have been increasing dramatically in women (by 600% from 1950 to 2000), they now appear to be stabilizing.

Smoking appears to be the primary risk factor in 85 - 90% of lung cancers. About 15% of all people who smoke develop lung cancer. The risk depends on the duration of the addiction and the number of pack years. (One pack year equals the number of packs of cigarettes smoked per day, multiplied by the number of years that the person has smoked.) Genetic damage in the lung occurs in nearly all chronic smokers, even if cancer has not developed.

An elevated risk for lung cancer can persist for more than 20 years after quitting smoking, although the risk drops significantly even in the first year after quitting. And, there are benefits to quitting smoking even for people who are well into middle age.


Quitting Age	Percentage
30	2%
40	3%
50	6%
60	10%

Second-Hand Smoke. The Environmental Protection Agency has classified second-hand smoke as a carcinogen (cancer-causing chemical). Exposure to second-hand tobacco smoke increases the risk of lung cancer in the nonsmoker by about 20 - 30%. A 2006 Surgeon General report found that about 3,000 nonsmokers die each year of lung cancer resulting from exposure to secondhand smoke.

There may be some ethnic differences in lung cancer risk. For example, African-Americans face a risk that is two to four times higher than that in Caucasians, regardless of smoking status. It is not clear what factors are responsible for this higher risk. Some African-Americans appear to have a genetic vulnerability to the harmful chemicals in cigarette smoke.

In China, an estimated one third of all young male smokers will eventually die because of tobacco-related illnesses. Their risk for lung cancer, however, is much less than it is for chronic lung disease, the opposite of the Western trend. A 2001 study reported that the lower rate of lung cancer among Chinese people might be due to a slow rate of clearing nicotine, which results in smoking fewer cigarettes.

People with High Exposure to Radon. Studies have shown that radon raises the risk of lung cancer in underground miners by 40%. It is unclear whether the results of these studies would apply to people exposed to radon in their homes One study suggests that people with intense or prolonged exposure to radon in their homes do indeed face the same risk as miners exposed to similar levels of radon. A cumulative long-term exposure to radon and smoking also increases the danger. Most people move an average of 10 or 11 times over their lifetime, so the risk of developing lung cancer through radon exposure is very low in most individuals, even for those who lived for awhile in areas with high radon levels. People with homes that have high radon levels and those who sleep or spend many hours to days in basements with detectable but moderate levels should consider taking protective measures.

Workers Highly Exposed to Carcinogens. An estimated 9,000 - 10,000 men and 900 - 1,900 women develop lung cancer each year because of occupational exposure to carcinogens. More than half of these cases are attributable to past exposure to asbestos, which has long been known to be a risk factor for mesothelioma (cancer of the pleura, the lining around the lung) and can increase the risk of lung cancer in smokers. With better protective measures, these rates are expected to fall in the future.

Other chemicals that put workers at risk for lung cancer include:

Arsenic (insecticide and herbicide sprayers, tanners, oil refinery workers)
Chloromethyl methyl ether (workers exposed to certain polymers, water repellents, or products using chloride and formaldehyde)
Chromium compounds (workers using certain alloys, paints, pigments, and preservatives)
Depleted uranium (soldiers exposed to weapons during battlefield conditions)
Crystalline silica

By contrast, agricultural workers seem to have a lower lung cancer rate, despite their possible occupational exposures to risky chemicals. While this rate has traditionally been attributed to good health habits, including low tobacco use, a 2000 study suggests that agricultural workers' exposure to endotoxin may be responsible. Endotoxin is a component of common bacteria found in soil and animals and may have cancer-preventing effects on the immune system.

Exposure to Smoke from Grills. Grilling and high-heat frying emit chemicals called heterocyclic amines, which are known to be carcinogenic. A 2000 study of Chinese women found that smokers who stir-fried meat daily and inhaled cooking fumes had a higher risk of lung cancer than did those who stir-fried meat less frequently. No higher risk was found among nonsmokers.

Air Pollution. Although any risk from air pollution is very small, it nevertheless may be a contributor to those lung cancers not obviously related to smoking. Some studies, including a major analysis of vital statistics in 2002, have found an association between increased risk for lung cancer and long-term exposure to very small particulates, especially sulfates, present in polluted air. The risk, if any, is very small.

A family history of lung cancer may play a role in increasing susceptibility to this disease. In one study, people who had parents or siblings with respiratory tract cancers had a 30% higher risk for lung cancer, compared to people without a family history. Women with mothers or sisters with lung cancer had triple the risk. A higher risk occurred in both smokers and nonsmokers. There was no association between a history of other cancers and lung cancer. Both genetic factors and secondhand smoke appeared to contribute to the danger in these individuals.

Smokers with emphysema or chronic inflammatory lung diseases, such as asthma, are at increased risk for lung cancer. Both smokers and nonsmokers whose lungs are scarred from recurrent lung diseases, such as pneumonia or tuberculosis, are also at increased risk, particularly for bronchoalveolar lung cancer.

Lifestyle Changes

Quitting improves lung function almost immediately. Some evidence suggests that the benefits for the lungs are even more significant for women who quit than for men. It should be noted, however, that it can take 20 years or longer, particularly in heavy smokers, for the lungs to be restored to a fully healthy condition in which the risk for lung cancer is as low as for nonsmokers. Quitting is extremely difficult. No one should be discouraged if they relapse. Everyone should keep trying to quit. With continued efforts, many people succeed.

The many methods of quitting smoking include counseling and support groups, nicotine patches, gums and sprays, and incremental reduction.

At this time perhaps the most effective method for quitting is a combination of the following:

Nicotine replacement products that reduce withdrawal symptoms and cravings.
The antidepressants bupropion (Zyban) or nortriptyline (Pamelor, Aventyl), which reduce emotional effects and cravings associated with withdrawal, and improve abstinence rates.
Professional counseling or support organizations that may be effective, in addition to the medication, in helping people maintain abstinence.

[See In-Depth Report #41: Smoking.]

While people are in the process of quitting (and afterwards), they should maintain as healthy a lifestyle as possible.

Phytochemicals. Some data suggest that diets rich in fresh fruits and vegetables may be protective against lung cancer in both smokers and non-smokers. Some studies have reported protection from specific plant chemicals (phytochemicals), such as the following:

Isothiocyanates. These chemicals are found in cruciferous vegetables (broccoli, cauliflower, and Brussels sprouts). They may help block the effects of carcinogens in smoke, suppress tumor growth, and inhibit growth-promoting steroid hormones.
Flavonoids. Major sources are apples, grapefruit, onions, red wine, and tea. In one study on flavonoids, apple eaters had the lowest cancer risk, 68% less than those who ate fruit infrequently. In another, those who ate relatively more onions, apples, and white grapefruit had less than half the lung cancer risk as people who ate relatively small amounts of these foods. Flavonoids are also found in soybeans, berries, broccoli, carrots, citrus fruits, eggplant, peppers, squash, and tomatoes. Specific flavonoids in dark chocolate may be protective against lung cancer (but not other cancers).
Lycopene. Lycopene is found in tomatoes, which have been associated with a lower risk for lung cancer. Cooking the tomatoes appears to increase the potency of lycopene.
Cryptoxanthin. Some studies suggest that eating foods rich in cryptoxanthin, a yellow-orange pigment, reduces the risk for lung cancer. Foods with high amounts of cryptoxanthin include pumpkin, corn, papaya, red bell peppers, tangerines, oranges, and peaches. More research is needed in this area, however.
Isoflavones. Isoflavones, found in soy beans and flax seed, behave like estrogen in some ways and not in others. Some evidence suggests the genistein (a type of isoflavone) in soy may have properties that are protective against lung cancer.

Click the icon to see an image of phytochemicals.

Note: Studies on these chemicals are not consistent. It is unlikely that individual phytochemicals offer protection, but rather that the benefits come from a collection of vitamins and plant chemicals contained in fruits and vegetables. Fruit, especially, appears to be protective.

Fats and Oils. Some studies have indicated that diets high in animal fats increase the risk for lung cancer. Others have suggested some protection from cod liver oil, which contains omega-3 fatty acids (found in fatty fish), omega-6 fatty acids (found in flax and in soybean and canola oils), and monounsaturated oils (found in olive and canola oils). Of interest was a 2002 study reporting that women who had a high intake of cheese had a lower risk of lung cancer. Despite these intriguing pieces of information, the ability of these substances to protect against lung cancer remains controversial, and discontinuation of smoking remains the best advice.

Click the icon to see an image of fats and oils.

Vitamin Supplements. Even with a healthful diet, smoking reduces the levels of a number of vitamins, importantly vitamin C. There is no evidence, however, to support any protection from antioxidant supplements, including vitamins E, A, or beta carotene.

In fact, evidence is now suggesting that high doses of vitamin C, vitamin E, and beta carotene supplements may have harmful effects. A 2000 study, for example, reported a higher risk for cancer in male smokers who took multivitamins plus A, C, or E. The strongest studies to date on negative effects of antioxidant supplements have reported an increase in lung cancer and overall mortality rates among smokers who took beta carotene supplements. In determining reasons for this disturbing effect, one animal study suggested that beta carotene increased enzymes in the lungs that actually promote cancerous changes. In other words, antioxidants may actually be harmful in people who already harbor cancer cells. This is particularly important information for smokers, who may carry precancerous or cancerous cells for years prior to developing the disease. The best way of achieving healthy levels of important nutrients is from healthy foods.

Click the icon to see the benefits of vitamin A.

Click the icon to see dietary sources of vitamin A.

Trace Element Supplements. Trace elements may be important in cancer risk and prevention.

Selenium appears to inhibit cell production and may have other anti-cancer properties. A few studies have reported some protection with selenium. However, a major 2002 analysis supports previous work, indicating that taking selenium helps only people who are deficient to begin with.

Click the icon to see the benefits of selenium.

Zinc may prove to be more important than selenium. Some research suggests that zinc may help protect smokers by blocking cadmium. Smokers have higher levels of cadmium in their body, and there may be a link between cadmium and a higher risk for lung cancer. Some laboratory studies have indicated that zinc might help protect against tumor progression. There is no evidence that taking zinc supplements will reduce the risk for lung cancer, however.

A 2003 study reported a lower risk in lung cancer in men and women who were physically active. Both moderate and intensive exercises were associated with protection.

People concerned about radon in their home or area can purchase a test approved by the Environmental Protection Agency. Methods for removing radon include installing a soil suction system. It should be noted, however, that home prevention measures rarely reduce radon levels to zero. Simply sleeping by an open window reduces the risk.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors (coxibs) both block cyclooxygenase (COX) enzymes. NSAIDs block COX-1 and 2, and coxibs selectively block COX-2. Evidence now strongly suggests that the COX-2 enzyme plays a role in blood vessel growth (angiogenesis) that can feed lung cancers.

NSAIDs. NSAIDs include aspirin, ibuprofen (Advil), and naproxen (Aleve, Naprosyn, Naprelan, Anaprox). These agents inhibit COX-2, but they also target another COX enzyme. Studies are now reporting an association between regular use of aspirin or other NSAIDs and a reduced risk for non-small cell lung cancer.

COX-2 Inhibitors. The COX-2 inhibitors are more recent forms of NSAIDs. Currently, only celecoxib (Celebrex) is still on the market. Rofecoxib (Vioxx) and valdecoxib (Bextra) were withdrawn from the market due to their high risk of causing strokes and heart attacks. Because they target the COX-2 enzyme specifically, researchers are focusing on these drugs for a possible role in treating lung cancer and preventing recurrence.

Diagnostic Tests

Chest X-Rays. In a small percentage of cases, a routine chest x-ray reveals the first signs of lung cancer. Usually, however, symptoms of existing lung cancer, such as coughing, chest pain, and blood in the sputum, will lead to a chest x-ray. If non-small cell lung cancer is present, chest x-rays may show lesions (damaged or abnormal tissue) in the center of the lung, cavities formed by squamous cell carcinoma, or lace-like pattern of cells spreading through the lungs. By the time lung cancer is diagnosed by chest x-rays, however, it has often spread so far that it cannot be surgically cured. Four major studies found no survival benefits in early detection from chest x-rays and sputum screening. Regular screening for lung cancer using x-rays is therefore not currently recommended.

Computed Tomography. Computed tomography (CT), particularly the specific technique called low-dose spiral (or helical) CT, is more effective than x-rays for detecting cancer in patients with suspected lung cancer. It is the standard imaging procedure for determining if and where the cancer has spread (metastasized). Surgeons also use CT scans to evaluate patients before lung surgery.

CT stands for computerized tomography. In this procedure, a thin x-ray beam is rotated around the area of the body to be visualized. Using very complicated mathematical processes called algorithms, the computer is able to generate a 3-D image of a section through the body. CT scans are very detailed.

The use of helical CT for early screening is still controversial. Studies of CT scans in smokers suggest that early screening will detect about 2% of lung cancers, most of these in early stages. In the studies, 62 - 82% of the patients with stage 1A cancer (when the tumor has not spread yet) were still alive at 5 years. Neither study, however, was controlled (compared with other groups, such as non-smokers). The survival figures were likely to be higher than in actual practice.

Click the icon to see an image of a CT scan of the chest.

Evidence regarding the survival benefits of early detection is not clear. Many experts are highly opposed to widespread screening for lung cancer. Some evidence, for example, suggests that lung cancer cells in non-small cell lung cancer are often very aggressive at microscopic levels (before a tumor is formed). If this were true, the cancer would be highly likely to have already spread, long before it was visible with CT scans. Moreover, some studies have found no association between tumor size at the time of diagnosis and survival times. On the other hand, some suspicious areas detected by CT scans may actually be innocent, and these patients might be more likely to die from aggressive treatments than from the disorder itself.

It should also be noted that about 98% of suspicious areas seen on CT scans turn out to be benign. Even after rescreening, many scans will show suspicious areas that turn out to be harmless but will require invasive and expensive biopsies. Additional experience with CT scans, however, may allow experts to better determine which abnormalities are likely to be benign.

High-risk individuals who are still interested in early screening with CT scans should ask their doctor about available clinical trials.

Computed tomography is the standard imaging procedure for determining if and where the cancer has spread (metastasized). Other imaging tests, however, may be useful for staging and tracking lung cancers (staging means finding out how advanced the cancer is).

Positron Emission Tomography. Positron emission tomography (PET), specifically a technique known as FDG/PET, is the most accurate noninvasive test for detecting early lung cancer. It is also the best imaging technique for staging lung cancers, not only those located in the lungs, but also those that have spread, particularly into the space between the two lungs (the mediastinum). With this imaging test, the patient is first injected with a specially formulated liquid sugar (called FDG), and then viewed with a machine that records energy given off by tumor cells.

PET is expensive and not widely available. However, its supporters suggest that it may prevent many unnecessary surgeries by identifying patients whose cancer has advanced past the stage at which surgery is helpful. There is some evidence that FDG/PET scan can detect a metabolic (processing) response to treatments that may help predict the outlook for the patient.

Scintigraphy. Scintigraphy is an imaging procedure in which patients are administered low-level radioactive agents that bind to cancer cells, which then can be tracked by special cameras to reveal the cancer cells' location and intensity. Agents selected are those that can best bind successfully with specific tumor types. For example, a 2001 study of the binding agent 111In-DOTA-LAN demonstrated excellent results in identifying non-small cell lung tumors. This study further suggests the possibility of using such highly-targeted binding agents as lung cancer treatments.

Magnetic Resonance Imaging. Magnetic resonance imaging (MRI), an imaging procedure that uses radio wave energy, is frequently used instead of CT scanning to locate brain and bone metastases that can be associated with lung cancer.

Biopsies of lung tissue are needed to confirm lung cancer. This requires invasive procedures that may vary from simple needle aspiration to chest surgery.

Needle Aspiration. Sometimes, a biopsy specimen is obtained by inserting a needle between the ribs, and then guiding it with the use of computed tomography scans, ultrasound, or fluoroscopy (a device allowing an x-ray view). Specific techniques include transbronchial or transthoracic needle aspiration (TBNA or TTNA) or endoscopic ultrasound-guided needle aspiration (EUS-NA). Their use depends on how much of the area can be observed with less invasive imaging methods. There is a 5 -10% risk for bleeding or collapsed lung with needle aspiration.

Thoracoscopy. Thoracoscopy is usually very effective for diagnosing cancer in the outer areas of the lungs, or those involving the pleura (membrane surrounding the lungs). This is a surgical procedure that uses a fiber-optic tube to view the area:

The procedure requires general anesthesia.
The surgeon passes surgical instruments and a fiber-optic tube through a small incision in the chest. The tube has a camera in it, which allows the surgeon to look at the lungs on a video screen.

Bronchoscopy. To locate cancer that develops in the central areas and major airways of the lung (usually squamous or small cell cancer), bronchoscopy is typically performed. The procedure is done as follows:

The patient is given a local anesthetic, supplementary oxygen, and sedatives.
The doctor inserts a bronchoscope, a hollow flexible tube often containing a fiber-optic light source, into the lower respiratory tract through the nose or mouth.
The tube acts like a telescope into the body, allowing the doctor to see the windpipe and major airways. In a procedure called fluorescence bronchoscopy, the doctor injects the patient with a drug that makes cancer tissue appear red when exposed to laser light from the bronchoscope.
The surgeon removes specimens for biopsy, ideally combining techniques to include cutting tissue, brushings, and a washing process called bronchoalveolar lavage (BAL). BAL involves injecting saline through the bronchoscope into the lung and then immediately suctioning the fluid back through the hollow tube of the bronchoscope; the fluid is then analyzed in the laboratory. Both brushing and washing procedures may be very valuable additions.

Advances in this procedure, such as laser-induced fluorescence endoscopic bronchoscopy, may improve early detection of cancer.

Bronchoscopy is usually very safe, but complications can occur; they include allergic reactions to the sedatives or anesthetics, asthma attacks in susceptible patients, and bleeding. Fever may follow the procedure.

Click the icon to see an image of bronchoscopy procedure.

Click the icon to see an image of a bronchoscope.

Mediastinoscopy. Mediastinoscopy uses a tube inserted between the lungs to locate the appropriate areas for biopsy. It is performed if the physician suspects that cancer has spread to nearby lymph nodes but has not yet metastasized.

Sputum Analysis for Presence of Cancer Cells. Some experts are now recommending an analysis of coughed-up sputum as a useful and cost-effective measure for identifying cancer cells, particularly those located in central areas of the lung. However, although sputum analysis appears to be as accurate as any other screening test currently conducted, it may miss cancers such as adenocarcinoma, which form in mucus-producing cells typically in the outer portion of the lungs. If a sputum analysis does not show cancer cells, but other signs of lung cancer are present, including blood in the sputum and suspicious areas on x-rays, other tests are performed.

Biomarkers. Biologic markers, called biomarkers, are high levels of substances that are released by tumors and indicate the presence of specific cancers. Biomarkers can be found in sputum, blood, and tissue samples. They can include enzymes, hormones, amino-acid compounds, antigens (identified by antibodies that specifically target them), growth factors, and other chemicals. Some biomarkers may prove to reveal the presence of cancer cells before they are evident on CT scans or other imaging tests. For example, genetic mutations, notably K-ras and p53, can now be detected in cells found in sputum, or cells taken during bronchoscopy. Such mutations occur only with cancerous changes and may enable early detection. Other markers that prove to be important for predicting aggressive cancers are high levels of matrix metalloproteinase (MMP9) and vascular endothelial growth factor (VEGF), which are compounds involved with angiogenesis (the process in which blood vessels serving the tumor develop).

As part of the doctor's initial examination, patients may have a pulmonary function test to evaluate lung health and capacity. In addition, since the heart and lungs are often involved in complications following lung cancer surgery, the doctor may be especially interested in taking a complete history of those systems in patients who might need surgery.

Staging Systems

Tests to Determine Cancer Stage. After diagnosing non-small cell lung cancer, the doctor makes treatment choices by determining the cancer's stage (how large the tumor is and how far the cancer has spread). To stage the cancer and determine other aspects of the disease, a number of tests are conducted:

The cancer cells are examined microscopically for size, shape, and other configurations.
Computer tomography (CT), magnetic resonance imaging (MRI), or both, are used to scan the lung and perhaps other locations, such as the liver, upper abdomen, and brain, to determine the extent of the disease.

Physical Examination. A detailed physical examination of the whole body is very important to identify or rule out the spread of cancer to other areas, and to determine the general condition of the patient. For example, questions about dizziness or headaches can help the doctor determine if the cancer has spread to the brain, while bone or joint pain might suggest that the cancer has spread to the bone. The doctor will also look for head and neck symptoms that might reveal the presence of other tumors. Also, according to a 2000 review, the patient's weight loss and ability to function are two very important factors for predicting survival following treatment. Patients who are mobile and have lost less than 10% of their pre-treatment weight tend to have better survival rates.

In lung cancer, the stage of the disease at the time of diagnosis is a major factor in determining how to treat the cancer, and how long the patient can expect to live. In general, survival is longest for patients with very early-stage disease and shortest for patients with very advanced disease that has spread to several regions of the body. Staging is based on the results of physical and surgical examinations, and laboratory and imaging tests, including biopsies.

To determine the stage, medical professionals first categorize each tumor by size and by how far it has extended. This identification method is called the TNM system.

The TNM categories then determine the stage (numbered 0 to IV), indicating how advanced the cancer is.

TNM stands for Tumor, regional lymph Nodes, and Metastasis (cancer spread beyond the original tumor).

T refers to the size and extension of the tumor itself. In TX and T0, the tumor is indicated by cancer cells in sputum or lung samples but cannot be seen. Tis: Carcinoma in situ. The cells are cancerous, but the tumor does not show evidence of spreading. In T1, the tumor is 3 cm or less in size, is still contained in the lung or the membrane covering the lung, and has not reached the main airway.

In T2, the tumor has one or more of the following features:

It is greater than 3 cm
It involves the main airway
It is 2 cm or more away from the ridge (the carina) at the lowest part of the windpipe
It has invaded the pleura
It is associated with collapsed lung tissue (atelectasis) or swelling that blocks part (but not all) of the lung

In T3, a tumor of any size has directly invaded any of the following:

Chest wall
Diaphragm
The membrane covering organs and structures in the chest
The outer wall of the membrane around the heart (pericardium)

In addition, one or more of the following conditions are present:

The tumor is in the main airway, less than 2 cm away from the carina, but is not in the trachea (windpipe).
The tumor is associated with a collapsed lung or swelling that blocks the entire lung.

In T4, the tumor has invaded any of the following:

The area between the lungs (mediastinum)
The heart
The great vessels (the blood vessels that carry blood from the heart)
Carina, trachea, or esophagus
Main portion of the spine

In addition, one or both of the following occurs: separate tumors are present in the same lobe; the tumor is accompanied by an increased amount of fluid between the pleural membrane and the lung.

N followed by a number from 0 to 3 refers to whether the cancer has reached regional (in the area of tumor) lymph nodes. In stage N0, the regional lymph nodes are still cancer-free.

In N1, the cancer has spread to the nearest lymph nodes around the airways, to the hilum (a central zone in the lung where blood and lymph vessels enter), or both. The tumor has extended directly into lymph nodes within the lung. In N2, the cancer has spread to lymph nodes in the middle of the chest that are still next to the affected lung, to the nodes below the carina, or to both regions.

In N3 the cancer has spread to lymph nodes in the middle of the chest that are next to the opposite lung, to the hilum in the opposite lung, to lymph nodes in nearby or opposite muscle tissue, or to lymph nodes above the collar bone.

M Stages refer to metastasis. In M0, metastasis has not occurred.

In M1 distant metastasis has occurred. This includes the presence of a separate tumor in a different lobe.

Staging factors are used to help determine treatment and outlook. The following suggest a more aggressive disease:

The presence of respiratory symptoms
A tumor larger than 3 cm
High numbers of blood vessels in the tumor

Researchers are always looking for more accurate ways to determine a treatment and outlook for lung cancer. For example, some research involves specific biomarkers and related blood vessel development within tumors. These markers might eventually help determine how aggressive a cancer is likely to be, and what the best treatment approach is.

If the cancer is still localized, surgery can produce 5-year survival rates of up to 75% in stage I patients and up to 50% in stage II patients. Unfortunately, very few patients are diagnosed at such early stages. In locally advanced stages, the standard treatment is concurrent radiation and chemotherapy. However, even with this approach average survival times are less than 2 years. Even if an initial tumor has been surgically removed or irradiated, cancer recurrence rates are very high. The risk for recurrence is lower in smokers who quit after treatment.

On an encouraging note, advances in therapies for later stage lung cancer are now offering some hope for improving survival. Still at this time, the mortality rate for lung cancer is still extremely high, and reports of improved response or survival rates using drugs or combinations of therapies do not mean cures. Ultimately, the patient must weigh a diminished quality of life using aggressive treatments against a chance for a modestly prolonged life.

Surgical Procedures

Surgery is performed in the following circumstances:

The surgical removal of an entire lobe or parts of a lung is the primary treatment for eligible patients in early stages of cancer. Recurrence is high after surgery, although the new tumor is often operable.
Some patients with stage IIIA cancer may also benefit from surgery. The intent at this stage is to extend survival time, rather than cure the disease.
Surgery is not out of the question in rare cases of metastasis when the cancer appears in a single operable location, such as the brain.

Unfortunately, lung surgery may be too risky for patients with other lung diseases or serious medical conditions, and because lung cancers tend to occur in smokers over 50, such health problems are likely to be present. Long-term survival rates appear to be better in patients treated at hospitals that perform large numbers of lung cancer surgeries, and when surgeries are performed by thoracic surgeons, who specialize in chest procedures.

The type of surgery depends on the amount of lung or other tissue that needs to be removed.

Wedge Resection or Segmentectomy. Wedge resection and segmentectomy remove only a small part of the lung; consequently, they preserve almost normal breathing function after the operation.

Lobectomy. Removal of one of the lobes of the lung is called lobectomy. The patient's lung function must be adequate before undergoing this procedure. The operation carries an overall mortality rate of 3 - 5%, with older patients having the highest risk.

Click the icon to see an illustrated series detailing surgery to remove diseased lobes of the lung.

Pneumonectomy. Pneumonectomy removes the entire lung. The procedure itself carries a mortality rate of 5 - 8%, with the oldest patients having the greatest risk. In such patients, recurrence almost always occurs.

Surgical advances are allowing a wider range of options, including minimal surgeries for early cancers and surgeries that relieve cancer symptoms in late stages of the disease.

Thoracoscopy. Thoracoscopy, also known as video-assisted thoracic surgery (VATS), is a less-invasive technique that employs a thin tube containing a miniature camera and surgical instruments. It requires much smaller incisions than open surgery and speeds recovery to the point that patients are up within hours. Though the procedure is not appropriate in all cases, it offers significant advantages, especially in older or frail patients. The death and complication rates following VATS are lower than those following conventional surgeries. Pain is reduced, and patients are released from the hospital quicker. Several studies found that the 5-year survival and recurrence rates in patients with stage I NSCLC treated with VATS were comparable to those in patients treated with traditional open chest surgeries.

Laser Surgery. Laser surgeries allow removal of minimal amounts of lung tissue and are proving useful for improving symptoms in stage II and IIIA patients. They may also be beneficial in treating cancers that have spread to the throat, obstructing it.

Photodynamic Therapy. Photodynamic therapy uses bronchoscopy and special laser light beams combined with a light-sensitive drug, called porfimer sodium (Photofrin), to kill cancer cells. The most common side effect is sun sensitivity. Serious side effects include bleeding in the lungs. Photodynamic therapy may be considered for patients in early-stage disease who are not candidates for other surgical procedures. It may also be used to reduce symptoms in late-stage disease.

Cryosurgery. Cryosurgery uses a probe chilled to below freezing to destroy the tumor cells on contact and is being investigated in combination with radiation therapy. It may also be an alternative in early stage cancer for patients who cannot have surgery.

Electric Cauterization. Electric cauterization, the use of electricity to produce heat that destroys tissue, is also under investigation as a treatment for early-stage disease.

Back Surgery. Spinal cord compression is a common cause of pain in patients with advanced lung cancer. Because such patients can live for a year or longer, some research indicates that back surgery followed by radiation therapy can significantly improve the quality of life for many of these patients.

Radiation Treatments

In addition to surgery, radiation is the other primary treatment for early-stage lung cancer. Doctors are also studying the benefits of radiation treatment in advanced lung cancer.

Radical Radiation in Early-Stage Cancer. Radical radiation is used as the sole procedure in stage I and some stage II patients who have adequate lung function but, for medical or other reasons, cannot be treated with surgery. In these cases, the 5-year survival rate is about 20%, and the cancer is likely to recur. Survival rates may be higher or lower, depending on the tumor size. In general, treatment with radiation therapy alone shows less benefit with larger tumors. A 2002 analysis suggested that the use of radiotherapy after surgery in patients whose tumors had been completely removed might be associated with reduced survival rates. Nevertheless, a recent study confirmed earlier results that show that radiation therapy by itself is as effective as surgery in patients who are unable or unwilling to have surgery for early stage non-small cell lung cancer.

Combined Treatments for Improving Survival in Advanced Cancer. Radiation is also being investigated in various combinations with chemotherapy, surgery, or both. At this time, concurrent radiation treatment plus platinum-based chemotherapy may extend survival times in advanced lung cancer. Other combinations are showing promise.

Palliative Radiation. Doctors use palliative radiation to shrink tumors and reduce pain and symptoms. Palliative radiation is appropriate for patients with advanced disease and poor lung functions, or in those with metastasized cancer. In up to 85% of patients with advanced disease, palliative radiation therapy helps relieve pain, shortness of breath, the superior vena cava syndrome, coughing up blood, and symptoms caused by brain metastases. Radiation, in these cases, is not generally used with the intention of reducing mortality rates, although it may increase survival in some patients, such as those with excellent lung function whose tumors are small.

Delaying radiation therapy until symptoms develop does not appear to reduce survival times or impair quality of life compared to starting it right away, in patients with minimal or no symptoms.

Radiation Therapy in Metastasis to the Brain. Radiation is the primary treatment when cancer has spread to the brain unless the cancer is small enough to be treated surgically. When radiation is used, a technique called stereotactic radiosurgery may be used to deliver powerful, highly targeted radiation to specific areas in the brain. Some trials are investigating using radiation to the head to prevent metastasis to the brain.

The goal of radiation treatment is to administer doses as high as possible to kill as many cancer cells as possible, without destroying surrounding healthy tissues or causing a dangerous reaction. Doctors may try different procedures for the same patient. The exact radiation procedure depends on the site of the cancer or how far it has spread:

External-Beam Radiation. External-beam radiation therapy focuses a beam of radiation directly on the tumor. It is generally used for metastasized cancer.
Brachytherapy. Brachytherapy involved the implantation of radioactive seeds through thin tubes directly into the cancer sites. Brachytherapy may be used for lung cancers that have spread to the throat and caused obstruction. High-dose-rate brachytherapy may also have some value for patients with inoperable tumors in the central region of the lung.

Hyperfractionated radiotherapy gives smaller than standard doses a number of times a day (usually two or three). This allows doctors to use a higher cumulative dose over the whole course of treatment. It is not as useful as therapy by itself, but should be combined with chemotherapy to have any survival benefits.

Hyperfractionated Accelerated Radiotherapy. Continuous hyperfractionated accelerated radiotherapy (CHART) administers multiple doses per day but uses standard doses. This allows the total dose of radiation to be administered over a shorter time period than the standard 6 weeks. CHART is proving to extend survival rates of patients with localized cancer over that of standard radiotherapy or non-accelerated hyperfractionated radiation. It can cause severe swallowing problems. A modification in which treatment is suspended for 2 days out of 7 may help reduce this effect.

Three-dimensional (3-D) conformal radiotherapy delivers external-beam radiation designed to closely match the specific targeted organs or tissues. This allows significantly higher doses to attack the cancer while reducing the risk to healthy cells. In a 2003 report, 3-year survival rates in stage IIIA patients were nearly 60%, and nearly half the patients experienced no side effects.

Stereotactic body radiotherapy, an advance on conformal radiation, uses a body frame and an abdominal press to immobilize the patient's body and limit breath movement. This allows a more accurate delivery of high-energy radiation. The technique is still investigational.

Radiation can have significant side effects when used as part of intensive treatments, such as hyperfractionated radiotherapy or radiotherapy in combination with chemotherapy. Among the most serious problems is severe inflammation in the esophagus (esophagitis) or the lungs (pneumonitis). Infection is also a danger.

The use of targeted approaches, such as conformal radiotherapy, may help reduce these complications. Investigators are also studying drugs, notably amifostine, which appear to help reduce throat and lung inflammation caused by radiation, without reducing its cancer-fighting effects.

Treatment Options by Stages

In the occult stage (TX, N0, M0), cancer cells are found in a sample of a patient's coughed-up sputum, but no cancer cells have yet been detected in the lung.

Treatment Options. Surgical removal of the tumor, if one can be located, allows identification of its stage and often results in cure.

Stage 0 or carcinoma in situ (Tis, N0, M0) are noninvasive cancers and only a few layers of cancer cells are detected within one local area. The cancer has not grown through to the top lining in the lung and can be surgically removed. There is a high risk for development of a second tumor, however.

Treatment Options:

Surgery, often a limited procedure, where only part of a lobe is removed from the lung.
In patients who cannot be treated surgically, consider photodynamic therapy, cryotherapy, or brachytherapy.

In stage I, the cancer has reached higher layers of the lung but has not spread into the lymph nodes or beyond the lung.

General Treatment Options. The primary treatment is surgery, such as lobectomy (removal of a whole lobe), if possible. Patients with poor lung function should undergo partial lobectomy, if possible. Radiation treatments may be appropriate and beneficial for patients who cannot have surgery. It is not clear if early-stage lung cancer patients, who have radiation or chemotherapy in addition to surgery, have higher survival rates. A 2002 analysis suggested that the use of radiotherapy after surgery in patients whose tumors had been completely removed might be associated with reduced survival rates. An analysis of studies using chemotherapy in addition to surgery or radiotherapy, however, indicated benefits in survival. The overall 5-year survival rates for early stage-cancer are in the range of 30 - 50%. Patients should consider clinical trials for prevention of recurring (returning) cancer after the initial treatment. The risk for recurrence is highest in patients who continue to smoke.

Stage IA (T1, N0, M0). The 5-year survival rates for stage IA patients after successful treatment can be as high as 80%. Treatment options are:
- Lobectomy or sometimes pneumonectomy (removal of one lung)
- Wedge or segment removal, particularly in patients with poor lung function who cannot withstand lobectomy
- Radiation in selected patients whose condition is inoperable (for example, frail patients with T1 tumors); 5-year survival rates can be equal to those with surgery, between 32 - 60%
- Clinical trials of adjuvant chemotherapy following surgery

Stage 1B (T2, N0, M0). Stage IB survival rates after treatment can be better than 60%. Treatment options are:
- Lobectomy or sometimes pneumonectomy; wedge or segment removal, particularly patients with poor lung function
- Clinical trials of chemotherapy following surgery
- Clinical trials of chemotherapy before surgery (induction therapy; studies are promising)
- Clinical trials for radiation treatments in selected patients whose condition is inoperable
- Clinical trials of chemotherapy before, after, or during radiation treatments

In stage II the cancer cells have spread to nearby lymph nodes.

General Treatment Options. Surgery, usually removal of a lobe (lobectomy) or one lung (pneumonectomy), is the treatment of choice. Five-year survival rates associated with stage II surgery can vary. A 2000 review of existing research places the numbers as high as 40 - 50%, but notes that they can drop to 25% and below if the cancer has spread beyond the immediate lymph nodes.

Patients whose cancer is inoperable may consider radiation treatments. In patients who can complete treatment, 5-year survival rates average 20 - 30%, with higher rates for stage IIA. Patients should consider clinical trials for prevention of recurring cancer after primary treatment. To date, however, supplementing surgical treatment with radiation or chemotherapy does not appear to prolong survival rates.

Stage IIA (T1, N1, M0). Survival rates can be as high as 60%. Treatment options are:
- Surgery
- Radiation
- Clinical trials of chemotherapy following surgery
- Clinical trials of chemotherapy before, after, or during radiation treatments
- Clinical trials of chemotherapy to reduce tumor size before surgery (induction therapy)
Stage IIB (T2, N1, M0) or (T3, N0, M0). Survival rates can be over 40%. Treatment options are:
- Surgery
- Radiation
- Clinical trials of chemotherapy following surgery
- Clinical trials of chemotherapy before surgery (induction therapy)
- Clinical trials of chemotherapy before, after, or given at the same time as radiation treatments

In stage III, the cancer cells have spread beyond the lung to the chest wall, diaphragm, or further lymph nodes, such as those in the neck.

General Treatment Options. Generally, the treatment of choice for stage III tumors is radiation and sometimes surgery, chemotherapy, or combinations of all three.

Combination approaches may be significantly more effective than single treatments. For example, of particular interest is a treatment approach that starts with chemotherapy and radiation, given at the same time, followed by surgery. In one study, 5-year survival in stage III patients treated this way was nearly 50%.

Stage IIIA (T1, N2, M0) or (T2, N2, M0) or (T3, N1, M0) or (T3, N2, M0).
- Surgery, if the tumor and affected lymph nodes can be completely removed. Consider platinum-based chemotherapy or radiation therapy after surgery.
- Radiation treatment plus platinum-based chemotherapy, given at the same time, is an option for those in otherwise good health. This regimen should be followed by surgery, if possible.
- Consider clinical trials using advanced radiation techniques, including continuous hyperfractionated accelerated radiation, or 3-D conformal radiation.
- Consider other clinical trials, including those of various combination treatments, preventive radiation therapy to the brain, and new second-line drugs.
Stage IIIB (Any T, N3, M0) or (T4, Any N, M0). Some patients may consider surgery if there is no lymph node involvement (T4, N0), and tumor can be removed. Surgery is not an option for other patients with stage IIIB cancer. Treatment options are:
- Radiation alone, usually for symptom control; it may improve survival in certain patients, such as those with lymph node involvement above the collar bone
- Chemotherapy alone
- Concurrent (given at the same time) cisplatin-based chemotherapy plus radiation, sometimes followed by surgery if possible
- Clinical trials using induction chemotherapy alone to shrink tumors, which may then be treated with surgery or radiation
- Clinical trials using advanced radiation techniques, including continuous hyperfractionated accelerated radiation, or 3-D conformal radiation
- Other clinical trials, including those of various combination treatments, preventive radiation therapy to the brain, and new second-line drugs

In stage IV (any T, any N, M1), the cancer has spread (metastasized) to other parts of the body.

Treatment Options are:

Combination of two- or three-drug chemotherapies that include platinum-based drugs and newer agents; the best patient candidates are those in otherwise good health, who have a limited number of distant metastasized sites. Chemotherapy is not recommended for patients who are too ill
External-beam radiation for symptom relief
Paclitaxel or gemcitabine as a single medication
Other clinical trials
If metastasized cancer involves only one or two areas in the brain, it may respond to surgery followed by radiation to the brain

Recurring or additional new tumors occur, usually in the lung again, in half of treated patients. Research shows that a single tumor in the lung is more often a new tumor that, in many cases, may be operable.

Treatment Options are:

Radiation for symptom control
Chemotherapy with or without bevacisumab (Avastin)
If the cancer spread to only one site in the brain, it may respond to surgery, followed by whole-brain radiation. Extended disease-free survival is possible. If the brain tumor is not operable, it is treated with radiation. Even if cancer returns in the brain (in 50% of cases), treating it again is possible in many patients, if the disease has not spread elsewhere
Laser therapy or interstitial radiation for tumors inside the airways
Stereotactic radiosurgery (in a few selected patients)

Chemotherapy Treatments

Chemotherapy is the use of drugs given by mouth or by injection to destroy cancer cells that may have spread beyond the tumor. Until recently, there has been some doubt about the effectiveness of chemotherapy for lung cancer. A major 2002 analysis of 52 trials supported its use, particularly with platinum-based regimens, and with the use of supportive care.

Chemotherapy in early stages: Chemotherapy is proving to be beneficial in many patients as an additional (adjuvant) treatment with surgery or radiation.
Chemotherapy in advanced disease: Chemotherapy may be used as first-line treatment in patients with inoperable or metastasized lung cancer. It is typically used in late stages to reduce symptoms and, in some cases, extend survival. Since 2006, the combination of bevacizumab (Avastin, a monoclonal antibody) and platinum-based chemotherapy is also a first line treatment choice for such patients, if the cancer is the non-squamous type

Powerful platinum compounds, either cisplatin (Platinol) or carboplatin (Paraplatin), are the basis for most chemotherapy regimens. Two-drug combinations, with one drug being a platinum-based agent, are currently the preferred regimens. Reasonable combinations include paclitaxel (Taxol) and carboplatin or cisplatin. This regimen can also include gemcitabine, docetaxel, or vinblastine or its derivative (vindesine or vinorelbine). There does not seem to be any significant differences in effectiveness among them. Gemcitabine and vinorelbine combination might be a good option for patients who cannot tolerate platinum compounds. Chemotherapy for lung cancer may have reached its peak. Still, investigative chemotherapeutic drugs may yet improve response. Many experts are pinning their hope on agents called biologic response modifiers, such as gefitinib (Iressa) or LY900003 (Affinitak). To date, however, they have not achieved better results than standard platinum-based chemotherapies. Gefitinib (Iressa), a second-line therapy for non-small cell lung cancer (NSCLC), is now available only for a limited group of patients. These patients have benefited from gefitinib in the past, or they are enrolled in a clinical study with the drug. While this medicine initially showed great promise in clinical trials, results from a newer study failed to show that it prolonged survival in advanced lung cancer patients who failed other treatments.

If you are currently taking gefitinib, do not stop taking it without talking to your doctor.

Erlotinib (Tarceva) is in the same medication class as gefitinib. It is approved for patients with locally advanced or metastatic NSCLC, who have failed one type of chemotherapy treatment in the past (it is a second-line treatment). Unlike gefitinib, erlotinib shows survival and progression-free benefits compared to placebo. However, it should not be combined with platinum-based chemotherapy.

Chemotherapy treatments are usually performed in an outpatient setting and in regular cycles for several months. How many chemotherapy cycles to administer in late-stage cancers, the timing of those cycles, and the sequences of the drugs are still matters of investigation. For instance, research suggests that a three- or four-course cycle may achieve the same survival times and better quality of life than the standard of six or more course cycles. Changing even one day in a drug sequence can sometimes significantly affect outcome. Such fine-tuning of chemotherapy regimens is likely to have the most effect on patients with advanced-stage disease, which requires more tailored treatment than early-stage disease.

Treatment for lung cancer depends on the type of cancer and the stage of the disease. Chemotherapy is a form of treatment for lung cancer that may cure, shrink, or keep the cancer from spreading.

Side effects of chemotherapy treatments are common, and they are more severe with higher doses. Side effects increase over the course of treatment. Some trials suggest that they can be reduced by giving the drugs for shorter durations, without loss of cancer-killing effects. Common side effects include the following:

Diarrhea
Temporary hair loss
Weight loss
Fatigue
Depression
Nausea and vomiting: Drugs known as serotonin antagonists, especially ondansetron (Zofran), can relieve these two side effects. Serotonin antagonists work well in nearly all patients given moderate drugs, and in most patients who take drugs that are more powerful. In one study, a combination of dexamethasone (a steroid) with ondansetron, taken within 24 hours of chemotherapy, achieved either a major or complete reduction in nausea and vomiting.
Anemia: Anemia, an abnormally low number of red blood cells, is common in lung cancer. Treatments include transfusions or injections of erythropoietin, an agent that causes more red blood cell production. Erythropoietin is available as epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp), which requires fewer injections. These agents improve well-being and quality of life. Trials are in progress to determine if they may have survival benefits as well.

These side effects are nearly always temporary. Most patients are able to continue with normal activities for all but perhaps 1 or 2 days per month.

Serious complications of chemotherapy can also occur and may vary depending on the specific drugs. They include the following:

Increased chance for infection from suppression of the immune system.
Severe drops in white blood cells (neutropenia): Certain chemotherapy drugs, such as taxanes, pose a higher risk for this complication than other drugs. White blood cell count can improve with the addition of a type of drug called granulocyte colony-stimulating factor (filgrastim and lenograstim).
Liver and kidney damage: Amifostine (Ethyol) reduces the risk for kidney damage in patients taking repeated regimens of cisplatin-based therapy. It is also a radioprotector; that is, it helps prevent severe effects in the esophagus from radiotherapy, with or without chemotherapy.
Abnormal blood clotting (thrombocytopenia).
Allergic reaction, particularly to platinum-based agents: A simple skin test is under investigation that may identify people with a potential allergic response.

Second-line chemotherapy is used for patients whose cancers have recurred after first-line chemotherapy. Some experts believe that the longer survival rates for advanced lung cancer seen for the past 5 years may be due to these drugs. Because platinum-based agents are most often used first, they are not beneficial for second-line therapy. The following are commonly used second-line agents.

Docetaxel (Taxotere). Docetaxel is the drug of choice at this time for cancers that do not respond to initial chemotherapy. Studies have reported that it achieves longer survival times than supportive care alone. It is usually given every 21 days. This regimen causes more side effects than pemetrexed, the newer major second-line drug. Weekly doses of docetaxel are effective and less toxic than the 3-week schedule. It is not clear if survival rates are comparable to those of pemetrexed with that schedule, however.

Pemetrexed (Alimta). Pemetrexed, known as an anti-folate, is another promising new agent for second-line therapy and possibly for first-line treatment as well. The drug targets a number of enzymes that play a role in how cancer cells increase. Some research suggests that it is as effective as docetaxel. Pemetrexed does have some serious toxic effects, but they can be significantly reduced with folic acid and vitamin B12 supplements. It is then less toxic than docetaxel, when docetaxel is given every 21 days, but not when it is given weekly.

Gefitinib (Iressa) and Other Tyrosine Kinase Inhibitors. Much research is focusing on drugs that block small molecules involved with the growth of blood vessels that feed the tumor (a process called angiogenesis). Compounds called growth factors, which may be important in cancer cell production, control the growth of these new blood vessels. Researchers, then, are interested in medications that literally turn off these growth factors or their receptors, such as epidermal growth factor receptor (EGFR). In so doing, the agents may be able to cut off cancer's lifeblood. Gefitinib and erlotinib are angiogenesis inhibitors that target receptors of an epidermal growth factor called tyrosine kinase. Interestingly, studies are finding that NSCLC tumors in people who have never smoked have a much higher rate of EGFR mutations. This helps to explain why gefitinib and erlotinib are more effective in treating NSCLC in people who have never smoked.

Gefitinib (Iressa) was approved in 2003 as a second-line therapy for non-small cell lung cancer. Many patients report significant improvement in symptoms and quality of life, and the drug initially showed great promise. In one study, gefitinib reduced tumor size by 50% in about 10% of the patients. However, recent large-scale clinical trial results have failed to confirm any survival advantage for most patients. At this time, gefitinib is available only for patients who have benefited from it in the past.
Erlotinib (Tarceva) was approved as a single agent second-line therapy in November 2004. Study results show that the drug prolonged survival by several more months than placebo (6.7 versus 4.7 months). Erlotinib is administered orally and has very low toxicity (rash and diarrhea are common).

Chemotherapy Following Surgery (Adjuvant Chemotherapy). Chemotherapy is being evaluated in combination with surgery, radiation therapy, or both. Fairly strong evidence is now supporting the use of platinum-based chemotherapy as adjuvant treatment after surgery in patients with lung cancers in stages Ib-IIIa, with some research indicating a 5% improvement in five-year survival rates. Not all studies confirm survival benefits, however, and trials are ongoing.

Chemotherapy before Surgery (Induction Chemotherapy). Some researchers are testing induction chemotherapy, which is used to shrink potentially operable tumors before surgery. Studies have been mixed in reporting any survival benefits in patients with advanced lung cancer.

Combined and Multi-Modal Therapy. In stage III cancers, investigators are researching very intensive treatments that use two or more combinations of chemotherapy, radiation, and surgery.

For example, radiation plus chemotherapy may be helpful in patients whose tumors are surgically removable.

In inoperable lung cancer, combining radiation with chemotherapy is proving to extend the time to recurrence, the overall duration of survival, or both, compared to radiation alone. Evidence also suggests that giving radiation treatments at the same time as chemotherapy (instead of in separate cycles) improves 5-year survival rates, compared to a sequential approach (separate cycles following each other). Chemotherapy and radiation treatments given at the same time are more toxic, however.

Other approaches use even more intensive multi-modal therapy. For example, some trials use radiation therapy with chemotherapy, followed by surgery. Patients are then sometimes given additional chemotherapy or radiation. In other promising regimens, patents are given concurrent radiation and chemotherapy followed by chemotherapy alone. Such approaches are very toxic but appear to improve survival in selected patients.

Severe inflammation in the esophagus is the most common severe side effect of the radiation and chemotherapy combination. There is also a very high risk of serious infections, including pneumonia, herpes zoster, and cytomegalovirus. Long-term antibiotic therapy may be needed.

Although patients over 70 may suffer more from toxic effects than younger patients, studies now suggest that they can achieve survival rates with combined treatments that are equal to those in younger patients.

There are many painkilling medications available. Research shows that aggressive pain relief can help patients manage cancer treatment symptoms (in addition to pain) better. For example, a 2001 study suggested that reducing pain in elderly cancer patients markedly lowered their fatigue levels, and improved other symptoms as well.

Opioids are the most potent painkillers. The correct use of these strong medications is very important for reaching acceptable pain relief, and preventing a toxic response. For example, the long-lasting version of oxycodone (OxyContin) must be swallowed whole; chewing, inhaling, or injecting it can create a deadly overdose.

Investigative Agents

According to a 2001 article, of the nearly 500 cancer drugs currently in development, 58 of them (about 13%) are aimed at fighting lung cancer. Only the number of breast cancer drugs exceeded that percentage. Unfortunately, none to date have shown any real benefit in terms of patient survival. However, some drugs are showing promise, and at this time, these agents are the best hope for improving lung cancer survival rates.

Monoclonal antibodies (MAbs) are genetically designed immune factors. MAbs mark foreign compounds called antigens for attack by the immune system. Trastuzumab (Herceptin) and cetuximab (Erbitux) are MAbs under investigation for lung cancer. Bevacizumab (Avastin) was approved in October 2006 as a first-line treatment (in combination with carboplatin and paclitaxel) for inoperable, locally advanced, metastatic, or recurrent non-squamous, non-small cell lung cancer.

All three of these MAbs block epidermal growth factor. These agents are of particular interest for patients who have cancers that produce too much of the protein called HER2. These agents show great promise in combination with chemotherapies and newer drugs, such as the tyrosine kinase inhibitors. For example, the disease-free survival time in patients with advanced NSCLC is longer when adding bevacizumab to platinum-based chemotherapy.

Antisense oligonucleotides are drugs being used to block molecules that result in too many cells that cause cancers. LY900003 (Affinitak), for example, targets an enzyme called PKC-alpha, which promotes tumor growth. Early studies with Affinitak showed some promising results. However, a 2003 study found no difference in survival when patients received Affinitak in combination with platinum-based chemotherapy, compared to patients receiving chemotherapy alone.

Genasense (G3139, oblimersen) blocks Bcl-2. Bcl-2 is a protein that is expressed in abnormally high amounts in some cancers. This antisense drug is also under investigation.

Advexin, a genetic therapy that contains the p53 tumor-suppressor gene, is showing promise. In one early study, 60% of patients experienced partial or total tumor shrinkage when the agent was used in combination with radiation therapy. A 2006 study in Japan found that out of 13 patients with advanced NSCLC receiving Advexin, 10 had stabilized. Three of the stabilized patients remained stable for over 9 months. One patient had a partial response to Advexin. The only side effect of the multiple doses given was a passing fever that disappeared within 24 hours. Advexin is in Phase II clinical trials for NSCLC.

Vaccines use inactivated genetic materials from cancer cells, such as defective p53 or ras genes, to cause a highly targeted immune response to attack the cancer.

Retinoids are vitamin A-like antioxidant chemicals that help repair cell damage and appear to support growth of lung cells. A number of retinoid-like agents (retinal palmitate, TAC-101, 23-cis-retinoic acid, N-acetyl-cysteine) are being studied for the treatment or prevention of lung cancer.

Resources

www.cancer.gov -- National Cancer Institute
www.cancer.org -- American Cancer Society
www.cancercare.org -- Cancer Care
www.lungusa.org -- The American Lung Association
www.asco.org -- American Society of Clinical Oncology
www.alcase.org -- Alliance for Lung Cancer
www.lungcancer.org -- Joint project of Cancer Care and the Oncology Nursing Society
www.nccn.org -- National Comprehensive Cancer Network
www.lungcanceronline.org -- Lung cancer information
www.epa.gov/iaq/radon -- National radon information
www.clinicaltrials.gov -- Find clinical trials
www.cancer.gov/clinicaltrials -- Find clinical trials

References

Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKena WG. Clinical Oncology. 3rd ed. Orlando, Fl: Churchill Livingstone; 2004:1690-1701.

American Cancer Society. Cancer Facts and Figures 2006. Atlanta, Ga: American Cancer Society; 2006.

American Cancer Society. Cancer Facts and Figures 2007. Atlanta, Ga.: American Cancer Society; 2007:34.

Janne PA. Non-small Cell Lung Cancer in Never-smokers: A Biologically and Clinically Distinct Type of Lung Cancer. In: ASCO 2007 Educational Book. Meeting of the American Society of Clinical Oncology, Chicago, Ill.: June 1-5, 2007.

Kagawa S, Fujiwara T, Saijo Y, et al. A multicenter phase I study of adenoviral p53 (ADVEXIN) in Japanese patients with advanced non-small cell lung cancer. Journal of Clinical Oncology. 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 2564.

Mehra R, Moore BA, Crothers K, Tetrault J, Fiellin DA. The association between marijuana smoking and lung cancer: a systematic review. Arch Intern Med. 2006 Jul 10;166(13):1359-67.

National Cancer Institute. Lung Cancer Home Page. Bethesda, Md.: U.S. National Institutes of Health. Available online.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 1.2007. Available online.

Tarceva [Package Insert]. Melville, NY: OSI Pharmaceuticals; 2005.

U.S. Department of Health and Human Services. The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General. Atlanta, Georgia: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Coordinating Center for Health Promotion, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2006.

U.S. Food and Drug Administration, Center for Drug Evaluation and Research. List of Approved Oncology Drugs with Approved Indications. In: Oncology Tools. Available online.

U.S. Preventive Services Task Force. Lung cancer screening. Ann Int Med. 2004;140:738-739.

Xin M, Deng X. Nicotine Inactivation of the Proapoptotic Function of Bax through Phosphorylation. J Biol Chem. 2005 Mar 18;280(11):10781-9.

Review Date:
8/3/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Prostate cancer

FitSugar — Wed, 08 Oct 2008 17:35:05 -0700

In This Report

Highlights
Introduction
Prognosis
Risk Factors
Symptoms
Conditions with Similar Sym...
Screening and Diagnosis
Tests to Determine Severity...
Treatment
Treatment Options by Stagin...
Treatment for Localized Pro...
Surgery
Radiation Treatments
Options if Treatments Fail...
Other Treatments
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

New Guidelines for Localized Prostate Cancer

In 2007, the American Urological Association (AUA) released updated guidelines for treatment of localized prostate cancer. The guidelines recommend that:

Patients should be classified as low, intermediate, or high risk, depending on their PSA levels, cancer stage, and tumor aggressiveness.
Doctors need to consider patients’ personal preferences and quality of life concerns as well as their clinical status.
Standard treatment options include active surveillance (watchful waiting), surgery, or radiation therapy. Initial androgen deprivation therapy (hormone therapy) is seldom recommended for localized prostate cancer.

New Guidelines for Androgen Deprivation Therapy

The American Society of Clinical Oncology (ASCO) 2007 guidelines recommend that doctors delay androgen deprivation therapy for advanced prostate cancer until patients develop symptoms. When treatment is started, ASCO recommends either removal of both testicles (orchiectomy) or luteinizing hormone releasing hormone (LHRH) drug treatment.
Androgen deprivation therapy can increase the risks for heart disease death and diabetes, according to a 2006 Journal of Clinical Oncology study.

Diagnosis

Experts do not recommend prostate specific antigen (PSA) tests for men over age 70, yet many of these men continue to receive unnecessary tests, indicates a 2006 Journal of the American Medical Association study.
A new investigational test for early prostate cancer antigen-2 (EPCA-2) may be more accurate than the PSA test and may eventually replace it, suggests a 2007 study in Urology.

Genetic Research

Researchers have identified a set of genetic variations that may account for about 68% of prostate cancer cases in African-American men. Scientists hope that further investigation of this chromosomal region may help in developing genetic tests for prostate cancer.

Introduction

Prostate cancer is a malignant tumor that arises in the prostate gland. As with any cancer, if it is advanced or left untreated in early stages, it can eventually spread through the blood and lymph fluid to other organs. Fortunately, prostate cancer tends to be slow growing compared to other cancers. As many as 90% of all prostate cancers remain dormant and clinically unimportant for decades. This high incidence of latent or incidental malignancy is unique to the prostate gland. Most older men eventually develop at least microscopic evidence of prostate cancer, but it often grows so slowly that, as one specialist has written, many men with prostate cancer "die with it, rather than from it."

The prostate gland is an organ that surrounds the urinary urethra in men. It secretes fluid which mixes with sperm to make semen.

Male hormones (androgens) play major roles in the development of prostate cancer. Some research, for example, reports a higher risk with increasing testosterone and a lower risk with increasing estrogen levels. Dihydrotestosterone (DHT) is the principal male hormone in the prostate gland. It affects the size of the prostate gland itself and may play a role in prostate cancer. Nevertheless, researchers have not yet fully clarified the specific mechanisms that may be important in the development of this disease. Most likely, genetic mutations affecting androgens trigger the process. Certain growth hormones, such as insulin-like growth factor-I, are unrelated to testosterone and may increase the risk for prostate cancer.

Description of the Prostate Gland

The prostate gland is located between the bladder and the rectum and wraps around the urethra (the tube that carries urine through the penis). It is basically composed of three different cell types:

Smooth muscle cells, which contract during sex and squeeze the fluid from the glandular cells into the urethra, where it mixes with sperm and other fluids to make semen
Glandular cells, which produce a milky fluid that liquefies semen
Stromal cells (which form the structure of the prostate)

The central area of the prostate that wraps around the urethra is called the transition zone. The entire prostate gland is surrounded by a dense, fibrous capsule.

Functions of the Prostate Gland

The prostate gland provides the following functions:

The glandular cells produce a milky fluid, and during sex the smooth muscles contract and squeeze this fluid into the urethra. Here, it mixes with sperm and other fluids to make semen.
The prostate gland also contains an enzyme, called 5 alpha-reductase, that converts testosterone to dihydrotestosterone, another male hormone that has a major impact on the prostate.

Changes During the Lifespan

The prostate gland undergoes many changes during the course of a man's life. At birth, the prostate is about the size of a pea. It grows only slightly until puberty, when it begins to enlarge rapidly, attaining normal adult size and shape, about that of a walnut, when a man reaches his early 20s. The gland generally remains stable until about the mid-forties, when, in most men, the prostate begins to enlarge again through a process of cell multiplication.

Click the icon to see an image of the male reproductive anatomy.

Prognosis

Prostate cancer is the most common male cancer in the U.S. Only lung cancer causes more cancer deaths in American men. The lifetime probability of developing prostate cancer is about 16%. Each year, approximately 218,890 men in the United States will be diagnosed with prostate cancer, and about 27,050 will die from the disease. According to the American Cancer Society, 5-year survival rates for all stages of prostate cancer have increased during the past 20 years from 67% to nearly 100%.

A survival rate indicates the percentage of patients who live a specific number of years after the cancer is diagnosed. For prostate cancer, the 10-year survival rate is 93% and the 15-year survival rate is 77%. After 15 years, survival rates stabilize. A 2006 study in the Journal of the American Medical Association found that men who are diagnosed with low-grade prostate cancers have a minimal risk of dying from prostate cancer up to 20 years after diagnosis. However, men diagnosed with more severe forms of prostate cancer have a higher risk of dying within 10 years.

Treatment of prostate cancer varies depending on the stage of the cancer (i.e., spread) and may include surgical removal, radiation, chemotherapy, hormonal manipulation or a combination of these treatments.

Because so many prostate tumors are low-grade and slow growing, survival rates are excellent when prostate cancer is detected in its early stages. Cure rates can be as high as 98% in some cases.

Click the icon to see an image of the pelvic lymph nodes.

Locally Advanced. If the disease is at the locally-advanced stage, in which it has spread beyond the prostate but only to nearby regions, it is more difficult to cure, but survival rates can be prolonged for years in many men. (When cancer has metastasized to the pelvic lymph nodes, the outlook is worse than if it has spread to other areas.)

Metastasized Cancer. If prostate cancer has spread to distant organs (metastasized), average survival time is 1 - 3 years, but some of these patients may live longer or die of other causes.

If cancer recurs after initial treatment for early-stage tumors, it is still potentially curable if it is contained within the prostate, although in most cases the cancer has spread. Hormone treatments for such recurring cancers can often prolong survival for years, although the cancer almost always returns again.

Risk Factors

The major risk factors for prostate cancer include genetic, dietary, and environmental factors that affect male hormones (androgens) and make a man more susceptible to this cancer.

Prostate cancer occurs almost exclusively in men over age 40 and most often after age 50. It is estimated that by age 70, about 65% of men have at least microscopic evidence of prostate cancers. Fortunately, the cancer is often very slow growing and older men with the cancer nearly always die of something else.

Heredity plays a role in some types of prostate cancers. Men with a family history of the disease have a higher risk of developing prostate cancer. Having one family member with prostate cancer doubles a man's own risk, and having three family members increases risk by 11-fold.

In 1998, scientists discovered a gene, located on chromosome 1, which may be involved in 1 in 500 cases of prostate cancer. They named this gene HPC1. (HPC stands for “hereditary prostate cancer.”) In 2005, scientists announced another major breakthrough in understanding the genetic components of prostate cancer. Research published in Science suggested that, in some cases, prostate cancer occurs when a specific set of genes merge. The genes are part of the ETS gene family and include ETV1, ETV4, and ERG.

In 2007, three separate studies published in Nature Genetics focused on DNA variations located on chromosome 8 in the 8q24 region. The research suggested that men who carry these genetic variations have a substantially increased risk of developing prostate cancer. The DNA variations may be associated with as many as 32% of prostate cancers in Caucasian men and 68% of prostate cancer cases in African-American men.

Doctors hope that future research will help develop genetic tests to identify men most at risk and, eventually, targeted drug therapy for prostate cancer.

A gene is a short segment of DNA which is interpreted by the body as a plan or template for building a specific protein. Genes reside within long strands of DNA which in turn make up the chromosomes.

African-American men have the world's highest risk for prostate cancer, more than 50% higher than the risk for Caucasian males. The disease is also more lethal among African-Americans. Men who live in Asia have lower risks for prostate cancer, but their risk increases if they move to North America. This indicates that there are unknown environmental or dietary factors that can alter a man's underlying genetic risk of developing this disease.

Socioeconomic Issues. The higher mortality rates in African-American men may be partly due to socioeconomic factors, such as lack of insurance, irregular screening and a late diagnosis, and unequal access to health care.

Dietary Factors. Dietary factors may play some small role in the higher risk in African-American men. This is suggested by the fact that prostate cancer is rare in many parts of Africa.

Biologic Factors. Evidence suggests that African-American and Asian men have certain genetic factors that may affect male hormones differently and may help account in part for the higher risk in the first group and the lower risk in the second.

Higher PSA Levels. African-American men also tend to have higher PSA levels than Caucasians. They are overdiagnosed with prostate cancer by 37% compared to 15% in Caucasians using PSA screening tests.

Chemicals. The relationship between prostate cancer and chemical exposure is controversial. Men whose work involves heavy labor and those exposed to certain metals and chemicals, including cadmium, dimethylformamide, and acrylonitrile, may be at higher risk for prostate cancer. Some studies have indicated that farmers might be at higher risk.

A 2001 study concluded that certain leisure activities may expose men to the same chemicals as those that pose a possible danger in the industrial setting. These chemicals included:

Home or furniture maintenance
Painting, stripping, or varnishing furniture
Activities that involved exposure to lubricating oils or greases, metal dust, or pesticides or garden sprays

Scientists think that specific genes that affect the body's response to viruses may be associated with certain types of prostate cancer. Some theories suggest that there may be a relationship between prostate cancer and infections, such as herpes virus, human papillomavirus, and cytomegalovirus. In 2006, scientists identified a new virus, XMRV, which is 30 times more common in men with prostate cancer who have a genetic mutation with the HPC1 gene. Scientists know that men who have the HPC1 genetic mutation are more likely to get prostate cancer. This new research suggests that the genetic mutation may make them more vulnerable to a virus that causes the cancer. Researchers will continue to investigate XMRV and other possible infectious causes of prostate cancer.

Obesity. Obesity may increase the risk for prostate cancer, particularly more aggressive forms of the disease. Obesity may also make prostate cancer more difficult to diagnose. A 2005 study found that overweight and obese men were more likely to be diagnosed with advanced prostate cancer and to die of the disease than normal-weight men.

Nonmelanoma Skin Cancers and Sunlight. Some studies report that patients with prostate cancer and a history of nonmelanoma skin may have a higher risk for a poorer outlook. Such skin cancers are highly associated with exposure to sunlight. However, sunlight triggers production of vitamin D in the body, which research indicates may help protect against prostate cancer. Prostate cancer rates are, in fact, lower in southern, sunny regions.

Vasectomy. Because testosterone levels remain higher for a longer period in men who had vasectomy, experts have theorized that such men have a greater chance for developing the cancer. While some studies have suggested a higher risk with vasectomy, other studies have reported no higher danger. A rigorous 2002 study from New Zealand, for example, which has the highest vasectomy rates in the world, found no increased risk of prostate cancer from the procedure, even 25 years after the operation. A 2002 study in California, in fact, reported a lower risk for prostate cancer in men who had had vasectomies. It is possible that the higher rates reported in earlier studies may have been due to earlier prostate screening in men who have had vasectomies. Indeed, one study reported that about 25% of doctors screened men with vasectomies earlier for prostate cancer than those without the operation. [See In-Depth Report #37: Vasectomy.]

Click the icon to see an illustrated series detailing a vasectomy.

Click the icon to see an animation on vasectomy.

A Western lifestyle is associated with prostate cancer, so obesity, high-meat intake, and dietary fats have been intensively studied. Results have been inconsistent, however. Certain factors, such as cancer-causing compounds in well-cooked meat or high-calorie intake, may help explain the associations between such dietary factors and cancer risk.

Click the icon to see an image on different types of weight gain.

Fats. Some studies have found an association between high fat-intake and prostate cancer. This association may be explained by other suspected dietary factors for prostate cancer, such as high-calorie diet, high meat intake, and calcium (found in dairy products), all of which are associated with fat intake. The effects of specific fatty acids (compounds that make up fats) may also help clarify the role of fats in prostate cancer. The omega-3 fatty acids in fish (EPA and DHA) and the omega-3 fatty acids found in certain vegetables (ALA) can all protect the heart, but they may have different effects on the prostate.

Marine Omega-3 Fatty Acids. Research indicates that docosahexanoic acid (DHA) and eicosapentaneoic acid (EPA), the omega-3 fatty acids found in fish, may be protective against prostate cancer. Some studies have reported a lower risk for prostate cancer in men who ate fish frequently (two or more times a week).
Alpha-Linolenic Acid. On the other hand, some research has indicated that alpha-linolenic acid (ALA), the omega-3 fatty acid found in certain plants and nuts (flaxseed, canola, walnuts), may increase the risk of prostate cancer. However, some studies suggest that flaxseed, a plant food that is also rich in omega-3 fatty acids, may help slow the growth of prostate tumors.

Meat and High-Temperature Cooking. Some evidence suggests that a high intake of red meat raises the risk for prostate cancer. Because red meat is high in saturated fat, such findings may explain the inconsistencies found in studies that simply look at fat content as a risk for prostate cancer. High-temperature cooking (grilling, broiling, or pan-frying) of meat or poultry has been specifically associated with increased risk for cancer in some studies. Over-cooking meat increases the amount of compounds called heterocyclic amines, which has been associated with cancerous changes in general and prostate cancer in particular, at least in some studies. Cooking meats in liquid does not appear to increase these compounds. As with all dietary studies, some have observed no association between high intake of well-cooked meat and prostate cancer.

Vegetarian Diet. Small studies suggest that a vegetarian diet may be protective. Specific foods may be especially helpful in reducing the risk of prostate cancer:

Whole grain cereals, seeds, and nuts have been associated with a lower risk for prostate cancer. Part of this protection may be due to their high fiber content. Fiber binds to sex steroids and is excreted, carrying the hormones with it. Whole grains also contain selenium, a trace mineral that may have some protective properties.
Many studies have reported a significantly lower risk for prostate cancer with high intake of cooked tomatoes, which are high in a beneficial plant chemical called lycopene. (However, other studies have not reported such protection.)
Soy may also be protective, which may partially explain the low rate of prostate cancer observed in Japanese men and vegetarians (who typically use soy as a protein replacement). Theoretically soy, which is a rich source of an estrogen-like plant compound, may inhibit hormones that promote prostate cancer. Laboratory studies are mixed on such effects, however.
Cruciferous vegetables (cauliflower and broccoli) may have cancer-fighting chemicals.
Boron-rich foods (nuts, red grapes, avocados, and dried fruits) may also be protective.
Green tea. Scientists have speculated that the antioxidants contained in green tea may help to inhibit prostate cancer growth. Investigators are researching the effects of both green tea and green tea extract supplements, but results to date have been inconclusive.

Dairy Products, Calcium, and Vitamin D. Studies have reported an association between consuming large amounts of dairy products and a modestly increased risk for prostate cancer. (Moderate intake has not been associated with a higher risk.) There is some evidence that calcium (contained in dairy products) may increase the risk for prostate cancer by reducing levels of the most active form of vitamin D (1,25 dihydroxyvitamin D). Many studies indicate that vitamin D may help protect against prostate cancer. Men should make sure they are getting enough vitamin D through sunlight exposure, food, or vitamin supplements.

Getting enough calcium to keep bones from thinning throughout a person's life may be made more difficult if that person has lactose intolerance or another reason, such as a tendency toward kidney stones, for avoiding calcium-rich food sources. Calcium deficiency also affects the heart and circulatory system, as well as the secretion of essential hormones. There are many ways to supplement calcium, including a growing number of fortified foods.

Click the icon to see an image of the benefits of vitamin D.

Click the icon to see an image of the sources of vitamin D.

There is some evidence that certain vitamin and mineral supplements (such as vitamin E and selenium) can protect against prostate cancer, and also some evidence that excessive use of supplements may increase risk. In a 2007 National Institutes of Health study, men who took multivitamin supplements more than seven times a week increased their risks for developing advanced prostate cancer and for dying from the disease. The risks were highest for men who had a family history of prostate cancer and for those who took individual supplements of selenium, beta-carotene, or zinc. However, using multivitamin supplements occasionally or once a day does not appear to increase prostate cancer risk.

The National Cancer Institute is conducting a large-scale clinical trial of more than 35,000 men to investigate whether selenium, vitamin E, or a combination of these two dietary supplements can help to prevent prostate cancer. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is the largest prostate cancer prevention trial ever initiated.

Click the icon to see an image of the benefits of vitamin E.

Click the icon to see an image of the sources of vitamin E.

In general, a healthy diet with nutritious fruits and vegetables is the best way to meet your daily requirement of vitamins and minerals.

Alcohol consumption does not appear to be associated with increased prostate cancer risk. A recent study, however, suggested a linear trend between red wine consumption and reduced risk of prostate cancer. In a study of over 1,400 newly diagnosed middle-aged patients with prostate cancer, researchers found that each additional glass of red wine consumed per week reduced the relative risk of prostate cancer by 6%. Researchers theorize that the flavonoids contained in red wine may inhibit tumor cell growth. More research is needed to confirm these results.

Regular physical activity may help reduce the risk of prostate cancer and slow the progression of the disease. The beneficial effects of exercise may be particularly important for older men. A 2006 study found that men ages 65 and older who exercised vigorously for at least 3 hours weekly had a 70% lower risk of being diagnosed with advanced prostate cancer.

Finasteride (Proscar) is a drug used to shrink the prostate in men with benign prostatic hyperplasia (BPH). It blocks an enzyme that converts testosterone to dehydroepiandrosterone (DHEA), the form of the male hormone that stimulates the prostate. Researchers are investigating whether finasteride may help prevent prostate cancer. In the 2003 Prostate Cancer Prevention Trial (PCPT), more than 18,000 men were randomly assigned to receive either finasteride or placebo. The men took the pills daily for 7 years. Results, published in 2003 in the New England Journal of Medicine, indicated that men who took finasteride were 25% less likely to develop prostate cancer than men who took placebo. However, although the finasteride group had fewer prostate cancers overall, those that did develop were higher-grade and more aggressive. Men who took finasteride had more sexual problems, including episodes of erectile dysfunction, but were less likely to have urinary problems, such as incontinence. It is still unclear if finasteride is an appropriate preventive approach.

Frequent ejaculations from masturbation or sexual activity have been associated with a lower risk for prostate cancer. Some experts speculate that certain carcinogens may be concentrated in prostate fluid, so that frequent ejaculation helps eliminate them. Of note, risky sexual activity, such as with multiple partners, increases the risk for sexually transmitted disease, which in turn may increase the risk for prostate cancer.

There is some evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) offer some protection against prostate cancer. NSAIDs suppress chemicals in the body called COX-2, a protein that may cause prostate cancer cells to spread. Standard NSAIDs include aspirin, ibuprofen (Advil), and naproxen (Aleve). However, NSAIDs taken on a long-term basis can increase the risk for heart and gastrointestinal problems.

Symptoms

Prostate cancer usually causes no symptoms in the early stages. As the malignancy spreads, it may constrict the urethra and cause urinary problems.

Urine flows from the kidney through the ureters into the urinary bladder where it is temporarily stored. As the bladder becomes distended with urine, nerve impulses from the bladder signal the brain that it is full, giving the individual the urge to void. By voluntarily relaxing the sphincter muscle around the urethra, the bladder can be emptied of urine. Urine then flows out through the urethra.

Later-stage urinary symptoms typically include:

Weak urinary stream
Inability to urinate
Blood in the urine
Interruption of urinary stream (stopping and starting)
Frequent urination (especially at night)
Pain or burning during urination

Significant pain in one or more bones may indicate the occurrence of metastases (spread of disease). This chronic pain occurs most often in the spine and sometimes flares in the pelvis, the lower back, the hips, or the bones of the upper legs. It may be accompanied by significant weight loss.

Conditions with Similar Symptoms

In up to half of men in their 40s, the prostate begins to enlarge through a process of cell multiplication called benign prostatic hyperplasia (BPH). The symptoms of BPH can mirror late-stage prostate cancer because the enlarging inner portion of the prostate puts pressure on the urethra, which can potentially cause urinary problems. About 80% of men eventually develop enlarged prostates, but only some experience significant symptoms. BPH is a normal condition and is not life-threatening. [See In-Depth Report #71: Benign prostatic hyperplasia.]

Benign prostatic hypertrophy (BPH) is a non-cancerous enlargement of the prostate gland, commonly found in men over the age of 50.

Relationship to Prostate Cancer. Because the prostate enlargement in BPH is affected by testosterone, many men are concerned that it may be related to prostate cancer. Fortunately, current evidence indicates that it has no effect one way or the other. The two conditions develop in different parts of the prostate. BPH occurs in the inner zone of the prostate, while cancer tends to develop in the outer area. A 10-year study found no higher risk for prostate cancer in men with BPH.

Click the icon to see an animation about benign prostatic hypertrophy.

Prostatitis is an inflammation of the prostate, often caused by bacterial infections. Symptoms include urgency, frequency, and pain in urination, sometimes accompanied by fever or blood in the urine.

Screening and Diagnosis

The prostate specific antigen (PSA) blood test is widely used for screening men for prostate cancer. However, there is great uncertainty over whether regular screening has major benefits for most men. The most recent guidelines from the U.S. Preventive Services Task Force report that there is no conclusive evidence that routine prostate screening saves lives. Indeed, it may lead to invasive testing, and to treatments for many men who, considering the slow growth of the cancer, might derive no benefits from them. It is a difficult subject, and men must discuss all aspects carefully with their doctor.

A 2006 study in the Archives of Internal Medicine also suggested that screening tests for prostate cancer may not reduce men’s risk of death. The small study of 1,000 men found no differences in survival between men who had prostate specific antigen tests or digital rectal exams, and men who were not screened. Doctors should inform men of the uncertainty of prostate cancer tests so that patients understand the relative risks and benefits of screening

Standard Screening Tests for Early Detection. Two standard tests are used for early detection of prostate cancer:

Digital rectal examination (DRE). With the DRE, a doctor palpates the prostate in order to feel lumps or masses.
PSA test. The PSA blood test measures the level of a protein called prostate-specific antigen. It is able to detect early prostate cancer, although it has limitations.

If the digital rectal examination indicates the possible presence of cancer, regardless of the PSA results, a doctor may also obtain a visual image of the prostate through an ultrasound procedure called transrectal ultrasonography (TRUS). Only a biopsy, however, in which a tiny sample of prostate tissue is surgically removed, can actually confirm a diagnosis of prostate cancer.

Candidates for Annual Screening. Until major studies report on the survival benefits of prostate screening, expert groups recommend the following:

Men ages 50 - 70 should be offered annual screening. (Some experts believe that men whose PSA levels are under 1.0 and possibly under 2.0 may safely be screened only every 2 years thereafter.)
Men with a family history of prostate cancer and all African-American men should consider annual screening at about age 45.
Experts agree that PSA testing is inappropriate for men over age 70. PSA testing in this age group can cause more harm than good by leading to overly aggressive treatment. Despite this fact, many elderly men continue to receive unnecessary PSA tests.

The best age to start annual screening is under debate. Some experts advocate performing a first PSA test in all men aged 40 and then monitoring anyone whose PSA levels are over 0.60 ng/mL. They argue that such men are at high risk for developing prostate cancer within 25 years. A study presented at the 2007 meeting of the American Urological Association suggested that even a small increase in PSA in men age 44 - 50 may predict whether advanced prostate cancer will develop later in life.

Researchers are working on developing more accurate tests that, hopefully, will one day replace the PSA test. A promising test in development measures a protein called early prostate cancer antigen-2 (EPCA-2). A 2007 study suggested that the EPCA-2 test is highly accurate. It can distinguish between benign prostatic hyperplasia (BPH) and prostate cancer and can evaluate whether or not a man has prostate cancer, regardless of what his PSA levels indicate. Researchers hope that this test may eventually provide better diagnoses of prostate cancer, and help prevent men from receiving unnecessary biopsies.


	DRE alone	PSA alone and in Combination with DRE
Chance of Cancer	Only 20% of men with abnormal DREs have cancer. Unfortunately, 70% of prostate cancers detected with DRE alone have already spread beyond the prostate gland.	The odds of cancer with PSA readings are: 3 ng/mL or below indicates 2% or less chance of cancer. 3 - 10 ng/mL indicates about a 25% chance of cancer. 10 ng/mL and over indicates a very strong chance. Men with abnormal results from both DRE plus PSA tests have a 60% chance for cancer.
Risk of Missed Cancers with Normal Results	About 60% of men who have prostate cancer have normal DRE results.	Some evidence suggests that only performing biopsies at levels above 4.0 would miss over 80% of cancers present below that level in men under 60 years and 65% in older men. As a result, some experts recommend biopsies with PSA levels at 3.0 or below in young men. Still, cancer at low PSA levels is very uncommon, particularly in younger men.

About 90% of all prostate cancers arise in the outer part of the prostate where they may be detected by a digital rectal exam (DRE), which is the simplest and most widely-performed screening procedure. The doctor inserts a gloved and lubricated finger into the patient's rectum and feels the prostate for bumps or other abnormalities. The exam is quick and painless but some men find it embarrassing. It is not very accurate in detecting early cancers, but studies indicate that regular DREs still save lives.

Prostate Cancer is the most common cancer in men in the United States. Prostate cancer forms in the prostate gland, and can sometimes be felt on digital rectal examination. This is one of the purposes of the digital rectal exam.

Prostate specific antigen (PSA) is a protein produced in the prostate gland that keeps semen in liquid form. Prostate cancer cells appear to produce this protein in elevated quantities. Measuring PSA levels increases the chance for detecting the presence of cancer when it is microscopic. There are many unresolved questions surrounding PSA testing. The test is not accurate enough to either completely rule out or confirm the presence of cancer. Relying too much on the test may lead to unnecessary biopsies. Not relying on it enough may miss cancers. It is still unclear if PSA testing is actually saving lives.

Click the icon to see an image of a PSA blood test.

Indications for Biopsy. A biopsy is usually performed to confirm or rule out cancer after screening tests that report:

PSA level of 4.0 ng/mL or higher. Some evidence indicates that men with an initial test showing PSA levels above 4.0 should take a second PSA test several weeks afterward before having a biopsy, since many non-malignant factors can increase PSA levels. (Some experts urge biopsies even if PSA levels fall below 4.0 mg, particularly in men under 60, since lower levels do not necessarily rule out cancer.)
Abnormal digital rectal examination (DRE).

Men with abnormal results from both tests have a 60% chance of prostate cancer. The chances for cancer if only one test is abnormal are considerably lower. To further complicate matters, biopsies themselves may miss very small cancers detected by PSA levels alone.

Factors Affecting PSA Levels. A number of factors and noncancerous conditions can influence PSA levels:

Ethnicity. Normal levels in Caucasian males may be different from those for African-American or Asian men. For example, using PSA screening, one study suggested that 15% of Caucasians and 37% of African-Americans are overdiagnosed with prostate cancer based upon PSA results. Some experts believe that there should be different scales for determining risk among these groups, but there is still not enough information to determine a specific range for various ethnic groups.
Age. PSA levels tend to rise naturally with age, so an elevated level in a man who is 70 may be less serious than the same level in a younger man. Some experts believe that men older than 65 who have low PSA levels are at such low risk for prostate cancer that they may be able to forgo further testing.
Benign Prostatic Hyperplasia (BPH) and Its Treatments. Between 25 - 56% of patients with BPH have elevated PSA levels. Certain treatments for this condition can also elevate PSA.
Prostatitis. About half of men with elevated PSA levels but no signs of cancer on biopsy have signs of prostatitis as indicated by urine and prostate secretion tests. (Prostatitis simply means inflammation in the prostate. Inflammation is usually due to bacterial infection, but it can also be caused by nonbacterial factors.) In one study, screening for prostatitis increased the accuracy of the PSA test significantly and reduced the number of unnecessary biopsies.
Other Noncancerous Conditions. Other noncancerous conditions that can increase PSA levels include surgical procedures or drug treatments for BPH, acute urinary retention, digital rectal examinations, and prostate biopsies themselves.
Ejaculation. Ejaculation within 48 hours before testing can raise PSA levels.

Even with its limitation, the PSA test has increased the number of detectable early-stage and therefore treatable cancers. Because of the slow-growing nature of prostate cancer, however, it is not known whether all of these very early cancers will result in significant or life-threatening disease. It is possible that PSA screening could result in the detection of some possible cancers that would never have bothered the patient and would never have posed a threat to his life.

To improve the accuracy of the PSA tests, particularly when PSA levels have risen to an intermediate range of between 4 - 10 ng/mL, researchers are developing methods for measuring other factors. To date, no test has emerged as clearly superior to the PSA test.

Free PSA Test. A small amount of prostate specific antigen leaks out of the prostate into the bloodstream. There, PSA can circulate without binding to other proteins and is referred to as free PSA. It can also form chemical combinations with other proteins. If cancer is present, PSA is more likely to be bound, and so there is less free PSA in circulation. The free PSA blood test, then, is a ratio of free PSA to the total PSA (free PSA plus chemically bound PSA).

The following results are used to determine if an elevated PSA level could mean cancer:

A free-to-total PSA ratio of 20% or lower, plus total PSA levels of 4 - 10 ng/mL, are suggestive of prostate cancer. (Some experts use 25% as a cut-off, but studies suggest that using this cut-off would miss cancers in many African-American and older men.)
A free-to-total PSA level of more than 20% plus normal or even moderately elevated total PSA tend to indicate the presence of other, benign conditions, such as benign prostatic hyperplasia (but it still does not rule out cancer).

Some studies have reported that adding a test for free PSA may improve prostate cancer detection by roughly 40% and may also reduce the need for unnecessary biopsies. In addition, any cancers that the test misses would not develop into significant disease for many years, providing ample opportunity to identify them before they became serious. Not all studies support its advantages, however, compared to measuring total PSA alone, and to date there is no consensus among doctors for how it can be used.

Complexed PSA Test. Complexed PSA (cPSA) is a form of circulating PSA that is bound to a molecule called alpha1-antichymotrypsin. It represents about 90% of the total PSA in men and is significantly higher in men with prostate cancer than in those with BPH. To date, studies have reported conflicting results on its benefits for diagnosing prostate cancer.

Transition Zone PSA Test. Some tests have been developed to measure the density of the PSA in the transition zone of the prostate gland. (The transition zone is the central area of the prostate that wraps around the urethra.) A major comparison study in 2002 reported more accurate results than with complexed PSA.

An ultrasound procedure called transrectal ultrasonography (TRUS) provides a visual image of the prostate and is used if the DRE indicates the presence of cancer. Ultrasound is not effective as a diagnostic tool by itself because it cannot differentiate very well between benign inflammations and cancer, but the procedure may help to confirm an uncertain preliminary diagnosis and is useful as a guide for needle biopsies. Ultrasound enhancements, such as Doppler imaging or computer modeling techniques called artificial neural networks (ANN), may increase the accuracy of TRUS.

Initial Biopsies. If preliminary tests raise the suspicion of cancer, doctors will perform a biopsy. Biopsy is used to diagnose prostate cancer, and is a very accurate method for predicting the severity of an existing cancer. However, biopsies can still miss cancers if they are very small.

Core Biopsy. The standard method is called a core biopsy, which uses a spring-loaded biopsy device inserted into the rectum. The device propels a needle into the prostate, obtaining a core of tissue, which is examined by pathologists.
Fine Needle Aspiration. A more recent procedure, called fine needle aspiration, is less painful and may be as accurate as a core biopsy if the sample obtained is sufficient for analysis and if it is analyzed by a skilled pathologist.

More than half of the men who have a biopsy experience discomfort and anxiety, with men under 60 reporting higher levels of discomfort than older men. Taking a sedative 1 - 2 hours before the procedure can help reduce distress. Complications of biopsy are low, but urinary tract infection, fever, or bleeding occurs in 0.1 - 4% of men.

Repeat Biopsies. Because a biopsy can miss very small cancer cells, sometimes three or even more biopsies are recommended if cancer is still suspected after negative results, such as when:

PSA levels are high. Two or more biopsies may be taken if a man has very high PSA levels and still has normal results on a biopsy. Even men with mildly elevated PSA (between 4 - 10 ng/mL) who test negative may be given a repeat biopsy. Cancer will be detected in about 10% of this group. Whether a third biopsy is useful in these men if they still test negative after a second biopsy is uncertain.
DRE results are abnormal.
Ultrasound results are abnormal.
The initial biopsy yields microscopic findings that are suspicious.
The initial biopsy detects precancerous cells known as high-grade prostatic intraepithelial neoplasia (PIN). No treatment is necessary with this finding, but these patients should be rechecked every 3 - 6 months for the next 2 years, and then annually.

Doctors may also perform a lymph node biopsy to see if the cancer has spread.

Tests to Determine Severity of Cancer

Once cancer is diagnosed, PSA levels may help to determine its extent. If PSA levels are less than 20 ng/mL, it is possible that the cancer has not spread to distant sites. PSA levels over 40 ng/mL are a strong indicator that cancer has metastasized (spread throughout the body). PSA levels are also monitored after treatments begin. Changes in the level can show if a treatment is working or if the cancer has come back.

Doctors also monitor how quickly PSA levels rise over time. This rate is called PSA velocity (PSAV). The PSAV is very helpful in determining when treatment should begin and which treatment should be used. A high rate of PSAV is considered to be 2 ng/mL a year. Recent research suggests that men with early-stage prostate cancer who have a slow PSAV are more likely to live longer than men with rapidly rising PSA levels.

A number of biological factors are being used or investigated as markers for cancer or its severity:

Chromosomal Sets. The number of chromosomal sets in the nucleus of the tumor's DNA, known as its ploidy, is an important marker for patients in late stages of prostate cancer. Tumors with the normal two sets of chromosomes, called diploid tumors, usually have a more favorable outcome than tumors that have four sets of chromosomes (tetraploid tumors) or have an abnormal number of individual chromosomes (aneuploid tumors).

Blood Vessel Density. The density of blood vessels in the tumor is an important indicator of outcome. The greater the density, the more likely the tumor is to be aggressive.

Serum Acid Phosphatase. High levels of this enzyme indicate a more aggressive disease and the need for intensive treatments.

Testosterone Levels. Higher total testosterone levels may increase the risk for metastasis. A 2000 study found an association with low free testosterone and more extensive prostate cancer, suggesting free testosterone could be a marker for aggressive disease. (Free testosterone, as with free PSA, is not chemically bound.)

Genetic Markers. Researchers have identified a genetic marker (EZH2), which may prove to be an important marker for aggressive prostate cancer. It may, in fact, prove to be a better predictor of outcome than the tumor grade, stage, or surgical margins. Other genes being studied are those that regulate tumor growth (p53, p27, bcl-2).

Other Markers. Other markers being investigated for predicting cancer progression include prostate-specific membrane antigen, prostatic acid phosphatase, and growth factors.

The ProstaScint is a scanning technique that uses tiny amounts of radioactive material with a monoclonal antibody that can attach specifically to prostate cancer cells. A special camera then can detect tumor cells that cannot be detected with other diagnostic tools. It may help doctors make better treatment decisions. The role of this test in the routine management of prostate cancer is still being defined.

If the biopsy indicates cancer, the doctor will order other tests to determine whether or how far the cancer has spread.

Bone Scans and X-Rays. Bone scans and x-rays may reveal whether the cancer has invaded the bones. To perform a bone scan, doctors inject low doses of a radioactive substance into the patient's vein, which accumulates in bones that have been damaged by cancer. A scanner then reveals how much of the radioactive material has accumulated. Arthritis and infections may also produce positive scans. Patients with PSA levels below 20 ng/mL are unlikely to have scans that show cancer in the bone.

A radiotracer is injected into a peripheral vein. As the radiotracer decays, gamma radiation is emitted and is detected by a Gamma camera. When the tracer has collected in the target organ the area is scanned. Radionuclide scans can detect abnormalities such as fractures, bone infections, arthritis, rickets, and tumors that have spread, among other diseases.

Computed Tomography and Magnetic Resonance Imaging. Computed tomography (CT) or magnetic resonance imaging (MRI) scans can further pinpoint the location of cancer that has spread beyond the prostate. Advanced MRI techniques are showing promise for staging and planning treatments.

Click the icon to see an image of a CT scan.

Click the icon to see an image of a MRI.

Bone Metastasis Markers. Researchers are investigating chemical markers, such as amino-terminal propeptide of type I procollagen (PINP), as early indicators of bone metastasis.

Treatment

Because BPH rarely causes serious complications, men usually have a choice between treating it or opting for watchful waiting:

Watchful Waiting. Watchful waiting (also called active surveillance) involves lifestyle changes and an annual examination. Even when choosing watchful waiting, an initial examination is critical to rule out other disorders.
Treatment Options. The primary goals of treatment for BPH are to improve urinary flow and to reduce symptoms. Many options are available. They include drug therapies, minimally invasive procedures, and major surgery.

The choice between watchful waiting and treatment usually depends on a number of factors, such as urine flow rates, prostate size, and PSA levels. Men with BPH who develop symptoms at around age 50 are more likely to need treatment within their lifetimes than older men. Unfortunately, there is no current way to determine who specifically might be at risk for serious problems and need early treatment.

The development of the International Prostate Symptoms Score (IPSS) has made the evaluation of symptoms somewhat easier. This scoring service serves as a benchmark for determining severity. The decision to treat or not to treat is typically based on the guidelines described below, but the ultimate choice is often guided primarily by a man's perception of his own symptoms.

Mild, or No, Symptoms. Men with mild, or no, symptoms (IPSS scores of 7 or below) usually choose watchful waiting even if their prostates are enlarged. BPH eventually progresses to the point of needing treatment in about 15% of men with mild symptoms who wait.

Moderate Symptoms. The choice is most difficult for men with moderate symptoms (scores between 8 - 19) and may simply depend on a man's ability to tolerate them. Some studies have reported that up to 40% of men with moderate symptoms eventually seek treatment, and a quarter require surgery. In a small percentage of patients, symptoms improve.

Severe Symptoms. Men with severe symptoms (scores over 20) nearly always choose treatment, although if their prostate glands are small or normal-sized, symptoms may improve.

If a man opts for treatment, there are several choices. Most experts recommend a staged approach as follows:

Mild Symptoms. Medications are the best choice for men with mild symptoms who decide to have their condition treated. There are two standard choices: alpha-blockers and anti-androgens, nearly always finasteride (Proscar). Specific conditions determine the choice, although most men take an alpha-blocker. Men with mild symptoms who choose surgery only experience minor improvement afterward but face the same risks as patients with more severe symptoms.
Moderate-to-Severe Symptoms. Men with moderate-to-severe symptoms often respond to the same medications as men with mild symptoms. (Combinations of alpha-blockers and finasteride are under investigation.) Recent developments in drug therapy have reduced the number of surgical procedures needed and delayed their use. However, a quarter of men with moderate symptoms, and even more men with severe symptoms, eventually need surgery. If a man chooses surgery, there are many choices. Transurethral resection of the prostate (TURP) is the standard procedure, but less invasive procedures, particularly those using heat or lasers to destroy prostate tissue, are gaining prominence.

Click the icon to see an illustrated series detailing transurethral resection of the prostate surgery.

The most common reason for choosing surgery is obstruction of the bladder outlet, which causes urinary retention. Surgery is also typically a reasonable option when BPH is clearly related to one or more of the following conditions:

Recurrent urinary tract infection.
Hematuria (blood in the urine). Studies have suggested that when hematuria is left untreated, two-thirds of patients continue to bleed and one third require surgery. The drug finasteride may help some men with this condition and should probably be tried before surgery.
Bladder stones.
Kidney problems.
Some experts believe that surgery might benefit patients for whom an early diagnosis of prostate cancer is important. Unsuspected prostate cancer is detected during surgery in about 15% of cases.

The greatest improvements resulting from surgery are usually increased urinary flow and reduced urine retention. In one study, men who chose surgery reported more worry and depression before the procedure, but afterward they had less depression and anxiety than those who had chosen medication. Often, however, the benefits of surgery are not permanent.

Treatment Options by Staging and Grading

Stages indicate the extent of the cancer:

Stage I and stage II cancer are considered early stage. The cancer is localized and has not spread outside the prostate gland.
Stage III, locally advanced cancer, means that the cancer has spread into the seminal vesicles (glands at the base of the bladder, which are connected to the prostate gland and help produce semen).
Stage IV is advanced cancer. The cancer has spread to the lymph nodes and other tissues or organs.

Experts have devised treatments based on classification systems, including staging and tumor grade. However, there are no clear-cut answers on the best treatments for particular stages. In addition to staging, other factors must be considered. These factors include the patient’s age, overall health status, and personal preferences concerning side effects and quality of life. In addition to standard treatments, patients may also wish to consider enrolling in clinical trials of investigational treatments.

The U.S. National Cancer Institute recommends the following treatment options by cancer stage:

Tumors: T1a, N0, M0, G1, Stage A

Active surveillance
Radical prostatectomy, usually with pelvic lymphadenectomy, with or without radiation therapy after surgery
External beam radiation therapy
Implant radiation therapy (brachytherapy)
Clinical trial options include high-intensity focused ultrasound

Click the icon to see an illustrated series detailing prostatectomy surgery.

Tumors: T1a - c, N0, M0, any G, Stage A2, B1, or B2

Radical prostatectomy, usually with pelvic lymphadenectomy, with or without radiation therapy after surgery
Active surveillance
External beam radiation therapy with or without hormone therapy
Implant radiation therapy (brachytherapy)
Clinical trial options include radiation therapy with or without hormone therapy; ultrasound-guided cryosurgery; hormone therapy followed by radical prostatectomy

Tumors: T3, N0, M0, any G, Stage C

External beam radiation with or without androgen deprivation therapy (hormone therapy)
Androgen deprivation therapy
Radical prostatectomy, usually with pelvic lymphadenectomy, with or without radiation therapy following surgery
Radiation therapy, androgen deprivation therapy or transurethral resection of the prostate (TURP) to relieve symptoms
Clinical trial options include ultrasound-guided cryosurgery

Click the icon to see an illustrated series detailing transurethral resection of the prostate.

Tumors: Any T, any N, any M, any G, Stage D1 - D2

Androgen deprivation therapy
External beam radiation therapy with or without androgen deprivation therapy
Radiation therapy or transurethral resection of the prostate (TURP) to relieve symptoms
Active surveillance
Clinical trial options include radical prostatectomy with surgery to remove both testicles (orchiectomy)

Treatment options are dependent on various factors, including prior treatment, site of recurrence, coexistent illnesses, and individual patient considerations.

Patients whose cancer recurs locally after prostatectomy: Radiation therapy, androgen deprivation therapy.
Patients whose cancer recurs locally after radiation therapy: Androgen deprivation therapy, prostatectomy (very select patients).
Patients whose recurrent cancer has spread: See treatment options for stage IV.

Treatment for Localized Prostate Cancer

Choosing the best treatment for localized prostate cancer (T1 or T2) is generally based on the patient's age, the stage and grade of the cancer, overall health status, and the patient's personal preferences for the risks and benefits of each therapy.

Patients have three main options:

Active surveillance, also called watchful waiting, involves monitoring the tumor for cancer progression to determine if and when treatment should be started.
Surgery (radical prostatectomy) removes the prostate gland. The vessels that carry semen and surrounding tissue may also be removed. Studies indicate that compared to watchful waiting, radical prostatectomy may lower the risk of cancer recurrence and death, particularly for younger men with aggressive tumors.
Radiation therapy targets the tumor either externally (external beam radiation) or internally (implanted “seeds”).

In 2007, the American Urological Association (AUA) released guidelines for the treatment of localized prostate cancer. The guidelines recommend that patients should be classified as low, intermediate, or high risk. Doctors determine the risk category by using criteria such as PSA tests, tumor aggressiveness, and the clinical stage of the tumor.

Among the AUA’s treatment recommendations:

Compared with active surveillance, radical prostatectomy may lower the risk of cancer recurrence and death.
For men at intermediate and high risk, adding androgen deprivation therapy to external beam radiation may improve survival. A higher dose of external beam radiation also improves the odds for survival.
Initial (first-line) androgen deprivation therapy is seldom recommended for localized prostate cancer except for the relief of symptoms in patients with poor prognoses. Androgen deprivation therapy can increase the risks for diabetes and heart disease.
Patients with localized prostate cancer should have the opportunity to enroll in clinical trials investigating new types of therapy.

Conflicting Data on Survival Rates. To date, neither treatment nor active surveillance has emerged with a definitive survival advantage. Several studies from 2005 and 2006 suggested that treatment provides a survival advantage over watchful waiting for some men with early-stage prostate cancer. A 2005 New England Journal of Medicine study reported that men who had a radical prostatectomy before age 65 had a reduced risk of death from prostate cancer, death from other causes, localized cancer progression, and metastases than men who chose watchful waiting.

Similarly, research presented at the 2006 Prostate Cancer Symposium found in a study of nearly 50,000 men with early-stage prostate cancer that men who had radiation or surgical treatment had a 30% lower risk of death than men who were randomly assigned to watchful waiting. However, a 2005 Journal of the American Medical Association study advised against aggressive treatment for localized low-grade prostate cancer. The study found that men with low-grade prostate cancer had a small risk of cancer progression even after 20 years of watchful waiting or hormonal drug therapy

Imperfection of Classification System. The classification systems are not perfect. Even if tumors are rated in low stages and grades and are treated accordingly, undetected cancer cells may escape and spread beyond the prostate. Other factors, such as the man's age and medical condition, must be included in determining whether aggressive treatments or conservative measures are appropriate.

Specialty Bias. Patients should be aware that doctors may be biased to prefer a specific treatment depending on their specialty. For example, in one study the following treatments were favored for patients who were generally appropriate candidates for either surgery, radiation, or watchful waiting:

93% of urologists recommended radical prostatectomy.
72% of radiation oncologists recommended radiation. (And 82% thought that radical prostatectomy was overused.)
Virtually none of the doctors recommended watchful waiting for higher-risk disease. When in doubt, patients should always seek a second opinion to help them make this important choice.

Quality of Life. Surgery and radiation both have potentially distressing side effects, including the possibility of impotence, incontinence, or both. A man must weigh his own emotional responses to the possibility of these side effects versus the possible stress of watchful waiting.

In general, differences in quality of life after surgery or radiation treatment have to do with the specific effects of each type of treatment:

Radiotherapy generally causes more bowel problems than surgery, 30 - 35% versus 6 - 7%, according to a 2001 study. In a 2003 review, the risk for impotence from radiotherapy varied from 25% with brachytherapy to 45% with external beam radiotherapy.
Prostatectomy causes more urinary incontinence (39 - 49% versus 6 - 7% for radiotherapy patients) than radiotherapy. Risks for impotence range from 66% after nerve-sparing prostatectomy to 87% after cryotherapy. In spite of these adverse effects, a 2002 study reported no meaningful differences in well-being or quality of life during a 4-year period for men who chose surgery versus those who chose watchful waiting.
Active surveillance could lead to cancer growth that eventually obstructs the urinary tract (which can happen with the treatments as well). It may also impose an emotional burden on men who live with the possibility of progressive cancer and its difficult treatments. Some who decide to wait become what some doctors refer to as the "walking worried," men who are constantly concerned with their PSA levels. Because aggressive treatment reduces such anxiety, some studies reported that years after surgery, about 75% of men said they would chose it again, in spite of the significant side effects.

Watchful waiting involves lifestyle change and careful monitoring for cancer progression. Over the last several years, watchful waiting has evolved into a strategy called “active surveillance” or “delayed surgical intervention.” With this approach, patients have a digital rectal exam and PSA blood test every 6 - 12 months. If test results indicate cancer progression, then treatment options (surgery, radiation, drugs) are considered. Patients should exercise and eat healthy foods. Patients should report symptoms such as weight loss, pain, urinary problems, fatigue, or impotence to their doctors.

Candidates. Active surveillance may be most appropriate for the following patients:

Men in their late 70s and older. More aggressive therapies (surgery and radiation) are usually recommended for men in their 50s and younger. The choice for men in their 60s and early 70s is more problematic. The general recommendation is that aggressive therapy is suitable for those who have a life expectancy of more than 10 years and who have localized but mid- to high-grade tumors. The tumor grade may be the best guide for determining the risks in choosing watchful waiting.
Elderly men with early-stage (T0 - T2) low-grade tumors.
Men with low-to-moderate (3 - 13 ng/mL) PSA levels.

Some experts think that because prostate cancer grows so slowly, it is likely that older men will die from causes unrelated to the cancer. There is therefore little potential benefit from surgery or radiation, with both posing a risk for impotence and incontinence. However, some recent surveys suggest that more men are choosing treatment (especially surgery) over active surveillance. The choice is a difficult one. It is important that patients find a doctor who can provide them with all the necessary information so that they can make an informed decision.

In men whose cancer is confined to the prostate, surgical resection (radical prostatectomy) offers the potential for cure. Cure rates from initial surgery in men with localized cancer are about 70%, depending on tumor stage, tumor grade, and PSA levels. Research suggests that surgery provides long-term cancer control. Most patients can consider themselves disease-free if their PSA levels remain undetectable 10 years after surgery.

Candidates. Radical prostatectomy is a consideration for men who meet all of the following criteria:

In good health and with a life expectancy of 10 years or more. As average life expectancy in men has increased, more older men are becoming candidates for surgery. Complication rates are higher the older a man is, however.
The cancer has not spread beyond the prostate gland.
The cancer is potentially life threatening. (In general, a life-threatening tumor is indicated by volumes more than 0.2 cc and Gleason grade scores greater than 5.)

The procedure is more likely to cause incontinence (up to 50%) than radiation treatment but has fewer bowel complications. Impotence rates are about the same. Surgery for prostate cancer may be particularly difficult in men who have had transurethral resection of the prostate (TURP).

Radiation therapy (or radiotherapy) is administered as external beam radiation or as brachytherapy (radiation implants). It may be used as the sole primary treatment for localized prostate cancer; 5-year survival rates are similar to those of surgery.

Candidates. Radiation is considered for men with one or more of the following characteristics:

Being older and, particularly, having other medical problems.
Cancer has extended beyond the prostate capsule but has not spread to the lymph nodes or further.
Being a good surgical candidate, but having decided against an operation.

The risk for incontinence (less than 10%) is much lower than with surgery, although bowel problems occur in about a third of patients. Impotence rates are about the same.

Androgen Deprivation Therapy With Radiation. Hormonal (“androgen deprivation”) drugs combined with radiation therapy may improve survival rates in moderate- or high-risk groups. Patients may need to take these drugs long-term to improve outcomes. Hormonal drugs before radiation (neoadjuvant therapy) may be helpful in shrinking enlarged glands so that brachytherapy (radiation implants) can be used. Hormone therapy can also be given at the same time or following radiation.

An important study published in 2004 in the Journal of the American Medical Association (JAMA) found that for men with localized prostate cancer, a 6-month course of androgen deprivation therapy combined with radiation treatments produced greater survival rates than radiation treatment alone. Standard medical practice has generally indicated that hormone therapy should be given for 3 years; the JAMA study suggests that a shorter regimen may be equally beneficial for some patients and may help reduce the side effects that typically accompany androgen-suppressing drugs.

A 2005 JAMA study suggested that PSA velocity (PSAV) may help doctors decide which patients should receive androgen deprivation drugs along with radiation therapy. PSAV lets doctors calculate how quickly a patient’s PSA level has risen. Researchers found that men who had at least a 2.0 ng/mL increase in PSA levels during the year before their cancer diagnosis had a high risk of dying after external beam radiation therapy, even though they had low-grade prostate cancer. The study suggests that men with this particular PSAV history should consider combining radiation therapy with androgen deprivation drugs.

Surgery

Radical prostatectomy is the surgical removal of the entire prostate gland along with the seminal vesicles (the vessels that carry semen) and surrounding tissue. The incision can be made in one of the following regions:

Retropubicly (through the abdomen and under the pubic bone, exposing the entire surface of the prostate).
Through the perineum (the skin between the scrotum and the anus).

The gland and other structures are then removed. The operation lasts 2 - 4 hours. Advanced surgical techniques, such as minilaparotomy and laparoscopy, are being developed for radical prostatectomy. These techniques use smaller incisions, are less invasive, and may cause fewer complications.

Click the icon to see an illustrated series detailing prostatectomy surgery.

Nerve-Sparing Techniques. Surgical procedures have been refined over the years, and many operations for localized low-grade prostate cancer now spare the nerves that control erection.

A bilateral nerve-sparing procedure saves the nerves on both sides of the sex organs.
A unilateral procedure saves nerves on only one side.

Nerve-sparing techniques can improve quality of life. The ability for sexual intercourse recovers in about a third of patients at 3 years and nearly 60% at 5 years after surgery. (Rates vary depending on certain factors, such as the patient's age -- the younger the better.) In cases where the tumor is bulky and undifferentiated, nerve-sparing techniques may not be appropriate.

Convalescence. Patients remain hospitalized for up to 2 weeks. A temporary catheter used to pass urine is kept in place when the patient is sent home and usually removed about 3 weeks after the operation. The convalescent period at home is about a month. In general, younger patients with early-stage cancers recover fastest and experience the fewest side effects.

Complication rates vary after radical prostatectomy and usually depend on the age of the patient and the experience of the surgeon and medical center. They can range from 4% in men in their 40s to 14% in men over age 70. Complication rates are 10 times higher in patients who have prostatectomy because of cancer recurrence after radiation treatment.

Complications include the usual risks of any surgery, such as blood clots, heart problems, infection, and bleeding. Complications specific to radical prostatectomy, (incontinence, impotence, and contracture of the bladder neck), are discussed below. The mortality rate is very low, about 0.4%.

Quality of life usually improves shortly after surgery, and recovery from certain complications, such as incontinence and sexual function, can continue to occur even over years.

Urinary Incontinence. Urinary incontinence is a common complication and a more distressing side effect of surgery for most men than sexual dysfunction. When the urinary catheter is first removed following surgery, nearly all patients lack control of urinary function and will leak urine for at least a few days and sometimes for months. Major medical centers report that continence returns within about 18 months for nearly all men younger than age 70 and in the great majority of men older than 70. The average time for return of continence in one center was just 1.5 months.

Click the icon to see an image of catheterization.

A number of approaches may help prevent or treat incontinence:

Nerve-sparing techniques can help prevent incontinence, although even in experienced centers, 8% of patients will have some postoperative incontinence, and this rate is much higher (up to 50%) in many community medical centers.
A procedure called endopelvic anterior urethral stitch (EAUS) used with prostatectomy appears to reduce urinary incontinence. In one small study, 75% of selected patients recovered continence in a month. The procedure requires a simple stitch at the front of the urethra.
Kegel exercises, contracting and relaxing the muscles used to shut off the urinary stream, strengthen the muscles on the pelvic floor and are reported to be very beneficial for many men.

If incontinence persists beyond a year, patients may require drug therapy or surgery. Collagen injections into the urethra, bladder neck suspension surgery, or a urinary sphincter implant may be helpful for men who have chronic incontinence. [See In-Depth Report #50: Urinary incontinence.]

Impotence. Studies suggest that about 40% of men have problems with erection after the procedure. In one study, however, more than 70% said they would have the procedure again. Nerve-sparing procedures are proving to be helpful in reducing impotence as well as incontinence.

Sildenafil (Viagra) may help restore potency on average in about a third of patients, but some men may do better than others. In one study, for example, 80% of younger men who were potent before surgery and had bilateral nerve sparing procedures responded to the drug. (Only 40% responded with only unilateral procedure.) Sildenafil is unlikely to be effective for men who had unilateral or no nerve sparing procedures. In those who respond, sildenafil may provide a benefit for years. Sildenafil may take 9 months or longer to become effective. Men who take it may benefit from alprostadil injections started right after surgery to preserve elasticity and help prevent scarring.

Early treatments with alprostadil injections may helpful in restoring erectile function in any case. This treatment maintains blood flow in the penis, and some research suggests that impotence after prostate surgery may be due in part to injury to these blood vessels. In one study, men administered injections every other night for 6 months. They then started taking sildenafil 3 months after surgery. At 6 months, 82% of these men achieved penetration compared to only 52% of men who took Viagra only. The vacuum pump may serve a similar purpose as the injections. [See In-Depth Report #15: Erectile dysfunction.]

Even when erectile function is preserved, men may experience other sexual problems:

Erections may not be as rigid as before the operation.
Orgasm and sexual sensation may be altered.
Patients who retain potency may suffer from retrograde ejaculation, also known as dry ejaculation. During ejaculation, semen travels backward into the bladder, causing infertility.

Fecal Incontinence. Radical prostatectomy can also cause fecal incontinence. The risk may actually be higher in men undergoing nerve-sparing procedures.

Contracture of the Bladder Neck. Another common postsurgical complication is contracture of the bladder neck at the point where it has been stitched to the remainder of the urethra. Contracture usually occurs within the first 3 months after the operation, causing a sharp decrease in urinary stream. The condition can be treated by dilation or surgery on the bladder neck, and rarely recurs.

Pelvic lymphadenectomy is the surgical removal of the pelvic lymph nodes. It is usually performed at the same time as prostatectomy. If the surgeon suspects that cancer has spread beyond the prostate, the surgeon will perform the lymphadenectomy as part of the operation. Some surgeons do this procedure as a matter of course when performing prostatectomy, since it has few complications and adds information on the state of the disease. The lymph nodes are removed through an incision in the lower part of the abdomen, using conventional surgery or laparoscopy, a less invasive variation. The nodes are immediately examined. If they show signs of cancer, metastasis has occurred. In such cases, the operation is usually stopped and the patient is offered radiation or hormone treatments.

Click the icon to see an image of the pelvic lymph nodes.

Transurethral resection of the prostate (TURP) involves removing a section of the prostate with a surgical instrument (resectoscope) that is inserted through the urethra. TURP may be used to control urinary symptoms in men who are not good candidates for curative therapy due to advanced age, health status, or other reasons. TURP is also used as a treatment for benign prostatic hyperplasia (BPH).

Cryosurgery is an alternative to standard prostatectomy. The goal of cryosurgery is destruction of the entire prostate gland and possibly surrounding tissue. Steel probes are inserted through the skin between the anus and the rectum and into the prostate. Liquid nitrogen is pumped through the probes to freeze all prostate cells, both healthy and cancerous. For success, cryosurgery requires a uniformly frozen area. The dead cells are absorbed and eliminated by the body. Patients can leave the hospital in 2 - 3 days.

Candidates. Cryosurgery may be considered for patients with:

Early stage local cancer
Cancer that has recurred after radiation treatments
Large primary tumors that the surgeon wishes to reduce
Possibly tumors that have spread beyond the prostate if they have not yet reached the lymph nodes

Strong predictors of treatment failure include:

A history of both hormonal and radiation treatments
Tumor grades 8 and above
PSA levels of more than 10 ng/mL

Complications. Complications are similar to those of standard prostatectomy, but incontinence rates are much lower. Impotence rates, however, are much higher. Nevertheless, 96% of patients report that they are satisfied with the results. Incontinence and other side effects may be higher in patients who have had previous radiation treatments. Other significant complications include scarring and narrowing of the urethra, and fistulas (abnormal passages from internal organs to the skin or between two internal organs).

Radiation Treatments

The two major radiation treatments are:

External beam radiation
Brachytherapy (internal radiation)

Both treatments have generally equal success rates. Research presented at the 2006 Prostate Cancer Symposium indicated that the two therapies work equally well for treating localized prostate cancer. In some cases, both techniques may be used in high-risk patients.

In external beam radiation therapy, a doctor focuses a beam of radiation directly on the tumor for 35 3-minute treatments given 5 times a week over 7 weeks. 3-D conformal techniques use computers and a three-dimensional image of the prostate to target the tumor precisely, using high-dose radiation beams. It poses a lower risk for inflammation. Men who have had transurethral resection of the prostate (TURP) or have a history of lower urinary tract symptoms may be particularly good candidates for 3D conformal techniques.

According to the 2007 American Urological Association guidelines for treatment of localized prostate cancer, patients considering external beam radiation should know that higher radiation doses may reduce the risk for cancer recurrence and improve survival outcome.

Brachytherapy is an outpatient technique that implants radioactive "seeds" directly into the prostate. Implants can be temporary or permanent. Temporary implants are usually accompanied by external beam radiation. This procedure requires more skill than external beam radiation therapy and, even with experienced doctors, the distribution of radioactive seeds is uneven in 15% of cases, increasing the risk for insufficient doses.

Computerized systems are being developed to help oncologists optimize seed placement and allow precise treatment for each patient and higher radiation doses. Eventually, it could improve tumor control, reduce side effects, and cut costs.

It is common for PSA levels to temporarily rise, or "bounce," following seed implantation without it being a signal for cancer recurrence. This effect can produce anxiety and can interfere with the diagnosis of true recurrence.

Candidates. Studies suggest that brachytherapy is useful for select patients, specifically those with prostate volumes less than 60 mL and who have early-stage prostate cancer (T1 or T2 tumors, a Gleason grade lower than 7, and PSA levels below 10 ng/mL). It may be beneficial in patients with inflammatory bowel disease or with cancer close to the bowel. Poorer candidates for brachytherapy include men who have had TURP and patients with advanced cancer, high-grade tumors, or very enlarged prostate glands.

The side effects of radiation therapy include most of those of surgery, but the risks for impotence and incontinence are considerably lower. A 2000 study concluded that adjuvant radiation therapy (given right after surgery) in moderate doses does not increase the risk for long-term urinary incontinence or sexual dysfunction beyond that of surgery alone.

Gastrointestinal Complications. Complications in the gastrointestinal are common. Short-term effects include nausea and loss of appetite. Diarrhea is a very common side effect and can last for the duration of therapy. It is usually treated with Lomotil. A few patients have diarrhea flare-ups for years afterwards. Less than 1% suffer more serious intestinal problems.

There is potential for injury to the rectum with brachytherapy. Ulcers in the rectum occur in more than 10% of patients, but the risk decreases with greater experience in the technique.

Urinary Problems. The risk for incontinence is about 7 - 20%. Patients treated with radiation may experience a painful, but usually temporary, urinary tract inflammation. About 10 - 15% of patients develop a long-term urgent and frequent need to void their bladder. Brachytherapy carries a lower risk for urinary incontinence.

Scarring and narrowing of the urinary tract (stricture) may occur, particularly in men who had TURP performed within a short time before radiation treatment. In such men, radiation treatments should be delayed by 4 - 6 weeks. If the prostate has been injured or damaged or the bladder is easily irritated, side effects with brachytherapy may actually be worse than with other procedures.

Impotence. In a 2003 review, the risk for impotence following radiotherapy varied from 25% with brachytherapy to 45% with external beam radiotherapy. Still, very few studies on brachytherapy have lasted more than 2 years, so more research is needed.

Sildenafil (Viagra) may help many men experiencing impotence following radiation therapy for local prostate cancer. Early use of both alprostadil injections and sildenafil may be even more effective. Other treatments may also be useful. [See In-Depth Report #15: Erectile dysfunction.]

Investigators are testing radiation treatments that use a combination of neutrons and protons (mixed-beam) or proton beams rather than the standard proton radiation therapy. Intensity-modulated radiation therapy is a promising technique that delivers different doses to multiple target areas using images of specific regions.

High-Intensity Focused Ultrasound (HIFU). Studies are reporting promising results with an intensive ultrasound procedure called transrectal high-intensity focused ultrasound (HIFU). It allows for very precise minimally invasive removal of tissue in local prostate cancers. It may eventually prove to be an alternative to radiation therapy. More research, with long-term follow up, is needed.

Radiofrequency. Radiofrequency is being used to heat and destroy the prostate. Early studies suggest that this is a promising approach.

Options if Treatments Fail

Rising PSA Levels. If prostate cancer has been eliminated, PSA levels should drop to 0.5 ng/mL or less after treatment. A sudden rise or persistently elevated PSA levels after treatment are often indications that prostate cancer persists:

If PSA levels are above 2.0 ng/mL, then cancer is most likely still present.
If PSA levels are between 0.5 - 2.0 ng/mL, the situation is less clear. One study indicated that measuring free PSA may help determine the status of the cancer in such patients. An average free PSA of 27% indicated that cancer had been eliminated, while an average of 15% meant that cancer was still present.

Note: It is common for PSA levels to temporarily rise following radiation seed implantation without signaling cancer recurrence.

Rising PSA levels do not necessarily mean that the cancer has spread or even that the cancer will recur during a man's lifetime. An actual cure is still possible if the cancer is localized within the prostate. In one study, 64% of patients with rising PSA levels after surgery still had cancer confined to the prostate. Indications of a poorer outlook in this study included:

Cancer penetration of the prostate capsule
Positive surgical margins (microscopic evidence of cancer cells at the very edge of the resected specimen)
Invasion of nearby vessels or lymph nodes

Still, among the men in the study, after 7 years only 3% of patients had died of prostate cancer. After 15 years, only 19% had evidence of recurrence. Other markers for persistent cancer are under investigation. For example blood tests that show low levels of acid phosphatase (ACP) before treatments may predict a higher chance for recurrence-free survival.

Treatment for recurring cancer is not always clear-cut. If the cancer recurs locally, cure may still be possible:

Surgery and androgen deprivation therapy may be considered for patients who were first treated with radiation.
For patients who were initially treated with surgery, radiation or androgen deprivation therapy are both options.

If the disease has already spread or if the doctor suspects that it may have spread, the patient is typically given androgen deprivation therapy. Chemotherapy drugs in combination with hormonal drugs are being investigated for patients who fail surgery or radiation.

A 2005 study in the Journal of the American Medical Association suggested three factors that may help doctors and patients decide if additional treatment is needed if cancer recurs after surgery:

How quickly PSA levels double after surgery (shorter time equals higher risk)
How quickly the cancer recurred after surgery (shorter time equals higher risk)
Gleason score (higher score suggests more aggressive tumors and greater risk)

Patients at high risk are more likely to die from the recurrent cancer and should be considered for additional treatments. Patients at low risk face a lower likelihood of death from prostate cancer and probably do not require more treatment. The study found that for patients at low risk, the time to death after cancer recurrence was very long, generally lasting more than 16 years.

Androgen Deprivation Therapy. Androgen deprivation therapy, also called androgen suppression therapy or hormone therapy, involves blocking the effect of male hormones such as testosterone through medical (drugs) or surgical castration. Androgen suppression therapy is not recommended as a first-line approach for most men with localized prostate cancer. It is usually given to patients with recurrent, progressive, or advanced prostate cancer. It may also be given for a relatively brief time in combination with external beam radiation.

Although androgen deprivation therapy slows the growth of most prostate cancers, it can have serious side effects. The American Society of Oncology’s (ASCO) 2007 guidelines do not recommend the early use of hormone therapy. However, ASCO does recommend that patients start therapy once they begin to experience cancer symptoms. Patients who defer therapy should have regular doctor visits every 3 - 6 months to monitor their condition.

Salvage Prostatectomy. Salvage prostatectomy is sometimes performed after unsuccessful radiation treatment if the cancer is still local. The odds of the procedure's success are only 10 - 64%. Many experts recommend against salvage prostatectomy in most cases of radiation failure. Severe complication rates for salvage prostatectomy are very high: 10 times that of men who have not had radiation. For example, incontinence after salvage prostatectomy is often untreatable with medications, collagen implants, or other standard treatment measures.

Salvage Cryosurgery. Salvage cryosurgery may be effective in certain patients who fail external beam radiotherapy. The best candidates are those with Stage II cancer or less and PSA levels below 10 ng/mL.

Adjuvant and Salvage Radiation. Radiation is proving to help patients who still show detectable levels of PSA after surgery (generally 2 ng/mL or less). It may even be useful years after surgery if PSA levels rise. Depending on timing, radiation after treatment failure is referred to as either:

Adjuvant radiation is radiation therapy performed within 6 months after radical prostatectomy. One area of controversy is whether to use adjuvant radiation after surgery on patients whose PSA levels are very low or undetectable but who have other test results that indicate the cancer is likely to spread. Patients with adverse findings and low PSA have to weigh the potential complications of radiation therapy against the odds of recurrence without it, which are about 20 - 30%. A small 2006 study found that adjuvant radiation worked much better than salvage radiation for men with advanced (stage III or IV) local prostate cancer. However, a 2007 study indicated that adjuvant radiation in men with advanced cancer may reduce the risk of cancer recurrence but does not improve length of survival.
Salvage radiation is radiation therapy more than 6 months after surgery. A 2004 study suggested that salvage radiation could be more beneficial than previously thought, even for men with aggressive prostate cancer. Researchers studied 501 men who had undergone radical prostatectomy (surgical removal of the prostate gland) and subsequently received radiation treatment for recurrent cancer (as indicated by rising PSA levels). Men with lower Gleason scores and lower PSA levels benefited the most from salvage radiation. However, even men with higher-grade cancers were able to delay metastatic cancer progression as long as they received radiation at an early stage while their PSA levels were relatively low (less than 2.0 ng/mL).

Other Treatments

Male hormones (called androgens), particularly testosterone and dihydrotestosterone, determine male secondary sex characteristics and stimulate prostate cell growth. When prostate cells, both healthy and cancerous, are deprived of androgens, they no longer proliferate and eventually die.

Androgen deprivation therapy (also called androgen suppression therapy or hormone therapy) uses drugs or surgery (orchiectomy) to suppress or block male hormones (androgen) -- particularly testosterone and dihydrotestosterone -- that stimulate the growth of prostate cells. Androgen deprivation therapy is used for advanced and metastatic cancer and may be used if treatment for localized prostate cancer has failed and cancer recurs (as indicated by rising PSA levels). Side effects can include decreased bone density, decreased muscle mass, hot flashes, depression, fatigue, weight gain, enlarged breasts, and high cholesterol levels. Evidence also indicates that androgen deprivation therapy increases the risk for diabetes and death from heart disease.

There has been some debate about when androgen deprivation therapy should be initiated. In 2007, the American Society of Clinical Oncology (ASCO) published clinical guidelines for androgen deprivation therapy in patients with recurrent, progressive, or advanced prostate cancer. The guidelines recommend that hormone therapy should, in general, be delayed until patients begin to experience symptoms from their cancer. However, when therapy is deferred, patients should regularly visit their doctors every 3 - 6 months for careful monitoring of their condition.

ASCO recommends either removal of both testicles (bilateral orchiectomy) or injections with luteinizing hormone-releasing hormone (LHRH) as initial androgen deprivation treatments. Combining nonsteroidal antiandrogen drug therapy with orchiectomy or LHRH may also be considered.

Doctors vary widely on their opinions of androgen deprivation therapy. A 2006 study found that the decision to use hormonal therapy depends more on a patient’s urologist than on the patient’s tumor or other factors.

Androgen deprivation therapy includes:

Hormonal Drugs. The primary drugs used for suppressing androgens are called luteinizing hormone-releasing hormone (LH-RH) agonists.

Orchiectomy. Orchiectomy is the surgical removal of the testicles. It is the single most effective method of reducing androgen hormones, but it is considered an extreme procedure. Studies do not indicate that it significantly improves survival rates. Orchiectomy plus radical prostatectomy may delay progression in patients with cancers that have spread only to the pelvic lymph nodes. Combining orchiectomy with antiandrogen drug therapy adds a modest benefit.

The median survival rate after the operation is about 55% over a 40-month period. An estimated 25% of patients survive 5 years or more. Nevertheless, orchiectomy, although irreversible, may produce fewer adverse effects than hormonal drugs, and interestingly, many patients report significantly higher quality of life after orchiectomy than those who opt for hormonal treatment, particularly total androgen ablation. Because orchiectomy is irreversible, about 75% of patients with advanced prostate cancer choose hormonal therapy to block androgens. Like all androgen deprivation therapies, orchiectomy increases the risk for osteoporosis.

Many men can still achieve erection after orchiectomy, but there is almost always a decline in sexual drive. Men who cannot achieve erection may be candidates for a penile implant. Patients do not experience a reversal of sex characteristics; the voice does not change and body hair is not affected.

Androgen Deprivation Therapy Before or With Radiation. Hormonal drugs combined with radiation therapy may improve survival rates in moderate- or high-risk groups. Patients may need to take these drugs long-term to improve outcomes. Hormonal drugs before radiation (neoadjuvant therapy) may be helpful in shrinking enlarged glands so that brachytherapy (radiation implants) can be used.

An important study published in 2004 in the Journal of the American Medical Association found that for men with localized prostate cancer, a 6-month course of hormone therapy combined with radiation treatments produced greater survival rates than radiation treatment alone. Standard medical practice has generally indicated that hormone therapy should be administered for 3 years; the JAMA study suggests that a shorter regimen may be equally beneficial for some patients and may help reduce the side effects that typically accompany androgen-suppressing drugs.

Androgen Deprivation Therapy Before or After Surgery. Some studies suggest benefits from using hormone therapy before surgery (neoadjuvant therapy) to reduce the tumor size, although it is not clear yet if this approach has survival benefits. Hormonal treatment may be useful after surgery in men who have high-grade tumors or tumors that have invaded the semen-carrying vessels or lymph nodes. Such men have a risk for failure after surgery of 50 - 80%.

The primary drugs used for suppressing androgens are called luteinizing hormone-releasing hormones (LHRH) agonists. They include:

Leuprolide (Lupron, Leuprogel). Studies report that disease progression is prevented in 72% of men taking daily leuprolide and up to 89% of those taking monthly injections. Certain men, however, may not respond to injections. Drug delivery using implants is under investigation.
Goserelin (Zoladex). Partial responses of 60 - 80% have been reported. A controlled release formulation has been developed that increases the time between injections from 4 weeks to 3 months.
Buserelin.

LHRH drugs block the pituitary gland from producing hormones that stimulate testosterone production. Patients must have injections of LHRH agonists for the rest of their lives.

Testosterone and PSA Surges. Treatment with LHRH agonists produces a testosterone surge in the first week, which may actually intensify symptoms. After this phase, testosterone levels drop to near zero. Leuprogel, a newer leuprolide, may pose a lower risk for this effect. Researchers are investigating other drugs, such as GnRH antagonists, that do not produce this surge.

LH-RH agonists can also cause PSA levels to rise temporarily. Administering flutamide, a drug known as an antiandrogen, for 2 weeks prior to LH-RH agonists may not only prevent PSA surge but also induce early declines in PSA levels.

Side Effects. Side effects include hot flashes and occasionally nipple and breast tenderness.

Gonadotropin-releasing hormone (GnRH) stimulates the pituitary gland to release luteinizing hormone-releasing hormones (LHRH). GnRH antagonist drugs such as abarelix (Plenais) and histrelin (Vanta) block this action. They have two advantages over LHRH agonists:

They do not cause the same testosterone surge that can temporarily worsen cancer symptoms.
They seem to reduce testosterone levels more quickly.

Anti-androgens are drugs used to block the effects of testosterone. They are used alone or in maximal androgen blockage (MAB), in which they are combined with LHRH agonists or orchiectomy to completely block androgen hormones. Anti-androgens are either steroidal or nonsteroidal.

Nonsteroidal Anti-androgens. Nonsteroidal anti-androgen drugs include:

Flutamide (Eulexin, Drogenil). Flutamide has produced extended response in some patients. Side effects may include diarrhea and liver damage, which has been fatal in rare cases; liver function must be monitored closely.
Nilutamide (Nilandron). Nilutamide is associated with reversible interstitial pneumonitis, nausea, alcohol intolerance, and visual disturbances.
Bicalutamide (Casodex). Bicalutamide is effective and appears to have fewer severe side effects than other anti-androgens, including loss of sexual interest, osteoporosis, visual disturbance, and interstitial pneumonia. This drug is proving to have survival rates equal to those of maximal androgen blockage.

Steroidal Antiandrogens. Steroidal antiandrogens act like female hormones and include:

Megestrol uppresses androgen production, but incompletely, and is generally not used as initial therapy.
Cyproterone combined with estrogen may prevent the testosterone surge that occurs with LH-RH agonists.

Men often experience fatigue, loss of energy, and emotional distress from androgen suppression treatment. Hormonal therapy may significantly impair quality of life, particularly in men who had no symptoms beforehand and whose cancer has not metastasized. Common side effects of androgen suppression drugs include:

Osteoporosis, the loss of bone density. This risk is higher with orchiectomy than with androgen suppressants. Some androgen suppressants, such as bicalutamide, may cause less bone loss. The use of estrogens may actually be bone protective. A number of medications, especially bisphosphonates, are available to help prevent or reduce bone loss.
Diarrhea
Loss of muscle mass
Psychological disturbances
Fatigue
Loss of sexual drive and sexual dysfunction
Swelling of the breasts (gynecomastia)
Nausea and vomiting
Hair loss
Anemia

In addition, there is growing evidence that androgen deprivation therapy increases the risks for diabetes and heart disease.

Prostate cancer that does not respond to hormonal treatment is called hormone-resistant, or hormone-refractory, cancer. There are various drug treatments for hormone-resistant cancer:

Docetaxel and Other Chemotherapy. Chemotherapy drugs for prostate cancer include docetaxel (Taxotere), mitoxantrone (Novantrone), estramustine (Emcyt), and various platinum-based drugs, such as carboplatin. These drugs are often combined with other cancer drugs (such as 5-fluorouacil) or corticosteroids (such as prednisone).

Docetaxel-based drug regimens are emerging as the main chemotherapy treatment for hormone-refractory prostate cancer. In 2004, the FDA approved docetaxel injection in combination with prednisone for treatment of patients with hormone-resistant prostate cancer. Patients who received this drug combination survived on average 2.5 months longer than patients who received mitoxantrone and prednisone. Another 2004 clinical trial found that a docetaxel and estramustine combination worked better than mitoxantrone and prednisone for advanced resistant prostate cancer. Side effects can be serious and may include gastrointestinal problems (nausea, vomiting, or diarrhea), fatigue, low blood cell counts, and increased risk for blood clots.

Researchers are continuing to investigate docetaxel combinations and compare them to other chemotherapy regimens. A large 2006 study reported that docetaxel and prednisone worked better than mitoxantrone plus prednisone in improving quality of life, pain relief, and survival. Docetaxel is also being investigated in combination with vitamin D-related drugs. A 2006 trial found that men with advanced prostate cancer who took docetaxel plus high-dose vitamin D (calcitriol) lived about 8 months longer than men who received docetaxel and placebo. Calcitriol also appeared to protect against docetaxel’s side effects, especially gastrointestinal problems and blood clots.

Doctors are also studying other ways to help patients cope with docetaxel’s side effects. Research presented at the 2006 Prostate Cancer Symposium suggested that patients may be able to take periodic breaks from docetaxel treatment instead of having continuous therapy. In the study, patients with advanced prostate cancer were given the option of suspending docetaxel treatment if their PSA levels improved within a certain range. Researchers found that patients were able to take 16-week breaks and still show improvement once they resumed treatment. This approach may work best for patients who experienced a good initial response to docetaxel.

Bisphosphonates. These drugs prevent bone loss and reduce bone pain in metastasized cancers. They are of particular interest because they may inhibit prostate cancer cell growth in the bone. The bisphosphonates showing most promise in prostate cancer are newer drugs called nitrogen-containing bisphosphonates (pamidronate, zoledronic acid).

Immunotherapies. The prostate organ offers special possibilities for genetic therapies because it contains highly specific antigens (factors that the immune system can target). There are a number of approaches currently under investigation, including:

Genetically designed vaccines (Provenge, Gvaz, JBT 1001) inject factors into prostate cancer cells that trick the immune system into attacking the cancer cells.
Antisense therapy for prostate cancer blocks expression of a protein called BCL-2, which tends to be genetically overexpressed in some patients with androgen-independent prostate cancer. This protein prevents apoptosis (a natural process by which all cells, including cancer cells, self-destruct).
Monoclonal antibodies (MAbs) are genetically designed immune factors that target foreign compounds called antigens for attack by the immune system. Monoclonal antibodies are being designed to target prostate-specific antigens.

Angiogenesis Inhibitors. Much research is focusing on drugs that block small molecules involved with the growth of blood vessels that feed the tumor (a process called angiogenesis ). The spread of new blood vessels is controlled by compounds called growth factors, which may be important in cancer cell proliferation. Researchers are interested in drugs that turn off these growth factors or their receptors, such as epidermal growth factor receptor (EGFR). In doing so, the drugs may be able to cut off cancer's life blood. Gefitinib (Iressa) and erlotinib (Tarceva) are angiogenesis inhibitors that target receptors of epidermal growth factors called tyrosine kinase. They are being used in lung cancer and are being investigated in a number of other cancers, include prostate cancer. Various drugs that inhibit angiogenesis in other ways (thalidomide, endostatin) are also under investigation.

Ketoconazole. Ketoconazole is an antifungal drug that blocks an enzyme that stimulates production of testosterone. It is effective in high doses but can have severe gastrointestinal effects, mainly nausea and anorexia. Long-term use can result in impotence, itchy skin, nail changes, and suppression of stress hormones. One center reported a consistent PSA response in more than 60% of patients who had failed other androgen deprivation treatments.

Aromatase Blockers. Aminoglutethimide (Cytadren) and similar drugs block aromatase, an enzyme important in estrogen production. Because the female hormone estrogen plays such a major role in the development of breast cancer, some experts think that blocking the small amount of estrogen found in men may also affect prostate cancer. Side effects include drowsiness and skin rash.

Atrasentan. Atrasentan is known as an ET(A)-receptor antagonist. It is showing promise in reducing bone loss and delaying progression of prostate cancer in men with advanced disease that no longer responds to hormone therapy. Side effects are relatively mild.

Resources

www.cancer.gov -- National Cancer Institute
www.cancer.org -- American Cancer Society
www.asco.org -- American Society of Clinical Oncology
www.plwc.org -- People Living with Cancer
www.prostatecancerfoundation.org -- Prostate Cancer Foundation
www.fightprostatecancer.org -- National Prostate Cancer Coalition
www.urologyhealth.org -- Urology Health
www.nccn.org -- National Comprehensive Cancer Network
www.cdc.gov/cancer/prostate -- CDC Cancer Prevention and Control
www.psa-rising.com -- PSA Rising: Prostate Cancer Survivor Info
www.ustoo.org -- Us Too! Prostate Cancer Education and Support
www.cancer.gov/clinicaltrials -- Find clinical trials

References

Greenspan SL, Nelson JB, Trump DL, Resnick NM. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial. Ann Intern Med. 2007 Mar 20;146(6):416-24.

Gudmundsson J, Sulem P, Manolescu A, Amundadottir LT, Gudbjartsson D, Helgason A, et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet. 2007 May;39(5):631-7. Epub 2007 Apr 1.

Haiman CA, Patterson N, Freedman ML, Myers SR, Pike MC, Waliszewska A, et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet. 2007 May;39(5):638-44. Epub 2007 Apr 1.

Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006 Sep 20;24(27):4448-56.

Lawson KA, Wright ME, Subar A, Mouw T, Hollenbeck A, Schatzkin A, et al. Multivitamin use and risk of prostate cancer in the National Institutes of Health-AARP Diet and Health Study. J Natl Cancer Inst. 2007 May 16;99(10):754-64.

Leman ES, Cannon GW, Trock BJ, Sokoll LJ, Chan DW, Mangold L, et al. EPCA-2: a highly specific serum marker for prostate cancer. Urology. 2007 Apr;69(4):714-20.

Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007 Apr 20;25(12):1596-605. Epub 2007 Apr 2.

Thompson I, Thrasher JB, Aus G, Burnett AL, Canby-Hagino ED, et al. Guideline for the management of clinically localized prostate cancer: 2007update. J Urol. 2007 Jun;177(6):2106-31.

Thompson IM, Tangen CM, Paradelo J, Lucia MS, Miller G, Troyer D, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA. 2006 Nov 15;296(19):2329-35.

Walter LC, Bertenthal D, Lindquist K, Konety BR. PSA screening among elderly men with limited life expectancies. JAMA. 2006 Nov 15;296(19):2336-42.

Yeager M, Orr N, Hayes RB, Jacobs KB, Kraft P, Wacholder S, et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet. 2007 May;39(5):645-9. Epub 2007 Apr 1.

Review Date:
6/27/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Vitamins

FitSugar — Wed, 08 Oct 2008 17:35:00 -0700

In This Report

Highlights
Introduction
Carotenoids
Phytochemicals
Healthy Foods
Dietary Health Benefits
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Cancer

Growing evidence suggests that vitamins and micronutrients, especially from foods, may play important roles in the prevention or treatment of certain cancers:

One study found that the risk of prostate cancer risk dropped as consumption of vegetables high in vitamin C, such as broccoli and bell peppers, rose.
A diet high in cruciferous vegetables has been found to reduce the risk of kidney cancer; low consumption of cruciferous vegetables increases the risk.

On the other hand, high amounts of folic acid (a B vitamin) may be associated with colorectal cancer, and beta-carotene supplements are associated with increased lung cancer risk in smokers and people exposed to asbestos.

Macular Degeneration

In 2007, the National Eye Institute recommended that people with intermediate or advanced macular degeneration in one eye take a vitamin formula shown to reduce the risk of macular degeneration in the other eye by 25%. The formula contains vitamin C, vitamin E, beta-carotene, and zinc.

Osteoporosis

Vitamin K is widely used in Japan to treat osteoporosis, and studies suggest it also may be effective in treating rheumatoid arthritis.

Heart Disease

Although people with high levels of homocysteine are prone to developing blood clots in their arteries and veins, a 2007 study found that lowering homocysteine with B vitamins and folic acid does not reduce the incidence of deep vein thrombosis (DVT). A 2007 trial in adults with stable coronary artery disease found that lowering homocysteine levels 33% with folic acid and other B vitamins had no effect on arterial inflammation, meaning that lower levels were unlikely to offer protection against heart attack or stroke.

Introduction

Vitamins do not share a common chemistry, but they do share certain characteristics. They are all organic nutrients that are necessary in small amounts for normal metabolism and good health. Your diet or supplements provide most vitamins. The body can manufacture only three vitamins (D, K, and the B vitamin biotin) from nondietary sources. Unlike carbohydrates, fats, and proteins, vitamins are not sources of energy. Instead, vitamins are chemical partners for the enzymes involved in the body's metabolism, cell production, tissue repair, and other vital processes.

Vitamins are either fat soluble or water soluble. The fat-soluble vitamins, which include A, D, E, and K, are absorbed by the body using processes that closely parallel the absorption of fat. They are stored in the liver and used up by the body very slowly. The water-soluble vitamins include C and the B complex vitamins. The body uses these vitamins very quickly. Excess amounts are eliminated in urine.

The Recommended Daily Allowance (RDA) for vitamins, set by the Food and Nutrition Board of the National Academy of Sciences-National Research Council, has been used for years as a guide for determining the amount of vitamins needed for a healthy diet. The RDA refers to an estimate of the average daily requirement. It is not completely adequate, however, for informing people about the amounts of vitamins they may need.

The RDA is gradually being enhanced using a new standard called the Dietary Reference Intake (DRI). The DRI is based on the following ratings, which will eventually appear on labels:

The recommended daily allowance (RDA). This is the current rating on most vitamins.
The estimated average requirement (EAR). This is the amount adequate for 50% of all people, which will be put on labels when it can be calculated.
Adequate intake (AI). This is an amount that will be used if there is insufficient data to calculate the EAR.
Tolerable upper intake level (UL). This is the maximum dose likely to be safe in nearly all individuals. It will be included on labels if this amount is known.

Food and supplement labels now typically list the Daily Value (DV). This is the percentage of the amount of a nutrient that experts believe a person needs in their daily diet. On food labels it is usually based on one serving size for a person who takes in 2,000 calories a day.

Regulation of dietary supplements by the U.S. Food and Drug Administration (FDA) is a complex issue.

Labels on vitamins and other dietary supplements now include nutrient information and list all ingredients, including identifying parts of plants from which ingredients may be taken. Unlike the labels for drugs, however, labels for vitamins and supplements may not claim to prevent or treat any specific disease. Labels for vitamins and supplements include one of the following:

Health claim -- description of how the substance may reduce the risk of a health-related condition
Nutrient claim -- description of the amount of the nutrient in the product or
Structure or function claim -- description of how the product may affect organs or systems of the body, without claiming to prevent or treat specific disease

The quality of dietary supplements depends on the manufacturer and is not ensured by FDA. The U.S. government does not require that supplements be standardized, meaning that the amounts or quality of nutrients may vary depending on the batch. So, more expensive supplements are not necessarily better than the less expensive ones. Government regulations are in the process of catching up to the boom in the supplement industry. In the meantime, some companies voluntarily adhere to rigorous quality controls, while others do not.

The U.S. Pharmacopeia (USP), an independent organization that sets quality standards for drugs, has also implemented standards for vitamins. Consumers may look for the USP label on products of companies that adhere to these standards. USP verification means the following:

What is in the bottle matches what is listed on the label.
There are no harmful levels of contaminants.
The supplement will be absorbed properly into the body.
It has been produced according to good manufacturing standards.

Before selling any supplement introduced after 1994, manufacturers must submit information as to why the product is considered safe for people. The FDA may refuse to allow it on the market if it finds the evidence insufficient. The FDA does not require manufacturers to provide any scientific evidence that dietary supplements are safe and effective before a product is sold (unlike drugs, which must be proven both safe and effective through clinical trials). If a supplement causes side effects in people once it is for sale, the government may place restrictions on the supplement or withdraw it from the market. The FDA may also withdraw products from the market if their labels are misleading or false.

About 30% of Americans take at least one vitamin or mineral supplement daily. In a large study that examined the death rates of 11,000 people, however, there was no difference in mortality rate between those who took vitamin supplements and those who didn't. Most people who have a healthy diet do not need vitamins, but there are some exceptions.

Pregnant and Breast-Feeding Women. Women who are pregnant or who are breast-feeding generally need additional vitamins. Vitamins B6, B12, and folic acid are particularly important. Women who are vegetarians must be sure to avoid deficiencies, which can harm their offspring. Folic acid reduces the risk for neural tube defects and possibly facial abnormalities, such as cleft palate. Studies also show that low folate levels during pregnancy are associated with low birth weight, a risk factor for the development of cardiovascular disease in adulthood. Multivitamins that contain folic acid also appear to be somewhat protective. A woman's best approach is to take extra folic acid plus multivitamin supplements (which have additional benefits), starting them before becomming pregnant.

The human body stores several years' worth of vitamin B12, so nutritional deficiency of this vitamin is extremely rare. Although, people who follow a strict vegetarian diet and do not consume eggs or dairy products may require vitamin B12 supplements.

Pregnant women with healthy diets may have low folate levels and need to take supplements. Requirements are as follows:

The recommended daily allowance (RDA) for folic acid prior to conception and during pregnancy is 400 mcg.
During breast-feeding 260 - 280 mcg is recommended.

The following vitamins may have some value for pregnant women:

Choline, another vitamin B, is also essential for pregnant (450 mg) and nursing women (550 mg). Choline plays a key role in brain development. Not getting enough during pregnancy can lead to memory and cognitive defects in the baby. Choline supplements can also lessen the cognitive defects of prenatal alcohol exposure.
Vitamin B6 may help improve morning sickness.
Vitamin C may reduce the risk of urinary tract infections during pregnancy.
Vitamin D may help prevent preeclampsia.
One study also suggested that if pregnant women took vitamin K supplements, their infants might not need the required injection of this vitamin after birth, but supplements of vitamin K during pregnancy are not currently recommended.

Some women have low vitamin A reserves in their liver. It is important to note, however, that too much vitamin A significantly increases the risk for birth defects. Daily amounts of 10,000 IU (international units) of vitamin A in supplements and food (an amount not far above the RDA level) can pose a danger. Experts recommend that pregnant women take in no more than 8,000 IU per day and avoid eating liver.

Infants and Children. Infants who are breast-fed by healthy mothers receive enough vitamins except, in some cases, vitamins K and D. Human milk has low levels of K, and the newborn's immature intestinal tract may not produce enough of the baby's own supply. Most babies are given an injection of this vitamin at birth. Infants being breast-fed by malnourished women or those who lack sufficient exposure to sunlight may be deficient in vitamin D. In these cases, supplements of 200 - 300 IU are recommended. Formulas are required to contain sufficient vitamins and minerals. One study suggests that vitamin supplements for infants under 1 year of age may help protect them from developing type 1 diabetes later on. Beyond infancy, most American children receive all the vitamins they need from their diet unless they are living in severely deprived circumstances.

Smokers. Smoking interferes with absorption of several vitamins, importantly vitamins C and D. In one study nearly 25% of female smokers and 31% of male smokers were deficient in vitamin C. Smoking can interfere with the metabolims of vitamin D, resulting in poor muscle function. Taking high doses of antioxidant vitamins, however, may actually be harmful in smokers, especially beta carotene. Instead of taking supplements, most smokers should be sure their diets are rich in fresh fruits and vegetables and whole grains. Of course, smoking cessation is the most important intervention of all.

Click the icon to see an image of sources for vitamin C.

Alcoholics. Alcoholics often suffer from multiple vitamin deficiencies. The most dangerous deficiencies are from vitamins B1 (thiamin), folic acid, B6 (pyridoxine), B2 (riboflavin), and vitamin C. Low levels of B6 are associated with increased risk of colorectal cancer in men who drink large amounts of alcohol.

Overweight Adults. Overweight and obesity causes many problems that often result in metabolic syndrome or type 2 diabetes. Evidence suggests that isoflavones can help regulate cholesterol levels and reduce body weight and fat mass. Because some medications used to control blood sugar levels reduce folic acid and vitamin B12, some people may need vitamin supplements.

People Who Have Had Gastric Bypass Surgery. Vitamin deficiency is a recognized complication of gastric bypass surgery. Women, African-Americans of both sexes, and adults who have had laparoscopic Roux-en-Y bypass surgery are at highest risk. The deficiency is treated with water-soluble vitamin supplements.

Strict Vegetarians. Strict vegetarians need supplements of vitamin B12, unless they get enough of it from fortified cereals and other grain products.

Dieters and Vegetarians. People on weight-reduction diets with less than 1,000 calories a day should probably take a multivitamin and should also check regularly with a physician.

Vegetarians may need riboflavin, vitamin B12, and vitamin D supplements. Vegans, who do not eat dairy or eggs as well as meat, may be at further risk for vitamin A deficiencies if they do not also have plenty of dark colored fruits and vegetables. Those who eat eggs and dairy products need only watch their iron levels.

Deficiencies in vegetarian children may be particularly harmful. (One study, for example, reported that adolescents who had been on macrobiotic diets before age 6 and were deficient in vitamin B12 scored lower on psychological tests.) Pregnant and breast-feeding women who are vegetarians must be sure to have sufficient vitamins. Of special note, maternal deficiencies in vitamin B12 may cause delayed growth and neurologic problems in their newborns.

Click the icon to see an image of sources for vitamin D.

Older Adults. Deficiencies of vitamins and important minerals have been observed in almost a third of elderly people. Often their dietary habits slip and they fail to eat balanced meals regularly. Multiple drug regimens may prevent absorption of some vitamins. Elderly people, particularly if they are not exposed to sunlight, may be deficient in vitamin D. They also may have low levels of important B vitamins. (Older adults showing signs of dementia should be checked for B12 deficiencies as well as other disorders causing mental disturbances.) One study reported that the immune systems of elderly people may benefit from higher levels of vitamin E than the daily recommended dosage. It should be noted, however, that metabolism slows down as a person ages, and in elderly people it takes the liver longer to eliminate drugs and vitamins from the body. The effect of some vitamin supplements, therefore, may be intensified. Dosage levels of vitamin A, for instance, which might be harmless in a younger adult, could be toxic in an elderly patient. Nevertheless, experts are increasingly recommending extra vitamin and mineral supplements for older people.

People Who Need to Avoid Sunlight. People who need to avoid sunlight or are housebound, and whose diet is low in foods that contain vitamin D should take supplements. People with darker skin are at higher risk for deficiencies than those with whiter skin. (Note: vitamin D is toxic in high doses, and no one should exceed the recommended daily intake of vitamin D except under the direction of a physician.)


Benefits	Essential for growth, bone development, night vision, reproduction, and healthy skin.
Recommended daily allowance (RDA) or dietary reference intake (DRI) (mcg = micrograms, mg = milligrams, IU = international units)	Vitamin A RDA and Upper Limit (when toxicity is risk) are the following: For children: 1,000 IU ages one to three (upper limit is 2,000 IU); 1,333 IU ages 4 - 8 (upper limit is 3,000 IU); and 2,000 IU for 9 - 13 (upper limit is 5,665 IU). For nonpregnant women: 2,330 IU ages 14 through adulthood. (Upper limit is 9,335 IU for ages 14 - 18 and 10,000 IU for women over 19.) For pregnant women: 2,500 IU for pregnant women under 18; 2,565 IU for pregnant women over 19. (Upper limit is 9,335 IU for ages 14 - 18 and 10,000 IU for women over 19. It should be noted that some experts recommend 8,000 IU as the upper limit during pregnancy.) Warning: Use of the topical acne medication tretinoin, a vitamin A derivative, during pregnancy can cause birth defects. For nursing women: 4,000 IU for nursing mothers under 18; 4,335 IU for nursing mothers over 19. (Upper limit is 9,335 IU for ages 14 - 18 and 10,000 IU for women over 19.) For men: 3,000 IU ages 14 - 18; 3,000 IU for ages 19 and above. (Upper limit is 10,000 IU.) Note: In determining the daily vitamin A allowance, experts also take note of provitamins, such beta carotene, that convert to vitamin A. Some experts recommend 3 - 6 mg of beta-carotene. Vitamin A is also now being measured with a new unit called the Retinol Activity Equivalent (RAE or RE). One RE is equal to 1 mcg. Retinol is the most active form of vitamin A and it is also converted in the liver from carotenoids. One RE is equal to 12 mcg of beta-carotene or 24 mcg of alpha-carotene or beta-cryptoxanthin).
Foods containing the vitamin	Animal products, such as liver, dairy products, eggs, and fish liver oil. Provitamin A carotenoids are also found in dark red, green, and yellow vegetables and fruits. Requires some dietary fat to be absorbed.
Effects of deficiencies	Skin disorders, severe diarrhea, and eye damage. In less developed countries severe deficiencies cause blindness in 250,000 children each year. Diets low in vitamin A may also increase the risk of developing cancer. Low dietary intake of vitamin A has been associated with impaired lung function in children.
People at risk for deficiencies	Preschool children and any child with inadequate intake of protein, calories, and zinc. Iron deficiency may also impair metabolism of vitamin A. People with asthma. People with serious disorders in the intestine, liver or pancreas, such as cystic fibrosis, steatorrhea, biliary obstruction, inflammatory bowel disease, cirrhosis, and others. People who have undergone Roux-en-Y gastric bypass surgery. Vegans (vegetarians who do not eat eggs and dairy). Such individuals should be sure to have plenty of deep-colored fruits and vegetables. People who abuse alcohol. It should be noted, however, that people with alcoholism may be at risk for vitamin A deficiency, but a combination of high-dose vitamin A and alcohol may cause toxic effects in the liver. Healthy adults usually have a year's store of vitamin A in the liver, so temporary nutritional deficiencies or problems with fat absorption are unlikely to cause serious vitamin A deficiency problems.
Toxicities	Very toxic when taken in high-dose supplements for long periods of time. Symptoms of overdose include dizziness, nausea, vomiting, headache, skin damage, mental disturbances, and, in women, infrequent periods. Can affect almost every part of the body, including eyes, bones, blood, skin, central nervous system, liver, and genital and urinary tracts. Severe toxicity can cause blindness and may even be life threatening. In children, chronic overdose can cause fluid on the brain and as well as adult complications. High consumption of vitamin A may also increase the risk of gastric cancer and the risk of osteoporosis and fractures in both men and women. Pregnant women who take amounts not much higher than RDA levels increase the risk for birth defects in their children. Liver damage can occur in children who take RDA-approved adult levels over prolonged periods of time or in adults who take as little as five times the RDA-approved amount for 7 - 10 years.


	B Vitamins: General Information	Vitamin B1 (thiamin)
Benefits	The B vitamins have a wide and varied range of functions in the human body. Most B vitamins are involved in the process of converting blood sugar into energy.	Essential for converting blood sugar into energy and is involved in metabolic activities in nerves, heart, and muscles and in the production of red blood cells.
Recommended daily allowance (RDA) or dietary reference intake (DRI) (mcg = micrograms, mg = milligrams, IU = international units)		RDA is 1.2 mg per day for men and 1.1 mg for women.
Foods containing the vitamin		Best source is pork and good sources are dried fortified cereals, oatmeal, corn, nuts, cauliflower, and sunflower seeds. Supplements for people with normal diets and health are unnecessary.
Effects of deficiencies	Deficiencies are uncommon in the U.S., but when they occur, they usually involve several B vitamins, since many of them come from the same food groups.	Severe vitamin B1 deficiency is known as beriberi. It can cause visual disturbances, paralysis, staggering, loss of sensation in the legs and feet, psychosis, and congestive heart failure.
People at risk for deficiencies	Alcohol interferes with these vitamins, and some of the physical and mental problems that alcoholics experience may be attributed to a deficiency of B vitamins. Elderly people are also at risk for deficiencies because of inadequate diets and potential interference with B-vitamin absorption by medications. Deficiencies can occur in severely malnourished people or in those receiving long-term dialysis or intravenous feeding. Vegetarians may be at risk.	See general vitamin B description.
Toxicities	Because the B vitamins are water-soluble and eliminated in the urine, toxic reactions from oral administration of most of them are extremely rare. (Exceptions are niacin and B6.) It should be noted that substances known as B15 (pangamic acid) and B17 (laetrile) are neither vitamins nor nutrients; both chemicals are highly dangerous and have no proven nutritional or health value.	No toxic effects have been reported from thiamin.


	Vitamin B2 (riboflavin)	Vitamin B3 (niacin) also known as nicotinic acid	Vitamin B5 (Pantothenic Acid)
Benefits	Important in the production of energy.	Helps break down blood sugar for energy. Acts as a vasodilator, widening blood vessels and increasing blood flow. May be prescribed for improving cholesterol levels.	Important for metabolism of fats, carbohydrates, and proteins, as well as production of steroid hormones and other important chemicals.
Recommended daily allowance (RDA) or dietary reference intake (DRI) (mcg = micrograms, mg = milligrams, IU = international units)	DRI is 1.7 mg.	DRI is 20 mg.	Adequate intake (AI) is 4 - 7 mg.
Foods containing the vitamin	Liver, dried fortified cereals, dairy products, fish. Some dark green vegetables. Supplements for people with normal diets and health are unnecessary.	Mackerel, swordfish, chicken, veal, dried fortified cereals, pork, salmon, and beef liver. Supplements are unnecessary in people with normal health and diets.	Whole grains, beans, milk, eggs, and liver. Supplements are unnecessary in people with normal health and diets.
Effects of deficiencies	Deficiencies affect the skin and mucous membranes and can cause cracks on the lips or corners of the mouth, eczema of the face and genitals, a burning sensation on the tongue, eye irritation. May contribute to anemia when iron levels are low and contribute to elevated levels of homocysteine, a heart risk factor.	Deficiency causes pellagra; symptoms can include eczema, intestinal and stomach distress, depression, headache, thinning of the hair, and excess saliva production.	Deficiency is unlikely except in company with other B vitamin deficiencies. Symptoms include abdominal distress, burning sensation in the heels, and sleep problems.
People at risk for deficiencies	See general vitamin B description.	Alcoholics and any malnourished persons.	Alcoholics and any malnourished persons.
Toxicities	Until recently, no toxic effects had been reported even from large doses of riboflavin. However, one study indicated that high consumption of vitamin B2 might increase the risk of stomach cancer. More research is needed. (In the same study, vitamins B1, B3, and B6 were protective.)	Even mildly high doses of niacin can cause hot flushing of the face and shoulders, headache, itchiness, and stomach problems. Some report heart disturbances and temporarily lowered blood pressure. Large doses may produce ulcers, gout, diabetes, and liver damage, which are usually reversed when high doses are discontinued.	Although no toxicity has been reported in humans, high dosages have caused liver damage in rats.


	Vitamin B6 (pyridoxine)	Vitamin B12 (cobalamin)
Benefits	Has an effect on over 60 proteins in the body, importantly, those that play a role in the nervous system, in red and white blood cell production, and in heart disease.	Essential for the production of blood cells, manufacturing genetic material, and for healthy functioning of the nervous system. New evidence suggests that high levels of B12 may protect against colon and rectal cancer.
Recommended daily allowance (RDA) or dietary reference intake (DRI) (mcg = micrograms, mg = milligrams, IU = international units)	RDA is 1.3 mg in adults under 50 and 1.7 mg for older men and 1.5 for older women. (Some experts recommend 3 to 6 mg for people who need heart protection.) Upper limit is 100 mg for adults.	RDA is 2.4 mcg in men and nonpregnant women, 2.6 mcg in pregnant women, and 2.8 mcg in nursing mothers.
Foods containing the vitamin	Meats, oily fish, poultry, whole grains, dried fortified cereals, soybeans, avocados, baked potatoes with skins, watermelon, plantains, bananas, peanuts, and brewer's yeast.	The only natural dietary sources are animal products, including meats, dairy products, eggs, and fish (clams and oily fish are very high in B12). Like other B vitamins, however, B12 is added to commercial dried cereals.
Effects of deficiencies	Increased levels of homocysteine, associated with heart disease and possibly Alzheimer's disease. Skin problems and nervous system disorders, including impaired memory and concentration. Increased risk for kidney stones. One study found a correlation between vitamin B6 deficiency and inability to conceive or carry a child to term. In unborn children, some evidence shows that lack of vitamin B6, in addition to vitamin B12 and folic acid, may be responsible for defects such as cleft lip and palate and spina bifida. Supplementation with these vitamins is advised during pregnancy. Note: People who have been taking more than 50 mg for some time and stop suddenly are at risk for a so-called rebound deficiency. When people stop, they should taper off slowly.	Deficiencies elevate homocysteine, a possible risk factor for heart disease and Alzheimer's disease. Increased risk of bone fractures. Abnormal gaits in the elderly. May cause severe depression, memory loss, instability, disorientation, and decreased reflexes, and possibly hearing loss. Children who are deficient may experience growth failure. Deficiencies in pregnant and breast-feeding women may cause neurologic harm in their offspring. A genetic defect that causes vitamin B12 deficiencies is responsible for pernicious anemia, a serious disorder that causes rapid heart rate, shortness of breath, dizziness, weakness, and fatigue. It must be treated with injections of vitamin B12 or else neurologic damage may occur.
People at risk for deficiencies	Alcoholics and any malnourished person. In rare cases, infants are born unable to metabolize pyridoxine; in such cases, seizures or convulsions can occur and vitamin B6 must be administered.	Alcoholics and any malnourished persons. Evidence suggests deficiencies may be caused by Helicobacter pylori (H. pylori) bacteria (a cause of ulcers). Nearly 30% of patients with inflammatory bowel disease have vitamin B6 deficiency, as well as low levels of iron and vitamin D. People who take the antibiotic isoniazid, high blood pressure medication hydralazine, and the drug penicillimine are at risk for vitamin B6 deficiency. The elderly and people with Crohn’s disease and those who have undergone ileal and ileocolonic resection may have trouble absorbing natural vitamin B12 and require supplements. Some evidence shows that patients with Parkinson’s disease treated with levodopa plus dopa decarboxylase inhibitor (DDC-i) and catechol-O-methyltransferase inhibitor (COMT-i) have low levels of both vitamin B12 and folate. As a result, they need to take supplements of these vitamins. Other studies have found that patients with diabetes treated with metformin, but not roziglitazone, are at risk for low levels of vitamin B12. Vitamin B12 deficiency is also common in patients with polyneuropathy. In up to one-third of patients, vitamin B12 deficiency is the sole or major contributing cause of their neuropathy. Treatment with vitamin B12 has a high success rate in improving the symptoms. Vegetarians are at higher risk for deficiencies.
Toxicities	Very high doses can cause nerve damage with symptoms of instability and numbness in the feet and hands, which may be permanent in some cases. Of specific concern are possible adverse effects on nerve development in the offspring of pregnant women who take large doses, such as for morning sickness.	There is no evidence of toxicity with this vitamin.


	Biotin (a B vitamin)	Choline (a B vitamin)	Folate, or Folic Acid, its synthetic form (a B vitamin)
Benefits	Involved in the production of amino acid proteins and fatty acids.	Essential for fetal brain development and for learning and memory.	Important for many metabolic processes in the body. It is used in the manufacturing of neurotransmitters (chemical messengers in the brain), in protecting the heart, and for synthesizing genetic materials (DNA) in the cells. It may improve blood flow.
Recommended daily allowance (RDA) or dietary reference intake (DRI) (mcg = micrograms, mg = milligrams, IU = international units)	There is no DRI for biotin; some experts suggest 30-100 mcg.	RDA 425 mg for nonpregnant women, 450 mg for pregnant women, and 550 mg for nursing women.	Supplements may be folate (natural) or folic acid (synthetic). Folic acid is nearly twice as potent as folate. DRI is 400 mcg (.4 mg) of folate for the general population, 600 mcg during pregnancy and 500 mcg while nursing. Women who are planning to be pregnant should certainly take 400 mcg of folic acid before conception, during pregnancy, and while nursing.
Foods containing the vitamin	Dietary sources are eggs, milk, liver, mushrooms, bananas, tomatoes, whole grains, nuts, and brewer's yeast. Also produced by bacteria in the intestines.	Peanuts, eggs, cauliflower, and meats, especially liver.	Avocado, bananas, orange juice, cold cereal, asparagus, green leafy vegetables, dried beans and peas, and yeast. Folic acid supplements are now added to commercial breads and cereals.
Effects of deficiencies	Deficiencies are almost unheard of.	Low levels during pregnancy increase risk of birth defects in newborns.	As with vitamins B6 and B12, deficiencies of folate elevate levels of homocysteine, an amino acid in the body that may increase the risk for heart disease, and possibly Alzheimer's disease. Folic acid supplements lower homocysteine levels, but with little or no impact on risk of atherosclerotic disease in the heart or in the peripheral arteries and veins. This suggests that homocysteine may be a marker of cardiovascular disease, rather than a cause. This being said, one 2007 study found that folic acid supplementation in patients with low folic acids levels substantially reduced the risk of a first stroke. Low levels during pregnancy increase risk of birth defects in newborns, and folic acid supplementation plays a key role in preventing birth defects. Folic acid deficiencies Deficiencies can also cause depression and megaloblastic anemia and impair concentration, memory, and hearing.
People at risk for deficiencies			Alcoholics, malnourished persons, people with conditions that disturb the small intestine, people taking certain drugs, particularly methotrexate. Other risk factors for deficiency: high-dose aspirin, smoking, treatment for seizures, taking oral contraceptives.
Toxicities		Excessive doses can cause intestinal problems, and there is also some concern that high doses can be carcinogenic.	Possible connection between high consumption of folate/folic acid and colorectal cancer now under exploration. Some link between high doses and central nervous system disorders, zinc deficiency, and seizures in epileptics. This risk appears to be low, but results indicate that megadoses should be avoided. High amounts in the elderly may mask symptoms of vitamin B12 deficiencies.


Benefits	Vitamin C is a water-soluble vitamin. Acts as an antioxidant (reduces harm from damaging chemical processes in the body). Essential for the production of collagen, the basic protein in bones, cartilage, tendons, and ligaments. A 2007 study found that vitamin C supplements can help prevent the development of complex regional pain syndrome following wrist fracture. Another study found that prostate cancer risk dropped as consumption of vegetables high in vitamin C, such as broccoli and bell peppers, rose. It may also protect against brochoconstriction during exercise in people with asthma. May help boost the immune system.
Recommended daily allowance (RDA) or dietary reference intake (DRI) (mcg = micrograms, mg = milligrams, IU = international units)	DRI is 75 mg (women) and 90 mg (men). (Smokers need an additional 35 mg.)
Foods containing the vitamin	Citrus fruits and juices, papayas, hot chili peppers, bell peppers, broccoli, potatoes, dark leafy greens, kale, red cabbage, cauliflower, cantaloupe, sweet potatoes, and Brussels sprouts. Orange juice is the most important source of vitamin C in the U.S., with frozen juice being the best source of the vitamin.
Effects of deficiencies	Scurvy is the primary deficiency disease. Affects most body tissues, particularly bones, teeth, and blood vessels. Early symptoms include tiredness, weakness, irritability, weight loss, and vague muscle aches. Later symptoms are bleeding gums, wounds that won't heal, rough skin, and wasting away of the muscles. Deficiencies may contribute to periodontal disease and gallstones. Low dietary intake of vitamin C has been associated with impaired lung function in children. Low intake may also increase lead levels in the blood.
People at risk for deficiencies	Deficiency has been uncommon in the U.S., usually occurring in the elderly, alcoholics, cancer patients, and some people on severely limited diets low in fresh fruits and vegetables. Surprisingly, however, studies now suggest that as many as 16% of middle-aged Americans, with the highest risk in smokers and middle aged men, are deficient in vitamin C. High doses of aspirin taken over a long period of time can interfere with vitamin C.
Toxicities	Tolerable upper limit is 2000 mg/day. High doses may cause headaches and diarrhea. Long-term high doses may increase risk for kidney stones. Ascorbic acid increases iron absorption so people with blood disorders, such as hemochromatosis, thalassemia, or sideroblastic anemia, should avoid high doses. Large doses may also thin blood and interfere with anticoagulant medications, blood tests used in diabetes, and stool tests. Rebound scurvy can occur after abrupt withdrawal from long-term large doses. This may affect infants or pregnant women who withdraw suddenly from high doses.


Benefits	Vitamin D is actually a single term for several hormones that are stored mainly in the liver and also in fat and muscle tissue. It is essential for the absorption of calcium into the bone and for normal bone growth.
Recommended daily allowance (RDA) or dietary reference intake (DRI) (mcg = micrograms, mg = milligrams, IU = international units)	RDA is 200 IU (5 mcg) per day for children and most adults to age 50, 400 IU (10 mcg) for people between ages 50 and 60, and 600 IU over age 70. and 1000 IU (15 mcg) for those over 70. People who are housebound, do not have sufficient exposure to sunlight, or are dark-skinned individuals, as well as breast-fed infants, should take need vitamin D supplements. The maximum tolerated dose after the age of 12 months is 2,000 IU/day
How the body gets the vitamin	There are two forms of vitamin D. Vitamin D3 is made in the body from a chemical reaction to the ultraviolet radiation in sunlight. Vitamin D2 is found in a few food sources, including vitamin D fortified milk, fatty fish, egg yolk, and liver.
Effects of deficiencies	Softening of the bones caused by low levels of calcium and phosphorous (called rickets in children and osteomalacia in adults). Also increases the risk for bone-related knee problems, and hip fractures in postmenopausal women. Associated with a higher risk for prostate cancer and breast cancer risk. Evidence suggests that vitamin D deficiency may be responsible for poor muscle strength after bone fracture. The deficiency is associated with high blood pressure and diabetes, but it is unknown whether supplementation with vitamin D impacts these diseases. Studies now suggest vitamin D plays a role in age-related macular degeneration (AMD), and that drinking milk with added vitamin D can help protect against AMD.
People at risk for deficiencies	Older people, particularly if they live in the North, who are underexposed to sunlight. Obesity may also increase risk. There is some concern, in fact, that vitamin D deficiency may be a growing problem in the US among younger adults as sunscreen use becomes widespread. Individuals at highest risk for vitamin D deficiency are those who assiduously avoid the midday sun, wear protective clothing, regularly use sunscreen, and have dark skin. Exposure to sunlight for about 15 - 20 minutes at mid-morning or mid-afternoon three times a week is recommended for most people who live in temperate climates.
Toxicities	Vitamin D is very toxic in high doses. In infants, daily amounts higher than 1,000 IU can cause mental and growth retardation, kidney failure, and death. In children and adults, daily amounts over 50,000 IU can cause weakness, anorexia, vomiting, diarrhea, and mental changes. Prolonged use of megadoses can cause calcification of soft tissue and life-threatening kidney failure. Low-calcium diets and withdrawal from the vitamin can usually reverse the side effects except for kidney failure.


	Vitamin E (Tocopherol or Tocotrienol)	Vitamin K
Benefits	A fat-soluble antioxidant vitamin that helps prevent cell membrane damage and may inhibit oxidation of LDL cholesterol (a process that increases its harmful effects on arteries). Researchers once thought that vitamin E might protect against cardiovascular disease. This theory has been debunked. However, a 2007 study found that vitamin E supplementation reduced the risk of deep vein thrombosis (DVT) in women at risk for, or with a history of, DVT. Vitamin E supplements have also been shown to produce a statistically significant decrease in menopausal hot flashes. There is also early evidence that vitamin E may protect against ovarian cancer.	The most important function of vitamin K is its role in blood clotting and prevention of bleeding. As a result, the vitamin may be able to help treat hepatoma, leukemia, and hepatocellular carcinoma, a form of liver cancer. The vitamin also contributes to maintaining healthy bones and healing fractures. Vitamin K is widely used in Japan to treat osteoporosis, and studies suggest it may be effective in treating rheumatoid arthritis.
Recommended daily allowance (RDA) or dietary reference intake (DRI) (mcg = micrograms, mg = milligrams, IU = international units)	RDA is 15 mg (22 IU) for all adults, including pregnancy women. Nursing mothers need 19 mg (28 IU). (Supplements should be taken along with some oil or fat to be absorbed.) Vitamin E is composed of 8 compounds (four tocopherols and four tocotrienols). Vitamin E is most often available as supplements of dl alpha tocopherol (a synthetic form). Other vitamin E compounds may prove to be more active than the standard synthetic supplement. They include natural vitamin E, called d-alpha- or RRR-alpha-tocopherol succinate (VES). Other vitamin E compounds of interest are tocotrienol and beta and gamma tocopherol. Supplements that contain a combination of some of these forms may be most beneficial.	RDA is 60 - 65 micrograms (women) and 70 - 80 micrograms (men).
Foods containing the vitamin	Vegetable oils (particularly wheat germ oil), sweet potatoes, turnip greens, mangos, avocados, nuts, sunflower seeds, and soybeans. Tocotrienol (a possibly beneficial form) is found in natural tropical oils. Palm oil sold in the US is refined and does not contain tocotrienol.	Best dietary sources are canola oil, cruciferous vegetables, and soybean oil. Good sources are beef liver, bran, and olive oil. Also produced by bacteria in the intestines.
Effects of deficiencies	Deficiencies have not been established.	Easy bruising, bleeding. May increase the risk of hip fractures in women.
People at risk for deficiencies	Low-birth weight infants. People who eat a low-fat diet. People with medical problems that impair fat absorption, such as Crohn's disease, cystic fibrosis, steatorrhea, liver diseases (such as cirrhosis). People with abetalipoproteinemia, a rare genetic disorder that impairs fat metabolism.	Deficiency may occur in patients who have problems absorbing fats, such as those with cirrhosis, people who are on long-term antibiotic therapy, or who are taking other medications, including cholestyramine, Dilantin, and phenobarbital. Some evidence suggests that more young people may be deficient than previously believed.
Toxicities	Upper level recommended is 1,500 IU of alpha tocopherol. Large doses may cause bleeding problems, particularly in people taking anti-clotting medications. Some research now indicates that vitamin E, like other antioxidants, may have pro-oxidant and damaging effects. Although vitamin E is one of the best studied vitamins, research has yielded conflicting results, and definitive conclusions about the benefits and toxicity of vitamin E have not yet been determined. In a major 2005 study, there was no significant difference in cancer rates between people who took 400 IU of vitamin E daily and those who did not, although those who took the supplement had a higher risk of heart failure. Additional studies also link high levels of vitamin E with a slightly increased risk of heart failure and death. On the other hand, studies show that vitamin E may reduce heart problems in high-risk patients such as certain people with diabetes.	Allergic-type responses, including rash and itching, to high doses have been reported. Those who are taking Coumadin, an anticoagulant, should not take vitamin K without consulting a physician. Vitamin K deficiency can cause anorexia, lethargy, growth retardation, bone loss, soft tissue calcification, and death.

Carotenoids

Carotenoids are a group of more than 700 fat soluble nutrients that produce the colors in foods such as carrots, pumpkins, sweet potatoes, tomatoes, and other deep green, yellow, orange, and red fruits and vegetables. Many are proving to be very important for health. Beta carotene is the most widely studied carotenoid, but others are proving to be of great interest. As with some, but not all, carotenoids, beta carotene is known as a provitamin A because it converts to the vitamin in the body.

They are categorized as either xanthophylls or carotenes according to their chemical composition.

Carotenes are hydrocarbons and most are found in yellow, orange, and red vegetables. They include beta and alpha carotene and lycopene.

Beta Carotene and other Provitamin A Carotenoids. Beta carotene, alpha-carotene, and beta-cryptoxanthin are carotenes that are converted into vitamin A or retinol (the active form of vitamin A) in the body. They are found in many yellow fruits and vegetables. Beta carotene is the most widely studied carotenoid. Evidence now strongly suggests that when taken as a separate supplement it can have harmful effects.
Lycopene. Lycopene is responsible for the red color in fruits and vegetables, including tomatoes, red grapes, watermelon, and pink grapefruit. It is also found in papayas and apricots. It does not convert to vitamin A but may have important cancer fighting properties and other health benefits.
The beneficial actions of most carotenes such as those tomatoes, corn, and carrots, appear to be enhanced by cooking them, especially in oil (preferably olive, canola, or another monounsaturated oil). (Note: Cooking can also destroy certain nutrients, such as vitamin C, in these vegetables.)

Xanthophylls contain oxygen and most are found in green vegetables, such as broccoli, cabbage, and kale. They are also in yellow fruits and vegetables. Xanthophylls include lutein and zeaxanthin, which are both stored in the retina of the eye. Neither converts to vitamin A. Both are powerful antioxidants and may be very important for healthy eyes. Unlike carotenes, cooking may reduce the antioxidant activity of some xanthophylls in foods, although probably not to any significant degree.

Phytochemicals

The word phytochemicals means plant chemicals. Hundreds of phytochemicals are being studied. Many are believed to have a major positive impact on human health. Some contribute to the bright and vivid colors found in fruits and vegetables. The results of studies on specific phytochemicals are not necessarily applicable to the vegetables or fruits that harbor small concentrations of these chemicals.

Nevertheless, it is obvious that vegetables and fruits are healthful, which is probably due to some balance of phytochemicals, carotenoids, vitamins, fibers, and minerals rather than any single substance.

The benefits of individual phytochemical supplements are largely unproven. Furthermore, they are not regulated and high concentrations of some may behave like drugs and can be toxic and possibly even contribute to cancer cell growth.

Polyphenols are important phytochemicals, and flavonoids (or catechins) are members of the polyphenol family that may have significant health benefits. Laboratory studies have shown that specific flavonoids suppress tumor growth, interfere with sexual hormones, prevent blood clots, and have anti-inflammatory properties. In general, flavonoids are found in celery, cranberries, onions, kale, dark chocolate, broccoli, apples, cherries, berries, tea, red wine or purple grape juice, parsley, soybeans, tomatoes, eggplant, and thyme. Most common berries contain flavonoids and are particularly rich in potent antioxidants.

Among the important flavonoids are resveratrol, quercetin, and catechin. Evidence suggests that resveratrol (found in red wine, grapes, olive oil) may be extremely potent. In laboratory studies, it increases cell survival and has been shown to increase the life span of worms and fruit flies. Catechins are the primary flavonoids in tea and may be responsible for its possible beneficial effects. Flavonoids in dark chocolate may also be health protective.

Isoflavones, commonly known as phytoestrogens, have actions that are similar to the female hormone estrogen. A high consumption of soy, which is primarily composed of isoflavones, may reduce symptoms resulting from estrogen depletion during menopause. In a recent study, supplementation with isoflavones decreased hot flashes by 57% and night sweats by 43%, but other research is less favorable.

Lignan is another phytoestrogen and is found in the fiber layers of whole-grains, berries, some seeds, some vegetables, and a few fruits.

Isothiocyanates and related substances, indoles, are also known as mustard oils and are responsible for the sharp taste in cruciferous (also called brassica) vegetables. Such vegetables include broccoli, cabbage, Brussels sprouts, cauliflower, collards, kale, kohlrabi, mustard greens, rutabaga, turnips, and bok choy. Isothiocyanates also stimulate enzymes that convert estrogen to a more benign form and may block steroid hormones that promote breast and prostate cancers. (Cruciferous vegetables are also high in fiber, vitamin C, and selenium.)

Monoterpenes have two important phytochemicals, perillyl alcohol and limonene. They block proteins that stimulate cell growth and reproduction and are being tested for actions against cancer. Limonene is found in the peels of citrus fruits.

Organosulfurs are part of the allium family of phytochemicals. Compounds, such as allicin, may have benefits on the immune system, assist the liver in rendering carcinogens harmless, and reduce production of cholesterol in the liver. These compounds are found in garlic, leeks, onions, chives, scallions, and shallots.

Capsaicin seems to reduce levels of substance P, a compound that contributes to inflammation and the delivery of pain impulses from the central nervous system. Research suggests that it may inhibit cancer-generating substances. It is found in hot red peppers.

Sterols, which include sitosterol, stigmasterol, campesterol, and squalene, are found in vegetable oils. Sitosterol is the most studied and appears to have cholesterol-lowering effects.

Beta-sitosterols may help improve urine flow and urinary symptoms in men with enlarged prostate glands (benign prostatic hyperplasia, or BPH). A recent review study of five randomized trials (519 men) found that urinary flow and other urinary symptoms improved in men who took the herbal remedy from 4 - 26 weeks. The study’s authors cautioned that while beta-sitosterols show effectiveness in the short term, their long-term effectiveness, ability to prevent complications from BPH, and safety are not known. More research is necessary. Beta-sitosterols come from South African star grass, Hypoxis rooperi, or species of Pinus and Picea.

Healthy Foods

Evidence increasingly suggests that a varied diet, not individual food chemicals, is essential for basic health and a longer life. Such diets are rich in fresh fruits and vegetables and whole grains, and low in saturated fats.


Foods	Phytochemicals and Carotenoids	Vitamins and other valuable food components	Benefits
Apples	Flavonoids		May have activity against certain cancers (lung). Also may help maintain healthy cholesterol. May protect against asthma.
Beans	Flavonoids	Folate, iron, potassium, and zinc	Some experts believe beans are the perfect food.
Berries, all kinds of dark colored	Ellegic Acid	Vitamin C, minerals	The anthocyanins in berries such as bilberries, blueberries, cranberries, elderberries, and others, have numerous healthful properties including anti-cancer and antioxidant effects. Bilberry (Vaccinium myrtillis) is widely used to prevent macular degeneration. Blueberries may protect the aging brain. (In one study blueberries were most effective.)
Broccoli (also kale, Brussels sprouts, cauliflower)	Flavonoids, isothiocyanates, lutein, beta and alpha carotene. Note: Young sprouts of broccoli and cauliflower contain much higher levels of isothiocyanates than their mature forms.	Vitamin C, folate, fiber, and selenium	Anticancer properties. Protective against heart disease and stroke.
Carrots and other bright yellow vegetables	Lutein, beta carotene and other provitamin A carotenoids	Vitamin A (converted from carotenoids), vitamin C	Protects eyes, lungs. (Cooking carrots may increase the potency of food nutrients.)
Chocolate, dark. Note: Milk chocolate does not have benefits.	Flavonoids		Heart protective (may improve lipids and help prevent blood clotting. May have protective properties against lung cancer (not other cancers).
Eggs	Lutein	Many B vitamins, vitamin A, vitamin D	Although egg yolks are high in cholesterol, very little of it has a negative effect on people with normal levels. And the health benefits of eggs are now known to be very high. (People with diabetes or those with high cholesterol should restrict eggs, however.)
Fish, oily (mackerel, salmon, sardines)		Vitamin B3, B12. Essential fatty acids, selenium	Heart and brain protective.
Garlic	Allium (organosulfurs)		Possibly protective against certain cancers, heart diseases, and infection. Heating garlic can reduce benefits. Allowing crushed fresh garlic to stand 10 minutes before heating, however, may preserve beneficial chemicals while cooking.
Ginger	Zingiberaceae		Cancer fighting properties.
Grains (whole)	Lignans (phytoestrogens)	Vitamin B, Selenium (important antioxidant mineral), fiber, folate	May help reduce the ability of cancer cells to invade health tissue.
Grapes, including purple grape juice, and red wine	Flavonoids, (resveratrol, quercetin and catechin)		Fight heart disease and cancer. May help lower the risk for asthma.
Nuts		Vitamin E, vitamin B1, essential fatty acids, folate	Protects the heart and may help prevent stroke.
Onions	Flavonoids, allium (organosulfurs)		May have activity against certain cancers (lung).
Oranges	Monoterpenes	Vitamin C, folate, potassium.	Many health benefits. Increases HDL levels.
Potatoes (Sweet)		Vitamin C, vitamin E, vitamin A	Many health benefits.
Soy. The best products are tofu, soy milk, or whole soy protein.	Isoflavones (phytoestrogens), flavonoids, phytosterol, phytate, saponins.		May have effects similar to estrogen, including maintaining bone and benefiting the heart in women. May also be protective against prostate cancer and possibly other cancers. More studies are needed. Effects on breast cancer are uncertain. (Note: Soy may have different effects in men than in women. Of some concern is one study reporting more mental decline in men who consume greater amounts of tofu.)
Spinach and other dark green leafy vegetables	Zeaxanthin, Beta carotene	Vitamin C, folate, vitamin A (converted from carotenoids)	Protects lungs and brain.
Tea (Both black and green tea are beneficial. Best results associated with green tea.)	Flavonoids (primarily catechins)		Cancer fighting properties, particularly in green tea, which may be especially beneficial for smokers. Both black and green tea may protect against heart disease and stroke, although studies are mixed. Tea drinking also may help with weight control and help prevent osteoporosis.
Tomatoes	Lycopene, Flavonoids	Vitamin C, biotin, minerals	Studies link to reductions in prostate and other cancers. Infection fighters.
Note on Organic versus Inorganic Products. There is some evidence that organic produce has higher levels of antioxidants and that some agricultural chemicals may destroy flavonoids. Nevertheless, organic produce is expensive, and fruits and vegetables, no matter how they are grown, are still filled with healthful nutrients.

Dietary Health Benefits

The benefits of any dietary factors are very difficult to prove, and, to date, there is little evidence that most dietary supplements protect against major diseases in otherwise healthy people with normal eating habits. An exception is lutein, which is known to reduce the risk of macular degeneration. However, a diet naturally high in vitamins and minerals can be the best defense against many diseases. Fresh fruits and vegetables and whole grains are the primary sources of vitamins, carotenoids, and vitamins, as well as of fiber and important minerals.

Description of Oxygen-Free Radicals (Oxidants). Currently, the most important benefit claimed for vitamins A, C, E, and many of the carotenoids and phytochemicals is their role as antioxidants, which are scavengers of particles known as oxygen-free radicals (also sometimes called oxidants). These chemically active particles are by-products of many of the body's normal chemical processes. Their numbers are increased by environmental assaults, such as smoking, chemicals, toxins, and stress. In higher levels, oxidants can be very harmful in the following way:

They can damage cell membranes and interact with genetic material, possibly contributing to the development of a number of disorders including cancer, heart disease, cataracts, and even the aging process itself.
Oxygen-free radicals can also enhance the dangerous properties of low-density lipoprotein (LDL) cholesterol, a major player in the development of atherosclerosis.

Description of Antioxidants and Warnings on High-Dose Supplements. Antioxidant vitamins (A, C, and E), carotenoids, and many phytochemicals can neutralize free radicals. Unfortunately, although it is clear that vitamins are required to prevent deficiency diseases, high doses of vitamin C, vitamin E, and beta carotene supplements may also have pro-oxidant effects, which can be harmful in patients with cancer. In these people, high doses of antioxidant vitamins may actually protect cancer cells just as they do healthy cells.

The strongest evidence on negative effects to date comes from studies reporting an increase in lung cancer and overall mortality rates among smokers who took beta carotene supplements. In determining reasons for this disturbing effect, one animal study suggested that beta carotene increased enzymes in the lungs that actually promote cancerous changes. One study also reported a higher risk for cancer in male smokers who took multivitamins plus A, C, or E.

Some evidence also indicates that high doses of vitamin C may speed up atherosclerosis, or hardening of the arteries. In one study, women with heart disease who took antioxidant vitamins had a higher risk for heart attack or death than those who didn't take one.

Another study also reported a higher incidence and greater severity of respiratory infections in older adults who took 200 mg of vitamin E daily. Some researchers speculate that certain immune factors generate oxidants to fight bacteria. This antioxidant vitamin, then, may block that action. Research published in 2005 suggests that those who take large amounts of vitamin E (1,500 IU/day) may slightly increase their risk for heart failure and death, but this evidence is not considered conclusive. Further study is necessary.

Vitamins and Heart Protection.

Antioxidant Vitamins A, C, and E. Deficiencies in vitamins A, C, E, and beta carotene have been linked to heart disease. All of these nutrients have antioxidant effects and other properties that should benefit the heart. A study in patients with heart failure has shown that vitamin C can work with dobutamine, a powerful intravenous medication, to strengthen the heart’s ability to contract following a heart attack. In fact, a 2005 study has found that taking high doses of vitamin E is associated with an increased risk of heart failure. In 2007, the Women’s Antioxidant Cardiovascular Study failed to find that vitamins C, E, and beta carotene could reduce the risk of heart attack, stroke, need for revascularization, or cardiovascular death in women. According to the U.S. Preventive Service Task Force, evidence is insufficient to confirm or refute the benefits of supplements of any of these vitamins in protecting against heart disease.
Folate and B12 Vitamins. Deficiencies in the B vitamins folate (known also as folic acid) and B12 have been associated with elevated blood levels of homocysteine, an amino acid that has been associated with a higher risk for heart disease, stroke, and heart failure. One study, reported lower failure rates after heart surgery in patients who took folic acid and vitamins B12 and B6. And a major 2002 study suggested that lowering homocysteine levels with folic acid would reduce the risk for heart disease by 16% and stroke by 24%. However, a 2007 trial in adults with stable coronary artery disease found that lowering homocysteine levels 33% with B vitamins and folic acid had no effect on arterial inflammation, meaning that lower levels were unlikely to offer protection against heart attack or stroke. More evidence is needed to determine whether homocysteine plays a causal role in cardiovascular disease and whether the B vitamins are protective. Folate improves blood flow through the arteries, which may be important for the heart, regardless of its effect on homocysteine. Although people with high levels of homocysteine are prone to damaging blood clots in their arteries and veins, a 2007 study found that lowering homocysteine with folic acid and other B vitamins does not reduce the incidence of blood clots in the peripheral veins (deep venous thrombosis).
Niacin. Niacin (vitamin B3) is used for lowering unhealthy cholesterol levels. Although vitamin B3 is available over the counter, it can have significant side effects. A physician should prescribe niacin in order to ensure its safety and effectiveness. [See In-Depth Report #23, Cholesterol.]

Carotenoids and Heart Protection. Studies have reported that a diet high in fruits and vegetables containing beta carotene, lycopene, and other carotenoids may reduce the risk of heart attack. A small Finish study found that a diet high in tomatoes reduced total cholesterol and LDL ("bad") cholesterol. Diets low in lycopene (particularly from tomatoes) were associated with a significantly higher risk of heart disease and stroke.

Atherosclerosis is a disease of the arteries in which fatty material is deposited in the vessel wall, resulting in narrowing and eventual impairment of blood flow. Severely restricted blood flow in the arteries to the heart muscle leads to symptoms such as chest pain. Atherosclerosis shows no symptoms until a complication occurs.

Phytochemicals and Heart Protection. Several phytochemicals are associated with heart protection.

Flavonoids. Certain flavonoids, found in both black and green tea, dark chocolate, onions, red wine or red grape juice, and apples, appear to be strongly heart protective. In one study, people who consumed the most flavonoids in foods had a 20% lower risk for heart disease than those with low consumption. Flavonoids may protect against damage done by cholesterol and help prevent blood clots. A number of studies have now reported heart protection from the flavonoid catechin, which is found in both black and green tea. The flavonoid resveratrol, which is found in grape skin, appears to be responsible for the well-known heart protective effects in red wine and purple grape juice.
Organosulfurs. Organosulfurs found in onions and garlic have been under investigation for possible beneficial effects on cholesterol levels. One study reported an association between taking garlic capsules and significantly lower cholesterol-build up in the arteries of older women but not in older men. In the study, daily garlic supplements dramatically reduced the build-up of newly formed plaque in the arteries, while having much less effect on older, harder plaque deposits. Garlic supplements for cardiovascular disease may be most beneficial when used during earlier years among men and later years among women.
Isoflavones. Soy protein is the most studied source of isoflavones (known as phytoestrogens, or plant estrogens). Not all studies are consistent, but the majority has shown an improvement in at least one of the cholesterol components in people who consumed at least 25 grams of soy protein. A 2007 meta-analysis of all soy protein studies performed from 1990 - 2006 found that soy protein significantly decreased total cholesterol and LDL cholesterol, but had no effect on HDL or triglycerides. The effect was particularly evident in people with hypercholesterolemia. A 2007 study found that 12 weeks of soy supplement lowered total cholesterol and LDL levels in both Caucasian and African-American postmenopausal women. Soy may also reduce other heart risk factors, at least in certain populations. For example, in one 2002 study, soy was beneficial for controlling blood sugar and lowering LDL in postmenopausal women with type 2 diabetes. In a 2007 study of overweight men and postmenopausal women, soy protein reduced blood pressure and arterial stiffness. In another study, soy protein was associated with lower systolic blood pressure in men. The best sources are soy products (tofu, soy milk) or whole soy protein. Powdered soy protein that contains at least 60 mg of isoflavones may provide similar benefits.
Sterols. The plant sterols, including sitosterol, are also proving to be potent cholesterol fighters by blocking the absorption of cholesterol in the intestine. Sitostanol, a derivative of sitosterol, is being used in new margarine products to lower cholesterol levels. Sterols and stanols are now found in breads, cereals, yogurt, and fruit juices.

A healthy diet rich in fruits and vegetables and low in salt and saturated fats may significantly lower the risk for a first stroke, perhaps by helping to protect against high blood pressure -- a major risk factor for stroke.

Vitamins and Stroke Protection. The effects of antioxidant vitamins and carotenoids on stroke, dementia, or both are being studied. Studies are conflicting, however. A 2007 study of 8,171 women with cardiovascular disease reported that vitamins C, E, and beta carotene offered no protection against heart attack and stroke.

The B vitamin folate (usually in the form of folic acid) may protect against stroke. However, exactly which people benefit from this therapy has yet to be determined. Studies have suggested that people who have higher blood levels of folate have a lower than average risk for stroke. Its primary benefit in this case appears to be to reduce levels of homocysteine, an amino acid that has been strongly linked to an increased risk of coronary artery disease, stroke, and Alzheimer's disease. A 2007 meta-analysis of 8 trials found that folate supplements decreased homocysteine 20% and lowered stroke risk 18%. Interestingly, lowering homocysteine with folic acid and B vitamins had no effect on heart attack, strokes, amputations, need for dialysis, or death in patients with chronic or end-stage kidney disease.

Carotenoids and Stroke Protection. Some, but not all, studies have reported a lower risk of stroke from carotenoids, including beta carotene and lycopene.

Many fresh fruits and vegetables contain chemicals that may fight many cancers, including lung, breast, colon, and prostate cancers. Examples of important cancer fighting foods include the following:

Cruciferous vegetables (such as cabbage, Brussels sprouts, and broccoli)
Tomatoes (which contain lycopene)
Carrots (which contain alpha carotene)

Some evidence suggests that antioxidants may enhance the anticancer effects of chemotherapy. In multiple studies, patients who maintained their antioxidant levels were better able to withstand the high stress caused by chemotherapy or radiation therapy compared to those with low antioxidant levels. Antioxidant nutrients that may help reduce the side effects of chemotherapy include vitamins E and C, beta carotene, genistein and daidzein (isoflavones found in soy), and quercetin (found in red wine an purple grape juice).

Any protective effects of vitamins or specific phytochemical against cancer, however, appear to depend on the cooperative effort among them. Individual supplements of any vitamin or food chemical have not as yet shown any benefits.

Additionally, certain supplements may actually encourage tumor growth, particularly when taken in large amounts. Two 2007 studies found a connection between folate supplements and colorectal cancer. In one study, which was designed to evaluate the benefits of folic acid in patients who had previous colorectal adenomas (precancerous polyps), the researchers instead found that folic acid was associated with a higher risk of having 3 or more adenomas and noncolorectal cancers. In another study, it was noted that the downward trend in colorectal cancer diagnoses abruptly started to rise in 1996 when mandatory folate enrichment of grains within the U.S. and Canada began. Rates continue to exceed pre-1996 levels. Additionally, a large 2007 National Cancer Institute/AARP study found an increased risk of advanced and fatal prostate cancer in men who took more than 7 multivitamins a week, but no association between multivitamin use and localized prostate cancer.

High consumption of cruciferous vegetables (at least once per week) was associated with lower risk of kidney cancer, and low consumption (less than once per month) of cruciferous vegetables was associated with higher risk of kidney cancer in a multinational 2007 European study. Cruciferous vegetables also appear to offer protection against head and neck cancer resulting from chemical toxins found in cigarettes and alcohol, for example.

Vitamins and Cancer Protection. Because many cancers are thought to be initiated by the effects of oxygen-free radicals on DNA, the antioxidants A, C, and E and beta carotene have been intensively studied. A major study found that men who took selenium for 6 or 7 years reduced their risk of prostate cancer by 52%. Nevertheless, most individual supplements have not been proven to protect against cancer, and high doses may be dangerous.

A 2007 review of the diets of men exposed to asbestos found a decreased risk of prostate cancer associated with increasing intakes of vitamin C-rich vegetables, but not fruits and vegetables high in vitamin A. The chemopreventive role of silymarin (Silybum marianum), found in milk thistle extract, has been extensively studied and has shown anticancer efficacy against various cancers, especially prostate and skin, by inhibiting UVB radiation.

A review of 13 cancer registries found 416,134 cases of skin cancer and 3,776,501 cases of non-skin cancer as a first cancer. Rates from cancer registries in sunny countries (such as Australia and Spain) and less sunny countries (such as Canada and Iceland) were compared. The researchers concluded that vitamin D production in the skin decreases the risk of several solid cancers, especially stomach, colorectal, liver and gallbladder, pancreas, lung, female breast, prostate, bladder, and kidney cancers. The apparently protective effect of sun exposure against second primary cancer is more pronounced after non-melanoma skin cancers than melanoma.

Consumption of aflatoxins, a common fungus-related toxin infecting cereal grains, oil seeds, spices, tree nuts, and the milk of animals fed contaminated feed, is known to cause hepatocellular carcinoma, a deadly form of liver cancer. Rodent studies have shown that phenolic antioxidants, dithiolethiones, isothiocyanates, and triterpenoids may act as chemopreventive agents, dispersing aflatoxins and protecting against hepatocellular carcinoma. Human trials are planned. A similar study found that several isothiocyanates, diallyl sulfide, and polyphenolic compounds can prevent esophageal dysplasia from progressing to squamous cell carcinoma.

A review of all articles on vitamins and cancer published through February 2007 found that multivitamin/mineral supplement use may prevent cancer in individuals with poor or suboptimal nutritional status. One trial on poorly nourished Chinese showed supplementation with combined Beta-carotene, vitamin E and selenium reduced gastric cancer incidence and mortality, and overall cancer mortality. In a French trial, combined vitamin C, vitamin E, beta-carotene, selenium, and zinc reduced cancer risk in men but not in women. With few exceptions, neither beta-carotene nor vitamin E had benefits for preventing cancer. Beta-carotene supplementation increased lung cancer risk in smokers and persons exposed to asbestos.

A 2007 study of nearly 82,000 men and women in Sweden found that high intake of methionine was associated with reduced risk of pancreatic cancer. The same relationship was not seen with vitamin B6 or folate.

Vitamin A, C, and E. Although some studies have reported an association between low blood levels of these antioxidant vitamins and a higher risk for cancer, supplements of vitamins A, C, and E appear to have few advantages in most cases. And there are some studies finding higher cancer risks with high intakes of antioxidants. For example, a 2003 study reported a higher risk in melanoma in people with vitamin-C rich diets. Another study also reported a higher risk for cancer in male smokers who took multivitamins plus A, C, or E. (Vitamin E may be protective against bladder cancer and ovarian cancer.)
Vitamin D. Some studies have suggested that certain vitamin D compounds may inhibit certain cancer cells, specifically prostate cancer, from proliferating. More research is needed. In 2007, the National Cancer Institute confirmed that ultraviolet (UV) radiation exposure may reduce the risk of developing non-Hodgkin lymphoma (NHL), but only in patients with certain variations in the D vitamin receptor gene. A second 2007 study found that variations in this gene increase the risk of diffuse large B-cell lymphoma. A 2007 prospective analysis of 31,500 women in the Women’s Health Study evaluated calcium and vitamin D intake. The researchers found a moderately lower risk of premenopausal, but not postmenopausal, breast cancer with higher intakes of total calcium and vitamin D. A 2007 review of breast cancer cases reported in Ontario, Canada, found reduced breast cancer risks were associated with increasing sun exposure in women ages 10 - 19, less evidence for associations in women ages 20 - 29, and no evidence for ages 45 - 54. Researchers concluded that sun exposure earlier in life, particularly during breast development, may be key in the connection between vitamin D exposure and breast cancer risk.
Folic acid and B12. These B vitamins convert the amino acid homocysteine to methionine, a substance that helps prevent cells from becoming malignant. Folic acid may provide some protection against cervical and colon cancer. One small study showed a reduction of lung cancer cells in smokers taking folic acid and vitamin B12, but the study was very small, of short duration, and other factors might have biased the results. Still another study reported that folic acid may reduce the risk for breast cancer among women who regularly drink alcohol. (In the study, folic acid had no other effect on breast cancer.)

In 2006, a study for the National Institutes of Health reviewed randomized trials evaluating the effectiveness and safety of multivitamin and mineral supplements in preventing cancer and chronic disease. The studies had mixed results, and some supplements reduced cancer rates in certain populations. However, the reviewers concluded that current evidence is not sufficient to determine whether multivitamin and mineral supplements may prevent cancer and chronic disease.

Carotenoids and Cancer Protection. A number of studies have reported that fruits and vegetables rich in carotenoids are associated with protection against many cancers. Lycopene, found in tomatoes, may have particular value in protection against prostate, colon, lung, and bladder cancer. A 2005 study found that in one out of four men with genetic variations that cause them to be more sensitive to oxidative stress, supplementation with selenium, vitamin E, and lycopene significantly reduces the risk of prostate cancer. Individual supplements, however, do not offer any advantage. In fact, evidence now strongly suggests that beta carotene supplements increase the risk for lung cancer in smokers and people exposed to asbestos

Phytochemicals and Cancer Protection. The following phytochemicals appear to have cancer-protecting properties.

Isothiocyanates. Isothiocyanates and sulforaphane, found in cruciferous vegetables, may block the effects of carcinogens and suppress tumor growth. In one study, for example, women with the highest consumption of cruciferous vegetables had a 24% lower risk of breast cancer than women with the lowest consumption.
Isoflavones. Isoflavones, found in soy beans and flax seed, behave like estrogen in some ways and not in others. Researchers are very interested, then, in their effects on hormone-related cancers, including breast and prostate cancers. Much research has focused on soy. In general, a number of Asian studies have reported an association between a higher intake of soy and a lower incidence of reproductive and breast cancers. The effects of phytoestrogens, however, in all women are far from settled. Some evidence suggests the genistein in soy may have properties that are protective against lung cancer. Nonfermented soy products (tofu, soy milk) also may protect against stomach cancer, while fermented soy products (miso, soy paste) appears to increase the risk.
Organosulfurs. The organosulfur compounds found in the onion and garlic family may have very potent properties in suppressing or blocking carcinogenic substances. A 2007 study found that synthetic organosulfur compounds act as selective inhibitors of growth in breast cancer cells. Studies indicate that people who regularly consume fresh or cooked garlic have about half the risk of developing stomach cancer and two thirds the risk of colorectal cancer as people who eat little or no garlic. One possible explanation for garlic's anti-cancer effect in the stomach is its antibacterial action against H. pylori, which can promote stomach cancer. Taking garlic supplements, however, did not offer these benefits.

It should be noted that studies on the health benefits of vitamins and minerals have some important limitations. Some are held to rigorous standards, while others are not. In most cases, the results of existing research are complex, as they can easily be complicated by factors such as diet, exercise, the presence of healthy or unhealthy lifestyle behaviors, environmental factors, and more.


Disease or Condition	Vitamins	Carotenoids, Phytochemicals, and Healthy Foods
Alzheimer's Disease	Vitamin E. Some reports, including a large 2002 population study, have suggested that vitamin E intake, from food or supplements, may protect against mental decline. (One study suggested that the vitamin protected only those who carried the apoE4 gene. No strong evidence to date has found any protection from antioxidant supplements.) Some studies performed since 2002 challenge this finding, while others agree with it. B Vitamins. Some studies suggest that deficiencies of the B vitamins B6, B12, and folate may be a risk factor for Alzheimer' diseases, possibly because deficiencies elevate homocysteine levels, which some research now associated with a higher risk for Alzheimer's disease. Of these, folates may offer the best protection. In 2007, researchers at Tufts-New England Medical Center reviewed all human studies on folate, vitamin B-6, vitamin B-12, and cognitive function in the elderly conducted between 1966 and November 2006. Six of 10 folate studies reported a significant association between low baseline blood folate concentrations and poor cognitive test performance; 4 of 9 folate studies found associations between low blood folate concentrations and increased prevalence of Alzheimer's disease. No association between vitamin B-6 and vitamin B-12 blood concentrations and cognitive-test performance or Alzheimer's disease was seen, and B-vitamin dietary intake was not associated with cognitive function. Although the majority of studies indicated that low blood folate concentrations predicted poorer cognitive function, data are not solid, due to variations in the way the studies were conducted and lack of agreement on what constitutes a low B-vitamin status.	According to several studies, eating plenty of darkly colored fruits and vegetables may slow brain aging. The estrogen-like properties in isoflavones are of interest in the study of Alzheimer's disease. Animal studies suggest that soy might be protective against AD, particularly in postmenopausal women. Of some concern, however, were one population and a few animal studies suggesting that soy intake may pose a risk for greater mental decline among older men. More research is needed to confirm the effects of soy on the aging brain and to determine if there are gender differences.
Infectious Disease	Studies are mixed whether vitamin supplements protect against upper respiratory infections. Large doses of vitamin C, for example, may help reduce the duration of a cold, but they do not appear to protect against one in the first place, even after exposure to a cold virus. Two studies in 2002 on multivitamins reported opposite results, with one finding fewer infections and one finding no difference. It is possible that vitamin C or multivitamin supplements may be helpful in specific people, such those who are vitamin deficient or have medical problems that impair their immune systems. A review of all studies on vitamin C and pneumonia prevention found only 1 placebo-controlled, randomized trial conducted in an English boarding school during World War II. The trial found a statistically significant (80% or greater) reduction in pneumonia incidence among boys consuming vitamin C. Two less-well-constructed trials arrived at the same conclusion. Therapeutic trials were even scarcer. Only one randomized, double-blind, placebo-controlled study of vitamin C for treatment of pneumonia was found. In this trial, elderly patients given vitamin C had lower mortality and respiratory symptom scores. However, the benefits were restricted to the sickest patients. One other trial of adults in the former Soviet Union found a dose-dependent reduction in the time to recover with two vitamin C doses. One 2007 study on vitamin D found that a single dose by mouth of this vitamin might prevent healthy individuals from activating the bacterium that causes tuberculosis in patients who harbor the infection. Studies on vitamin E specifically have been mixed. A 2002 study, in fact, reported a higher incidence and greater severity of respiratory infections in older adults who took 200 mg of vitamin E daily. However, a 2004 clinical trial conducted among elderly nursing home residents found that daily supplementation with 200 IU of vitamin E did provide protection from upper respiratory infections, especially the common cold. At present, there is not enough evidence to recommend vitamin E for infection prevention. Diarrhea is a worldwide problem, particularly in developing countries and those with poor sanitation. Taking supplements with B-complex vitamins, vitamin C, vitamin E, and selenium may reduce the risk of diarrhea, depending upon the organism that causes the disease. Meanwhile, iron supplements appear to increase the risk of infection from organisms that cause diarrhea. Vitamin A has not been shown to prevent diarrhea. Urinary tract infections (UTIs) may affect as many as 25% of pregnant women. A 2007 study found that women who took vitamin C (100 mg) for 3 months had significantly fewer UTIs than women who did not take vitamin C supplements. Rotavirus is a common cause of acute gastric pain in children under age 5. A 2007 study showed that the high amount of isoflavones found in soy-based infant formula can help prevent rotavirus infection.	Lycopene, found in tomatoes, appears to have properties that protect infection-fighting white blood cells. Saponins extracted from ginseng and allicin (found in garlic) have properties that boost the immune system. Both ginseng and garlic have long been traditionally used for their health benefits.
Asthma	Vitamin C from diet has been associated with lower risk for asthma. In one study, some people with exercise-induced asthma benefited from taking vitamin C one hour before strenuous physical activity. In a 2007 study, taking 1,500 mg supplements of vitamin C for 2 weeks helped prevent exercise-induced airway narrowing in patients with asthma.	Flavonoids found in apples and red wine may help lower the risk for asthma. Some evidence indicates that a low dietary intake of antioxidant nutrients could increase the risk for lung damage. Such nutrients should be obtained from fresh, deep green and yellow-orange fruits and vegetables. A 2007 study found low blood lycopene levels in people with asthma. Increasing lycopene- and vitamin A-rich foods may help raise lycopene levels.
Eye Disorder	Cataracts and Macular Degeneration. Oxygen-free radicals play a role in cataract formation and age related macular degeneration, the most common cause of irreversible blindness in the elderly. Bilberry (Vaccinium myrtillis), which contains powerful anthocyanins, is widely used to prevent macular degeneration. Low levels of vitamin C in the lens of the eye have been particularly strong predictors of cataracts. People with cataracts are frequently deficient in vitamin A, the carotenes, lutein, and zeaxanthin. Studies on protection against cataracts using antioxidant supplements have been mixed, including two identically conducted studies that reported opposite results. Vitamin C currently has the strongest evidence for protection, but even with this antioxidant studies are not consistent. A combination of zinc and antioxidants, including vitamin C and E, may slow the progression of macular degeneration. (Vitamin E alone does not appear to be protective.) Glaucoma. Although no evidence exists that antioxidants will prevent glaucoma, some studies reported an association between vitamin E and improved visual fields in patients with glaucoma.	Several studies report that the consumption of antioxidant-rich foods is associated with a decreased risk for cataracts. Carotenoids, especially lutein, lycopene, and zeaxanthin, are especially eye-protective and may help prevent cataracts and macular degeneration. The National Eye Institute in 2007 suggested that people with intermediate- or advanced macular degeneration in one eye may want to take a vitamin formula shown to reduce the risk of macular degeneration in the other eye by 25%. The formula contains vitamin C, vitamin E, beta-carotene, and zinc. They also suggest that a diet high in lutein and zeaxanthin may help reduce the risk of advanced age-related macular degeneration. Several studies report that the consumption of antioxidant-rich foods is associated with a decreased risk for cataracts. Carotenoids, especially lutein lycopene, and zeaxanthin are especially eye-protective and may help prevent cataracts and macular degeneration.
Skin Disorders and Wrinkles	Topical vitamin A (retinol) has been shown to improve fine wrinkles due to aging, by increasing glycosaminoglycan, which retains water, and increasing collagen production. One small study found that taking a combination of vitamins oral C and E supplements may help reduce sunburn reactions, although the protection is much less than from sunscreens. Taking the vitamins singly did not have any effect. In fact, a 2002 study reported that oral vitamin C had no effect on sunburn reaction. Of concern, in the same study some natural antioxidants in the body were reduced in people who took the vitamin. Also of concern are studies reporting no benefits and possibly harm from topical vitamin C in the form of ascorbyl palmitate, which is soluble in fat. One study reported that older adults had fewer wrinkles if they ate whole grains, fresh fruits and vegetables, and the use of healthy oils (such as olive oil). Diet played a role in improving skin regardless of whether the people in the study smoked or lived in sunny countries.	The following foods and phytochemicals may be especially skin protective: Both green tea and ginger appear to have properties that may provide some protection against skin cancer. Green tea skin care products are now available. The substance silymarin, found in the milk thistle family (which includes artichokes), may inhibit UVB-promoted cancers in animals. In one interesting study, eating garlic protected animals very effectively against UVB damage by interfering with urocanic acid in the skin. Whether these results may apply to humans (and what quantities of garlic might be beneficial) is still unknown.
Osteoporosis	Vitamin D. Vitamin D is the essential companion to calcium in maintaining strong bones. Supplements may be needed for people who have poor exposure to sunlight. It should be noted that diet supplies most people's need and high amounts of vitamin D can be toxic. Of interest: Taking vitamin D supplements does not prevent bone loss in post-menopausal African American women, according to research published in 2005. Further study will be needed to determine whether vitamin D prevents bone loss in women from other ethnic groups. Vitamin K. Studies suggest that vitamin K has properties that protect bone and prevent fracture. Vitamin K2 (menatetrenone), a form of vitamin K, is proving to prevent fractures in people with osteoporosis. Vitamin K affects blood clotting, and supplements are not recommended without specific physician instruction. Vitamin B12. One study reported that in people with osteoporosis and pernicious anemia, taking vitamin B12 (which is used to treat the anemia) also increased bone density. Vitamin C and E. There has been some indication of a positive association between vitamin C and E intake and bone density, although evidence proving actual benefits is weak. Note on Vitamin A. High amounts of dietary vitamin A reduces bone density and may even increase the risk for fracture in both postmenopausal women and men. (A form of vitamin A, retinoic acid, has been found to stimulate bone break down.) Beta carotene does not appear to increase risk. Studies suggest that diets rich in fresh fruits and vegetables (which include those high in potassium and magnesium) reduce elimination of calcium from the body and help preserve bones.	Studies suggest that diets rich in fresh fruits and vegetables (which include those high in potassium and magnesium) reduce elimination of calcium from the body and help preserve bones. Studies are suggesting that isoflavones-rich soy products may actually improve bone density in postmenopausal women. A 2007 study of postmenopausal women in Italy found that 24 months of treatment with genistein plus calcium and vitamin D increased bone density, while women who took calcium and D alone lost bone density. Flavonoids and other compounds in tea may protect the bones.
Menstrual Disorders	Vitamin B6. Limited clinical evidence suggests that vitamin B6 may be beneficial in reducing premenstrual symptoms, including depression. Typically, women take 100 mg per day, although one study suggested that a lower dose (50 mg) may have the same effect. Other preliminary research indicates that women who receive the equivalent of 1,200 mg of calcium and 400 IU of vitamin D per day (through food or supplements) have a significantly lower incidence of premenstrual symptoms than women who did not. Vitamin B1. One study reported relief from menstrual pain using vitamin B1 (thiamin). Vitamin E. Several randomized controlled trials have shown that vitamin E significantly improves both physical and emotional premenstrual symptoms. One study reported that high doses of vitamin E helped reduce menstrual cramps. The doses were much higher than those recommended and could possibly increase the risk for bleeding. Although anecdotal evidence reports that vitamin E helps reduce the frequency of hot flashes for menopausal women, there is no clinical evidence to support this claim.

Resources

http://fnic.nal.usda.gov -- The Food and Nutrition Information Center
http://dietary-supplements.info.nih.gov -- Office of Dietary Supplements, National Institutes of Health
www.ars.usda.gov/ba/bhnrc/ndl -- Nutrient Data Laboratory
www.fda.gov -- Food and Drug Administration
www.eatright.org -- The American Dietetic Association
www.acsh.org -- American Council on Science and Health
www.aicr.org -- American Institute for Cancer Research
www.nutritiondata.com -- Information on vitamins and nutrients in foods
www.consumerlab.com -- Independent testing of nutritional supplements' contents and quality
www.usp.org -- US Pharmacopeia
www.herbs.org -- Herb Research Foundation

References

Age-Related Eye Disease Study Research Group, SanGiovanni JP, Chew EY, Clemons TE, Ferris FL 3rd, Gensler G, Lindblad AS, Milton RC, Seddon JM, Sperduto RD. The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22. Arch Ophthalmol. 2007;125(9):1225-1232.

Ambrosini GL, de Klerk NH, Fritschi L, Mackerras D, Musk B. Fruit, vegetable, vitamin A intakes, and prostate cancer risk. Prostate Cancer Prostatic Dis. 2007 May 22; [Epub ahead of print]

Aubertin-Leheudre M, Lord C, Khalil A, Dionne IJ. Six months of isoflavone supplement increases fat-free mass in obese-sarcopenic postmenopausal women: a randomized double-blind controlled trial. Eur J Clin Nutr. 2007 Feb 21; [Epub ahead of print]

Bermudez Y, Ahmadi S, Lowell NE, Kruk PA. Vitamin E suppresses telomerase activity in ovarian cancer cells. Cancer Detect Prev. 2007;31(2):119-28. Epub 2007 Feb 28.

Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM. Maternal vitamin d deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab. 2007 ;92(9):3517-22. Epub 2007 May 29.

Clements RH, Katasani VG, Palepu R, Leeth RR, Leath TD, Roy BP, Vickers SM. Incidence of vitamin deficiency after laparoscopic Roux-en-Y gastric bypass in a university hospital setting. Am Surg. 2006;72(12):1196-202.

Coull DB, Tait RC, Anderson JH, McKee RF, Finlay IG. Vitamin B12 deficiency following restorative proctocolectomy. Colorectal Dis. 2007;9(6):562-566.

Dietary Guidelines for Americans 2005. Dept of Health and Human Services, US Dept of Agriculture. Accessed 10/3/2007.

Fischer Walker CL, Black RE. Micronutrients and diarrheal disease. Clin Infect Dis. 2007;45 Suppl 1:S73-S77.

Glynn RJ, Ridker PM, Goldhaber SZ, Zee RY, Buring JE. Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism: report from the Women's Health Study. Circulation. 2007;116(13):1497-503.

Headstrom PD, Rulyak SJ, Lee SD. Prevalence of and risk factors for vitamin B(12) deficiency in patients with Crohn's disease. Inflamm Bowel Dis. 2007 Sep 20; [Epub ahead of print]

Inderjeeth CA, Glennon D, Petta A, Soderstrom J, Boyatzis I, Tapper J.Vitamin D and muscle strength in patients with previous fractures. N Z Med J. 2007;120(1262):U2730.

Ishihara J, Otani T, Inoue M, Iwasaki M, Sasazuki S, Tsugane S; Japan Public Health Center-based Prospective Study Group. Low intake of vitamin B-6 is associated with increased risk of colorectal cancer in Japanese men. J Nutr. 2007;137(7):1808-1814.

J.G. Ray, C. Kearon, Q. Yi, P. Sheridan, and E. Lonn, for the Heart Outcomes Prevention Evaluation 2 (HOPE-2) Investigators. Randomized Trial of Homocysteine-Lowering Therapy and Risk for Venous Thromboembolism. Ann Intern Med. 2007;146(11):761-767.

Kitchin B, Morgan SL. Not just calcium and vitamin D: other nutritional considerations in osteoporosis. Curr Rheumatol Rep. 2007;9(1):85-92.

Kune G, Watson L. Colorectal cancer protective effects and the dietary micronutrients folate, methionine, vitamins B6, B12, C, E, selenium, and lycopene. Nutr Cancer. 2006;56(1):11-21.

Lim MR, Huang RC, Wu A, Girardi FP, Cammisa FP Jr. Evaluation of the elderly patient with an abnormal gait. J Am Acad Orthop Surg. 2007;15(2):107-117.

Martin H, Lindblad B, Norman M. Endothelial function in newborn infants is related to folate levels and birth weight. Pediatrics. 2007;119(6):1152-1158.

Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G, Rosenberg IH. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev. 2007;16(7):1325-1329.

Nardin RA, Amick AN, Raynor EM. Vitamin B(12) and methylmalonic acid levels in patients presenting with polyneuropathy. Muscle Nerve. 2007;36(4):532-535.

Ochoa-Brust GJ, Fernández AR, Villanueva-Ruiz GJ, Velasco R, Trujillo-Hernández B, Vásquez. Daily intake of 100 mg ascorbic acid as urinary tract infection prophylactic agent during pregnancy. Acta Obstet Gynecol Scand. 2007;86(7):783-787.

Parekh N, Chappell RJ, Millen AE, Albert DM, Mares JA. Association between vitamin D and age-related macular degeneration in the Third National Health and Nutrition Examination Survey, 1988 through 1994. Arch Ophthalmol. 2007;125(5):661-669.

Pham DQ, Plakogiannis R. Vitamin E supplementation in Alzheimer’s disease, Parkinson’s disease, tardive dyskinsia, and cataract: Part 2. Ann Pharmacother. 2005;39(12): 2065-2072.

Riccioni G, Bucciarelli T, Mancini B, Di Ilio C, Della Vecchia R, D'Orazio N. Plasma lycopene and antioxidant vitamins in asthma: the PLAVA study. J Asthma. 2007;44(6):429-432.

Ronnenberg AG, Venners SA, Xu X, Chen C, Wang L, Guang W, Huang A, Wang X. Preconception B-vitamin and homocysteine status, conception, and early pregnancy loss. Am J Epidemiol. 2007;166(3):304-12. Epub 2007 May 2.

Sahin M, Tutuncu NB, Ertugrul D, Tanaci N, Guvener ND. Effects of metformin or rosiglitazone on serum concentrations of homocysteine, folate, and vitamin B12 in patients with type 2 diabetes mellitus. J Diabetes Complications. 2007;21(2):118-123.

Tamori A, Habu D, Shiomi S, Kubo S, Nishiguchi S. Potential role of vitamin K(2) as a chemopreventive agent against hepatocellular carcinoma. Hepatol Res. 2007;37 Suppl 2:S303-307.

Tecklenburg SL, Mickleborough TD, Fly AD, Bai Y, Stager JMAscorbic acid supplementation attenuates exercise-induced bronchoconstriction in patients with asthma. Respir Med. 2007;101(:1770-1778.

Triantafyllou NI, Kararizou E, Angelopoulos E, Tsounis S, Boufidou F, Evangelopoulos ME, Nikolaou C, Vassilopoulos D. The influence of levodopa and the COMT inhibitor on serum vitamin B12 and folate levels in Parkinson's disease patients. Eur Neurol. 2007;58(2):96-99.

Vagianos K, Bector S, McConnell J, Bernstein CN. Nutrition assessment of patients with inflammatory bowel disease. J Parenter Enteral Nutr. 2007;31(4):311-319.

Velasquez MT, Bhathena SJ. Role of dietary soy protein in obesity. Int J Med Sci. 2007; 4(2):72-82.

Wang Y, Hodge AM, Wluka AE, English DR, Giles GG, O'sullivan R, Forbes A, Cicuttini FM. Effect of antioxidants on knee cartilage and bone in healthy, middle-aged subjects: a cross-sectional study. Arthritis Res Ther. 2007;9(4):R66 [Epub ahead of print]

Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y, Sun N, Liu L, Xu X. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet. 2007;369(9576):1876-1882.

Weingärtner J, Lotz K, Fanghänel J, Gedrange T, Bienengräber V, Proff P. Induction and Prevention of Cleft Lip, Alveolus and Palate and Neural Tube Defects with Special Consideration of B Vitamins and the Methylation Cycle. J Orofac Orthop. 2007; 68(4):266-277.

Wierzbicki AS. Homocysteine and cardiovascular disease: a review of the evidence. Diab Vasc Dis Res. 2007;4(2):143-50.

Zeisel SH. The fetal origins of memory: the role of dietary choline in optimal brain development. J Pediatr. 2006;149(5 Suppl):S131-136.

Ziaei S, Kazemnejad A, Zareai M. The Effect of Vitamin E on Hot Flashes in Menopausal Women. Gynecol Obstet Invest. 2007;64(4):204-207 [Epub ahead of print]

Zollinger PE, Tuinebreijer WE, Breederveld RS, Kreis RW. Can vitamin C prevent complex regional pain syndrome in patients with wrist fractures? A randomized, controlled, multicenter dose-response study. J Bone Joint Surg Am. 2007;89(7):1424-1431.

Review Date:
10/29/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Non-Hodgkin's lymphoma

FitSugar — Wed, 08 Oct 2008 17:35:06 -0700

In This Report

Highlights
Introduction
Risk Factors
Symptoms
Diagnosis
Outlook
Staging and Treatment Guide...
Chemotherapy
Biologic Therapy (Immunothe...
Radiation
Transplantation
Surgery
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Warning

Chemotherapy can cause anemia, a drop in red blood cell (hemoglobin) levels. Erythropoiesis-stimulating drugs, which boost the production of red blood cells, are administered to counteract this complication. However, these drugs, which include epoietin alfa (Epogen, Procrit) and darbepoietin alfa (Aranesp), can also cause serious side effects and adversely affect survival when hemoglobin levels are raised too high.

In 2007, the U.S. Food and Drug Administration (FDA) made several changes to the prescribing labels for erythropoiesis-stimulating drugs. The new labels have stronger warnings and updated dosing-related safety information.

The FDA advises that for treating anemia associated with chemotherapy, dosing should increase hemoglobin levels to no more than 12 g/dL. Treatment with these drugs should stop as soon as the chemotherapy course is completed. Erythropoiesis-stimulating drugs are not safe or appropriate for all patients undergoing chemotherapy. Patients should discuss the risks and benefits with their oncologists. The FDA is currently reviewing additional data concerning the safety of these drugs.

Positron Emission Tomography (PET) Scans and Lymphoma

PET scans are used to help diagnose and stage lymphoma, and they may also be helpful in assessing treatment outcomes for some types of lymphoma. In 2007, an international team of cancer specialists drew up new guidelines for evaluating how well lymphoma responds to treatment in clinical trials. The guidelines now recommend that PET scans be used to help determine if a patient has achieved remission.

Introduction

Lymphomas are malignancies of the lymph system that are generally subdivided into two groups, Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Hodgkin's disease accounts for about 15% of all lymphomas. [For more information, see In-Depth Report #83: Hodgkin's disease.]

Non-Hodgkin's lymphomas is a term for malignancies that range from a very slow disease to an extremely aggressive but curable condition. They have certain features in common.

The lymphatic system filters fluid from around cells. It is an important part of the immune system. When people refer to swollen glands in the neck, they are usually referring to swollen lymph nodes. Common areas where lymph nodes can be easily felt, especially if they are enlarged include the groin, armpits (axilla), above the clavicle (supraclavicular), in the neck (cervical), and the back of the head just above hairline (occipital).

Lymphomas, such as non-Hodgkin's lymphomas and Hodgkin's disease, represent tumors of the lymphatic system. This system is a network of organs, ducts, and nodes. The system interacts with the blood's circulatory system to transport a watery clear fluid called lymph throughout the body. The lymphatic system contains lymphocytes, important cells involved in defending the body against infectious organisms. This system also restores 60% of the fluid that leaks out from blood capillaries back into circulation, and its ducts provide transportation for fats, proteins, and other substances collected from the body's tissues.

Lymphocytes. The lymphatic system is involved in the production and transportation of lymphocytes, white blood cells that are a primary component of the immune system. Among other vital functions, certain lymphocytes are responsible for producing antibodies, factors that can target and attack specific foreign proteins (antigens). To understand the lymphatic system, it is helpful to track part of the life cycle of these lymphocytes:

Lymphocytes develop in the bone marrow or thymus gland and are therefore categorized as either B cells (bone marrow-derived cells) or T cells (thymus gland-derived cells).
B cells complete their structural growth and definition (known as differentiation) and mature in the bone marrow.
T cells also start out in the bone marrow but differentiate and mature in the thymus gland, located beneath the breastbone (sternum). This small gland is active mostly in the fetal stage through the first 10 years of life, after which it atrophies (shrinks).
B-cell and T-cell lymphocytes leave these organs through the bloodstream, which eventually branches out into the tiny blood vessels called capillaries.
Some lymphocytes, along with fluid, proteins, and other substances, migrate out of the capillaries into the surrounding tissues. A proportion of these lymphocytes and other substances then enter the lymphatic vessels.
Lymphatic vessels begin as tiny, blind-ended tubes and lead to larger lymphatic ducts and branches until they drain into two ducts in the neck, where the fluid re-enters the bloodstream.
Along the way, the fluid passes through lymph nodes, oval structures composed of lymph vessels, connective tissue, and white blood cells. Here, the lymphocytes are either filtered out or added to the contents of the node.

Lymph Nodes. In the lymph node, lymphocytes receive their initial exposure to foreign substances (antigens), such as bacteria or other microorganisms, activating the lymphocytes to perform their immune functions. The size of a lymph node varies generally from that of a pinhead to a bean. Most nodes are in clusters located throughout the system. Important node clusters are found in the neck, lower arm, armpit, and groin.

Other Structures in the Lymphatic System. The tonsils and adenoids are secondary organs composed of masses of lymph tissue that also play a role in the lymphatic system. The spleen is another important organ that processes lymphocytes from incoming blood.

Click the icon to see an animation about lymph nodes.

Click the icon to see an image of lymph nodes in the head and neck.

Click the icon to see an image of the immune system structures.

Non-Hodgkin's lymphomas occur most often in lymph nodes in the chest, neck, abdomen, tonsils, and the skin. NHLs may also develop in sites other than lymph nodes such as the digestive tract, central nervous system, and around the tonsils.

About 85% of non-Hodgkin's lymphomas (NHLs) arise in B cells; the rest occur in T cells. Activation of a gene called BCL-2 is believed to be partly responsible for many B-cell lymphomas. This defect prevents apoptosis (a natural process whereby cells self-destruct) in the lymphoma cells.

There are more than 20 distinct types of non-Hodgkin's lymphomas. Most first arise in the lymph nodes, but about 20 - 30% of cases are now found outside the nodes, most often in the stomach, small intestine, skin, and brain.

Even experts disagree about the exact groupings. Lymphomas are categorized in a number of ways.

Classification by Cell Type, Appearance, and Genetic Make-up: The REAL System. Different classification systems for lymphoma have been proposed. The system used in this report is called REAL (Revised European-American Lymphoma Classification). It classifies all lymphomas by appearance, cell type, and genetic make-up:

Non-Hodgkin's lymphomas are first grouped as B cell or T cell.
Next, they are categorized by whether the B-cell and T-cell lymphomas were derived from immature (precursor) cells or mature (peripheral) cells.
The peripheral B and T cells are then classified by their appearance, genetic make-up, and specific chemical "markers," which further identify them.

T-cell lymphomas, Hodgkin's disease, and certain leukemias and aggressive lymphomas are covered in the REAL classification but are not discussed in any depth in this report.

Groups by Slow or Fast Growth. Each non-Hodgkin's lymphoma is further defined by its grade, or how aggressive it is:

Indolent (slow-growing), also called low-grade
Aggressive (fast-growing), also called intermediate- or high-grade

According to one report, half of new cases are now intermediate-grade lymphomas. Low-grade makes up 30%, while high-grade makes up 10% of all lymphomas.

Groups by Properties. Lymphomas are also grouped by certain properties:

Size (large versus small)
Shape (round versus irregular)
Whether they are or resemble blood plasma cells
Whether they are follicular (organized in round clusters) or diffuse (spread evenly throughout the lymph node)

Staging. Staging the disease is the next important step in classifying lymphomas. The stage (I - IV) of an NHL is determined by the number of tumors and whether they are still localized or have spread beyond the lymph node. In general, the higher the stage, the poorer the outcome, but other factors are important for a precise prognosis.

Indolent (Slow-Growing) Lymphomas (also Called Low-Grade Lymphomas)

Follicular lymphomas (FLs). Follicular small cleaved cell lymphoma (grade I) and follicular mixed small and large cell lymphoma (grade II). FLs account for 70% of indolent tumors and 20% of all NHLs in industrialized countries. It is very rare in developing countries and in Asia.

Lymphoplasmacytoid/Waldenstrom's macroglobulinemia. Often found in bone marrow, lymph nodes, and spleen. Can cause blood to become viscous and "sticky."

Marginal zone lymphomas (MZL). MZLs often occur as a result of a pre-existing disorder such as hepatitis C, bacterial infection in the stomach (H. pylori ), or an autoimmune disorder (Sjögren syndrome in the salivary glands or Hashimoto's thyroiditis in the thyroid gland). They may be classified as:

Monocytoid B-cell lymphoma, which involves only lymph nodes
Splenic marginal zone lymphoma, which affects the spleen, blood, and bone marrow
Mucosa-associated lymphoid tissue (MALT) lymphoma, which usually involves the gastrointestinal tract, thyroid, lung, breast, or skin

There is some controversy over whether MALT is a variation of MZL or a completely separate type of lymphoma that is more suitably classified as a separate low-grade lymphoma. At this time, it is classified as an MZL.

Aggressive Lymphomas (also Called Intermediate- and High-Grade Lymphomas)

Diffuse large-cell lymphomas (DL). DLs are the most common NHLs, accounting for about 40% of all cases. Subtypes include the following:

Primary mediastinal large B-cell lymphoma
Follicular large cell lymphoma
Anaplastic large cell lymphoma
T-cell lymphomas (not covered in this report)

In about 40% of cases, these DL lymphomas appear in areas outside lymph nodes, including digestive tract, skin, bone, thyroid, and testes.

Burkitt's lymphoma/diffuse, small noncleaved cell lymphoma. This is the most common childhood NHL. In African children, it often involves facial bones and is associated with Epstein-Barr infection.

Mantle cell lymphoma. Mantle cell lymphomas are found in lymph nodes, the spleen, bone marrow, blood, and sometimes the gastrointestinal system (lymphomatous polyposis). This lymphoma is similar to indolent lymphomas at the time of diagnosis, but it is more aggressive.

Lymphoblastic lymphoma. This lymphoma often occurs in young people. It is associated with a large mediastinal mass (occurring in chest cavity between the lungs) and carries a high risk for spreading to bone marrow and central nervous system.

Risk Factors

About 63,000 Americans were diagnosed with non-Hodgkin's lymphomas in 2007, and nearly 19,000 people died of the disease. For the past 25 years, the incidence in NHL has increased continuously. Most of this increase has occured in people over age 65.

Part of the reason for the dramatic rise was AIDS, which increases the risk for high-grade lymphomas. However, even after eliminating changes in diagnosing NHLs and known causes (such as AIDS), the incidence over the past 40 years is 40% higher. The number of cases in which lymphomas first occur outside the lymph nodes has also increased compared to those limited to the nodes. (This observed increase, however, may in large part be due to different methods of diagnosing lymphomas).

The cancer can develop in people at all ages, including children, although it is most common in those ages of 45 - 60. In general, the incidence of NHL is 50% higher in men than in women. This higher rate has been observed in many countries. Nevertheless, recent reports suggest that the rate is leveling off or even declining in men, but is increasing in women, particularly African-American women. Overall, the risk is slightly higher in Caucasians than in African-Americans.

The risks for NHL among men versus women and among African-Americans versus Caucasians may vary by lymphoma subtype. For example, follicular lymphomas were significantly higher in Caucasians than in African-Americans, and there was little gender difference. High-grade lymphomas were the most rapidly increasing type, particularly among men, with follicular lymphomas increasing most rapidly in African-American men.

Other studies have also reported ethnic differences by specific lymphoma subtypes. For example, follicular lymphomas constitute 20% of all NHLs in Western nations but are very uncommon in Asia and in developing countries.

The brother or sister of a person with the disease has more than twice the risk of developing NHL than the general population. Some cases of NHL in such cases are due to inherited disorders of the immune system. Studies suggest, however, that such family clusters are more likely to be due to environmental conditions that trigger the genetic factors.

Because of the rapid rise in NHL, investigators are looking for lifestyle factor that may contribute to this increase. No real association between lymphomas and body weight or shape or amounts of exercise has been found.

A number of reports suggest an influence of diet in the development of non-Hodgkin's involvements. However, for the most part a strong association remains speculative. Some of the possible dietary risk factors include:

A number of studies have observed an association between an increased risk for non-Hodgkin's lymphomas and high consumption of red meat (beef, pork, and lamb).
A higher risk for lymphoma has also been suggested for trans fatty acids (hydrogenated polyunsaturated fats, which are contained in hard margarines and commercial baked goods and fast foods). There appears to be no higher risk with natural polyunsaturated fats (found in most vegetable and fish oils).
Fish may be protective.
Some evidence suggests that milk may also be protective.
One major study observed a reduction in risk with high intake of vegetables. Another found no protection from vegetables, but did with diets rich in fruit.
Vitamin supplements have no effect on NHL.

Despite these kinds of reports, the influence of diet on the development of non-Hodgkin's lymphomas remains speculative.

Alcohol Use. Studies on alcohol have been mixed, with some showing a higher risk, some a lower risk, and some no difference at all.

Smoking. There is no evidence that smoking increases the risk for NHL itself, although it has been linked with high-grade and follicular NHLs in people with lymphomas.

Viruses or other microorganisms also play a role in some lymphomas. A number are being investigated:

Epstein-Barr virus, the cause of mononucleosis, is highly associated with Burkitt's disease and NHLs associated with immunodeficiency diseases. It is also a risk factor for Hodgkin's disease
Adult T-cell leukemia-lymphoma, which appears to be caused by a virus known as HTLV-I, has been found in southwestern Japan, the Caribbean, and the southeastern United States.
People who have stomach inflammation due to Helicobacter pylori or H. heilmannii bacteria are at increased risk for mucosa-associated lymphoid tissue lymphomas (MALT). (The use of antibiotics to get rid of the bacteria may cause remission in some patients who have an early stage form of lymphoma in an early stage.)
Human herpes virus 8 has been associated with NHL.
Borrelia burgdorferi, the bacteria that causes Lyme disease, has been associated with primary B-cell lymphoma.
Heavy antibiotic use during adulthood may increase risk. A 2005 study found that adults who used antibiotics more than 10 times had 1.8 times the risk of developing NHL than nonusers. However, researchers were not certain if antibiotics themselves, or the underlying infections they treated, were responsible for the increased risk.

Click the icon to see an image of Lyme disease.

Studies are reporting a higher prevalence of viral hepatitis C and B in patients with lymphomas, although such viruses do not appear to play a major role in triggering lymphoma.

Patients with diseases or conditions that affect the immune system may be at higher risk for lymphomas:

HIV-positive patients and those with full-blown AIDS are at higher risk for NHL, and the disease is more likely to be widespread in these patients than in those without the immune disease. Most AIDS-related NHLs are high-grade lymphomas. Burkitt's lymphoma is often seen in patients with AIDS. Although these patients have had a very poor prognosis, advances in antiviral therapy for HIV now allow better management of NHL with some success in achieving favorable outcomes. Part of the dramatic increase in NHL incidence over the past decades can be traced to AIDS.
Patients with a history of autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus, Hashimoto's thyroiditis, Crohn's disease, and Sjögren syndrome, are at an increased risk for certain NHLs, such as marginal zone lymphomas.
People who have organ transplants are at higher risk for NHL, probably due to multiple factors, including the drugs used to suppress the immune system and the transplanted organ itself.
Patients who have had high-dose chemotherapy with stem-cell transplantation are at higher risk.
Other immunodeficiency syndromes that put people at risk for NHL include Chediak-Higashi syndrome, ataxia-telangiectasia, B-cell lymphoproliferative syndrome, Bruton agammaglobulinemia, common variable immunodeficiency, and Wiskott-Aldrich syndrome.

Note on Allergies: There appears to be no association between NHL and allergies, overactive responses of the immune system. Allergies are the most common immune disorder.

Overexposure to a number of industrial and agricultural chemicals has been frequently linked to an increased risk for lymphomas. The data, however, are not consistent.

Organochlorines are chemicals produced when solid waste is burned. These by-product chemicals include dioxin, polychlorinated biphenyls (PCBs), and furans. Many studies have indicated that exposure to these chemicals increases the risk of developing NHL.
A number of studies have found an association between NHL and certain pesticides and herbicides, although more research is needed to confirm any definitive risk.
White spirits, thinners, phenoxy herbicides, wood preservative, aviation gasoline, plastic, and rubber chemicals have been associated with a higher risk for lymphomas. Specifically, in one study, painters and lumberjacks had a higher risk for NHL, while office and house workers had a lower risk.
Some studies have found an association with long duration and early use of permanent dark hair dyes. There is no consistent evidence, however, that hair dye increases the risk for lymphomas.

Symptoms

The most common first sign of lymphomas is painless enlargement of one or more lymph node, usually in the neck, armpits, or groin. Patients should see their doctors if these symptoms do not go away within 2 - 3 weeks.

The most common lumps or swellings in the neck are enlarged lymph nodes. They can be caused by bacterial or viral infections, cancer, and other rare causes.

Lymphomas sometimes cause systemic symptoms -- symptoms that affect the whole body, rather than a specific location. Some systemic symptoms are referred to as B symptoms. Patients who have B symptoms have a more severe condition than asymptomatic patients with the same cancer stage or tumor location or size.

B systemic symptoms include:

Drenching night sweats and weight loss
Fever (may occur sporadically and only at night)

Other systemic symptoms include:

Itching all over the body caused by the release of histamines, substances ordinarily triggered by an allergic response. In the case of NHL, this is due to abnormalities in the immune system. Although this is a systemic symptom, it is not usually considered a B symptom if other systemic symptoms are not also present.
In late stages, some patients develop a skin rash.
Tumor masses in the chest can cause coughing or breathlessness.
Lymphomas in the stomach can cause nausea and vomiting.

Many patients seek medical help for abnormally swollen lymph nodes (commonly referred to as "swollen glands"). Swollen glands can be caused by many conditions, most often infections, and are rarely serious.

Infections. In the great majority of cases, swollen glands are caused by an infection:

Enlarged lymph nodes in the neck are much more likely to be a sign of strep or other throat infection than NHL.
Infectious mononucleosis (caused by the Epstein Barr virus) is a common cause of swollen lymph nodes in young people.
Travel, particularly to countries with a high incidence of tropical diseases, can trigger similar symptoms.
Other infections that cause swollen glands include cat scratch fever, Lyme or other tick-borne disease, HIV, tularemia, tuberculosis, syphilis, herpes simplex virus, cytomegalovirus, and hepatitis.

Hodgkin's Disease. Although both Hodgkin's disease and non-Hodgkin's lymphomas are malignancies of the lymph nodes, they can usually be distinguished by certain characteristics. It is extremely important to differentiate between Hodgkin's lymphomas and non-Hodgkin's lymphomas, since the treatments for these two conditions differ. In particular, a subtype of lymphoma called anaplastic large-cell lymphoma (ALCL) might be confused with Hodgkin's disease under some circumstances. [For more information, see In-Depth Report #83: Hodgkin's disease.]


Characteristics	Hodgkin's Disease	Non-Hodgkin's Lymphomas
Age and Prevalence	Average age is 28 with two age peaks, the major one occuring between 15 - 24, anda lesser peak after age 55. It is less common than NHL.	Average age is about 67. It is more common than HD.
Location	In both malignancies, the disease occurs most often in lymph nodes above the collarbone. However, in HD it is also more likely to appear in the chest cavity between the lungs (the mediastinum), particularly in younger patients. Only about 15 - 20% of cases are found in areas below the diaphragm. Disease occurs outside the nodes in about 4% of cases.	In both malignancies, the disease occurs most often in lymph nodes above the collarbone. In NHL, however, it is also more likely to appear in the nodes in the abdomen (called the mesenteric nodes). The disease occurs in the chest cavity in less than 40% of patients. (An exception, lymphoblastic lymphoma, which is seen most often in young people, is likely to first appear in the chest.) Disease occurs outside the nodes in about 23% of patients. Slow-growing lymphomas are common in the liver and bone marrow.
Symptoms	More likely than NHL (40%) to have systemic symptoms (such as fever and night sweats) at the time of diagnosis.	Less likely to have systemic symptoms (27%) at the time of diagnosis.
Progression	Less likely than NHL to be diagnosed in stage IV (10%). Hodgkin's disease usually progresses in an orderly way from one lymph node region to the next. This process may be slow, particularly in younger people, or very aggressive. The disease typically spreads downward from the initial site. If it spreads below the diaphragm, it usually reaches the spleen first; the disease then may spread to the liver and bone marrow. If the disease starts in the nodes in the middle of the chest, it may spread outward to the chest wall and areas around the heart and lungs.	More likely than HD to be diagnosed in stage IV (36%). The lymphomas are less predictable in their course than Hodgkin's disease and they are more apt to spread.

Other Cancers or Serious Conditions in the Lymphatic System. Other cancers that can travel to lymph nodes include breast cancer and leukemia.

Very serious causes of enlarged lymph nodes include disorders of the lymph system, such as Castleman's disease, lymphomatoid granulomatosis, and angioimmunoblastic lymphadenopathy. These lymph system disorders, although noncancerous, involve abnormal lymph cells. They are often fatal and can be very difficult to distinguish from lymphomas. Many of the other serious illnesses involving diseased lymph nodes develop simultaneously at multiple sites, while Hodgkin's nearly always starts at one location before spreading to nearby nodes. [For more information, see In-Depth Report #83: Hodgkin's disease or Report #86: Acute lymphocytic leukemia.]

Exposure to Medications. Exposure to certain medications such as phenytoin (Dilantin) may cause enlarged nodes. Other drugs, such as cephalosporins, penicillins, or sulfonamides, can cause enlarged nodes and other symptoms, including fever and rash, which may resemble Hodgkin's disease.

Diagnosis

The doctor will first ask questions about the patient's medical history and perform a physical examination to detect any node enlargements. If these steps point to lymphoma, additional tests will be done to rule out other diseases or to confirm the diagnosis and extent of the lymphoma.

It is sometimes reasonable to wait a little while for the swelling and symptoms to go away before deciding that additional testing is necessary. In some cases, lymph node swelling may be due to a temporary infection. However, some lymphomas cause off and on lymph node swelling. This is particularly true with small cleaved cell lymphoma (the most common NHL). Lymph nodes should be checked periodically for any return of swelling.

The doctor will examine not only the affected lymph nodes but also the surrounding tissues and other lymph node areas for signs of infection, skin injuries, or tumors. The consistency of the node sometimes indicates certain conditions. For example, a stony, hard node is often a sign of cancer, usually one that has metastasized (spread to another part of the body). A firm, rubbery node may indicate lymphoma. Soft nodes suggest infection or inflammatory conditions.

Blood tests help rule out infection and other diseases. Such tests include those blood counts and blood chemistries for kidney and liver function, uric acid, calcium, and phosphate levels. In a patient already diagnosed with lymphoma, blood tests that measure the enzyme lactate dehydrogenase are important in determining the prognosis. High levels indicate bulkier tumors. The presence of anemia may indicate specific NHLs, such as diffuse, small lymphocytic lymphoma.

A biopsy is the most important test for diagnosing lymphomas and can be used to tell the difference between non-Hodgkin's and Hodgkin's disease. A biopsy has risks and should be performed only by a qualified and experienced doctor. Sometimes a doctor may choose to wait and observe the involved lymph nodes, which will usually go away on their own if a temporary infection is causing the swelling. (However, some lymphomas may go away and appear to be benign, only to reappear at a later time.)

The Procedure. The doctor removes the node and checks the surrounding areas. The tissue in the node is then examined under a microscope for signs of infection and abnormalities indicating cancer or other conditions.

Results. Even if biopsies do not show any problems, disease may still be present in some cases. The doctor should continue to observe the patient until swelling or other signs of disease are gone. Biopsied tissue samples should be frozen in case special tests are later required. Such tests may include detection of particular antibodies, genetic and immune factors, and certain markers (substances that may indicate disease) located on the surface of the cells. If lymphoma has been diagnosed, the tissue will be examined for its histology, the cellular structures that will determine the lymphoma type.

Bone marrow aspirate and biopsy are routinely performed to determine whether the disease has spread. With bone marrow aspirate, bone marrow cells are sucked out through a special needle. A biopsy may be performed before or after the aspiration. In this procedure, a special needle removes a core of the marrow that is structurally intact.

Click the icon to see an image of bone marrow aspiration.

Chest X-Ray. A chest x-ray shows the lymph nodes in the chest and neck area. It is particularly useful in detecting Hodgkin's disease and enlarged lymph nodes.

Click the icon to see an image of an x-ray machine.

Computer Tomography. Computed tomography (CT) scans are more accurate than x-rays. They can detect abnormalities in the chest and neck area, as well as revealing the extent of the cancer and whether it has spread. CT scans are used to evaluate symptoms and help diagnose lymphomas, help with staging of the disease, monitor response to treatment, and evaluate when the symptoms occur. A CT scan is also often used in detecting lymphomas in the abdominal and pelvic areas, the brain, and chest area.

Click the icon to see an image of a CT machine.

Magnetic Resonance Imaging (MRI). MRIs may be used to detect the spread of the disease to the brain, spine, chest, pelvis, and abdomen.

Click the icon to see an image of a MRI machine.

Positron Emission Tomography (PET). PET scans can help tell whether or not an enlarged lymph node is benign or cancerous. PET scans are more accurate than CT scans or other imaging tests for staging lymphomas. PET scans may also help doctors determine how well a patient has responded to treatment, if any residual cancer exists, and if a patient has achieved remission.

Tests of lymphoma's DNA are in use or are being developed to detect particular genetic abnormalities that help determine outlook and may eventually lead to new treatments. Examples of such abnormal genetic arrangements are those that affect normal cell death, resist chemotherapy, or trigger aggressive cancer growth.

An advanced approach called the microarray technique uses chips that contain up to thousands of DNA sequences that represent specific normal and abnormal genes. Such sequences have been compiled for lymphomas. Eventually, experts may be able to match a patient's DNA to these patterns and identify specific subtypes.

Biologic markers, also called biomarkers, are high levels of substances released by tumors. They indicate the level of cancer activity. Biomarkers can be found in sputum, blood, and tissue samples. Biomarkers can be enzymes, hormones, amino-acid compounds, antigens (identified by antibodies that specifically target them), and growth factors. Some under investigation include:

CD44. This molecule binds to the surface of cells and may be involved in metastasis. High levels of this molecule may suggest a more aggressive disease.
BCL-6. This cancer gene is implicated in diffuse large B-cell lymphoma. High levels of this gene in these patients indicate a better outlook after treatment.

Outlook

Five-year survival rates for NHL range from 20 - 95%, depending on the lymphoma type, stage, age of the patient, and other variables. Because the outlook varies so widely, making a definite prognosis is very difficult. For example, patients with very slow growing (indolent) lymphomas can live many years. However, they are usually diagnosed at a late stage, after the cancer has spread, thus reducing the survival rate. Aggressive lymphomas are more likely to cause rapid death, but they are also often curable. New drugs that target specific factors in the tumor cells are improving survival rates.

Follicular lymphomas, the most common indolent (slow-growing) NHLs, are potentially curable in early stages I and II. Unfortunately, however, these slow-growing malignancies produce no symptoms until they are in advanced stages. In most cases, these lymphomas are not diagnosed until they have spread to other sites, including the spleen and bone marrow. In such cases, they are difficult to cure. Predicting outcome for indolent follicular lymphomas is more difficult than for aggressive lymphomas. Even if treatment achieves a response, these tumors almost always recur. Even after relapse, however, the tumors can be treated again if they are still very slow-growing.

In general, the average survival rate for follicular lymphoma is 7 - 10 years, depending on other risk factors. New drug treatments, particularly monoclonal antibodies, have significantly improved survival rates. According to a 2005 study, 91% of patients with follicular lymphoma now survive the first 4 years after diagnosis, compared with 69% of patients treated in the past with older types of drugs. The research team found the best 4-year survival rates for patients treated with the CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy regimen followed by monoclonal antibody biologic drugs (rituximab or iodine-131 tositumomab).

Factors for Predicting Outlook in Indolent Lymphomas. Six risk factors are proving to be useful for predicting outlook:

Being male
Being older
Having stage III or IV disease
Elevated levels of the enzyme lactate dehydrogenase (LDH)
The presence of B symptoms
Erythrocyte sedimentation rate over 30

Patients with a good chance for a positive outcome (65% chance for survival rates of 10 years or greater) have one or none of these factors. Those with intermediate risk (23%) have two factors, and those likely to have a poor outcome (11%) have three or more factors. MALT lymphomas generally have a good prognosis. Primary gastric lymphomas have a 3-year survival rate of 89%.

High-grade aggressive lymphomas are often symptomatic early on and are potentially curable with aggressive treatments. Diffuse large-cell lymphomas, the most common aggressive non-Hodgkin's lymphomas, while fatal if not treated, are often curable with intensive chemotherapy combinations. If relapse occurs after chemotherapy, it usually does so within 2 years.

Most other aggressive lymphomas respond to aggressive chemotherapy. Mantle cell lymphoma is less responsive to chemotherapy. The average survival time is 3 - 5 years.

Factors for Predicting Outlook in Aggressive Lymphomas: A scoring system called the International Prognostic Index has proved to be fairly accurate for predicting outcome in patients with most aggressive B-cell lymphomas. It uses five risk factors to help predict whether the disease will be aggressive:

Being older than 60 -- this age group tends to have other medical conditions, which contribute to the poorer prognosis
Having a disseminated tumor (stage III or IV)
Disease that has spread to more than one site beyond the lymph nodes
A poor performance status
Having elevated levels of lactate dehydrogenase (LDH)

Having one or none of these risk factors indicates the best outlook. Two factors indicate a low-to-intermediate likelihood of a poor outlook. Three factors predict an intermediate-to-high likelihood of poor outlooks. Finally, four or five factors pose the highest likelihood of poor survival.

Lymphoma can spread to the central nervous system, or it can appear there first. Called primary CNS lymphomas (PCNSL), this condition is a very serious, particularly if it occurs at relapse.

The central nervous system is comprised of the brain and spinal cord. The peripheral nervous system includes all peripheral nerves.

Risk Factors for CNS Involvement After a Diagnosis of NHL. AIDS-related lymphomas often involve the central nervous system (CNS), including the brain and spinal column. CNS involvement also occurs with aggressive lymphomas, such as Burkitt’s lymphoma.

Risk Factors of Primary CNS Lymphomas. PCNSL used to account for only about 2% of lymphomas, but the incidence is on the rise in all age groups and in both. The reason for the increase is not known.

Medical Problems. The radiation and chemotherapies used in treating NHL can have long-term effects on many organs in the body and can increase the risk for serious illnesses, including heart disease and certain cancers.

Negative Emotional Problems. Depression and anxiety are common in survivors, particularly those who suffer additional medical conditions. Many patients also suffer from fatigue and aches and pains, called somatic symptoms, which have no apparent physical basis. In one study, such symptoms were more highly associated with intensive chemotherapy. Women and people in lower social and economic groups are at higher risk for depression and somatic symptoms -- just as they are in the general population.

Staging and Treatment Guidelines

Treatment for non-Hodgkin's lymphoma is highly specific for each patient and is determined by the tumor classification. It includes the following factors:

Stage
Grade
Histologic type (cellular structure)
Location
Other factors, such as blood levels of lactate dehydrogenase

Treatment for lymphomas has been primarily dependent on chemotherapy (particularly intensive regimens using several drugs) or a combination of chemotherapy and radiation. For advanced or refractory lymphomas and for relapse, patients may undergo bone marrow or stem cell transplantation. New treatments, especially those known as immunotherapies, or biological response modifier (BRM) therapies, are showing promise. Some experts recommend that patients ask their doctors about getting into well-designed clinical trials as early as possible.

Click the icon to see an illustrated series detailing bone marrow transplant surgery.

In assessing the success of a clinical trial, experts often refer to the tumor response. A complete response, for example, means that there is no longer any evidence at all of the disease by examination, blood tests, or x-ray studies. It does not necessarily mean, however, that the disease is cured. It may still recur later on.

In judging the success of a treatment for NHL, the most important criteria are overall survival and the duration of time until the disease progresses or the patient dies.

In Stage I, lymphoma is found in only one lymph node area or in only one area or organ outside the lymph nodes. Either of the following indicates stage II:

Lymphoma is found in two or more lymph node areas on the same side of the diaphragm.
Lymphoma is found in only one area or organ outside the lymph nodes and in the lymph nodes around it. Other lymph node areas on the same side of the diaphragm may also have lymphoma.

Early Stage Indolent (Low-Grade) Lymphoma. Below are the general treatment options:

Radiation therapy. Radiation to local areas can achieve a cure in 40 - 50% of patients.
Chemotherapy. Chemotherapy uses drugs to kill cancer cells.
Watchful waiting. Patients who choose watchful waiting must be aware of signs and conditions indicating the need for treatment. These include B symptoms, endangered organs, massive bulky tumors, or a steady progression that lasts at least 6 months.
Investigative treatments, such as conjugated and unconjugated monoclonal antibodies or radiation plus chemotherapy. In one study, a combination of therapies worked better than radiation alone.

The following are treatment options for some specific low-grade lymphomas:

Mucosa-associated lymphoid tissue (MALT) lymphoma. When disease is in the stomach (gastric MALT) and the patient is infected with H. pylori bacteria, antibiotics can cause regression in a significant number of patients with stage I lymphoma. In certain patients where antibiotics fail, or are not appropriate, radiation alone can achieve significant cure rates. Surgery with or without radiation, or chemotherapy with or without radiation, are possible options. Treatment options for patients with MALT localized in other sites depend on the location of the specific disease and range from radiation to chemotherapy to biologic therapies, such as interferon.
Primary gastric lymphoma (indolent). Radiation is the typical treatment for this lymphoma, which is located only in the stomach, small intestine, or other nearby regions. Surgery is being reconsidered since it seems to offer no advantage.

Click the icon to see an image of the digestive system.

Early Stage Aggressive (Intermediate- to High-Grade) Lymphomas. Treatment options include:

Chemotherapy alone
Combinations of chemotherapy (usually CHOP) plus radiation therapy
Radiation alone (rarely)
Chemotherapy alone or with surgery for lymphoma in the gastrointestinal region
Immunotherapies (rituximab, Bexxar) with or without chemotherapy (usually CHOP), or high dose chemotherapy and bone marrow or stem cell transplantation

In stage III, lymphoma is found in lymph node areas on both sides of the diaphragm (for instance, in both the chest and the abdomen). The lymphoma may also have spread to the spleen. In stage IV, lymphoma has spread via the bloodstream to organs outside the lymph system, such as the bone marrow or brain. Lymphoma cells may or may not be in the lymph nodes near these organs.

Advanced Stage Indolent (Low-Grade Lymphomas). Treatment options are controversial because of the low-cure rate and yet slow-growing nature of these lymphomas. Patients without symptoms are often managed by watchful waiting, in which the disease is monitored closely for development of symptoms or bulky tumor masses, particularly if they threaten major organs. At such times, treatment is started. Treatment may include:

Chemotherapy combinations (CHOP, CVP, CMOPP)
Nucleoside analogs (for example, fludarabine) alone or with chemotherapy
Oral alkylating chemotherapy drugs such as cyclophosphamide or chlorambucil with or without steroids
Monoclonal antibodies (MAbs) such as rituximab alone or in combinations with CHOP or nucleoside analogs
Chemotherapy plus interferon
Clinical trials involving intensive chemotherapy and radiation followed by bone marrow or stem cell transplantation

Advanced Stage Aggressive (Intermediate- to High-Grade) Lymphomas. Treatment options may include:

Doxorubicin-based combination chemotherapy with or without rituximab
Chemotherapy plus radiation therapy
Immunotherapies with or without chemotherapy
Treatments to prevent disease from spreading to the central nervous system in high-risk patients
Clinical trials for patients at high risk for relapse, involving intensive chemotherapy, high dose chemotherapy, and bone marrow or stem cell transplantation

Indolent-Lymphomas Relapses. Nearly all patients with indolent lymphomas relapse after initial treatment, with length of remission after a first treatment averaging 18 - 50 months. Successful retreatment is often possible, but disease-free periods become increasingly shorter with each subsequent treatment.

Older patients may choose watchful waiting. Other treatment options may include:

Radiation alone or with chemotherapy -- in one study low-dose involved-field radiotherapy was very effective in recurring indolent lymphoma
Chemotherapy
High-dose chemotherapy with autologous stem cell transplant
Clinical trials involving monoclonal antibodies, radioimmunotherapy, nucleoside analogues alone or in combination with other drugs, or stem cell transplantation followed by biologic therapies

Aggressive Lymphomas Relapse. After initial treatment, more than half of patients with aggressive lymphomas are cured, while about 20% progress, and the other 30% relapse after a disease-free period. Among those who relapse, many can still be cured with aggressive treatments.

Treatment options:

Bone marrow or peripheral stem cell transplantation
Bone marrow transplantation with radiation
Clinical trials that involve continuous infusion chemotherapy, biologic therapies (monoclonal antibodies) alone or in combination with transplantation

Click the icon to see an illustrated series detailing bone marrow transplant surgery.

Treating Lymphoma Restricted to the Central Nervous System. Treatment options may include:

High-dose methotrexate regimens alone or in combination with radiation
Corticosteroids and radiation
Clinical trials that involve biologic therapies, such as rituximab or interferon alpha administered directly into the spinal fluid (intrathecal administration) for meningitis related to central nervous system lymphoma

Preventing (Prophylactic Treatment) Lymphomas in High-Risk Patients. Treatment to prevent the spread of NHL to the central nervous system may be appropriate in some patients. It is not recommended for patients with low-grade NHL. Preventive treatment may be appropriate for certain patients with high-grade NHL, such as those with lymphoblastic and Burkitt's lymphoma or if they have 4 - 5 of the following risk factors: Elevated levels in the blood of the enzyme acetate dehydrogenase and albumin (a common protein), being older than 60, and having lymph nodes beyond the peritoneum (the lining of the abdomen) and involvement of more than one site outside a lymph node.

Chemotherapy

Chemotherapy plays a role in the treatment of nearly all lymphoma patients and has achieved remarkable results, even in late stages. It uses drugs to kill cancer cells. Such drugs are called cytotoxic drugs. Chemotherapy is referred to as bodywide or systemic therapy because the drugs travel throughout the bloodstream to the entire body.

Studies indicate that chemotherapy as sole treatment is adequate for most children and young adults in early, and perhaps in many advanced, stages. (Radiation has been commonly used for these patients but can be particularly dangerous for children.)

A chemotherapy cycle is usually 21 - 28 days. Patients take the drugs for a few days, then have a period of rest. The drugs may be taken by mouth or given by injection. Chemotherapy is injected into the spinal fluid if the cancer has spread to the brain. This is called intrathecal chemotherapy. Intrathecal chemotherapy is also used as a preventive measure in patients at high risk for central nervous system involvement. Chemotherapy may be administered at a medical center or in a doctor's office. Some patients receiving chemotherapy need to remain in the hospital for several days so the effects of the drug can be monitored. Patients with lymphoblastic lymphoma may need long-term maintenance chemotherapy. Such therapy does not seem to benefit patients with small-noncleaved-cell and large-cell lymphomas.

CHOP. The current standard chemotherapy regimen for NHL is CHOP. CHOP is a combination of cyclophosphamide, doxorubicin hydrochloride (Adriamycin), vincristine (Oncovin), and prednisone. It is proving to be particularly effective for many stages of lymphoma when used in combination with rituximab (Rituxan), a monoclonal antibody. (See Biologic Therapy section.) Some studies of this combination in low-grade lymphomas have reported response rates of 70 - 100%. CHOP alone is still preferred for HIV patients, who tend to have a toxic response to rituximab.

CVP. This stands for cyclophosphamide, vincristine, and prednisone. It may be used with CHOP in certain cases.

Fludarabine and Nucleoside Analogues. Fludarabine (Fludara) is a type of drug called a nucleoside analogue. It is one of the most active drugs for treating low-grade lymphomas and may be effective for other NHLs, including mantle cell lymphomas. Promising regimens containing fludarabine are under investigation. For example, FND (fludarabine, mitoxantrone, and dexamethasone) may be helpful in combination with rituximab for certain patients, including those with indolent NHL. Other nucleoside analogues include gemcitabine and cladribine. Toxicities and infection rates from high dose nucleoside analogues have been high. Fludarabine also has been associated with a risk for leukemia.

Bendamustine. This potent drug has shown to be effective for indolent NHLs and possibly aggressive lymphomas. One study suggested that a single dose of low-dose etoposide, taken by mouth, may be beneficial for elderly patients.

Antibiotics. Antibiotics, such as doxycycline, may cure or put into complete remission about half of mucosa-associated lymphoid tissue (MALT) lymphoma cases. MALT lymphoma is a type of lymphoma that sometimes affects the eyes. It is associated with the bacterium Helicobacter pylori (H. pylori ), which also causes stomach ulcers. Recent studies indicate that antibiotics are a good alternative to chemotherapy or radiation for patients with this type of lymphoma. Patients most likely to respond positively to antibiotics are those with MALT lymphoma in its early stages.

Vorinostat. Vorinostat (Zolinza) was approved in 2006 for treatment of cutaneous T-cell lymphoma (CTCL), a rare form of NHL.

Side effects and complications of any chemotherapeutic regimen are common. They are more severe with higher doses. Side effects may increase over the course of treatment.

Common Side Effects. Common side effects include:

Nausea and vomiting -- Drugs known as serotonin antagonists, such as ondansetron (Zofran) or granisteron (Kyril), can relieve these side effects in nearly all patients given moderate drugs and in most patients who take more powerful drugs.
Diarrhea
Hair loss
Weight loss
Depression

These side effects are nearly always temporary. Most patients are able to continue with normal activities for all but perhaps a few days a month.

Serious Side Effects. Serious chemotherapy side effects can also occur and may vary depending on the specific drugs used. They include:

Neutropenia is a severe drop in white blood cells. Neutropenia increases the chance for infection from suppression of the immune system and is a potentially life-threatening condition. Drugs known as granulocyte colony stimulating factor (G-CSF) are used to help boost white blood cell count. These drugs, which include filgrastim (Neupogen) and pegfilgrastim (Neulasta), can help lessen the risk for neutropenia occurrence and, if neutropenia does occur, to reduce its length and severity.
Anemia is a lack of red blood cells. Erythropoietin stimulates red blood cell (hemoglobin) production and can help reduce or prevent this side effect. It is available as epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). In 2007, the FDA released strict dosing guidelines for these drugs. In patients with cancer, they should be used to treat only anemia associated with chemotherapy and to increase hemoglobin levels to no more than 12 g/dL. Treatment should stop as soon as chemotherapy is complete. These drugs may not be safe or appropriate for all patients.
Liver and kidney damage
Abnormal blood clotting (thrombocytopenia)
Allergic reaction

Long-Term Complications.

Fatigue and Somatic Symptoms. Chemotherapy has been associated with long-term somatic symptoms, which are general conditions, such as fatigue and aches and pains that have no apparent physical basis. Fatigue is especially common after chemotherapy and can even last for years.
The most serious long-term complications from chemotherapy are secondary cancers, particularly in people over age 40.
Infertility is a risk, particularly with the use of cyclophosphamide.
Some patients get osteoporosis (bone thinning) and damage in bone cells.
Regimens containing certain drugs, particularly doxorubicin or mitoxantrone, increase the risk for future heart failure.

Click the icon to see an image of the uterus and ovaries.

In general, these serious late side effects are dependent on the cumulative drug dose and rate of administration.

Doctors are particularly concerned about the effects of combinations of chemotherapy with radiation, especially leukemia and heart problems. Interestingly, in one study on patients with intermediate- and high-grade NHL, those on chemotherapy alone had more toxic effects than those on combined modality, most likely because it employed fewer cycles of chemotherapy. Better radiation techniques are also reducing the risks of combined modality treatments.

Biologic Therapy (Immunotherapy)

Biological response modifier therapy, also called immunotherapy, uses the body's own immune system to fight cancer using natural or laboratory-developed factors. These drugs are often combined with other treatments.

Monoclonal antibodies (MAbs) are designed in the laboratory to produce the same effects as natural antibodies and are exciting new weapons in the anti-cancer armament. They bind to specific proteins called antigens and make them vulnerable to attack by other factors in the immune system. Lymphomas carry antigens that provoke strong immune responses and so are believed to be particularly good candidates for MAb therapy.

MAbs are called either unconjugated or conjugated, depending on how they are designed to destroy the cancer cell.

Unconjugated monoclonal antibodies rely on a strong natural immune system. The antibody builds up at the tumor site until it is able to trigger an immune response against the cancer. A possible downside to this form is the potential development of tolerance to the antibody so that it loses its effectiveness. Rituximab is an unconjugated form and the first MAb to be approved for any cancer.
Conjugated monoclonal antibodies are linked to a plant or bacterial toxin or radioisotope. The antibody specifically attacks the antigen on the lymphoma cell, and the toxin or radioactive material from the isotope kills it.

Unconjugated MAbs (Rituximab). Rituximab (Rituxan) was the first monoclonal antibody approved for cancer. This drug targets the CD-20 antigen, which is found on most B-cell lymphomas.

First approved in 1997 for treatment of relapsed or refractory NHL, rituximab has received several expanded indications since that time. As of 2006, rituximab is approved for:

Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell, NHL
First-line treatment of diffuse large B-cell (DLBC), CD20-positive, NHL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens
First-line treatment of follicular, CD20-positive, B-cell NHL in combination with CVP (cyclophosphamide, vincristine and prednisolone) chemotherapy
Low-grade, CD20-positive, B-cell NHL in patients with stable disease or patients who have been partially or completely helped by first-line treatment with CVP chemotherapy

Rituximab in combination with CHOP (a regimen called R-CHOP, or CHOP-R) is used for first-line treatment for aggressive lymphomas, with studies reporting 3-year event-free survival of 53% compared to 35% with CHOP alone. A 2006 study also indicated that rituximab provides benefits when used as maintenance treatment after CHOP or R-CHOP induction therapy. Rituximab plus CHOP is also showing promise as a first-line treatment for mantle cell lymphoma.

Rituximab is given by infusion. The treatment has mild-to-moderate short-term side effects, including nausea, fever, chills, hives, dizziness, and headache. Uncommon and more serious side effects are severe allergic reactions, very low blood pressure, blood abnormalities, wheezing, infections, and sudden heart events.

Rituximab has also been associated with cases of progressive multifocal leukoencephalopathy (PML), a rare and potentially deadly brain infection. Patients who experience any of the following symptoms should immediately contact their doctors:

Vision problems or unusual eye movements
Confusion
Dizziness or loss of balance
Difficulty talking or walking

Patients who have previously had hepatitis B, or who are at high-risk for this viral infection, should be tested before taking rituximab because the drug has been linked to reactivation of the hepatitis B virus. Patients who are HIV-positive may experience more adverse effects from rituximab than with CHOP.

Conjugated Monoclonal Antibodies with Radioimmunotherapy. Conjugated MAbs with radioimmunotherapy contain tiny amounts of radioactive materials. When the drug is injected, the monoclonal antibody targets an antigen (protein) on the surface of the tumor. The radioisotope is then delivered directly into the tumor where it kills the cancer. Ibritumomab and tositumomab both target the CD-20 antigen. Treatment with these drugs takes about 7 - 9 days to complete, compared to several months for traditional chemotherapy treatments.

Ibritumomab (Zevalin) is approved for patients with relapsed or refractory low-grade, follicular or transformed B-cell NHL. It is also approved for patients with follicular NHL who have not responded to rituximab (Rituxan). Research indicates it may also be safe for patients with advanced NHL who have had stem cell transplantation. Zevalin uses an yttrium-90 (90-Y) radioactive isotope.
Tositumomab and Iodine I-131 (Bexxar) combines the monoclonal antibody tositumomab with the radioisotope I-131. The Bexxar treatment is approved for treatment of relapsed or refractory low-grade, follicular, or transformed B-cell NHL. Overall response rates of 56% have been reported with Bexxar, with up to 30% being complete responses (no evidence of cancer). Recent studies suggest that when Bexxar is used as a first treatment, it may produce long-term complete remission in patients with advanced stage follicular lymphoma. In a 2005 New England Journal of Medicine study, 95% of previously untreated patients with advanced follicular lymphoma responded to Bexxar, and 75% had complete responses. Seventy percent who had complete responses from Bexxar treatment were still disease-free 4 - 7 years later.

In general, these drugs cause fewer side effects than traditional chemotherapy. However, serious complications may include skin infections, severe allergic reactions, and temporary lowering of blood counts.

Other Monoclonal Antibodies. Other MAbs are being developed that target other antigens on lymphomas. For example, epratuzumab targets CD-22 and is showing promise in early studies. Some are being studied in both conjugated and unconjugated forms and also in combination with MAbs that target different antigens.

Interferon alpha (Intron A) is used as an antiviral drug that also has properties that are effective against some common forms of NHL, particularly low-grade, follicular NHL in advanced stages. It is usually combined with chemotherapy regimens such as CHOP that contain an anthracycline drug (usually doxorubicin). The combination is toxic, however, and outcomes vary. Interferon is also being studied for lymphomas in the central nervous system. It may be useful after autologous stem cell transplantation.

Side Effects. Side effects of interferon include flu-like symptoms, severe depression, irritability, weight loss, vomiting, general weakness and loss of strength, and fever. About a third of patients have a severe drop in white blood cells. About 10% of patients cannot tolerate the drug's side effects.

Cytotoxic Deoxyguanosine Analogue Prodrugs. Nelarabine (Arranon) is approved for treating T-cell lymphoblastic lymphoma (T-LBL). T-LBL is a rare form of lymphoma that accounts for less than 2% of all cases of NHL.

Proteasome Inhibitors. In 2006, bortezomib (Velcade) was approved for treatment of mantle cell lymphoma in patients who have received at least one prior therapy.

Cyclin-Dependent Kinase Inhibitors. Flavopiridol, a drug known as a cyclin-dependent kinase inhibitor, is showing some effect in patients with mantle-cell lymphoma. This drug is designed to block enzymes that regulate cell cycles and help block their growth.

Vaccines. Although still experimental, lymphoma vaccines are used to treat -- not prevent -- cancer. They are part of an immunotherapy approach called personalized medicine; each vaccine is individually tailored to the genetic composition of the patient’s tumor. The vaccine is usually given a few months after a patient receives chemotherapy. Several different vaccines, including the BiovaxID and MYVax, are in late-stage clinical trials.

Radiation

Radiation is commonly used to treat indolent lymphomas. The dose administered ranges from 35 - 50 Gy and depends on a number of factors: The type of lymphoma, the age of the patient, whether the intent is to cure or relieve symptoms, how close sensitive organs are to the diseased area, and whether radiation is being combined with chemotherapy.

Radiation is tailored to the individual and usually limited to the diseased areas and possibly nearby regions:

If the lymphoma is confined to tissues above the diaphragm, radiation is delivered to the neck, chest, and under arms (called the mantle-field) and sometimes to lymph nodes in the upper abdomen or spleen or both.
If the lymphoma is below the diaphragm, subtotal nodal radiation may be used, which is directed to other regions, including lymph nodes in the upper abdomen, spleen, and pelvis, in addition to the mantle-field.
Radiation to the brain is called cranial radiation.
Total body irradiation is sometimes performed, although it is not clear whether its high toxicity outweighs any advantages.

Devices called planning simulators allow doctors to plan x-ray treatments that accurately conform to the patient's anatomy so that protective shields can be created to precisely protect the regions outside the treatment areas.

Side effects and complications of radiation generally depend on the target site in the body. They include:

Dental problems
Inflammation in the lungs -- with carefully conducted therapy, the risks for lung complications are small. Lung impairment may not even be evident, and the lungs usually recover after 2 - 3 years.
Hypothyroidism
Infections
Long-term risk for heart disease
Long-term risk for certain cancers -- of particular concern is a possible increased risk for breast cancer. Studies indicate that young women and adolescent girls are at highest risk, with the incidence increasing significantly 15 years after treatment. The risk is greater in those who had higher radiation doses. Radiation may also increase the risk over time for other cancers, including lymphoma and thyroid, lung, and colon cancers, although the risk is still low. Smoking, of course, increases the risk for lung cancer. Radiation of bone marrow increases the risk for leukemia.
Impaired bone growth -- children and adolescents are at special risk for bone problems caused by radiation. Experts are finding that radiation for many children and young adults in early stages or NHL is no more effective and has more serious long-term effects than chemotherapy. Some believe that radiation should play no role in the treatment of young people, except in special cases, such as lymphomas that require radiation to the brain.
Infertility -- the negative effects on fertility may be worse in women than in men; sperm usually recover within 5 years. To protect the ovaries, a technique called ovarian transposition is sometimes used. Transposition may sometimes be performed through a laparoscope, a thin tube containing tiny instruments and cameras, which is introduced through a small incision. The doctor uses the laparoscope to move the ovaries out of the range of areas being treated with radiation.

Click the icon to see an image of the lungs.

Click the icon to see an image of hypothyroidism.

Click the icon to see an image of the uterus and ovaries.

Transplantation

Stem cell procedures have proven to produce long-term survival and even cures in some patients with intermediate- and high-grade non-Hodgkin's lymphomas.

Stem cell transplantation involves removing and replacing stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments harm growing cells as well as cancer cells, and so the healthy stem cells must be replaced by transplanting them from the donor into the patient.

Sources of Cells. Stem cells must first be collected in one of the following ways:

Directly from blood, called peripheral blood stem cell transplantation
From bone marrow, called bone marrow transplantation
From umbilical cords or placentas -- this procedure uses donor cells, but has a lower risk for immune system rejection of the cells than with a standard donor transplant. It takes longer to restore blood cells with this process, so it is generally used for children and sometimes adults with low weight.

Some evidence suggests that both stem cell and bone marrow procedures produce similar benefits in terms of response rates and duration of remission. However, in one study, stem cell transplantation was associated with better overall survival rates. It also seems to be superior in terms of cost, quality of life, and the need for less supportive care.

Donor or Patient Cells. The marrow or blood stem cells can be taken from the patient (autologous) or from a matched donor (allogeneic):

In an autologous transplant, the marrow or blood cells used for replacement are taken from the patient. There is some danger, however, that these cells may contain tumor cells, and that the cancer can regrow. It is unclear if this approach improves survival compared to standard chemotherapy for newly diagnosed disease. However, it clearly has benefits in the treatment of some forms of relapsed non-Hodgkin's lymphomas. There is also a higher risk for leukemia. (This risk is lower in peripheral stem cells transplants than in bone marrow transplants.)
In an allogeneic transplant, bone marrow or stem cells are taken from a donor. Siblings are the best donors. Relapse rates can be very low with this approach, and cure may be possible in some cases. However, it is highly toxic and donor and recipient must be matched as closely as possible to avoid rejection by the immune system, a serious complication called graft-versus-host disease. Advances in techniques are reducing the toxicities associated with this approach. Older patients who cannot tolerate the preparatory treatment required for a standard allogeneic transplant may be able to receive a non-myeloblative transplant (“mini-transplant), which uses lower doses of chemotherapy and radiation.

The Blood Stem Cell Collection Procedure. With peripheral blood stem cell transplantation:

The donor is usually given a drug called granulocyte colony-stimulating factor, or G-CSF (filgrastim, lenograstim, pegfilgrastim) to stimulate stem cell growth.
The patient (or donor in an allogeneic procedure) then undergoes apheresis. With this process the blood is withdrawn from one of the patient's veins, then passes through a machine that filters out the white cells and platelets, which contain the stem cells. The blood is returned through another vein. The entire procedure takes 3 - 4 hours but needs to be repeated several times.
The stem cells are treated to remove contaminants and then are frozen to keep them alive until the patient is ready to receive them back.

Blood is the only fluid tissue in the body. Blood transports oxygen and nutrients to body tissues, and returns waste and carbon dioxide. Blood distributes nearly everything that is carried from one area in the body to another place within the body. For instance, blood helps transport hormones from the endocrine organs to their target organs. Blood also helps maintain body temperature. The protective functions of blood include clot formation and the prevention of infection.

Allogeneic transplants are preceded by chemotherapy treatment known as conditioning. The point of this treatment is to inactivate the immune system and to kill any residual malignant cells. It is extremely toxic since it also destroys non-malignant marrow cells. Drugs used are typically cyclophosphamide, carmustine, and etoposide. Alternative conditioning to reduce toxicity includes total-body radiation plus drugs. Monoclonal antibodies, such as rituximab, are promising drugs, since they have low toxicity and may add benefits for all stages of transplantation.
A few days after treatment, the patient given the stored stem cells, which are administered through a vein. This may take several hours. Patients may have a fever, chills, hives, shortness of breath, or a fall in blood pressure during the procedure.
The patient may be treated with granulocyte colony-stimulating factor after chemotherapy. The goal is to stimulate the growth of infection-fighting white blood cells. Adding thrombopoietin may help enhance stem cell production.
The patient is kept in a protected environment to minimize infection. Patients who have received an allogeneic transplant may need blood cell replacement, nutritional support, and drugs to treat graft-versus host disease. They usually can leave the hospital within 3 - 5 weeks.

Candidates. These procedures are typically used for patients with relapsed aggressive lymphoma who are still sensitive to the effects of chemotherapy. The procedures do not work for patients whose tumors are not responsive to drugs. Some evidence suggests that certain primary (non-relapsed) lymphomas initially unresponsive to a first round of chemotherapy but who respond to a second round may benefit from combination of high-dose chemotherapy and radiation followed by transplantation. Transplantation is also being investigated as first-line therapy for patients with aggressive lymphomas, although at this time evidence does not support its use.

Success Rates. Success rates vary depending on many factors. The following are survival rates reported by a few studies of patients with different lymphomas:

In patients with refractory or relapsed intermediate grade NHL who received autologous transplantation, 5-year survival rates averaged 34%.
In a study of allogeneic bone marrow transplantation, 58% of patients with late-stage low-grade lymphoma had survived after an average of 29 months.
Patients with anaplastic large-cell lymphoma were treated with autologous stem cell transplantation with intensified chemotherapy as first line-therapy. Survival rates were 87% at 5 and more years afterward. (Survival was much lower with other lymphomas.)
Patients with diffuse aggressive NHL who did not achieve a first remission but who are still sensitive to chemotherapy achieved a 5-year survival rate of up to 37% after autologous stem cell transplantation.
In one study, 35% of patients with an initial poor prognosis were still alive 5 years after an allogeneic stem cell transplantation, although mortality probability from the treatment itself was very high (48%).

Common side effects include nausea, vomiting, fatigue, mouth sores, and loss of appetite.

The procedures themselves are fairly dangerous and carry a small risk for death. When it was first used, transplantation procedures had 10 - 25% morality rates. Now mortality rates are below 5%.

Infection resulting from a weakened immune system is the most common side effect. Because the stem cell procedure is done more swiftly, the risk period is shorter than with bone marrow transplantation. The risk for infection is most critical during the first 6 weeks following the transplant, but it takes 6 - 12 months post-transplant for a patient’s immune system to fully recover. Immune systems of patients with graft-versus-host disease can take even longer to function normally.

Many patients develop severe herpes zoster virus infections (shingles) or have a recurrence of herpes simplex virus infections (cold sores and genital herpes). Pneumonia, cytomegalovirus, aspergillus (a type of fungus), and Pneumocystis carinii (a protozoan) are among the most important life-threatening infections.

It is very important that patients take precautions to avoid infections. Guidelines for post-transplant infection prevention include:

Discuss with your doctor what vaccinations you need and when you should get them.
Avoid crowds, especially during cold and flu season.
Be diligent about handwashing and make sure that visitors wash their hands.
Avoid eating raw fruits and vegetables -- food should be well cooked. Do not eat foods purchased at salad bars or buffets. In the first few months after the transplant, be sure to eat protein-rich foods to help restore muscle mass and repair cell damage caused by chemotherapy and radiation.
Boil tap water before drinking it.
Dental hygiene is very important, including daily brushing and flossing. Schedule regular visits with your dentist.
Do not sleep with pets. Avoid contact with pets’ excrement.
Avoid fresh flowers and plants as they may carry mold. Do not garden.
Swimming may increase exposure to infection. If you swim, do not submerge your face in water. Do not use hot tubs.
Report to your doctor any symptoms of fever, chills, cough, difficulty breathing, rash or changes in skin, and severe diarrhea or vomiting. Fever is one of the first signs of infection. Some of these symptoms can also indicate graft-versus-host disease.
Report to your ophthalmologist any signs of eye discharge or changes in vision. Patients who undergo radiation or who are on long-term steroid therapy have an increased risk for cataracts.

Graft-versus-host disease (GVHD) is a serious attack by the patient's immune system triggered by the donated new marrow in allogeneic transplants. Mild cases of GVHD can actually be helpful as they can cause graft-versus-lymphoma where the immune system kills remaining lymphoma cells. Still, severe GVHD can pose serious complications.

To reduce the risk for GVHD, doctors remove some immune T-cells from the donor’s stem cells before the transplant. Researchers are investigating new techniques to refine this process of T-cell depletion.

Acute GVHD occurs in 30 - 50% of allogeneic transplants, usually within 25 days. Its severity ranges from very mild symptoms to a life-threatening condition (more often in older patients). The first sign of acute GVHD is a rash, which typically develops on the palms of hands and soles of feet and can then spread to the rest of the body. Other symptoms may include nausea, vomiting, stomach cramps, diarrhea, loss of appetite and jaundice (yellowing of skin and eyes). To prevent acute GVHD, doctors give patients immune-suppressing drugs such as steroids, methotrexate, cyclosporine, tacrolimus, and monoclonal antibodies.

Chronic GVHD can develop 70 - 400 days after the allogeneic transplant. Initial symptoms include those of acute GVHD. Skin, eyes, and mouth can become dry and irritated, and mouth sores may develop. Chronic GVHD can also sometimes affect the esophagus, gastrointestinal tract and liver. Bacterial infections and chronic low-grade fever are common. Chronic GVHD is treated with similar medicines as acute GVHD.

Too much sun exposure can trigger GVHD. Be sure to always wear sunscreen (SPF 15 or higher) on areas of the skin that are exposed to the sun. Stay in the shade when you go outside.

Secondary cancers. There is a small long-term risk for leukemia after transplantation in young people. Use of newer chemotherapeutic drugs, however, may not pose as high a danger as older treatments.

Other potentially serious complications include:

Bleeding because of reduced platelets (highest risk within the first 4 weeks); blood transfusions may be required
Infertility
Organ complications to the liver, heart, kidney, or lungs
Failure of the transplant
Muscle problems including stiffness, cramps, and joint pain
Frequent urination and bladder control problems
Older patients should be screened for osteoporosis (bone thinning) and hypothyroidism (underactive thyroid)

Surgery

Surgery is sometimes used to remove as much malignant tissue as possible before administering chemotherapy. This is particularly useful for bulky tumors that occur in the stomach.

Surgery is sometimes performed for primary gastric lymphoma, but its advantages are uncertain. Some studies indicate that chemotherapy alone or with radiation may be sufficient and could spare many patients from surgery.

Resources

www.cancer.gov -- National Cancer Institute
www.cancer.org -- American Cancer Society
www.leukemia.org -- The Leukemia and Lymphoma Society
www.canceradvocacy.org -- National Coalition for Cancer Survivorship
www.marrow.org -- National Marrow Donor Program
www.asco.org -- American Society of Clinical Oncology
www.lymphoma.org -- Lymphoma Research Foundation
www.plwc.org -- People Living with Cancer
www.oncolink.org -- Cancer information
www.fhcrc.org/science/clinical/ltfu/patient -- Fred Hutchinson Cancer Research Center -- Transplant Infection Guidelines for Patients
www.lymphomainfo.net -- Lymphoma Information Network
www.cancer.gov/clinicaltrials -- Find clinical trials

References

Boffetta P, de Vocht F. Occupation and the risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2007: 16(3):369-72.

Ferrara JL. Novel strategies for the treatment and diagnosis of graft-versus-host-disease. Best Pract Res Clin Haematol. 2007. 20(1):91-7.

Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol. 2007 Feb 10;25(5):571-8. Epub 2007 Jan 22.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphoma. V.3.2007.

Seam P, Juweid ME, Cheson BD. The role of FDG-PET scans in patients with lymphoma. Blood. 2007 Nov 15;110(10):3507-16. Epub 2007 Aug 20.

Review Date:
1/21/2008
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A.D.A.M. Copyright

adam.com

Psoriasis

FitSugar — Wed, 08 Oct 2008 17:35:27 -0700

In This Report

Highlights
Introduction
Types of Psoriasis
Causes
Risk Factors
Diagnosis
Treatment
Topical Medications
Systemic Medications
Phototherapy
Managing Psoriasis
Outlook
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Treatment

Psoriasis that develops on the hands or feet is often very difficult to treat. However, an advanced clinical trial showed that a medication called efalizumab (Raptiva) effectively cleared or nearly cleared moderate-to-severe symptoms in adults after 12 weeks.

Several studies have shown that most people with severe psoriasis who are treated with infliximab (Remicade) have significant improvement in symptoms by week 10. The findings were presented at the 2007 annual meeting of the American Academy of Dermatology.

Continuing etanercept (Enbrel) after 12 weeks improves disease severity without an increase in infections or side effects, according to a study published in the Archives of Dermatology.

Disease classification

The National Psoriasis Foundation has proposed a new way to classify psoriasis. Instead of being grouped as mild, moderate, or severe, the group suggests a new two-tiered system that classifies patients as needing either local or body-wide (systemic) treatment.

Coexisting conditions

Studies from Newfoundland and Germany have revealed increased cases of diabetes, obesity, arthritis, and cancer in patients with psoriasis. Previous research has found an increased risk of heart disease in psoriasis patients. Research is underway to determine if there are genetic links between psoriasis and these conditions.

Severe psoriasis has been linked to a significant increase in a patient's risk of death. A study of more than 713,000 patients showed that severe psoriasis increased mortality by 50%. Such patients should receive comprehensive health examinations to reduce the risk, the authors recommended. Study participants were considered to have severe psoriasis if they required systemic treatment.

Smoking and psoriasis

Introduction

Psoriasis is a chronic skin disorder marked by periodic flare-ups of sharply defined red patches, covered by a silvery, flaky surface. The main disease activity leading to psoriasis occurs in the epidermis, the top five layers of the skin.

The process starts in the basal (bottom) layer of the epidermis, where keratinocytes are made. Keratinocytes are immature skin cells that produce keratin, a tough protein that helps form hair, nails, and skin. In normal cell growth, keratinocytes grow and move from the bottom layer to the skin's surface and shed unnoticed. This process takes about a month.

In persons with psoriasis, the keratinocytes multiply very rapidly and travel from the basal layer to the surface in about 4 days. The skin cannot shed these cells quickly enough, so they build up, leading to thick, dry patches, or plaques. Silvery, flaky areas of dead skin build up on the surface of the plaques before being shed. The underlying skin layer (dermis), which contains the nerves and blood and lymphatic vessels, becomes red and swollen.

Types of Psoriasis

Various forms of psoriasis exist. Some can occur alone or at the same time as other types, or one may follow another. The most common type is called plaque psoriasis, also known as psoriasis vulgaris.

Plaque psoriasis leads to skin patches that start off in small areas, about one-eighth of an inch wide. They usually appear in the same areas on opposite sides of the body.

The patches slowly grow larger and develop thick, dry plaque. If the plaque is scratched or scraped, bleeding spots the sizes of pinheads appear underneath. This is known as the Auspitz sign.

Some patches may become ring shaped (annular), with a clear center and scaly raised borders that may appear wavy and snake-like.

As the disease progresses, eventually separate patches may join together to form larger areas. In some cases, the patches can become very large and cover wide areas of the back or chest. This is known as geographic plaques because the skin lesions resemble maps.

Plaque psoriasis may persist for long periods. More often it flares up periodically, triggered by certain factors such as cold weather, infection, or stress.

Patches most often occur on the:

Elbows
Knees
Lower back

The may also be seen on the:

Upper pelvic bone area
Bottom of the feet
Calves and thighs
Genital areas
Palms of hands

Psoriasis of the scalp affects about 50% of patients. In some cases, the psoriasis may cover the scalp with thick plaques that extend down from the hairline to the forehead.

Psoriasis patches rarely affects the face in adulthood. In children, psoriasis is most likely to start in the scalp and spread to other parts of the body. Unlike in adults, it also may occur on the face and ears.

Psoriatic arthritis (PsA) is an inflammatory condition characterized by stiff, tender, and inflamed joints. Estimates on its prevalence among those with psoriasis range from 2 - 42%. AIDS patients and those with severe psoriasis are at higher risk for developing PsA.

About 80% of PsA patients have psoriasis in the nails. Arthritic and skin flare-ups tend to occur at the same time. It is not clear whether psoriatic arthritis is a unique disease or a genuine variation of psoriasis, although evidence suggests they are both caused by the same immune system problem.

Although patients with psoriatic arthritis tend to have mild skin symptoms, the disease affects the entire body. PsA, therefore, is more serious than the more common plaque psoriasis. Infrequently, the course of PsA has been associated with a syndrome known by the acronym SAPHO, which stands for:

Synovitis (inflammation in the joints)
Acne
Pustule eruptions
Hyperostosis (abnormal bony growths)
Osteolysis (bone destruction)

Some experts group PsA into five forms. The forms differ according to the location and severity of the affected joint:

Symmetric PsA: Symptoms occur in the same location on both sides of the body. It usually affects multiple joints. In about half of the cases, the condition will get worse. The condition is very similar to, but less disabling than, rheumatoid arthritis. The psoriasis itself is often severe.
Asymmetric PsA: This form involves periodic joint pain and redness, usually in only one to three joints, which can be the knee, hip, ankle, wrist, or one or more fingers. The pain does not occur in the same location on both sides of the body.
Distal interphalangeal predominant (DIP): DIP involves the joints of the fingers and toes closest to the nail. It occurs in about 5% of PsA cases.
PsA in the spine: Inflammation in the spinal column (spondylitis) is the primary symptom in about 5% of PsA cases. Such patients may have stiffness and burning sensations in the neck, lower back, sacroiliac, or spinal vertebrae. The spine can be involved in many patients with PsA, even though stiffness and burning sensations in these areas are not the primary symptoms. When it affects the spine, psoriatic arthritis most frequently targets the sacrum (the lowest part of the spine). Movement is difficult.
Arthritis mutilans: This is a severe, deforming, and progressive form of arthritis. It affects less than 5% of PsA cases. It mainly affects the small joints of the hands and feet, but it can also be found in the neck and lower back. Arthritic and skin flares and remissions tend to coincide.

People who start to smoke after developing psoriasis may delay the onset of psoriatic arthritis, according to research presented at the 2007 annual meeting of the Society for Investigational Dermatology. Researchers found that in nonsmokers, the time between psoriasis diagnosis and psoriatic arthritis development was 13 years, compared to 23 among those who started smoking after the onset of psoriasis. Study participants who smoked before developing psoriasis had psoriatic arthritis occur in about 8 years. However, smoking causes serious health problems and should not be considered as a way to delay this type of psoriasis.


Psoriasis Form	Description of Skin Patches	Comments
Guttate Psoriasis	The patches are teardrop-shaped and appear suddenly, usually over the trunk and often on the arms, legs, or scalp. They often disappear without treatment.	Guttate psoriasis can occur as the initial outbreak of psoriasis, often in children and young adults 1 - 3 weeks after a viral or bacterial (usually streptococcal) respiratory or throat infection. A family history of psoriasis and stressful life events are also highly linked with the start of guttate psoriasis. Guttate psoriasis can also develop in patients who have already had other forms of psoriasis, most often in people treated with widely-applied topical (rub-on) products containing corticosteroids.
Inverse Psoriasis	Patches usually appear as smooth inflamed patches without a scaly surface. They occur in the folds of the skin, such as under the armpits or breast, or in the groin.	Inverse psoriasis may be especially difficult to treat.
Seborrheic Psoriasis	Patches appear as red scaly areas on the scalp, behind the ears, above the shoulder blades, in the armpits or groin, or in the center of the face.	Seborrheic psoriasis may be especially difficult to treat.
Nail Psoriasis	Tiny white pits are scattered in groups across the nail. Toenails and sometimes fingernails may have yellowish spots. Long ridges may also develop across and down the nail. The nail bed often separates from the skin of the finger and collections of dead skin can build up underneath the nail.	Over half of patients with psoriasis have abnormal changes in their nails, which may appear before other skin symptoms. In some cases, nail psoriasis is the only symptom.
Generalized Erythrodermic Psoriasis (also called psoriatic exfoliative erythroderma)	This is a rare and severe form of psoriasis, in which the skin surface becomes scaly and red. The disease covers all or nearly all of the body.	About 20% of such cases evolve from psoriasis itself. The condition may also be triggered by certain psoriasis treatments, and other medications such as corticosteroids or synthetic antimalarial drugs.
Pustular Psoriasis	Patches become pus-filled and blister-like. The blisters eventually turn brown and form a scaly crust or peel off. Pustules usually appear on the hands and feet. When they form on the palms and soles, the condition is called palmar-plantar pustulosis.	Pustular psoriasis may erupt as the first occurrence of psoriasis, or it may evolve from plaque psoriasis. A number of conditions may trigger pustular psoriasis, including infection, pregnancy, certain drugs, and metal allergies. It can also accompany other forms of psoriasis and be very severe.

Causes

The precise causes of psoriasis are unknown. It is generally believed to be due to damage in factors in the immune system, enzymes, and other materials that control skin cell division. This prompts an abnormal immune response, which causes rapid production of immature skin cells and inflammation.

The Normal Immune System Response. The inflammatory process is the result of the body's immune response, which fights infection and heals wounds and injuries:

When an injury or an infection occurs, white blood cells are mobilized to rid the body of any foreign invaders, such as bacteria or viruses.
The masses of blood cells that gather at the injured or infected site produce factors to repair wounds, clot the blood, and fight infections.
In the process, the surrounding area becomes inflamed (red and swollen), and some healthy tissue is injured.

The Infection Fighters. The primary infection-fighting units are two types of white blood cells: lymphocytes and leukocytes.

Lymphocytes include two subtypes known as T cells and B cells. Both types of cells are designed to recognize foreign substances (antigens) and launch an offensive or defensive action against them:

B cells produce antibodies, which are designed to attack the antigens. Antibodies can either ride along with a B cell or travel on their own.
T cells have special receptors attached to their surface that recognize the specific antigen.

T cells are further categorized as killer T cells or helper T cells (TH cells).

Killer T cells directly attack antigens found on bacteria or other cells.
Helper T stimulate B cells and other white cells to attack the antigen.

The actions of the helper T cells are of special interest. Researchers have found high numbers of helper T cells in psoriatic plaques. Helper T cells normally stimulate B cells to produce antibodies. In psoriasis, however, they appear to direct the B cells to produce autoantibodies ("self" antibodies), which attack skin cells. In psoriatic arthritis, cells in the joints also come under attack.

Helper T cells also release or stimulate the production of powerful immune factors called cytokines. In small amounts, cytokines are very important for healing. If overproduced, however, they can cause serious damage, including inflammation and injury during the psoriasis disease process. In psoriasis, researchers are particularly interested in cytokines known as GRO-alpha, tumor necrosis factor, and certain interleukins.

Cytokines attract large numbers of other large white blood cells known as neutrophils. Neutrophils stimulate the production of arachidonic acid, producing two key players in the inflammatory process:

Leukotrienes: These chemicals attract even more white blood cells to the inflamed area.
Prostaglandins: These chemicals widen blood vessels and increase blood flow.

A combination of genes is involved with increasing a person's susceptibility to the conditions leading to psoriasis.

HLA Molecules. The processes leading to all autoimmune diseases involve the human leukocyte antigen (HLA) system. HLA molecules pick off parts of antigens and present them on the surface of a cell so that the various infection-fighting factors in the immune system can recognize and destroy them. Most immune disorders, including psoriatic arthritis, are due to problems with this system. For example, psoriasis patients with an HLA genetic factor called HLA-CW6 tend to develop psoriasis at an earlier than average age. However, only 10% of people who have this gene develop psoriasis. Other genetic and environmental factors are required to actually trigger the disease.

PSORs. Researchers have now identified four key genes (named PSOR 1 - 4) that are involved with psoriasis. Of particular interest are the genes located in regions on specific chromosomes that are linked to HLA and tumor necrosis factor, another immune factor strongly associated with psoriasis.

Weather, stress, injury, infection, and medications, while not direct causes, are often important in triggering the disease process leading to the start and worsening of psoriasis.

Weather. Cold, dry weather is a common trigger of psoriasis flare-ups. Hot, damp, sunny weather helps relieve the problem in most patients. However, some people have photosensitive psoriasis, which actually improves in winter and worsens in summer when skin is exposed to sunlight.

Stress and Strong Emotions. Stress, unexpressed anger, and emotional disorders, including depression and anxiety, are strongly associated with psoriasis flare-ups. In one study, nearly 40% of patients remembered a specific stressful event that occurred within a month of a psoriasis flare. Other research has suggested that stress can trigger specific immune factors associated with psoriasis flares.

Infection. Infections caused by viruses or bacteria can trigger some cases of psoriasis. For example:

Streptococcal infections in the upper respiratory tract, such as tonsillitis, sinusitis, and strep throat, are known to trigger guttate psoriasis in children and young adults. The infections may make ordinary plaque psoriasis worse.
Human immunodeficiency virus (HIV) is also associated with psoriasis.
An uncommon form of human papillomaviruses (HPV) called EV-HPV has been associated with psoriasis. Although EV-HPV is probably not a direct cause, it may play a role in the continuation of psoriasis. This HPV form is not the virus associated with cervical cancer and genital warts.

Skin Injuries and the Köbner Response. The Köbner response is a delayed response to skin injuries, in which psoriasis develops later on at the site of the injury. In some cases, even mild abrasions can cause an eruption, which may be a factor in the frequency of psoriasis on the elbows or knees. It should be noted that psoriasis can develop in areas with no history of skin injury.

Medications. Drugs that can trigger the onset of the disease, worsen symptoms, or cause a flare-up include:

Angiotensin-converting enzyme (ACE) inhibitors, drugs used to treat high blood pressure and heart problems
Beta-blockers, drugs used to treat high blood pressure and heart problems
Chloroquine, a medicine used to treat malaria
Lithium for bipolar disorder treatment
Indomethacin, a nonsteroidal anti-inflammatory drug (NSAIDs) -- Note: Other NSAIDs, such as meclofenamate, may actually improve the condition.
Progesterone, used in female hormone therapies

Flare-ups of severe psoriasis may occur in persons who stop taking steroids taken by mouth, or who discontinue use of very strong steroid ointments that cover wide skin areas. The flare-ups may be of various psoriatic forms, including guttate, pustular, and erythrodermic psoriasis. Because these drugs are also used to treat psoriasis, this rebound effect is of particular concern.

Medications that cause rashes, a side effect of many drugs, can trigger psoriasis as part of the Köbner response.

Risk Factors

Between 5.8 and 7.5 million Americans have psoriasis. Risk factors for psoriasis include:

Age under 20. About 40% develop the condition before age 20. Psoriasis (most often plaque psoriasis) can even occur in infants.
Climate. Some studies have found that the disorder develops earlier and more frequently in colder climates. For example, psoriasis occurs more frequently in African-Americans and in Caucasians who live in colder climates than in people of any ethnicity who live in Africa.
Ethnicity. Psoriasis is uncommon in Native Americans of either North or South American descent.
Family history of the disease. About 35% of those with psoriasis have one or more family members with the disorder.
Male gender. Some studies have indicated that more men than women have psoriasis.

Diagnosis

A microscopic examination of tissue taken from the affected skin patch is needed to make a definitive diagnosis of psoriasis and to distinguish it from other skin disorders. Usually in psoriasis, the examination will show a large number of dry skin cells, but without many signs of inflammation or infection. Specific changes in the nails are often strong signs of psoriasis.

Several conditions produce symptoms that resemble those of psoriasis. For example:

Seborrheic psoriasis is hard to distinguish from seborrheic dermatitis (dandruff is one form of this condition). Seborrheic dermatitis patches are usually greasy, yellowish, and crusty. Nail involvement may also help differentiate psoriasis.
Generalized erythrodermic psoriasis may be confused with drug allergic reactions, atopic eczema, and symptoms of lymphomas.
Fungal infections, other skin conditions, or circulation problems may also cause nail changes typical of psoriasis.

Symptoms of psoriatic arthritis may also resemble the following:

Rheumatoid arthritis (RA). As in rheumatoid arthritis, psoriatic arthritis can cause pain or tenderness in one or more joints, and morning stiffness is common. People with psoriatic arthritis, however, lack a particular antibody, called rheumatoid factor, which is found in the blood of many people with rheumatoid arthritis.
Systemic lupus erythematosus (SLE). Symptoms of SLE may include both a psoriasis-like rash and arthritis, which could make the diagnosis difficult.
Reiter's disease. Reiter's disease is a syndrome that includes arthritis and inflammation in the eyes and urinary tract. It also causes skin lesions that are very similar to psoriasis, which are usually raised patches on the lips, penis, palms, and soles.
Gout. Gout causes pain, often in the fingers and toes.

Some evidence now indicates that inflammation in psoriatic arthritis may be distinguished from other arthritic conditions by its occurrence in sites where muscle tissue inserts into the bone (called enthesitis) rather than in the joint, which is a common site in other inflammatory arthritic conditions.

Severity of psoriasis itself ranges from one or two flaky inflamed patches to widespread pustular psoriasis that, in rare cases, can be life threatening. To help determine the best treatment for a patient, doctors usually classify the disease as mild to severe. The classification depends on how much of the skin is affected:

Mild psoriasis affects less than 3% of the body surface. Most cases of psoriasis are limited to less than 2% of the skin.
Moderate psoriasis covers 3 - 10% of the skin.
If more than 10% of the body is affected, the disease is considered severe.

The palm of the hand equals 1% of the body. The severity of the disease is also measured by its effect on a person’s quality of life.

However, the National Psoriasis Foundation has proposed a new classification method. The group suggests a new two-tiered system that classifies patients as needing either local or body-wide (systemic) treatment.

While disease severity impacts treatment success, some forms of psoriasis can be very resistant to treatment even though they are not categorized as severe. They include:

Any psoriasis on the palms and soles (hand and foot psoriasis)
Inverse psoriasis (which occurs in the folds of the skin)
Scalp psoriasis
Psoriatic arthritis

Treatment

Many creams, ointments, lotions, and pills are available for the treatment of psoriasis. Many patients require only over-the-counter treatment, or even none at all during relapses.

About a third of patients with psoriasis, however, do not respond to over-the-counter remedies and lifestyle changes, and require aggressive treatments. In some cases, such treatments need to be lifelong.

In general, there are three treatment options for patients with psoriasis.

Topical medications such as lotions, ointments, creams, and shampoos
Body-wide (systemic) medications, which involve pills or injections that affect the whole body, not just the skin
Phototherapy, which uses light to treat psoriasis lesions

Individual requirements vary widely, and treatment selection must be carefully discussed with the doctor.

Giving treatment in a particular order is a strategy for providing both quick relief of symptoms and long-term maintenance. It involves three main steps:

The quick fix, to clear the psoriatic lesions during an acute outbreak (for example, a high-strength topical steroid in mild-to-moderate psoriasis, or an oral immunosuppressant in more severe cases)
The transitional phase, intended to gradually introduce the maintenance drug
Ongoing maintenance therapy

Choices for transitional or maintenance treatments depend on the severity of the condition. Some examples are described in the following sections.

In severe chronic cases, a doctor may recommend rotational therapy. This approach alternates treatments. The goal is to prevent severe side effects or build-up of resistance from long-term use of a single medicine. An example of a rotational schedule may be the following:

The patient gets phototherapy for about 2 years.
The patient then takes one or two powerful body-wide drugs for 1 - 2 years and stops.
Phototherapy starts again, and the cycle repeats.

Some doctors use the Koo-Menter Psoriasis Instrument (KMPI) to decide which patients should receive a pill or an injection. The KMPI’s questions include:

Does psoriasis cover at least 5% of the patient’s body?
Is the patient disabled by psoriasis?
Does psoriasis affect the patient’s quality of life?

If the answer to these questions is "yes," three additional questions are considered:

Is light therapy inappropriate for the patient?
Is the patient’s psoriasis resistant to light therapy?
Does the patient have psoriatic arthritis?

If the answer to these questions is “yes,” a doctor may decide to prescribe a pill or injected drugs.

Doctors increasingly use combinations of pills, creams, ointments, and phototherapy instead of single medications. Combinations of oral treatments are particularly useful, since the doses of each drug can be reduced. This lowers the risk of severe side effects. Thousands of combinations are possible, and the patient and doctor should discuss the best treatment for individual needs.

Topical Medications

Topical medications are those applied only to the surface of the body. They come in the following forms:

Creams
Foams
Gels
Lotions
Occlusive tapes
Ointments
Shampoos
Solutions
Sprays

In general, topical treatments are the first line for mild-to-moderate psoriasis, but they may also be used, alone or in combination, with more powerful treatments for moderate-to-severe cases. Topical medicines rarely produce complete clearance, however.

Corticosteroid topical treatments are the mainstay of psoriasis treatments in the United States. They work for most patients. Such treatments:

Decrease inflammation
Block cell production
Relieve itching

Corticosteroids are available in a wide range of strengths, and are generally given as follows:

Less potent drugs are used for mild-to-moderate psoriasis.
Stronger drugs are reserved for more severe disease.

In the past, topical steroids have been used twice a day. Studies are reporting, however, that certain drugs may work just as well if taken once a day. Most studies have evaluated high-potency steroids, but one study suggested that those of medium strength, such as triamcinolone (Aureocort, Tri-Adcortyl), may be equally beneficial as a once-daily treatment. However, corticosteroids used alone clear psoriasis in only 4 - 36% of patients.

Combination therapy. Combinations with other drugs are often needed. For example, an effective, topical regimen uses the following combination for maintenance therapy:

A high-potency steroid (such as halobetasol) on the weekend
A vitamin D3 topical medication called calcipotriene, twice daily on weekdays

In one study, more than 75% of patients with mild-to-moderate psoriasis remained in remission for at least 6 months with this regimen.

Side Effects. The more powerful the corticosteroid, the more effective it is. But it also has a higher risk for severe side effects. Side effects may include:

Burning
Irritation
Dryness
Acne
Thinning of the skin; skin may become shiny, fragile, and easily cut
Dilated (widened) blood vessels
Loss of skin color

Loss of Effectiveness. In most cases, the patients become tolerant to the effects of the drugs, and the drugs no longer work as they should. Some experts recommend using intermittent therapy (also called weekend or pulse therapy). This type of treatment involves applying a high-potency topical medication for 3 full days each week.

Note: This list is not all inclusive.
Low potency (some are available over the counter)	Desonide (Tridesilon, DesOwen) Flumethasone pivalate (Locorten) Fluocinolone acetonide (Synalar, Derma-Smoothe) Hydrocortisone (Hytone, Penecort, Synacort, Cort-Dome, Nutracort, Westcort) Triamcinolone acetonide (Aristocort)
Low to medium potency	Alclometasone dipropionate (Aclovate) Hydrocortisone (Locoid, Pandel) Hydrocortisone valerate (Westcort) Prednicarbate (Dermatop)
Medium to upper-mid potency	Clocortolone pivalate (Cloderm) Fluticasone propionate (Cutivate) Mometasone furoate (Elocon) Triamcinolone acetonide (Aureocort, Tri-Adcortyl, Kenalog)
High potency	Betamethasone (Diprosone) Amcinonide (Cyclocort) Desoximetasone (Topicort) Diflorasone diacetate (Florone, Maxiflor) Fluocinonide (Lidex) Halcinonide (Halog)
Very high potency	Halobetasol propionate (Ultravate) Betamethasone (Diprolene, Luxiq) Clobetasol propionate (Temovate, Olux) Diflorasone diacetate (Florone, Maxiflor, Psorcon)

Coal tar preparations have been used to treat psoriasis for about 100 years, although their use has declined with the introduction of topical vitamin D3-related medicines. Crude coal tar stops the action of enzymes that contribute to psoriasis, and helps prevent new cell production. Tar is often used in combination with other drugs and with ultraviolet B (UVB) phototherapy.

Side Effects. Preparations have the following drawbacks:

Stains on clothing
Skin irritation
Sun sensitivity and increased risk of sunburn for up to 24 hours after use

Anthralin (Dritho-Scalp, Drithocreme, Micanol) is related to a medication called chrysarobin, in use since the early 1900s. Anthralin slows skin cell reproduction and can produce remissions that last for months. It is recommended only for chronic or inactive psoriasis, not for acute or inflamed eruptions. Persons with kidney problems should use anthralin with caution.

As with tar, its use has also declined with introduction of the topical vitamin D-related medicines, but newer formulations, such as Micanol, have made its use more tolerable. Micanol (Psoriatec) is an anthralin formulated in microcapsules, which dissolve and allow the drug to be delivered directly to the target skin areas. It is particularly useful for scalp psoriasis, and it is less likely to stain.

Side Effects. Anthralin may cause the following side effects:

Skin irritation and burning
Staining of clothes, hair, fabrics, plastics, and other household products

Patients should not use anthralin on their faces. Fair skinned people should generally avoid it. Triethanolamine (CuraStain) is a chemical that can neutralize anthralin and help reduce irritation from short-contact anthralin treatment. It should be applied 1 or 2 minutes before washing off the anthralin. It is then reapplied after drying the skin.

Washing stained items with hypochlorite (Clorox) detergents can help remove stains. Many people use disposable gloves while applying the treatment to avoid staining hands.

Application. Apply anthralin only to the psoriasis plaques. Rub the cream in well, and wipe off any excess. Wash off only with lukewarm water, not soap. Using hot water will trigger the staining action. A technique called short-contact anthralin therapy (SCAT), also called minute therapy, is useful for local areas of psoriasis. In such cases, anthralin is applied for only 10 minutes to an hour.

A topical form of vitamin D3, calcipotriene (Dovonex) is proving to be both safe and effective. It is now available in a foam preparation, which makes compliance even easier. Several other topical vitamin D3 related drugs showing promise include maxacalcitol (Oxarol), tacalcitol, and calcitriol (Silkis).

Calcipotriene appears to:

Block skin cell reproduction
Enhance the maturity of keratinocytes (the impaired skin cells in psoriasis)
Acts as an anti-inflammatory

It works just as well as moderate topical corticosteroids, short-term anthralin, and coal tar in improving mild-to-moderate plaque psoriasis. Unlike steroids, patients do not develop thinning of the skin or tolerance to the drug.

Using the drug in combination with other topical and systemic treatments may improve effectiveness. Calcipotriene doesn't work as well as the highest potency corticosteroids, but products or regimens that combine both medications are proving to be more effective than either one alone. Taclonex, an ointment containing both calcipotriol and betamethasone, was approved by the U.S. Food and Drug Administration (FDA) in January 2006 for the treatment of adults with psoriasis. Studies show the combination works better than either drug alone.

Combining vitamin D ointments with systemic medicines, notably methotrexate, acitretin, or cyclosporine, increases effectiveness and allows lower doses or either medication, thereby reducing side effects.

Studies also report success in some patients who use vitamin D ointments in combination with phototherapy treatment.

Side Effects. Calcipotriene may cause the following side effects:

A possible lowering of vitamin D levels, which may affect bone growth in some children
A possible increase in blood calcium levels (seen in some people who apply calcipotriene to large areas)
Skin irritation in about 20% of patients, particularly on the face and in skin folds

Calcipotriene appears to cause greater skin irritation than potent corticosteroids. Diluting the drug with petrolatum or applying topical corticosteroids to sensitive areas may prevent this problem.

Retinoids are related to vitamin A. They are used for various skin disorders. Tazarotene (Tazorac) is the first topical retinoid found to be effective for mild-to-moderate psoriasis. It is available in cream or gel form.

Unlike steroids, patients do not develop thinning of the skin or tolerance to the drug. Only a very small amount is needed on each lesion. It can be used on the scalp and nails, but it is not recommended for the genital areas or around the eyes. The gel should be used on only 20% of the body at anytime; the cream on up to 35%. (Note: The palm of the hand is about 1% of the body surface.)

Combining topical retinoids with other psoriasis treatments, such as with topical steroids, works better than using the drug by itself.

Side Effects. Tazarotene may cause dryness and irritation of healthy skin. Applying zinc oxide and moisturizer around the treated area can protect the healthy skin.

At levels high enough to be effective for psoriasis, tazarotene can cause severe skin irritation on treated areas. This medicine, then, is usually used in combination with other treatments, therefore allowing a lower dose. Mixing the drug in equal amounts with petroleum jelly (Vaseline) initially and then gradually increasing the amount of tazarotene may help the skin areas become less sensitive. It should be noted that the skin can become very red while it is actually improving.

Vitamin A derivatives (drugs related to vitamin A) have been associated with birth defects and should not be used by women who are pregnant, who wish to conceive, or who are nursing.

Salicylic acid applied to the skin helps remove scaly plaque and enhance the actions of other medications. It should not be used to cover wide areas of the body, since it can cause nausea and ringing in the ears. Combinations with high potency steroids, such as mometasone furoate (Combisor), clobetasol propionate, and betamethasone, are proving to be very helpful. Only Combisor is available in the United States.

Watertight (occlusive) tapes or wrappings may help heal psoriasis. Occlusive tapes are particularly useful for psoriatic cuts on the palms and soles. In such cases, the tape should be applied across the cuts until they heal.

Occlusive tapes retain sweat, which helps restore moisture to the outer skin layer and prevent scaling. They also protect against abrasion and irritation.

High-Potency Corticosteroid Tapes. Applying a corticosteroid beneath an occlusive tape, or using a tape that already has a potent corticosteroid (Cordran Tape) such as flurandrenolide may be especially beneficial. Studies are showing that high-potency corticosteroid-containing tapes are more effective than using high-potency corticosteroid ointments alone.

However, the tapes are expensive and are associated with a high rate of skin irritation, increased secondary infections, and a greater chance of symptoms relapse after treatment is stopped. Infection risk may be reduced by changing tapes every 12 hours.

The use of corticosteroids under occlusive tapes on large areas of psoriasis also increases the risk for adrenal insufficiency, a sometimes dangerous condition that occurs because the body loses its ability to produce natural steroids. Children are especially vulnerable to this effect.

Other Medications with Occlusive Tapes or Wrappings. The tapes may be used in combination with other medications, such as fluorouracil. Occlusive wrappings are not usually used with tazarotene (Tazorac) and should never be used without a doctor's recommendation.

Numerous topical medications are under investigation. One such medication, tacrolimus (Protopic), is an immunosuppressant that is proving to be useful in allergic skin disorders and is being studied for psoriasis. Studies have been mixed on its benefits, although new delivery methods may make it more effective. It may prove to be safe for sensitive areas, such as the face. Pimecrolimus (Elidel), a similar medication, is also being studied.

Systemic Medications

Systemic treatment uses various medications that affect the whole body, not just the skin. Many systemic drugs used for psoriasis are also used for other severe diseases, including autoimmune diseases (especially rheumatoid arthritis) and cancer.

Systemic treatments for psoriasis may be taken by mouth or injection. The medicines can have significant side effects and are generally reserved for severe psoriasis.

At this time, the only systemic medications specifically approved for psoriasis are:

Cyclosporine
Methotrexate
Retinoids

As with all medications for psoriasis, the patient should use the lowest strength medication first. The primary treatment is called a first-line treatment, the next is known as a second-line treatment, and so on. Combinations of medications are often used.

Methotrexate (Rheumatrex) is a biologic drug that interferes with cell reproduction and has anti-inflammatory properties. It is a first line, or primary, systemic drug used to treat adults with severe psoriasis. The medicine is one of the few systemic drugs proven to help patients with psoriatic arthritis.

The drug is taken weekly, not daily. (Deadly reactions have been reported in people who mistakenly took it once a day.)

Side Effects. Common side effects of methotrexate include:

Anemia
Headache
Mild hair loss
Mouth sores
Nausea
Possible muscle aches
Rash
Vomiting

Many of these side effects are due to folic acid deficiency. Patients should ask their doctor if folic acid supplements (generally recommended at 1 - 5 mg daily) are necessary.

More serious side effects include:

Increased risk for infections, particularly shingles and pneumonia. Methotrexate suppresses the immune system. Patients with active infections should avoid this drug.
Infertility, miscarriage, and birth defects. If used during pregnancy, the drug can cause miscarriages or birth defects in the baby. It may harm fertility in men.
Kidney complications.
Liver damage. In one study, 25% of patients taking methotrexate for 5 years developed scarring of the liver. Those with existing liver problems should not take this medicine, if possible. Regular monitoring for liver toxicity, including blood tests and liver biopsies, is important in patients who take the drug.
Lung disease. This side effect can be sudden and severe, and occurs in up to 5% of people who take methotrexate. Risk factors include diabetes, existing lung inflammation, protein in urine, and use of rheumatoid arthritis drugs called DMARDs.
Lymphomas. A few cases have been reported, which are most likely related to the drug's immune-suppressing (lowering) effects. In most instances, the disease has gone into remission when the drug was stopped. Most studies have found no significant risk for cancers in patients taking methotrexate.
Osteoporosis. Low doses of methotrexate do not appear to have any significant effect on bone loss, but long-term studies are needed to confirm this.
Radiation recall: An uncommon side effect in patients who have previously been burned by radiation cancer treatments or sunburns. In such cases, a flare-up of symptoms occurs in the previously affected skin areas.
Severe anemia. Folic acid supplements can offset this effect.
Toxic effects on bone marrow. This can cause reduced blood cell production.

Despite its side effects, some experts view methotrexate as the best therapy for widespread plaque psoriasis. It may also be effective for some patients with other severe forms of the disease, including psoriatic arthritis, generalized erythrodermic, and pustular psoriasis.

Methotrexate appears to be effective in children, but more safety research is needed.

Drug Interactions. Many drugs interact with methotrexate, occasionally with harmful results. For example, the antibiotic trimethoprim-sulfamethoxazole increases the toxicity of methotrexate.

A serious, harmful reaction can occur if methotrexate is taken with common, nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, or naproxen. Other NSAIDs, namely ketoprofen, flurbiprofen, and piroxicam, appear to be safe when given with methotrexate and may be used in patients with psoriatic arthritis. Rheumatoid arthritis (RA) patients who take methotrexate often take NSAIDs as well, but methotrexate doses in psoriasis patients are usually much higher than those in RA.

People Who Should Avoid Methotrexate. Pregnant and nursing mothers should never take methotrexate because it increases the risk for severe, even fatal, birth defects and miscarriage. The drug should be discontinued several months before planning a pregnancy. It may also cause temporary impairment of fertility in men.

Persons with the following conditions should also avoid taking methotrexate:

Alcoholism
Anemia or other blood abnormalities
Immunosuppression
Kidney problems
Liver problems (including hepatitis)
Rheumatoid arthritis
Peptic ulcers

Patients at risk for liver complications include those with diabetes and obesity. Anyone with a history of hepatitis should have a liver biopsy before taking methotrexate.

Oral retinoids are vitamin A-related medications taken by mouth. This group of medicines is also a first-line treatment for adults with severe psoriasis. Oral retinoids used for psoriasis include acitretin (Soriatane) and isotretinoin (Accutane).

Acitretin is the retinoid of choice and may be dramatically effective for severe psoriasis, particularly pustular or erythrodermic variants. When used alone, it is much less effective against more common forms, such as plaque or guttate psoriasis. However, combinations with PUVA phototherapy can markedly improve the response even in these patients.

Accutane, more commonly used to treat acne, is far less potent than acitretin, but may still be effective against pustular psoriasis and also be effective with phototherapy.

Oral retinoids help control cell reproduction and have anti-inflammatory properties. They may even improve arthritis that accompanies psoriasis.

Combination therapy. Acitretin may work the best when combined with other treatments, usually topical drugs and especially phototherapy. Combination therapy allows lower doses of oral retinoids to be used, which diminishes many skin and mucous membrane side effects. Acitretin combined with phototherapy has some of the highest clearance rates of any treatment.

Side Effects. All retinoids have the same potentially serious toxicities as do high doses of vitamin A. Side effects include:

Bone and joint pain
Bruising
Depression and possible suicide risk (with isotretinoin)
Eye problems, including blurred vision, cataracts, conjunctivitis, and a sudden deterioration in night vision
Fatigue
Headache
Increased bone growth, particularly in the ankles, pelvic area, and knees
Increased triglyceride levels
Liver damage
Nail problems
Skin and mucous membrane problems, including dry nose, nosebleeds, dry eyes, chapped lips, thinning hair, dry or "sticky" feeling skin, and peeling of the palms and soles

In rare cases, retinoids, particularly isotretinoin, may cause a condition called benign intracranial hypertension (pseudotumor cerebri), which occurs in the brain. Symptoms include headache, nausea, vomiting, and blurred vision. Patients experiencing these symptoms should call a doctor immediately and stop taking the drug.

Oral retinoids should not be taken during pregnancy.

Despite these side effects, oral retinoids remain among the safest systemic therapies for psoriasis. A low-fat diet, aerobic exercise, and fish oil supplements may help reduce the side effects. Certain cholesterol-lowering drugs, including gemfibrozil (Lopid) or certain statins, such as atorvastatin (Lipitor), may help control triglyceride levels.

Maintenance doses should be as low as possible and should be taken every second or third day.

Taking retinoids during pregnancy significantly increases the risk for severe birth defects in the unborn child. Pregnant or nursing women or those planning to become pregnant should not use these drugs. Women of childbearing age who take retinoids should have regular pregnancy tests.

Doctors recommend that acitretin should not be given to any woman who may become pregnant within 3 years of taking it. Drinking alcohol changes acitretin to a retinoid that is stored in fat cells for 3 years. It may have the potential for causing birth defects during that time. It's important to note that cooking products and over-the-counter preparations, such as cough syrup, may contain alcohol and be inadvertently consumed.
Women who are pregnant or plan to become pregnant should not use isotretinoin. As of December 31, 2005, everyone who takes, prescribes, or dispenses the drug must enroll in a national registry called iPLEDGE.

Cyclosporine (Neoral, Sandimmune, SangCya) blocks certain immune factors and may be effective for all forms of psoriasis. It is also a first line, or primary, systemic drug used to treat adults with severe psoriasis. Neoral is the preparation used most often for psoriasis and clears psoriasis in many patients within 8 - 12 weeks.

Side Effects. Cyclosporine has significant side effects if used for a long time, notably kidney problems and non-melanoma skin cancers. It should be reserved for patients who do not respond to phototherapy or less potent systemic medications (for example, methotrexate or acitretin).

Common and temporary side effects include:

Fatigue
Gingivitis
Gout
Hair growth
Headaches
Joint pain
Tremor

More serious complications may include:

Kidney damage
High blood pressure (Some doctors advise treating high blood pressure with calcium channel blockers, since other standard blood pressure drugs may worsen psoriasis. Calcium channel blockers also help prevent kidney problems.)
High cholesterol and lipid levels
High levels of calcium and low levels of magnesium
Increased risk for infections
Liver problems
Lymphomas
Skin cancers (Patients who have taken cyclosporine after PUVA therapy have a higher incidence of squamous cell skin cancer. According to a 2003 study, the risk is six times that of the general population. The risks are highest with long use and previous use of PUVA, methotrexate, or other immunosuppressants.)

To reduce complications of cyclosporine, the dosage is decreased after improvement occurs. Maintenance therapy is usually limited to a year, although some experts believe that a microemulsion form of Neoral (Neoral-Neo) may be safe for up to 2 years. Patients should be monitored regularly for high blood pressure and signs of kidney or liver problems and skin cancers.

Patients Who Should not Use Cyclosporine. Because the drug suppresses the immune system, people with active infections or cancer should avoid it. Patients with uncontrolled high blood pressure and impaired kidney function should also not use this medication. Cyclosporine therapy for children with psoriasis has not been well studied.

Drug and Food Interactions. Cyclosporine interacts with numerous drugs -- both prescription and over-the-counter preparations -- and also grapefruit and grapefruit juice.

Biological response modifiers, sometimes called "biologics," belong to a new class of drugs that are considered the most exciting development in psoriasis treatment. Biologics are genetically engineered drugs that interfere with specific components of the autoimmune response. Because of their precise targets, these drugs do not damage the entire immune system the way that general immunosuppressants do.

Biologics are considered second- or third-line treatments, and may be used alone or sometimes in combination with first-line systemic drugs.

There are different types of biologics used to treat psoriasis:

T cell blockers block immune cells linked to inflammation.
Tumor necrosis factor (TNF) blockers target the chemical messenger TNF-alpha, which is released during the inflammatory response.

Types of T-cell blockers:

Alefacept (Amevive). This drug is approved for the treatment of moderate-to-severe plaque psoriasis. Studies suggest that the drug produces 50 - 75% improvement in symptoms. Alefacept is given in a doctor's office or clinic. Patients receive weekly injections for 12 weeks. Patients need weekly blood tests to make sure T cell levels do not drop too low. Side effects are generally mild and include sore throat, dizziness, and cough. There have been a few reports of serious infection and cancer.
Efalizumab (Raptiva). This drug is approved for the treatment of moderate-to-severe plaque psoriasis. Many patients experience 50 - 75% improvement in symptoms within 4 - 6 weeks of starting the drug. Patients give themselves shots of this drug for 12 weeks. Some clinical trials suggest that a longer course of treatment (24 weeks) may also be safe and effective for patients with chronic plaque psoriasis. Some patients have flare-ups of psoriatic lesions after stopping efalizumab. Very serious, but rare, side effects include hemolytic anemia and antibiotic-resistant infections.

Types of TNF blockers:

Etanercept (Enbrel) is approved for the treatment of psoriatic arthritis and moderate-to-severe plaque psoriasis. The drug is given either alone or in combination with methotrexate. Side effects include infections and lymphoma, a type of cancer. Patients inject themselves under the skin, once or twice a week for 12 weeks. However, a 2007 study published in the Archives of Dermatology found that continuing etanercept after 12 weeks lowers the severity of disease without increasing infections or side effects. Study participants randomly received 50 milligrams of the drug or a placebo biweekly up to 84 weeks. Strongest improvements were noted at 48 weeks among those who received the drug.
Infliximab (Remicade) is approved for the treatment of psoriatic arthritis. Patients receive three intravenous infusions during the first 6 weeks of treatment. After the initial treatment period, patients receive an infusion every 8 weeks. Therapy takes 2 hours and is given in a doctor’s office or clinic. Patients with a history of infection or heart failure should not take this drug. Several studies have shown that symptoms improve significiantly by week 10 in the majority of patients with severe psoriasis who are treated with infliximab.
Adalimumab (Humira) is being tested in clinical trials for treatment of psoriasis and psoriatic arthritis. Results from a Phase III (late-stage) study show that the drug works better than methotrexate in the treatment of moderate-to-severe psoriasis.
Efalizumab (Raptiva) appears to effectively clear or nearly clear moderate-to-severe hand and foot psoriasis after 12 weeks. This type of psoriasis is often very difficult to control and treat.

Interleukins (IL) being investigated as sources or targets of therapy include IL-4, IL-2, IL-8, IL-11, and IL-12. For example, in a 2003 study, 75% of patients with severe psoriasis who were treated with interleukin-4 (rhuIL-4) experienced improvement rates of more than 68%.

A study of 180 patients with moderate-to-severe plaque psoriasis has shown that an investigational medicine called ABT-874 greatly reduced symptoms in most patients. ABT-874 targets proteins that are responsible for psoriasis-related inflammation.

Leflunomide. Leflunomide (Arava) is a disease-modifying antirheumatic drug (DMARD), which blocks autoimmune antibodies and is a powerful anti-inflammatory medication. It is proving to be active against psoriatic arthritis. Reports of adverse effects are comparable to those with methotrexate. Common problems include nausea, diarrhea, hair loss, and rash. Potentially serious side effects include infections and liver injury.

Sulfasalazine. Sulfasalazine (Azulfidine) is sometimes used for psoriasis. In one major analysis, sulfasalazine and methotrexate were the only medications proven to help patients with psoriatic arthritis. Many people, however, stop taking the drug because of common side effects that include headaches, gastrointestinal complaints, and rash. Benefits, if any, should be apparent in 4 - 6 weeks.

Immunosuppressants. Some immunosuppressants being studied for psoriasis include tacrolimus (Prograf), pimecrolium, and sirolimus. In one study, for example, tacrolimus showed an 83% reduction in symptoms in patients with psoriasis who used the drug. Studies have been limited, however. Side effects of these medications are similar to those of cyclosporine. Pimecrolimus may specifically target the skin and so have fewer side effects. (Some are also being studied as topical treatments.)

Phototherapy

Phototherapy means to treat with light.

When sunlight penetrates the top layers of the skin, this ultraviolet radiation bombards the DNA inside skin cells and injures it. This can cause wrinkles, aging skin, and skin cancers. However, these same damaging effects can destroy the skin cells that form psoriasis patches.

Phototherapy for psoriasis can be given as ultraviolet A (UVA) light in combination with medications, or as variations of ultraviolet B (UVB) light with or without medications. Not everyone is a candidate. For example, it may not be appropriate for patients who should avoid sunlight or those with very severe psoriasis.

Ultraviolet A (UVA) is a main part of sunlight. UVA phototherapy uses a photosensitizing medication (usually psoralen) in combination with UVA radiation to be effective. A photosensitizing medication makes a person more sensitive to light. Treatment with psoralen and UVA is referred to as PUVA. This approach is very powerful and effective in more than 85% of patients who use it. However, it poses a higher risk for skin cancers than UVB.

PUVA treatments cause inflammation and redness in the skin to develop within 2 - 3 days after treatment. Such damage inhibits skin cell proliferation and reduces psoriasis plaque formation.

Forms of psoralen include methoxsalen, 8-methoxypsoralen (8-MOP), or bergapten (5-MOP). The effectiveness of the treatment is based on a chemical reaction in the skin between the psoralen and light, which creates redness and inflammation that prevents the psoriasis disease process.

People should avoid this treatment if they are taking drugs or have conditions that cause them to be light sensitive. They should also take protective measures before, during, and after each treatment.

Initial PUVA Treatment Phase. The initial phase typically follows these steps:

Psoralen is typically taken by mouth in the form of 8-methoxypsoralen (for example, Oxsoralen) 75 minutes to 2 hours before the treatment starts. Psoralen reaches the skin through the bloodstream, where it increases the skin's sensitivity to UVA radiation.
Topical preparations of psoralen are alternatives to pills. They can be "painted on" or applied to the affected areas by soaking or bathing in a psoralen solution. PUVA-bath therapy may be especially useful for persistent psoriasis on the palms and soles or for patients with liver disease or who get severe nausea from taking the pill form. UVA should be given within 15 minutes of using topical psoralen.
The patient enters and stands in a light box, a unit lined with ultraviolet lamps. The initial UVA exposure time is very short (seconds to several minutes), and then increases to 20 minutes or longer. The amount of time a person is exposed to UVA rays depends on the skin type, with the shortest times recommended for fair-skinned patients.
Treatments may be repeated two or three times a week. They should never be performed more frequently than once every other day, since the full effects of the treatments are not evident for 48 hours.

It takes an average of about 25 PUVA treatments for full effect, but during that period, treatment intensity may vary.

If there is no response after 10 treatments, the doctor may increase the UVA energy.
If there is still no response after 15 treatments, the psoralen dosage may be increased.
If a patient's skin does not improve at all or worsens after these changes, the treatment is temporarily stopped. PUVA may be causing a toxic response in such cases, and, often, the condition gradually improves over the following 2 weeks.
If the skin does not improve over the following 2 weeks, PUVA treatment has failed. If skin improves during this resting period, treatment resumes.

Maintenance Phase. Once the psoriasis has improved by about 95%, the patient may be put on a maintenance schedule. Often only one or two treatments a month are needed, but some people may need more frequent treatments. As maintenance continues and the interval between treatments lengthens, the patients may become more susceptible to tanning and sunburn. They should reduce exposure to natural sunlight during this time.

Success Rates. Nearly 90% of patients achieve marked improvement or clearing within 20 - 30 treatment sessions.

Combinations. Combining acitretin, calcipotriene, methotrexate, or tazarotene gel with PUVA may enhance effectiveness or increase response. In addition, combinations may allow for lower doses of radiation or medications to be used, minimizing side effects. Retinoids may also help protect against skin cancers, while methotrexate may increase the risk. In some cases, patients resistant to PUVA or UVB may respond when the phototherapies are combined.

Side Effects and Complications of PUVA.

The psoralen methoxsalen causes a general ill-feeling and nausea in 20% of patients. Dividing up the dose and taking it in 15-minute intervals with food, or taking ginger 20 minutes before taking the drug, may be helpful.
Skin reactions, including itching, sunburn, and blistering, are common. These can generally be avoided with careful administration of PUVA therapy and protective measures. Antihistamines, baths with special oatmeal preparations (Aveeno), and capsaicin ointment (Zostrix) may be helpful.
After treatment, white spots commonly develop where psoriasis plaques had been, particularly in people with naturally darker skin. If they are troublesome, tanning products may help darken them. Small, dark raised spots called PUVA lentigines may also develop in affected areas with long-term treatment
Prolonged standing may trigger fainting in people with certain heart or blood pressure problems.
People with liver disease should discuss using topical psoralens, since oral forms may have adverse effects on the liver.
UVA penetrates the skin more deeply than UVB, so there is a greater danger of deep skin damage, accelerated skin aging, and skin cancers. Anyone who needs to avoid sunlight should not get this treatment.
The procedure increases the risk for cataracts if eyes are not protected for up to 24 hours after treatment.

Special Warning on PUVA and Skin Cancers. It has been known for some time that PUVA can change DNA and cause genetic mutations. PUVA is known to increase the risk for squamous cell skin cancer and slightly increase the risk for basal cell skin cancer, both of which are nearly always curable. One study reported an increased risk of melanoma. The risk for skin cancers is higher in persons who have:

A family or personal history of skin cancer
Light skin and fair or red hair
Received radiation or x-ray treatments or taken immunosuppressant drugs
Received over 200 PUVA treatments

Discussions are under way about discontinuing PUVA for psoriasis. The arguments generally are as follows:

Opponents of PUVA argue that studies suggest a long-term risk for melanoma, starting about 15 years after treatment, particularly in people who receive more than 250 treatments. In one long-term study, only 9 out of 1,380 patients developed melanoma. However, 7 of these cases occurred in the last 5 years of the study, indicating that the danger persists and more patients in this study are likely to develop this serious skin cancer as time goes on.
Supporters of PUVA argue that it is not yet known if the people who developed melanoma experienced sunburn during the procedures or if they already had risk factors for skin cancers. If so, then properly given treatments could still be considered safe for patients without risk factors. They also argue that PUVA is still the most effective treatment for severe psoriasis, and the alternatives are usually very powerful and relatively new drugs that may have even more serious side effects. Furthermore, the addition of retinoids may protect against skin cancers while proving to be a very effective combination.

Side effects of UVA radiation can be severe. Protective measures are needed during, before, and after treatment. Patients should avoid prolonged exposure to the sun for 24 hours before the oral treatment starts.

Protective Measures During Treatment:

Patients should wear specially designed goggles to protect the eyes from UVA radiation.
Sensitive areas, such as genitals, abdominal skin, and breasts, should be covered until tanning occurs in the exposed areas, after about a third of the treatment period. Note that PUVA is associated with a high risk for genital skin cancers, so male genitals must be covered throughout the process.

The following safety features should be available in the PUVA chamber:

Lamps with protective shields
A viewing window for a health professional to check the patient periodically
A door that can be opened by the patient easily and with little pressure
A timer that terminates the session automatically
An accessible alarm device

Protective Measures After Treatment. The drugs used in PUVA increase susceptibility for a natural sunburn for hours after treatment. The patient should take the following precautions:

Patients should wear UVA absorbing wrap-around sunglasses that are designed to completely block out stray radiation. They should begin wearing them as soon as they take the drug, and for at least 12 hours after the treatment. This is important to prevent a PUVA reaction around the eyes that can cause cataracts. There is no need to wear these glasses after sundown.
For about 8 hours after taking the drug, patients must also avoid exposure to daylight, even if the day is cloudy or exposure occurs through windows.
Patients who must go out should wear heavy opaque clothing (clothes that do not let light through), including hats and gloves.
Patients should apply sunblock over all exposed areas, including the lips. The sunblock should have an SPF (sun protection factor) of more than 15 and include ingredients that block both UVB and UVA radiation.
No patient should spend a long time in sunlight for at least 2 days after the combined treatment.

Ultraviolet B is another main part of sunlight, and is the main cause of sunburn. It generally affects the outer skin layers. UVB radiation reduces the abnormally rapid skin cell growth that occurs with psoriasis.

Types of UVB therapy:

Broadband UVB
Narrowband UVB (NB-UVB)
Laser treatments

Broad spectrum or broad band UVB is radiation in the wavelength of 290 - 350 nanometers, and is the standard UVB phototherapy treatment in the United States. It is not as potent as the treatments that use narrow-band UVB or PUVA, and is not useful for chronic psoriasis.

Broadband UVB may be given with or without medications. When used without medication (known as selective ultraviolet phototherapy), UVB treatment generally is given as follows:

Treatment starts in the doctor's office or another medical setting. Once the disease has stabilized, the patient can obtain a prescription for equipment that can be used at home. Even at home, treatment must always be supervised.
In preparation, the patient fully undresses, although unaffected areas may be covered to avoid overexposure.
The initial session may last as little as a few seconds, depending on whether the patient has a lighter or darker skin, with the lightest skin exposed to the briefest session. The duration increases with each treatment until the skin clears or the patient experiences itching or irritation. It should be noted that the condition may worsen initially.
UVB therapy usually requires about 20 - 40 treatments (about three per week). Full results take about 3 weeks.

Use of Medication. UVB was commonly used with coal tar (the Goeckerman regimen) in past decades, and then with anthralin (the Ingram regimen). Other medications are being studied with some success, and may prove to be tolerated better.

The Goeckerman regimen requires daily treatments for up to 4 weeks. The coal tar or anthralin are applied once or twice each day and then washed off before the procedure. Studies indicate that a low-dose (1%) coal tar preparation is as effective as high dose (6%). Such regimens are unpleasant, but still useful for some patients with severe psoriasis, since they can achieve long-term remission (up to 6 - 12 months).

Some evidence suggests that using a simple emollient (such as Vaseline or mineral oil) that enhances UVB light penetration can be effective. This addition to the treatment increases the risk for sunburns, however, and patients must be careful to avoid sun exposure. Researchers are tring combinations of other topical and oral medications. For example, combining UVB with methotrexate, or retinoids such as a tazarotene gel or oral acitretin, is producing positive results. Combinations with any of these drugs, however, must be supervised carefully to avoid serious reactions.

Side Effects of UVB. The treatment can cause itching and redness. UVB radiation from sunlight is known to increase the risk for skin cancers. There is no strong evidence, however, that UVB treatments pose any risk for skin cancers except on male genitalia. This risk, however, can be significant (4.5%) at high doses.

Narrow band radiation may be safer than other approaches, and some experts now believe it should be the first option for patients with chronic plaque psoriasis.

NB-UVB is used without medications and is very strong. Whether it has any affect, however, on the disease process itself is unclear. The light wavelength is between 310 - 312 nanometers, which, theoretically, is the most beneficial part of sunlight.

Exposure times are shorter but of higher intensity than with broadband UVB. This therapy is probably less likely than PUVA to cause skin cancers.

Clearance of 75% typically occurs after 10 - 12 treatments. NB-UVB treatments performed three times a week achieve results that are equal to twice-weekly PUVA treatments. Weekly NB-UVB treatments are not effective. Studies so far are mixed on whether NB-UVB remission rates are equal to those of PUVA.

Patients prefer NB-UVB over other PUVA treatments because they do not have to wear protective eyewear, take medications, or experience unpleasant side effects, notably nausea. It is also safe for pregnant women and children.

Combinations with topical medications, such as tazarotene or psoralens, may help NB-UVB therapy work better.

Laser UVB Treatment. A recent variation of a device called an excimer laser (Xtrac) delivers a precise UVB wavelength of 308 nanometers. The laser is more effective than narrow-band UVB for localized psoriasis, since it allows very specific areas of skin to be targeted. (Note: The therapy is not suitable for the scalp.) Generally, 8 - 10 treatments given twice a week will clear psoriasis. Remission rates are similar to NB-UVB, but the excimer laser can clear the psoriasis faster and at lower doses. It also spares the healthy skin around it. Blistering is a common side effect. More comparison studies are needed to determine risk and benefits compared to NB-UVB, particularly any long-term risk for skin cancer.

Pulsed-Dye Lasers. Pulsed-dye lasers give off high-intensity yellow light, which destroys the tiny blood vessels that make up psoriatic plaques. This treatment has been used for years to remove birthmarks, such as port wine stains and unsightly blood vessels on the skin. Some studies have reported significant (but not complete) improvement, and remissions that have lasted up to 13 months. Treatment sessions last up to 30 minutes and can feel uncomfortable (similar to being repeatedly snapped with a rubber band). It typically takes up to six sessions to clear the target areas. Bruising is common, and there is a small risk for scarring.

Home tanning devices and tanning salons are not usually recommended, but they may be helpful for patients without access to a medical unit. In a 2003 study, many patients achieved a significant reduction in symptoms when taking acitretin and exposed to a UVB commercial tanning unit (specifically, a Wolff tanning bed).

However, UV outputs can vary widely among tanning beds and salons. Some units emit UVA radiation, which poses a higher risk for skin cancers. Adverse effects of tanning salons that use UVA or UVB radiation are the same as with any UV phototherapies, including a risk for skin cancer.

Managing Psoriasis

Although sunburn carries a risk for skin cancer and can make psoriasis worse, regular exposure to the sun helps clear psoriasis in people with mild-to-moderate conditions. People should cover non-affected areas with clothing or sunscreen and sun bath only until the skin starts to tan.

Vacations in sunny areas, such as Hawaii or the Caribbean, can offer relief. For those who can afford it, a prolonged stay of several weeks at the Dead Sea in Israel has proven to significantly improve or clear 88% of those with psoriasis who go there. The region offers a unique combination of intense but naturally filtered UVA radiation combined with minerals and salts from the sea.

Because of the association between negative emotions and psoriatic flare-ups, relaxation and anti-stress techniques may be helpful. A small 1999 study found that hypnosis aimed at reducing stress may relieve symptoms.

Another study found that some patients with psoriasis had a traumatic or stressful event coincide with the appearance of psoriasis. Talking to a psychiatrist about the issue resulted in significant symptom improvement in 62% of study patients who recalled such an event.

If skin becomes dry and itchy, the patient may try the following:

Soak in a warm bath for about 15 minutes.
Afterward, apply salicylic acid first, which removes scaly skin and may promote the penetration of both moisturizers and topical prescription medications.
Then, apply a thick moisturizer or emollient, such as Vaseline, Cetaphil cream, or Eucerin cream. Lotions are not good enough moisturizers.
Special gloves made of Gore-Tex (DermaPore) may be worn at night over a thick moisturizer cream. These gloves are protective but also allow moisture to escape.

Some experts suggest that many common moisturizers may actually increase water loss in psoriasis, but studies still have to confirm this. In the meantime, if moisturizers help relieve the condition, patients should use them.

Capsaicin (Zostrix) is an ointment prepared from the active ingredient in hot chili peppers. It is used to relieve arthritic pain and may help relieve psoriatic itching. Capsaicin should be handled using a glove and applied to affected areas three or four times daily. The patient will usually have a burning sensation when the drug is first applied, but this sensation lessens with use.

Folic Acid. Patients should be sure they get enough of the B vitamin folate (folic acid). Folate-rich foods include liver, asparagus, fruits, green leafy vegetables, dried beans and peas, orange juice, and yeast. Many types of bread and other commercial grain products now have added folic acid.

Omega-3 Fatty Acids. Omega-3 fatty acids, particularly those found in some fish oil, have anti-inflammatory properties that may benefit some patients with psoriasis and other autoimmune conditions.

Patients with persistent psoriasis may be tempted to try alternative or untested treatments, including herbs and other nontraditional therapies. Researchers at the Medical College of Georgia say green tea slowed the growth of skin cells in animal studies and may one day prove to be useful in treating psoriasis. More research is needed.

Several traditional remedies for psoriasis include various other herbal supplements, but to date no clinical studies have been reported on these substances. No one should use any unproven therapy without consulting a doctor to be sure such treatment is not harmful, and does not interfere with any standard medications they take.

Herbal remedies and dietary supplements are not regulated by the FDA. This means that manufacturers and distributors do not need FDA approval to sell their products. In addition, any substance that affects the body's chemistry can, like any drug, produce side effects that may be harmful. There have been many reported cases of serious and even deadly side effects from herbal products.

The following are special concerns for people taking natural remedies for psoriasis:

Zinc pyrithione is sometimes used, but its effectiveness is doubtful. A number of so-called natural psoriasis products (Skin-Cap, Blue Cap, Miralex) that contain this compound also contain prescription-strength corticosteroids. Such steroids have the same side effects as those in standard psoriasis agents. These products have been banned in the U.S. and Canada, but similar untested medications are available over the Internet.
Gotu Kola (Centella asiatica) is sometimes applied in a cream for psoriasis. The oral form of the herb has serious side effects, however, including increasing the risk for miscarriage in pregnant women.

Outlook

Psoriasis is lifelong and not curable. Although it is also marked by rapid cell growth, psoriasis is neither cancerous nor contagious.

In general, studies report the following features of its course:

The condition almost always relapses. In a few cases, large areas of plaque can persist for years.
Psoriasis nearly always goes into remission, however, often clearing on its own. In one study, 30% of patients reported untreated psoriasis going into remissions that lasted 1 - 54 years.
Psoriasis can improve during pregnancy, especially during the second and third months. Increased levels of estrogen may be responsible for this improvement. Relapse may occur after giving birth.

The emotional and social consequences of psoriasis should not be underestimated.

Many patients suffer severe humiliation and depression if plaques are visible. Some even withdraw from society and become isolated.
Some patients are forced to leave their jobs and go on disability if the condition becomes incapacitating.

Researchers have reported the following:

Surveys of patients with psoriasis report a negative mental and physical impact that is nearly equivalent to that of other major chronic conditions, including cancer, high blood pressure, diabetes, heart disease, and depression.
In one study, 75% of patients reported that psoriasis hurt their confidence.
Another study reported that 8% of people with psoriasis felt their life was not worth living.

Some patients, particularly men, use alcohol and smoking as self-medication to reduce the emotional consequences of psoriasis. In fact, studies have found that people with psoriasis have higher mortality rates, mostly from heavy drinking. Smoking has also been cited as a major risk, particularly for pustular psoriasis. Some experts believe that drinking and smoking may actually cause biological damage that contributes to psoriasis itself.

However, smoking may delay the onset of psoriatic arthritis in some patients, depending on when they started the habit. Psoriatic arthritis tends to occur about a decade after psoriasis develops. The review of 281 psoriasis patients showed that the condition appeared after about 13 years in nonsmokers, compared to 23 years in those who began smoking after the first onset of psoriasis. Psoriatic arthritis appeared after 8 years in people who smoked before developing psoriasis.

Folate Deficiency in Severe Psoriasis. Severe psoriasis can also cause folate deficiency. Folate is a B vitamin that is important for nerve function, preventing birth defects. It also prevents elevations of homocysteine, a factor that may play a critical role in heart disease.

Skin Cancers. In one study, patients with severe psoriasis (who receive medications that affect the whole body) were at higher than normal risk for developing cancers, primarily skin cancers and lymphomas. The risk was not any higher for patients with milder psoriasis. There is some indication, however, that patients with psoriasis have a higher risk for non-melanoma skin cancers regardless of treatments.

Heart Attacks. A study released in October 2006 shows an increased risk of heart attacks in people with psoriasis. The risk was highest in young patients with severe psoriasis.

Other Coexisting Conditions: Studies done in Newfoundland and Germany have also revealed increased cases of diabetes, obesity, arthritis, and cancer in patients with psoriasis. Research is underway to determine if there are genetic links between psoriasis and these conditions.

Increased Risk of Death. Severe psoriasis has been linked to a significant increase in a patient's risk of death. A study of more than 713,000 patients showed that severe psoriasis increased mortality by 50%. Study authors encourage patients to receive comprehensive health examinations to reduce the risk. Study participants were considered to have severe psoriasis if they required systemic treatment.

Impaired Temperature Regulation. Erythrodermic psoriasis, in which psoriasis covers the entire skin, can cause abnormalities in the body's ability to regulate temperature.

Zumbusch Psoriasis. A combination of erythrodermic and pustular psoriasis causes a serious condition called Zumbusch psoriasis:

The condition can develop abruptly.
Symptoms may include fever, chills, weight loss, and muscle weakness.
Patients may develop excessive fluid build-up, protein loss, and electrolyte imbalances. In such cases, hospitalization is required. Fluid and chemical balances must be restored and temperature stabilized as soon as possible.

Zumbusch psoriasis can be life threatening, particularly in the elderly. The condition is very rare in children and, if it occurs, tends to improve more quickly than in adults, possibly even without medication.

Most cases of psoriatic arthritis (PsA) are mild, but complications can occur:

Severe joint deformity and destruction (called arthritis mutilans) may develop, generally in the small joints of the hands and feet. Studies report this happens in about 5 - 16% of patients. Psoriasis patients with other arthritic conditions (osteoarthritis or rheumatoid arthritis) in the joints of the fingers tend to have a higher risk.
People with PsA may have a higher risk for respiratory illnesses.

Some earlier studies indicated that patients with psoriatic arthritis had a shorter lifespan than the general population, but more recent studies found no significant difference.

Resources

www.psoriasis.org -- National Psoriasis Foundation
www.aad.org -- American Academy of Dermatology
www.niams.nih.gov -- National Institute of Arthritis and Musculoskeletal and Skin Diseases
www.clinicaltrials.gov -- Find clinical trials

References

Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006 Oct 11;296(14):1735-41.

U.S. Food and Drug Administration. CDER Drug and Biologic Approvals for Calendar Year 2006 -- Updated through August 31, 2006. Last accessed on 15 October, 2006.

FDA Announces Strengthened Risk Management Program to Enhance Safe Use of Isotretinoin (Accutane) for Treating Severe Acne. US Food and Drug Administration. Rockville, MD: National Press Office; August 12, 2005.

Anstey AV and Kragballe K. Retrospective assessment of PASI 50 and PASI 75 attainment with a calcipotriol/betamethasone dipropionate ointment. Int J Dermatol. 2006 Aug;45(:970-5.

National Psoriasis Foundation. About Psoriasis: Statistics. Last Accessed 9 October, 2006.

Antoni CE, Kavanaugh A, Kirkham B, Tutuncu Z, Burmester GR, Schneider U. Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum. 2005;52(4):1227-1236.

Bowcock AM, Cookson WO. The genetics of psoriasis, psoriatic arthritis and atopic dermatitis. Human Mol Genet. 2004;13 Spec No 1:R43-55.

Feldman SR, Koo JY, Menter A, Bagel J. Decision points for the initiation of systemic treatment for psoriasis. J Am Acad Dermatol. 2005;53(1):101-107.

Murase JE, Chan KK, Garite TJ, Cooper DM, Weinstein GD. Hormonal effect on psoriasis in pregnancy and post partum. Arch Dermatol. 2005;141(5):601-6.

Review Date:
9/19/2007
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Weight control and diet

FitSugar — Wed, 08 Oct 2008 17:34:58 -0700

In This Report

Highlights
Introduction
Biological and Medical Caus...
Cultural and Emotional Caus...
Risk Factors
Complications
Weight Loss and Maintenance...
Weight Management
Medications
Other Treatments
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Cancer and Weight Control:

Cancer prevention guidelines from the American Cancer Society stress the importance of maintaining a healthy weight throughout life. A healthy weight is even more important than eating specific healthy foods, when it comes to cancer prevention.

Drug Warning:

The US Food and Drug Administration (FDA) is warning consumers not to buy a product known as the "Brazilian diet pill." This product is labeled as a dietary supplement, but contains several chemicals found in powerful prescription drugs. The products are also known as Emagrece Sim and Herbathin dietary supplements.

New Over-the-Counter Medication:

In February 2007, the FDA approved the first over-the-counter (OTC) weight-loss drug. Orlistat, previously available only by prescription as Xenical, will be available OTC at half its prescription strength. It will be sold under the name alli. Those eager to use the new pill should consider its cost and modest benefits compared with its side effects, most commonly oily diarrhea. This pill, which prevents fat absorption from food, also increases the risk of not absorbing important nutrients from food while using it. The FDA recommends taking a daily multivitamin supplement when using alli.

Research News:

A small study in Norway found that a diet low in fat and high in carbohydrates ("carbs") increases symptoms of psychological distress, such as depression and anger. The study compared three different diets with varying amounts of fat and carbohydrates.
A study released in March 2007 found that obesity in young girls results in early puberty -- as early as age 9.

Effects of Obesity on the Body:

Obesity is associated with certain problems related to infertility, such as uterine fibroids or menstrual irregularities. In men, obesity can contribute to reduced testosterone levels.
People who are obese are at higher risk for carpal tunnel syndrome and other problems involving nerves in their wrists and hands.
The Pickwickian syndrome, named for an overweight character in a Dickens novel, occurs in severe obesity when lack of oxygen produces intense and chronic sleepiness and, eventually, heart failure.

Introduction

A stable weight depends on a good balance between the energy you get from food and the energy you use. You use energy during the day in three ways:

As energy expended during rest (basal metabolism)
As energy used to break down food (thermogenesis)
As energy used during physical activity

Basal metabolism accounts for about two-thirds of spent energy. Your body generally uses this energy to keep your body temperature steady and keep the muscles of your heart and intestine working. Thermogenesis accounts for about 10% of spent energy.

When a person consumes more calories than the energy they use, the body stores the extra calories in fat cells. Fat cells function as energy reservoirs. They enlarge or shrink depending on how people use energy. If people do not balance energy input and output by eating right and exercising, fat can build up. This can lead to weight gain.

When energy input is equal to energy output, there is no expansion of fat cells (lipocytes) to accommodate excess. It is only when more calories are taken in than used that the extra fat is stored in the lipocytes and the person begins to accumulate fat.

Obesity is determined by measuring body fat, not just body weight. People might be over the weight limit for normal standards, but if they are very muscular with low body fat, they are not obese. Others might be normal or underweight, but still have excessive body fat. The following measurements and factors are used to determine whether or not a person is overweight to a degree that threatens their health:

Body mass index (BMI) (a measure of body fat)
Waist circumference (size around the waist)
Waist-hip ratio
Skin fold measurement (anthropometry)
The presence or absence of other disease risk factors (e.g., smoking, high blood pressure, unhealthy cholesterol levels, diabetes, relatives with heart disease)

A person's disease risk factors plus BMI may be the most important components in determining health risks with weight.

The Body Mass Index (BMI). The current standard measurement for obesity is the body mass index (BMI). In general, a BMI of 25 - 29.9 means you are overweight. Obesity is a BMI of 30 and above. Obesity is then classified into three categories:

Class 1: BMI of 30 - 34.9
Class II: BMI 35 - 39.9
Class III: BMI of 40 and greater

These guidelines are very important for people at risk for diabetes, heart disease, or certain cancers. It is also used to determine treatment approaches such as when surgery may be appropriate. The higher the BMI, the greater the risk for significant health problems.

Calculating Body Mass Index (BMI). One's body mass index (BMI) is calculated by multiplying a person's weight in pounds by 703, dividing by the height in inches, and then dividing that number by the height in inches. The steps are as follows:

Multiply one's weight in pounds by 703
Divide that answer by height in inches
Divide that answer again by height in inches

For example, a woman who weighs 150 pounds and is five feet eight inches (or 68 inches) tall has a BMI of 22.8.

Waist Circumference and Waist-Hip Ratio. The extent of abdominal fat can also be used in assessing risk of disease. Some studies suggest that:

Women whose waistlines are over 31.5 inches and men whose waists measure over 37 inches should watch their weight.
A waist size greater than 35 inches in women and 40 inches in men is associated with a higher risk for heart disease, diabetes, and impaired functioning.

Evidence strongly suggests that more body fat around the abdomen and hips (the apple-shape) is a more consistent predictor of heart problems and health risks than BMI.

The distribution of fat can be evaluated by dividing waist size by hip size. For example, a woman with a 30-inch waist and 40-inch hip circumference would have a ratio of 0.75; one with a 41-inch waist and 39-inch hips would have a ratio of 1.05. The lower the ratio the better. The risk of heart disease rises sharply for women with ratios above 0.8 and for men with ratios above 1.0.

Click the icon to see a depiction of the waist-to-hip ratio.

Anthropometry. Anthropometry is the measurement of skin fold thickness in different areas, particularly around the triceps, shoulder blades, and hips. This measurement is useful in determining how much weight is due to muscle or fat.

Biological and Medical Causes

Obesity results when a person consumes more calories than they need for the energy they use. Several different factors may influence weight gain.

About 90% of people who lose weight through dieting gain every pound back regardless of their weight-loss method.

Some evidence suggests that every person has an inherited weight. This range varies by only about 10% either up or down from some set point. For instance, a man whose "genetically-determined" weight is 200 pounds would tend to swing from 180 - 220 pounds. He would be unlikely to lose or gain more than this.

Genetic factors may play some part in 70 - 80% of obesity cases.

Appetite is determined by processes that occur both in the brain and gastrointestinal tract. Eating patterns are controlled by areas in the hypothalamus and pituitary glands (in the brain). The body produces a number of molecules that increases or decreases appetite. In some cases, the following factors may produce imbalances in this process:

Insulin. Insulin is a hormone that helps change blood sugar (glucose) into energy. During digestion, carbohydrates from our diet break down into different types of sugar molecules (including glucose). Proteins from our diet break down into smaller molecules called amino acids. Immediately after eating, blood glucose levels rise. This triggers the release of insulin, which pours into the bloodstream. Insulin pushes the glucose and amino acids into cells and muscles. Insulin and other hormones determine which nutrients will be burned for energy or stored for future use. The inability to use insulin efficiently (insulin resistance) has been associated with both obesity and diabetes.
Leptin. Leptin is a hormone that is released by fat cells. A number of scientists think this hormone may also be released by cells in the stomach. Leptin appears to play an important role in insulin resistance and fat storage in the body, but its role in obesity is unclear. The most likely scenario is that leptin levels rise as the cells store more fat. This increase in leptin levels decreases appetite. Falling levels of leptin make you feel hungry. In people who have genetically lower levels of leptin, however, the brain may be tricked into thinking that it is always starving because there is no leptin to decrease appetite. This can lead to weight gain.
Resistin. Resistin is a hormone produced by fat cells. It makes the body resistant to insulin activity. Some experts believe it may help explain the role of obesity in diabetes type 2.
Intestinal Chemicals. Ghrelin is a chemical produced in the stomach. It appears to be important in triggering the desire to eat. Peptide YY3–36 (PYY) is a substance secreted in the intestines after a meal. The level of PYY is proportionate to the number of calories a person eats. PYY tells the brain that you feel full. Deficiencies in ghrelin and PYY may contribute to some cases of obesity. Researchers are hoping that blocking ghrelin or infusing PYY may be possible treatments for obesity.
Other Chemicals. Many brain chemicals are being studied for their role in appetite stimulation and weight gain. Among them are neuropeptide Y, melanocortins, agouti-related protein, and melanocyte stimulating hormone. Pain-relieving chemicals called endorphins may be critical in reducing appetite and regulating energy use. Cholecystokinin, a hormone released in the upper intestine that stimulates digestive juices, may work to control meal size.

Insulin is a hormone produced by the pancreas that is necessary for cells to be able to use blood sugar.

Genetics may directly contribute to severe obesity in people with family histories of the problem. Genetic factors such as slow metabolisms may also make people more likely to be overweight. At least seven genetic mutations have been associated with specific and uncommon cases of severe obesity. Some are outlined below.

HOB1 (human obesity 1) is a gene that is linked to a high BMI in women.
Leptin gene variants have been linked to leptin deficiencies and obesity.
Melanocortin-4 receptor is a gene that helps turn off the urge to eat. It may not work properly in those with a family history of obesity.
Researchers have also identified a mutation in a gene for a protein called proopiomelanocortin, which results in a syndrome of obesity, red hair, and deficiencies in stress hormones.
A protein called agouti-related protein increases hunger. About 5% of severely obese people have mutations that over-respond to agouti-related protein.

Genetics also determine the number of fat cells a person has. Some people are simply born with more. It should be noted that even when genetic factors are present, a person can still control their diet.

The Thrifty Gene. Some experts think the existence of a so-called "thrifty" gene regulates changes in hormone levels, to accommodate seasonal changes. Theoretically, it works in the following manner:

In certain populations, hormones are released during seasons when food supplies have traditionally been low. This leads to insulin resistance and increased fat storage.
The process is reversed in seasons when food is readily available.
Because modern industrialization has made high carbohydrate and fatty foods available all year long, the gene no longer serves a useful function. Fat, originally stored for famine situations, is not used.

This theory could explain why the previously nomadic Native American tribes who now have Western dietary habits have such high rates of Type 2 diabetes and obesity. In the past, the traditional low-fat, high-fiber foods tribe members ate may have protected them from obesity and type 2 diabetes. Today, these tribes' diet consists of more Western foods, which are higher in fat. Furthermore, these foods are readily available year-round, and many members of the tribe are sedentary. The result is a very high incidence of Type 2 diabetes and obesity. Although genetic abnormalities may make it harder or easier to lose weight, the occurrence of obesity has dramatically increased over the past two decades, and genes cannot have changed within that short amount of time. Our ability to use the food that we eat evolved so that our body could conserve energy and store fat during times of famine. Most cases of obesity now occur in people with normal body function who live in industrialized nations, where there is more than enough food.

A number of medical conditions may contribute to being overweight, but rarely are they a primary cause of obesity.

Hypothyroidism is sometimes associated with weight gain. But, patients with an underactive thyroid generally show only a moderate weight increase of five to 10 pounds.
Very rare genetic disorders, including Froehlich's syndrome in boys, Laurence-Moon-Biedl, and the Prader-Willi syndromes, cause obesity.
Abnormalities or injury to the hypothalamus gland can cause hypothalamic obesity.
Cushing's disease is a rare condition caused by high levels of steroid hormones. It results in obesity, a moon-shaped face, and muscle wasting.
Obesity is also linked to polycystic ovarian syndrome, a hormonal disorder in women.

Click the icon to see an image of polycystic ovaries.

Some prescription medications contribute to weight gain, usually by increasing appetite. Such drugs include the following:

Corticosteroids
Female hormone treatments, including some oral birth control pills (effect is usually temporary), and certain progestins (such as Megestrol) used to treat cancer
Antidepressants and anti-psychotic drugs, including lithium and valproate
Insulin and insulin-stimulating drugs used to treat diabetes often lead to weight gain, a particularly unfortunate conflict of interest for obese individuals with type 2 diabetes

You should not stop taking any medications without your doctor's knowledge.

Cultural and Emotional Causes

Enough food is produced in the US to supply 3,800 calories every day to each man, woman, and child in the country, far more than the average person needs to sustain life. In a 2002 study, participants carefully recorded everything they ate and drank, and all activities and psychological factors surrounding the eating events. The people who gained weight ate more and their portions were larger than those who did not. This may be an obvious conclusion, but the public press often plays up biologic factors involved with obesity and overlooks the simple notion that Americans eat too much and exercise too little.

Obesity is dramatically increasing not only in American children and adults, but also in every country that has adopted similar cultural habits. The World Health Organization now considers obesity to be a global epidemic and a public health problem as more nations become "Westernized." In spite of the proven health risks of obesity, the government, insurance companies, and the medical profession do not spend nearly enough money to balance the commercial and cultural pressures that are producing millions of overweight people.

In 2007, the Robert Wood Johnson Foundation sounded a positive note with the announcement of a $500 million initiative, aimed at “reversing the childhood obesity epidemic by 2015.” The money will be used for research, education, and activities that promote healthy eating among America’s children.

Perhaps the primary reason for the dramatic rise in obesity is the sedentary (inactive) lives led by most Americans, including children and young people. In a 2003 study comparing modern life to the past, researchers found that labor saving devices had reduced a person's energy use by 111 calories a day -- adding up to an extra 11 pounds a year. Half the difference in energy use was due to less walking. At the same time, according to the U.S. Centers for Disease Control and Prevention, between 1970 and 2000 the typical American man increased his caloric intake by 168 calories a day (good for 17 pounds a year) while the average woman added 335 calories a day.

Regular television watching has been singled as the most hazardous pastime. According to a major 2003 study, for every 2 hours a person spends in front of the TV each day, the risk for obesity increases by 23% and for type 2 diabetes by 14%. In the study, TV watching produced the lowest metabolic rates compared to sewing, playing board games, reading, writing, and driving a car. Just the act of watching TV encourages unhealthy snacks and eating patterns. In addition, the advertising on the television complicates the problem by promoting fast foods, cereal, and snack products that are high in salt, fats, and carbohydrates. Even worse, much of these advertisements are directed at children -- the most vulnerable group.

People are not only eating more food than they did 20 years ago, they are also replacing home cooking with packaged foods, fast food, and dining out. This behavior, according to studies, places people at higher risk for obesity. Fast foods may be more harmful than restaurant cooking. These foods tend to be served in larger portions. They generally contain more calories and unhealthy fats, and less nutritious ingredients, than homemade or restaurant meals. Snack foods and sweet beverages, including juice and soft drinks, are specific problems that add to the increasing rates of obesity. Frequent small, healthy meals (instead of two or three large daily meals) have been associated with lower weights.

People react differently to stress. Some overeat and gain weight and others stop eating and lose weight. People who gain weight in response to stress often overeat foods high in sugar, fats, and salt. A 2003 study on rats suggested that stress hormones increase the pleasure of eating such so-called "comfort foods." Furthermore, the study supported previous research showing that stress-related eating was connected to the unhealthy accumulation of abdominal fat.

Risk Factors

Where you live plays a role in your risk for obesity. Simply living in the United States makes a person more susceptible to obesity. The prevalence of obesity in America has risen dramatically over the past few years and continues to increase.

According to the latest figures available, 32.2% of American adults (aged 20 and older) are obese (BMI over 30) -- up from about 23% in the early 1990s.
The number of Americans aged 20 - 74 who were overweight also increased -- from about 44.8% in 1960 to 65.2% in 2002.
The rate of extreme obesity (BMI > 40) increased from 0.8% in 1960 to 4.9% in 2002.
Obesity has increased in every state, in both men and women, across all age groups, and in every ethnic group, although some groups may face slightly higher risks than others.

Fat tends to settle in certain regions, depending on gender. Women gain fat predominantly in the stomach, hips and thighs, while men tend to gain fat in the belly and waist.

Risk by Age. People of any age are at risk for obesity. More children and adolescents are overweight in America than ever before. Gaining some weight is inevitable with age and adding about 10 pounds to a normal base weight over time is not harmful. The current weight gain in American adults over 50, however, is significant. By age 55, the average American has added nearly 40 pounds of fat during the course of adulthood. This condition is made worse by the fact that muscle and bone mass decrease with age.

Risk by Gender. In men, BMI tends to increase until age 50 and then it levels off. In women, weight tends to increase until age 70 before it plateaus. A 2000 study found that there are three high-risk periods for weight gain in women.

The first is at the onset of menstruation, particularly if it is early. In fact, a study released in March 2007 found that obesity in young girls results in early puberty -- as early as age 9. This, in turn, increases the risk for more weight gain as girls enter puberty.
The second is after pregnancy, with higher risk for women who are already overweight.
Finally, many women gain weight after menopause.

These findings are significant because they may allow women to target high-risk times, and consequently prevent unnecessary weight gain.

Risk by Economic Group. Obesity is more prevalent in lower economic groups. One 2002 study reported that women who reported that they did not have enough food were more likely to be overweight than those who said they had sufficient food. Researchers discovered that the low-income women tended to have fewer fruits and vegetables but were actually taking in more calories a day than higher-income women. However, obesity is increasing in young adults with college education as well as in other groups.

Ethnic Groups. Among ethnic groups in general, African-American women are more overweight than Caucasian women but African-American men are less obese than Caucasian men. (Currently, 80% of African-American women are overweight.) Hispanic men and women tend to weigh more than Caucasians.

US Regions. Regionally, the prevalence of obesity is lowest in the Western states and highest in the South.

A number of dietary habits put people at risk for becoming overweight:

Night-Eating Syndrome. Night-eating syndrome is defined as having no appetite in the morning, insomnia, and consuming more than half of daily food intake after 6:00 PM. It is associated with obesity and is difficult to treat. Stress reduction and relaxation techniques may be helpful.
Binge Eating and Eating Disorders. About 30% of people who are obese are binge eaters who typically consume 5,000 - 15,000 calories in one sitting. To be diagnosed as a binge eater, a person has to binge at least twice a week for 6 months. Many experts believe that binge-eating carbohydrates causes an increase in a natural opiate leading to dependence on carbohydrates. Therefore, this condition should be treated as an addiction. Other eating disorders are bulimia and anorexia. Bulimia is binge eating followed by purging in order to lose weight. Anorexia nervosa is a mental illness in which the person refuses to maintain weight at the normal level. The patient with anorexia has a terrible fear of getting fat, and an abnormal perception of what his or her body looks like. Both conditions pose risks for serious medical problems, and anorexia nervosa can be life-threatening. A combined approach using behavioral therapy and antidepressants may help these individuals. [See In-Depth Report #49: Eating disorders.]
Restrained Eating. Some people, mostly middle-aged women who have normal weight, have a pattern referred to as restrained eating. This pattern requires a high level of conscious control and usually maintains a lower weight. However, such restraint places these individuals at higher risk for loss of control and subsequent overeating.
Infrequent Eating. There is some evidence to suggest that eating small frequent meals uses more calories than infrequent large meals. It should be strongly noted, however, that packaged snack foods add calories and some do not produce a feeling of being full, so that people simply eat more than they should.

Anyone with Sedentary Lifestyles. Office workers, drivers, and anyone whose lifestyle involves sitting for long periods are at higher risk for obesity.

Ex-Smokers. The trend toward weight increase has followed the trend for quitting smoking. Nicotine increases the metabolic rate, and quitting, even without eating more, can cause weight gain, which may be considerable. It is important to note that weight control is not a valid reason to smoke. People in previous centuries did not smoke cigarettes, nor were they usually obese.

Shift-Workers. A recent study found that individuals who work late shifts (between 4 p.m. and 8 a.m.) tend to eat more and take longer naps than day workers and are more likely to gain excess weight.

People with Disabilities. Obesity rates are higher than average in people with physical or mental disabilities. Those with disabilities in the lower part of the body, such as the legs, are at highest risk.

Overweight in children and adolescents is rising at an alarming rate. In 2004, 19% of young children aged 6 - 11 were overweight, an increase of 8% from 1994. Among children aged 25, 13.9% were overweight in 2004, up from 7.2% 10 years earlier.

Definition of Overweight in Children

Children and adolescents are considered to be overweight if their BMI is above 95% of the children in their age and sex categories. Ethnic variations, timing of growth spurts, and higher normal fat levels around puberty can affect these measurements.

Causes and Risk Factors for Overweight in Children

Lifestyle Factors. Without educational or parental guidance, children are extremely vulnerable to the intense cultural pressures that are largely responsible for the obesity epidemic. The following are some specific problems created by the culture:

Excessive television watching plays a critical role in obesity in children. Not only is it a sedentary activity, but television also offers innumerable temptations with its advertisements for fast foods, sugar cereals, and unhealthy snacks. In one study obesity rates were lowest in children who watched television 1 hour or less a day and highest in those who watched 4 or more hours.
Sugar, particularly from soda, other sweetened beverages, and fruit juice, may be the major contributor to childhood obesity. One study reported that drinking soda regularly increases a child's risk for obesity by 60%. The average American adolescent consumes 15 - 20 extra teaspoons of sugar a day just from soda and sugary drinks. (Juice, while better than soda, is still filled with sugar.)
Less physical exercise and greater sedentary activities play another significant role in obesity in children. A high level of physical activity -- not just using up energy -- is important for weight control in young people. Unfortunately, according to one study, the annual distance walked by children has fallen by nearly 30% since 1972, partially because more parents are driving their children to school out of fear of abduction, molestation, and traffic accidents. Schools are also offering fewer opportunities for daily physical activities than in the past.

Neither the media nor the educational system has strong well-financed programs that encourage healthy alternatives, including exercise and healthy foods.

Family History. Parental obesity more than doubles the risk that a young child, whether thin or overweight, will become obese as an adult. In older children and teenagers, obesity in parents starts to count less as a predictor for body weight than their own weight. The risk for obesity may be due to environmental or genetic factors, or both.

Ethnic and Socioeconomic Factors. As in adult populations, children from lower socioeconomic groups and minority populations are at higher risk for obesity. For example, among young Mexican Americans and African-Americans, there has been an increase in overweight prevalence of about 13% to over 23%.

Factors Surrounding Birth. The following factors surrounding birth are associated with a child's weight:

Low birth weight is a risk factor for later obesity and diabetes. One theory is that humans have a "thrifty gene" that produces metabolic changes in infants with low birth weight. Such changes affect insulin and fat accumulation, in order to produce a "catch-up" weight in these young children as quickly as possible. This rapid weight gain in infancy increases the risk for obesity in children and young adults.
In a study of African-American children, having an overweight pregnant mother increased the risk for later weight gain, but low birth weight did not.

Although some small studies have reported protection against obesity from breastfeeding, evidence is weak. In a 2003 study, for example, children who were breast fed for 3 - 5 months had a lower risk for obesity, but prolonged breastfeeding had no effect. Nevertheless, given the healthful effects of breast feeding and the possibility that it may have even a slight impact on childhood obesity, it is highly recommended.

Biological Effect of Childhood Overweight on Adult Weight

Achieving a healthy weight becomes more difficult as children get older. The odds of obesity persisting into adulthood ranges from 20% in 4 year olds to 80% in teenagers. One reason for the persistence is biological. The fat cells change in number or mass depending on a person's age:

Fat cells themselves multiply during two growth periods: early childhood and adolescence. Overeating during those times increases the number of fat cells. Some people are also just born with more fat cells.
After adolescence, fat cells tend to increase in mass rather than quantity, so that adults who overeat and gain weight tend to have larger fat cells, not more of them. This growth in mass may be responsible for the greater risk of persistent obesity among teenagers compared to small children who are overweight. Losing weight after adolescence reduces the size of the fat cells but not their number, so weight loss becomes much more difficult.

Health Consequences of Childhood Overweight

Children and adolescents who are overweight have poorer health than other children. Studies are reporting unhealthy cholesterol levels and high blood pressure in overweight children and adolescents. Of great concern is the dramatic increase in type 2 diabetes in young people, which is largely due to the increase in overweight children. Overweight in children is also linked to asthma, gallbladder problems, sleep apnea, and liver abnormalities. Overweight girls are more likely to enter puberty early, according to a new study, and subsequently be at higher risk for breast cancer.

It is not clear yet how many of these childhood problems persist in people who achieve normal weight as adults. Staying overweight into adulthood certainly carries health risks.

Managing Overweight Children

Childhood obesity is best treated by a non-drug, multidisciplinary approach including diet, behavior modification, and exercise. Evidence suggests that reducing calories by only 200 - 260 per day would prevent weight gain in most overweight children. Here some tips for children who are overweight:

Limit (or avoid, if possible) take out, fast foods, high-sugar snacks, commercial packaged snacks, soda, and sugar-sweetened beverages (including too much juice).
Let children snack but make sure the snacks are healthy. Eating small frequent healthy meals (instead of two or three large ones) has been associated with being thinner and having a better cholesterol profile.
Let children choose their own food portions. One study indicated that children naturally ate 25% less when they chose their own portion size. When they were given larger portions their bite sizes were larger and they ate more.
Do not criticize a child for being overweight. It does not help and such attitudes could put children at risk for eating disorders, which are equal or even greater dangers to their health.
Limit television, video games, and computer use to a few hours a week. This can contribute significantly to weight control, regardless of diet and physical activity.
For young children, try the traffic-light diet. Food is designated with stoplight colors depending on their high caloric content: Green for go (low calories); yellow for "eat with caution" (medium calories); red for "stop" (high calories).
Try a low glycemic index diet. This may be as beneficial, and possibly more, than a standard reduced-fat diet in overweight children. Such a diet focuses on certain carbohydrates (for example, dried beans and soy), which raise blood sugar more slowly than other types of carbohydrates. This diet is sometimes used in diabetes, and as a dietary approach in overweight adults. [See In-Depth Report #42: Diabetes diet.]

Click the icon to see an image about TV watching.

Click the icon to see an image of childhood overweight.

Complications

General Adverse Effects of Obesity. Obesity, defined as a BMI of 30 or over, accounts for nearly 300,000 deaths in the U.S. each year. It is associated with more chronic health problems than smoking, heavy drinking, or poverty. Furthermore, given the current increase in obesity, it will surpass smoking as the most important preventable cause of death in America.

Some studies indicate the following health risks by body mass:

The lowest risks for heart disease, diabetes, and some cancers are in people with BMI values of 21 - 25.
The risks increase slightly when BMI values are between 25 - 27.
The risks are significant in BMIs between 27 - 30.
The same risks are dramatic at BMIs over 30.

Anyone with chronic health problems such as heart or lung disease, stroke, or arthritis, should be concerned about extra weight. This same concern also applies to people with known risk factors for such conditions.

Metabolic Changes. As fat stores increase, the fat cells themselves enlarge and produce chemicals that increase the risk for several diseases. Such diseases may include diabetes, high blood pressure, gallbladder disease, and some cancers.
Increased Mass. The increased body weight itself causes problems that result in injury and diseases, including osteoarthritis and sleep apnea.
Harmful Fat Cell Types. Weight concentrated around the abdomen and in the upper part of the body (the apple shape) poses a higher health risk than fat that settles around the hips and flank (the pear shape). Fat cells in the upper part of the body appear to have different qualities from those found in the lower parts. In fact, studies suggest a higher risk for diabetes in people with the "apple shape" and lower risk in those who are "pear shaped."

Weight gain in the area of and above the waist (apple type) is more dangerous than weight gained around the hips and flank area (pear type). Fat cells in the upper body have different qualities than those found in hips and thighs.

General Adverse Effects of Being Overweight (Not Obese). It is still not clear if being overweight (a BMI of 25 - 29.9) hurts healthy people with no risk factors for serious illnesses.

According to one 2001 study, just being overweight increased the risk for developing diabetes, gallstones, hypertension, heart disease, stroke, and colon cancer. The risk rose according to how much the individuals were overweight. In any case, adults who are overweight in middle age face a poor quality of life as they age, with the quality declining the greater the weight. One study suggested, however, that being over 65 and overweight (but not obese) is not associated with higher mortality rates.

Some experts argue, in fact, that in anyone who is not severely obese, it is the unhealthy diet and sedentary lifestyle that causes harm -- not weight per se. In support of this argument, a British study found that overweight fit individuals had half the death rate of unfit trim individuals.

Being somewhat overweight may also have some benefits under specific circumstances:

In older women, some excess fat may produce extra estrogen that helps slow down bone loss, and insulates bones from fall-related injuries. It should be strongly noted, however, that when older overweight women lose weight they report less pain, improved vitality, and improved physical function. The same positive effect of overweight does not appear to hold in older men.
Conditioned athletes may have high BMIs because of very dense muscle tissue. Being fit in general may protect many overweight people.
Some evidence suggests that Caucasians have the lowest mortality with BMIs of 24.3 - 24.7 while African-Americans are better off in the range of 26.8 - 27.1.
Children may have higher normal fat levels during growth spurts and around puberty.

Individuals with a BMI of at least 30 have a 10 - 50% increased rate of death from all causes, compared with individuals with a BMI of 20 - 25. Mortality rates from many causes are higher in obese people, but heart disease is the primary cause of death. People who are obese have almost three times the risk for heart disease as people with normal weights. Being physically unfit adds to the risk.

Weight concentrated around the abdomen and in the upper part of the body (apple shape) is particularly associated with insulin resistance and diabetes, heart disease, high blood pressure, stroke, and unhealthy cholesterol levels. Fat that settles in a pear shape around the hips and lower body appears to have a lower association with these conditions.

Obesity poses many dangers to the heart and circulatory system.

Damage in the Blood Vessels. As people age, changes in body fat (particularly increasing abdominal fat) seem to cause stiffness in the aorta, the major blood vessel leading from the heart. Studies are finding higher levels of a factor called C-reactive protein (CRP) in people with obesity and abdominal fat. CRP is now considered to be a marker for inflammation and damage in the arteries. (Losing weight reduces CRP levels.)

High Blood Pressure. High blood pressure is the health problem most commonly associated with obesity, and the greater the weight, the greater the risk. High blood pressure carries serious risks of stroke, heart attack, and heart failure. The link between obesity and high blood pressure is complex, and may be a combination of genetic, population, and biological factors. Many studies have reported that modest weight loss is beneficial for reducing existing high blood pressure. [See In-Depth Report #14: High blood pressure.]

Heart Failure. An important 2002 study reported that obesity might account for 11% of heart failure cases in men and 14% in women. This link existed independently of other risk factors, such as high blood pressure, sleep apnea, and diabetes, which are also associated with obesity. The biologic mechanisms involved in obesity that lead specifically to heart failure are not clear. [See In-Depth Report #13: Heart failure.]

Unhealthy Cholesterol Levels and Lipid Levels. The effect of obesity on cholesterol levels is complex. Although obesity does not appear to be strongly associated with overall cholesterol levels, among obese individuals triglyceride levels (the major form of fat storage in the body) are usually high, while HDL levels (the "good" cholesterol) tend to be low. Both conditions are risk factors for heart disease. [See In-Depth Report #23: Cholesterol.]

Click the icon to see an image of coronary artery disease.

Stroke. Obesity is also associated with a higher risk for stroke. [See In-Depth Report #45: Stroke.]

Type 2 Diabetes and Insulin Resistance. Most people with type 2 diabetes are obese and, in fact, studies strongly suggest that weight loss may be the key in controlling the current epidemic of type 2 diabetes. The common factor appears to be insulin resistance. Insulin is a critical hormone in the use of sugar. In type 2 diabetes, different factors cause the body to become insulin resistant -- that is, the body can no longer respond properly to insulin. This has the effect of increasing sugar levels in the blood, the hallmark of diabetes. Both obesity and insulin resistance, at different phases, are marked by high levels of certain chemicals. It is not known yet if the higher levels are simply a product of obesity, or play some role in causing diabetes.

Insulin resistance is also associated with high blood pressure and abnormalities in blood clotting. Some research indicates that obesity, in fact, is the one common element linking insulin resistance, diabetes type 2, and high blood pressure. [See In-Depth Report #60: Diabetes - type 2.]

Metabolic Syndrome. Metabolic syndrome (also called syndrome X) is a pre-diabetic condition that is significantly associated with heart disease and higher mortality rates from all causes. The syndrome consists of obesity marked by abdominal fat, unhealthy cholesterol levels, high blood pressure, and insulin resistance. A 2002 study estimated that nearly a quarter of the U.S. population now has this condition. Even worse, according to a 2003 study, nearly a million American teenagers have this syndrome. A combination of weight loss and exercise is an effective treatment for this syndrome.

The American Cancer Society released new cancer prevention guidelines in September 2006. The guidelines stress the importance of keeping a healthy weight throughout life. The Society indicates that healthy weight is even more important than eating specific healthy foods, when it comes to cancer prevention.

Obesity has been associated with a higher risk for cancer in general and specific cancers in particular. Studies have also suggested that restricting calories reduces the risk for cancer. Some experts believe that effective weight control for children and adults could reduce cancer rates by 30 - 40%. One way obesity may increase the risk for cancer is its association with high levels of hormones called growth factors, which can trigger rapid cell production leading to cancer.

Uterine Cancers. The risk of uterine cancer in obese women appears to be two or three times higher than in thinner women.

Prostate Cancer. New studies from 2005 and 2006 report that obesity is associated with an increase in prostate cancer mortality, although not with the risk for less aggressive forms of prostate cancer.

Click the icon to see an image of prostate cancer.

Breast Cancer. Studies are mixed on the association between obesity and breast cancer. A number of studies have linked obesity to breast cancer in postmenopausal women, particularly in women who begin to gain weight after age 18.

Click the icon to see an illustrated series detailing a breast cancer surgery (mastectomy).

Gallbladder Cancer. Obese women are at higher risk for gallbladder cancer.

Gastrointestinal Cancers. A number of cancers in the gastrointestinal tract have been associated with obesity:

Cancer of the esophagus may be due to a higher incidence of gastroesophageal reflux disorder (heartburn) in people who are overweight.
Colon cancer has been linked to increased body mass in both men and women.
Pancreatic cancer and obesity have been weakly linked, with one study reporting a lower risk in overweight people who are physically active.

Click the icon to see an illustrated series detailing a colon cancer surgery.

Muscles and Bones

Obesity places stress on bones and muscles. Studies report that the incidence of osteoarthritis is significantly increased in people who are overweight. People who are obese are also at higher risk for carpal tunnel syndrome and other problems involving nerves in their wrists and hands. It should be noted that some weight may be protective against osteoporosis (loss of bone thickness).

Obesity increases the risk for the following mouth and eye disorders:

Gum disease
Cataracts
Maculopathy, an eye disease related to aging

Infertility. Abnormal amounts of body fat, either 10 - 15% too high or too low, can contribute to infertility in women. Obesity is specially related to certain infertility problems, such as uterine fibroids or menstrual irregularities. In men, obesity can contribute to reduced testosterone levels.

Effect on Pregnancy. Obesity has many dangerous effects on pregnancy. These include high blood pressure, gestational diabetes (diabetes, usually temporary, that occurs during pregnancy), urinary tract infections, blood clots, prolonged labor, and higher fetal death rate in late stages of pregnancy. Obesity is also associated with increased rates of cesarean delivery. Infants of women who are obese are also at higher risk for neural tube birth defects, which affect the brain or spine. Folic acid supplements, ordinarily effective in preventing these conditions, may not be as protective in overweight women.

Obesity is thought to be a risk factor for symptoms of adult-onset asthma. Though there is evidence that obesity causes wheezing and shortness of breath, it does not appear to be strongly associated with the disease mechanisms in the lungs that cause true asthma.

Obesity also puts people at risk for hypoxia, a condition in which there is not enough oxygen to meet the body's needs. Obese people need to work harder to breathe. They tend to have breathing muscles and lungs that do not work as well as those in thinner people.

The Pickwickian syndrome, named for an overweight character in a Dickens novel, occurs in severe obesity when lack of oxygen produces intense and chronic sleepiness and, eventually, heart failure.

Nonalcoholic Fatty Liver Disease. People with obesity, particularly if they also have type 2 diabetes, are at higher risk for a condition called nonalcoholic fatty liver disease, also called nonalcoholic steatohepatitis (NASH). This condition causes liver damage that is similar to liver injury seen in alcoholism. In some cases, it can be very serious and require liver transplantation. It occurs in about half of people with diabetes, and 20 - 50% of obese people, depending on how severe their obesity is. NASH can also occur in overweight children.

Gallstones. The incidence of gallstones is significantly higher in obese women and men. The risk for stone formation is also high if a person loses weight too quickly. In people on ultra-low calorie diets, gallstones may be prevented by taking ursodeoxycholic acid (Actigall).

Click the icon to see an image of gallstones.

People who are obese and nap tend to fall asleep faster and sleep longer during the day. At night, however, it takes them longer to fall asleep, and they sleep less than people with normal weights. In an apparent vicious circle, studies have suggested that obesity not only interferes with sleep but that sleep problems may actually contribute to obesity.

Sleep Apnea. Obesity, particularly the apple shape, is strongly associated with sleep apnea, which occurs when the upper throat relaxes and collapses from time to time during sleep. This collapse temporarily blocks the passage of air. Sleep apnea is increasingly being viewed as a potentially serious health problem, which may lead to complications such as heart disease and stroke. Some studies suggest that among overweight people, those who have sleep apnea have a greater risk of heart disease than those without it. In one study, the more obese a person with sleep apnea was, the higher the pressure on the airway, and therefore the greater the obstruction of the airway. Obstructive sleep apnea may also add to obesity, however, as sleepy people tend to be sedentary. Some studies indicate that treating sleep apnea may help people lose abdominal fat.

Narcolepsy. A small European study found a link between narcolepsy (a sleep disorder characterized by excessive daytime sleepiness with frequent daily sleep attacks) and high BMI.

Depression. A number of studies have reported an association between depression and obesity, particularly in obese women. There may be a number of factors to explain the link. In some cases of atypical depression, people overeat and may gain weight. Overweight people may also become depressed because of social problems and a poor self-image. In these cases, depression usually disappears when people lose weight.

There is evidence, however, that obesity itself may impair levels of tryptophan -- a chemical needed to make serotonin, a brain chemical associated with mental well-being. In one study, even after people lost weight, tryptophan levels were lower than normal.

There does not appear to be any association between depression and obesity in men.

Social Problems. One long-term study reported that overweight young women completed fewer years of school, were 20% less likely to be married, and had 10% higher rates of household poverty than their thinner peer. Obese young men were also less likely to be married, and their incomes were lower than their thinner peers. Nevertheless, studies consistently show that overweight males (both boys and men) are not as severely emotionally affected as females of any age. Women and girls tend to blame themselves for being heavy, while males tend to blame being overweight on outside factors.

Weight Loss and Maintenance

Even modest weight loss can reduce the risk factors for heart disease and diabetes. The simplest (but still difficult) approach to weight loss is reducing calories and exercising at least 150 minutes a week. Behavioral and mental changes in eating habits, physical activity, and attitudes about food and weight are also essential to weight management. For people who are very overweight and cannot lose weight through lifestyle changes, a number of effective weight-loss medications are available. For those with severe obesity, surgical procedures are proving to be very beneficial.

Some Tips for Losing Weight. The following are some general suggestions for dieters:

Start with realistic goals. Diet failure is extremely common, and the odds of significant weight loss are low, particularly in people with the highest weights. People who are able to restrict calories, engage in an exercise program, and get help in making behavioral changes can expect to lose between 5 - 10% of their current body weight. That is generally all that is needed to achieve meaningful health changes. Certainly, the distorted image of a super-thin female shape should not be anyone's goal.
Maintain a regular exercise program, assuming you have no health problems that will stop you. Choose a program that you enjoy. Check with your doctor about any health considerations. [See In-Depth Report #29: Exercise.]
Do not use hunger pangs as cues to eat. A stomach that has been stretched by large meals will continue to signal hunger for large amounts of food until its size reduces over time with smaller meals.
Be honest about how much you eat and start by recording all calories in writing. Studies suggest that when many people report their own calories intake they significantly underestimate their consumption of high-calorie and over-estimate the low-calorie foods. People who do not carefully note everything they eat tend to take in too many calories when they believe they are dieting.
Observe weekend eating. People tend to eat more on the weekends. If it is difficult to monitor all meals during the week, it be may be useful to at least track eating habits during the weekends.
Once the pounds are lost, do your best to keep the healthier weight. Make daily, even hourly, conscious decisions about eating and exercising activities. Such thinking, in many cases, can become automatic and not painful.
Don't give up, even after repeated weight loss failures. Most studies indicate that yo-yo dieting or weight cycling have no bad psychological or physical effects. Repeated dieting also does not harm the body's ability to burn calories efficiently.
Weight loss, in any case, should not be the only or even the primary goal for people concerned about their health. The success of weight loss efforts should be evaluated according to improvements in disease risk factors or symptoms, and by the adoption of healthy lifestyle habits, not just by the number of pounds lost.


Lifestyle	Reduce rate of eating. Keep food records. Eliminate environmental triggers to eating. Identify high-risk situations for overeating. Separate eating from other activities.
Exercise	Face up to emotional barriers to exercise. Understand the link between exercise and weight control. Establish reasonable exercise goals. Develop a plan for regular activity. Add increased activity into daily lifestyle.
Attitudes	Develop reasonable weight-loss goals. Avoid "all or none" thinking. Focus attention away from the scale and toward behavior. Uncouple weight from self-esteem. If you "fall off the wagon," take steps to ensure the situation does not repeat (recover from lapses with constructive action).
Relationships	Understand the key role of social support to health. Identify supportive others. Match personal style to support-seeking activities. Be specific in making support requests. Be assertive but reinforcing in drawing help from others.
Nutrition	Resist the temptation of popular fad diets. Eat with your health in mind; do not concentrate on what should be "off-limits." Eat with moderation in mind. Maximize fiber. Develop a tailored plan.
From Brownell KD. The LEARN Program for Weight Control. 7th ed. Dallas, Tex: American Health Publishing Company; 1998.

Weight Management

There are many approaches to dieting and many claims for great success with various fad diets. To date, although many diets achieve effective immediate weight loss, none has emerged as an effective tool for maintaining healthy weight. The only definite recommendation that can be made about any diet plan is to be sure it includes an exercise program, assuming there are no health problems to forbid it.

The original food pyramid, with four food groups, has been replaced with an updated food guide called "My Pyramid." This illustrates the relative proportions of different foods that make up a nutritious, well-balanced diet and includes exercise.

Calorie restriction has been the cornerstone of obesity treatment. The standard dietary recommendations for losing weight are the following:

As a rough rule of thumb, one pound of fat equals about 3,500 calories. A person could lose a pound a week by reducing daily caloric intake by about 500 calories a day. Naturally, the more severe the daily calorie restriction, the faster the weight loss. Very-low calorie diets have also been associated with better success, but extreme diets can have some serious health consequences.
To determine your daily calories requirements, multiply the number of pounds of ideal weight by 12 - 15 calories. The number of calories per pound depends on gender, age, and activity levels. For instance, a 50-year old woman who wants to maintain a weight of 135 pounds and is mildly active might require only 12 calories per pound (1,620 calories a day). A 25-year old female athlete who wants to maintain the same weight might require 25 calories per pound 2,025 (calories a day).
Fat intake should be no more than 30% of total calories. Most fats should be in the form of monounsaturated fats (such as olive oil). Saturated fats (found in animal products) should be avoided.

Extreme diets of less than 1,100 calories carry health risks. They are also often followed by bingeing or overeating, and a return to the obese state. Such diets often do not have enough vitamins and minerals, which must then be taken as supplements. Most of the initial weight loss is in fluids. Later, fat is lost, but so is muscle, which can account for more than 30% of the weight loss. No one should be on severe diets for longer than 16 weeks, or fast for more than 2 or 3 days. Severe dieting has unpleasant side effects including fatigue, intolerance to cold, hair loss, gallstone formation, and menstrual irregularities. There have been rare reports of death from heart arrhythmias when liquid formulas did not have sufficient nutrients. Pregnant women who excessively diet during the first trimester put their unborn children at risk for birth defects. Of note, those whose diets include a high intake of fluids and much reduced protein and sodium are at risk for hyponatremia, which can cause fatigue, confusion, dizziness, and in extreme cases, coma and death.

This dietary approach requires counting only grams of fat with the goal of achieving 30% or fewer calories from fat. One gram of fat contains nine calories, while one gram of carbohydrates or protein has only four calories. Fat in your diet converts more readily to fat in the body, compared with carbohydrates or proteins. Simply switching to low-fat or skimmed dairy products may be enough for some people.

There are possible drawbacks to this approach:

Some people who reduce their fat intake may not get enough basic nutrients, including vitamins A and E, folic acid, calcium, iron, and zinc. People on low-fat diets should eat a wide variety of foods and take a multivitamin supplement, if appropriate. Calcium deficiencies may be particularly harmful in women at risk for osteoporosis.
Many people start eating foods with too many carbohydrates, believing that they are not adding calories. No one should use a low-fat diet as an excuse for eating too many carbohydrates, particularly starchy foods and sugar. A high-calorie diet from any source will add pounds.
A small study in Norway found that a diet low in fat and high in carbohydrates ("carbs") increases symptoms of psychological distress, such as depression and anger. The study compared three different diets that had varying amounts of fat and carbohydrates in each. The diets contained the same amount of calories, but differed in the percentage and type of fat. People on the low-fat, high-carbohydrate diet reported more anger and depression compared with the other two diets.
Replacing fatty foods, such as cakes, cookies, and chips, with their commercial "low-fat" counterparts does not constitute a low-fat diet. These foods generally contain more sugar and hence calories, not to mention other ingredients, which have virtually no nutritional value. In fact, a 2002 study suggested that increasing sugar may, over time, reduce levels of HDL ("good") cholesterol.
Very low-fat diets may increase the risk for stroke from hemorrhage in the brain.

Some fat in a diet is essential. It should come from plant oils and fish, however, and not from animal products or hardened oils, such as margarine. Trans-fatty acids, found in hardened oils, are actually more of a risk factor for obesity than saturated fats from animal products, although both should be avoided.

Fiber and Complex Carbohydrates. In all cases, complex carbohydrates found in whole grains and vegetables are preferred over those found in starch-heavy foods, such as pastas, white-flour products, and potatoes. Fiber is an important component of many complex carbohydrates. Fiber is almost always found only in plants, particularly vegetables, fruits, whole grains, nuts, and legumes (beans and peas). One exception is chitosan, a dietary fiber made from shellfish skeletons. Fiber cannot be digested but passes through the intestines, drawing water with it, and is eliminated as part of feces content. The following are specific advantages from high-fiber diets (up to 55 grams a day):

Insoluble fiber (found in wheat bran, whole grains, seeds, nuts, and fruit and vegetable peels) has been associated with weight loss. Studies also suggest that diets rich in fiber from whole grains reduce the risk for type 2 diabetes.
Soluble fiber (found in dried beans, oat bran, barley, apples, citrus fruits, and potatoes) has important benefits for the heart, particularly for achieving healthy cholesterol levels and possibly benefiting blood pressure as well. Simply adding breakfast cereal to a diet appears to reduce cholesterol levels. People who increase their levels of soluble fiber should also increase water and fluid intake.

High-protein, low carbohydrate diets, such as the Atkins and South Beach diets, have been touted as effective ways to produce short-term weight loss. Because of their emphasis on fats and proteins, many experts are concerned about long-term health problems. A report in the March 2006 Lancet linked the Atkins diet to life-threatening complications that caused the death of one woman. The 40-year-old woman had a deadly buildup of acids called ketones in her blood, a condition called ketoacidosis. Ketoacidosis can cause coma and death. Ketones are a known by-product of high protein, low carbohydrate diets. At low levels they can cause nausea, lightheadedness, and bad breath.

The long-term effects of these diets are still unknown. For example, the Atkins diet restricts some vegetables and most fruits, which are known to protect against serious diseases such as heart problems and cancer. The diet may also cause too much calcium to build up in the urine. This can increase the risk for kidney stones and osteoporosis. In addition, high-protein intake, particularly from meat, can be harmful in people with kidney problems. Individuals at risk for kidney stones, or those who have other kidney problems, should not go on high-protein diets without talking to their doctor first. Unfortunately, many people with diabetes are at risk of kidney problems, which could reverse any possible benefits a high-protein diet may bring them. Eating a lot of meat has also been associated with certain common cancers, notably prostate and colon cancers. A 2002 study suggested that such diets during pregnancy may increase the risk for high blood pressure in the child.

Still, significant studies say that such diets improve cholesterol and blood sugar levels. Studies in 2002 and 2003 have indicated that these diets lower blood glucose levels, which can be important in people who are diabetic. The diets also reduce triglyceride levels (unhealthy fat molecules) and increases HDL (" good") cholesterol levels. High triglyceride and low HDL levels are important risk factors for heart disease, and are common in people with type 2 diabetes. Studies are mixed on whether this type of diet reduces overall cholesterol or LDL ("bad") cholesterol levels.

Experts that promote the low carbohydrate approach argue that heart problems from obesity are due to insulin disturbances from sugar imbalances. Therefore, they believe that restricting carbohydrates is the best approach for obesity -- especially for overweight people with diabetes. More research is needed, however, to determine the long-term impact of such diets on health.

High-protein, low-carbohydrate diets include Atkins, Protein Power, Sugar Busters, and Dr. Stillman. The Atkins diet is one of the most popular and has a four-phase program:

Induction. For the first 2 weeks, individuals consume no more than 20 grams of carbohydrates a day. The diet consists of pure protein and fats. There is no fruit, bread, grains, starchy vegetables, or dairy products other than cheese, cream, or butter. This phase is not suitable for children, pregnant women, or anyone with kidney disease.
On-going Weight Loss. After the first phase, individuals continue to lose weight while they increase carbohydrate levels by five grams each day.
Premaintenance. When individuals get close to their weight goal, they add another 10 grams of carbohydrates per day as long as they do not begin to gain weight. Weight loss is very slow at this time, but the individual is now getting used to maintenance.
Maintenance. Lifetime maintenance is usually between 40 and 100 grams of carbohydrates a day, depending on steady weight level.

Anyone who chooses this diet should prefer fish or soy products to meat as protein sources. Fish may reduce leptin, a hormone associated with fat storage and heart diseases, and would be the best protein source. People on this diet should also choose monounsaturated fats (as in olive oil) over saturated fats or trans-fatty acids fat. Patients often need supplements, at least a multivitamin and possibly calcium, chromium, omega-3 fatty acids (found in fish oil), and other supplements.

The South Beach and Zone diets encourage healthy fats. They also allow certain carbohydrates. For example the Zone uses healthy carbohydrates (vegetables and dried beans) and unsaturated fats. The South Beach diet uses carbohydrates that have a lower impact on blood sugar levels. This is called a low-glycemic index. Low-glycemic foods include barley, dried bean and peas, milk, strawberries, and apples. High-glycemic foods include refined grains, white bread, white potatoes, and bananas and other tropical fruits. The glycemic index was developed for use in diabetes -- not for weight loss. Nevertheless, there is some evidence that foods with low glycemic indexes may produce a feeling of fullness and so discourage further eating. As with any high-protein diets, people at risk for kidney stones, or those who have other kidney problems, should avoid these plans.

Replacing fats and sugars with substitutes may help many people who have trouble maintaining weight. In fact, in one 2003 study, people with type 2 diabetes used the artificial sweetener sucralose and a beta-glucan fat substitute (derived from oats) as part of a low-calorie diet. At the end of the 4 weeks, they achieved better weight, glucose control, and HDL levels than those on a standard diabetic diet.

Fat Substitutes. Fat substitutes added to commercial foods or used in baking deliver some of the desirable qualities of fat, but do not add as many calories. It should be stressed that eliminating all fats from a diet can be harmful to general health.

Fat substitutes include the following:

Stanols. Stanols are plant compounds used in margarines (Benecol, Take Control). Benecol is derived from pine bark and Take Control from soybeans. Two servings a day of either brand, as part of a low-fat, diet can lower LDL and total cholesterol by impairing its absorption in the intestinal tract. Some studies have reported that the use of stanols can allow lower doses of statins (cholesterol lowering medications). Stanols do not appear to block absorption of fat-soluble nutrients or vitamins, as olestra does.
Olestra (Olean) passes through the body without leaving behind any calories from fat. Studies suggest that it improves cholesterol levels and helps people lose weight when it is used to replace a third of normal dietary fats. (Note that simply adding snacks containing olestra does not appear to have any effect on cholesterol or weight loss.) Early reports of cramps and diarrhea after eating food containing olestra have not proven to be significant. Of greater concern is the fact that even small amounts of olestra deplete the body of certain vitamins and nutrients that may help protect against serious diseases, including cancer. The FDA requires that the missing vitamins be added back to olestra products, but not other nutrients. The side health effects, if any, are unknown.
Beta-glucan is a soluble fiber found in oats and barley. Products using this substance (e.g., Nu-Trim) may reduce cholesterol and have additional health benefits.

A number of other fat-substitutes are also available. Although studies to date are not showing any significant side effects, these products' effect on weight control is uncertain, since many of the products containing them may be high in sugar.

Artificial Sweeteners. Many artificial or low-calories sweeteners are available. A 2002 study confirmed that people who consumed artificial sweeteners and reduced their sugar intake weighed less over time than those who took in similar types and amounts of drinks and food containing sugar. It should be noted that using these artificial sweeteners should not give dieters a license to increase their fat intake. Studies indicate that consuming some sugar is not a significant contributor to weight gain, as long as the total amount of calories in the diet is under control. There is some public concern about chemicals used to produce many of these sweeteners, and the side effects seen in studies using rats. Natural low-calories sweeteners are available that may be more acceptable to many people.

Saccharin (Sugar Twin, Sweet n' Low, Sucaryl, and Featherweight). Saccharin has been used for years. Some studies found that large amounts of saccharin cause bladder cancer in rats. However, the rats were fed huge amounts that do not apply to human diets. Currently there is no evidence that saccharin causes cancer in humans.
Aspartame (Nutra-Sweet, Equal, NutraTase). Aspartame has come under scrutiny because of rare reports of nervous system disorders, including headaches or dizziness, associated with its use. People with phenylketonuria (PKU), a genetic condition, should not use it. Studies have not reported any serious health dangers, but some people may be sensitive to it.
Sucralose (Splenda). Sucralose has no bitter aftertaste and works well in baking, unlike other artificial sweeteners. It is made from real sugar by replacing part of the sugar with chlorine. Some people are concerned because chlorinated molecules used in major industrial chemicals have been associated with cancer and birth defects. Over 100 studies have been conducted on sucralose over a 20-year period, with no reports of such risks.
Acesulfame-potassium (Sweet One, SwissSweet, Sunette). It has been used in the U.S. since 1988 with no reported side effects.
Neotame (Neotame). Neotame is a synthetic variation of aspartame, but was developed to avoid its side effects. The association with aspartame has raised some concerns. Studies to date have reported no effects that would cause alarm, and it appears to be safe for general consumption.
D-tagatose (Tagatose). This reduced-calorie sweetener is made from lactose, which is the sugar found in dairy products and other foods. It may be especially beneficial for people with type 2 diabetes. It may also have additional benefits that help the intestinal tract.
Alitame (Aclame) is formed from amino acids, the building blocks of proteins. It has the potential to be used in all products that contain sugar, including baked goods.
Stevioside (Stevia). This is a natural sweetener derived from a South American plant. It is available in health food stores. People with diabetes should avoid alcohol-based forms. It has not been carefully tested.

Other sugar substitutes being investigated include glycyrrhizin (derived from licorice) and dihycrochalcone (derived from citrus fruits).

Some studies have reported good success with meal replacement beverages (Slim-Fast, Sweet Success). They contain major nutrients needed for daily requirements. Each serving typically contains between 200 - 250 calories and replaces one meal. (Note: Using them for all meals reduces calories to a severe extent and can be harmful.)

One study reported that most subjects who had undergone a 12-week weight loss program and then used Ultra Slim Fast supplements as directed for maintenance kept off more than half their weight loss after more than 3 years. A quarter of the subjects were still losing weight.

Medical evidence suggests that a diet rich in magnesium could reduce a person's risk of metabolic syndrome, a cluster of problems including obesity, high blood pressure, and high cholesterol. Metabolic syndrome can lead to diabetes and heart disease. A long-term study of thousands of Americans found that the risk for metabolic syndrome decreased in those who consumed the most magnesium from meals. The findings were published in the journal Circulation.

Commercial and Non-Profit Support Programs for Weight Loss. There are many different types of weight-loss program. (This report cannot address all of the many commercial and nonprofit weight-loss programs currently available, nor can it assess their claims.)

Taking off Pounds Sensibly (TOPS), a nonprofit support organization with many local chapters, is one of the least expensive programs, costing $20 a year.

Most of the commercial programs such as Weight Watchers, Jenny Craig, and NutriSystem offer individual or group support, lifestyle changes and packaged meals. These programs tend to be expensive. There are few well-conducted studies on these programs. One 2003 study reported modest weight loss over 2 years with Weight Watchers compared to a self-help program. There were no differences in heart risk factors.

Cognitive Behavioral Approaches. Most support programs use some form of cognitive-behavioral methods to change the daily patterns associated with eating. They are very useful for preventing relapse after initial weight loss. The following is a typical approach:

The patient first records in a diary all activity related to eating patterns, including the times of day, length of meal, emotional states, companions, and, of course, the kind and amounts of food eaten. Most people -- even professional dieticians, according to one study -- tend to underreport their daily calorie intake. However, writing it down is still a good method for increasing a person's awareness of eating patterns. (One patient said that recording circumstances surrounding relapses was a particularly valuable guide for understanding the stresses leading to her own eating behaviors.)
The patient reviews the diary with a therapist or group to set realistic goals and identify patterns that the patient can change. For instance, if food is normally eaten while watching television, then the patient may be advised to eat in another room instead.
Good eating habits are reinforced by rewards. These rewards are other pleasures that substitute the high calorie consumption and sedentary activities.

Behavioral modification has been shown to be helpful particularly for people who have an overly strong response to the taste, smell, and appearance of food. It also may be useful for binge eaters.

Stress-Reduction Techniques. Stress reduction and relaxation techniques may be helpful for some people with obesity, such as those whose weight is related to night-eating syndrome. [See In-Depth Report #31: Stress.]

Changing Sedentary Habits. Making even small changes in physical activity can expend energy. For example, simply getting up to turn the TV on and off instead of using the remote, and standing (instead of sitting) while talking on the phone may help a person lose up to five pounds a year. Other suggestions include cooking one's own food (instead of eating take-out or fast food), walking to as many places as possible, using stairs instead of escalators or elevators, and gardening. Even fidgeting may be helpful in keeping pounds off, and, in one study, chewing gum increased energy expenditure.

No one should rely on such mild activities, however, for serious weight loss. Only high levels of physical activity -- not just using up energy -- help prevent obesity.

Approach to Exercise. Exercise, which replaces fat with muscle, is the critical companion for any weight control program. In a one-year study, women who regularly averaged 3.5 days (176 minutes) of exercise each week lost significantly more weight than women who did not exercise regularly. Women who exercised more than 195 minutes a week lost nearly 7% of their abdominal fat.

People who exercise are more apt to stay on a diet plan. Exercise improves psychological well-being and replaces sedentary habits that usually lead to snacking. Exercise may even act as a mild appetite suppressant. Moreover, exercise improves overall health even with modest weight loss. In support of this, a British study found that overweight fit individuals had half the death rate of unfit trim individuals.

Be aware, however, that the pounds won't melt off magically. Losing significant weight requires both intensive exercise and calorie restriction. In addition, if a person exercises but doesn't diet, any actual pounds lost may be minimal, because denser and heavier muscle mass replaces fat. Nonetheless, regardless of weight loss, a fit body will look more toned and be healthier. In addition, exercise benefits the heart even with modest weight loss.

The following are some suggestions and observations on exercise and weight loss:

The more strenuous the exercise, the better the chances for short-term and long-term success. With intense exercise, the metabolism continues to burn calories before returning to its resting level. This state of elevated metabolism can last for as little as a few minutes after light exercise to as long as several hours after prolonged or heavy exercise.
Of the standard aerobic machines, the treadmill burns the most calories. It may be particularly effective when used in short multiple bouts during the day. In fact, frequent exercise sessions as short as 10 minutes in duration (about four times a day) may be the most successful exercise program for obese people.
Resistance, or strength, training is excellent for replacing fat with muscles. It should be performed two or three times a week.
As people slim down, their initial level of physical activity becomes easier and they burn fewer calories per mile of walking or jogging. The rate of weight loss slows down, sometimes discouragingly so, after an initial dramatic head start using diet and exercise combinations. People should be aware of this phenomenon and keep adding to their daily exercise program.
As people age, they also need to exercise more to keep off the same amount of weight.
Changes in fat and muscle distribution may differ between men and women as they exercise. Men tend to lose abdominal fat (which lowers their risk for heart disease faster than reducing general body fat). Exercise, however, does not appear to have the same effect on weight distribution in women. In one interesting study, women in aerobic and strength training programs lost fat in their arms and trunk, but did not gain muscle tissue in these regions.

Warning Note. Because obesity is one of the risk factors for heart disease and diabetes, anyone who is overweight must discuss their exercise program with a doctor before starting. Sudden demanding exercise, in such cases, can be very dangerous. [See In-Depth Report #29: Exercise.]

Medications

There are several different drugs used for weight loss. Unless specifically instructed by a doctor, people should use non-drug methods for losing weight. Except under rare circumstances, pregnant or nursing women should never take diet medications of any sort, including herbal and over-the-counter remedies.

A 2001 study reported that 7% of American adults use nonprescription weight-loss products. People must be cautious when using any weight-loss medications, including over-the counter diet pills and herbal or so-called natural remedies. Buying unverified products over the Internet can be particularly dangerous.

Green tea. Perhaps the best alternative advice for people who are overweight is to drink tea. Studies have indicated that regular tea drinking is associated with lower weight, particularly in people who drink it for years. Green tea specifically has been associated with increased energy expenditure. One study reported that people who took a green tea extract (Exolise) lost weight and reduced their waist size. Better evidence is needed to confirm the results on this supplement.

Thermogenic Approach to Weight Loss. An approach to weight loss called thermogenic (also hepatothermic) therapy is based on the idea that certain natural compounds have properties that enable the liver to increase energy in the cells and stimulate the metabolism. Theoretically, the result would be fat loss. Among the natural substances used in such products are EPA-rich fish oil, sesamin, hydroxycitrate, pantethine, L-carnitine, pyruvate, aloe vera, aspartate, chromium, coenzyme Q10, green tea polyphenols, aloe vera, DHEA derivatives, cilostazol, diazoxide, and fibrate drugs.

Nearly all the current over-the-counter dietary aids contain some combination of these ingredients. There is no evidence that any of these ingredients can produce weight loss, and some may even have harmful effects.

Chromium is a common ingredient in many diet supplements (e.g., Xenadrine, Dexatrim, Acutrim Natural, Twinlab Diet Fuel). It is claimed to specifically promote fat loss, rather than lean muscle loss. Some evidence suggests that niacin-bound chromium may improve insulin sensitivity. On the negative side, animal studies have suggested that chromium may have damaging effects on genetic materials in cells. This could cause sterility.

Ephedra, Ephedrine, and Ma Huang. The FDA does not allow the sale of drugs that contain ephedrine. In May 2004, the FDA banned the sale of dietary supplements that contain ephedra (also called Ma Huang). Ephedra has been linked to serious side effects, including strokes and heart attacks.

Brazilian Diet Pill. The US Food and Drug Administration (FDA) is warning consumers not to buy a product known as the "Brazilian diet pill." This product is labeled as a dietary supplement, but contains several chemicals found in powerful prescription drugs. The products are also known as Emagrece Sim and Herbathin dietary supplements.

Conjugated Linoleic Acid (CLA). Conjugated linoleic acid is found in many dietary products (e.g., Biosculpt Liquid, Body Success, GNC Optibolic Body Answers Dietary Formula). There is no evidence that it produces weight loss. Furthermore, there is some concern that CLA might increase insulin resistance and a dangerous inflammatory response in people with obesity.

Tiratricol. Over-the-counter products containing tiratricol, a thyroid hormone, have been sold for weight loss. Such products may increase the risk for thyroid disorders, heart attack, and stroke.

Laxative Actions in Natural Substances. Many dietary herbal teas contain laxatives, which can cause gastrointestinal distress, and, if overused, may lead to chronic pain, constipation, and dependency. In rare cases, dehydration and death have occurred. Some laxative substances found in teas include senna, aloe, buckthorn, rhubarb root, cascara, and castor oil.

Guar Gum. Some fiber supplements containing guar gum have also caused obstruction of the gastrointestinal tract.

Chitosan. Chitosan, a dietary fiber from shellfish, prevents a small amount of fat from being absorbed in the intestine. Well-conducted studies, however, have not found it to be effective. Products containing it include Cheat & Lean Fat Blocker, Natrol, Chroma Slim, and Enforma. People who are allergic to shellfish should not take these supplements.

Plantain. Dietary remedies that list the ingredient plantain may contain digitalis, a powerful chemical that affects the heart. NOTE: This substance should not be confused with the harmless banana-like plant also called plantain.

Orlistat (Xenical) can help about one-third of obese patients with modest weight loss, and can assist in long-term maintenance of weight loss. It works by slowing the absorption of fat (by about 30%) in the intestine. Studies indicate that between 50 - 80% of patients can achieve weight loss of 5% or greater, depending on other lifestyle changes. However, many people regain a significant portion of this weight back within 2 years. It does not work for all patients, however. In one survey of patients who took it, 10% gained weight or did not lose any, and 43% lost less than 5%. Nevertheless, orlistat may delay or even prevent the onset or progression of diabetes and improve cholesterol levels, regardless of weight loss.

The drug can cause gastrointestinal problems and may interfere with absorption of the fat-soluble vitamins A, D, and E and other important nutrients. The most unpleasant side effect is oily leakage of feces from the anus. Restricting fats can reduce this effect. People with bowel disease should probably avoid it. In spite of these side effects, most patients are able to tolerate this agent.

In February 2007, the FDA approved an over-the-counter (OTC) version of orlistat. It will be sold under the name alli, and will be available at half the prescription strength of Xenical. Those eager to use the new pill should consider its cost and modest benefits compared with its side effects, most commonly oily diarrhea. This pill, which prevents fat absorption from food, also increases the risk of not absorbing important nutrients from food while using it. The FDA recommends taking a daily multivitamin supplement when using alli.

Sibutramine (Meridia) helps balance the brain chemicals serotonin and norepinephrine. This helps increase metabolism, causes a feeling of fullness, and increases energy levels. It may be particularly useful for binge-eaters. Studies indicate that sibutramine is effective in achieving weight loss, although the weight loss slows considerably after the first 3 months. The drug also appears to improve cholesterol and lipid (fat) levels, and may have other effects that benefit the heart.

Side effects of sibutramine are common. They include dry mouth, constipation, and insomnia. In one study, almost half the patients dropped out as a result of these side effects. There have been reports of increases in heart rate and blood pressure while taking this medication, although a 2001 study indicates that blood pressure stabilizes over time.

At this time, people who have a history of high blood pressure, stroke, heart disease, or arrhythmias should not take this drug. People taking decongestants, bronchodilators (such as for asthma), monoamine oxidase inhibitors, or serotonin reuptake inhibitors should also avoid sibutramine.

Phentermine and Other Sympathomimetics. Sympathomimetics are drugs that act like the stress hormone (and chemical messenger) norepinephrine. These medications act as stimulants in the brain. Some are approved for treating obesity, but only for short-term use. They include:

Phentermine (Ionamin, Adipex-P, Fastin)
Benzphetamine (Didrex)
Phendimetrazine (Adipost, Bontril, Melfiat, Plegine, Prelu-2, Statobex)

Phentermine is the most commonly prescribed appetite suppressant, and is less expensive than orlistat or sibutramine. Its effects are not long lasting, however. It can also raise blood pressure. In addition, phentermine is associated with depression, which is already a problem in many cases of obesity. A combination (Phen-Pro) containing phentermine and the antidepressant fluoxetine (Prozac) is being investigated to help reduce this problem. Note: Neither phentermine nor such combinations are associated with the heart problems linked to the previous phentermine combination known as Fen-Phen (phentermine and fenfluramine).

Amphetamines. The amphetamines dextroamphetamine (Dexedrine), methamphetamine (Desoxyn), and phenmetrazine (Pleudin) are powerful stimulants. They were used most often in the past but are no longer prescribed for weight loss. These drugs improve mood and produce some modest weight loss over the short term, but carry serious risks of addiction, agitation, and insomnia.

Rimonabant. Rimonabant (Accompli) belongs to a new class of drugs called selective CB1 blockers. The drug is designed to block receptors in the brain associated with the regulation of eating. Rimonabant also targets receptors in fat tissue. The Rimonabant in Obesity-Lipids (RIO-Lipids) study looked at how rimonabant affected metabolic risk factors in high-risk overweight or obese patients with blood fat disorders. The study involved more than 1,000 participants. The findings, published in the November 2005 New England Journal of Medicine, said that people who took the drug significantly reduced their body weight and size of their waist.

Earlier studies involving the drug reported that obese patients treated with 20 mg of rimonabant lost significantly more weight and inches from their waist than patients who received placebo. The drug also appeared to have beneficial effects on raising HDL ("good") cholesterol levels.

Note: Fake rimonabant has been found for sale on several web sites. Patients should be aware that this drug is still experimental, and rimonabant is not available for sale. Buying and taking counterfeit drugs can have serious health consequences. In addition, an FDA advisory panel in April 2007 rejected the drug, citing fears it may cause psychiatric problems and seizures in some patients.

Axokine. Axokine is a type of drug called a ciliary neurotrophic factor. It signals the brain to suppress one's appetite. It is proving to be effective in achieving weight loss, and also improves cholesterol, lipid, and glucose levels regardless of food intake. It could be particularly helpful for people with type 2 diabetes. Early study results found that severely obese patient who took the drug lost more weight than those who took a dummy pill (placebo). Nearly half (46%) of patients who took the drug lost at least 10 pounds, compared to 5% of those who received the placebo. Study participants tolerated the drug well. There were no reports of serious side effects.

Zonisamide. Zonisamide (Zonegran) is an anti-seizure medication that is also being investigated for weight loss. In one study, patients who took it lost more weight than those on placebo. Zonisamide increases the risk for kidney stones, which can be reduced with increased fluid intake and citrate. It has also been associated with reduced sweating and a sudden rise in body temperature, especially in hot weather. Other side effects include dizziness, forgetfulness, headache, and nausea.

Topiramate. Topiramate (Topamax) is another anti-seizure medication being investigated for weight reduction. Three clinical trials have reported that patients given topiramate lost more weight than those receiving placebo. Weight loss was sustained for up to 1 year. The drug is also being studied for binge-eating disorders associated with obesity.

Other Treatments

Surgical procedures for obesity may be appropriate for some dangerously obese people, and may reduce heart problems and many of the risks associated with obesity. These risks include high blood pressure, sleep apnea, and diabetes. In fact, some evidence suggests that surgery may provide much greater control of weight and diabetes than nonsurgical weight-loss methods. Studies are reporting significant reductions in diabetes, and the need for diabetic medications, after surgery. Other medical conditions that often improve after surgery include heartburn, arthritis, and other joint and circulation problems.

Bariatric surgeries produce weight loss through one of two approaches:

Restrictive Banding Procedures. These procedures restrict the amount of food by closing off parts of the stomach with bands.
Malabsorptive Bypass Procedures. This approach restricts the amount of food and also reduces absorption by using a bypass of parts of the intestine.

The malabsorptive procedures are more successful in achieving weight loss than the banding approach, but they carry a greater risk for nutritional deficiencies.

Most people who have bariatric surgery lose about two-thirds of excess weight within 2 years. In addition, diseases associated with obesity (such as diabetes, high blood pressure, sleep apnea, joint pain, and incontinence) often improve.

Researchers at the Mayo Clinic looked at records from patients who had the surgery between 1990 and 2003. They found that those who had bariatric surgery reduced their risk of cardiovascular events such as a heart attack much more than those who lost weight without surgery. The findings were published in the September 2005 Mayo Clinic Proceedings.

Other studies have shown that even though most patients maintain significant weight loss, the majority regain about to 10% of their weight. Patients must still develop a healthy life style and be calorie conscious after the operation. Follow-up must be life-long.

Any surgical candidate must have failed consistently in losing weight through less invasive methods. Experts recommend bariatric surgery only for the following:

Those whose BMI is above 40 (about 100 pounds overweight)
Those with BMIs of over 35 who have type 2 diabetes or serious obesity-related medical problems
Those with severe obesity that interfered with employment, normal physical activity (e.g., walking), and important relationship

About a third of people who undergo these procedures achieve normal weight, and 80% experience some weigh loss. They are less successful than the bypass procedures, but carry a lower risk of nutritional deficiencies.

Vertical Banded Gastroplasty. Vertical banded gastroplasty (VBG) was the most common restrictive procedure. It involves creating a hole through both stomach walls and sealing the edges with a staple. This narrows the stomach, similar to a funnel, and allows only small amounts of food to pass through.

Laparoscopic Gastric Banding. Laparoscopic gastric banding (the Lap-Band) usually does not require a major incision and avoids some of the major complications of gastric bypass:

It employs an adjustable silicone band that is placed around the upper part of the stomach.
A small balloon-like reservoir attached to the band under the abdominal skin contains saline, which can be added or removed to tighten or loosen the band.
The procedure restricts the amount of food a person can eat and gives the feeling of fullness.

The band is removable, if necessary. Studies to date indicate that the intestinal tract returns to normal afterward. Studies, including those done in the elderly, have reported significant weight loss and improved quality of life with the procedure.

Malabsorptive procedures produce greater weight loss than restrictive procedures. Patients generally achieve about two-thirds of their weight loss within 2 years. Furthermore, in a 2003 study, after standard bypass surgery, 83% of patients with type 2 diabetes experienced normal blood glucose levels and the rest had significant reductions.

Roux-en-Y Gastric Bypass Procedure. This is the most common and successful malabsorptive surgery in the United States. It involves creating a small stomach pouch that serves as a reservoir and restricts food intake. The pouch eventually holds up to 3 ounces of food and has a small outlet that delays emptying and causes a feeling of fullness. Then the surgeon creates a Y-shaped section in the small intestine that attaches to the pouch. This section allows food to bypass the lower stomach and upper part of the intestine. One 2003 study reported that this procedure was associated with significant weight loss, and 80% of patients with type 2 diabetes were able to reduce their medications. A more recent study, published in the March 14, 2006, issue of Archives of Surgery, found that gastric bypass surgery also helps lower the blood pressure of very obese patients.

The procedure produces greater and more sustained weight loss than banding procedures, but it is also more complicated, and carries a higher risk of nutritional deficiencies. Laparoscopy techniques, which are less invasive, are now preferred over open surgery. They achieve equally good results with fewer complications.

Biliopancreatic Diversion. This procedure is more complicated and removes portions of the stomach. The pouch that is created attaches directly to the lower part of the small intestine. It poses a higher risk for nutritional deficiencies than other procedures and is not used as often.

Click the icon to see an image of gastric bypass surgery.

General Side Effects and Complications. Side effects and complications of bariatric procedures are common, and up to 25% of patients require corrective or repeat procedures. After any of these procedures people must chew all their food carefully, and they cannot eat large amounts of food at one time. If patients do not follow these guidelines, they will experience nausea, abdominal distress, or both.

Complications from any bariatric procedure includes the following:

Vomiting: This is the most common complication, and it is most common with banding procedures.
Nutritional deficiencies: There is a strong risk of nutritional deficiencies, particularly with malabsorptive operations. This complication can lead to anemia and increase the risk of bone loss and osteoporosis. Taking enough mineral and vitamin supplements is important after bariatric surgery.
Deep-vein thrombosis: There is a significant risk for deep-vein thrombosis (blood clots in the veins).
Abdominal hernia: This is another common complication. Newer, laparoscopic techniques do not carry this risk, but not all individuals are candidates for this less-invasive approach.
Rapid weight loss after surgery: This complication puts people at high risk for gallstones.
Women who wish to be pregnant should wait until their weight has stabilized. Rapid weight loss and nutritional deficiencies can harm the fetus.

People at highest risk for complications are those with heart or lung problems, severe obesity, and a history of abdominal surgeries. The mortality rate from bariatric surgeries is 0.2%, which is lower than the morality rates from severe obesity itself. Other surgical variations and less invasive techniques using laparoscopy have been developed.

Specific Complications of Restrictive Banding Procedures. Nausea, vomiting, or both occurs in half the patients, and severe heartburn occurs in a third. Device-related complications include band slippage, pouch dilation (widening), or both in nearly a quarter of patients, and obstruction in 12% of patients. Very serious complications are rare, but include blood clots, bleeding, infection, pneumonia, and perforation (tearing) of the stomach.

Specific Complications of Malabsorptive Bypass Procedures. Vomiting often occurs. Nutritional deficiencies occur more often in these procedures. The so-called dumping syndrome is a common unpleasant side effect, which occurs when food waste moves too quickly through the intestine. Symptoms include nausea, weakness, sweating, and faintness (particularly after eating sweets).

Spot Exercising. Anyone seeking to lose weight must expect that the results may not be as cosmetically satisfying as one would wish. Spot exercising (training particular areas of the body) is ineffective in reducing fat in specific locations because exercise draws on fat stores throughout the body. Gimmicky devices such as bust developers, vacuum pants, and exercise belts do absolutely nothing to reduce fat or add bulk in specific locations. Electrical pads wrapped around the waist, arms, or thighs were reported to cause burns and fires.

Cellulite-Removal Creams. Many women try to reduce fat in their thighs (cellulite) with creams that contain aminophylline (Skinny Dip, Thermojetics Body Toning Cream, Smooth Contours). Studies provide no evidence that these creams are effective. Their apparent effect on fat may simply be from narrowing blood vessels and forcing water from the skin, which could be dangerous for people with blood flow problems.

Endermologie. Endermologie uses motorized rollers and regulated suction to smooth out cellulite. In one study, about 28.6% of patients reported improved appearance after using it.

Liposuction. Liposuction eliminates fat in specific areas, such as the abdomen, thighs, buttocks, or knees. Special instruments are inserted through the skin into the pockets and suction is used to move the fat, break it up, and remove it. Small tubes may be used to drain blood and fluid during the first few days. The pain after the operation can be severe and often the skin does not contract, resulting in a flabby look. Complications can include burns from the vibrators, bruising, blood clots, and bleeding. Weight gain generally tends to develop in other locations after the operation. Some doctors are using this procedure in overweight people with diabetes to remove abdominal fat. Although there is no proof that it has an effect on diabetes, some experts believe the procedure deserves attention.

Liposuction is not recommended for major weight loss.

Resources

www.healthierus.gov/dietaryguidelines -- Dietary Guidelines for Americans 2005
www.naaso.org -- North American Association for the Study of Obesity
www.eatright.org -- American Dietetic Association
www.nutrition.gov. -- Nutrition.gov
www.asbs.org -- American Society for Bariatric Surgery
www.cnpp.usda.gov -- Center for Nutrition Policy and Promotion
http://fnic.nal.usda.gov -- Food and Nutrition Information Center
www.americanheart.org -- American Heart Association
www.nationaleatingdisorders.org -- National Eating Disorders Organization
www.aabt.org -- Association for Advancement of Behavior Therapy
www.fda.gov -- Food and Drug Administration
http://win.niddk.nih.gov -- Weight-Control Information Network

References

US Food and Drug Administration FDA Approves Orlistat for Over-the-Counter Use. Rockville, MD: National Press Office; February 7, 2007.

Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. Journal of the American Medical Association. 2006; 295:1549-1555.

National Center for Health Statistics. Chartbook on Trends in the Health of Americans. Health, United States, 2005. Hyattsville, MD: Public Health Service. 2005

National Institute of Diabetes and Digestive and Kidney Diseases - Weight-control Information Network. Statistics Related to Overweight and Obesity. Available online.

National Center for Health Statistics. Prevalence of Overweight Among Children and Adolescents: United States, 2003-2004.

Morino M, Toppino M, Bonnet G, Rosa R, et al. Laparoscopic vertical banded gastroplasty for morbid obesity. Assessment of efficacy. Surg Endosc. 2002 Nov;16(11):1566-72.

Brethauer SA, Schauer PR, Chand B. Risks and benefits of bariatric surgery: Current evidence. Cleveland Clinic Journal Of Medicine. 2006 Nov; 73(11): 993-1007.

Rosenthal RJ, Szomstein S, Kennedy CI, et al. Laparoscopic surgery for morbid obesity: 1,001 consecutive bariatric operations performed at The Bariatric Institute, Cleveland Clinic Florida. Obes Surg. 2006 Feb;16(2):119-24.

He K, Liu K, Daviglus ML, et al. Magnesium Intake and Incidence of Metabolic Syndrome Among Young Adults. Circulation. 2006: Published online before print. March 27, 2006.

Chen TY, Smith W, Rosenstock JL, Lessnau KD. A life-threatening complication of Atkins diet. Lancet. 2006 Mar 18;367(9514):958.

Lopez-Jimenez F, Bhatia S, Collazo-Clavell ML, Sarr MG, Somers VK. Safety and efficacy of bariatric surgery in patients with coronary artery disease. Mayo Clin Proc. 2005 Sep;80(9):1157-62.

Sidhaye A, Cheskin LJ. Pharmacologic treatment of obesity. Adv Psychosom Med. 2006;27:42-52.

Fernstrom JD, Courcoulas AP, Houck PR, Fernstrom MH. Long-term changes in blood pressure in extremely obese patients who have undergone bariatric surgery. Arch Surg. 2006 Mar;141(3):276-83.

Despres JP, Golay A, Sjostrom L; Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005 Nov 17;353(20):2121-34.

Lanningham-Foster L, Nysse LJ, Levine JA. Labor saved, calories lost: the energetic impact of domestic labor-saving devices. Obes Res. 2003 Oct;11(10):1178-81.

Review Date:
6/14/2007
Reviewed By:
A.D.A.M. Editorial Team: Greg Juhn, M.T.P.W., David R. Eltz, Kelli A. Stacy. Previously reviewed by Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital (4/30/2007).

A.D.A.M. Copyright

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