FitSugar

5 Ways Pets Improve Your Health

FitSugar — Wed, 12 Nov 2008 16:00:00 -0800

When I come home from a long day of blogging, my dear dog Bonnie greets me at the door with blind adoration. All that love is such an ego boost. Pets are good for more than your self-esteem. Besides being great buddies, according to WebMD pets can also improve your health in these five ways:

Prevent allergies: Many new studies show that children who grow up in a household with furry animals or on a farm, have less risk for allergies, and asthma and a stronger immune system.
Friend magnets: Pets are natural conversation starters so your pet can help you meet people if you have social anxiety or chronic shyness.
Benefit the aged: For the elderly, caring for a pet can offer exercise and companionship. Studies have also shown that for Alzheimer's patients, those who have a pet have fewer anxious outbursts.
Good for the mind and soul: Those who have pets are less likely to suffer from depression, are better equipped to handle stressful situations, and they also have lower blood pressure.
Good for your heart: Pet owners who suffer from a heart attack will live longer than those who are petless. Studies have also shown that men who own pets have lower cholesterol.

Source

Volunteer and Get Fit With Fido

FitSugar — Wed, 23 Sep 2009 12:30:57 -0700

Exercise and volunteering can seem like extras in our lives that we just don't have time for, so why not combine the two? There are organizations such as Get Fit With Fido in Seattle where you can volunteer to exercise shelter dogs. Walking or running with a dog is a great skill you can offer, and not only will the pooch love the attention and fresh air, but you'll also benefit from the furry companionship. Not to mention, both of you can stay fit together. Another plus is that when you take the dogs out, you can help them find a home faster since more people will get to meet them. Obese dogs that trim down will also find homes quicker since pudgier pooches tend to get overlooked by people wanting to adopt. Exercised dogs are also calmer and train more easily, so their good manners and friendly demeanor are also a bonus for prospective pet owners.

So if you don't have your own dog to run with, borrow one that is in need of your love and attention. Call up your local shelter to see if they offer programs where a group of volunteers take dogs out together. If they don't, I'm sure they'll be excited to have you exercise dogs on your own. Go on your lunch break once a week, a few times a week, or for longer workouts, go on your days off.

Alzheimer's disease

FitSugar — Wed, 08 Oct 2008 17:35:13 -0700

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Alzheimer’s Disease Toll Increasing

More than 5 million Americans now have Alzheimer’s disease, and the number could increase to 16 million by mid-century, according to a 2007 report from the Alzheimer’s Association.

New Drug Indication

In 2006, the FDA expanded the use of donepezil (Aricept) to include treatment of people with severe dementia associated with Alzheimer’s disease. Donepezil was previously approved only for people with mild-to-moderate dementia.

Managing Psychotic and Behavioral Symptoms

Newer antipsychotic drugs are no better than placebo for controlling psychosis, aggression, and agitation in patients with Alzheimer’s disease, indicates an important study in the New England Journal of Medicine. In addition, these drugs can cause severe side effects and have been associated with increased death rate.
Non-drug approaches, such as behavioral techniques and bright light boxes, may be helpful for these patients, suggests an Archives of Internal Medicine study.

Brain Exercises Prevent Mental Decline

Cognitive training exercises that help boost memory, reasoning, and processing speed may help slow mental decline and improve functional abilities in older adults, indicates a Journal of the American Medical Association study.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Do Not Prevent Alzheimer’s

The NSAIDs naproxen (Aleve) and celecoxib (Celebrex) do not protect against Alzheimer’s disease, indicates a data analysis from a large-scale U.S. National Institutes of Health (NIH) clinical trial.

Docosahexaenoic Acid (DHA) for Alzheimer’s Prevention

DHA, an omega-3 fatty acid found in some types of fish, may lower the risk for dementia and Alzheimer’s disease as well as delay its progression. However, researchers are uncertain whether DHA dietary supplements provide the same benefits as food sources (salmon, mackerel, and other types of fatty fish). In 2007, the NIH announced the launch of a national clinical trial to evaluate whether DHA can slow cognitive and functional decline in people with mild-to-moderate Alzheimer’s disease.

Support for Caregivers

Intensive programs that combine counseling, support groups, and problem-solving techniques can dramatically improve caregivers’ quality of life and may help delay patients’ transfers to nursing homes, several recent studies suggest.

Introduction

Alzheimer's disease (AD) is a degenerative disease of the brain from which there is no recovery. The disease slowly attacks nerve cells in all parts of the cortex of the brain and some surrounding structures, thereby impairing a person's abilities to govern emotions, recognize errors and patterns, coordinate movement, and remember. Ultimately, a person with AD loses all memory and mental functioning.

The major areas of the brain have one or more specific functions.

Causes

Researchers are finding specific biologic factors involved with Alzheimer's disease. Various environmental and genetic players appear to contribute to or trigger the process by which these factors destroy nerve cells leading to this disease.

Imaging techniques in patients with Alzheimer's disease have found significant loss of cells and volume in the regions of the brain devoted to memory and higher mental functioning. Important abnormalities have specifically been observed during biopsies:

Twisted nerve cell fibers, known as neurofibrillary tangles
A sticky protein, beta amyloid

Other factors also play a role.

Click the icon to see an animation about Alzheimer's disease.

The Effects of Neurofibrillary Tangles and Beta Amyloid in Alzheimer's Disease. These biologic factors appear to be involved in the development Alzheimer's disease in the following ways:

Neurofibrillary tangles are the damaged remains of microtubules, the support structure that allows the flow of nutrients through the neurons (nerve cells). A key component in these tangled fibers is an abnormal form of the tau protein, which in its healthy version helps in the assembly of the microtubule structure. The defective tau, however, appears to block the actions of the normal version.
Beta Amyloid (also called A beta) is the second significant finding. This insoluble protein accumulates and forms sticky patches called neuritic plaque, which are found surrounded by the debris of dying nerve cells in the brains of Alzheimer's victims.
Amyloid precursor protein (APP) is a large nerve-protecting protein that is the source of beta amyloid. In Alzheimer's certain enzymes, particularly those called gamma-secretases, snip APP into beta amyloid pieces. This process is controlled by factors called presenilin proteins. (Genetic abnormalities that affect either APP or presenilin proteins occur in some inherited cases of early-onset Alzheimer's.)
High levels of beta amyloid are associated with reduced levels of the neurotransmitter acetylcholine. (Neurotransmitters are chemical messengers in the brain.) Acetylcholine is part of the cholinergic system, which is essential for memory and learning and is progressively destroyed in Alzheimer's disease.
Beta amyloid may also disrupt channels that carry sodium, potassium, and calcium. These elements serve the brain as ions, producing electric charges that must fire regularly in order for signals to pass from one nerve cell to another. If the channels that carry ions are damaged, an imbalance can interfere with nerve function and signal transmission.

Click the icon to see an image of amyloidosis.

Other Proteins. Researchers have now identified other important proteins in the areas of the brain affected by Alzheimer's disease.

ERAB (endoplasmic-reticulum associated binding protein) appears to combine with beta amyloid, which in turn attracts new beta amyloid from outside the cells. High amounts of ERAB may also enhance the nerve-destructive power of beta amyloid.
AMY plaques resemble beta amyloid so closely that researchers were able to detect them only with the use of highly sophisticated techniques.
Elevated levels of a protein called prostate apoptosis response-4 (Par-4) may cause nerve cells to self-destruct.

Researchers are also attempting to discover why beta amyloid is so toxic to nerve cells. Some researchers are focusing on two processes in the body that may be involved with Alzheimer's disease: oxidation and the inflammatory process. There is some evidence that such events can begin decades before Alzheimer's disease actually develops. One scenario for their role in Alzheimer's is as follows:

The Role of Oxidation.

As beta amyloid breaks down it releases unstable chemicals called oxygen-free radicals. Once released, oxygen-free radicals bind to other molecules through a process called oxidation.
Oxidation is the result of many common chemical processes in the body, but when oxidants are overproduced, they can cause severe damage in cells and tissue, including even affecting genetic material in cells (its DNA). Oxidation is known to play a role in many serious diseases, including coronary artery disease and cancers, and experts believe it may also contribute to Alzheimer's.

The Inflammatory Response.

One result of oxidation is the marshaling of immune factors to repair the cellular injuries it produces. Overproduction of some of these factors, however, produces the so-called inflammatory response, in which the immune process itself can actually damage the body's own cells themselves.
Principle immune cells in the brain are called macrophage/microglia (M phi). In the healthy brain, they play an important protective role against invading organisms. However, when they are activated by beta amyloid oxidation, they release toxic molecules called cytokines, which are known to cause harm. For example, significantly high levels of interleukin-6, a specific cytokine, have been detected in people with Alzheimer's.
Other inflammatory factors of specific interest in Alzheimer's research are the enzyme cyclooxygenase (COX) and its products called prostaglandins. Excess amounts of these factors may increase levels of glutamate. Glutamate is an amino acid that excites nerves and, when overproduced, is a powerful nerve-cell killer.
The inflammatory process has also been associated with the release of soluble toxins called amyloid beta-derived diffusible ligands, which some investigators believe may prove to key players in the destructive process.

Major research targets in Alzheimer's disease are the factors responsible for beta amyloid build-up and concentration in certain people and not in others. Genetic factors are believed to play a role in many cases. In 2003, the National Institute on Aging (NIA) launched the ambitious AD Genetics Initiative, a 3-year national project to bank genetic material from families who have at least two members with late-onset Alzheimer's.

The ApoE Gene and Late-Onset Alzheimer's. The major target in genetic research on late-onset Alzheimer's disease (called LOAD) has been apolipoprotein E (ApoE), which plays a role in the movement and distribution of cholesterol for repairing nerve cells during development and after injury.

The gene for ApoE comes in three major types:

ApoE4. Studies have reported the greatest deposits of beta amyloid in people with ApoE4, which is now believed to be a major risk factor for late-onset Alzheimer's. Some evidence suggests that the ApoE protein removes beta amyloid but the ApoE4 variant does so less efficiently than other ApoE types. (ApoE4 has also been studied for years as a risk factor for heart disease.)
ApoE3 and ApoE2. Fewer beta amyloid deposits have been observed in people with the ApoE3, and the fewest deposits have been observed in people with ApoE2, which may actually be protective.

People inherit a copy of one type from each parent, but Alzheimer's disease is not inevitable even in people with two copies of the ApoE4 gene. Reports vary widely in estimating the extent of risk:

People without ApoE4 have an estimated risk of between 9 - 20% for developing Alzheimer's by age 85.
In people with one copy of the gene, the risk is between 25 - 60%.
In people with two copies, the risk ranges from 50 - 90%. (Only 2% of the population carries two copies of the ApoE4 gene.)

Some researchers suspect that some specific variation of the ApoE4 gene or combinations with other genes are critical for the disease, since many people who carry the ApoE4 exhibit no signs of Alzheimer's. For example, evidence suggests that genetic factors play a role in a common subtype of late-onset Alzheimer's disease that also includes psychosis. An important 2002 genetic study has identified certain genetic linkages associated with ApoE4 that appear to play a strong role in this subtype.

Other Genetic Factors in Late-Onset Alzheimer's. Most people with late-onset Alzheimer's disease do not carry the ApoE4 gene. Increasingly, researchers believe that many cases of late-onset Alzheimer's result from a combination of genetic factors that participate in the process of producing or degrading beta amyloid. Some under investigation include:

Researchers are targeting chromosomes 9, 10, and 12 as possible locations for genetic factors involved with Alzheimer's disease. (The ApoE4 gene is on chromosome 19.) In 2005, researchers announced that mutations linked to the ubiquilin 1 (UBQLN1) gene, located on chromosome 9, might be associated with increased risk for late-onset Alzheimer's disease.
Researchers have detected mutations in the proteins amyloid precursor protein (APP) and ubiquitin-B (Ubi-B), which may account for some cases of late- and early-onset Alzheimer's. Such mutations are not inherited, however, but appear to be genetic mistakes that occur during transcription, the coding process in which DNA establishes the pattern for the production of its proteins and other molecules.
In 2007, researchers identified mutations in the SORL1 gene as a possible factor in late-onset Alzheimer’s disease. Researchers think that variations in this gene may contribute to amyloid plaque formation in Alzheimer’s disease.

Genetic Factors for Early-Onset Alzheimer's. Scientists are coming closer to identifying defective genes responsible for early-onset Alzheimer's, an uncommon, but extremely aggressive form of the disease.

Mutations in genes known as presenilin-1 (PS1) and presenilin-2 (PS2) account for most cases of early-onset inherited Alzheimer's disease. The defective genes appear to accelerate beta amyloid plaque formation and apoptosis, a natural process by which cells self-destruct.
Genetic mutations in the genes that control amyloid precursor protein (APP) are also being targeted as causes of early-onset Alzheimer's. The genetic disease Down syndrome, for example, overproduces beta-amyloid precursor protein (APP), the source of beta amyloid, and almost always leads to early Alzheimer's. Other APP mutations are being identified.

Researchers are also investigating environmental factors (infections, metals, industrial and other toxins) that may trigger oxidation, inflammation, and the disease process, particularly in people with a genetic susceptibility to Alzheimer's.

Infectious Organisms. Slow, infectious viruses cause a number of other degenerative neurologic diseases, such as kuru and Creutzfeldt-Jakob disease.

Click the icon to see an image of Creutzfeldt-Jakob disease.

Although no specific virus has been linked to Alzheimer's, some researchers theorize that people with a genetic susceptibility to Alzheimer's may be vulnerable to the actions of certain viruses, particularly under circumstances when the immune system may be weakened.

Metals. Some laboratory studies have reported excessive amounts of metal ions such as zinc, copper in the brain of people with Alzheimer's disease. Such ions may possibly change the chemical architecture of normal beta amyloid, making it more harmful. A mildly acidic environment appears to be important in the process that binds these metals to beta amyloid. Experts observe that such conditions (acidic environment and higher levels of zinc and copper) commonly occur as part of the inflammatory response to local injury.

Electromagnetic Fields. Some studies on people exposed to intense electromagnetic fields (EMF) have reported a higher incidence of Alzheimer's. However, the association between EMF and Alzheimer's is very weak.

Risk Factors

Alzheimer's disease is the seventh leading cause of death in American adults. It affects about 5 million Americans and 8 million more people worldwide. According to the U.S. Alzheimer’s Association, 1 in 8 people age 65 and older, and nearly 1 in 2 people over age 85, have Alzheimer’s disease.

Age is the greatest risk factor for Alzheimer's disease. The number of cases of Alzheimer's disease doubles every 5 years in people over 65. By age 85, almost half of all people are afflicted. People with the disease survive, on average, half as long as similarly aged adults without the disease.

With the increasing numbers of aging adults, unless effective methods for prevention and treatment are developed, Alzheimer's disease will reach epidemic proportions, afflicting about 16 million Americans within 50 years. Evidence points to older age, high blood pressure, cholesterol levels, and a family history of the disease as the most important risk factors for Alzheimer's disease.

Several studies have reported that women have a much higher risk for Alzheimer's disease than men. If there is a gender difference, it is likely to be due estrogen, the primary female hormone, which appears to have properties that protect against the memory loss and lower mental functioning associated with normal aging. Such actions include blocking production of beta amyloid, offering antioxidant protection, and regulating blood sugar (glucose) levels in the brain. The drop in estrogen levels after menopause may explain a higher risk for Alzheimer's disease in older women than in men. (Testosterone, the male hormone, converts to estrogen, which may help protect men.) Studies have been mixed, however, on the association between the decline in natural estrogen levels and mental functioning in older women.

People with a family history of the disease are at higher than average risk for Alzheimer's disease. Researchers are identifying important genetic factors, notably the ApoE4 gene, that may be responsible for late- and early-onset cases.

Dietary and other cultural factors that increase the risk for hypertension and unhealthy cholesterol levels may also play a role. For example, a study of Japanese men showed that their risk increased if they emigrated to America. And the disease is much less common in West Africa than in African-Americans, who share the same or higher risk with Caucasians in America.

High blood pressure and unhealthy cholesterol levels -- the same important risk factors for heart disease and stroke -- may also be risk factors for Alzheimer's disease. In fact, they appear to be more important than ApoE4, the genetic factor most commonly associated with Alzheimer's disease.

Blood pressure is the force applied against the walls of the arteries as the heart pumps blood through the body. The pressure is determined by the force and amount of blood pumped and the size and flexibility of the arteries.

High Blood Pressure. Studies have reported an association between Alzheimer's disease and systolic hypertension (the higher and first number in blood pressure measurement). High blood pressure can cause problems with the vascular system, which is responsible for delivering blood to the brain. Recent research suggests that some types of blood pressure medication may lower Alzheimer's risk.

High Cholesterol Levels. Research indicates an association between high cholesterol levels and Alzheimer's disease in some people. One theory is that cholesterol regulates the processing and accumulation of amyloid beta-protein.

Click the icon to see an image of cholesterol.

Stroke. High blood pressure and heart disease can increase the risk for stroke. For people who have Alzheimer’s disease or mild cognitive impairment, stroke can increase the decline of cognitive function and accelerate dementia.

Diabetes. Patients with diabetes often have high blood pressure, lipid imbalances, and circulatory disorders that affect the heart and vascular system, which in turn increases the risk for Alzheimer’s. In patients who do not have other risk factors for Alzheimer’s, diabetes itself may increase risk. Research also suggests that diabetes can increase the risk for mild cognitive impairment, a condition that often precedes Alzheimer’s disease.

High Homocysteine Levels. Homocysteine is an amino acid that has been identified as a modest risk factor in heart disease. It has also been associated with a higher risk for Alzheimer's disease. High levels are general due to deficiencies of the B vitamins B6, B12, and folate. Such vitamins are also related to nerve protection. Researchers theorize that homocysteine impairs the ability of DNA to repair nerve cells. The weakened cells are then more vulnerable to the harmful effects of oxidized beta amyloid.

Nearly all patients who inherit Down syndrome develop changes in the brain that resemble Alzheimer's if they live into their 40s, although onset varies and can occur as late as age 70. Women under the age of 35, but not older mothers, who give birth to children with Down syndrome are also at much higher risk for Alzheimer's.

Lower Education and Economic Groups. A number of studies have reported either a higher risk for Alzheimer's disease in people with less education or a lower risk for Alzheimer's disease in those who remain mentally active. Some experts speculate that learning itself may stimulate more neurons to grow and thus create a larger reserve in the brain so that it takes longer for brain cells to be destroyed. Some evidence suggests that early malnutrition, which is more likely to occur in lower income and educational groups, has been associated with smaller brains and with Alzheimer's disease in old age. Low-birth weight can cause problems in growth factors that could affect both mental and physical health later on in adulthood.

Small Head Size. The size of the skull is fixed by age 7. Brain size approximates the head size until old age, when it begins to shrink. Some evidence has reported an association between small head size (and therefore less brain volume) and Alzheimer's disease, possibly because people who start with larger brains can sustain more injury over time. For example, a 2002 study indicated that it was reduction in overall brain volume, not specific regions, that contributed to mental impairment in older healthy adults. Another study reported that people who had small heads plus the ApoE4 gene had 14 times the risk for Alzheimer's disease than those without this combination. Nevertheless, other studies have found no association between a small head size and Alzheimer's disease.

Some experts suggest that the relationship observed in other research may simply be due to social and economic factors, such as malnutrition or low birth weight, which have been associated with both Alzheimer's disease and small head size. Small head size independent of other factors, they argue, does not pose a higher risk for either Alzheimer's disease or low intelligence

Depression. There is a significant overlap between depression and dementia in the elderly. In fact depression itself is often an early symptom of Alzheimer's disease. In a 2002 study of Catholic nuns, for each of four depressive symptoms, the risk for developing Alzheimer's disease increased by an additional 19%. For example, for a woman with four depressive symptoms the risk increased by 76%. Some evidence suggests that there may even be common genetic factors in people who have both early depression and Alzheimer's disease.

Head Injury. Some studies have found an association between serious head injuries in early adulthood and the development of Alzheimer's. It is not yet known if such injuries directly cause Alzheimer's or simply accelerate the disease in people who are already susceptible to it.

Prevention

Although there is no strong evidence that any lifestyle change can prevent Alzheimer's disease, studies suggest that certain behaviors may help protect against mental decline. In particular, medications and lifestyle choices that protect the heart may be of specific importance. Various preventive drugs are under investigation, including antioxidant and anti-inflammatory therapies.

In 2004, the National Institutes of Health (NIH) halted a large clinical trial that was investigating the use of anti-inflammatory drugs in preventing Alzheimer's disease. While prior data had confirmed that NSAIDs were not effective in treating AD, research continued to explore these drugs' potential preventive benefits.

The Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) was launched in 2001 to investigate whether long-term use of naproxen (Aleve) or celecoxib (Celebrex) could decrease the risk of developing AD. The trial was based on the premise that because inflammation is known to be involved in the process of Alzheimer’s disease, anti-inflammatory drugs may help to prevent it. The NIH suspended this trial due to evidence that the NSAID naproxen was associated with increased incidence of cardiovascular and cerebrovascular events among participants. No adverse effects appeared during this trial for the COX-2 inhibitor celecoxib. However, heart safety concerns about this drug had been raised in other trials, and investigators did not believe that celecoxib's potential benefits outweighed its risks.

Since 2004, the ADAPT investigators have continued to monitor the trial’s participants to see if these treatments had any effect in changing their risk for Alzheimer’s. In an update analysis of ADAPT data published in 2007, the researchers announced that neither naproxen nor celecoxib appear to reduce the risk for Alzheimer’s.

The same lifestyle and medical choices that reduce risk factors for heart disease and diabetes are important for reducing the risk for Alzheimer's disease. And, experts believe that treating high blood pressure and diabetes may help slow the progression of Alzheimer’s disease. The following are some heart-protective medications that may also protect the brain.

Blood Pressure Drugs. Because high blood pressure is associated with increased risk of Alzheimer’s, researchers have been studying whether blood pressure medication can reduce this risk. In a 2006 study of patients who took high blood pressure drugs, researchers found that potassium-sparing diuretics reduced the risk of developing Alzheimer’s by 70%. Beta-blockers and certain calcium channel blockers also helped to a lesser extent. ACE inhibitors appeared to offer no protection.

Statins. Statins are common drugs used to lower cholesterol levels. In past years, a number of studies reported a significantly lower risk for Alzheimer's disease in patients who took statins. However, newer studies have failed to prove that statins can help prevent Alzheimer's disease. In these recent studies, large numbers of elderly people had their dementia evaluated at baseline and then monitored over several years. The results indicated that statin use did not predict onset of AD. In the meantime, the NIH is conducting a clinical trial to investigate whether simvastatin can slow the progression of AD.

Hormone Replacement Therapy. Hormone replacement therapy (HRT) has been studied for years for health effects after menopause, including its effect on mental decline. A number of studies, including a major 2003 analysis, have found no differences in mental performance and no protection from Alzheimer's disease in women taking HRT compared to non-users. The 2003 trial, called the Women's Health Initiative Memory Study (WHIMS), enrolled 4,500 women over 65 years of age. The WHIMS study showed that older postmenopausal women who took combination HRT (estrogen plus progestin) had twice the risk of developing dementia than similarly aged women who received placebo pills. In addition to increasing the risk for dementia (including Alzheimer's disease), combination HRT failed to prevent the development of mild cognitive impairment. Based on these results, the researchers from the National Institute on Aging (NIA) recommended against prescribing combination hormone therapy to older women for maintaining or improving cognitive function. The NIA continued to research whether estrogen-only therapy could prevent or delay the onset of Alzheimer's disease. Results released in 2004 indicated that women ages 65 years and older who took estrogen-only HRT had a slightly increased risk of developing dementia.

Testosterone. Some testosterone converts to estrogen, which may be why older men appear to have a lower risk for Alzheimer's disease than older women. Animal studies have suggested that testosterone may help reduce levels of beta amyloid. There is also some evidence that low testosterone levels may be a particular risk factor in men with the ApoE4 gene. Some experts believe that giving testosterone to elderly men, and combinations of testosterone and estrogen to older women, may prove to be protective. Side effects of testosterone in women include increased body hair, acne, fluid retention, anxiety, and depression. Long term benefits or serious adverse effects are unknown.

DHEA. Dehydroepiandrosterone (DHEA) is a male-like hormone in the body that declines with age. Some evidence suggests that it may help reduce mental decline in older women, but not in older men. Studies are under way. The hormone may, however, reduce HDL (the so-called good cholesterol) when taken in higher doses. While its effect on cancer-cell growth is unknown, some evidence indicates that high levels may increase cancer risk. In any case, DHEA is not regulated, and brands vary widely in their content.

Because Alzheimer's disease rates vary among different populations, investigators are researching how diet can help in prevention. Caloric intake itself may play a role in brain health. In one study on animals, restricting calories below normal (but above starvation levels) helped prevent age-related nerve degeneration. However, in patients with existing Alzheimer's, weight loss is a strong indicator of mental decline.

Fats and Oils. Some studies suggest an association between fat and Alzheimer's disease:

In China and Nigeria, where fat intake is low, the risk of developing Alzheimer's is 1% at age of 65 compared to 5% in the U.S.
A study in the Netherlands reported an association between dementia and diets high in total fat, saturated fat, and cholesterol.
A number of studies suggest that a high-fat high-calorie diet in people who carry the ApoE4 gene may confer a particularly high risk. For example, in one study, adults who carried the ApoE4 gene and whose diet consisted of 40% fat calories had 29 times the risk for Alzheimer's compared to non-ApoE4 carriers on the same high-fat diet.

The recommended dietary goal is to limit total fat intake to 25 - 35% of total daily calories. But not all fats are alike. Unhealthy fats include saturated fats (contained in animal products such as meat) and trans-fatty acids (contained in fast foods and commercially baked products). The American Heart Association recommends limiting saturated fat intake to less than 7% of total daily calories and trans-fatty acid intake to less than 1% of total daily calories.

It is best to replace saturated fats and trans-fatty acids with unsaturated fats from plant and fish oils. Omega-3 fatty acids are excellent sources of unsaturated fats. Plant sources of omega-3 fatty acids include canola oil, soybeans, flaxseed, and certain types of nuts such as walnuts. For fish sources, salmon, mackerel, sardines, lake trout, herring, and albacore tuna are especially high in marine omega-3 fatty acids. For heart health, and possibly brain health, experts recommend eating these types of fish at least twice a week.

Two types of omega-3 fatty acids are found in fish oils: Docosahexaenoic acid (DHA) and eicosapentaneoic acid (EPA). Researchers are particularly interested in the role that DHA may play in Alzheimer’s disease prevention. DHA has been linked to many brain cell functions, and appears to have particular importance for aging brains. Studies indicate that people who have higher blood levels of DHA have a much lower risk of developing dementia and Alzheimer’s disease.

Although evidence suggests that consuming DHA-rich foods later in life helps to increase DHA levels in the brain, it is unclear whether dietary supplements can provide similar benefits. A 2007 study indicated that omega-3 fatty acid supplements may help slow cognitive decline in some patients with very mild Alzheimer’s disease, but that the supplements have little effect for advanced stages of the disease. In 2007, the U.S. National Institutes of Health launched a large-scale clinical trial to evaluate whether DHA supplements can slow the progression of cognitive and functional decline in people with mild-to-moderate Alzheimer’s disease.

Mediterranean diet is an eating plan that has specific heart-health benefits. It is rich in fiber and nutrients, including omega-3 fatty acids and antioxidant vitamins. The diet emphasizes fish, fruits, vegetables, and monounsaturated (“good”) fats, particularly olive and canola oils. A 2006 study suggested that the Mediterranean diet may also be good for the brain. In the study, patients who strictly followed the diet had a 40% lower risk of developing Alzheimer’s disease than patients who ate a conventional American diet. Other studies also indicate the Mediterranean diet is associated with a lower risk for Alzheimer’s.

Omega-3 fatty acids, found plentifully in oily fish and flaxseed and canola oils, are beneficial to people afflicted with IBD (inflammatory bowel disease).

Fruits and Vegetables. According to several studies, eating plenty of darkly colored fruits and vegetables may slow brain aging. Blueberries, which are very rich in antioxidants, are of particular interest. A 2006 study of over 3,000 elderly adults found that consumption of vegetables (especially green leafy vegetables) helped reduce the rate of cognitive decline, but fruit intake had no effect.

Alcohol. Some studies have suggested that moderate intake of alcohol (one or two drinks a day) may protect the aging brain, possibly by releasing acetylcholine, the chemical in the brain that is deficient in Alzheimer's disease. Not all studies have been positive. In any case, heavy alcohol consumption offers no protection and is dangerous.

Folate and Vitamin B12. Some studies suggest that deficiencies of vitamins B6, B12, and folate (folic acid) may be a risk factor for Alzheimer' diseases. Deficiencies in these vitamins can increase homocysteine levels, which some research associates with a higher risk for Alzheimer's disease. Foods containing folate include avocados, bananas, oranges, asparagus, green leafy vegetables, and dried beans. In the United States and some other countries, grain and cereal products are fortified with folate. B12 is found only in animal, dairy, and fish products. B6 is found in a variety of foods, including fortified cereals, beans, meat, fish, and some fruits and vegetables.

Click the icon to see an image of vitamin B12 sources.

Click the icon to see an image of folate sources.

Research is still inconclusive and conflicting about whether increased consumption of folate, through food or dietary supplements, can help prevent Alzheimer’s disease or slow its progression. A small 2006 study of healthy older adults, published in the New England Journal of Medicine, found that supplements containing folate, vitamin B12, and vitamin B6 did not help improve cognitive performance. A 2007 Lancet study indicated that folic acid supplements may help slow cognitive decline. People in the Lancet study took 800 mcg of folic acid daily, which is twice the recommended daily allowance of 400 mcg. However, this study was conducted in the Netherlands, where people tend to get less folate in their daily diets than in the United States.

Another 2007 study found that elderly people who consumed folate from both diet and supplement sources had a reduced risk for Alzheimer’s disease. Neither diet alone nor supplements alone affected Alzheimer’s risk; only the combination of the two produced an effect. The study also indicated that vitamins B6 and B12 do not affect Alzheimer’s risk.

Antioxidant Supplements. Much research on Alzheimer's disease has indicated that oxidation (release of damaging unstable particles) may play an important role in the disease process. Some reports, including a large 2002 population study, have suggested that vitamin E intake, from food or supplements, may protect against mental decline. Other studies suggest that vitamin E protects only those who carried the ApoE4 gene. Most of the evidence finding any benefits from other antioxidants comes from using a combination of antioxidant vitamins, such as vitamins C and E, but not from using them separately. However, there is no strong evidence of protection to date from using antioxidant supplements.

Physical Exercise. Studies indicate that exercise may help prevent the development of Alzheimer’s disease and other forms of dementia. A 2006 study found that older adults (65 years and older) who exercised three times a week reduced their risk for Alzheimer’s by about 40%. Exercise in the study included walking, hiking, aerobics, calisthenics, swimming, water aerobics, weight training, and stretching.

Mental Exercise. Cognitive training that includes exercises to stimulate memory, reasoning, and mental processing speed may help improve both mental ability and daily functioning. In an important 2006 study in the Journal of the American Mental Association, older community-dwelling adults who received cognitive training showed reductions in cognitive decline. In addition, they were better able to handle daily living tasks -- such as performing housework, managing money, and preparing meals -- than people who did not receive the training. The benefits of cognitive training lasted for up to 5 years afterwards. Other studies indicate that participating in intellectually engaging activity -- such as doing crossword puzzles or learning a new language -- may help reduce the risk of Alzheimer’s disease.

Social Interaction. Social interaction is also important for maintaining emotional health as well as keeping the mind active and energized. A 2007 study indicated that adults who are lonely have twice the risk of developing Alzheimer’s dementia as those who are not socially isolated.

Symptoms

The early symptoms of Alzheimer's disease (AD) may be overlooked because they resemble signs of natural aging. Older adults who begin to notice a persistent mild memory loss of recent events may have a condition called mild cognitive impairment (MCI). MCI is now believed to be a significant sign of early-stage Alzheimer's in older people. Studies now suggest that older individuals who experience such mild memory abnormalities can later develop Alzheimer's disease.

Early symptoms of Alzheimer's disease may include:

Forgetfulness (particularly of recent events or information)
Loss of concentration (having trouble planning or completing familiar tasks, difficulty with abstract thinking such as simple arithmetic problems)
Language problems (forgetting the names of objects, mixing up words, difficulty completing sentences)
Confusion about time and place (difficulty recognizing familiar neighborhoods or remembering how you arrived at a location, confusion about months or seasons )
Impaired judgment (dressing inappropriately or making poor financial decisions)
Impaired movement and coordination (slowing of movements, halting gait, reduced sense of balance)
Mood and behavior changes (rapid mood swings, emotional outbursts, personality changes, increased fear or suspicion)
Apathy and depression (loss of interest in activities, increased sleeping, sitting in front of the television for long periods of time)

Diagnosis

A definitive test to diagnose Alzheimer's disease, even in patients showing signs of dementia, has not yet been developed. A number of expert groups have developed criteria to help diagnose Alzheimer's disease and rule out other disorders. A diagnosis often involves answering questions about the patient:

Do psychological tests indicate dementia?
Does the patient have deficits in two or more areas of mental functioning (such as language, motor skills, and perceptions)?
Has memory and mental functions gotten progressively worse?
Is consciousness disturbed? (It is not in Alzheimer's disease.)
Is the patient over age 40?
Are other medical or physical conditions present that could account for the same symptoms?
Are daily activity impaired or has the behavior changed?
Is there a family history of Alzheimer's disease?
Are there other symptoms, such as depression, insomnia, incontinence, delusions, hallucinations, dramatic verbal, emotional or physical outbursts, sexual disorders, and weight loss?

Other steps involved in making a decision include laboratory tests (EEG and possibly tests to rule out other diseases) and psychological testing to determine the presence of dementia.

Although some memory impairment occurs in many people as they age, only some of these people develop Alzheimer's disease. Many similar symptoms can occur in healthy older individuals from other conditions associated with aging:

Fatigue
Grief or depression
Illness
Vision or hearing loss
The use of alcohol or certain medications
Simply the burden of too many details to remember at once

The first step in diagnosing Alzheimer's disease is to rule out other conditions that might cause memory loss or dementia. There are a number of causes for dementia in the elderly besides Alzheimer's disease:

Vascular dementia (abnormalities in the vessels that carry blood to the brain)
Lewy bodies variant (LBV), also called dementia with Lewy bodies
Parkinson's disease
Frontotemporal dementia

Experts believe that 60% of cases of dementia are due to Alzheimer's, 15% to vascular injuries, and the rest are a mixture of the two or caused by other factors.

Vascular Dementia. Vascular dementia is primarily caused by either multi-infarct dementia (multiple small strokes) or Binswanger's disease (which affects tiny arteries in the midbrain). One major analysis suggested that patients with vascular dementia have better long-term verbal memory than patients with Alzheimer's disease, but poorer executive function (less ability to integrate and organize).

Lewy Bodies Variant. Lewy bodies are abnormalities found in the brains of patients with both Parkinson's disease and Alzheimer's. They can also be present in the absence of either disease; in such cases, the condition is called Lewy bodies variant (LBV). In all cases, the presence of Lewy bodies is highly associated with dementia. LBV was defined in 1997, and some experts believe it may be responsible for about 20% of people who have been diagnosed with Alzheimer's. They can be difficult to distinguish. Compared to Alzheimer's disease patients, those with LBV may be more likely to have hallucinations and delusions early on, to walk with a stoop (similar to Parkinson's disease), to have more fluctuating attention problems, and to perform better than Alzheimer's disease patients on verbal recall but less well with organizing objects.

Parkinson's Disease. Dementia is about six times more common in the elderly Parkinson patient than in the average older adult. It is most likely to occur in older patients who have had major depression. Unlike in Alzheimer's, language is not usually affected in Parkinson's related dementia. Visual hallucinations occur in about a third of people on long-term medications.

Parkinson's disease is a slowly progressive disorder that affects movement, muscle control, and balance. Part of the disease process develops as cells are destroyed in certain parts of the brain stem, particularly the crescent-shaped cell mass known as the substantia nigra. Nerve cells in the substantia nigra send out fibers to tissue located in both sides of the brain. There the cells release essential neurotransmitters that help control movement and coordination.

Frontotemporal Dementia (FTD). Once considered rare, FTD is now considered to be the second most common cause of early-onset dementia. People who develop this condition tend to be in their mid-fifties although it can develop later on. It results in greater behavioral impairment (apathy, reduced empathy, poor self-care, unrestrained behavior) than with Alzheimer's disease. It may also be marked by speech problems and early incontinence. Brain imaging scans can help diagnose this problem.

Other Conditions that Cause Similar Symptoms. Some elderly people have a condition called mild cognitive impairment, which involves more severe memory loss than normal but no other symptoms of Alzheimer's. A number of conditions, including many medications, can produce symptoms similar to Alzheimer's:

Severe depression
Drug abuse
Thyroid disease
Severe vitamin B12 deficiency
Blood clots
Hydrocephalus (excessive accumulation of spinal fluid in the brain)
Syphilis
Huntington's disease
Creutzfeldt-Jakob disease
Brain tumors

It is important that the doctor recognize any treatable conditions that might be causing symptoms or worsening existing dementia caused by Alzheimer's or vascular abnormalities.

A number of psychological tests are used or being developed to assess difficulties in attention, perception, and memory and problem-solving, social, and language skills. Experts are researching specific tests that may help identify early on people with mild memory impairment who are at high risk for Alzheimer's disease.

Two commonly used tests that are very useful in identifying individuals who may be at risk for Alzheimer's are the Mini-Mental State Exam (MMSE) and the Mattis Dementia Rating Scale. Still, these tests have limitations.
A clock drawing test is also a good test for Alzheimer's disease. The patient is given a piece of paper with a circle on it and is first asked to write the numbers in the face of a clock and then to show "10 minutes after 11." The score is based on spacing between the numbers and the positions of the hands.

Electroencephalography (EEG) traces brain-wave activity; in some patients with Alzheimer's disease this test reveals "slow waves." EEG data helps distinguish a potential patient with Alzheimer's disease from a patient with severe depression, whose brain waves are normal.

Imaging tests include magnetic resonance imaging (MRI), positron-emission tomography (PET), and single photon emission computed tomography (SPECT). These tests are sometimes used to rule out other disorders, such as multi-infarct dementia, stroke, blood clots, and tumors. Research is being conducted to determine if these tests can help to confirm a diagnosis of Alzheimer's disease and improve understanding of disease progression. Researchers hope that imaging tests may also be able to provide diagnoses of Alzheimer’s disease while it is still in its early stages.

In 2006, scientists developed a new imaging molecule called FDDNP that they hope will enable earlier detection of Alzheimer’s disease. Research also continues on Pittsburgh compound B, a tracer molecule used in PET brain scans to highlight beta-amyloid protein deposits. Results from all this research may help to define potential drug targets and aid in the development of new Alzheimer's drugs.

Click the icon to see an image of an MRI of the brain.

In 2005, the National Institute of Aging, in collaboration with industry partners, launched the $60 million Alzheimer's Disease Neuroimaging Initiative (ADNI). This landmark 5-year clinical trial, which will be conducted at 50 sites throughout the United States and Canada, will investigate whether neuroimaging techniques, such as MRI and PET scans, can be combined with biomarkers and neuropsychological tests to measure the progression of AD and mild cognitive impairment. In 2004, the U.S. Medicare system expanded insurance coverage of PET scans for eligible beneficiaries who meet specific diagnostic criteria for both Alzheimer's disease and fronto-temporal dementia. Medicare also covers the costs for patients enrolled in its agency-approved imaging clinical trials.

Blood Tests. Blood tests are currently used to check for anemia and other disorders that can produce dementia symptoms. Investigators are researching serum biomarkers, such as the iron transport protein p97, that might help detect the presence of Alzheimer's disease.

Cerebrospinal Fluid Test. Scientists are developing new nanotechnology screening methods that may eventually be used to identify Alzheimer's disease while it is still in its earliest stages and before plaque deposits accumulate. In 2005, a research team announced it had used a bio-barcode assay to detect tiny amounts of a protein called amyloid-beta-derived diffusable ligand (ADDL) in cerebrospinal fluid. ADDLs may be involved in cognitive decline and are a potential biomarker for early stage Alzheimer's disease. Tests for other proteins are also being developed.

Odor Test. Investigators are also using the impairment of smell in Alzheimer's disease to develop tests that require patients to distinguish between odors.

Once a diagnosis has been made, some experts observe that certain factors at the time of diagnosis indicate a higher risk for a more rapid decline:

Older age
Being male
The presence of high blood pressure
Signs of loss of motor control and coordination
Tremor
Social withdrawal
Loss of appetite and severe weight loss
Accompanying sensory problems, such as hearing loss and a decline in reading ability
General physical debility

Medications

Most drugs used to treat Alzheimer's, and those under investigation, are aimed at slowing progression. There are no cures to date. In addition, the improvements from some of these drugs may be so modest that even the patients and their families are not aware of them. Even in these cases, however, the drugs may delay the need for admission to nursing homes.

There are currently two drug classes that have been approved by the U.S. Food and Drug Administration (FDA) to treat the cognitive symptoms of Alzheimer's disease:

Cholinesterase inhibitors (generally used to treat mild-to-moderate Alzheimer's; donepezil is also approved for treatment of severe dementia )
N-methyl-D-aspartate (NMDA) receptor antagonists (used to treat moderate-to-severe Alzheimer's)

Cholinesterase inhibitors are designed to protect the cholinergic system, which is essential for memory and learning and is progressively destroyed in Alzheimer's. These drugs work by preventing the breakdown of the brain chemical acetylcholine and are recommended for the treatment of mild-to-moderate Alzheimer's. The first cholinesterase inhibitor, tacrine, was approved in 1993 but is rarely prescribed today due to safety concerns. The three most commonly prescribed cholinesterase inhibitors are donepezil (approved in 1996), rivastigmine (approved in 2000), and galantamine (approved in 2001).

Cholinesterase inhibitors may increase the risk for gastrointestinal bleeding or ulcers, and patients should be cautious about using these medicines with NSAIDs (which can also cause gastric irritation). Common side effects of cholinesterase inhibitors, especially when taken at higher doses, may include nausea, vomiting, diarrhea, and upset stomach.

Donepezil. Donepezil (Aricept) is the only Alzheimer’s drug approved for all stages of dementia, from mild to severe. It is taken once a day and has only modest benefits, but it does help slow loss of function and reduce caregiver burden. It works equally in patients with or without the ApoE4 gene. Several trials, including an important 2005 New England Journal of Medicine (NEJM) study, have found that donepezil may have short-term benefits for patients with mild cognitive impairment by delaying progression to AD. In the NEJM study, donepezil slowed progression during the first year of therapy, but demonstrated no benefits by the conclusion of the 3-year trial. Studies also suggest that donepezil may help improve behavior and memory in patients with moderate-to-severe Alzheimer’s when it is given in combination with memantine (Namenda).
Rivastigmine. Rivastigmine (Exelon) targets two enzymes: Acetylcholinesterase and butyrylcholinesterase. It is taken as a pill twice a day. (The FDA approved a skin patch version of the drug in 2007.) Rivastigmine may be particularly helpful for patients with rapidly progressing disease. It has slowed or slightly improved disease status even in patients with advanced disease. Rivastigmine may cause significantly more side effects than donepezil, including nausea, vomiting, and headache.
Galantamine (Razadyne). Galantamine not only protects the cholinergic system but also acts on nicotine receptors, which are also depleted during Alzheimer's. Studies report that it improves daily living, behavior, and mental functioning, including in patients with mild to advanced-moderate Alzheimer's disease and those with a mix of Alzheimer's disease and vascular dementia. Some studies have suggested that the effects of galantamine may persist for a year or longer and even strengthen over time. In 2005, the name of galantamine was changed from Reminyl to Razadyne.
Tacrine. Tacrine (Cognex) was the first cholinergic protective drug. It needs to be taken four times a day, has only modest benefits, and has no benefits for patients who carry the ApoE4 gene. In high doses, it can also injure the liver. In general, newer cholinergic protective drugs that do not pose as great a risk for the liver are now used for Alzheimer's.

About half of patients with mild-to-moderate disease show slight improvement with these drugs. Comparative studies have reported little differences in effectiveness among them. All drugs have gastrointestinal side effects, including nausea. Of note, some of the drugs often used in elderly Alzheimer's disease patients are known as anticholinergics and may offset the effects of the Alzheimer's disease pro-cholinergic drugs. Such drugs include antihistamines, antipsychotic drugs, and some anti-incontinence drugs.

In any case, the benefits of these drugs are far from dramatic. In fact, many experts have reservations about developing any additional drugs that affect the cholinergic system since, at best, they only slow progression and do not appear to affect the basic destructive disease process. When patients go off the drugs, the deterioration continues. In 2005, the United Kingdom’s National Institute for Clinical Excellence (NICE) recommended against the use of donepezil, rivastigmine, galantamine, and memantine for Alzheimer’s disease treatment. The agency contended that the costs of these drugs outweigh their modest benefits.

Memantine (Namenda) is approved for treatment of moderate-to-severe Alzheimer’s disease. (Most cholinesterase inhibitors are used to treat mild-to-moderate stages of the disease.) By blocking NDMA receptors, memantine protects against the overstimulation of glutamate, an amino acid that excites nerves and, in excess, is a powerful nerve-cell killer.

Memantine is prescribed either alone or in combination with donepezil. Studies indicate that memantine may help improve cognitive function and delay the progression of Alzheimer’s disease for up to 1 year. Side effects are generally mild but may include dizziness, drowsiness, or fainting.

In one study of effects on moderate-to-severe Alzheimer's, patients who received memantine showed a small but statistically significant benefit in cognitive function and performance of daily abilities compared with those patients who were given placebo. In a 2004 study, memantine was added to the drug regimen of patients with moderate-to-severe Alzheimer's who had taken donepezil for at least 6 months. In comparison to patients who took only donepezil, patients who received the combination donepezil-memantine therapy showed a greater improvement in measures of cognitive function, activities of daily living, and behavior parameters. A 2006 study indicated that memantine combined with donepezil may help reduce behavior problems -- such as agitation, aggression, and irritability -- and improve disturbances in appetite and eating.

Although cholinesterase inhibitors and memantine are the best available medications for Alzheimer's, their benefits are, unfortunately, quite modest. More effective methods of prevention and treatment are urgently needed.

There has been considerable controversy over whether NSAIDs may help in the treatment of Alzheimer's disease. As inflammation is involved in the destruction of brain cells, it has been suggested that anti-inflammatory drugs might be able to halt this process and thus slow the progression of the disease. In a rigorous 2003 study, patients with mild-to-moderate Alzheimer's were randomized to receive either naproxen (Aleve) or rofecoxib (Vioxx) or placebo. After 12 months of treatment, patients in the anti-inflammatory groups did not show any difference in cognitive improvement compared to those patients who received placebo.

Results from another large study, published in 2004, also failed to demonstrate improvement in cognitive function for patients with mild-to-moderate Alzheimer's who were treated with rofecoxib. Since the completion of these studies, rofecoxib was withdrawn from the market, and the NIH suspended a clinical study assessing naproxen’s preventive benefits (see Nonsteroidal Anti-Inflammatory Drugs as Prevention). As mentioned earlier, patients should be cautious about taking NSAIDs in combination with cholinesterase inhibitors as they may increase the risk of gastrointestinal bleeding.

Nicotine enhances the actions of the cholinergic system (which is depleted in Alzheimer's disease) and is known to improve concentration and memory in the short term. Some studies have suggested that nicotine may protect nerve cells and help prevent the formation of beta amyloid. One study indicated that nicotine might help protect against Alzheimer's disease in carriers, but not noncarriers, of the ApoE4 gene. Another reported improvement in verbal recall and word retrieval in healthy relatives of Alzheimer's disease patients who wore a low-dose nicotine patch. Research to date, however, has found no strong evidence of improvement in Alzheimer's disease patients with nicotine replacement methods. No one should smoke to prevent or treat Alzheimer's disease.

Manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been several reported cases of serious and even lethal side effects from herbal products. Always check with your doctor before using any herbal remedy or dietary supplement.

Ginkgo Biloba. Ginkgo biloba is a common herb that has antioxidant properties and appears to increase blood flow to the brain. A 2002 study of healthy people who took over-the-counter ginkgo for 6 weeks reported no improvements in memory or mental function. Studies are reporting that a ginkgo biloba extract, called Egb 761, may slightly improve the memory of patients with mild to moderate Alzheimer's disease. The herb poses a small increased risk for bleeding, which may be hazardous in combination with other blood-thinning medications, such as warfarin or high-doses of vitamin E.

Turmeric. Studies suggest that circumin, a compound found in the spice turmeric, has properties that may protect against the Alzheimer's disease process.

Melatonin. Melatonin, a natural hormone involved in sleep regulation, is of interest to researchers. It is an antioxidant, may break down beta amyloid, and is able to pass through the blood-brain barrier. Deficiencies have been observed in patients with Alzheimer's disease. A number of studies (but not all) report that melatonin may improve sleep habits in these patients. Some studies reported slower progression of mental impairment.

A number of drugs are being investigated for treatment and prevention of Alzheimer's disease. Intense areas of research are focusing on drugs that prevent beta amyloid build-up, its toxic effects on nerve cells, or other mechanisms of the disease process. Promising research in late-stage clinical trials include.

Tramiprosate (Alzhemed) is an experimental drug designed to prevent beta-amyloid accumulation in the brain.
Flurizan (MPC-7869) may help reduce amyloid plaque development. It is currently being studied in Phase III trials for adults with mild Alzheimer’s disease.
Rosiglitazone XR (Avandia) is an extended-release formulation of a drug used to treat type 2 diabetes. Its anti-inflammatory properties are being studied as a treatment for patients with mild-to-moderate Alzheimer’s who do not carry the APOE-e4 gene. Phase III results have been promising, but this drug has been linked to increased risk for heart attack deaths in patients with diabetes. In 2007, a panel of experts from the Food and Drug Administration (FDA) agreed the drug increases the risk of heart attacks -- but concluded it should remain on the market. The panel did, however, recommend the FDA require rosiglitazone's maker to add warnings to the drug's label. Patients or caregivers of patients who take rosiglitazone, especially those who have heart disease or who are at high risk for heart attack, should discuss their treatment options with their doctors.
Dimebon is an antihistamine, which researchers think may help prevent brain cell death. The drug is currently in Phase II trials.
Antioxidants such as vitamin E and selenium are being investigated for their preventive effects. Antioxidant treatment trials include curcumin (the yellow pigment found in turmeric spice) and a combination trial with fish oil and alpha-lipoic acid.

Depression. Major depression with dementia that occurs in elderly people may be an early sign of Alzheimer's. In such cases, it precedes Alzheimer's by 2 years or less. (It is, in fact, sometimes difficult to differentiate major depression from early-stage Alzheimer's disease.) Antidepressants known as selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac) and sertraline (Zoloft), may be effective in relieving depression, irritability, and restlessness associated with Alzheimer's in some patients.

Apathy. Depression is often confused with apathy. An apathetic patient lacks emotions, motivation, interest, and enthusiasm while a depressed patient is generally very sad, tearful, and hopeless. According to one study, apathy is more common than depression in patients with Alzheimer's disease. It responds to stimulants, such as methylphenidate (Ritalin), rather than antidepressants.

Psychosis. Antipsychotic drugs are used to treat verbally or physically aggressive behavior and hallucinations. Because older antipsychotic drugs, such as haloperidol (Haldol), have severe side effects, most doctors now prescribe newer atypical antipsychotics, such as risperidone (Risperdal) or olanzapine (Zyprexa).

However, these newer antipsychotic drugs still can cause serious side effects, including confusion, sleepiness, and Parkinsonian-like symptoms. In addition, studies indicate that their safety risks may outweigh any possible benefits. A 2005 study showed that these drugs produce a slightly increased rate of death in patients with Alzheimer’s disease or dementia. In addition, several studies from 2006 and 2007 published in the New England Journal of Medicine suggested that atypical antipsychotics work no better than placebo in controlling psychosis, aggression, and agitation in patients with Alzheimer’s.

Most experts now recommend that doctors delay prescribing antipsychotic medication unless absolutely necessary. They recommend first trying behavioral treatments and controlling changes in the patient’s environment and routine. Anti-seizure drugs, such as carbamazepine (Tegretol) or valproate (Depakote), can also sometimes treat agitation and other psychotic symptoms. Non-drug treatments, such as bright light boxes, are also showing promise for managing psychotic and behavioral symptoms.

Disturbed Sleep. Patients with Alzheimer's disease commonly experience disturbances in their sleep/wake cycles. Moderately short-acting sleeping drugs, such as temazepam (Restoril), zolpidem (Ambien), or zaleplon (Sonata), or sedating antidepressants, such as trazodone (Desyrel, Molipaxin), may be useful in managing insomnia. Some research suggests that exposure to brighter-than-normal artificial light during the day for patients with normal vision may help reset wake/sleep cycles and prevent nighttime wandering and sleeplessness. Trials on melatonin, a natural hormone that helps trigger sleep at night, are in progress.

Stages

The lifespan of patients with Alzheimer's is generally reduced, although a patient may live anywhere from 3 - 20 years after diagnosis. The final phase of the disease may last from a few months to several years, during which time the patient becomes increasingly immobile and dysfunctional. Caregivers should understand the phases of this illness in order to help determine their own capacities for dealing with this painfully sad disease.

Telling the Patient. Often doctors will not tell patients that they have Alzheimer's. If a patient expresses a need to know the truth, it should be disclosed. Both the caregiver and the patient can then begin to address issues that can be controlled, such as access to support groups and drug research.

Mood and Emotional Behavior. Patients display abrupt mood swings, and many become aggressive and angry. Some of this erratic behavior is caused by chemical changes in the brain. But it may also be due to the experience of losing knowledge and understanding of one's surroundings, causing fear and frustration that patients can no longer express verbally.

The following recommendations for caregivers may help soothe patients and avoid agitation:

Keep environmental distractions and noise at a minimum if possible. (Even normal noises, such as people talking outside a room, may seem threatening and trigger agitation or aggression.)
Speak clearly. Most experts recommend speaking slowly to a patient with Alzheimer's disease, but some caregivers report that patients respond better to clear, quickly spoken, short sentences that they can more easily remember.
Use a combination of facial expressions, voice tones, and words for communicating emotions. (One study suggested that patients may have difficulty in recognizing the meaning of facial expressions, particularly those signaling sadness, surprise, and disgust.)
Limit choices (such as clothing selection).
Offer diversions, such as a snack or car ride, if the patient starts shouting or exhibiting other disruptive behavior.
Simply touching and talking may also help.
Maintain as natural an attitude as possible. Patients with Alzheimer's disease can be highly sensitive to the caregiver's underlying emotions and react negatively to patronization or signals of anger and frustration.
Showing movies or videos of family members and events from the patient's past may be comforting.

Although much attention is given to the negative emotions of patients with Alzheimer's disease, some patients become extremely gentle, retaining an ability to laugh at themselves or appreciate simple visual jokes even after their verbal abilities have disappeared. Some patients may seem to be in a drug-like or "mystical" state, focusing on the present experience as their past and future slip away. Encouraging and even enjoying such states may bring some comfort to a caregiver.

There is no single Alzheimer's personality, just as there is no single human personality. All patients must be treated as the individuals they continue to be, even after their social self has vanished.

Appearance and Cleanliness. For the caregiver, grooming the patient may be an alienating experience. For one thing, many patients resist bathing or taking a shower. Some spouses find that showering with their afflicted mate can solve the problem for a while. Often patients with Alzheimer's disease lose their sense of color and design and will put on odd or mismatched clothing. It is important to maintain a sense of humor and perspective and to learn which battles are worth fighting and which ones are best abandoned.

Driving. As soon as Alzheimer's is diagnosed, the patient should be prevented from driving. One study found that more than half of elderly people involved in fatal accidents had some degree of neurologic damage.

Wandering. A potentially dangerous trait is the patient's tendency to wander. At the point the patient develops this tendency, many caregivers feel it is time to seek out nursing homes or other protective institutions for their loved ones. For those who remain at home, the following precautions are recommended:

Locks should be installed outside the door, which the caregiver can open, but the patient cannot.
Alarms may be installed at exits.
A daily exercise program should be implemented, which may help tire the patient. One study showed that walking 30 minutes, three times a day, also improved communication.
The caregiver should contact organizations, such as Alzheimer's Association or Medic Alert, for identification supplies and procedures that help locate patients who wander away from home and become lost.
Some experts are discussing the benefits versus the ethics of electronic tagging, which would emit a radio signal or alarm that allows the patient to be tracked using a detector.

Speech Problems. Some evidence suggests that speech therapy combined with Alzheimer's disease medications may be helpful for maintaining verbal skills patients with mild symptoms.

Sexuality. In many cases, the patient becomes uninhibited sexually. At the same time, the patient's physical deterioration and receding capacity to recognize the spouse as a known and loved individual can make sexual activity unattractive for the caregiving spouse. Other patients may lose interest in sex. If sexual issues are a problem, they should be discussed openly with the doctor. Ways should be found to maintain non-sexual physical affection that can bring comfort to both the patient and the spouse.

Patients with Alzheimer's disease need 24-hour a day attention. Even if the caregiver has the resources to keep the patient at home during later stages of the disease, outside help is still essential. If available, home visits by a health profession can have a favorable impact on survival and delay the need for a nursing home. Medicare now covers many Alzheimer's services, and patients should be able to stay at home longer than previously.

Incontinence. A patient's incontinence is generally devastating to the caregiver and a primary reason why many caregivers decide to seek nursing home placement when the patient reaches this stage. When the patient first shows signs of incontinence, the doctor should make sure that it is not caused by an infection. Urinary incontinence may be controlled for some time by trying to monitor times of liquid intake, feeding, and urinating. Once a schedule has been established, the caregiver may be able to anticipate incontinent episodes and get the patient to the toilet before they occur.

Immobility and Pain. As the disease progresses, patients become immobile, literally forgetting how to move. Eventually, they become almost entirely wheelchair-bound or bedridden. Bedsores can be a major problem. Sheets must be kept clean, dry, and free of food. The patient's skin should be washed frequently, gently blotted thoroughly dry, and moisturizers applied. The patient should be moved every 2 hours and the feet kept raised with pillows or pads. Exercises should be administered to the legs and arms to keep them flexible.

Dehydration. Dehydration can become a problem. It is essential to encourage fluid intake equal to 8 glasses of water daily. Coffee and tea are diuretics and will deplete fluid.

Eating Problems. Weight loss and the gradual inability to swallow are two major related problems in late-stage Alzheimer's and are associated with an increased risk of death. Weight gain, however, is linked to a lower risk of dying. The patient can be fed through a feeding syringe, or the caregiver can encourage chewing action by pushing gently on the bottom of the patient's chin and on the lips. The caregiver should offer the patient foods of different consistency and flavor. Because choking is a danger, the caregiver should learn to administer the Heimlich maneuver, which may be taught by the local Red Cross. In very late stages, some caregivers choose feeding tubes for the patient. They should be aware that feeding tubes have no measurable impact on survival.

About 80% of patients with Alzheimer's disease are cared for by family members, who often lack adequate support, finances, or training for this difficult job. Few diseases disrupt patients and their families so completely or for so long a period of time as Alzheimer's. The patient's family endures two separate losses and grieves twice:

First, they must grieve for the ongoing disappearance of the personality they recognize. Dealing with the patient throughout the course of the disease is like Alice's fall down the rabbit hole into Wonderland. No sooner has the caregiver grappled with one set of problems, when the patient's further deterioration creates new and more intractable ones.
Finally, the caregiver must grieve the actual death of the person.

Often, caregivers themselves begin to show signs of mental disorder or ill health. Depression, empathy, exhaustion, guilt, and anger can play havoc with even a healthy individual faced with the care of a loved one suffering from Alzheimer's.

Fortunately, research shows that intensive support services can greatly improve caretakers’ quality of life and make it easier for them to continue caring for patients in their homes. In a 2006 study, caregivers who received individual and family counseling, telephone counseling, support groups, and stress management and problem-solving techniques reported reduced rates of depression and improved self-confidence compared with those who received only written educational materials. Another 2006 study indicated that improving caregivers’ access to counseling and support services can help delay nursing home placement of patients. National and local Alzheimer's associations can provide important support and other services.

A point comes when the most devoted caregiver will probably need to institutionalize the patient. That point is determined not only by the caregiver's emotional endurance, but also by their physical strength and stamina, as a patient typically takes on the random, undisciplined behavior of a very young child. Financial considerations in finding a nursing home are often paramount, but the kind of care is equally important. Although fully half of all nursing home patients suffer from Alzheimer's, not all nursing homes have programs specifically designed for them. Some institutions may claim that they do, but often they simply group patients together without offering any special programs. If a caregiver manages to find a facility that offers good services, it may be located far from home, making visits difficult. The caregiver must then decide whether superior care at a distant institution is worth seeing the patient less frequently. When the patient's illness becomes terminal, a hospice program may be another option.

1. Although I cannot control the disease process, I need to remember I can control many aspects of how it affects my relative.

2. I need to take care of myself so that I can continue doing the things that are most important.

3. I need to simplify my lifestyle so that my time and energy are available for things that are really important at this time.

4. I need to cultivate the gift of allowing others to help me, because caring for my relative is too big a job to be done by one person.

5. I need to take one day at a time rather than worry about what may or may not happen in the future.

6. I need to structure my day because a consistent schedule makes life easier for me and my relative.

7. I need to have a sense of humor because laughter helps to put things in a more positive perspective.

8. I need to remember that my relative is not being difficult on purpose; rather their behavior and emotions are distorted by the illness.

9. I need to focus on and enjoy what my relative can still do rather than constantly lament over what is gone.

10. I need to increasingly depend upon other relationships for love and support.

11. I need to frequently remind myself that I am doing the best that I can at this very moment.

12. I need to draw upon the Higher Power, which I believe is available to me.

Source: The American Journal of Alzheimer's Care and Related Disorders & Research, Nov/Dec 1989

Resources

www.alzheimers.org -- Alzheimer's Disease Education and Referral Center
www.alz.org -- Alzheimer's Association
www.alzforum.org -- Alzheimer's Research Forum
www.alzfdn.org -- Alzheimer's Foundation of America
www.alz.co.uk -- Alzheimer's Disease International
www.nia.nih.gov -- National Institute on Aging
www.ninds.nih.gov -- National Institute of Neurological Disorders and Stroke
www.aan.com -- American Academy of Neurology
www.medicalert.org -- Medic Alert
www.ahaf.org -- American Health Assistance Foundation
www.clinicaltrials.gov -- Find clinical trials
www.medicare.gov/NHCompare/Home.asp -- Find a nursing home

References

ADAPT Research Group, Lyketsos CG, Breitner JC, Green RC, Martin BK, Meinert C, et al. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology. 2007 May 22;68(21):1800-8. Epub 2007 Apr 25.

Akomolafe A, Beiser A, Meigs JB, Au R, Green RC, Farrer LA, et al. Diabetes mellitus and risk of developing Alzheimer disease: results from the Framingham Study. Arch Neurol. 2006 Nov;63(11):1551-5.

Ayalon L, Gum AM, Feliciano L, Arean PA. Effectiveness of nonpharmacological interventions for the management of neuropsychiatric symptoms in patients with dementia: a systematic review. Arch Intern Med. 2006 Nov 13;166(20):2182-8.

Belle SH, Burgio L, Burns R, Coon D, Czaja SJ, Gallagher-Thompson D, et al. Enhancing the quality of life of dementia caregivers from different ethnic or racial groups: a randomized, controlled trial. Ann Intern Med. 2006 Nov 21;145(10):727-38.

Cummings JL, Schneider E, Tariot PN, Graham SM; Memantine MEM-MD-02 Study Group. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology. 2006 Jul 11;67(1):57-63.

Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, Katan MB, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007 Jan 20;369(9557):208-16.

Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, Basun H, Faxen-Irving G, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006 Oct;63(10):1402-8.

Gamaldo A, Moghekar A, Kilada S, Resnick SM, Zonderman AB, O'Brien R. Effect of a clinical stroke on the risk of dementia in a prospective cohort. Neurology. 2006 Oct 24;67(:1363-9.

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McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med. 2006 Jun 29;354(26):2764-72.

Mittelman MS, Haley WE, Clay OJ, Roth DL. Improving caregiver well-being delays nursing home placement of patients with Alzheimer disease. Neurology. 2006 Nov 14;67(9):1592-9.

Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS. Associations of vegetable and fruit consumption with age-related cognitive change. Neurology. 2006 Oct 24;67(:1370-6.

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Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007 Feb;39(2):168-77. Epub 2007 Jan 14.

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Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava S, Robins SJ, Au R, et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol. 2006 Nov;63(11):1545-50.

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Review Date:
7/31/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

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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

Allergic rhinitis

FitSugar — Wed, 08 Oct 2008 17:35:27 -0700

In This Report

Highlights
Introduction
Causes
Symptoms
Risk Factors
Prognosis
Diagnosis
Treatment
Other Treatments
Decongestants
Antihistamines
Corticosteroids
Immunotherapy
Prevention
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approval

Ciclesonide (Omanaris), a corticosteroid nasal spray, has been approved for treatment of seasonal and perennial allergic rhinitis (hay fever) in adults and children age 12 years and older.

FDA Drug Warnings

The antihistamine promethazine (Phenergan) should not be given to children younger than age 2 because it may cause serious breathing problems.
Omalizumab (Xolair) may cause a life-threatening allergic reaction (anaphylaxis). This drug is used to treat allergy-related asthma, but is also being investigated as an allergy treatment.

Cough and Cold Medicines for Children

In 2007, the FDA began reviewing the safety and effectiveness of cough and cold medicines for children. These medicines contain antihistamines, decongestants, expectorants, and cough suppressants. The FDA is particularly concerned about the use of these medicines in children younger than 2 years of age. Overdoses can cause serious heart problems and death. However, many experts are concerned that the currently recommended dosages are themselves not safe.

Immunotherapy (Allergy Shots)

Immunotherapy is safe and effective for patients with allergic rhinitis, particularly those who have not been helped by other treatments, indicates a 2007 review in the Cochrane Database.
An experimental DNA-based ragweed vaccine is showing promise in early clinical trials. In a 2006 pilot study published in the New England Journal of Medicine, six weekly injections of the vaccine helped improve symptoms with benefits lasting into the following ragweed season.

Allergic Rhinitis and Sleep

Allergic rhinitis can cause sleep disorders and interfere with sleep quality, indicates a 2006 study in the Archives of Internal Medicine. In the study of nearly 600 patients with allergic rhinitis, patients with severe allergic rhinitis experienced worse sleep problems than those with mild allergic rhinitis.

Allergic Rhinitis and Parkinson’s Disease

Allergic rhinitis may be associated with the later development of the neurological disorder Parkinson’s disease, suggests a 2006 study in Neurology. Both conditions are associated with an inflammatory response.

Introduction

The nose is separated into two passages by a wall of cartilage called the septum. The nasal passages are lined with a membrane that produces a clear liquid called mucus. Mucus is a one of the body's defense systems:

The mucus traps small particles and bacteria, which may enter the nose as a person breathes.
The trapped bacteria usually do not cause harm in healthy individuals.
However, the bacteria can lead to a daily cycle of congestion and decongestion.
When one side of the nose is congested, air passes through the open (decongested) side. The sides alternate between being wide-open and partly or completely blocked.

If the congestion becomes severe or other changes occur that irritate the nasal passage, rhinitis develops. To be diagnosed with rhinitis, the patient must experience at least two of the following symptoms for an hour or more on most days:

Runny nose
Obstruction in the nasal passage
Nasal itching
Sneezing

Click the icon to see an image showing symptoms of allergic rhinitis.

These symptoms may occur as a result of colds or environmental irritants, such as allergens, cigarette smoke, chemicals, changes in temperature, stress, exercise, or other factors.

Infectious Rhinitis. If symptoms last less than 6 weeks, the condition is referred to as acute rhinitis and is usually caused by a cold or infection, or temporary overexposure to environmental chemicals or pollutants. [See In-Depth Report #94: Colds and the flu.]

Chronic Rhinitis. When rhinitis lasts for a longer period, the condition is called chronic rhinitis. Allergies are often the cause, but structural problems or chronic infections could also be to blame.

Aging Process. The elderly are at risk for chronic rhinitis as the mucous membranes become dry with age. In addition, the cartilage supporting the nasal passages weakens, causing changes in airflow. In such cases, therapy involves avoiding possible allergens and airborne irritants as well as measures to keep the nasal passages moist. Decongestants are not helpful.

Irritative Rhinitis. Irritative rhinitis is caused by an overreaction to irritants, such as cigarette smoke, dozens of other air pollutants, strong odors, alcoholic beverages, and exposure to cold. The nasal passages become red and engorged. This reaction is not the same as an allergic reaction, although both are associated with increased numbers of white blood cells called eosinophils.

Vasomotor Rhinitis. Vasomotor rhinitis, also sometimes called idiopathic or irritant rhinitis, is congestion and stuffy nose that is produced by the changes in blood vessels and nerve cells in the nasal passages. It occurs in response to irritants, including smoke, environmental toxins, changes in temperature and humidity, stress, and even sexual arousal. This over-reaction is not associated with any immune response. The biologic causes are unknown. Some research has found an association between vasomotor rhinitis and gastroesophageal reflux disorder (GERD, a common cause of heartburn), which some experts think may be due to a common defect in the nervous system that controls muscle action. Symptoms of vasomotor rhinitis are similar to most of those caused by allergies. Usually, however, they are more severe and occur predominantly on one side of the nose.

Foreign Objects. Blockage in young children is very often caused by foreign objects that they have pushed up their nose. If they are left in place, they may eventually cause infection and nasal discharge, (usually in one side of the nose), which may be yellow or green and foul smelling.

Blockage in the Nose from Polyps or Structural Abnormalities. A number of conditions may block the nasal passages. Surgery may be helpful for certain cases.

Polyps. These are soft, gray, fluid-filled sacs that develop off stalk-like structures on the mucus membrane. They impede mucus drainage and restrict airflow. Polyps usually develop from sinus infections that cause overgrowth of the mucus membrane in the nose. They do not regress on their own and may multiply and cause considerable obstruction.
Deviated Septum. A common structural abnormality that causes rhinitis is a deviated septum. The septum is the inner wall of cartilage and bone that separates the two sides of the nose. When deviated, it is not straight but shifted to one side, usually the left.
Other Causes of Blockage. Rarely, cleft palates, overgrowth of bones in the nose, or tumors cause rhinitis.

Nonallergic Rhinitis in Children. Chronic nasal congestion in children often accompanies a susceptibility to ear, sinus, or adenoid infections. Adenoids are spongy tissue masses located between ends of the nasal passages and the soft tissue in the back of the throat. Enlarged adenoids may also cause ear problems. The bacteria that cause these other infections, however, are not usually the cause of this chronic rhinitis.

Medications and Illegal Drugs. A number of drugs can cause rhinitis or worsen it in people with conditions such as deviated septum, allergies, or vasomotor rhinitis:

Overuse of decongestant sprays used to treat nasal congestion can, over time (3 - 5 days) cause inflammation in the nasal passages and worsen rhinitis.
Many people with allergies and asthma are sensitive to common painkillers known as nonsteroidal anti-inflammatory drugs (NSAIDs). These include aspirin, ibuprofen (Motrin, Advil, Nuprin, Rufen), and naproxen (Aleve), among many others. Aspirin and products containing aspirin can even cause life-threatening asthma attacks in some highly susceptible individuals. NSAIDs vary, however, and some patients may not have a reaction to all of them. For minor pain, acetaminophen (Tylenol), which is not an NSAID, is usually recommended for patients with intolerance to NSAIDs. A pharmacist should be consulted if the ingredients of any over-the-counter preparations are not known.
Other medications that may cause rhinitis include oral contraceptives, hormone replacement therapy, anti-anxiety drugs (particularly alprazolam), some antidepressants, and some blood pressure medications, including beta-blockers and vasodilators.
Sniffing cocaine damages nasal passages and can cause chronic rhinitis.

Estrogen in Women. Elevated levels of estrogen appear to increase mucus production and swelling in the nasal passages and can cause congestion. This effect is most apparent in women during pregnancy. In such cases the condition usually clears up after delivery. Oral contraceptives and hormone replacement therapies that contain estrogen have also been associated with nasal congestion in some women.

Medical Conditions. Hypothyroidism is associated with chronic rhinitis. People with certain genetic or other medical conditions that specifically affect the mucous membranes are at also risk, although rhinitis in such people is apt to be only one of many more serious conditions, including chronic sinusitis and respiratory problems. Wegener's granulomatosis, for example, is a serious but very rare illness that causes long-term swelling and tumor-like masses in air passages.

Rare genetic disorders that cause chronic rhinitis include the following:

Cystic fibrosis, in which the mucus is very thick.
Kartagener's syndrome. With this condition the body's major internal organs are located in the mirror-image position of their normal location. In addition, the body's cilia (hair-like-projections on many body tissues that help to move mucus and other fluids) are impaired or motionless.

In both disorders, mucus build-up also produces an environment favorable to infection-causing organisms.

Click the icon to see an image of a deviated septum.

Click the icon to see an image of the adenoids.

Causes

The allergic process, called atopy, and its connection to asthma is not completely understood. It involves various airborne allergens or other triggers that set off a cascade of events in the immune system leading to inflammation and hyperreactivity in the airways.

The conductor in an orchestra of immune factors that contribute to allergies and asthma appears to be a category of white blood cells known as helper T cells, in particular a subgroup called Th2 cells.
Th2 cells overproduce interleukins (ILs), immune factors that are molecular members of a family called cytokines, which are involved in the inflammatory process.

Interleukins 4, 9, and 13 may be responsible for a first-phase asthma attack. These interleukins stimulate the production and release of antibody groups known as immunoglobulin E (IgE). People with both asthma and allergies appear to have a genetic predisposition for overproducing IgE.
During an allergic attack, these IgE antibodies bind to special cells in the immune system called mast cells, which are generally concentrated in the lungs, skin, and mucous membranes. This bond triggers the release of a number of active chemicals, importantly potent molecules known as leukotrienes. These chemicals cause airway spasms, overproduce mucus, and activate nerve endings in the airway lining.
Another cytokine, interleukin 5, appears to contribute to a late-phase inflammatory response. This interleukin attracts white blood cells known as eosinophils. These cells accumulate and remain in the airways after the first attack. They persist for weeks and mediate the release of other damaging particles that remain in the airways.

One theory blames the dramatic increase in asthma and allergies on the reductions in childhood infections that have occurred with modern hygiene and antibiotic use. The basic theory rests on the idea that infections stimulate production of specific immune factors called Th1 cells. As these cells build up, they replace other immune factors called Th2 cells, which react to allergens -- a less serious threat to the body. Without infections to stimulate the production of the Th1 infection fighters, the Th2 allergen fighters are not replaced, and they persist at high levels, making the growing child more susceptible to allergies and asthma.

A number of different studies support this theory:

Some studies suggest that being part of a large family or attending day care increases the risk for early respiratory infections but reduces the risk of childhood asthma. The occasional cold, then, may be protective.
In a 2002 study, researchers measured levels of bacterial byproducts called endotoxins in the mattress dust of 812 children. Those with the highest levels had an 80% lower rate in allergies and asthma.
Another study further found a strong association between allergy development and the absence of certain beneficial bacteria (called probiotics) in infants' intestines. Infants who were born in more hygienic environments tended to lack these bacteria. Antibiotic overuse and modern hygiene may reduce these helpful organisms. (Probiotics are available in active yogurt cultures and in supplements, which are being studied for protection.)

According to many studies, the standard vaccinations against serious childhood infections pose no risk for developing asthma or hay fever. Some studies have even reported lower risk for asthma and allergies in the second and third years after vaccinations.

Some evidence suggests that the increase in allergies and asthma may be due to overexposure to indoor allergens. These may include wall-to-wall carpeting, cats, and mold produced by dampness in homes. Children who spend hours indoor each day may become overexposed to indoor allergens. This exposure is intensified by the recent trend of making homes more energy-efficient, which may result in more dust mites being trapped inside. However, other studies suggest that early exposure to allergens may actually prevent the development of allergies in children.

Seasonal allergic rhinitis occurs only during periods of intense airborne pollen or spores. It is commonly, although inaccurately, called hay fever or rose fever, depending on whether it occurs in the late summer or spring. No fever accompanies this condition, and the allergic response is not dependent on either hay or roses. In general, triggers of seasonal allergy in the U.S. include:

Ragweed. Ragweed is the most dominant cause of allergic rhinitis in the U.S., affecting about 75% of allergy sufferers. One plant can release 1 million pollen grains a day. Ragweed occurs everywhere in the U.S., although it is less common in western coastal states, southern Florida, northern Maine, Alaska, and Hawaii. The effects of ragweed in the northern states are first felt in middle to late August and last until the first frost. Ragweed allergies tend to be most severe before midday.
Grasses. Grasses affect people in mid-May to late June. Grass allergies are experienced more in the late afternoon.
Tree Pollen. Small pollen grains from certain trees usually produce symptoms in late March and early April.
Mold Spores. Mold spores that grow on dead leaves and release spores into the air are common allergens throughout the spring, summer and fall. Mold spores may peak on dry windy afternoons or on damp or rainy days in the early morning.

Click the icon to see an animation about allergies.

Major weather changes, such as El Nino, can affect the timing of allergy seasons. For example, in 1998, when the effects of El Nino were very strong, allergy attacks were markedly increased, and maximum tree pollen counts occurred 2 - 4 weeks earlier and mold counts 2 - 3 months earlier than the previous year.

Allergens in the House. Allergens in the house can trigger attacks in people with year-long allergic rhinitis, called perennial rhinitis. Household allergens may include the following:

House dust and mites. Dust mites, specifically mite feces, are coated with enzymes that contain a powerful allergen.
Cockroaches
Pet dander
Molds growing on wallpaper, house plants, carpeting, and upholstery

However, some studies are suggest that early exposure to some of these allergens, including dust mites and pets, may prevent allergies from developing in the first place in children.

Fossil Fuels. There may be an association between traffic-related air pollution and allergic rhinitis. Some experts believe that refined fossil fuels, such as diesel fuel and particularly kerosene, are important triggers for allergic rhinitis. In people who already have allergies or asthma, exposure to such fossil fuels may worsen symptoms.

Symptoms

The general symptoms of rhinitis are congestion, runny nose, and postnasal drip, in which mucous drips into the throat from the back of the nasal passage, especially when lying on the back. Symptoms may vary depending on the cause of rhinitis. Symptoms of influenza and sinusitis must also be differentiated from allergies and colds.

Symptoms of allergic rhinitis occur in two phases, early and late.

Early Phase Symptoms. The early phase occurs within minutes of exposure to the allergens and includes:

Runny nose
Frequent or repetitive sneezing
Itching in the nose, eyes, throat, or roof of the mouth

Late-Phase Symptoms. The late phase occurs 4 - 8 hours later and may include one or more of these symptoms:

Nasal congestion and possibly plugged ears. Children may push their nose upward with the palm of their hand or twitch their nose rabbit-like to clear the obstruction.
Fatigue.
Mental changes can include irritability, a slight decrease in attention span, worsened memory, and slower thinking.
Other common physical symptoms include a decreased sense of smell, plugged ears, sinus headache, postnasal drip or some combination. In severe allergies, dark circles may develop under the eye. The lower eyelid may be puffy and lined with creases.

Risk Factors

Allergic rhinitis affects between 20 - 40 million Americans of all ages. As with asthma and many upper respiratory infections, the incidence in allergic rhinitis is increasing. Allergies most often appear first in childhood, and allergic rhinitis is the most common chronic condition in childhood, although it can develop at any age. About 20% of allergic rhinitis cases are due to seasonal allergies, 40% to perennial (chronic) rhinitis, and the rest are mixed.

Genetic factors are the major determinants of allergies.

If both parents have an allergy, the child's risk is 75%.
If one parent is allergic, the child's risk is 50%.

Having other allergies increases the risk for allergic rhinitis. Here are some examples:

Young children who have eczema (an allergic skin reaction) have a later risk for allergic rhinitis and asthma. In fact, a family history of eczema increases the risk.
Food allergies are associated with allergic rhinitis and asthma. (Early feeding patterns, time of weaning, and introduction of solid food do not appear to affect this risk.)
Asthma, especially in patients who develop it as adults, may increase allergic sensitivity to ragweed and other allergens. Patients who have asthma and a genetic tendency towards allergies (atopy) are also at risk for rhinitis.

Birth Month. Some studies report a higher risk of allergies and asthma in children born in winter months and lower risk in those born during the summer.

Breastfeeding. Some researchers suggest that the dramatic increase in asthma and allergies may be due to fewer women breastfeeding their infants. In a number of studies, breastfeeding has been associated with a lower risk for allergies and asthma -- at least until age 2. Breastfeeding can also help prevent other upper respiratory infections. The American Academy of Pediatrics recommends feeding infants exclusively breast milk for the first 6 months of life.

Prognosis

Seasonal allergic rhinitis tends to diminish as a person ages. The earlier the symptoms start, the greater the chances for improvement. People who develop hay fever in early childhood tend not to have the allergy in adulthood. In one study, over half of allergic subjects reported that by 40 years of age their symptoms had decreased, and a quarter were symptom-free. In some cases, allergies go into remission for years and then return later in life. People who develop allergies after age 20, however, tend to continue to have hay fever at least into middle age.

People with allergic rhinitis may be at higher risk for other allergies, including potentially serious food or latex allergies.

Although allergic rhinitis is not considered a serious condition, it nonetheless can interfere with many important aspects of life. A 2006 survey of nasal allergy sufferers reported that symptoms made patients feel tired (80%), miserable (65%), irritable (62%), and interfered with work performance (52%).

People with allergic rhinitis, particularly those with perennial allergic rhinitis, may experience sleep disorders and daytime fatigue. Often they attribute this to medication, but studies suggest congestion may be the culprit in these symptoms. In addition, a 2002 study indicated that patients with seasonal allergies experience hundreds of brief, subtle awakenings, called "microarousals," each night. In such cases, people are not aware that they wake up, but such events can cause fatigue the next day. A 2006 study of nearly 600 patients with allergic rhinitis found that sleep disorders and poor sleep quality were prevalent. Patients who had severe allergic rhinitis had worse sleep problems than those with mild allergic rhinitis.

Asthma and allergies often coexist, and the allergic response plays a strong role in childhood asthma. About 70 - 85% of children with asthma have allergies. Aggressive treatment of allergies in children with asthma can lower the risk for asthma attacks. Treating allergies in children may also help prevent the onset of asthma.

Any chronic rhinitis, whether allergic or nonallergic, can cause swelling in the turbinate, which may become persistent (turbinate hypertrophy). The turbinate is a tiny shelf-like bony structure that protrudes in the nasal passageways. It helps warm, humidify, and clean the air that passes over it. If turbinate hypertrophy develops, it causes persistent nasal congestion and, sometimes, pressure and headache in the middle of the face and forehead. This condition requires surgery.

Children with severe allergies may have a higher risk for behavioral problems than those without allergies. Some research suggests that allergic rhinitis is responsible for 2 million missed school days each year.
There have been reports that 30 - 45% of people with allergic rhinitis also suffer from ear infections (otitis media).
Chronic nasal obstruction from year-round allergies can affect a child's appearance. If a child can only breathe through the mouth, the continual force of air passing through the oral cavity can change facial development. Such changes may include an elongated face and an overbite from teeth coming in at an abnormal angle.
Chronic rhinitis can cause headaches and also affect a child's sleep, concentration, hearing, appetite, and growth.

Depression. Some evidence has linked depression with allergies. A 2002 study, for example, found that people with depression reported a higher rate of allergic disorders (71%) compared to nondepressed individuals (43%). During allergy season, patients with allergies were more likely to experience mood changes, including sadness, lethargy, and mental fatigue, than at other times. Some evidence suggests that specific immune factors in the allergic response can cause depressive symptoms. Other research indicates that both may have a common cause.

Parkinson’s Disease. A 2006 study suggested that allergic rhinitis may be associated with the later development of the neurological disorder Parkinson’s disease. The researchers think that the inflammatory response may be the link between the two conditions. However, there is not yet any evidence that treating allergic rhinitis can prevent Parkinson’s disease.

Chronic Fatigue Syndrome (CFS). Some, although not all, studies have reported that a majority of patients with CFS also have allergies to foods, pollen, metals (such as nickel or mercury), or other substances. One theory is that allergens, like viral infections, may trigger a harmful overreaction of the immune system that can cause fatigue, joint aches, and fever as well as hormone and brain chemical disturbances. (However, most people with allergies do not have CFS.)

Diagnosis

To determine the cause of allergic rhinitis, the doctor will ask a number of questions about:

Time of day and year of rhinitis episodes. Rhinitis that appears seasonally is typically due to pollens and outdoor allergens. If symptoms occur throughout the year, the doctor will suspect perennial allergic or non-allergic rhinitis.
Family history of allergies.
History of medical problems.
In women, if they are pregnant or taking drugs that contain estrogen (oral contraceptives, hormone replacement therapy).
Use of other medications including decongestants, which can cause a rebound effect.
Pets.
Any additional unusual symptoms. As examples, bloody nasal discharge and obstruction in only one nasal passage could suggest a tumor. Fatigue, sensitivity to cold, weight gain, and depression may be signs of hypothyroidism.

The doctor will examine the inside of the nose with an instrument called a speculum. This is a painless examination allowing the doctor to check for redness and other signs of inflammation. The doctor will also usually check the eyes, ears, and chest.

A skin test is a simple method for detecting common allergens. Patients are usually tested for a panel of common allergens. Skin tests are rarely needed to diagnose mild seasonal allergic rhinitis, since the cause is usually obvious. The skin test is not appropriate for children younger than age 3.

The procedure is as follows:

Patients should not take antihistamines for at least 12 - 72 hours before the test. Otherwise an allergic reaction may not show up.
Small amounts of suspected allergens are applied to the skin with a needle prick or scratch or are injected a few cells deep into the skin. The injection test may be more sensitive than the standard prick test.
If an allergy is present, a hive (a swollen reddened area) forms within about 20 minutes.

The test is not completely accurate. For instance, a 2001 study reported that testing detected allergies in less than half of children with rhinitis. Furthermore, about 15 - 20% of people may have a skin reaction without actually having an allergy.

Nasal Smear. The doctor may take a nasal smear. The nasal secretion is examined microscopically for factors that might indicate a cause, such as increased numbers of white blood cells, indicating infection, or high counts of eosinophils. High eosinophil counts indicate an allergic condition, but low counts do not rule out allergic rhinitis.

Tests for IgE. Blood tests for IgE immunoglobulin production may also be performed. One test is called the radioallergosorbent Test (RAST), used to detect increased levels of allergen-specific IgE in response to particular allergens. Blood tests for IgE may be less accurate than skin tests. They should be performed only on patients who cannot undergo skin testing or when skin test results are uncertain.

In people with chronic rhinitis, the doctor may also check for sinusitis. Imaging tests may be useful if other tests are ambiguous.

A test called transillumination, in which a doctor shines a bright light against the patient's cheek or forehead, is an inexpensive method for checking for abnormalities in the sinus cavities, although it is not highly accurate.
CT scans may be useful for some cases of sinusitis.

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

In certain cases of chronic or unresponsive seasonal rhinitis, a doctor may use endoscopy to examine for any irregularities in the nose structure. Endoscopy uses a tube inserted through the nose that contains a miniature camera to view the passageways.

Treatment

If rhinitis is caused by non-allergic conditions, particularly if there are accompanying symptoms indicating a serious problem, the doctor should treat any underlying disorders. If rhinitis is caused by medications, such as decongestants, the patient may need to stop taking them or find alternatives.

Patients with chronic allergic rhinitis may require daily medications. Patients with severe seasonal allergies should start medications a few weeks before the pollen season and continue taking them until the season is over. Effective medications include:

Drugs that reduce the inflammatory response are important for preventing severe allergic rhinitis. Nasal corticosteroids (commonly called steroids) are now considered to be the most effective measure for preventing allergy attacks. Other anti-inflammatory drugs include leukotriene-antagonists and nasal cromolyn.
Antihistamine tablets relieve sneezing and itching and can prevent nasal congestion before an allergy attack. Many brands are available by prescription and over-the-counter.
Immunotherapy ("allergy shots") may be considered for patients with severe seasonal allergies that do not respond to treatment. It may also prevent asthma and the development of new allergies in children. Many experts now recommend immunotherapy for people with both asthma and allergies. Newer immunotherapeutic approaches using specially designed antibodies and vaccines are also showing promise.

All drug treatments have side effects, some very unpleasant and, in rare cases, serious. Patients may need to try different drugs until they find one that relieves symptoms without producing excessively distressing side effects.

Because seasonal allergies generally last only a few weeks, most doctors do not recommend the more potent prescription treatments for children. It is important for parents to determine if the child is actually under severe distress and that the parent is not simply responding to their own anxiety when they hear the child snorting or snoring. Prescription drugs are required only in severe cases. However, in children with both asthma and allergies, treatments for allergic rhinitis may also improve asthmatic symptoms.

Treating Mild Allergy Attacks. Mild allergy attacks usually require little more than reducing exposure to allergens and using a nasal wash. Dozens of treatments are available for allergic rhinitis. Many are available over-the-counter, but some require a prescription. They include the following:

Nasal washes
Decongestants that relieve nasal congestion and itchy eyes
Decongestant/antihistamine combinations

Due to side effects, decongestants should not be used in children ages 14 years or younger. Also, overuse of nasal decongestions can actually worsen sinus congestion.

Treating Severe Allergic Rhinitis. Patients with chronic allergic rhinitis, particularly if they also have asthma, may require daily medications. These drugs include:

Antihistamines. The newer non-sedating antihistamines -- such as cetirizine (Zyrtec), loratadine (Claritin), fexofenadine (Allegra), or desloratadine (Clarinex) -- cause less drowsiness than older antihistamines, such as Benadryl. Some of the newer drugs, such as Zyrtec and Clarinex, may also relieve nasal congestion.
Anti-inflammatory drugs. Nasal corticosteroids are now considered to be the most effective measure for preventing allergy attacks. They are recommended for patients with very severe allergies that do not respond to antihistamines.
Leukotriene-antagonists and nasal cromolyn may be beneficial in specific cases of allergies
Immunotherapy ("allergy shots") works well for many patients with severe allergies. It is also proving to reduce asthma symptoms and the use of asthma medications in patients with known allergies.

Itching and redness in the eyes sometimes respond to oral antihistamines. Eye drops, however, provide faster relief, and a combination of the two may be best. The following are eye drops for itchy eyes. Others are also available. Individual responses vary, and patients need to find which specific treatment works best for them.

Antihistamine eye drops: azelastine (Optivar), olopatadine (Patanol), ketotifen (Zaditor), levocabastine (Livostin) for relief of both nasal symptoms and itchy red eyes
Decongestant eye drops: phenylephrine (Allergan Relief), naphazoline (Naphcon, Opcon-A, VasoClear), tetrahydrozoline (Murine Plus, Visine)
Combination decongestant/antihistamine: Visine A.
Corticosteroids: loteprednol (Lotemax, Alrex), pemirolast (Alamast).

General Side Effects and Warning.

All eye drops can cause stinging, and some may result in headache and congestion.
No one should continue taking eye drops if they experience pain, changes in vision, worsened redness, or irritation, or if the condition lasts more than 3 days.
Do not touch the tip of the device to the eye or touch other surfaces with it. Replace the cap after using. Discard any solution that changes color or becomes cloudy.
People who have heart disease, high blood pressure, an enlarged prostate gland, or glaucoma should talk to their doctor before taking these types of eye drops.

Other Treatments

For mild allergic rhinitis, a nasal wash can be helpful for removing mucus from the nose. You can purchase a saline solution at a drug store or make one at home (one cup of warm water, half teaspoon salt, pinch of baking soda). Over-the-counter saline nasal sprays that contain benzalkonium chloride as a preservative may actually worsen symptoms and infection.

Simple method for administering a nasal wash:

Lean over the sink head down.
Pour some solution into the palm of the hand and inhale it through the nose, one nostril at a time.
Spit the remaining solution out.
Gently blow the nose.

The solution may also be inserted into the nose using a large rubber ear syringe, available at a pharmacy. In this case the process is:

Lean over the sink head down.
Insert only the tip of the syringe into one nostril.
Gently squeeze the bulb several times to wash the nasal passage.
Then press the bulb firmly enough so that the solution passes into the mouth.
Repeat the process in the other nostril.

Nearly half of asthma or allergy sufferers resort to alternative treatments. To date, however, little evidence supports treatments such as high-dose vitamins, homeopathic remedies, and most herbal remedies. Some relaxation methods, such as massage therapy, may be beneficial in reducing stress related to allergy symptoms. According to research presented at a 2004 allergy conference, acupuncture is now the most popular alternative treatment among allergy sufferers. The following are examples of recent areas of research:

Acupuncture may provide symptom relief for persistent allergic rhinitis in children, according to results published in a 2004 pediatrics journal. The study compared the effects of active versus sham acupuncture. Larger trials are needed to confirm these results.
Butterbur (also known as Petasites hybridus, butter dock, blatterdock, bog rhubarb, and exwort) is a plant found in Europe, North American, and parts of Asia. It is a traditional herbal remedy used for seasonal allergies and asthma. In a 2002 study, it was as effective and less sedating than a commonly prescribed antihistamine for treating seasonal allergies over a 2-week period.
Probiotics are beneficial bacteria that may help protect against allergies and asthma. Probiotics are available in active yogurt cultures and in supplements, which are being studied for protection.

Generally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Always check with your doctor before using any herbal remedies or dietary supplements.

The following are special concerns for people with allergic rhinitis:

Grapeseed extract is sometimes touted as a natural antihistamine. A 2002 study, however, reported no benefits from it.
A 2002 study found no benefits with homeopathy immunotherapy for asthmatic patients allergic to dust mites.
Some patients have reported worse symptoms after drinking herbal teas, which may contain leaves or pollens the patient is sensitive to. Herbal remedies themselves can trigger an allergic reaction. For example, echinacea is of special concern. This herbal remedy actually boosts the immune system. People with nasal congestion may mistakenly take it because it is often used to treat colds. In the case of allergies, however, echinacea may worsen symptoms or even trigger them in people who haven't experienced them. People with autoimmune diseases or who have plant allergies should particularly avoid it.
A Chinese herbal cold and allergy remedy sold as Aller Relief contains trace amounts of aristolochic acid, a chemical that is toxic to the kidneys and a carcinogen. Products containing aristolochic acid have been associated with several reports of kidney failure in Europe. Of specific concern are studies suggesting that up to 30% of herbal patent remedies imported from China have been laced with potent pharmaceuticals such as phenacetin and steroids. Asian herbal remedies may also contain toxic metals.
Aromatherapy is often used for relaxation. Some of the exotic plant extracts in these formulas have been associated with a wide range of skin allergies.

Decongestants

For mild allergic rhinitis, a nasal wash can be helpful for removing mucus from the nose. Decongestants may help dry nasal congestion. They work by shrinking vessels in the nose. By reducing blockage, they decrease the risk of developing sinusitis caused by viruses or bacteria. Many over-the-counter decongestants are available, either in tablet form or as nasal or inhaled decongestants that are applied directly into the airways as sprays, drops, or vapors.

Nasal-delivery decongestants are applied directly into the nasal passages with a spray, gel, drops, or vapors. Nasal decongestants come in long-acting or short-acting forms. The effects of short-acting decongestants last about 4 hours; long-acting decongestants last 6 - 12 hours. The active ingredients in nasal decongestants include oxymetazoline, xylometazoline, and phenylephrine. Nasal forms work faster than oral decongestants and may not cause as much drowsiness. However, they can cause dependency and rebound.

Dependency and Rebound. The major hazard with nasal-delivery decongestants, particularly long-acting forms, is a cycle of dependency and rebound effects. The 12-hour brands pose a particular risk for this effect.

With prolonged use (more than 3 - 5 days), nasal decongestants lose effectiveness and can cause swelling in the nasal passages.
The patient then increases the frequency of the dose. As the congestion worsens, the patient may respond with even more frequent doses.
This causes dependency and increased nasal congestion.

Tips for Use. The following precautions are important for people taking nasal decongestants:

When using a nasal spray, spray each nostril once. Wait a minute to allow absorption into the mucosal tissues, and then spray again.
Do not share droppers and inhalators with other people.
Discard sprayers, inhalators, or other decongestant delivery devices when the medication is no longer needed. Over time, these devices can become reservoirs for bacteria.
Discard the medicine if it becomes cloudy or unclear.

Oral decongestants also come in many brands, which have similar ingredients. The most common active ingredient is pseudoephedrine (Sudafed, Actifed, Drixoral), sometimes in combination with an antihistamine. [The alternative decongestant, phenylpropanolamine (PPA) was taken off the market.] A small 2006 study reported that over-the-counter pseudoephedrine works just as well as the prescription drug montelukast (Singulair) in controlling allergic rhinitis symptoms. Patients in the study received a once-daily morning dose (240 mg) of ephedrine. Researchers suggest that taking pseudoephedrine in the morning, as opposed to later in the day or before bedtime, can help patients avoid side effects such as insomnia and nervousness.

Decongestants have certain adverse effects, which are more apt to occur in oral than nasal decongestants. These side effects include:

Agitation and nervousness
Drowsiness (particularly with oral decongestants and in combination with alcohol)
Changes in heart rate and blood pressure
Avoid combinations of oral decongestants with alcohol or certain drugs, including monoamine oxidase inhibitors (MAOI) and sedatives.

Individuals at Risk for Complications from Decongestants. People who may be at higher risk for complications are those with certain medical conditions, including disorders that make blood vessels highly susceptible to contraction. Such conditions include:

Heart disease
High blood pressure
Thyroid disease
Diabetes
Prostate problems that cause urinary difficulties
Migraines
Raynaud's phenomenon
High sensitivity to cold
Emphysema or chronic bronchitis. (Individuals with these conditions should particularly avoid high-potency, short-acting nasal decongestant.)
Medications that increase serotonin levels, such as certain antidepressants, anti-migraine drugs, diet pills, St. John's wort, and methamphetamine. The combination of these medicines and decongestants can cause blood vessels in the brain to narrow suddenly, causing severe headaches and even stroke.

Anyone with these conditions should not use oral or nasal decongestants without a doctor's guidance. Other people who should not use decongestants without first consulting a doctor include:

Pregnant women
Children. The American College of Chest Physicians advises against the use of over-the-counter decongestants and other cold medications in children ages 14 years or younger. Children are at particular risk for side effects that depress the central nervous system. Such symptoms cause changes in blood pressure, drowsiness, deep sleep, and, rarely, coma. In 2007, the FDA began reviewing the safety and effectiveness of cough and cold remedies for children.

In 2000, the Food and Drug Administration (FDA) took action to ban oral decongestants containing phenylpropanolamine (PPA) from the U.S. market. This action was in response to reports of an increased risk of stroke in young women who took products containing this ingredient. All major brands that previously contained PPA have now substituted other active ingredients (usually pseudoephedrine) and are safe to use.

Anyone with old forms of decongestant should check the labels and discard them if they contain phenylpropanolamine.

Antihistamines

Histamine is one of the chemicals released when antibodies overreact to allergens. It is the cause of many symptoms of allergic rhinitis. Antihistamines can help relieve:

Itching, sneezing, and nasal discharge
Other allergy symptoms unrelated to rhinitis, including hives and some rashes
Nasal congestion, for some of the newer antihistamines, such as cetirizine (Zyrtec) and desloratadine (Clarinex)

If possible, patients should take antihistamines before an anticipated allergy attack.

Many antihistamines are available. They include short-acting and long-acting forms and are available as tablets, nasal-inhalers, eye drops, and syrups. Antihistamines are generally categorized as first- and second-generation. First-generation antihistamines may cause more side effects than newer second-generation ones.

There are some notes of caution when taking any antihistamine:

Antihistamines may thicken mucus secretions and can worsen bacterial rhinitis or sinusitis.
Antihistamines can lose their effectiveness over time, and a different one may need to be tried.

First-Generation Antihistamines Ingredients and Brand Names. The older, so-called first generation antihistamines include:

Diphenhydramine (Benadryl)
Carbinoxamine (Clistin)
Clemastine (Tavist)
Chlorpheniramine (Chlor-Trimeton). Some health professionals recommend this drug if antihistamines are required during pregnancy. It may be as effective as the second generation antihistamines and much less expensive.
Brompheniramine (Dimetane)
Promethazine (Phenergan). This antihistamine should never be used for children younger than age 2 because it may cause life-threatening breathing problems.

First-generation antihistamines contain compounds called anticholinergics, which tend to produce more side effects than second-generation antihistamines.

Side Effects

Drowsiness and impaired thinking
Dry mouth
Dizziness
Agitation
Insomnia or nightmares
Sore throat
Rapid heart beat and chest tightness (uncommon and should be reported)
Men with enlarged prostate glands may experience difficulty urinating

Drowsiness and First-Generation Antihistamines. Drowsiness is the most distressing side effect reported from first-generation antihistamines, and is potentially serious. It may pose a higher than average risk for work-related and automobile accidents than alcohol, narcotics, or prescription sedatives. However, some studies have not found any strong differences in sedation between the first- and second-generation antihistamines. Still, experts caution against the first-generation antihistamines for people most at risk from sedative effects, particularly elderly individuals. To reduce risks, take the antihistamine at home a few hours before bedtime, and do not combine it with alcohol or tranquilizers. Do not drive or operate heavy machinery.

The newer second-generation antihistamines do not contain anticholinergics, so they do not usually cause drowsiness to the extent that the first generation antihistamines do. They are sometimes referred to collectively as nonsedating antihistamines.

A major 2003 analysis reported that although Benadryl, the most common first-generation antihistamine, had a more negative effect on daily activities than the newer antihistamines, the differences were modest. Researchers in the study concluded that no clear distinction exists between the first- and second-generation antihistamines.

Brand Names. The second-generation drugs include:

Loratadine (Claritin). Claritin is available over-the-counter and is approved for children ages 2 and older. Desloratadine (Clarinex) is similar to Claritin but stronger and longer-lasting. It is available only by prescription.
Cetirizine (Zyrtec). Zyrtec is approved for both indoor and outdoor allergies. It is the only antihistamine to date approved for infants as young as 6 months. It is available over-the-counter.
Fexofenadine (Allegra) is also available over-the-counter.
Acrivastine (Semprex)
Ebastine, norastemizole, levocetirizine, and mizolastine are other second-generation antihistamines under investigation in the U.S. and Europe. Some may prove to be useful for specific populations.

For nonprescription antihistamines, some studies suggest that cetirizine (Zyrtec) is more effective than Allegra or Claritin in improving symptoms, including those in children. However, cetirizine can cause drowsiness when taken at high doses.

Zyrtec and Claritin are approved for children younger than 5 years, although most antihistamines appear to be safe in children. Zyrtec is the only antihistamine approved for both indoor and outdoor allergies and for infants as young as 6 months. Both are available in syrup form. Studies with Zyrtec have reported fewer symptoms in children allergic to dust mites, and one study reported that infants with allergies who were given Zyrtec were much less likely to develop asthma later on than untreated infants. Claritin, at this time, is generally the preferred drug for young people, however, because it has the least negative effect on concentration and learning. Women who are pregnant or nursing should avoid these medications unless recommended by a doctor.

Side Effects and Precautions

Common side effects include headache, dry mouth, and dry nose. (These are often only temporary and go away during treatment.)
Drowsiness occurs in about 10% of adults and between 2 - 4% of children.
Uncommon side effects include rapid heart beat and chest tightness. Tell your doctor if these effects occur.
Extended-release forms of Claritin and Zyrtec have other ingredients that can cause other symptoms, including nervousness, restlessness, and insomnia. Some patients taking Claritin-D 24 Hour Extended Release tablets have reported obstruction in the upper gastrointestinal tract, including difficulty swallowing.

Drug and Food Interactions. Two earlier second generation drugs, terfenadine (Seldane) and astemizole (Hismanal), in rare cases, caused dangerous heart rhythm abnormalities, particularly in high doses or in people who had liver disease. They also caused interactions with certain other medications and grapefruit juice. Both Seldane and Hismanal have been taken off the market. Allegra, Zyrtec, and Claritin do not appear to pose any of the dangers associated with Seldane.

Until more is known, however, anyone who takes a second-generation antihistamine should probably avoid or use with caution combinations with grapefruit juice or the drugs that caused problems with Seldane and Hismanal. Such medications include:

The antibiotics clarithromycin (Biaxin) and troleandomycin
Certain HIV protease inhibitors
Antidepressant serotonin-reuptake inhibitors (Prozac, Paxil, and Serzone)

Azelastine (Astelin) and levocabastine (Livostin) are available in nasal spray form. They can reduce nasal congestion as well as allergy symptoms. Both reduce symptoms, although azelastine may be more effective in some patients. Their disadvantages are a bitter taste, drowsiness, and expense. They are not as effective as steroid nasal sprays.

Many prescription and non-prescription products that combine antihistamines and decongestants are available. Combinations sold over-the-counter include Allerest, Sudafed Severe Cold Formula, Vicks DayQuil, Benadryl Allergy/Sinus, Contac Day/Night Allergy & Sinus. Prescription combinations include Claritin-D, Allegra D, and Zyrtec-D. Symptoms may improve within 60 minutes, with congestion clearing up first.

Corticosteroids

A number of drugs are available for reducing the inflammatory response in allergies. These drugs can help prevent an allergy attack from occurring.

Nasal-spray corticosteroids (commonly called steroids) are considered the most effective drugs for treating severe allergic rhinitis. Corticosteroids suppress important stress and other hormones in a region of the brain called the HPA axis. The suppression of these hormones blocks the inflammatory response that triggers an allergic attack. Steroids do not relieve symptoms immediately. It may take several hours before their effects are felt. Nasal spray steroids benefits include:

Reducing inflammation and mucus production
Improving night sleep and daytime alertness in patients with perennial allergic rhinitis
Treating polyps in the nasal passages

Comparison studies report that nasal steroid sprays work better than second generation antihistamines, such as loratadine (Claritin) and cetirizine (Zyrtec), and are possibly even more effective than allergy shots. They have no effect on itchy eyes, however.

Nasal-Spray Brands. Corticosteroids available in nasal spray form include:

Triamcinolone (Nasacort). Approved for children over age 6.
Mometasone furoate (Nasonex). Approved for use in patients age 3 and older.
Fluticasone (Flonase, Flounce, generic). Approved for children over age 4.
Beclomethasone (Beconase, Vancenase), flunisolide (Nasalide), and budesonide (Rhinocort). Approved for children over age 6.
Ciclesonide (Omnaris). Approved for patients age 12 and older.

Side Effects. Corticosteroids are powerful anti-inflammatory drugs. Although oral steroids can have many side effects, the nasal-spray form affects only local areas and has less risk for widespread side effects unless the drug is used excessively. Side effects of nasal steroids may include:

Dryness, burning, stinging in the nasal passage
Sneezing
Headaches and nosebleed (uncommon but should be reported to your doctor immediately)

Possible Long-Term Complications. All corticosteroids suppress stress hormones. This effect is known to produce some serious long-term complications in people who take oral steroids. Researchers have found far fewer concerns with nasal administration or inhaled forms, but there may be certain problems:

Effect on growth. The major concern for children is whether nasal steroids, like other forms of steroids, will adversely affect growth. Studies report either a temporary and slight (about half an inch) early effect on growth or no effect at all.
Effect on eyes. Glaucoma is a known side effect of oral steroids. Some ophthalmologists have observed higher pressure in the eye (a sign of glaucoma) in some patients taking nasal steroid sprays. (Studies have found no increased risk for cataracts in young people who have taken intranasal steroids). The eye pressure appears to return to normal after stopping the steroid, but periodic eye examinations are advised.
Use during pregnancy. Steroids appear to be safe during pregnancy, but pregnant women should talk to their doctor about other options before taking them.
Nasal passage injury. Steroid sprays may injure the nasal septum (the bony area that separates the nasal passage) if the spray is directed onto it. This complication is very rare.
Lower resistance to infection. People with any infectious disease or injury in the nose should not take these drugs until the disease or wound has been treated and cured.

Cromolyn serves as both an anti-inflammatory drug and a specific blocker for allergens. The standard cromolyn nasal spray (Nasalcrom) is not as effective as steroid nasal sprays but does work well for many people with mild allergies. It is one of the preferred first-line therapies for pregnant women with mild allergic rhinitis. It may take up to 3 weeks to experience full benefit.

Side Effects. Cromolyn has no major side effects, but minor ones include nasal congestion, coughing, sneezing, wheezing, nausea, nosebleeds, and dry throat. The spray can cause burning or irritation.

Leukotriene-antagonists are oral drugs that block leukotrienes, powerful immune system factors that are important in causing airway constriction and mucus production in allergy-related asthma. Leukotriene-antagonists include zafirlukast (Accolate), montelukast (Singulair), zileuton (Ziflo), and pranlukast (Ultair, Onon). These drugs are mainly used to treat asthma. Montelukast was approved in 2003 to treat seasonal allergies, and in 2005 to treat indoor allergies.

Immunotherapy

Immunotherapy (commonly referred to as "allergy shots") is a safe and effective treatment for patients with allergies. It is based on the premise that people who receive injections of a specific allergen will lose sensitivity to that allergen. The most common allergens for which shots are given are house dust, cat dander, grass pollen, and mold.

Immunotherapy benefits include:

Targeting the specific allergen.
Reducing sensitivity in airways in the lungs as well as in the upper airways.
Preventing the development of new allergies in children.
Reducing asthma symptoms and the use of asthma medications in patients with known allergies. Research suggests it may also help prevent the development of asthma in children with allergies.

Candidates for Immunotherapy. Immunotherapy may be given to anyone over age 7 whose allergies are severe and who do not respond to medication. Many experts agree that immunotherapy should be considered as soon as possible for children with asthma and allergies. Immunotherapy is safe for pregnant women who are already receiving it, although half-strength doses are generally recommended, and it should not be started during pregnancy.

Individuals at Risk for Complications. People who should probably avoid immunotherapy include those who have:

An extreme response to skin tests (this may predict an allergic reaction).
Wheezing.
Uncontrolled severe asthma or lung disease.
Patients taking certain medications (such as beta-blockers).
The health status of anyone should be determined before starting treatment.

The major downside to immunotherapy is that it requires a prolonged course of weekly injections. The process generally includes:

Injections of diluted extracts of the allergen are given on a regular schedule, usually twice a week to weekly at first, then in increasing doses until a maintenance dose has been reached. It usually takes several months and may take up to 3 years to reach a maintenance dose.
At that time, intervals between shots can be 2 - 4 weeks, and the treatment is continued for another 3 - 5 years.
Patients can experience some relief within 3 - 6 months. If there is no benefit within 12 - 18 months, discontinue the shots.

After stopping immunotherapy, about a third of allergy sufferers no longer have any symptoms, a third have improved symptoms, and a third relapse.

The use of an injection series is effective, but patients often fail to comply with the regimens. Some other schedules and delivery methods are being investigated that might make the program easier and less distressing.

Rush Immunotherapy. Investigators are studying "rush immunotherapy," in which patients achieve the full maintenance dose with several shots a day over a period of 3 - 5 days. Rush therapy uses modifications that reduce the risk of severe reactions to excessive doses. Studies suggest that it is effective and safe, with few side effects other than itching. Patients must be monitored closely during this period, however, for severe reactions.

Oral Forms. Trials are underway to test oral forms of immunotherapy as an alternative to allergy shots. These methods include using a pill taken by mouth or a sublingual (under-the-tongue) tablet. Although oral and sublingual immunotherapy is prescribed in many countries in Europe and South America, it is not approved in the United States and is not considered accepted therapy at this time.

Injections for ragweed and, sometimes, dust mites have higher risks for side effects than other allergy shots. If complications or allergic reactions develop, they usually occur within 20 minutes, although some can develop up to 2 hours after the shot is given.

Side effects of immunotherapy include:

General itching, swelling, red eyes, hives, soreness at the injection site.
Less common side effects are low blood pressure, asthma worsening, or difficulty breathing. This is due to an extreme hypersensitivity response called anaphylaxis. It can also occur if excessive doses are given.
In rare cases, particularly because of excessive doses or if a patient has a serious lung problem, severe reactions can occur, which can be life threatening.
Premedicating patients with antihistamines and corticosteroids may help reduce the risk of reactions to immunotherapy, although this could mask early warning signs.

In a 10-year study, the incidence of any adverse effect was less than two-tenths of 1%, and the great majority of events were mild. The risk for a fatal response is estimated to be 1 in 63 million injections. (As a comparison, the risk for a fatal reaction to penicillin is much higher, 1 in 7.5 million injections.)

Vaccines. Of particular interest is the development of immunotherapeutic vaccines that use more specific targets to produce an insensitivity to allergens. One such vaccine uses a small protein from the allergen, which is injected into the patient. Other vaccines under investigation are those that use the allergen's genetic material (its DNA) to promote tolerance to the allergen. In a promising 2006 pilot study, patients who received 6 weekly injections of a DNA-based experimental ragweed vaccine had symptom reductions that lasted a year later into a second ragweed season. Researchers will be testing this vaccine in further clinical trials.

Monoclonal Antibodies. Monoclonal antibodies (MAb) are genetically-developed antibodies that are designed to target and attack very specific factors. A MAb known as omalizumab (Xolair) prevents the antibody immunoglobulin E (IgE) from triggering the inflammatory events that lead to allergies. Studies in recent years have suggested that omalizumab may help reduce symptoms and improve quality of life for patients with non-seasonal allergic rhinitis. A 2006 study suggested that treatment with omalizumab before and during ragweed allergy shots may help reduce immunotherapy side effects. The drug is currently approved for asthma. In 2007, the FDA warned that omalizumab may cause a life-threatening allergic reaction (anaphylaxis) in some patients.

Prevention

People with existing allergies should avoid irritants or allergens. These triggers include:

Pollen. This is the primary cause of allergic rhinitis.
Dust mites, specifically mite feces, which are coated with enzymes that contain a powerful allergen. These are the primary allergens inside the home.
Animal dander (flakes of skin) and hair from cats, house mice, and dogs. House mice are proving to be significant sources of allergens, particularly in urban children.
Molds.
Fungi.
Cockroaches are major asthma triggers and may reduce lung function even in people without a history of asthma.
Some research suggests that alcohol intake may influence allergy severity. One study found that as little as one drink a day is enough to worsen dust mite allergies.
Some studies suggest that early exposure to some of these allergens, including dust mites and pets, may actually prevent allergies from developing in children.

Controlling Pets. People who already have pets and are not allergic to them are probably at low risk for developing such allergies later on. When children are exposed to more than one dog or cat during their first year, they have a much lower risk for not only pet allergies but also seasonal allergies and asthma. (Pet exposure does not protect them from other allergens, notably dust mites and cockroaches).

In children who have an existing allergy to pets, however, the pets should be given away or kept outside. If this isn't possible, they should at least be confined to carpet-free areas outside the bedroom. Cats harbor significant allergens, which can even be carried on clothing. Dogs usually present fewer problems. Washing animals once a week can reduce allergens. Dry shampoos, such as Allerpet, that remove allergens from skin and fur and are now available for both cats and dogs and are easier to use than wet shampoos.

For small children, stuffed animals might serve as a comforting replacement, although they might harbor dust mites. Putting stuffed animals in the freezer for 24 hours before washing them kills the dust mites. For best effect, this process should be done weekly.

Preventing Exposure to Cigarette and Cooking Smoke. Parents who smoke should quit. Studies show that exposure to second-hand smoke in the home increases the risk for asthma and asthma-related emergency room visits in children. [For help in quitting, see In-Depth Report # 41: Smoking.]

Controlling Dust. Spray furniture polish is very effective for reducing both dust and allergens. Air cleaners, filters for air conditioners, and vacuum cleaners with High Efficiency Particulate Air (HEPA) filters can help remove particles and small allergens found indoors. Neither vacuuming nor the use of anti-mite carpet shampoo, however, is effective in removing mites in house dust. Vacuuming actually stirs up both mites and cat allergens. People with these types of allergies should avoid having carpets or rugs in their homes.

Bedding and Curtains. Many experts recommend reducing exposure to dust mites by enclosing mattresses and pillows in semipermeable coverings. (Vinyl mattress covers limit airflow and may worsen, or even cause, asthma in children.) However, several 2005 studies suggested that such covers do not prevent allergies or asthma. Curtains should be replaced with shades or blinds and bedding washed using the highest water temperature setting.

Reducing Humidity in the House. Dust mites thrive in humidity, and damp houses increase the risk for mold. On-going humidifiers can worsen the problem. If they are used, humidity levels should not exceed 40%, and humidifiers should be cleaned daily with a vinegar solution.

Exterminating Pests (Cockroaches and Mice). Use professional exterminators to eliminate cockroaches. (One study reported that ridding a home of cockroaches and cleaning the house using standard housecleaning techniques failed to eliminate the cockroach allergens themselves.) Exterminate mice and attempt to remove all dust, which might contain mouse urine and dander.

Avoiding Outdoor Allergens. The following are some recommendations for avoiding allergens outside:

Start taking allergy medications 1 - 2 weeks before ragweed season begins. Be sure to take allergy medications before going outside. If regular medications do not work, ask your doctor about allergy shots.
Camping and hiking trips should not be scheduled during times of high pollen count (May and June for grass pollen and September to October for ragweed).
Patients who are allergic should avoid barns, hay, raking leaves, and mowing grass. (A mask can be worn during outdoor chores to help reduce pollen exposure.)
Sunglasses can help prevent pollen from getting into eyes.
After being outdoors, clean off pollen residue by bathing, washing hair and clothes, and using a nasal salt water rinse.

Some evidence suggests that people with allergic rhinitis and asthma may benefit from a diet rich in omega-3 fatty acids (found in fish, almonds, walnuts, pumpkin, and flax seeds) and fruits and vegetables (at least five servings a day). Some studies also suggest reducing sodium, trans fatty acids (hydrogenated fats found in commercial products and baked goods), and omega-6 fatty acids (found in most vegetable oils). Investigators are also studying probiotics -- so-called good bacteria, such as lactobacillus and bifidobacterium, which can be obtained in supplements.

Resources

www.aaaai.org -- American Academy of Allergy, Asthma & Immunology
www.acaai.org -- American College of Allergy, Asthma & Immunology
www.niaid.nih.gov -- National Institute of Allergy and Infectious Diseases
www.njc.org -- National Jewish Medical and Research Center
www.lungusa.org -- The American Lung Association

References

Bower JH, Maraganore DM, Peterson BJ, Ahlskog JE, Rocca WA. Immunologic diseases, anti-inflammatory drugs, and Parkinson disease: a case-control study. Neurology. 2006 Aug 8;67(3):494-6.

Calderon M, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD001936.

Creticos PS, Schroeder JT, Hamilton RG, Balcer-Whaley SL, Khattignavong AP, Lindblad R, et al. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med. 2006 Oct 5;355(14):1445-55.

Leger D, Annesi-Maesano I, Carat F, Rugina M, Chanal I, Pribil C, et al. Allergic rhinitis and its consequences on quality of sleep: An unexplored area. Arch Intern Med. 2006 Sep 18;166(16):1744-8.

Review Date:
3/22/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Relax Already: Play With a Pet

FitSugar — Wed, 20 May 2009 16:00:00 -0700

People de-stress in different ways, and if soaking in a warm bath doesn't do it for you, try something a little more active and playful in the four-legged variety. Many studies show the health benefits of pets for relieving stress, reducing high blood pressure, and boosting your mood.

Calm your mind by playing with your pet. If you don't have one, canoodle with your friend's goldendoodle. Pet your neighbor's cat. Visit a shelter and play with the animals there. Aside from a cute face, cats and dogs provide unconditional affection, which is great after a stressful day.

Source

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

Colon and rectal cancers

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

In This Report

Highlights
Introduction
Causes
Symptoms
Risk Factors
Dietary Factors
Prevention
Diagnosis
Staging
Prognosis
Surgery
Medications
Radiation Treatment
Follow-up Testing
Treatment for Metastasized ...
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approval

In September 2006, the Food and Drug Administration approved panitumumab (Vectibix) for the treatment of patients with colorectal cancer that has spread to other parts of the body following chemotherapy. Like cetuximab (Ertibux), panitumumab targets the epidermal growth factor receptor (EGFR) on cancer cells. Panitumumab is the first new colorectal cancer drug approved since 2004. The FDA granted accelerated approval to panitumumab based on a clinical trial of patients with metastatic cancer. The average time to disease progression or death was 96 days in patients treated with panitumumab compared to 60 days in patients who received standard care.

Diet and Colorectal Cancer Recurrence

Evidence indicates that diet plays a role in colorectal cancer prevention. Now, a 2007 study in the Journal of the American Medical Association (JAMA) suggests that dietary factors also affect the risk of cancer recurrence. Patients with stage III colorectal cancer who ate lots of red meat, refined grains, and sweets had a higher risk of cancer recurrence and death than patients whose diets were high in fruits and vegetables, poultry, and fish.

Folic Acid No Good for Prevention?

Many experts have long believed that folic acid supplements may help protect against colorectal cancer. But according to a 2007 JAMA study, high-dose folic acid supplements may not prevent colorectal cancer and may actually increase the risk for adenomatous polyp formation. Adenomatous polyps are benign colorectal tumors that can potentially become cancerous. In the study, patients who took folic acid supplements had a greater risk of developing new, more numerous, and larger adenomatous polyps than patients who did not take the supplements.

NSAIDS Not Recommended for Colorectal Cancer Prevention

In March 2007, the U.S. Preventive Services Task Force (USPSTF) recommended against the routine use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent colorectal cancer in people who are at average risk for this disease. Several recent studies have indicated that aspirin, and NSAIDs such as celecoxib (Celebrex), can help prevent colorectal cancer. But the USPSTF notes that the risks of these drugs outweigh the benefits. Long-term daily use of NSAIDs increases the risk for gastrointestinal bleeding, kidney function problems, and heart attack and stroke.

Introduction

Cancers of the colon and rectum, often referred to collectively as colorectal cancer, are life-threatening tumors that develop in the large intestine.

More than 80% of colorectal tumors evolve from adenomatous polyps. These gland-like growths develop on the mucous membrane that lines the large intestine. They are usually either:

Tubular polyps, which protrude mushroom-like
Villous adenomas, which are flat and spreading and are more apt to become malignant (cancerous)

Polyps are very common and almost always benign. Their numbers increase with age. Polyps are found in about 25% of people by age 50, and 50% of people by age 75. Fewer than 1% of polyps under 1 centimeter (slightly less than half an inch) become cancerous. About 10% of larger polyps become cancerous within 10 years, and about 25% of these larger polyps become cancerous after 20 years. Certain inherited polyps can become cancerous more rapidly.

Digestion takes place in the gastrointestinal (GI) tract, essentially a long tube that extends from the mouth to the anus. It is a complex organ system that first carries food from the mouth down the esophagus to the stomach. Food then travels through the small and large intestines before being excreted through the rectum and out the anus.

The esophagus, stomach, large and small intestine -- aided by the liver, gallbladder, and pancreas -- convert the nutritive components of food into energy and break down the non-nutritive components into waste to be excreted.

The esophagus is a narrow muscular tube, about 9 1/2 inches long that begins below the tongue and ends at the stomach.

In the stomach, acids and stomach motion break food down into particles small enough so that the small intestine can absorb nutrients.

Click the icon to see an image of stomach anatomy.

The small intestine, despite its name, is the longest part of the gastrointestinal tract, extending for about 20 feet. Food passes from the stomach through its three parts: first the duodenum, then the jejunum, and finally the ileum. Most of the digestive process occurs in the small intestine.

Click the icon to see an image of small intestine anatomy.

Undigested material, such as plant fiber, is passed next to the large intestine, mostly in liquid form. The large intestine is wider than the small intestine but only about 6 feet long. It is the final portion of the digestive tract and includes the cecum, the appendix, the colon, and the rectum, which extends to the anus.

Cecum and Appendix. The cecum and the appendix are located in the lower-right quadrant of the abdomen.

Colon. The colon absorbs excess water and salts into the blood. The remaining waste matter is converted to feces through bacterial action. The colon is divided into four major sections.

Click the icon to see an image of large intestine anatomy.

The first section, the ascending colon, extends upward from the cecum on the right side of the abdomen.
The second section, the transverse colon, crosses the upper abdomen to the left side.
The third section extends downward on the left side of the abdomen toward the pelvis and is called the descending colon.
The final section is the sigmoid colon.

Rectum and Anus. Feces are stored in the descending and sigmoid colon until they are passed through the rectum and anus. The rectum extends through the pelvis from the end of the sigmoid colon to the anus.

Causes

In most cases of colon or rectal cancers, the cause or causes are unknown. Defects in genes that normally protect against cancer play the major role in causing polyp cells to continuously spread and become cancerous. Some of these cases are caused by inherited genetic defects, and such patients usually have family histories of colorectal cancer. Most of the genetic mutations involved in colon cancers, however, appear to arise spontaneously (no strong family history) rather than being inherited. In such cases, environmental or other factors trigger genetic changes in the intestine that lead to cancer.

About 6% of cases of colon cancer are due to inherited factors.

APC Gene and Familial Adenomatous Polyposis (FAP). When the adenomatous polyposis coli (APC) gene is normal, it helps suppress tumor growth. In its defective form, it permits high levels of the protein beta-catenin to accumulate, which accelerates cell growth leading to polyps. Various genetic mutations that affect the APC gene directly or indirectly have been identified:

Familial adenomatous polyposis (FAP) is a rare and serious disorder in which the patient inherits an adenomatous polyposis coli (APC) mutation from either parent. It occurs in about 1 in 8,000 people. During early adulthood, hundreds to thousands of polyps grow in the colon. FAP causes less than 1% of all cases of colorectal cancer, but if untreated, virtually everyone who inherits this condition develops cancer before the age of 40. Many of the deaths attributed to FAP can be prevented with early and aggressive surgical treatment.
Non-inherited mutations of the APC gene have been detected in nearly all patients with spontaneous colon cancers.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, accounts for at least half of colorectal cancers that run in families. (However, only 3% or less of all colorectal cancers are due to this problem). About 50 - 80% of people who inherit the abnormal gene will develop colon cancer. HNPCC tends to develop in the right side of the colon, often in young individuals. (Left-sided cancers can still occur as well.)

People who inherit HNPCC and other defects are prone to other cancers, including uterine and ovarian cancers, as well as cancers of the small intestine and kidney system (very rare). HNPCC is highly associated with genes containing an abnormality called microsatellite instability (MSI), which is a sign of defective DNA repair. Testing tumors for MSI in people with newly diagnosed colon cancer who also have a family history of the disease may prove to be an effective method for identifying patients with hereditary nonpolyposis colorectal cancer. Tests are being developed that can detect the actual HNPCC genetic abnormality (mutation) that was inherited from a father or mother. The two most commonly affected genes are MSH2 and MLH1.

Cyclooxygenases and Prostaglandins. Cyclooxygenase 1 and 2 (COX-1 and COX-2) are enzymes involved in the production of prostaglandins, substances produced by the body that cause inflammation, widen and narrow blood vessels, control muscle contractions, and inhibit hormones that regulate fat metabolism. COX-2, but not COX-1, appears to play a role in the development and spread of colorectal tumors. COX-2 increases the levels of prostaglandin E2 (PGE2), which, in turn, stimulates factors that inhibit apoptosis, the natural process whereby all cells, including cancerous ones, self-destruct. It also activates interleukin-6 (IL-6), a factor in the immune system that is associated with cancer cell invasion.

C-Reactive Protein (CRP). CRP is another indicator of inflammation. In a 2004 study published in the Journal of the American Medical Association, elevated CRP levels predicted the development of colon -- but not rectal -- cancer.

Bile Acid Salts. Deoxycholic acid, which is found in the fat-digesting bile salts released by the gallbladder, appears to have carcinogenic properties. Its effects are now believed to play a role in some cases of colon cancer. Levels of the acid can rise as a result of high-fat diets or certain diseases.

Growth Factors. Chronically higher circulating levels of growth factors, including insulin-like growth factor, have been associated with colorectal cancer.

Inflammatory bowel diseases include Crohn's disease and ulcerative colitis. These chronic disorders cause persistent injuries in the intestinal tract that can, in some cases, produce cancerous changes.

Symptoms

It is possible to have colon or rectal cancer without symptoms. Many patients are free of symptoms until their tumors are quite advanced.

Weight loss and changes in bowel movements are general symptoms for colon cancer, but these symptoms also occur in many other diseases.

Blood in the stools is a common sign of many intestinal cancers. It may appear red if it is fresh or black if it is old. It should be reported to a doctor immediately, even though it is often caused by conditions other than cancer, including:

Hemorrhoids
Minor tears around the rectal or anal areas
Diverticulosis

In addition, stool can change color by:

Eating certain red foods, such as beets or red licorice (red)
Taking iron supplements and medications that have bismuth subsalicylate, most commonly Pepto-Bismol (black)

Nevertheless, blood in the stools is an abnormal finding that should never be ignored. Always report it to your doctor for further advice.

Symptoms of colorectal cancer vary widely depending on the location of the cancer within the large intestine.

Tumors in the Cecum and Ascending Colon (Right Colon). The waste matter in the first portion of the colon is in liquid or semi-liquid form. Tumors that develop here do not change bowel habits or stool formation, but they may cause intermittent or chronic bleeding. Although the stools look normal, patients may develop symptoms of anemia from iron deficiency. Such symptoms include weakness, fatigue, heart palpitations, shortness of breath, and exercise intolerance.

Tumors in the Transverse Colon. As waste material passes across the upper quadrants of the abdomen (the transverse colon), the intestine absorbs water, and the waste matter becomes more solid. In addition to bleeding, tumors here may cause cramps, gas, partial or complete obstruction, and even perforation of the bowel. Anemia can also occur.

Tumors in the Descending Colon and Rectum (Left Colon). When tumors partially block the lower intestine, thin, pencil-shaped stools may form. Bowel habits can change. Tumors in the rectum and lowest part of the intestine can cause pain and a feeling of fullness. Defecation may be painful, or patients may feel the urge to defecate but nothing happens. Bleeding from these locations may be brisk and bright red or maroon, but cancer is often detected before symptoms of chronic anemia develop.

Risk Factors

Colorectal cancer is the third most common cancer in the U.S., with Americans facing a lifetime chance of 5.5 - 6% for this cancer. In 2007, colorectal cancer was expected to cause 153,760 new cases and 52,180 deaths in the United States. About 73% of cancers occur in the colon and 27% in the rectum.

The lifetime risk of cancer of the colon or rectum is 5.9% for men and 5.5% for women.

Colorectal cancer risk increases with age. More than 90% of these cancers occur in people over age 50. The rate of colorectal cancer in patients under 20 years is less than 1 in 100,000 per year. At age 50 about 1 in 2,000 people per year will develop colorectal cancer. After age 65, this rate increases to almost 3 in 1,000.

African-Americans have the highest risk of being diagnosed with, and dying from, colorectal cancer. Among Caucasians, Jews of Eastern European (Ashkenazi) descent have an elevated rate of colorectal cancer. Asian Americans/Pacific Islanders, Hispanics/Latinos, and American Indians/Alaska Natives have a lower risk than Caucasians.

About 20 - 25% of colorectal cancers occur among people with a family history of the disease. (Seventy-five percent of cases are due to other causes.) People who have more than one first-degree relative (sibling or parent) with the disease are especially at high risk. The risk is even higher if the relative was diagnosed with colorectal cancer before the age of 60.

About 5 - 10% of patients with colorectal cancer have an inherited genetic abnormality that causes the disease. Genetic mutations associated with colorectal cancer include familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer.

The risks for colon cancer are far higher in industrialized nations than less developed countries. A Western lifestyle, being sedentary, smoking, and having excess weight have all been associated with increased risk for colorectal cancer. (However, about 75% of cases occur without a known predisposing factor.)

Dietary Factors. Eating a lot of red meat increases the risk for colorectal cancer. Other types of animal protein (low-fat dairy products, fish, poultry) may decrease the risk of developing polyps and colorectal cancer. Studies on fruits, vegetables, and fiber are mixed. Some evidence suggests that diets very low in fruits and vegetables may increase the risk. In any case, eating a variety of fruits and vegetables should be part of a healthy diet.

A 2007 study in the Journal of the American Medical Association suggested that diet may play a role in colorectal cancer recurrence, as well as prevention. The study evaluated patients with stage III colon cancer who had been treated with surgery and chemotherapy. Patients who ate diets high in red and processed meats, refined grains, and sweets had a higher risk of cancer recurrence and poorer survival than patients whose diets were high in fruits and vegetables, poultry, and fish.

Alcohol and Smoking. Alcohol use and smoking increase the risk for colorectal cancer. Patients who smoke and drink may also be diagnosed with colorectal cancer at a younger age than non-drinkers and non-smokers. Several studies suggest that women who smoke are at especially high risk of developing colorectal cancer.

Obesity. There is a demonstrated link between body mass and colon cancer risk for both men and women. The Centers for Disease Control and Prevention has reported that the risk of colon cancer rises as body mass index increases. Obesity has been associated biologically with higher circulating levels of insulin and a hormone called insulin-like growth factor. Chronically high levels of these substances may increase colorectal cancer risk.

Physical Inactivity. More than 50 studies from around the world suggest that physical activity helps prevent colon cancer. In contrast, exercise does not protect against rectal cancer.

Crohn's disease and ulcerative colitis are chronic afflictions of the large intestine known as inflammatory bowel diseases (IBD). Both have been linked to increased risk for colorectal cancer. (Patients with ulcerative colitis have a higher risk than those with Crohn's disease.) Family histories are helpful in determining risk associated with inflammatory bowel disease. Some studies suggest the following:

Patients with IBD who have a family history of colorectal cancer face up to a five-fold risk of colon cancer themselves.
Individuals without IBD who have relatives who suffered from both IBD and colorectal cancer may face a higher risk for developing colorectal cancer themselves.
Individuals without IBD but with a family history of IBD and no colon cancer most likely face no higher risk for cancer themselves.

Crohn's disease, also called regional enteritis, is a chronic inflammation of the intestines that is usually confined to the terminal portion of the small intestine, the ileum. Ulcerative colitis is a similar inflammation of the colon, or large intestine. These and other inflammatory bowel diseases have been linked with an increased risk of colorectal cancer.

Polyps. Polyps are tissue growths, usually benign, that develop in the color or rectum, most often in patients over 50 years of age. When pathologists examine polyps removed from the colon, they classify them as either hyperplastic or adenomatous. Both types are benign, but some adenomas will become malignant. As a preventive measure, polyps should be removed (polypectomy).

Ureterosigmoidostomy. People who have had ureterosigmoidostomy, a surgical procedure to correct a birth defect in the bladder or to treat some bladder cancers, may develop tumors near the site of the defect, which is chronically exposed to urine and feces. Such patients have a 5 - 10% chance of developing colon cancer 15 - 30 years after the operation.

Diabetes. Many studies have identified an association between type 2 diabetes and colon cancer. Both diseases share common risk factors of obesity and physical inactivity, but diabetes itself is a risk factor for colorectal cancer. Both men and women who have diabetes are at risk.

Heart Disease. Coronary artery disease (CAD) increases the risk for colorectal cancer. Both CAD and colorectal cancer share important risk factors, including smoking, high fat diet, sedentary lifestyle, and obesity.

Dietary Factors

Some, but not all, studies have suggested that a high intake of fruits and vegetables can lower the risk for colorectal cancer. One study, for example, reported that these foods do not prevent polyps from forming but may help prevent them from becoming cancerous.

Phytochemicals. Many studies have demonstrated the cancer-fighting effects of plant chemicals called phytochemicals. Fruits and vegetables that contain phytochemicals can often be identified by colors:

Dark green (broccoli, spinach, kale, collard greens, mustard greens). These vegetables contain chemicals called isothiocyanates, which have been associated with a lower risk for cancer in general.
Red (red pepper, tomatoes, watermelon, raspberries, pink grapefruit). Lycopene is a chemical found in these foods that may have strong cancer-protective properties. Cooking tomatoes appears to increase their benefits.
Yellow-orange (carrots, pumpkin, sweet potatoes, oranges, tangerines). The colors in these foods are due to carotenoids. Carotenoids have been associated with health protection, although they may not have much effect on colon cancer itself.
Blue-black (many berries). Dark berries appear to have potent antioxidant chemicals that may be protective against cancer.

Organosulfurs are important food chemicals that are part of the allium family. Studies have reported health benefits from foods containing them. These compounds are found in garlic, leeks, onions, chives, scallions, and shallots. A review of 300 studies concluded that people who eat raw or cooked garlic regularly experience about two-thirds the risk of colorectal cancer as people who eat little or none. Another analysis, however, found the available evidence about garlic to be inconclusive. Garlic supplements, in any case, do not appear to be protective.

Fiber. Studies have been mixed on whether fiber (found in fruits, vegetables, and whole grains) protects the colon from cancer. For example, three major studies in 2002 and 2003 reported no difference in the development of colorectal polyps or cancer recurrence with high intake of fiber. On the other hand, results of the 2003 European Prospective Investigation into Cancer and Nutrition (EPIC) -- the largest study ever conducted on the role of diet in the development of cancer -- suggested that fiber is protective regardless of its source. However, in the study, the greatest benefits were observed for the left side of the colon and the least for the rectum. In any case, fiber, which is only found in plant products, may be beneficial for the heart and have other health advantages.

The role of fats in inflammatory bowel disease is complex and not fully known. A 2006 study from the Women’s Health Initiative found that a low-fat diet did not help reduce the risk for colorectal cancer. However, the study did not distinguish between types of fat.

Monounsaturated fats (olive, peanut, canola oils; avocados, nuts) and omega-3 polyunsaturated fats (fish, flaxseed oil, walnuts) are the healthiest types of fats.
Saturated fats (red meat, butter, high-fat dairy products) and trans-fats (hydrogenated fat found in snack foods, fried foods, commercial baked goods) are unhealthy types of fats.

Dietary guidelines recommend that adults limit the total fat in their diet to 25 - 35% of total daily calories. Saturated fat intake should be less than 7%, and trans fats less than 1%, of total daily calories. (Patients with heart disease or diabetes may need to limit unhealthy fat in their diet even further.) Most fats should come from polyunsaturated and monounsaturated fat sources.

[See In-Depth Report #43: Heart healthy diet; and #42: Diabetes diet.]

Evidence strongly suggests that red meat raises the risk for colon cancer development, and perhaps also recurrence. Red meat contains dietary iron, which has been associated with a higher risk for colon cancer.

High-temperature cooking (grilling, broiling, or pan-frying) has been specifically associated with increased risk for colon polyps and colon cancer. Overcooking meat increases the amount of carcinogens called heterocyclic amines, which has been associated with cancerous changes.

Milk, Lactose, and Probiotics. In one study, adults who drank the most milk had the lowest risk for colon cancer. A 2004 study published in the Journal of the National Cancer Institute supported this conclusion. In this review of 10 epidemiologic studies that included more than 500,000 people, those who consumed more milk and calcium had a lower risk of developing colorectal cancer. Milk contains not only calcium but also other compounds, such as lactose, that may help protect against colon cancer.

Yogurt specifically has been associated with a lower risk for colon cancer if it contains live active bacterial cultures, such as Lactobacillus acidophilus, that are called probiotics. These "friendly bacteria" appear to protect the colon from cancerous changes. (Acidophilus and other probiotic capsules are also available in health food stores.)

Calcium. Calcium, which is found in dairy products, is associated with colon cancer protection. Many studies have shown a possible protective effect from either high-calcium diets or calcium supplements. However, a 2006 study from the Women’s Health Initiative found that calcium and vitamin D supplements do not reduce women’s colorectal cancer risk. Many doctors still recommend that postmenopausal women take these supplements for bone health.

Obesity has been associated with colon cancer. In some studies of people under 67 years old, the amounts of fat and protein were less important than the total number of calories consumed: the higher the energy intake, the greater the risk for developing colon cancer. In older adults, high calorie intake did not make any significant difference. Other studies have indicated that eating too much sugar may increase the risk for colon cancer.

Studies conducted in several countries have found that drinking four or more cups of coffee a day is associated with a lower risk for colorectal cancer. Green tea may have also beneficial properties, but more research is needed in both of these areas.

Folate and B Vitamins. For years, many doctors have believed that the B vitamin folate (called folic acid) may help protect against colorectal cancer, particularly for people who are genetically predisposed to this disease. Folate is found in beans, citrus fruits, and green vegetables, but some studies have indicated that the greatest protective benefits come from taking supplements.

However, an important study published in 2007 in the Journal of the American Medical Association challenged this assumption. The study suggested that high-dose folic acid supplements do not prevent colorectal cancer, and may actually increase the risk for developing certain types of colorectal tumors. The study evaluated over 1,000 men and women who had a recent history of non-cancerous colorectal polyps. (Adenomatous polyps, also called colorectal ademomas, are the most common type of polyp found in colorectal cancer screenings.) The results indicated that patients who took 1 mg/day of folic acid supplements were more likely to develop new adenomatous polyps than patients who did not take supplements. Patients in the folic acid supplement group were also more likely to have advanced adenomas and more numerous adenomas.

Adenomatous polyps are benign tumors, but they can potentially develop into cancerous tumors. Researchers are continuing to investigate the role that folic acid plays in colorectal cancer risk and prevention. It is possible that folic acid may help prevent the initial appearance of adenomatous polyps, but increase the risk for additional polyp formation once they have begun to occur.

Antioxidant Supplements. Antioxidants are chemicals that help eliminate harmful particles called oxygen-free radicals that have been associated with cancerous changes. Some studies have associated supplements of the antioxidants selenium and vitamins A, C, D, and E with lower colon cancer risk, but most studies have found no protective effect.

Prevention

Studies indicate that daily exercise is one of the best ways to reduce the risk of colorectal cancer. The more vigorous the activity, the greater the benefit, but even moderate exercise (walking, stair-climbing) can help reduce colorectal cancer risk. The American Cancer Society (ACS) recommends that people engage in at least moderate exercise for 30 minutes or more at least 5 days a week. The ACS also notes that 45 minutes or more of moderate-to-vigorous activity at least 5 days a week may help further reduce cancer risk.

Some studies also suggest that regular exercise may be beneficial for patients who have been diagnosed with colorectal cancer. Two 2006 studies indicated that exercise may reduce the risk of colorectal cancer recurrence and death for patients with stage I - III cancer.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are very common pain relievers that are available over-the-counter and by prescription. They include aspirin, ibuprofen (Motrin), naproxen (Aleve), and the COX-2 inhibitor celecoxib (Celebrex). Several studies have reported that NSAIDs help reduce the risk of colorectal cancer. However, regular use of NSAIDs, even in low doses, can increase the risk of gastrointestinal bleeding and stomach ulcers. Long-term use of NSAIDs can also increase the risk for heart attack and stroke, especially in people who have a history of heart disease. Several 2006 and 2007 studies in the New England Journal of Medicine reported that celecoxib prevented precancerous polyps, but the drug more than doubled patients’ risk for heart attack and other cardiovascular events.

A 2005 Nurse’s Health Study found that aspirin, but not other NSAIDs, does provide protection against colorectal cancer. However, the risk was only reduced for women who took 2 aspirin a day for more than 10 years. In addition, this dose level greatly increases the risk for gastrointestinal bleeding. Furthermore, a 2007 study in the New England Journal of Medicine suggested that aspirin’s protective effects may only apply to some types of colorectal cancer tumors. Another 2007 study, published in the Lancet, indicated that long-term daily use of aspirin can protect against polyps and colorectal cancer, but experts agree that aspirin’s risks do not outweigh its benefits for most people. (Some people who are at high risk for developing colorectal cancer may benefit from aspirin therapy.)

In March 2007, the U.S. Preventive Services Task Force (USPSTF) recommended against the routine use of aspirin and other NSAIDs to prevent colorectal cancer in people at average risk for this disease. (This recommendation does not apply to people who have a family history of colorectal cancer or who are at high risk for developing colorectal cancer due to other risk factors.) Long-term use of NSAIDs can increase the risk for gastrointestinal bleeding, kidney function problems, and heart problems. Aspirin can also increase the risk for hemorrhagic stroke. Due to these risks, the American Cancer Society and other professional associations also recommend against the use of NSAIDs or other types of medications for colorectal cancer prevention.

Medications containing 5-aminosalicylate (5-ASA) are sometimes given to patients with ulcerative colitis to help control inflammation. These drugs, which include sulfasalazine and mesalamine, are chemically related to aspirin. A 2005 review of clinical trials found that patients with ulcerative colitis who used 5-ASA were 49% less likely to develop colorectal cancer than patients who did not use these drugs

Some studies have suggested that cholesterol-lowering statin drugs may help reduce colorectal cancer risk. A 2006 study in the Journal of the National Cancer Institute did not find any protective benefit for statins.

Estrogen has been associated with a lower risk for colon cancer, perhaps because of specific enzymes that prevent cell proliferation. Drugs containing estrogen, then, may help high-risk women:

There is some evidence that hormone replacement therapy (HRT) reduces the risk of colon cancer in postmenopausal women. It carries other risks, however, including a higher risk for breast and uterine cancer and blood clots. A 2004 New England Journal of Medicine study found that while short-term use of estrogen plus progestin reduced the risk of developing colon cancer, combination HRT users who were diagnosed with the disease had more advanced forms of the cancer. Older women who are at higher risk for colon cancer might discuss risks and benefits of HRT with their doctor.
Oral contraceptives may reduce younger women's risk of colon cancer. Duration of use does not seem to be associated with decreased risk, but protection appears stronger for women who have more recently used oral contraceptives.

Diagnosis

Colon and rectal cancers are diagnosed using the screening tests discussed below. These tests can detect precancerous polyps and colorectal cancers at stages early enough for complete removal and cure.

Unfortunately, only 30 - 40% of adults over 50 years old (mostly in the upper socioeconomic group) have regular screening tests that could detect a cancer early enough for curative treatment. A survey reported that many people are not screened because they are too embarrassed. Those who had already had the tests were willing to have them again if they saved one additional day of their lives.

There is some debate about what is the best screening method. Current screening guidelines offer several different options for patients. Doctors agree that not enough people are screened and that these tests, if adopted with the same regularity as such screening tests as Pap smears, would save many lives. It is especially important for anyone at increased risk or with symptoms, such as rectal bleeding or ulcerative colitis, to have testing at an earlier age.

There is also debate about when people should stop being screened. A 2006 study in the Journal of the American Medical Association indicated that screening provides little benefit for elderly people, especially because colorectal cancers grow very slowly. The researchers suggest that doctors should carefully consider the risks versus benefits of screening patients age 80 and older.

Individuals should discuss with their doctors the risks and benefits of all screening procedures. Some controversy exists over how often people without risk factors for cancer should be screened and which detection method should be used for them.

Guidelines for Adults Age 50 and Over with Average Risk. The following are the five screening options recommended for people age 50 and over who have no symptoms and no family history of colon cancer:

Fecal occult blood test (FOBT) or fecal immunochemical test (FIT) every year
Flexible sigmoidoscopy every 5 years
FOBT or FIT every year plus sigmoidoscopy every 5 years
Double-contrast barium enema every 5 years
Colonoscopy every 10 years

Choosing between Colonoscopy and Sigmoidoscopy. The choice between colonoscopy and sigmoidoscopy for routine screening for older adults with average risk is an area of intense debate. The issues are as follows:

Sigmoidoscopy is less costly, less invasive, quicker, and safer than colonoscopy. Although it allows inspection of only the left side of the colon, any abnormal findings from sigmoidoscopy trigger a full colonoscopy. Therefore, experts estimate that sigmoidoscopy can detect 80% of all significant problems.
Colonoscopy is more sensitive than any other current screening method for detecting colon cancer. It can find 75 - 90% of colorectal cancers. If the goal were to reduce the number of cancer cases, regardless of cost, colonoscopy would be the preferred approach. Colonoscopy, however, is more expensive than sigmoidoscopy and has a slightly higher risk for complications (bowel tears or bleeding when a polyp is removed).

There are 3 basic tests for colon cancer: a stool test (to check for blood), sigmoidoscopy (inspection of the lower colon), and colonoscopy (inspection of the entire colon). All 3 are effective in catching cancers in the early stages, when treatment is most beneficial.

Screening, particularly with colonoscopy, in increased- and high-risk populations can save lives. The most important risk factors are a family history of colorectal cancer and personal history of colorectal cancer, polyps, or chronic inflammatory bowel disease. People with these risk factors should be screened before age 50 and may need more frequent screenings.

Guidelines for Increased-Risk Groups. Anyone with first-degree relatives diagnosed with colon cancer younger than 60, or with two relatives who have been diagnosed with colon cancer at any age, should consider beginning the standard screening regimen with a colonoscopy every 5 years, beginning at age 40 or 10 years before the youngest case in the family (whichever is earlier).

Men of African descent are also considered to be at increased risk for colon cancer and should discuss similar screening guidelines with their doctors.

Guidelines for High-Risk Groups. The following guidelines may be useful for specific high-risk groups.

People who have the mutated hereditary nonpolyposis colorectal cancer gene (MSH2 or MLH-). Frequent colonoscopy (for instance, every 1 - 2 years) beginning in their early 20s. (Regular screening for other cancers, such as uterine cancer, is also reasonable.)
People who have the mutated familial adenomatous polyposis (FAP) gene. Frequent screening with endoscopy (flexible sigmoidoscopy or colonoscopy) beginning in early puberty. Genetic testing is now recommended for family members of people with known FAP.
People with predisposing intestinal problems, such as widespread and active ulcerative colitis or Crohn's disease. Annual screening with colonoscopy with biopsies of suspicious areas.

Guidelines for Follow-Up After Detection of Precancerous Polyps. Patients who have had a previous examination in which polyps were detected (and removed) should have a repeat colonoscopy 1 - 3 years later, depending on the size, number, and type of polyps removed.

The digital rectal examination is used to detect tumors in the rectum, lower intestine, and prostate gland. The doctor inserts a lubricated-gloved finger into the patient's rectum and feels for lumps or other abnormalities. The exam is quick and painless but embarrassing for some. Fewer than 10% of colon cancers develop within the region that can be evaluated by a DRE, so it is not useful as a sole screening test.

Blood in bowel movements is not always visible, in which case it is called occult (hidden) blood. Fecal occult blood tests (FOBTs) are used to detect this hidden blood. The most common FOBT method is called the guaiac-based test. The patient is asked to supply up to six stool specimens in a specially prepared package. A small quantity of feces is smeared on specially treated paper, which reacts to hydrogen peroxide. If blood is present, the paper turns blue.

Accuracy. FOBTs can miss more than 75% of advanced cancers. Nevertheless, large studies have indicated that this simple test, performed annually, saves lives and may reduce the risk of dying from colon cancer by 15 - 33%. The following factors may affect its accuracy:

The levels of iron in the blood can affect results. Patients should not take iron supplements or eat red meats several days before the test.
Certain raw fruits and vegetables that contain the chemical peroxidase (cauliflower, horseradish, radishes, melons, and turnips) can cause a positive test reaction even if no blood is present.
Aspirin and NSAIDs are anticoagulants that can cause minor bleeding. They should not be taken for a week before the test. However, a 2005 study suggested that the prescription anticoagulant warfarin does not affect FOBT results.
Vitamin C and foods rich in this vitamin may cause a false negative reaction and should be avoided a few days before the test.
Bleeding from other causes, such as menstruation, hemorrhoids, gingivitis, or urinary infections, can produce blood in the stools and affect results.

Even if none of these conditions is present, a test that shows hidden blood does not necessarily mean that cancer is present. About 20 - 30% of people with occult blood have noncancerous polyps or other conditions, such as gastritis, and only 5 - 10% actually have cancer. Any abnormal result, however, requires further testing, such as colonoscopy.

Lack of Compliance. Compliance is a major problem. Patients are asked to perform the tests at home and send the test cards to the laboratory. Only 35 - 50% of patients actually follow through. Occult-blood tests that give results at home are available but are extremely inaccurate. In one large study, these tests failed to detect advanced cancer in about 62% of cases, although they may detect some early cancers.

If a digital rectal exam (DRE) or fecal occult blood test (FOBT) shows signs of trouble, several methods to visualize the colon are available. They include colonoscopy, sigmoidoscopy, and double-contrast barium enema. They have the following similarities and differences:

Sigmoidoscopy can only view the rectum and the left side of the colon, while colonoscopy and barium enemas allow a view of the entire large intestine.
Both flexible sigmoidoscopy and colonoscopy involve snaking a fiber optic tube through regions of the rectum and colon to view the walls of the intestine. The tube contains a tiny camera that transmits the image to a video screen. The use of an ultrasound (sound wave) scanner is proving to enhance viewing quality. Barium enemas simply use x-rays.
During either sigmoidoscopy or colonoscopy, the doctor is able to remove polyps or other abnormalities revealed by these procedures with surgical instruments inserted through the tube. It is not possible to remove polyps with a barium enema, which is not invasive.

Sigmoidoscopy. Sigmoidoscopy examines the rectum and the lower two feet of the colon. It cannot, however, detect the roughly half of cancers that occur in the right colon. Right-sided cancers are more common in older people.

The procedure uses a flexible fiber optic tube (it is thus referred to as flexible sigmoidoscopy) that contains a tiny camera and surgical instruments.
It lasts about 10 minutes and may be mildly uncomfortable, but it is not painful and is generally very safe. In one study, 70% of patients reported that the procedure was far less unpleasant than they had expected.

This procedure has been found to reduce the risk of fatal cancers in the rectal and sigmoid area by 60%. If polyps are detected, a colonoscopy is then used.

Colonoscopy. Colonoscopy is the most accurate testing method and can reduce cancer incidence by up to 90%. It is clearly indicated for anyone with an increased risk for colorectal cancer, including those with a personal or family history of the disease. As with sigmoidoscopy, a colonoscopy uses a flexible tube, but it is snaked through the entire large intestine.

For about a day before the procedure the patient eats nothing and drinks a laxative solution that cleans out the colon. The taste of the solution is unpleasant, although it has improved in recent years.
The procedure typically uses a sedative that produces a "twilight" sleep and often makes the procedure more comfortable than sigmoidoscopy.
Air may be introduced into the intestine to widen it and allow the tube to navigate curves. A colonoscopy avoids the risk of radiation associated with a barium enema, but it is important to note that even a colonoscopy does not detect all cancers.

Complications are rare, but include the following:

Hyponatremia. Hyponatremia is a low concentration of sodium in the blood. The complication may be caused by the effects of bowel cleaning before the procedure that can result in water retention and reductions in sodium. When severe, it can cause temporary neurological symptoms, such as confusion, lethargy, unsteadiness, and slurred speech. Researchers suggest that sodium concentrations be measured in patients who develop such symptoms after colonoscopy.
Bowel perforation (very low risk, about 2 in 1,000 procedures). The risk for bowel perforation is greater with colonoscopy than flexible sigmoidoscopy.
Bleeding at the site of biopsy or polyp removal.

Overall, colonoscopy is a safe procedure. However, according to a 2006 study in the Annals of Internal Medicine, serious complications occur in about 5 of every 1,000 colonoscopies. Most of these complications occurred when a biopsy or polyp removal was performed. (The risk for complications without biopsy or polyp removal is about 1 in every 1,000 colonoscopies.) This study looked at colonoscopies in general, including those that are done to diagnose the causes of a patient's symptoms. The risk may be lower for colonoscopies performed solely to screen for colorectal cancer.

Barium Enema. The double-contrast barium enema, which uses an x-ray image, is the less expensive alternative for viewing the entire colon. It is not as accurate as colonoscopy, and if any polyps or abnormalities are revealed on x-ray, a colonoscopy is then required to remove suspicious tissue, so it is now recommended much less often than in the past.

The barium enema is a valuable diagnostic tool that helps detect abnormalities in the large intestine (colon). The barium enema, along with colonoscopy, remains the standard in the diagnosis of colon cancer, ulcerative colitis, and other diseases of the colon.

Screening for familial adenomatous polyposis. Genetic screening for familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC) is now available and may be recommended for high-risk patients. The test for FAP detects a mutation in the adenomatous polyposis coli in up to 90% of people who carry it. Testing for HNPCC mutation is somewhat more complex.

Screening for insulin-like growth factor. A gene that regulates insulin-like growth factor (IGF-2) is functional during fetal development and then becomes inactive. Some evidence now suggests that people who have IGF-2 in adulthood have a higher risk for colon cancer. Blood tests for detecting IGF-2, then, may be helpful in identifying patients who should have more intensive screening. Currently, however, this is only used as a research tool.

Stool DNA Testing. A promising technique for colorectal cancer screening is the detection of altered DNA in cancer cells that have shed from the colon and are excreted in the stool. Such tests may prove to detect both inherited and noninherited genetic mutations. This may become a widely used tool in the future. However, larger clinical studies are needed.

Virtual Colonoscopy. A promising experimental technique called virtual colonoscopy allows three-dimensional imaging of the colon without using invasive instruments. As with standard colonoscopy, the patient takes a laxative first to clear out the intestine. The procedure itself involves pumping air into the colon and scanning the intestine using computed tomography (CT). It is very safe and takes about only 10 minutes. The procedure is similar in accuracy to conventional colonoscopy for detection of larger polyps (6 mm or more in diameter) and is also potentially less expensive. Colonoscopy is required, however, if suspicious areas are found, which may occur frequently with the CT procedure, since it erroneously identifies a high number of nonexistent polyps.

A study published in April 2004 in the Journal of the American Medical Association compared results of standard colonoscopy versus virtual colonoscopy in over 600 patients at nine major medical centers. Virtual colonoscopy had much lower rates of successfully finding polyps than standard colonoscopy. Virtual colonoscopy detected polyps of at least 6 mm in 39% of patients and polyps of at least 10 mm in 55% of patients. By contrast, standard colonoscopy detected 99% of polyps of at least 6 mm, and 100% of polyps of at least 10 mm. In addition, accuracy rates varied widely among the different hospitals. The authors advised that until more improvement in training and technique is achieved, virtual colonoscopy "is not yet ready for widespread clinical application."

Magnetic Resonance Colonography. Magnetic resonance colonography (MRC) is another non-invasive technique for visualizing the colon. The patient receives an enema containing a contrast substance, and then magnetic resonance images are taken. MRC is fast, comfortable, and less invasive than colonoscopy. Currently, however, there is a poor detection rate for flat tumors and for polyp tumors less than 10 mm in diameter.

Staging

A diagnosis of cancer will lead to staging and other tests to help determine the outlook and the appropriate treatments.

The large intestine is a long hollow organ lined with mucous membrane (mucosa). Muscle layers wrap around the entire length and help move food material through to the rectum.

Unlike many other cancers, the size of the tumor is not a major factor in determining the outcome of colorectal cancer. Of greater importance is how far the cancer has spread. To determine this, doctors will assign a stage to the tumor. There are several methods for staging. The older system, known as Dukes', categorizes four basic stages: A, B, C, and D. A more recent system refers to these stages as I, II, III, and IV but divides the categories slightly differently. The term "5-year survival" means that patients have lived at least 5 years since diagnosis. Most patients who live 5 years without a recurrence are considered to be cured of their disease.


Stage	Condition	5-Year Survival
A or I	Tumor superficially involves the inner lining of the intestine.	More than 90%
B or II	Tumor has penetrated through the muscle wall of the intestine but has not reached the lymph nodes.	70 - 85%
C or III	Lymph nodes are involved.	65% or below
D or IV	Tumor has spread to other organs (metastasized), usually the liver first.	5 - 9%

Click the icon to see an image of the stages of cancer.

Researchers are continually seeking to identify tumor markers, substances (usually found in blood samples) that will assist in the diagnosis of cancer and in monitoring effects of treatment.

Carcinoembryonic Antigen. High blood levels of a protein called carcinoembryonic antigen (CEA) sometimes indicate the presence of colon cancer. Unfortunately, it is also elevated in other cancers and in some noncancerous conditions. CEA is not effective as a screening tool for healthy people, but might eventually be helpful for patients with cancer.

An advanced diagnostic technique called polymerase chain reaction (PCR) can detect genetic evidence of CEA. One study indicated that when these microscopic footprints of colon cancer are detected in the lymph nodes of patients with Stage II cancer (whose lymph nodes otherwise appear to be not involved with cancer), the outlook is similar to that of patients with Stage III cancer. Patients without this so-called micrometastasis have a very favorable prognosis. Further research is needed, however, before PCR can be used in widespread practice.
In patients with a history of, or active, colon cancer, follow-up measuring of blood CEA levels may be helpful in detecting recurrence of the cancer and effectiveness of treatments.

Defective P53 Gene. The presence of a defective p53 gene is a marker for very poor prognosis in patients with advanced colon cancer. In its normal state, the gene is important for regulation of cell growth. Testing for this abnormality, however, is not widely done because it is not clear how to use this information.

Other Tumor Markers. Other tumor markers under investigation include a protein called GLUT1, cancer antigen 19-9 (CA 19-9), matrix metalloproteinase-9 (MMP-9) RNA, HER-2/neu oncoprotein, transforming growth factor beta-1 (TGF-beta-1), and CD44.

Click the icon to see an image of drawing blood for culture.

A technique known as a sentinel node biopsy is increasingly performed by experienced surgeons in selected patients. This procedure is used to determine if cancer has spread beyond the nodes, possibly reducing the need for complete axillary lymphadenectomies. It involves the following:

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 via the lymphatic system into the so-called 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 remainder of the lymph nodes will be cancer free, and further surgery becomes unnecessary.

It is still not known if the sentinel node biopsy has any survival advantages compared to the standard procedures with lymph nodes removal. However, one study indicated that careful and complete removal of potentially cancerous lymph nodes is still very important for improving survival in patients with Stage II and III colorectal cancer.

Whole-body imaging scans that combine positron emission tomography (PET) and computed tomography (CT) may be helpful in accurately staging colorectal cancer, according to preliminary research published in 2006 in the Journal of the American Medical Association.

Prognosis

Survival rates for colorectal cancer have been rising in recent years. The 5-year survival rate is as high as 90% for cancer that has not spread to the lymph nodes (localized cancer). When cancer has spread to lymph nodes and other parts of the body, survival rates drop to 65% and below. Because many cancers are detected at later stages, the overall survival rate is currently about 60%. African-Americans and other minorities tend to have lower survival rates than Caucasians. Studies suggest, however, these higher mortality rates are largely due to less access to optimal health care, including appropriate surgical care and aggressive treatments.

In most cases, age is not a factor in treatment success. Good survival rates are achieved in the elderly as well as in young people. Chances for survival are less in Stage II cancers if the intestine is obstructed or perforated. If cancer has spread to lymph nodes (Stage III), the outlook is better if three or fewer lymph nodes are involved. Treatment can prolong life even when cancer has spread.

Surgery

Surgical removal of the tumor ("resection") along with any affected surrounding tissue is the standard initial treatment for potentially curable colorectal cancers (cancers that have not spread beyond the colon or lymph nodes). Drug and radiation therapy are often used for advanced cancers and are continuously being tested with surgery in different combinations and sequences.

Although choosing a qualified surgeon is critical, choosing a hospital experienced in procedures is also important. The more often colon cancer surgery is performed at a given hospital, the lower the mortality rate at that hospital is likely to be.

Unless cancer is very advanced, most tumors are removed by an operation known as colectomy:

Colectomy involves removing the cancerous part of the colon and nearby lymph nodes.
The surgeon then reconnects the intestine.
If the surgeon cannot reconnect the intestine, usually because of infection or obstruction, the surgeon will perform a colostomy. The need for colostomies is higher after surgery for rectal cancer. In most cases of colon cancer, colostomies are not needed. [See "Colostomy" below.]

Click the icon to see an illustrated series detailing colon cancer treatment.

The Surgical Approach. The standard technique for a colectomy is open, invasive surgery. Laparoscopy, sometimes called “keyhole surgery,” is a less invasive method. Laparoscopy is still considered an investigational technique for treating colon cancer, but it is gaining more acceptance and showing good results in clinical trials.

Open Surgery:

Open surgery uses a wide incision to open the patient's abdomen. The surgeon then performs the procedures with standard surgical instruments. This is the usual method for performing colectomy.

Laparoscopy:

Laparoscopy uses a few small incisions through which the surgeon passes a fiber optic tube (laparoscope) containing a small camera or tiny instruments. It is generally used for early colon cancer (for tumors less than 2 centimeters or for well-defined tumors less than 3 centimeters).
A 2004 New England Journal of Medicine study found that patients who received laparoscopic colectomy had similar rates of surgical complications, cancer recurrence, and survival as those who received traditional open surgery. However, the patients who had laparoscopy recovered faster and did not need as many narcotic painkillers.
Several 2005 studies indicated that laparoscopy works as well as conventional surgery for treatment of colon cancer. However, laparoscopy does not appear to be as effective for rectal cancer.

Click the icon to see an image detailing pelvic laparoscopy.

Click the icon to see an illustrated series detailing a resection of the large intestine.

Other Investigational Measures. Researchers are testing expandable metal tube-like devices called stents to keep the intestine open. Stents may be used before a procedure to allow bowel cleansing or for long-term use to keep open colons that can't be operated on.

A colostomy is performed in order to bypass or remove the lower colon and rectum. The procedure generally involves creating a passage, called a stoma, through the abdominal wall that is connected to the colon. The feces pass through this passage and are eliminated. Patients must learn how to care for the stoma and keep the area sanitary.

A colostomy usually will have one opening (single-barreled), or there may be two loops opening through the skin (double-barreled).

Usually the colostomy is temporary and can be reversed by a second operation after about 3 - 6 months. It the rectum and sphincter muscles in the rectum need to be removed, the colostomy is permanent. Permanent colostomies are more common when the cancerous regions are within 2 - 3 centimeters of the anus. Fortunately, surgical advances and knowledge of the extent of safe margins are reducing the need for permanent colostomies.

Click the icon to see an illustrated series detailing a colostomy procedure.

Managing Permanent Colostomies. In cases where the colostomy is permanent, the patient must wear a colostomy pouch, which sticks to the skin using a special glue. Pouches are available as one- or two-piece systems. The one-piece system is simpler, but the two piece system allows replacement of the pouch without removing the tape.

For best results, the pouch should be emptied when about one-third full. It should be replaced 1 - 2 times a week, depending on signs of leakage (itching or burning of the skin near the stoma). The pouches are odor proof.

Surgical treatments for cancer in the rectum are complex since they involve muscles and tissue that are critical for urinary and sexual function.

Local Excision or Polypectomy for Early Stages. In order to preserve the function of the anal sphincter and prevent the need for colostomy, Stage I and Stage II tumors may be removed by local excision, sometimes followed by chemotherapy and radiation. In this procedure, the tumor is cut out without removal of a major section of rectum. In some cases cancer recurs, but a second operation may be possible. Another treatment for early-stage rectal cancer, called electrocoagulation, destroys tumors using a high frequency electric current. It is being tested in clinical trials.

Radical Resection. In about a third of cases of rectal cancer, the cancer occurs in the lower part of the rectum, where between 70 - 80% of cancers have spread beyond the rectal wall. These patients need a radical resection, in which surrounding structures, including the sphincter muscles that control bowel movements, must often be removed.

The use of chemotherapy and radiation prior to surgery may prevent the need for permanent colostomy in some patients. This is an active area of clinical research, and trials are under way to address this issue. Another technique, called coloanal anastomosis, reconstructs the area to avoid the need for colostomy, and may be appropriate in some patients.

Total Mesorectal Excision. Total mesorectal excision (TME) involves dissection and removal of the entire cancerous area of the rectum along with surrounding fatty regions where the lymph nodes are located (the mesorectum). When successful, TME preserves the sphincter muscle, reducing the need for a permanent colostomy. Increasing use of this procedure is resulting in lower recurrence rates, lower levels of impotence and incontinence, and better overall survival rates compared to other resection techniques. Some experts now recommend it as a first choice for certain patients with locally advanced rectal cancer.

Combining chemotherapy and radiation either before or after TME is yielding promising long-term results and a low risk for local recurrence. There are many questions, however, and it is not clear which approach is better for specific patients.

Side effects of colon surgery include:

Sexual dysfunction. This is of particular concern. In general, colostomy does not usually affect sexual function. However, wide rectal surgery can cause short- or long-term sexual dysfunction. Sildenafil (Viagra) may help men who experience this after surgery.
Irregular bowel movements.
Gas and flatulence. Pouching filters are available to reduce gas. Certain foods produce more gas than others -- usually within 6 - 8 hours after ingestion for colostomy patients. They include beans, oat bran, most fruit, and certain vegetables (cabbage, cauliflower, Brussels sprouts, broccoli, and asparagus). To prevent swallowing air, patients should avoid sipping through straws, chewing gum, and chewing with their mouths open.
Diarrhea.
Bladder complications.
Sense of urinary urgency.
Fecal incontinence. Patients with rectal surgery have a higher risk for bowel dysfunction than those who had a colostomy.
Complications in or around the stoma. These can occur early after surgery to many years after the procedure. They include skin infection or breakdown, hernias, narrowing of the stoma, bleeding, and collapse.

There are no dietary restrictions, although many patients avoid foods that can produce gas. Everyone should drink plenty of fluids and get sufficient fiber.

The potential side effects of sexual and bowel dysfunction for colorectal surgical patients can be devastating, although many patients do very well and live normal productive lives. Positive emotions play a strong role in recovery. Patients who are depressed should discuss with a doctor all aspects of treatment that affect the quality of life, and consider seeking support groups.

Medications

Chemotherapy uses drugs that kill cancer cells throughout the body. There are two situations in which chemotherapy is used:

The adjuvant setting. Adjuvant refers to the use of chemotherapy after surgery in patients with Stage III tumors and selected patients with high-risk Stage II tumors (disease that is potentially curable). The goal of this therapy is to eliminate any cancer cells that surgery may have missed, thereby preventing recurrence and increasing the chance of cure. Patients of all ages, including the elderly, can benefit.
In metastatic disease. In patients with metastatic disease (where the cancer has spread to other parts of the body) the goal of chemotherapy is to shrink tumors, improve symptoms and quality of life, and lengthen life.

In the adjuvant setting, there are some differences in chemotherapy treatments between colon and rectal cancers:

Chemotherapy for Stage II is considered standard care for Stage II rectal cancer but is under debate for colon cancer.
Chemotherapy is standard for patients with Stage III colon cancer. Chemotherapy is also standard for patients with Stage III rectal cancer but is used in combination with radiation.

Chemotherapy for Stage II Colon Cancer. Adjuvant chemotherapy for Stage II colon cancer is controversial. Such patients tend to have a good outcome after surgery, and the positive effects of chemotherapy have been difficult to demonstrate. To date, the survival advantage of adjuvant chemotherapy in this group has been reported to be only in the range of 2%. However, better trials are still needed to confirm or refute the benefits in specific patient groups.

Although not yet known with certainty, some data suggest that certain patients with Stage II cancer may be at higher risk of recurrence and would theoretically benefit from adjuvant therapy. These include patients with cancers that have:

Obstructed the bowel
Perforated the wall of the colon
Adhered to structures outside the intestine

Advanced diagnostic techniques are under investigation for helping to select appropriate candidates for adjuvant therapy. None of these methods, however, are ready to be used routinely to help make treatment decisions. The decision whether to pursue chemotherapy for Stage II disease should be made after careful discussion between the patient and their oncologist, especially after features, such as bowel perforation or obstruction, are taken into account.

Chemotherapy for Stage III Colon Cancer. Since the early 1990s, adjuvant chemotherapy with 5-FU and leucovorin has been the standard of care for Stage III colon cancer. In recent years, the FOLFOX (5-FU, leucovorin, oxaliplatin) regimen has also been used for chemotherapy following surgery. Numerous trials have shown that adjuvant chemotherapy in this setting reduces the absolute risk of death from colon cancer by about one-third and improves survival by 10%. Clinical trials are also investigating combinations of other drugs.

Chemotherapy for Advanced Colorectal Cancer. Chemotherapy is either given directly into the arteries of the liver or intravenously (through a vein) with 5-FU and leucovorin. Oxaliplatin is sometimes added, but recent evidence suggests that the targeted therapy biologic drug bevacizumab may be a better addition. Other alternative chemotherapy choices are capecitabine, or irinotecan combined with cetuximab. Radiation therapy may be used in place of chemotherapy or in combination with it. Studies indicate that chemotherapy offers only a modest improvement in survival, but may help reduce symptoms.

Seven drugs are currently approved for colorectal cancer chemotherapy:

5-fluorouracil (5-FU, Adrucil), which is often given in combination with leucovorin (Wellcovorin). Leucovorin is a vitamin that helps boost the effectiveness of 5-FU.
Capecitabine (Xeloda)
Oxaliplatin (Eloxatin)
Irinotecan (Camptosar)
Bevacizumab (Avastin)
Cetuximab (Erbitux)
Panitumumab (Vectibix)

Capecitabine is a pill form of 5-FU. The other drugs are administered intravenously. Many of these drugs are given in combination with each other. Common chemotherapy combination regimens include:

5-FU / LV (5-FU and leucovorin)
FOLFOX (5-FU with leucovorin and oxaliplatin)
FOLFORI (5-FU with leucovorin and irinotecan)
IFL (Irinotecan, 5-FU, leucovorin)
XELOX (Capecitabine and oxaliplatin)

Side effects occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment. Because cancer cells grow and divide rapidly, anticancer drugs work by killing fast-growing cells. This means that healthy cells that multiply quickly can also be affected. The fast-growing normal cells most likely to be affected are blood cells forming in the bone marrow, and cells in the digestive tract, reproductive system, and hair follicles. Nausea and vomiting is a very common side effect, but drugs such as ondansetron (Zofran) can help provide relief. In general, side effects are nearly always temporary, and medications can help manage them. Most patients are able to continue with normal activities for all but perhaps 1 - 2 days a month.

5-Fluorouracil (5-FU) with Leucovorin. Adjuvant therapy using 5-fluorouracil, either alone or with leucovorin (5-FU/LV), is the standard treatment for patients with high-risk colon cancer (Stage III or select patients with Stage II tumors). Leucovorin, also called folinic acid, is a form of the B vitamin folic acid, which helps increase 5-FU’s effectiveness. Patients are given a series of cycles that usually continue for at least 6 months.

There are many different ways of giving 5-FU, including intravenously over several hours once a week, intravenously daily for 5 consecutive days every month, or as continuous infusion with a portable pump.

The side effects can be quite different, depending on the way 5-FU is given, and women may be more susceptible than men. In one analysis, 53% of women and 40% of men experienced severe side effects, while response rates and survival were similar for both sexes. Many patients, however, tolerate 5-FU with leucovorin well, with manageable side effects. The most common side effects include nausea and vomiting, diarrhea, loss of appetite, hair loss, swelling of hands and feet, rashes, and mouth sores.

Irinotecan. Irinotecan (Camptosar) blocks an enzyme essential for cell division. Irinotecan can be given alone or in combination with 5-FU and leucovorin. This combination therapy (irinotecan plus 5-FU/LV) is also referred to as the "Salz regimen," or IFL. When it was approved in the mid 1990s, irinotecan was the first new drug developed for colon cancer in over 30 years. Studies have shown that irinotecan combined with 5-fluorouracil and leucovorin (5-FU/LV) significantly delays the time at which tumors progress and improves survival in metastatic cancer compared to 5-FU/LV alone. While the survival advantage is small, the combination has become the standard of care for metastatic cancer. Of concern, however, are studies that have reported an increased risk of death from toxic effects with the use of the three-drug combination. These deaths appeared to be related to blood-clotting complications. Doctors should carefully monitor dosages. Diarrhea is a common side effect of irinotecan.

Capecitabine. Capecitabine (Xeloda), an oral form of 5-FU, was approved in 2001 as a treatment for metastatic colorectal cancer. It is the only pill approved for colorectal cancer. A major 2005 study, published in the New England Journal of Medicine, found that capecitabine works as well as the standard 5-FU/LV regimen and causes significantly fewer side effects. The study involved patients with Stage III colon cancer who had undergone surgical removal of the tumor. In 2005, capecitabine was approved for postsurgical treatment of patients with Dukes’ C colon cancer. Capecitabine is also showing promise in combination with radiation therapy for rectal cancers.

Oxaliplatin. Oxaliplatin (Eloxatin) is related to cisplatin, a widely used platinum-based chemotherapy drug. Oxaliplatin is used in combination with 5-FU and leucovorin. (This triple combination therapy is called the FOLFOX regimen.) Oxaliplatin was first approved in 2002 for use in combination with 5-FU and leucovorin as a second-line treatment for cancer that has progressed after initial therapy.

Since 2002, oxaliplatin has received additional approvals as a first-line treatment for advanced colorectal cancer, and as a post-surgical treatment for patients who have undergone tumor resection.

Oxaliplatin can cause pain and tingling sensations in the hands and feet (neuropathy) that is worsened by exposure to cold. Recent research suggests that adding xaliproden (Xaprila) to the FOLFOX regimen may help reduce the frequency of neuropathy without interfering with the benefits of chemotherapy. Xaliproden is a drug used to treat the neurological disease amyotrophic lateral sclerosis (also known as Lou Gehrig's disease).

Bevacizumab. Bevacizumab (Avastin) was approved in February 2004 as a first-line treatment for patients with metastatic colorectal cancer (advanced cancer that has spread in the body). It is used in combination with IFL (irinotecan, 5-FU, leucovorin). Bevacizumab is a genetically engineered monoclonal antibody that targets and inhibits vascular endothelial growth factor (VEGF), a protein that regulates angiogenesis (the development of new blood vessels that feed a tumor's blood supply). It is the first anti-angiogenic therapy approved for the treatment of colorectal cancer.

In a study of 800 patients with metastatic colorectal cancer, bevacizumab administered intravenously along with IFL extended survival by about 5 months longer than IFL alone. Common side effects of bevacizumab include nosebleeds, fatigue, diarrhea, and high blood pressure. Less common side effects include stroke, heart attacks, angina, and formation of holes in the colon and stomach (gastrointestinal perforation).

Cetuximab. Cetuximab (Erbitux) was approved in February 2004 for the treatment of metastatic colorectal cancer. This monoclonal antibody drug targets epidermal growth factor receptor (EGFR), a protein required by cancer cells in order to proliferate. It can be used either in combination with irinotecan or alone for patients who have not responded to irinotecan. Studies of the cetuximab-irinotecan combination suggest it can help in tumor shrinkage. It has a modest effect on survival, prolonging patients’ lives by about an additional month.

Panitumumab. Panitumumab (Vectibix) was approved in September 2006 for treatment of colorectal cancer that has metastasized following standard chemotherapy. Like cetuximab, panitumumab is a monoclonal antibody drug that targets EGFR. In clinical trials, panitumumab helped delay disease progression and prolong survival by about 3 months. About 8% of patients experienced tumor shrinkage. Common side effects of this drug include skin rash, fatigue, abdominal pain, nausea, and diarrhea or constipation. Serious side effects include pulmonary fibrosis, severe skin rash, and skin reactions at the infusion site.

One of the most promising recent developments in cancer treatment research has been the emergence of so-called "targeted therapies." Traditional chemotherapy drugs can be effective, but because they do not distinguish between healthy and cancerous cells their generalized toxicity can cause severe side effects. Targeted therapies work on a molecular level by blocking specific mechanisms associated with cancer cell growth and division. Because they selectively target cancerous cells, they may induce less severe side effects. In addition, these drugs hold the promise of creating options for more individualized cancer treatment based on a patient's genotype. In the future, diagnostic tests may help doctors identify which patients are more likely to respond successfully to specific drugs.

Biologic therapies use the body's immune system to attack the cancer (immunotherapy). These drugs are derived from biological sources and include vaccines, monoclonal antibodies (MAbs), and gene therapies. Many targeted therapies are classified as biologics. Bevacizumab (Avastin), cetixumab (Erbitux), and panitumumab (Vectibix) are currently the three biologic drugs approved for colorectal cancer treatment, but many other drugs are in development.

Targeted therapies involve many different types of drugs and molecular pathways. These include:

Angiogenesis Inhibitors. Anti-angiogenesis drugs inhibit the formation of new blood vessels that supply tumors with the blood, oxygen, and nutrients vital to tumor growth. Angiogenesis inhibitors, such as the monoclonal antibody bevacizumab (Avastin), target vascular endothelial growth factor (VEGF). Cediranib (Recentin), formerly AZD2171, is a new angiogenesis inhibitor that is in Phase III clinical trials for treatment of colorectal cancer.

Tumor Growth Factor Inhibitors. Tumor growth factors, such as epidermal growth factor, stimulate cell growth. Cetixumab (Erbitux) and panitumumab (Vectibix) are the two currently approved colorectal cancer drugs that target the epidermal growth factor receptor (EGFR). Nimotuzumab (TheraCIM) is currently being studied in combination with irinotecan in Phase III trials.

Tyrosine Kinase Inhibitors. Tyrosine kinase is an enzyme associated with EGFR that is involved with the signaling mechanisms that prompt cell growth. The EGFR/tyrosine kinase inhibitor erlotinib (Tarceva), which is approved for the treatment of pancreatic and lung cancers, is being investigated as an adjuvant treatment for metastatic colorectal cancer. Sunitinib (Sutent), which is approved for renal cell carcinoma, is another tyrosine kinase inhibitor in Phase III trials for colorectal cancer.

Radiation Treatment

Radiation therapy uses x-rays to kill cancer cells that might remain after an operation or to shrink large tumors before an operation so that they can be removed surgically. The object of radiation therapy is to damage the tumor as much as possible without harming surrounding tissues. Radiation may be administered in the following ways:

Externally by an x-ray machine (external beam radiation).
By passing radioactive pellets through thin plastic tubes inserted into the intestine.
By implanting tiny radiation seeds directly into the tumor (brachytherapy).
Computer imaging techniques providing 3-dimensional pictures of the cancerous area are allowing precise targeting of radiation to the tumor.

Postoperative radiation treatment combined with chemotherapy is common practice for patients with rectal cancer in Stages II and III. Such patients are at risk of recurrence both at the site of their original tumor and elsewhere in the body. Although there can be significant long-term side effects, the combination of 5-FU and radiation is still considered standard after surgery.

The standard procedure in the U.S. is to apply radiation after surgery (postoperative). Pre-operative chemotherapy and radiation, however, are sometimes used to preserve sphincter-muscle function and reduce the chance that a patient will need a colostomy. Furthermore, some studies suggest that the use of radiation before surgery reduces the likelihood of recurrences and may slightly prolong survival in some patients with rectal cancer. (It has no additional advantages, however, if the subsequent surgery does not completely remove the cancerous regions.) Studies comparing preoperative and postoperative chemotherapy and radiation are currently under way.

Radiation therapy can also be used during surgery (a procedure called intra-operative radiotherapy). It allows the surgeon to move healthy tissue out of the path of the radiation beam.

Short-term side effects of radiation include:

Diarrhea
Skin irritation around the anus
Incontinence
Fatigue
Bowel movement problems

Longer-term complications may include:

Incontinence
Hip and pelvic fractures
Diarrhea
Increased risk for bowel obstruction

Follow-up Testing

The American Society of Clinical Oncology (ASCO) sets guidelines for follow-up testing to detect recurring cancer after the completion of treatment. The following guidelines are based on ASCO’s 2005 updated recommendations.

Most colorectal cancer recurrences happen within 3 years after surgery. American Society of Clinical Oncology recommends that a colorectal cancer patient sees their doctor for a physical examination every 3 - 6 months for the first 3 years, every 6 months for the fourth and fifth years, and at the doctor's and patient's discretion during subsequent years.

Patients should have a colonoscopy 3 years after surgery. If the results are normal, patients should then receive a colonoscopy every 5 years. Some patients with hereditary types of colorectal cancer may need more frequent screenings.

A flexible sigmoidoscopy is recommended every 6 months for 5 years for patients with Stage II or III rectal cancer who did not receive radiation therapy.

Carcinoembryonic antigen (CEA) levels should be measured every 3 months after surgery for 3 years in patients with Stage II or III cancer. High CEA levels in the blood may indicate that the cancer has spread to other parts of the body.

Patients at high risk for cancer recurrence should receive an annual computerized tomography (CT) scan for the first 3 years after treatment. The CT scan can help determine if cancer has spread to the lungs or liver. Patients who have had rectal cancer, and did not have radiation therapy, should receive a pelvic CT scan. The scan is not recommended for most lower-risk patients with Stage I or II colorectal cancer.

American Society of Clinical Oncology does not recommend other follow-up blood tests such as complete blood count, liver function tests, fecal occult blood tests. There appears to be no additional benefit for these tests.

Treatment for Metastasized Colorectal Cancer

The liver is the most frequent site for colorectal cancers to spread (metastasized). Here, treatments may slow the spread of cancer and even prolong survival. Cure is very rare.

When cancer has spread, surgery to remove or bypass obstructions in the intestine may be performed. In these circumstances, surgery is considered palliative in that it may improve symptoms but will not lead to cure. In rare cases, metastatic colon cancer may be cured with surgical removal of tumors in areas to which the cancer has spread, such as the liver, ovaries, and lung. The liver is the most common site of spread. Only selected patients may be eligible for such surgery, but in these patients, 5-year survival has been 25% or higher.

Chemotherapy may help improve symptoms and possibly prolong survival in metastasized colorectal cancers. Several investigational drugs are being tested. Doctors are also testing chemotherapy administered directly into the liver -- a treatment called hepatic arterial infusion (HAI). A 2006 study found that hepatic arterial infusion improves survival and quality of life for patients whose cancer has spread to the liver. The study indicated that HAI works better for these patients than chemotherapy delivered intravenously.

Other investigative techniques used to destroy liver tumors include:

Cryosurgery. This approach freezes the tumor or surrounding tissue.
Embolization. Embolization employs a catheter to deliver substances into the liver that block blood vessels and therefore starve the tumor. Chemotherapy is often administered during this procedure.
Radiation.

For end-stage cancer, hospice care is a compassionate option.

Resources

www.cancer.org -- American Cancer Society
www.cancer.gov -- National Cancer Institute
www.oncolink.org -- OncoLink cancer information
www.asco.org -- American Society of Clinical Oncology
www.plwc.org -- People Living with Cancer
www.nccn.org -- National Comprehensive Cancer Network
www.cancer.gov/clinicaltrials -- Find clinical trials

References

Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med. 2007 May 24;356(21):2131-42.

Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007 Jun 6;297(21):2351-9.

Flossmann E, Rothwell PM; British Doctors Aspirin Trial and the UK-TIA AspirinTrial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidencefrom randomised and observational studies. Lancet. 2007 May 12;369(9573):1603-13.

Kerr DJ, Dunn JA, Langman MJ, Smith JL, Midgley RS, Stanley A, et al. Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. N Engl J Med. 2007 Jul 26;357(4):360-9.

Levin TR, Zhao W, Conell C, Seeff LC, Manninen DL, Shapiro JA, Schulman J. Complications of colonoscopy in an integrated health care delivery system. Ann Intern Med. 2006 Dec 19;145(12):880-6.

Meyerhardt JA, Niedzwiecki D, Hollis D, Saltz LB, Hu FB, Mayer RJ, et al. Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer. JAMA. 2007 Aug 15;298(7):754-64.

U.S. Preventive Services Task Force. Routine aspirin or nonsteroidal anti-inflammatory drugs for the primary prevention of colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2007 Mar 6;146(5):361-4.

Veit-Haibach P, Kuehle CA, Beyer T, Stergar H, Kuehl H, Schmidt J, et al. Diagnostic accuracy of colorectal cancer staging with whole-body PET/CT colonography. JAMA. 2006 Dec 6;296(21):2590-600.

Review Date:
9/8/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Brain tumors - primary

FitSugar — Wed, 08 Oct 2008 17:35:12 -0700

In This Report

Highlights
Introduction
Symptoms
Risk Factors
Causes
Prognosis
Diagnosis
Common Brain Tumors
Treatment
Surgery
Radiotherapy
Chemotherapy
Other Treatments
Treatment of Complications...
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Radiation Therapy Complications

Radiation therapy in children with cancer increases the risk of new brain and spinal cord tumors, suggests a study in the Journal of the National Cancer Institute. The risk appears to increase along with the radiation dosage. Children who receive radiotherapy before age 5 are especially at risk for second primary tumors.
Survivors of childhood brain tumors who received cranial radiotherapy as part of their treatment are at risk for later having a stroke, indicates a study in the Journal of Clinical Oncology. The average length of time from brain tumor diagnosis to post-treatment stroke was 14 years.

Radiation Therapy for Elderly Patients

Radiotherapy provides modest improvement in survival for elderly patients (age 70 years and older) with glioblastoma, with no detriment to quality of life or cognition function, according to a 2007 study in the Journal of the American Medical Association.

Temozolomide (Temodar)

The chemotherapy drug temozolomide (Temodar) has become an important and effective treatment for patients newly diagnosed with glioblastoma. However, not all patients respond equally well to this drug. A 2007 study in the journal Neurology suggests that a patient’s genotype may explain differences in response. Though genetic testing, researchers found that temozolomide works best in people who are missing a particular gene.

Investigational Treatments

Vorinostat (Zolinza), a cancer drug used for T-cell lymphoma, may help patients with recurrent glioblastoma multiforme, according to research presented at the 2007 annual meeting of the American Society of Clinical Oncology.
Bevacizumab (Avastin), a targeted therapy drug used for lung and colorectal cancers, may help prolong survival in patients with advanced glioma, indicates a 2007 study in Clinical Cancer Research. Another anti-angiogenesis drug, cediranib (Recentin), may help make glioblastomas more responsive to chemotherapy and radiotherapy, according to recent interim trial results.
Vitespen (Oncophage), an experimental vaccine for glioma, is showing promise in early clinical trials, suggests research presented at the 2007 meeting of the American Association of Neurological Surgeons.

Introduction

Brain tumors are composed of cells that exhibit unrestrained growth in the brain.

The major areas of the brain have one or more specific functions.

They can be benign (noncancerous, meaning that they do not spread elsewhere or invade surrounding tissue) or malignant (cancerous).

Cancerous brain tumors are further classified as either primary or secondary tumors. Primary tumors start in the brain, whereas secondary tumors spread to the brain from another site such as the breast or lung. (In this report, the term "brain tumor" will refer mainly to primary malignant tumors, unless otherwise specified.)

Benign tumors represent half of all primary brain tumors. Their cells look relatively normal, grow slowly, and do not spread (metastasize) to other sites in the body. Benign tumors can still be serious and even life-threatening if they are in vital areas in the brain where they exert pressure on sensitive nerve tissue or if they increase pressure within the brain. While some benign brain tumors may pose a health risk, including risk of disability and death, most are usually successfully treated with techniques such as surgery.

Click the icon to see an image of a primary brain tumor.

A secondary (metastatic) brain tumor occurs when cancer cells spread to the brain from a primary cancer in another part of the body. Secondary tumors are about three times more common than primary tumors of the brain. Usually, multiple tumors develop. Solitary metastasized brain cancers may occur but are less common. Most often, cancers that spread to the brain to cause secondary brain tumors originate in the lung, breast, kidney, or from melanomas in the skin.

A primary malignant brain tumor is one that originates in the brain itself. Although primary brain tumors often shed cancerous cells to other sites in the central nervous system (the brain or spine), they rarely spread to other parts of the body.

Brain tumors are generally named and classified according to the following:

The normal brain cells from which they originate, or
The location in which the cancer develops

The biologic diversity of these tumors, however, makes classification difficult, and some experts believe that more specific categories are needed.

About half of all primary brain tumors are known collectively as gliomas. They are cancerous forms of glial cells, the building-block cells of the connective, or supportive, tissue in the central nervous system. There are several glial cells types from which gliomas form. Their names are:

Astrocytomas are primary brain tumors derived from astrocytes, which are star-shaped glial cells. Normal astrocytes provide nutrients, support, and insulation for nerve cells and are one of the primary neurologic cells in the body. The malignant astrocytomas called glioblastomas account for 23% of brain tumors and are the most common ones.
Oligodendrogliomas develop from oligodendrocyte glial cells, which form the protective coatings around nerve cells. Although oligodendrogliomas were thought to represent about 5% of all gliomas, more recent evidence suggests they may comprise about 20% of gliomas. Pure oligodendrogliomas, however, are rare. In most cases they occur in mixed gliomas.
Ependymomas are derived from ependymal cells, which line the ventricles (fluid-filled cavities) in the lower part of the brain and the central canal of the spinal cord. They constitute about 6% of all primary tumors in the central nervous system. About 30% of these tumors occur in the spinal cord.
Mixed gliomas contain a mixture of malignant gliomas. About half of these tumors contain cancerous oligodendrocytes and astrocytes.

It should be noted that gliomas may also contain cancer cells derived from brain cells other than glial cells.

Some brain tumors are categorized by their location in the brain. Such tumors often contain gliomas but are also frequently a mixture of different cell types.

Meningiomas. Meningiomas are usually benign tumors that develop in the membranes that cover the brain and spinal cord (the meninges).

Click the icon to see an image of the meninges.

They are not technically classified as brain tumors, but they have similar symptoms and develop within the brain. So in practical terms, they are considered brain tumors. In fact, meningiomas comprise 20% of all primary brain tumors. They occur more often in women than in men. Most grow very slowly, and the majority of people who have them never know they are present. Malignant forms called anaplastic meningiomas and hemangiopericytomas are less common and are difficult to remove surgically.

Cerebral Astrocytomas. Gliomas that develop inside the brain often occur in the cerebral hemispheres (the right and left sides of the brain). In such cases, they are referred to as cerebral astrocytomas. Gliomas sometimes occur in another part of the brain, called the cerebellum. The cerebellum is responsible for balance and coordination. In such cases, the term cerebellar astrocytoma is used.

Click the icon to see an image of the function of the left cerebral hemisphere.

Click the icon to see an image of the function of the right cerebral hemisphere.

Brain Stem Gliomas. Brain stem gliomas develop in the lowest portion of the brain. The brain stem connects the cerebrum (the higher centers of the brain) to the spinal cord. The brain stem is thought to be the primitive brain because it controls the most basic functions.

Click the icon to see an image of the function of the brainstem.

The brain stem consists of three primary parts:

The medulla regulates breathing, swallowing, blood pressure, and heart rate.
The pons links the cerebellum to the cerebrum.
The midbrain helps control vision and hearing.

Click the icon to see an image of the structures of the brain.

Medulloblastomas. Medulloblastomas are always located in the cerebellum, which is at the base and toward the back of the brain. They represent about 3% of all brain tumors.

Click the icon to see an image of the function of the cerebellum.

Pituitary Tumors. Pituitary tumors comprise about 10% of primary brain tumors and are often benign, slow-growing masses in the pituitary gland.

Click the icon to see an image of the pituitary gland.

Other Brain Tumor Locations. Optic nerve gliomas occur in the optic nerve, which is located behind the eye. Acoustic neuromas make up 7.5% of brain tumors.

Click the icon to see an image of the optic nerve.

Symptoms

Brain tumors produce a variety of symptoms, ranging from headache to stroke. They are great mimics of other neurologic disorders. Symptoms occur if the tumor directly damages the nerves in the brain or central nervous system or if its growth imposes pressure on the brain. Some gliomas develop gradually, and symptoms may be subtle for a long time, making an early diagnosis difficult.

Headache is probably the most common symptom of a brain tumor. It should be strongly emphasized, however, that everyone has headaches, and they rarely represent an underlying brain tumor. Headaches caused by brain tumors may vary depending on the location, and many different features.

Steady and worse upon waking in the morning and clears up within a few hours
Persistent non-migraine headache that occurs while sleeping and is also accompanied by at least one other symptom (such as vomiting or confusion)
May or may not be throbbing, depending on location of the tumor
Accompanied by double vision, weakness, or numbness
May worsen with coughing or exercise or with a change in body position
Sometimes accompanied by neck pain

Gastrointestinal symptoms, including nausea, are also common. Nausea and vomiting, in fact, often occur in children with brain tumors and in all people with brain stem cell tumors.

Seizures occur in between 15 - 95% of patients, depending on the location of the tumor.

Tumors are more likely to be localized and affect one area of the brain. In such cases they can cause partial seizures. In this case, a person does not lose consciousness but may experience confusion, jerking movements, tingling, or odd mental and emotional events.
Generalized seizures, which can cause loss of consciousness, are less common, since they are caused by disturbances of nerve cells in diffuse areas of the brain.

Sometimes the only symptoms are mental changes, which may include the following:

Memory loss
Impaired concentration
Problems with speech and reasoning
Increased sleep

Gradual loss of movement or sensation in an arm or leg
Unsteadiness
Unexpected visual disturbance (especially if it is associated with headache), including vision loss (usually of peripheral vision) in one or both eyes or double vision
Hearing loss with or without dizziness
Speech difficulty

Specific symptom syndromes may help identify the tumor. The following are some examples.

Symptoms of Brain Stem Gliomas. Sudden onset of symptoms that include vomiting (usually just after waking), a clumsy walk, muscle weakness on one side of the face, difficulty in swallowing, slurred or nasal speech, as well as impaired hearing or vision.

Symptoms of Glioblastoma Multiforme. Rapid onset and worsening of symptoms that include headaches, seizures, memory loss, and changes in behavior.

The below symptoms indicate an emergency condition and require immediate medical attention:

Pupil dilation
A fixed gaze
Paralysis on one or both sides of the body
Blindness or defective vision in one eye

Risk Factors

Nearly 360,000 people in the U.S. are living with brain cancer. Men are at higher risk than women for most brain tumors. Primary malignant brain tumors are still uncommon and represent only 1.3% of all cancers diagnosed in the United States and 2.4% of all deaths due to cancer.

Primary brain cancers are rare, occurring in slightly more than 11 people per 100,000 per year. There has been some evidence of a growing incidence of brain cancer among the elderly since the 1980s. The increase, however, is most likely due to the rise in incidence of non-Hodgkin's lymphomas -- which can occur in the brain. When this malignancy is eliminated, any increase in other tumors is not significant.

The average age of diagnosis for brain tumors is 57, and about 90% of primary brain tumors occur in adults. These tumors can develop at all ages, usually peaking in two age groups.

In adults, ages 55 - 65
In children, ages 3 - 12

Risk Factors in Children. Tumors in the central nervous system are now the most common primary cancers in children, but they are still rare. An estimated 3,110 benign or malignant brain tumors are expected to be diagnosed in children each year. Brain tumors in children are more likely to occur in the cerebellum, the midbrain, or the optic nerve.

The incidence has increased over the past years, but there is some evidence that this increase is only due to better diagnostic procedures. The mortality rate has actually decreased. Researchers have attempted to uncover risk factors for childhood brain cancer. There may be some association between a higher risk and the following conditions:

Children treated with radiation to the head for leukemia and who have a specific genetic defect may face a high risk for brain cancer. (It should be noted that for children without this defect, the risk is very small.)
Having parents with specific cancers. (According to one study, having parents with nervous system cancers, colon cancer, or cancer in the salivary glands increased the risk of specific brain tumors in their children.)

Click the icon to see an illustrated series detailing colon cancer surgery.

The risk for primary brain tumors in Caucasians is higher -- as much as twofold depending on type -- than in African-Americans.

Radiation Exposure. People who receive radiation therapy to the head during cancer treatment have an increased risk of developing brain tumors 10 - 15 years later. Workers in the nuclear industry are also at increased risk.

There is no evidence that electromagnetic field exposure from power lines or household appliances poses any risk. Several recent epidemiological studies, including a 2006 study in the British Medical Journal, found that cell phones, cordless phones, and wireless devices are also safe and do not increase the risk for gliomas.

Chemical and Metals in Brain Tumors. High exposure to numerous metals and chemicals have been associated with brain tumors:

Industrial chemicals, including vinyl chloride and petroleum products
Lead, arsenic, or mercury exposure
Exposure to pesticides. A major study of pesticides is underway, but results are not in yet. A 2003 study indicated that parental exposure to pesticides or herbicides did not appear to be important in increasing risk for brain cancer in their children.

Brain cancer is uncommon, and, over the course of their lifetime, many people are exposed to these chemicals, many of which are very common. To date, there has been no clear evidence that implicates any specific industrial chemical or metal.

One study reported a higher risk for brain cancers in patients who had undergone organ transplantations. Researchers believed that the drugs used to suppress the immune response after the procedures may increase the risk.

One study reported lower risks for brain cancers in individuals with allergies and autoimmune diseases (such as type 1 diabetes). Autoimmune diseases were also associated with a lower risk for meningiomas. The cause of this possible association remains unknown.

Studies have also found an association between lower risk for gliomas and a history of infection with varicella zoster, the virus that causes chicken pox and shingles.

Click the icon to see an image of the chicken pox.

Causes

Only 5 - 10% of primary brain tumors are associated with genetic disorders. These inherited conditions and associated genes include:

Von Recklinghausen disease, also called neurofibromatosis 1 (NF1 gene) and neurofibromatosis 2 (NF2 gene)
Turcot's syndrome (APC gene)
Gorlin syndrome, also called basal cell naevus syndrome (PTCH gene)
Tuberous sclerosis (TSC1 and TSC2 genes)
Li-Fraumeni syndrome (TP53 gene)

Certain types of brain tumors are specifically linked with these genetic conditions. For example, neurofibromatosis 1 is associated with about 15% of cases of pilocytic astrocytomas, the most common type of childhood glioma. Neurofibromatosis results from defects in the tumor suppressor genes NF1 and NF2. Li-Fraumeni syndrome results from mutations in the tumor suppressor gene TP53. These mutations affect the production of tumor suppressor protein p53.

Tumor suppressor genes regulate cell division and help repair DNA damage. When mutations that affect protein encoding occur, unregulated cell division and growth can lead to the development of a tumor. Tumor suppressor genes are sometimes described as being in a tug-of-war with cancer-causing genes called oncogenes. Oncogenes derive from mutations or overexpressions of proto-oncogenes. Proto-oncogenes encode for proteins that regulate cell growth and differentiation. When proto-oncogenes become oncogenes, normal cells start to grow uncontrollably. Cancer can occur when tumor suppressor genes are turned off, or when oncogenes are turned on.

Many different oncogenes are involved in cancer. Growth factors are a particularly important type of oncogene associated with brain tumors. Growth factors attach to receptors (connectors) that stimulate cell growth. Epidermal growth factor receptor (EGFR) has been shown to play a role in high-grade brain tumors such as glioblastoma multiforme. In 2007, scientists identified insulin-like growth factor binding protein (IGFBP2) with an oncogene that may be associated with the development of astrocytoma and oligodendroglioma.

Knowing the molecular origin of a brain tumor may help determine the treatment course, both for standard chemotherapy and "targeted therapy" biologic drugs. For example, patients with tumors marked by high EGFR proliferation may benefit from treatment with the EGFR kinase inhibitor drugs gefitinib (Iressa) or erlotinib (Tarceva).

Most genetic abnormalities that cause brain tumors are not inherited but occur as a result of environmental or other factors that affect genetic materials (DNA) in the cells. Researchers are studying various environmental factors (viruses, hormones, chemicals, radiation) that may trigger the genetic disruptions that lead to brain tumors in susceptible individuals. They are also working to identify the specific genes that are affected by these environmental triggers. For example, in a 2007 study, scientists proposed that genetic susceptibility may explain why some people develop meningioma, a rare type of brain tumor, following exposure to ionizing radiation. Future investigations will hopefully identify the specific genes involved and help determine which people would potentially be most at risk.

Prognosis

About 13,100 people die from cancerous brain tumors each year. Recent advances in surgical and radiation treatments have significantly extended average survival times and can reduce the size and progression of malignant gliomas. In general, survival rates are highest in younger people and lowest in the elderly.


Age	Survival Rates
0 - 19 years	63.1%
20 - 44 years	50.4%
45 - 64 years	14.2%
Over 65	4.9%
Data From: 2002 - 2003 Primary Brain Tumors in the United States Statistical Report. Fact Sheet (1973- 1999 data). Brain Tumor Registry of the United States www.cbtrus.org/factsheet/factsheet.html.

In general, studies are reporting that patients who survive the first 2 years after a diagnosis of a brain tumor have at least a 70% chance of surviving for at least 5 years. The best recent progress has been made for:

Medulloblastomas in both children and adults. Long-term survival rates are now about 60% in children after treatment for medulloblastomas, the most common malignant brain tumor in this age group. (New treatments, however, may significantly improve these rates.)
Nonmalignant astrocytomas and oligodendrogliomas in adults.

Unfortunately, the majority of primary brain tumors, notably anaplastic astrocytomas and glioblastoma multiforme, are only rarely curable.

The specific effects of tumors on the brain can cause seizures, mental changes, and mood, personality, and emotional changes. Such effects can be devastating to the patient and the caregivers. Numerous treatments are available that help alleviate these complications, and patients and family members should discuss these with their doctors.

Diagnosis

A neurological exam is usually the first test given when a patient complains of symptoms that suggest a brain tumor. The exam includes checking eye movements, hearing, sensation, muscle movement, sense of smell, and balance and coordination. The doctor will also test mental state and memory.

X-rays of the skull were once standard diagnostic tools but are now performed only when more advanced procedures are not available. Advanced imaging techniques have dramatically improved the diagnosis of brain tumors in recent years.

Magnetic Resonance Imaging. Magnetic resonance imaging (MRI) is the gold standard for diagnosing a brain tumor. It does not use radiation and provides pictures from various angles that can enable doctors to construct a three-dimensional image of the tumor. It gives a clear picture of tumors near bones, smaller tumors, brainstem tumors, and low-grade tumors. MRI is also useful during surgery to show tumor bulk, for accurately mapping the brain and for detecting response to therapy.

An MRI (magnetic resonance imaging) of the brain creates a detailed image of the complex structures in the brain. An MRI creates a three-dimensional picture of the brain, which allows doctors to more precisely locate problems such as tumors or aneurysms.

A variant called magnetic resonance spectroscopy (MRS) is capable of providing information on the activity of the brain using magnetic resonance imaging. MRS is proving to be accurate for distinguishing dead (necrotic) tissue caused by previous radiation treatments from recurring tumor cells in the brain, a difficult diagnostic issue.

Computed Tomography. Computed tomography (CT) uses a sophisticated x-ray machine and a computer to create a detailed picture of the body's tissues and structures. It is not as accurate as an MRI and does not detect about half of low-grade gliomas. It is useful in certain situations, however. Often, doctors will inject the patient with an iodine dye, called contrast material, to make it easier to see abnormal tissues. A CT scan helps locate the tumor and can sometimes help determine its type. It can also help detect swelling, bleeding, and associated conditions. In addition, computed tomography is used to check the effectiveness of treatments and watch for tumor recurrence.

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

Positron Emission Tomography. Positron emission tomography (PET) provides a picture of the brain's activity rather than its structure by tracking substances that have been labeled with a radioactive tracer. As with magnetic resonance spectroscopy (MRS), it is also able to distinguish between recurrent tumor cells from dead cells or scar tissue, although MRS is more widely available. PET is not routinely used for diagnosis, but it may supplement MRIs to help determine tumor grade after a diagnosis. Data from PET may also help improve the accuracy of newer radiosurgery techniques.

Other Imaging Techniques. Numerous other advanced imaging techniques may be used for specific purposes, if available or under investigation.

Single photon emission tomography (SPECT) is similar to PET but is not as effective in distinguishing tumor cells from destroyed tissue after treatments.
Magnetoencephalography (MEG) scans measure the magnetic fields created by nerve cells as they produce electrical currents.
Cerebral angiography involves x-rays of blood vessels in the brain. A long, thin tube (catheter) is threaded through blood vessels from a distant site to the brain, and a radiopaque substance (a substance that is impenetrable to x-rays) is injected through it. The role of angiography in glioma is usually limited to planning surgical removal of a tumor suspected of having a large blood supply.
Radionuclide brain scintigraphy uses a radioactive substance that is administered and absorbed by capillaries in the tumor, which are then viewed using imaging techniques.
Digital holography, a new technique that provides full three-dimensional mapping, is under investigation.

A lumbar puncture is used to obtain a sample of spinal fluid, which is examined for the presence of tumor cells. A computed tomography (CT) scan or magnetic resonance imaging (MRI) should generally be performed before a lumbar procedure to be sure that the procedure will be safe.

Click the icon to see an image of a lumbar puncture.

A biopsy is a surgical procedure in which a small sample of tissue is taken from the suspected tumor and examined under a microscope for malignancy. The results of the biopsy also provide information on the cancer cell type.

In some cases, such as brain stem gliomas, a biopsy might be too hazardous because removing any healthy tissue from this area can affect vital functions. In such cases, diagnosis must rely on less invasive and possibly less accurate measures. Of promise is the stereotactic technique (also called stereotaxy), which uses computers to provide three-dimensional views of very small areas. This may allow precise biopsies of cancer cells without affecting healthy brain tissue. Expertise in this technique is extremely important, however, and the technique is not widely available.

The survival rates in people with brain tumors depend on many different variables:

Whether the tumor is malignant or benign
Cancer cell type and location (location affects whether the tumor can be removed surgically or not)
The tendency to spread and the growth rate (tumor grade)
Patient's age
Patient's ability to function
Duration of symptoms

The outlook is poorer in the very youngest and very oldest patients, although younger patients who survive 2 years after diagnosis have a much better outlook than older patients.

Grading Tumors. Malignant primary brain tumors are classified according to tumor grade. Grade I is the least cancerous, and Grades IV and V are the most dangerous. Grading a tumor attempts to predict its tendency to spread and its growth rate. It is based on the appearance of the tumor cells as seen under a microscope.

Lower-grade (I and II) tumor cells are well defined and almost normal-shaped. (Some primary low-grade brain tumors are curable by surgery alone, and some are curable by surgery and radiotherapy. Low-grade tumors tend to have the most favorable survival rates and high-grade the least. However, this is not always the case. For example, some low-grade II gliomas are at very high risk for progression.)
Higher-grade (III and IV) tumor cells are abnormally shaped and are more diffuse, which indicates more aggressive behavior. (High-grade brain tumors usually require surgery, radiotherapy, chemotherapy, and possibly investigational treatments.)
In tumors that contain a mixture of different-grade cells, the tumor is graded using the highest-grade cells in the mixture, even when there are very few of them.

Biologic Markers. Elevated levels of certain cancer-associated molecules or compounds may be correlated with prognosis. For example, evidence of genetically mutated p53 indicates a poorer prognosis in younger patients with glioblastoma multiforme.

Elevations of epidermal growth factors (EGF) or vascular endothelial growth factors (VEGF) suggest aggressive tumors. High levels of the receptor for EGF (EGFR), in fact, are found in 70% of glioblastoma specimens.

Genetic Profiles of Cancer Cells. Analyses that identify genetic types may soon help clinicians determine if patients with specific brain tumor cells might respond better to one treatment than another. For example, specific genetic profiles of oligodendrogliomas can help predict how patients respond to nitrosourea alkylating drugs such as carmustine. Genetic variation tests are also being used to determine how patients may respond to epidermal growth factor receptor (EGFR) kinase inhibitors, such as erlotinib (Tarceva) and gefitinib (Iressa).

A genetic profile can also help give doctors a better idea of a patient’s prognosis and survival. In a 2006 study of patients with anaplastic oligodendroglioma, the status of specific chromosomal deletions within tumors was a better predictor of survival than which kind of treatment patients received. In fact, the researchers suggested that gliomas be classified according to chromosomal deletion status, and recommended that chromosomal testing be a regular part of diagnosis and treatment decisions.

Common Brain Tumors


GENERAL DESCRIPTION OF ASTROCYTOMAS: Derived from star-shaped glial cells called astrocytes.

Low-Grade (Usually I) Astrocytomas. Pilocytic gliomas.	Pilocytic gliomas occur mostly in children. Tumors are well differentiated. Cells are relatively normal and rarely metastasize. They grow relatively slowly. Pilocytic astrocytomas have the highest 5-year survival rates (greater than 70%). However, even well differentiated astrocytomas are life threatening if they are inaccessible.	Cancer may sometimes be completely removed through surgery, particularly if it occurs in the cerebellum. For recurrence or residual tumors, reoperation, radiotherapy, or chemotherapy may be given, depending on the circumstances. Repeat surgery for cerebellar astrocytoma is often very successful. For those who fail radiotherapy and chemotherapy, investigative drugs are used.
Low-Grade (II) Astrocytomas. Fibrillary, protoplasmic, and protoplasmic astrocytomas. Some pleomorphic xanthoastrocytomas.	Tumors are well differentiated. Cells are relatively normal and less malignant than those in higher grades. They grow relatively slowly but can spread. Survival rates average 5 years, but people can survive for a decade or more. Pleomorphic xanthoastrocytomas have a relatively favorable prognosis, but can recur and demonstrate aggressive clinical behavior. Low-grade astrocytomas generally occur in young adulthood, with a peak incidence in 30s and 40s.	Surgery, if possible, plus radiotherapy. Surgery alone in certain children, if possible. Trials on postoperative radiotherapy include the following: radiotherapy with or without chemotherapy; low-versus-high radiotherapy doses (studies suggest results are the same and high-dose causes more side effects); deferring radiotherapy until tumor progresses and symptoms occur. (A major study confirmed earlier ones that suggest that this approach has the same 5-year survival benefits -- about 65% -- as immediate postoperative radiotherapy.)
Malignant (High-grade III and IV) Astrocytomas. Anaplastic astrocytoma (gemistocytic and some pleomorphic xanthoastrocytomas). Usually mid-grade (III).	Tumors grow more rapidly than lower grades and infiltrate other nearby healthy cells. Not well-differentiated. Five-year survival rates are about 30%. Recurrence is common.	Treatment same for all high-grade malignant astrocytomas. Surgery, with removal of as much of tumor as possible followed by radiotherapy, with or without chemotherapy. The addition of chemotherapy, particularly being able to take more than 6 cycles, appears to improve survival rates. Carmustine (BCNU) most effective drug at this time. Other drugs and treatment sequences are under investigation. For example, temozolomide is showing promise for many patients, including the elderly. Topotecan may also be useful with other drugs or with radiation. For recurring gliomas, surgery with placement of wafers that release carmustine (Gliadel wafers) is the only proven beneficial therapy to date. Combinations, such as procarbazine and carmustine, provide benefits for recurrent anaplastic astrocytomas. Single drugs may be less toxic and as helpful for other recurrent gliomas. Temozolomide has been approved in Europe for high-grade recurrent gliomas and is proving to be beneficial. Other trials include the following: drugs that block small molecules involved in tumor growth; radioimmunotherapy using monoclonal antibodies; advanced radiotherapy techniques; intraarterial chemotherapy.
High-grade (IV and V). Glioblastoma (notably glioblastoma multiforme or GBM).	Very rapidly growing tumors that spread quickly. Represents about 25% of all primary brain tumors. Most common in older adults (over age 55) and affect more men than women. Recurrences are common in patients who achieve long-term survival.


GENERAL DESCRIPTION OF EPENDYMOMAS: Derived from cells that line the ventricles (fluid-filled brain cavities) and spinal cord central canal. Do not usually spread into normal brain tissue. Can block exits for cerebrospinal fluid and cause hydrocephalus. They constitute about 4% of all central nervous system tumors in adults and 10% of these tumors in children. About 30% of ependymomas develop in the spinal column.

Low-grade (I). Myxopapillary ependymoma (found in the spine). Subependymoma (found in one of the ventricles).	No or very slow growth. In addition to grade, risk is also based on location of the tumor. Tumors on the spinal cord are more accessible than those in the fourth ventricle or in the middle of the lower back portion of the brain.	Can often be removed and cured with surgery, particularly those on spinal cord. Radiation may be needed. Chemotherapy (avoid radiation, if possible) in children under age 6).
Low-grade (II). Papillary, cellular, and clear cell ependymomas.	Slow growth. Usually affect adults.	Surgery alone or followed by radiotherapy. For those who fail radiotherapy, possible use of nitrosourea-based chemotherapies or investigative drugs.
Grade III. Anaplastic ependymomas.	Spreads to the spinal fluid.	Surgery followed by radiotherapy to brain and spinal cord. Possible shunt.
Grade IV. Primitive neuroecto-dermal tumor (PNET). Composed of malignant forms of early, undeveloped nerve cells called neuroblasts. (This malignancy is also referred to as neuroblastoma.)	Very rare, but more common in children. Primitive nerve cells that grow very rapidly. Usually occur in cerebellum.	Surgery followed by radiotherapy to brain and spinal cord. Chemotherapy in young children. Investigative high-dose chemotherapy with stem cell rescue for children with relapsed cancer.


DESCRIPTION OF OLIGODENDROGLIOMAS: They develop from oligodendrocyte glial cells. These cells form the protective coatings around nerve cells. Pure cell types are rare. Most often occur in mixed gliomas. Categorized as either low- or high-grade. Most are low-grade II.

Low-grade: Low grade difficult to tell from astrocytomas, although they are usually calcified. Very likely to bleed. Usually spread along nerve pathways of the brain and spine and rarely outside this area. In spite of difficulty in removing surgically, in some patients survival can be 30 - 40 years. Usually have better prognosis than astrocytomas of equal grade. Occur mostly in middle-aged adults, although there is also a small peak of incidence in children.	Treatment usually delayed until progression causes symptoms. Surgery to remove whole tumor. Radiotherapy often follows in all adults over age 40 or in anyone in which tumor cannot be completely removed. Solid evidence is lacking on this approach, however, and there is some debate on its benefits. Trials using chemotherapy after radiation are promising. Two-thirds of patients respond to PCV (combination of procarbazine, lomustine and vincristine.) Sustained remissions averaging 16 years often achieved. Pure oligodendrogliomas respond better than mixed gliomas. Temozolomide is showing promise as second-line treatment. Others under investigation. Trials of additional chemotherapy for less well-differentiated tumors or for residual tumors after surgery.
High-grade. Anaplastic oligodendrogliomas.	Immediate treatment. Surgery to remove the whole tumor, if possible. Radiation typically follows surgery. Chemotherapy treatments either before or with radiation. Standard drugs are limited. Experts recommend trying investigative drugs. Temozolomide and retinoic acid may be useful. Possible additional drugs include melphalan, thiotepa, carboplatin, cisplatin, and etoposide. (Numerous biologic markers may help identify specific oligodendrogliomas that will respond better or worse to specific treatments.)


GENERAL DESCRIPTION OF MIXED GLIOMAS: Mixed gliomas contain a mixture of malignant gliomas. About half of these tumors contain cancerous oligodendrocytes and astrocytes.

Grade determined by the highest-grade cell present in the tumor.	Same as for oligodendroglioma.



Meningiomas	They are found in the membranes around the brain and spinal column. They are usually benign and rarely invasive. In such cases, long-term outlook is very favorable. (Malignant forms, anaplastic meningiomas, and hemangiopericytomas are uncommon and occur in about 2% of cases.)	Usually watchful waiting. Aggressive surgery the treatment of choice, if possible, although 20% recur after 10 years. Malignant forms and those at the base of the skull difficult to impossible to remove surgically. Stereotactic radiosurgery or fractionated external beam radiotherapy showing promising results for some patients.
Cerebellar astrocytomas (located in cerebellum)	Located in the cerebellum. Usually low-grade, but depends on cell type. If surgical removal is complete, up to 90% survival rates. More common in children than adults.	Surgery primary treatment. Radiotherapy if removal is incomplete.
Brain Stem Gliomas	About 60 - 70% of brain stem tumors are diffuse, which are likely to spread and have a rapid onset of symptoms. Focal tumors tend to be solid or cyst-like. They generally develop gradually. Occurs in both children and young adults.	Radiation is usual treatment. Tumors in this area are rarely removed surgically since the nerve tissue in this area is responsible for vital life functions. Slow-growing tumors may only require watchful waiting. Trials using advanced radiotherapy techniques, gene therapy, immunotherapy, and other experimental drugs.
Medulloblastomas	Occurs in cerebellum (the lower portion of the brain), brainstem, and spinal cord. Usually fast-growing aggressive cells. Most common brain tumors in children and young people, causing between 15 - 20% of brain tumors. With aggressive therapy, in children 5-year survival rates between 60 - 80%. In patients who survive for 2 years after diagnosis, long-term survival rate is nearly 80%.	Treatment is usually surgery and radiotherapy followed by chemotherapy. A 2005 study found that a combination chemotherapy regimen may replace radiation for very young children. A 2006 study suggested that radiation and chemotherapy doses should be adjusted based on disease severity.
Optic Tract Gliomas	Spread along the optic nerve. Usually slow growing. Most often in children under age 10. Children with these tumors often have vision and hormonal problems.	Usually surgery if one eye is involved. Possible chemotherapy or radiation.

Treatment

The approach for treating brain tumors is to reduce the tumor as much as possible using surgery, radiation treatment (also called radiotherapy), chemotherapy, or investigative procedures. Such treatments are used alone or, more commonly, in combinations. With some very slow-growing cancers, such as those that occur in the midbrain or optic nerve pathway, patients may be closely observed and not treated until the tumor shows signs of growth. The intensity, combination, and sequence of these treatments depends on the glioma subtype, its size and location, and patient age, health status, and medical history.

Recent advances in surgical and radiation treatments have significantly extended average survival times compared to those of standard therapy. Investigative treatments, such as monoclonal antibodies, are also showing promise. Patients or their caretakers should discuss all options thoroughly with a specialist in brain cancer. Different specialists may be needed to help manage symptoms.

Because of the low-cure rates of most malignant brain tumors, support for the patients and their families is a critical component of treatment and management. In response to one survey of patients with gliomas, experts made several recommendations to help both patients and caregivers:

Any physical impairment that could benefit from home equipment or physical therapy should be identified and treated.
Patients should discuss emotional as well as physical issues with their doctors. Depression, for instance, can be medically treated. Caregivers should also seek help for the inevitable stress, depression, and tension arising from their difficult role.
Relaxation techniques, meditation, and spiritual resources can be extremely helpful. Support groups are beneficial, but experts recommend separate groups for patients and their families.

Surgery

Surgery is usually the first step in treating most brain tumors. In some cases, however, such as most brain stem gliomas, it may be too dangerous to perform surgery. The object of most brain tumor surgeries is to remove or reduce as much of its bulk as possible. By reducing the size, other therapies, particularly radiotherapy, can be more effective. (Although there have been significant advances in brain surgeries, some experts argue that in high-grade gliomas extensive surgery may not improve survival rates at all and patients are best served by radiation therapy.)

The standard procedure is called craniotomy.

The neurosurgeon removes a piece of skull bone to expose the area of brain over the tumor.
The tumor is located and then removed.

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

There are various surgical options for breaking down and removing the tumor. They include:

Standard surgical procedures
Laser microsurgery (which produces great heat and vaporizes tumor cells)
Ultrasonic aspiration (which uses ultrasound to break the glioma tumor into small pieces, which are then suctioned out)

Relatively benign, grade I gliomas may be treated only by surgery. Some controversy exists over whether surgery for low-grade astrocytomas improves survival, although insufficient research has been conducted to prove its benefits for these gliomas. Most malignant tumors require additional treatments, including repeat surgery.

The surgeon's skill in removing the tumor as completely as possible is critical to survival. No one should be shy about asking the surgeon the number of similar procedures they have performed. (Asking for complication rates may not be useful, since a very experienced surgeon might operate on many high-risk patients.)

In most cancers outside the brain, surgical removal of a tumor usually involves taking out surrounding healthy tissue to be sure all cancer cells are gone. In the brain, however, removing healthy nearby nerve tissue can be as disastrous for the patient as the cancer itself. Special techniques have been developed to allow maximum removal of tumors while protecting healthy brain cells.

Stereotaxy. Stereotaxy has become a useful adjunct to both surgery (stereotactic surgery) and radiotherapy (stereotactic radiotherapy).

Cortical Localization. Cortical localization, or stimulation, uses a probe that passes a tiny electrical current to delicately stimulate a specific area of the brain. This produces a visible response of the body part (such as a twitch in a leg), which the stimulated region of the brain controls. The surgeon then knows to avoid those areas during the operation.

Image-Guided Surgery. Image guided surgery uses a three-dimensional picture of the patient's brain derived from computed tomography (CT) or magnetic resonance imaging (MRI) scans. An advanced technique called high-field interventional MR imaging (iMRI) is particularly accurate in identifying the tumor, but it is not widely available. The image, with various views of the brain, is displayed on a monitor in the operating room. During surgery, as the surgeon's instrument touches a part of the brain, a camera sends the image to a computer, which calculates the position of the surgical tool and displays it in its proper location on the 3-D image. The surgeon then can look at the monitor and see what structures to avoid.

Magnetic-Tipped Catheters. Neurosurgeons are investigating a technique in which external magnetic fields direct a magnet-tipped flexible catheter to the tumor site through a path that avoids harming certain important areas of the brain.

Heparin. Heparin, a blood-thinning drug, should be given at the time of surgery to help prevent blood clots.

Radiotherapy

Radiotherapy plays a central role in the treatment of most brain tumors, whether benign or malignant.

Radiotherapy after Surgery. Even when it appears that the entire tumor has been surgically removed, microscopic cancer cells often remain in the surrounding brain tissue. Radiation targets the residual tumor with the goal of reducing its size or stopping its progression. If the entire tumor cannot be removed safely, postoperative radiotherapy is often recommended. Even some benign gliomas may require radiation, since they may be life-threatening if their growth is not controlled.

Radiotherapy When Surgery Is not Appropriate. Radiotherapy may be used instead of surgery for inaccessible tumors or for tumors that have properties that are particularly responsive to radiotherapy.

Radiotherapy and Chemotherapy (Radiochemotherapy). Combining chemotherapy with radiotherapy is beneficial in some patients with high-grade tumors.

Various radiation treatments are now available.

Conventional radiotherapy uses external beams aimed directly at the tumor and is usually recommended for large or infiltrating tumors. It begins about a week after surgery and continues 5 days per week for 6 weeks. Older adults tend to have a more limited response to external-beam radiation therapy than younger people. According to a 2007 study in the New England Journal of Medicine, radiotherapy leads to a modest improvement in survival in elderly patients (70 years or older) with glioblastoma, and causes few negative impacts on quality of life or cognition.

For tumors that are highly localized, the radiation therapist has a choice of other radiation treatments:

Brachytherapy (also called interstitial radiation) uses radioactive "seeds" implanted directly in the tumor site. It is used as a booster to external beam radiation for patients with malignant astrocytoma. Brachytherapy appears to prolong survival in some aggressive gliomas. It may also be a safe and effective treatment for some children.
Intensity-modulated radiation therapy (IMRT) uses high-dose radiation beams that conform to the three-dimensional shape of the tumor.
Hyperfractionated radiation uses many small radiation doses to deliver a high total dosage of radiation.
A balloon catheter (GliaSite) that delivers radiation to the tumor cavity after surgery is showing promise.

Stereotactic radiosurgery has been developed to allow highly targeted radiation to be delivered directly to the small tumors while avoiding healthy brain tissue. The term radiosurgery is used because the destruction is so precise that it acts almost like a surgical knife. Some studies suggest that stereotactic radiosurgery improves survival, even in patients with the highly aggressive glioblastoma multiforme brain cancer. The procedure is being tested to boost standard radiotherapy.

Benefits of Stereotaxy. There are numerous benefits for stereotaxy:

Stereotaxy allows precisely focused, high-dose beams to be delivered to gliomas less than 1.25 inch in diameter.
Investigators have found that stereotactic radiosurgery can help them reach small tumors located deep in the brain that were previously considered inoperable.
Sometimes with stereotaxy only a single treatment may be needed.
Unlike traditional radiotherapy, stereotactic radiotherapy can be repeated, so it is useful for recurrent tumors when a patient has already received standard radiation treatments.
Combining stereotaxy with techniques that gauge speech and other mental functions in patients who are awake during the procedure can allow removal of brain tissue with a lower risk for complications in areas that affect such functioning.

The Planning Procedure. Stereotactic radiosurgery usually begins with a series of steps designed to plan the radiation target:

First, the patient is given a local anesthetic. In the standard operation, the patient's head must be totally immobilized by screwing a device known as a stereotactic frame into the patient's skull. (The frame procedure is effective only on brain tumors that have regular margins.) The frame is removed as soon as the whole procedure has been completed (about 3 - 4 hours).
A three-dimensional map, usually using magnetic resonance imaging (MRI) scans, is made of the patient's brain.
A computer program calculates dosage levels and specific areas for radiation targeting.

Advanced imaging techniques are now allowing frameless stereotaxy, which eliminates the frame and may be effective on more tumors. For example, high-field interventional MR imaging (iMRI) uses a guidance system based on cruise-missile technology to calculate the slightest variations in movements of the head and the location of the tumor relative to these movements. These calculations are then used to target the radiation beams directly on the tumor, even if the patient's head is moving slightly.

Delivery of Radiation Beams. Once the preliminary planning stage has been completed, treatment begins. Several advanced machines, such as the gamma knife, adapted linear accelerator (LINAC), and cyclotron, are being used with stereotaxy and can deliver very focused beams of radiation. Actual treatment takes 10 minutes to 1 hour.

The gamma knife uses gamma rays that are sent from multiple points to converge at a single point on the tumor. Although each gamma-ray beam is very low dosage, when the beams converge, the intensity and destructive power is very high. The gamma knife is limited to very small tumors and so is generally useful as a booster after standard radiation, surgery, chemotherapy, or combinations.
The linear accelerator (LINAC) produces photons (positively-charged atomic particles) in patterns that are matched to the tumor shape. The patient is positioned on a bed that can be moved to allow flexible positioning. It allows treatment over multiple sessions of small doses (fractionated stereotactic radiotherapy), instead of a single session. This means that larger tumors can be treated.
The cyclotron is basically an atom smasher, which produces protons that can be directed toward the tumor. As part of this procedure, some researchers are using boron neutron capture therapy (BNCT). BNCT employs intravenous administration of a boron compound, which is picked up more selectively by tumor cells than by normal brain tissue. The cyclotron delivers a single dose of radiation that triggers the release of high-energy particles from the boron to destroy nearby tumor cells. The cyclotron is available only in a very few locations, and there have been few trials to date.

Researchers are studying drugs that may be used along with radiation to increase the effectiveness of the treatment.

Radioprotectors. Drugs such as amifosistine (Ethyol) may protect healthy cells during radiation.

Radiosensitizers. Drugs such as fluorouracil (5-FU) and cisplatin (Platinol) may help make cancerous cells more sensitive to radiation.

Common Side Effects. Side effects of radiotherapy may vary depending on the tumor type and radiation treatment. Side effects may include hair loss, fatigue, and nausea and vomiting. Skin irritation and sensitivity may develop in the areas being treated. To prevent further irritation, avoid scratching or rubbing, avoid direct sunlight and heating pads, and do not attempt to treat the symptoms yourself. (Ask your doctor or radiation therapist for advice.) Brain swelling (edema) is another common radiotherapy side effect, which can sometimes cause an increase in brain tumor symptoms. Edema can be treated with steroids.

Tissue Injury. Radiation necrosis (total destruction of nearby healthy tissue) occurs in about 25% of patients treated with intensive radiation. Radiation necrosis can cause brain swelling and reduction in mental functions. The condition is treated with steroids. If steroids prove ineffective, surgery may be required to remove the damaged tissue.

New Tumors. Radiation therapy for childhood cancer is the most important risk factor for developing new brain and spinal column tumors, according to a 2006 study. The risk appears greatest for children who received radiation therapy before age 5. Researchers found that the risk of second primary tumors increased in relation to the radiation dose used to treat the first cancer.

Stroke. Survivors of childhood brain tumors who were treated with high doses of cranial radiation (especially doses greater than 50Gy) may be at increased risk of having a stroke later in life. In a study of nearly 2,000 brain tumor survivors, the average length of time from cancer diagnosis to stroke was 14 years.

Chemotherapy

Chemotherapy involves the use of drugs to kill or alter cancer cells. Chemotherapy is not an effective initial treatment for low-grade brain tumors, mostly because standard drugs cannot pass through the blood-brain barrier, the functional system that protects the brain by preventing certain molecules from reaching the central nervous system. In addition, not all types of brain tumors respond to chemotherapy. In general, chemotherapy for brain tumors is usually administered following surgery or radiation therapy.

The type of drug determines how it is administered. "Systemic delivery" drugs, which pass to the brain from the bloodstream, may be given by mouth, injected into a vein through an IV, or injected into an artery or a muscle. "Local delivery" drugs are placed within or around the brain tumor.

Scientists are working on several approaches to overcome the blood-brain barrier. Newer delivery methods include:

Interstitial chemotherapy uses disc-shaped polymer wafers (known as Gliadel wafers) soaked with carmustine, the standard chemotherapeutic drug for brain cancer. The surgeon implants the wafer directly into the surgical cavity after a tumor is removed.
Intrathecal chemotherapy delivers chemotherapeutic drugs directly into the spinal fluid.
Intraarterial chemotherapy delivers high-dose chemotherapy into arteries in the brain using tiny catheters. In one study, this approach was used within 2 weeks of radiotherapy in patients with high-grade astrocytomas, and the survival rates for glioblastoma multiforme tripled (20 months) compared to those who had chemotherapy and radiation at the same time.
Convection-enhanced delivery (CED) involves placing catheters into the brain tumor or nearby brain tissue to deliver slowly and continuously a cancer drug over several days.

Many different drugs, and drug combinations, are used for chemotherapy. Standard ones include:

Temozolomide (Temodar). Temozolomide, the first new drug approved for brain tumors in several decades, is taken by mouth as a pill. Temozolomide was first approved in 1999 for adult patients with anaplastic astrocytoma that did not respond to other treatments. In 2005, it was approved for use during and after radiation therapy for patients newly diagnosed with glioblastoma multiforme. The current first-line treatment for patients with glioblastoma is combined radiotherapy and temozolomide, followed by monthly doses of temozolomide after radiation treatment ends. A 2005 study, published in the New England Journal of Medicine, reported that adults with newly diagnosed glioblastoma who received temozolomide during and after radiation therapy had a higher rate of 2-year survival than patients who received radiation alone. A 2007 study in Neurology suggested that temozolomide works best for patients who are missing a particular gene (1p/19q). Temozolomide’s side effects are relatively minor, but may include constipation, nausea and vomiting, fatigue, and headache.

Carmustine (BCNU, BiCNU). Carmustine is used to treat many types of brain tumors, including glioblastoma, medulloblastoma, and astrocytoma. Carmustine is usually administered into the vein by IV. It can also be delivered through a wafer implant (Gliadel), which is surgically placed into the brain cavity after tumor removal. If carmustine is administered intravenously, side effects may include nausea and vomiting, fatigue, respiratory problems, and lung scarring (pulmonary fibrosis). Intravenous carmustine may cause bone marrow impairment, which results in decreased production of blood cells (a condition called myelosuppression). If carmustine is delivered through a wafer, side effects may include seizures, brain swelling, and infection within the brain cavity.

PCV Drug Regimen. PCV is an abbreviation for a chemotherapy regimen that combines procarbazine (Matulane), lomustine (CCNU), and vincristine (Oncovin). PCV is commonly used to treat oligodendrogliomas and oligoastrocytomas. The drugs may also be used alone or in other combinations. Procarbazine and lomustine are taken by mouth. Vincristine is given by either injection or IV. These drugs can cause significant side effects, including a drop in blood cell counts, nausea and vomiting, constipation, fatigue, and mouth sores. Procarbazine can cause high blood pressure when taken with foods high in tyramine. Patients should avoid foods such as beer, red wine, cheese, chocolate, processed meat, yogurt, and certain fruits and vegetables.

Platinum-Based Drugs. Cisplatin (Platinol) and carboplatin (Paraplatin) are standard cancer drugs that are sometimes used to treat glioma, medulloblastoma, and other types of brain tumors. These drugs are delivered by IV. In addition to nausea and vomiting, carboplatin can cause hair loss, and cisplatin can cause muscle weakness.

Patients with brain tumors, especially tumors that are in advanced stages, should consider enrolling in clinical trials. Many clinical trials are conducted through academic medical centers. Some promising areas of drug research include:

Other Chemotherapy Drugs. Researchers are investigating whether drugs used to treat other types of cancer may have benefits for brain tumors. These drugs include tamoxifen (Nolvadex) and paclitaxel (Taxol), which are used to treat breast cancer; topotecan (Hycamtin), which is used to treat ovarian and lung cancers; and vorinostat (Zolinza), which is approved for treatment of cutaneous T-cell lymphoma. Research presented at the 2007 meeting of the American Society of Clinical Oncology indicated that vorinostat may help patients with glioblastoma multiforme. Irinotecan (Campath) is another cancer drug that is being studied in combination treatment.

Molecular Targeted Therapy Drugs. One of the most promising developments in cancer treatment research has been the emergence of so-called "targeted therapies." Traditional chemotherapy drugs can be effective, but because they do not distinguish between healthy and cancerous cells their generalized toxicity can cause severe side effects. Targeted therapies work on a molecular level by blocking specific mechanisms associated with cancer cell growth and division. Because they selectively target cancerous cells, they may induce less severe side effects. In addition, these drugs hold the promise of creating options for more individualized cancer treatment based on a patient's genotypes.

Promising targeted therapies for brain tumors include:

Anti-angiogenesis drugs block molecules involved with the growth of blood vessels that feed the tumor (a process called "angiogenesis," which is particularly important in the growth of glioblastomas.) These drugs starve tumors of vital nutrients and oxygen. Bevacizumab (Avastin) is being studied in combination with irinotecan for treatment of recurrent malignant gliomas. Bevacizumab targets vascular endothelial growth factor (VEGF), a specific angiogenesis growth factor. Cediranib (Recentin, AZD2171) is another VEGF inhibitor. In 2007 clinical trials, cediranib appeared to help make recurrent glioblastomas more responsive to chemotherapy and radiation treatment.
Tyrosine kinase inhibitor drugs block proteins involved in tumor cell growth and production. Drugs that specifically target epidermal growth factor receptors (EGFR) are a type of tyrosine kinase inhibitor of special interest in brain tumor research. These drugs include erlotinib (Tarceva), imatinib (Gleevac), and gefitinib (Iressa).
Farnesyl protein transferase inhibitors, such as tipifarnib (Zarnestra) and lonafarnib (Sarasar), are drugs that target a protein involved in the functioning of the cancer-causing Ras protein. Lonafarnib is being studied in combination with temozolomide, and tipifarnib in combination with radiation therapy.
MTOR inhibitors target other enzymes involved in cell growth and replication. Everolimus (RAD-001) is being studied for glioblastoma multiforme and astrocytoma. Everolimus is related to rapamycin (Siroliumus) and tacrolimus (Prograf), which are also being investigated for brain tumor treatment. These drugs are commonly used to suppress the immune system to prevent rejection after organ transplantation.

Other Treatments

Researchers are testing several drugs that target specific mechanisms associated with brain cancer. Combinations of some of these drugs, with or without standard chemotherapy and radiotherapy, may prove to be more effective than the use of any one treatment. It should be noted that none of these drugs at this time are producing cures, although some are improving survival.

Immunotherapy aims at using modalities that boost the patient's own immune system's ability to seek out and destroy cancerous cells.

Radioimmunotherapy with Monoclonal Antibodies. Radioimmunotherapy is showing special promise as a treatment approach to brain tumors. It typically uses monoclonal antibodies (MAbs), genetically engineered drugs designed to work against a specific target. MAbs are bound with radioactive substances and delivered directly into the brain and sometimes into the tumor. The MAbs are specifically designed to lock with the surface of certain cells in the tumor. Once they do so, the radioactive substances destroy the cell. The approach is essentially mini-radiation therapy without the damage or severe side effects of standard radiation treatments. Numerous different radioimmunotherapies are being investigated, and trials of some are reporting improved survival rates in high-grade gliomas. Some doctors believe this approach could prove to be the most effective therapy against these cancers.

Interleukins. Interleukins are natural proteins created by the immune system. Certain tumor cells carry receptors for specific interleukins, which are being investigated for a possible therapeutic role. For example, some drugs combine an interleukin with a drug that is toxic to cancer cells. The interleukin locks onto the receptor on the cancer cell, and the toxic chemical enters the tumor with the intent to kill it. Some interleukins are also being investigated alone for their own tumor-cell killing properties.

Tumor Vaccines. Tumor vaccines are being created, in which tumor cells are removed from the patient and inactivated. When the tumor cells are transferred back to the patient, they are harmless but can elicit a powerful immunologic response against the tumor. Vitespan (Oncophage) is a tumor vaccine that is showing promise against recurrent high-grade glioma, according to preliminary results from early trials presented at the 2007 annual meeting of the American Association of Neurological Surgeons.

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). Such drugs, when effective, would starve tumors of vital nutrients and oxygen. Angiogenesis is particularly important in the growth of glioblastomas, the most malignant brain tumors. Of particular promise are drugs that inhibit enzymes called tyrosine kinase, farnesyl protein transferase, and matrix metalloproteinase, which play critical roles in angiogenesis.

Farnesyl Protein Transferase Inhibitors. Farnesyl protein transferase inhibitors, such as tipifarnib, also called R115777 (Zarnestra) and lonafarnib (Sarasar), are drugs in a new class that block a mutated gene called the Ras gene, which is responsible for about 30% of cancers. Lonafarnib is in early trials in combination with temozolomide. Tipifarnib is also currently in early trials and may prove to be effective.

Tyrosine Kinase Inhibitors. Drugs that target growth factor receptors, such as tyrosine kinase, interfere with the pathway leading to angiogenesis. Some tyrosine kinase inhibitors -- including erlotinib (Tarceva), imatinib (Gleevac), gefitinib (Iressa), and others -- are being investigated in early trials for brain tumor treatment. Side effects include rash, diarrhea, nausea and vomiting. Some of these drugs may reduce white blood cell count or cause liver damage. Researchers are trying to identify biomarkers that could help predict which patients would best respond to tyrosine kinase inhibitor therapy.

Matrix metalloproteinase Inhibitors. Matrix metalloproteinase is an important enzyme in angiogenesis. Inhibitors of these enzymes, including marimastat, metastat, and prinomastat, are in early trials. Marimastat has been studied and has shown some benefits in early trials for patients with recurrent glioblastoma and anaplastic gliomas, particularly in combination with temozolomide.

Phophoinositide 3-Kinse (Pi3K) Inhibitors. Rapamycin and its analog (CCI-779) inhibit Pi3K, an enzyme involved in cell growth. Early trials using CCI-779 are underway. (Another rapamycin analog, everolimus, has different effects but is also being studied for its actions in inhibiting cell growth.)

Other Drugs that Block Angiogenesis. Thalidomide was one of the first drugs used to inhibit angiogenesis and has undergone several trials. There is some evidence that it may work more effectively for metastasized brain tumors than primary tumors. Other drugs in early trials with various effects on tumor growth include suramin, cilengitide, semaxanib, PTK787, and atrasentan.

Retinoids. Retinoids are vitamin A derivatives and act as differentiating drugs in cancer treatments. That is, they can convert immature, dividing tumor cells into mature cells, stopping tumor growth. Studies suggest that they have little benefits as single drugs. Combination with radiotherapy and other drugs may hold promise.

Inactivated Viruses. Investigators are finding that certain genetically inactivated viruses, such as the poliovirus or herpes virus, may prove to be valuable fighters of brain cancers. Such viruses can enter cells and destroy them but do not pose any danger for infection. For example, one specially designed herpes virus targets the enzyme thymidine kinase (an enzyme that promotes tumor growth). Some researchers believe that a combination of this virus with retinoids may be effective with few serious side effects. Other viruses are being investigated. A drug based on this model is years away, however.

Immunotoxins. Drugs called immunotoxins use natural toxins to kill malignant brain cells.

Drugs that use diphtheria toxins, including TransMID-107R and DAB(389)EGF), are the first immunotoxins to show some promise. Clinical trials are investigating them for gliomas and metastatic brain cancers. Other toxins under investigation include irofulven (a mushroom toxin) and chlorotoxin (a substance derived from scorpions).

Taurolidine. Taurolidine is a unique drug that prevents tumor formation and growth in animals. An early clinical trial in patients with high-grade gliomas is under way.

Protein-Blocking Drug. Another development is the discovery of a protein called BEHAB (Brain-Enriched Hyaluronan Binding Protein). BEHAB is produced only by invasive glioma tumor cells, not by normal brain tissue or noninvasive tumor cells. Breakdown of BEHAB releases a substance called HABD (hyaluronan-binding domain), which appears to give glioma cells the ability to invade other areas of the brain. Both BEHAB and HABD represent potential targets for new therapies.

Chemotherapy destroys not only cancer cells but also healthy cells, including special blood cells in the bone marrow called stem cells. Stem cells are immature cells from which all blood cells develop. Transplantation procedures using bone marrow or stem cells allow high-dose chemotherapy to be administered while protecting blood cells. The procedures are being tested for patients with recurrent brain tumors, such as medulloblastoma, primitive neuroectodermal tumors, and germ cell tumors. A 2003 study reported long-term survival in some patients who underwent this procedure

Photodynamic therapy uses a special drug (Photofrin) that is absorbed by the tumor and causes the cancer cells to become fluorescent when a laser is directed at them. It is being investigated in trials in combination with other treatments. A 2003 study reported encouraging results, notably in patients with recurring glioblastoma multiforme. In the study, more than half of these patients survived for at least a year.

Treatment of Complications

Some tumors, particularly medulloblastomas, interfere with the flow of cerebrospinal fluid and cause hydrocephalus (accumulation of fluid in the skull). This causes a build-up fluid in the ventricles (the cavities) in the brain. Symptoms include nausea and vomiting, severe headaches, lethargy, difficulty staying awake, seizures, visual impairment, irritability, and tiredness.

The ventricles of the brain are hollow chambers filled with cerebrospinal fluid (CSF), which supports the tissues of the brain.

Corticosteroids (commonly called steroids) such as dexamethasone (Decadron), prednisolone, and prednisone are used to treat hydrocephalus. Side effects include high blood pressure, mood swings, increased risk of infection, stronger appetite, facial swelling, and fluid retention.

Human corticotropin-releasing factor (hCRF), a naturally occurring neurohormone, appears to possess substantial anti-swelling properties and thus has been proposed as an alternative to corticosteroids in brain edema, with potentially fewer side effects. A hCRF drug called Xerecept is currently in clinical trials.

A shunt procedure may be performed to drain fluid. Shunts are flexible tubes used to reroute and drain the fluid.

Seizures are common in brain tumor cases, with younger patients having higher risks than older ones. Anti-epileptic medications, such as carbamazepine or phenobarbital, may treat seizures and are helpful in preventing recurrence. These drugs are not useful in preventing a first seizure, however, and they should not be used routinely to treat patients with newly diagnosed brain tumors. Anti-seizure medications should be used only for patients who are experiencing seizures. Despite these guidelines, a 2005 study in the Journal of the American Medical Association reported that nearly 90% of patients with newly diagnosed malignant glioma are treated with anti-epileptic drugs, although only 32% of the patients actually have seizures. Anti-seizure medications can interact with some of the chemotherapies used to treat brain cancers, including paclitaxel, irinotecan, interferon, and retinoic acid. Patients should discuss these interactions with their doctors.

Antidepressants are very useful for treating the emotional side effects of this disease. However, according to a 2005 Journal of the American Medical Association study, only 8% of patients with malignant gliomas receive antidepressant medication even though over 90% report depressive symptoms. Support groups can also have great benefit for both patients and families.

Resources

www.abta.org -- American Brain Tumor Association
www.cbtf.org -- Children's Brain Tumor Foundation
www.virtualtrials.com -- Musella Foundation for Brain Tumor Research and Information
www.braintumor.org -- National Brain Tumor Foundation
www.neurosurgery.org -- American Association of Neurologic Surgeons
www.cancer.org -- American Cancer Society
www.cancer.gov -- National Cancer Institute
www.asco.org -- American Society for Clinical Oncology
www.cancer.gov/clinicaltrials -- Find clinical trials
www.radiologyinfo.org -- RadiologyInfo
www.plwc.org -- People Living with CAncer

References

Bowers DC, Liu Y, Leisenring W, McNeil E, Stovall M, Gurney JG, et al. Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2006 Nov 20;24(33):5277-82. Epub 2006 Nov 6.

Dunlap SM, Celestino J, Wang H, Jiang R, Holland EC, Fuller GN, et al. Insulin-like growth factor binding protein 2 promotes glioma development and progression. Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11736-41. Epub 2007 Jul 2.

Flint-Richter P, Sadetzki S. Genetic predisposition for the development of radiation-associated meningioma: an epidemiological study. Lancet Oncol. 2007 May;8(5):403-10.

Kaloshi G, Benouaich-Amiel A, Diakite F, Taillibert S, Lejeune J, Laigle-Donadey F, et al. Temozolomide for low-grade gliomas: predictive impact of 1p/19q loss on response and outcome. Neurology. 2007 May 22;68(21):1831-6.

Keime-Guibert F, Chinot O, Taillandier L, Cartalat-Carel S, Frenay M, Kantor G, et al. Radiotherapy for glioblastoma in the elderly. N Engl J Med. 2007 Apr 12;356(15):1527-35.

Neglia JP, Robison LL, Stovall M, Liu Y, Packer RJ, Hammond S, et al. New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2006 Nov 1;98(21):1528-37.

Sharma MK, Mansur DB, Reifenberger G, Perry A, Leonard JR, Aldape KD, et al. Distinct genetic signatures among pilocytic astrocytomas relate to their brain region origin. Cancer Res. 2007 Feb 1;67(3):890-900.

Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA,et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007 Feb 15;13(4):1253-9.

Review Date:
11/1/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Asthma in children and adolescents

FitSugar — Wed, 08 Oct 2008 17:35:28 -0700

In This Report

Highlights
Introduction
Causes
Prognosis
Risk Factors
Symptoms
Diagnosis
Treatment
Quick-Relief Medications...
Long-Term Relief Medication...
Other Treatments
Managing Asthma
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Warning

In 2007, the FDA requested the manufacturers of omalizumab (Xolair) to include a “boxed warning” emphasizing that this drug may cause a severe and life-threatening allergic reaction (anaphylaxis). Health care providers need to carefully observe patients for 2 hours after they receive an omalizumab injection. However, because an allergic reaction can occur up to 24 hours after the injection, patients need to know the signs and symptoms of anaphylaxis and how to self-administer emergency treatment. Omalizumab is approved for patients ages 12 and older who have moderate-to-severe asthma related to allergies.

Drug Approval

In 2006, budesonide/formoterol (Symbicort) was approved for patients age 12 years and older. Symbicort combines a corticosteroid and a long-acting beta2-agonist into a single inhaler.

Inhaled Corticosteroids

Inhaled corticosteroids may help reduce wheezing in young children with breathing problems, but they do not help prevent the development of asthma, according to several 2006 studies in the New England Journal of Medicine.
Inhaled corticosteroids work better than a corticosteroid/long-acting beta2-agonist combination or a leukotrine receptor antagonist drug in treating children with mild-to-moderate asthma, suggests a 2007 study in the Journal of Allergy and Clinical Immunology.

Long-Acting Beta2-Agonists

Long-acting beta2-agonist drugs such as salmeterol (Serevent Diskus) and formoterol (Foradil Aerolizer) may worsen asthma symptom severity and increase the risk for asthma-related death, indicates a 2006 review in the Annals of Internal Medicine.
Products that contain salmeterol and formoterol now have strengthened warning labels detailing these risks.

Childhood Asthma Statistics

Asthma death rates among children have largely declined since 1999 while doctors’ office visits for asthma treatment have more than doubled, indicates a recent report from the U.S. Centers for Disease Control and Prevention.

Introduction

The word asthma originates from an ancient Greek word meaning panting. Essentially, asthma is an inability to breathe properly. When any person inhales, the air travels through the following structures:

Air passes into the lungs and flows through progressively smaller airways called bronchioles. The lungs contain millions of these airways.
All bronchioles lead to alveoli, which are microscopic sacs where oxygen and carbon dioxide are exchanged.

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.

Asthma is a chronic condition in which these airways undergo changes when stimulated by allergens or other environmental triggers. Such changes appear to be two specific responses:

The hyperreactive response (also called hyperresponsiveness)
The inflammatory response

These actions in the airway cause patients to cough, wheeze, and experience shortness of breath (dyspnea), the classic symptoms of asthma.

In the hyperreactive response, smooth muscles in the airways constrict and narrow excessively in response to inhaled allergens or other irritants. Airways in everyone's lungs respond by constricting when exposed to allergens or irritants but there are major differences in the hyperreactive response that occurs in people with asthma:

When people without asthma breathe in and out deeply, the airways relax and open in order to rid the lungs of the irritant.
When people with asthma try to take those same deep breaths, their airways do not relax but instead narrow, causing the patients to pant for breath. Smooth muscles in the airways of people with asthma may have a defect, perhaps a deficiency in a critical chemical that prevents the muscles from relaxing.

The hyperreactive stage is followed by the inflammatory response, which generally contributes to asthma in the following way:

The immune system responds to allergens or other environmental triggers by delivering white blood cells and other immune factors to the airways.
These so-called inflammatory factors cause the airways to swell, fill with fluid, and produce a thick sticky mucus.

Click the icon to see an image of a normal versus asthmatic bronchiole.

This combination of events results in wheezing, breathlessness, inability to exhale properly, and a phlegm-producing cough.

Inflammation appears to be present in the lungs of all patients with asthma, even those with mild cases, and plays a key role in all forms of the disease.

Causes

Asthma occurs in about 5 million American children. Each year about 200,000 of them are hospitalized. It is the most common chronic childhood illness. About half of all cases of asthma develop before the age of 10, and about 80% of patients develop symptoms before they are 5 years old.

The mechanisms that cause asthma are complex and vary among population groups and even individuals. For example, asthma in children is highly associated with allergies. However, only a minority of children with allergies have asthma, and allergic response cannot explain all cases of asthma. Other factors, such as genetics or environmental conditions are probably involved in the development of asthma. Most likely, several genes combine to make a child susceptible to environmental triggers, not only allergens but also possibly infections, dietary patterns, or air pollution. Physical factors, particularly having smaller lungs, affect the chances for later asthma.

Asthma and allergies often coexist, and the allergic response plays a strong role in childhood asthma. About 70 - 85% of children with asthma also have allergies. Some studies suggest that children who have allergies are also at greater risk for developing asthma as adults. A 2006 study found that children who are allergic to dust mites are three times more likely to later develop asthma than children who were not allergic.

However, the evidence is clearly mixed. Several other 2006 studies suggested that avoiding dust mites does not help prevent asthma and, in fact, early exposure to dust mites may even protect children from developing asthma and allergic responses. Some experts think that giving immunotherapy (“allergy shots”) to children with allergies may help prevent asthma development.

An asthma attack can be induced or aggravated by direct irritants to the lungs. Studies indicate that the more indoor allergens a child is allergic to, the higher the risk for severe asthma. Important irritants or allergens include the following:

Dust mites, specifically mite feces, which are coated with enzymes that contain a powerful allergen. These are the primary allergens in the home.
Animal dander. Cats harbor significant allergens, which can even be carried on clothing; dogs usually present fewer problems.
Molds.
Cockroaches. Cockroaches are major asthma triggers and may reduce lung function even in people without a history of asthma.
Pollen. An asthma attack from an allergic response to pollen is more likely to occur during extreme air changes, such as thunderstorms. Major weather changes, such as El Nino, can affect the timing of allergy seasons because they cause seasonal changes (and pollen) to start earlier.
Food allergies. About 8 - 10% of children with asthma also have food allergies. These children also appear to have a high risk for very serious reactions to such foods. In infants and toddlers, allergy to eggs appears to be a predictor of asthma.
Fossil Fuels. Certain chemicals may trigger allergic rhinitis. Some experts believe that refined fossil fuels, such as diesel fuel and particularly kerosene, may be important triggers for allergic rhinitis. In people who already have allergies or asthma, exposure to such fossil fuels may worsen symptoms.

The Allergic Response. The allergic process, called atopy, and its connection to asthma are not completely understood. It involves various airborne allergens or other triggers that set off a cascade of events in the immune system leading to inflammation and hyperreactivity in the airways. One description is as follows:

The conductor in an orchestra of immune factors that contribute to allergies and asthma appears to be a category of white blood cells known as helper T cells, in particular a subgroup called Th2 cells.
Th2 cells overproduce interleukins (ILs), immune factors that are molecular members of a family called cytokines, which are involved in the inflammatory process.
Interleukins 4, 9, and 13, for example, may be responsible for a first-phase asthma attack. These interleukins stimulate the production and release of antibody groups known as immunoglobulin E (IgE). (People with both asthma and allergies appear to have a genetic predisposition for overproducing IgE.)
During an allergic attack, these IgE antibodies can bind to special cells in the immune system called mast cells, which are generally concentrated in the lungs, skin, and mucous membranes. This bond triggers the release of a number of active chemicals, importantly potent molecules known as leukotrienes. These chemicals cause airway spasms, overproduce mucus, and activate nerve endings in the airway lining.
Another cytokine, interleukin 5, appears to contribute to a late-phase inflammatory response. This interleukin attracts white blood cells known as eosinophils. These cells accumulate and remain in the airways after the first attack. They persist for weeks and mediate the release of other damaging particles that remain in the airways.

Researchers are investigating the role that T cells play in asthma. T cells are white blood cells that are involved in the immune response. Researchers had focused on the T cell called type 2 helper (ThH2) cells. However, a 2006 breakthrough study in the New England Journal of Medicine suggested that a different type of T cell may play a stronger role in asthma than previously thought.

Researchers discovered that these cells, called natural killer T cells, are far more common in the lungs of people with asthma than in the lungs of healthy people. Natural killer T cells are very rare, but researchers found them in 60% of people with moderate-to-severe persistent asthma. While this research is preliminary, it may explain why corticosteroid drugs do not work well for some patients with asthma: Steroid drugs target Th2 and other inflammatory cells, not natural killer T cells. Researchers think that further investigation of natural killer T cells may lead the way to new types of asthma drugs. If these cells prove to be involved in asthma, then drugs that eliminate them might become an important new treatment.

Over the course of years the repetition of the inflammatory events involved in asthma can cause irreversible structural and functional changes in the airways, a process called remodeling. The remodeled airways are persistently narrow and can cause chronic asthma. Researchers are trying to determine how this process occurs:

Interleukins. Some researchers are looking at potent immune factors, including interleukins 11 and 13. They have been linked to a number of processes possibly involved in remodeling, including scarring in the airways and overgrowth of cells in the smooth muscles that line the airways.

Growth Factors. Compounds known as vascular endothelial growth factor (VEGF) have been observed in the airways of patients with asthma. VEGF is a powerful promoter of cell growth in blood vessel linings and some researchers believe it may be major factor in remodeling.

About one-third of all persons with asthma share this condition with another member of their immediate family. Asthma may be more likely to be passed to children from the mother than from the father. Both allergies and asthma are strongly associated with hereditary factors, sharing certain genetic markers, but they are not always inherited together.

Research on the genetics of these conditions is confusing. Of some significant promise, researchers have identified a gene (ADAM33), which has been linked to asthma. The gene regulates one of the enzymes called metalloproteases, which are involved with the smooth muscle in the airway. A mutation of this gene could play a role in airway changes that occur after inflammation.

The role of early childhood respiratory and intestinal infections is very complex. Viral respiratory infections certainly worsen existing asthma, but the most common ones are unlikely to be causes of childhood asthma. In fact, early respiratory and intestinal infections may offer some protection against asthma.

Early Respiratory Infections as Causes of Asthma. Studies suggest that most respiratory infections are not important causes of asthma in children, except in certain cases. An important exception is the respiratory syncytial virus (RSV), which has been implicated in the development of asthma. RSV is the major viral cause of infant pneumonia. Studies also indicate that infants who have reduced lung function within a few days after birth are at increased risk of developing asthma by the time they are 10 years old.

Common Respiratory Infections Worsen Asthma. Common respiratory infections viruses that cause colds (such as the rhinovirus) may in some cases be associated with the development of asthma. A 2007 study suggested that children who have a wheezing rhinovirus during infancy are at increased risk for developing asthma by age 6. Even if these viruses do not directly cause asthma, they can worsen asthma in children who already have it. Rhinovirus has been reported to be the most common infection associated with asthma attacks. In one study, it was associated with 61% of asthma worsening in children. Some research suggests that colds promote inflammation in patients with existing asthma and increase the intensity of airway responsiveness for weeks.

The Hygiene Theory: Early Infections as Protection Against Asthma. Another blames the dramatic increase in asthma on the reductions in childhood infections that have occurred with modern hygiene and antibiotic use. The basic theory rests on the idea that infections stimulate production of specific immune factors called Th1 cells. As these cells build up, they replace other immune factors called Th2 cells, which react to allergens -- a less serious threat to the body. Without infections to stimulate the production of the Th1 infection fighters, the Th2 allergen fighters are not replaced, and they persist at high levels, making the growing child more susceptible to allergies and asthma.

A number of different studies support this theory:

Some studies suggest that being part of a large family or attending day care increases the risk for early respiratory infections but reduces the risk of childhood asthma. The occasional cold, then, may be protective.
In one study, researchers measured levels of bacterial byproducts called endotoxins in the mattress dust of 812 children. Those with the highest levels had 80% lower rates in allergies and asthma.
Another study further found a strong association between allergy development and the absence of certain beneficial bacteria (called probiotics) carried in the infant's intestines. Infants who were born in more hygienic environments tended to lack these bacteria. Antibiotic overuse and modern hygiene may be reducing these helpful organisms. (Probiotics can be obtained in active yogurt cultures and in supplements, which are being studied for protection.)

The standard vaccinations against serious childhood infections, according to several important studies, pose no risk for asthma. One of the studies even reported some lower risk for asthma and allergies in the second and third years after vaccinations. Infections killed thousands of children every year before immunization became widespread. Asthma, although serious, is rarely fatal in children. No one should stop giving their children vaccinations against childhood killers.

GERD. At least half of patients with asthma also have gastroesophageal reflux disease (GERD), the cause of heartburn. It is not entirely clear which condition causes the other or whether they are both due to common factors.

Heartburn is a condition where the acidic stomach contents back up into the esophagus causing pain in the chest area. This reflux usually occurs because the sphincter muscle between the esophagus and stomach is weakened. Standing or sitting after a meal can help reduce the reflux which causes heartburn. Continuous irritation of the esophagus lining as in gastroesophageal reflux disease is a risk factor for the development of adenocarcinoma.

Some theories for the causal connection between GERD and asthma are:

Acid leaking from the lower esophagus in GERD stimulates the vagus nerve, which runs through the gastrointestinal tract. This stimulated nerve, in turn, triggers the nearby airways in the lung to constrict, causing asthma symptoms.
Acid back-up that reaches the mouth may be inhaled into the airways (aspirated). Here, the acid triggers a reaction in the airways that cause asthma symptoms.

GERD is sometimes hard to detect and might be suspected as a contributor in the following patients:

Those who do not respond to asthma treatments.
Those whose asthma attacks follow episodes of heartburn.
Those whose attacks are worse after eating or exercise.
Those whose coughs follow episodes of acid reflux. (One study found that GERD was associated with about half of the episodes of coughs and wheezes in patients with asthma.)

Treating GERD symptoms with anti-acid drugs may resolve asthma in some (but not all) patients who share both conditions. A small 2005 observational study found that while GERD was common in patients with asthma, treatment of GERD had no effect on asthma symptoms. [See In-Depth Report #85: Heartburn and gastroesophageal reflux disease.]

Sinusitis. Almost half of children and adults with allergic asthma have sinus abnormalities, and in various studies, between 17 - 30% of patients with asthma develop true sinusitis. The presence of sinusitis, however, does not appear to increase the severity of asthma.

Click the icon to see an image of sinusitis.

Parental Migraines and Childhood Asthma. Some studies have reported a link between childhood asthma and parental migraines, with one small study suggesting that children are about five times more likely to develop asthma if their parents have a history of migraines.

Exercise-induced asthma (EIA) is a limited form of asthma in which exercise triggers coughing, wheezing, or shortness of breath.

About 10% of adults and some fewer children have aspirin-induced asthma (AIA). With this condition, asthma gets worse when patients take aspirin. Aspirin is one of the drugs known as nonsteroidal anti-inflammatory drugs (NSAIDs). Although aspirin is used to reduce inflammation in other disorders, it appears to have the opposite effect in many asthma cases. It is not wholly known why this occurs. AIA often develops after a viral infection. It is a particularly severe asthmatic condition and is associated with up to 25% of asthma-related hospitalizations. In about 5% of cases, aspirin is responsible for a syndrome that involves multiple attacks of asthma, sinusitis, and nasal congestion. Such patients also often have polyps (small benign growths) in the nasal passages.

Patients with aspirin-induced asthma (AIA) should avoid aspirin and most likely NSAIDs, including ibuprofen (Advil) and naproxen (Aleve).

Acetaminophen (Tylenol) has been the traditional alternative for relief of minor pain for patients who are aspirin-sensitive. Unfortunately, recent evidence has muddied these recommendations. Moreover, some asthmatic episodes have been linked to high consumption of acetaminophen among adults. And a study of children with asthma reported that those who took ibuprofen were less likely to be hospitalized for asthma than those taking acetaminophen. This is of particular concern, since acetaminophen is the pain reliever of choice in small children.

Asthma occurs primarily at night (nocturnal asthma) in as many as 75% of patients with the condition. Attacks often occur between 2 - 4 a.m. Factors that might play role in nocturnal asthma may include one or more of the following:

Chemical and temperature changes in the body during the night that increase inflammation and narrowing of the airways
Delayed allergic responses from exposure to allergens during the day
The wearing off of inhaled medications toward the early morning
An increase in acid reflux (back up of stomach acid) that causes airways to narrow
Postnasal drip that occurs during sleep
Conditions relating to sleep, such as sleep apnea or sleeping on one's back, which may worsen any asthma attack that occurs at night

Some experts believe that nocturnal asthma may actually be a unique form of asthma with its own specific biologic mechanisms that occur only at night and which reduce natural steroid hormones (which block inflammation).

Exercise-induced asthma (EIA) is a limited form of asthma in which exercise triggers coughing, wheezing, or shortness of breath. This condition generally occurs in children and young adults, most often during intense exercise in cold dry air. Symptoms are generally most intense about 10 minutes after exercising and then gradually resolve.

EIA is triggered only by exercise and is distinct from ordinary allergic asthma in that it does not produce a long duration of airway activity, as allergic asthma does. (However, some people have both forms of asthma.) People who have only EIA do not appear to require long-term maintenance therapy. A study of military recruits with EIA also reported that the condition does not hinder a person's overall physical performance.

Medications. Cromolyn, a mild anti-inflammatory drug, or short-acting beta2-agonists have been the treatments of choice for preventing EIA. Newer approaches for people who work out regularly include pretreatment with long-acting beta2-agonists, such as salmeterol (Serevent) or the regular use of inhaled corticosteroids.

Hints for Reducing EIA. EIA occurs only after exercise and is more likely to occur with regular paced activities in cold, dry air. The following are some suggestions for reducing its impact:

Warm-up and cool-down periods are important.
Patients with EIA might do better with activities that involve short bursts of exercise (tennis, football) than with exercises involving long-duration regular pacing (cycling, soccer, and distance running).
Breathing through a scarf or through the nose helps warm up the airways.
Restricting dietary salt might help reduce EIA.

Click the icon to see an image of exercise-induced asthma.

Prognosis

Asthma is the third major cause of hospitalization in children under age 15. The condition can be very serious in children, particularly those younger than age 5, because their airways are very narrow.

The severity of asthma is graded as mild intermittent and mild, moderate, and severe persistent. A patient in any of these categories, even mild intermittent, can still experience a severe and even life-threatening attack. According to one report, 30% of asthma deaths occur in patients with mild asthma.

Asthma is rarely fatal in children, with only 187 asthma deaths reported in 2002 in children under age 18. In fact, a 2006 study from the U.S. Centers for Disease Control and Prevention reported that asthma death rates for children have steadily declined since 1999. (During the same time, the number of doctor visits for asthma treatment more than doubled.) Even low mortality numbers are unacceptable, however, since asthma deaths are largely preventable.

Factors associated with an increased risk of death from asthma in children include:

Previous life-threatening episodes of asthma
Lack of adequate and ongoing health care. (Most likely the reason for the higher fatalities rates in minority children.)
Significant behavioral problems
Underestimating the severity of an acute attack poses the greatest threat. Unfortunately, one study of children found that nearly 40% of them were unaware of asthmatic symptoms when they occurred.

African American children have more than six times the death rate of Caucasians in the age groups of 4 years and younger and 15 - 24 years. Hispanic children also have a higher risk.

The following signs and symptoms may indicate a life-threatening situation:

As the chest labors to bring enough air into the lungs, breathing often becomes shallow.
Lacking sufficient oxygen, the skin becomes bluish.
The flesh around the ribs of the chest appears to be sucked in.
The patient may begin to lose consciousness.

Asthma often progresses very slowly to a serious condition or may develop to a fatal or near-fatal attack within a few minutes. It is very difficult to predict when an attack will become very serious. Early symptoms or lack thereof do not always reflect the ultimate severity of an attack. Some studies even suggest that people at high risk for fatal or near-fatal asthma attacks are those with poor awareness of their own reduced ability to breathe and who are slow in seeking help. Monitoring peak flow rates is, therefore, an important management component, since it provides a more accurate assessment of lung function than symptoms alone.

In a 2003 study, researchers followed people with asthma for longer than 30 years. About a third of children had outgrown their asthma in adulthood. In general, the more severe the childhood asthma, the greater the likelihood that it will persist. For example, only 23% of children who experienced wheezy bronchitis (wheezing during respiratory infections) suffered from frequent or persistent asthma in adulthood.

There is evidence that severe asthma can cause long-lasting damage and possibly permanent scarring in some patients. The risk for such injury is highest, however, when asthma strikes children in the first 3 - 5 years. There does not appear to be any significant risk for long-term lung damage for children who develop mild-to-moderate persistent asthma between ages 5 - 12. Children adapt well to living with asthma, and even with severe asthma they can function as well as healthy children in virtually all areas of life.

Studies are mixed over the effects of emotional disorders on the severity of asthma. One study indicated that parents of children with asthma may suffer greater psychological stress than their children. A 2000 study reported that mild-to-moderate asthma does not significantly affect the psychological well-being of most children ages 5 - 12. Teenagers and preteens may have particular difficulty coping with what they perceive as the social stigma of asthma. Parents and older children should not hesitate to seek help from support groups, doctors, friends, or family members. Support programs may help children to better manage their asthma and even reduce hospitalization.

Although there have been few studies on the effects of asthma on schooling, a 2000 study reported that nocturnal (nighttime) asthma affected school attendance and performance in children and work attendance in their parents.

Risk Factors

Asthma affects about 5 million American children between the ages of 5 - 14. Asthma has dramatically increased worldwide over the last few decades, in both developed and developing countries. From 1980 - 1994, asthma increased 160% in American children younger than 4 years and has also dramatically risen worldwide. Experts are puzzling over the cause of this phenomenon. Possible causes and risk factors that are suspects in the dramatic rise in asthma in children include:

Survival rates are now higher in low-birth-weight babies, who may be more susceptible to asthma.
Declining rates in nursing may be a contributor. Breast milk contains important anti-inflammatory substances, such as omega-3 fatty acids, which might protect against asthma.
Western dietary habits (which commonly include more fast foods and less fruits, vegetables, fiber, minerals, and other nutrients) may contribute to the development of childhood asthma.
Children are spending more time indoors watching television, playing video games, or using the computer and are, therefore, overexposed to indoor allergens.
The trend of making homes more energy-efficient may result in dust mites being trapped inside them.

Among younger children, asthma develops twice as frequently in boys as in girls, but after puberty it may be more common in girls.

Urban Life. Urban life is strongly associated with a higher risk. Although poverty plays a significant role, urban life has been associated with a higher risk for asthma in any income group and among both children and adults. In some urban areas, as many as 25% of children have asthma or show signs of wheezing. In fact, it may be greatly underdiagnosed in city children. A 1999 study reported that almost a third of children in inner-city kindergartens had asthma symptoms without a diagnosis of the disorder; 10% had actually been diagnosed with asthma, mainly because their symptoms were severe.

Ethnicity. Since 1980, asthma rates have risen the most dramatically among African American children, and they have significantly higher rates of asthma than Caucasian children. Hispanic children are also at higher risk. Both groups of minority children are more likely to have fatal asthma than Caucasian children.

Some studies indicate that the difference in risk exists simply because African Americans and other minority groups are more likely to live in urban areas. Poverty and lack of access to health care also play a role. However, Caucasian children who live in cities also face a high risk for asthma, and rural African American children do not.

Urban life and socioeconomic factors, however, may not fully explain the ethnic disparity.

Low Birth Weight. Infants of low birth weight are at higher risk for lung problems and asthma.

Winter Birth. Children born in the winter may have a greater risk for asthmatic allergies to cockroaches than children born at other times of the year.

Vitamin D. A 2006 study suggested a link between vitamin D intake during pregnancy and development of early childhood asthma. Pregnant women who had a higher intake of vitamin D were less likely to give birth to children who developed asthma.

Breast Feeding. Most studies on breastfeeding report some protection against wheezing and asthma in the first year of life. Breastfeeding has many other benefits for the child as well. The American Academy of Pediatrics recommends exclusively breastfeeding for the child's first 6 months of life.

Complications of Pregnancy. According to a 2000 study, complications of pregnancy, specifically those involving the mother's uterus (such as post-birth hemorrhage, pre-term contractions, insufficient placenta, and restricted growth of the uterus), are associated with an increased risk of childhood asthma. Another study reported that delivery procedures such as Cesarean section, the use of vacuum extraction or forceps also raised the risk of childhood asthma.

In both adults and children, the incidence of obesity and asthma has been increasing over recent years. Studies report a strong association between the two conditions. Some experts suggest that excess weight pressing on the lungs may trigger the hyperreactive response in the airways typical of asthma. Others believe that asthma leads to obesity by inhibiting physical activity, although several studies have found no difference in activity levels between people with or without asthma. Some studies suggest that many obese people may be misdiagnosed as having asthma when they are simply short of breath, possibly because of the increased effort required for breathing.

In any case, there is evidence that losing weight can relieve asthma symptoms. Some evidence also suggests that people who are overweight (body mass index greater than 25) have more difficulty getting their asthma under control. Weight loss in anyone who is obese and has asthma or shortness of breath reduces airway obstruction and improves lung function. [See In-Depth Report #53: Weight control and diet.].

Damp Homes. Studies suggest that children who live in damp homes have a much higher risk for asthma.

Mental Health. Research indicates that poor mental health of parents and children are significant predictors of more severe symptoms in childhood asthma. A 2000 study suggested that high stress levels can predict the onset and severity of asthma in children genetically at risk for the condition.

Symptoms

In children with asthmatic symptoms, it is important to first consider as a possible cause inhaled foreign objects such as peanuts; viral infections such as croup; and bacterial infections, which may be accompanied by high fever and progress rapidly. Any child who has frequent coughing or respiratory infections should be checked for asthma.

The classic symptoms of an asthma attack include:

Wheezing when breathing out is nearly always present during an attack. Usually the attack begins with wheezing and rapid breathing, and, as it becomes more severe, all breathing muscles become visibly active.
Shortness of breath (dyspnea). Shortness of breath is a major source of distress in patients with asthma, although severe dyspnea does not always reflect a serious attack or reduced lung function.
Coughing. In some people, the first symptom of asthma is a nonproductive cough.
Chest tightness or pain. Initial chest tightness without any other symptoms may be an early indicator of a serious attack.
Neck muscles may tighten, and talking may become difficult or impossible.
Rapid heart rate
Sweating
Chest pain occurs in about 75% of patients. It can be very severe, although its intensity is not necessarily related to the severity of the asthma attack itself.

The end of an attack is often marked by a cough that produces thick, stringy mucus. After an initial acute attack, inflammation persists for days to weeks, often without symptoms. (The inflammation itself must still be treated, however, because it usually causes relapse.)

Diagnosis

The doctor will consider a diagnosis of asthma if a child has a history of periodic attacks of shortness of breath, coughing, and wheezing, perhaps accompanied by tightness in the chest. The parent should describe the pattern of symptoms and possible precipitating factors, including:

Whether symptoms are more frequent during the spring or fall (allergy seasons)
Whether exercise, a respiratory infection, or exposure to cold air has ever triggered an attack
Any family history of asthma or allergic disorders such as eczema, hives, or hay fever

A number of disorders may cause some or all of the symptoms of asthma. Panic disorder can coincide with asthma or be confused with it. Other diseases that must be considered during diagnosis are pneumonia, bronchitis, severe allergic reactions, psychosomatic illnesses, and certain rare disorders (such as tapeworm and trichomoniasis).

If symptoms and a patient's history are indicative of asthma, the doctor will usually perform tests known as pulmonary function tests to confirm the diagnosis and determine the severity of the disease.

Using a spirometer, an instrument that measures the air taken into and exhaled from the lungs, the doctor will determine several values:

Vital capacity (VC), which is the maximum volume of air that can be inhaled or exhaled.
Peak expiratory flow rate (PEFR), commonly called the peak flow rate, which is the maximum flow rate that can be generated during a forced exhalation.
Forced expiratory volume (FEV1), the maximum volume of air expired in 1 second.

If the airways are obstructed, these measurements will fall. Depending on the results, the doctor will take the following steps:

If measurements fall, the doctor typically asks the patient to inhale a bronchodilator. This drug is used in asthma to open the air passages. The measurements are taken again. If the measurements are more normal, the drug has most likely cleared the airways, and a diagnosis of asthma is strongly suspected.
If measurement results fail to show airway obstruction, but asthma is still suspected, the doctor may perform a challenge test. It involves administering a specific drug (histamine or methacholine) that usually increases airway resistance only when asthma is present.

The patient may be given skin or blood allergy tests, particularly if a specific allergen is suspected and available for testing. Allergy skin tests may be the best predictive test for allergic asthma, although they are not recommended for people with year-round asthma.

One of the most common methods of allergy testing is the scratch test or skin prick test. The test involves placing a small amount of the suspected allergy-causing substance (allergen) on the skin (usually the forearm, upper arm, or the back), and then scratching or pricking the skin so that the allergen is introduced under the skin surface. The skin is observed closely for signs of a reaction, which usually includes swelling and redness of the site. With this test, several suspected allergens can be tested at the same time, and results are usually available within about 20 minutes.

Tests that either rule out other diseases or obtain more information about the causes of asthma include the following:

A complete blood count
Chest and sinus x-rays
Computed tomography (CT) scans. CT scans may be helpful in certain cases, such as for determining wall thickness in airways in patients who are difficult to treat, which could signify a higher risk for lung damage.
Examination of the patient's sputum for eosinophils (white blood cells that in high levels are associated with severe allergic asthma).
Researchers are investigating measurements of certain chemicals in sputum or exhaled air that indicate airway inflammation. Such chemical markers include nitric oxide and hydrogen peroxide. For example, high levels of nitric oxide may prove to be a simple and noninvasive way of diagnosing asthma.

Treatment

Treating an Acute Attack in the Hospital. An acute attack may require hospitalization. Laboratory tests, an electrocardiogram (ECG), and a chest x-ray are performed to determine lung function, oxygen levels, and other indications of severity or rule out other causes. Depending on the results, the following treatments may be given:

Beta2-agonists are the standard therapy. They are typically administered with a nebulizer (a device that administers the drug in a fine spray). Studies suggest, however, that even very small children may be able to use metered-dose inhalers (MDIs), which are just as effective and more convenient than nebulizers. (Intravenous delivery is not recommended in most cases.)
An anticholinergic drug (ipratropium) is sometimes added to improve symptoms.
A corticosteroid (commonly called a steroid) given within the first hour helps reduce the need for hospitalization. Steroids may be administered intravenously, as a shot, or orally. Children may respond well to oral steroids.
Oxygen is usually administered, and can be life saving in severe cases.
Infusions of magnesium sulfate open airways and are an important emergency treatment for adults. Its benefits for children need to be further demonstrated.
In life-threatening situations, the patient may require mechanical ventilation.

Antibiotics are not useful for asthma attacks if there is no strong evidence of the presence of a bacterial infection. Viral infections, most often colds and the flu, are more likely to trigger an asthma attack. In such cases, antibiotics are not helpful and may have adverse effects.

Discharge and Relapse After Hospitalization. It typically takes about 3 - 4 hours to determine if a patient can be safely sent home or if they need to stay. Patients are generally discharged when:

Symptoms are gone or minimal, and
The peak expiratory flow rate is 70% or more of the predicted rate

Despite reasonable precautions, between 12 - 16% of patients relapse within 2 weeks of leaving the hospital. Receiving a steroid shot at discharge or taking an oral corticosteroid for a few days can reduce this risk.

Avoiding allergens, following appropriate drug treatments, and home monitoring are key elements in preventing dangerous asthma attacks and hospitalization. In addition, good communication between the doctor and patient is a key factor in a successful management program.

Medications for asthma fall into two categories:

Rescue Medications. Medications that open the airways (bronchodilators, or inhalers) are used to quickly relieve any moderate or severe asthma attack. These drugs are usually short-acting beta-adrenergic agonists (beta2-agonists). Other drugs used in special cases include corticosteroids taken by mouth and anticholinergic drugs. None of these drugs have any effect on the disease process itself. They are only useful for treating symptoms.
Maintenance Medications. Simply coping with asthma symptoms without also controlling the damaging inflammatory response is a common and serious error. For adults and children over age 5 with moderate-to-severe persistent asthma, experts now recommend inhaled corticosteroids and long-acting beta2-agonists.

Parents can greatly reduce the frequency and severity of their children’s asthma attacks by understanding the difference between coping with asthma attacks and controlling the disease over time. Unfortunately, many patients do not understand the difference between medications that provide rapid, short-term relief and those that are used for long-term symptom control. Many patients with moderate or severe asthma overuse their short-term medications and underuse their corticosteroid medications. The overuse of bronchodilators can have serious consequences; not using steroids can lead to permanent lung damage.

Patients need to understand that asthma symptoms can change quickly over time and that treatment strategies may need to change in response. In 2005, the two leading U.S. allergy associations published joint guidelines on controlling asthma. The guidelines emphasize that asthma treatment decisions need to be made on an individual basis. It is important that patients have a close relationship with their doctor. The doctor needs to evaluate a patient’s asthma symptoms at each visit to determine any need for changes in medication. According to the guidelines, asthma management is classified as either “well-controlled” or “not well-controlled.” The doctor may need to change some medications, or increase or decrease the dosage, depending on whether a child’s asthma is well-controlled or not well-controlled.

These are the signs of well-controlled asthma:

Asthma symptoms occur twice a week or less
Rescue bronchodilator medication is used twice a week or less
Symptoms do not cause nighttime or early morning awakening
Symptoms do not limit work, school, or exercise activities
Peak flow meter readings are normal or the patient’s personal best
Both the doctor and the patient consider the asthma to be well controlled


Classification	Symptom Frequency	Children Age 5 Years and Younger: Recommended Treatment	Children Older Than 5 Years: Recommended Treatment
Mild intermittent	At least 2 days per week. At least 2 nights per month.	No daily medication.	No daily medication. If severe attacks occur, systemic corticosteroids recommended.
Mild Persistent	More than 2 days per week, but less than once per day. More than 2 nights per month.	Preferred treatment: Low-dose inhaled corticosteroids with nebulizer, or MDI with holding chamber with or without face mask. Alternative treatment: Cromolyn or leukotriene-antagonist.	Preferred treatment: Low-dose corticosteroids. Alternative treatment: Cromolyn, leukotriene modifier, nedocromil, OR sustained release theophylline.
Moderate Persistent	Daily daytime symptoms. More than 1 night per week.	Preferred treatment: Low-dose inhaled corticosteroids and long-acting beta2-agonists OR medium-dose inhaled corticosteroids. Alternative treatment: Low-dose inhaled corticosteroids and either leukotriene receptor antagonist or theophylline. If needed (especially if severe attacks occur): Medium-dose inhaled corticosteroids and long-acting beta2-agonists; medium-dose inhaled corticosteroids and either leukotriene receptor antagonist or theophylline.	Preferred treatment: Low-to-medium dose inhaled corticosteroids and long-acting beta2-agonists. Alternative treatment: Low-to-medium dose inhaled corticosteroids and either leukotriene receptor antagonist or theophylline, or increased medium dose inhaled corticosteroids. If needed (especially if severe attacks occur): Increase dosage of medium-dose inhaled corticosteroids with add-on long-acting beta2-agonists. Alternatively, increase dosage of medium-dose inhaled corticosteroids plus either leukotriene receptor antagonist or theophylline.
Severe Persistent	Continual daytime symptoms. Frequent nighttime symptoms.	Preferred treatment: High-dose inhaled corticosteroids and long-acting beta2-agonists plus (if needed) oral corticosteroids.	Preferred treatment: High-dose inhaled corticosteroids combined with long-acting inhaled beta2-agonists. Add, if needed: Oral corticosteroids. Repeat attempts should be made to reduce use of systemic corticosteroid and maintain control with inhaled corticosteroid.
Adapted from National Asthma Education and Prevention Program (NAEPP) Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma – Update on Selected Topics 2002 (EPR-2 Update).

Most asthma drugs are inhaled using various forms of inhalers or nebulizers. Inhaled drugs must be used regularly as prescribed and the patient carefully trained in their use in order for them to be effective and safe. Studies suggest that many children fail to use the devices properly, although newer devices are easier to use than others. The basic devices are the metered-dose inhaler (MDI), breath-actuated inhalers, dry powder inhalers, and nebulizers.

MDIs have used chlorofluorocarbons (CFCs) as their propellants. CFCs are damaging to the environment and are now being replaced with other propellants (hydrofluoroalkane) that are more environmentally safe, and do not chill the device as CFCs do. Devices that don't use any propellants are also now available.

Metered-Dose Inhaler. The standard device for administering any asthma medication is the metered-dose inhaler (MDI). This device, particularly when used with a spacer, allows precise doses to be delivered directly to the lungs. (The spacer is a tube that is attached to the inhaler. It serves as a holding chamber for the medication that is sprayed by the inhaler.) MDI-delivered drugs must be used regularly as prescribed and the patient carefully trained in their use in order for them to be effective and safe. Some patients hold the MDI too close to their mouths, or even inside them. Others may exhale too forcefully before inhalation.

The spacer helps improve medication delivery by allowing the patient additional time to inhale. They vary, however, in their effectiveness. It should be noted that MDIs can continue to deliver propellant even after the drug has been used up. Patients should track their medicine and throw the device away when the last dose has been administered.

Nebulizers (not MDIs) are typically used in very small children, both at home and in the emergency room. However, recent studies suggest spacers may be better than nebulizers for children and shorten the time spent in emergency rooms. Studies also indicate that with the use of a face mask and a spacer, the MDI works well even for infants in the emergency room and may prove to be useable at home.

Click the icon to see an illustrated series detailing a metered dose inhaler.

Breath-Actuated Inhalers. Breath-actuated rotary inhalers (Easi-Breathe and Autohaler) deliver the drug directly to the back of the throat as the user inhales. Their primary advantage over the MDI is their ease of use. They also do not use CFCs as propellants. In comparison studies, patients have been very successful with the breath-actuated inhalers. They are not recommended for children under 8 years old.

Dry Powder Inhalers. Dry powder inhalers (DPIs) deliver a powdered form of beta2-agonists or corticosteroids directly into the lungs. Such devices include Rotahaler, Spinhaler, Turbohaler, Clickhaler, Easyhaler, Diskhaler, Discus, Twisthaler, Spiros, and others. DPIs are as effective as the older devices, and generally have a better taste and are easier to manage. They may differ among themselves, however, in their ability to deliver drugs into the airways. In one study, for example, the Turbohaler was easier to use than the Diskhaler and so achieved better delivery.

Humidity or extreme temperatures can affect DPIs' performance, so they should not be stored in humid places (bathroom cabinets) or locations subject to high temperatures (glove compartments during summer months).

Dry-powder may cause tooth erosion. Children are advised to rinse their mouths out right after using these inhalers and to brush twice a day with a fluoride toothpaste.

Other Hand-Held Inhalers. Respimat delivers a fine-mist spray that is created by forcing the liquid medication through nozzles. It does not use any propellant.

Nebulizers. A nebulizer is a machine that delivers a fine spray of medication-containing liquid. Nebulizers are often used for children younger than 3 years and sometimes for older children who have difficulty using the MDI. It takes 5 - 10 minutes to administer medication using a nebulizer. Because the spray is less targeted than with the inhaler, it must deliver large amounts of the drug. This increases the risk for toxicity and severe side effects. Nebulizers should not be used by children who can manage an inhaler. Their use has been associated with a higher rate of hospitalizations and longer duration of symptoms than inhalers. A 2007 study also suggested that the misuse of home nebulizers may be an important factor in asthma deaths in children and young adults. If children must use an albuterol nebulizer, parents should be sure that it does not contain the preservative benzalkonium, which actually narrows the airways.

Click the icon to see an illustrated series detailing the use of a nebulizer.

Asthma triggers a vicious emotional-physical cycle:

Breathlessness and wheezing incite a fear of suffocation and death, even in very small children.
This anxiety produces further constriction on the muscles surrounding the airways, which makes breathing even more difficult.

Caregivers must first focus on alleviating their own anxiety, which can heighten a child's own fears. The next step is to help the child relax. One method for this is as follows:

The child sits comfortably, bending slight forward with the eyes closed.
The hands are placed gently over the navel.
The child is then told to pretend the stomach is a balloon.
The "balloon" must be "blown up" by inhalation, not exhalation. The child can tell if this working because the hands will move slightly apart.
When the child breathes out, the "balloon" will be made flat.

This exercise both relaxes the child and discourages shallow, oxygen-poor breathing. Massaging the child in gentle circles on the chest is relaxing and may also loosen mucus.

Other recommendations include:

A child may also find relief by lying stomach-down on several pillows so that the head is slightly lower than the chest while the caregiver gently pats the back between the shoulder blades.
Warm liquids, such as soup or hot cider, are effective in loosening mucus and may also relax bronchial muscles. Cold fluids, like cold air, should be avoided.
Overhydration (too much liquid) can be harmful, however, so these drinks should not be forced on the child.
Warm, moist air from vaporizers can greatly ease and moderate asthma attacks.
Daily massages and breathing and relaxation techniques to reduce stress can be very helpful.

Many adults self-manage their asthma using daily monitoring of peak air flow with adjustments of the medications as needed. This involves the use of a peak flow meter, which measures peak expiratory flow rate (PEFR).

Click the icon to see an image of a peak flow meter.

Studies suggest, however, that for most children with asthma, an educational program is just as effective for managing the condition as monitoring. Most children do not need to monitor their peak air flow on any regular basis.

Quick-Relief Medications

These medications quickly control acute asthma attacks.

Beta2-agonists do not reduce inflammation or airway responsiveness but serve as bronchodilators, relaxing and opening constricted airways during an acute asthma attack. A short-acting inhaled beta2-agonist, taken as needed, is often the only medication used by children with chronic mild asthma.

Asthma is a disease in which inflammation of the airways causes airflow into and out of the lungs to be restricted. When an asthma attack occurs, mucus production is increased, muscles of the bronchial tree become tight, and the lining of the air passages swells, reducing airflow and producing the characteristic wheezing sound.

Specific short-acting beta2-agonists include:

Albuterol (Proventil, Ventolin), called salbutamol outside the U.S., is the standard short-acting beta2-agonist in America. Other similar beta2-agonists are isoproterenol (Isuprel, Norisodrine, Medihaler-Iso), metaproterenol (Alupent, Metaprel), pirbuterol (Maxair), terbutaline (Brethine, Brethaire, Bricanyl), and bitolterol (Tornalate). Isoetharine (Bronkometer, Bronkosol) is available in nebulizers.
Newer beta2-agonists, including levalbuterol (Xopenex), have more specific actions than the standard drugs. Xopenex is administered with a nebulizer, and studies have indicated that it is as effective as albuterol with fewer side effects. The original formulation of Xopenex was administered with a nebulizer. A new metered-dose inhaler formulation was launched at the end of 2005. It is approved for children age 4 years and older.

Short-acting bronchodilators are generally administered through inhalation and are effective for 3 - 6 hours. They relieve the symptoms of acute attacks, but they do not control the underlying inflammation. If asthma continues to worsen with the use of these drugs, a doctor may prescribe corticosteroids or other drugs to treat underlying inflammation.

Side Effects of Beta2-Agonists. Side effects of all beta2-agonists may include:

Anxiety
Tremor
Restlessness
Headache
Fast and irregular heartbeats. A doctor should be notified immediately if this side effect occurs.
These drugs should be taken with caution by children with diabetes or a history of seizures.
Beta2-agonists have serious interactions with certain drugs and parents should tell the doctor about any other medications their child is taking.

Loss of Effectiveness and Overdose. There has been some concern that short-acting beta2-agonists become less effective when taken regularly over time, increasing the risk for overuse. Over time, some patients may become tolerant to many effects of short-acting beta2-agonists. The degree to which this affects the airways is uncertain. In some studies, the duration of action has declined but the peak effect appears to be preserved, making these drugs still useful for acute attacks. Regular use of long-acting beta2-agonists may increase the chances of a reduced effect from the short-acting forms.

A 2005 landmark study suggested that patients’ differing clinical response to albuterol may be based on their genotype. Albuterol targets the beta-adrenergic receptor. In the Beta-Adrenergic Response by Genotype (BARGE) trial, researchers studied the effects of albuterol on patients with two different forms of this receptor. The results suggested that patients with the arginine form of the receptor did not respond to albuterol. These patients’ asthma symptoms actually improved when albuterol was not used. By contrast, patients with the glycine form of the receptor had improved asthma control with albuterol.

Inhaled ipratropium bromide (Atrovent) acts as a bronchodilator over time. Ipratropium bromide alone is only modestly beneficial for acute asthma attacks. In fact, the drug is not approved specifically for asthma. Some parents report benefit for treating wheezing in infants. It is also sometimes used in the emergency room to treat children with severe asthma to enhance the effects of intravenous beta2-agonists.

Common oral corticosteroids include prednisone/prednisolone, dexamethasone, methylprednisolone, and hydrocortisone. They reduce inflammation very effectively. A 2006 study indicated that oral prednisolone worked better than inhaled fluticasone for treating mild-to-moderate asthma attacks in children in emergency rooms. However, children often have difficulty taking these drugs because they have a bitter taste and can cause vomiting. Taking oral dexamethasone for 2 days may be as effective and more tolerable than the standard 5-day regimen of prednisone/prednisolone. Prolonged use of oral steroids has widespread and sometimes serious side effects, so they are not generally give to children for longer than a few days.

[See In-Depth Report #4: Asthma in adults.]

Long-Term Relief Medications

These medications are taken on a regular basis to prevent asthma attacks and control chronic symptoms.

Corticosteroids, also called glucocorticoids or steroids, are powerful anti-inflammatory drugs. Steroids are not bronchodilators (they do not relax the airways) and have little effect on symptoms. Instead, they work over time to reduce inflammation and prevent permanent injury in the lungs. They can also help prevent asthma attacks from occurring. Many studies have shown that the use of inhaled corticosteroids in patients with moderate-to-severe asthma significantly reduces the rate of rehospitalizations and deaths from asthma.

Inhalation of corticosteroids makes it possible to provide effective local anti-inflammatory activity in the lungs with minimal systemic effects. (By contrast, oral steroids have considerable side effects throughout the body.) Inhaled corticosteroids are recommended as the primary therapy under the following circumstances:

For any asthmatic condition more serious than occasional episodes of mild asthma. (Low-doses of inhaled steroids may even be safe and effective for some people with mild asthma, particularly those who find themselves using beta2-agonists daily.)
When treatment with bronchodilators is not effective.

Examples of inhaled corticosteroids:

Inhaled steroids include fluticasone (Flovent), budesonide (Pulmicort), triamcinolone (Azmacort and others), and flunisolide (AeroBid). In general, the newer drugs are more powerful than the older generation of inhaled drugs. Budesonide (Pulmicort Respules) is available in a jet nebulizer for children from 12 months to 8 years. It is the first such medication to be approved for children in this age group.
The FDA approved a new inhaled corticosteroid, mometasone furoate (Asmanex) was approved in 2005 for patients age 12 and older.
The older corticosteroid inhalants are beclomethasone (Beclovent, Vanceril) and dexamethasone (Decadron Phosphate Respihaler and others). They are less powerful than the newer steroids when delivered with standard inhalers. New inhalers that use very fine sprays (QVAR, Autohaler) to deliver the drugs deep into the lungs may prove to be as effective as the newer, more potent steroids.
Inhalers that combine both long-acting beta2-agonists and corticosteroids are also available. These include Symbicort (budesonide/formoterol), which was approved in 2006 for patients ages 12 years and older.

Expert guidelines recommend inhaled corticosteroids as the preferred first-line therapy for children with mild-to-moderate asthma. Nevertheless, they are still significantly underprescribed in the patients who need them most. An important 2007 study of 6 - 14 year old children with asthma compared inhaled corticosteroid therapy (fluticasone) with an inhaled corticosteroid/long-term beta2 agonist (fluticasone/salmeterol) and a leukotrine receptor antagonist (montelukast). The results indicated that fluticasone alone worked better than the other two treatments.

Researchers have been investigating whether early treatment with corticosteroids can help prevent the development of asthma in at-risk children. Two important 2006 studies in the New England Journal of Medicine suggested that while inhaled corticosteroids helped ease symptoms and reduce breathing problems in pre-school children at risk for asthma, they did not help protect against asthma development.

For now, experts caution against corticosteroids for infants and toddlers with mild asthma and urge close monitoring especially for children under age 5 with severe asthma who are receiving high doses. Because the newer potent drugs, particularly fluticasone, may produce major side effects similar to oral steroids, it is important when treating all children to aim for the lowest effective dose possible. Fortunately, studies suggest that low doses of fluticasone may achieve the same benefits as with high ones, thus reducing risks for serious side effects. Better delivery methods may also allow lower doses.

Side effects of inhaled steroids may include:

The most common side effects are throat irritation, hoarseness, and dry mouth. These effects can be minimized or prevented by using a spacer device and rinsing the mouth after each treatment.
Rashes, wheezing, facial swelling (edema), fungal infections (thrush) in the mouth and throat, and bruising are also possible but not common with inhalators.
Some children experience changes in mood, memory, and behavior. These changes are not permanent.
Some studies have suggested a higher risk for gum inflammation.
Oral steroids reduce bone density. Research reports that inhaled steroids -- both older and newer drugs -- may also affect bone growth and density. However, a number of studies report only a slight effect (about half an inch) on children's growth, which may be only temporary. It is still unknown if these drugs have any significant long-term effect on bone density. Calcium supplements may help prevent bone loss that is due to inhaled steroids.
It is not yet known whether inhaled steroids affect lung growth in very young children. Steroids administered using nebulizers are of particular concern.
There is also some concern that the stronger drugs, particularly fluticasone, suppress the adrenal system to a greater degree than other steroid inhalants. This effect, in turn, reduces levels of natural steroids -- notably cortisol, the major stress hormone. (This is a serious side effect of oral steroids).

Long-acting beta2-agonists are used in combination with inhaled corticosteroids for treating children with moderate-to-severe asthma. These drugs include include salmeterol (Serevent Diskus) and formoterol (Foradil Aerolizer). A single inhaler (Advair Diskus) that combines both salmeterol and the corticosteroid fluticasone is available for children age 4 years and older, and an inhaler (Symbicort) combining formoterol and the corticosteroid budesonide is approved for children age 12 years and older.

Long-acting beta2-agonists are used for preventing an asthma attack (not for treating attack symptoms). The effects of one dose of a long-acting beta2-agonist last for about 12 hours, so they are particularly effective during the night. These drugs also may be used for prevention of exercise-induced asthma in people and to protect against aspirin-induced asthma.

However, research indicates that long-acting beta2-agonists can worsen asthma by increasing symptom severity. These drugs may also increase the risk for asthma-related deaths. Experts are still trying to determine when long-acting beta2-agonists should be added to an asthma treatment plan. If a child’s symptoms do not improve or if symptoms worsen with this type of drug, the doctor will recommend discontinuing it. Patients should not, however, stop taking this drug or other asthma medications without first talking with their doctors.

Side Effects. Side effects of long-acting beta2-agonists are similar to the short-acting drugs.

Specific Warning on Salmeterol and Formoterol. In 2003 a "black box" warning was added to product packaging for drugs that contain salmeterol, including Serevent Diskus, and Advair Diskus. Serevent and Advair are approved for patients age 12 years and older. The warning was based on a study that demonstrated more serious and even fatal asthma episodes in patients who used the drug than in patients who used a placebo.

In 2006, the FDA updated the warning to include formoterol (Foradil Aerolizer, approved for patients 5 years and older). Warnings for salmeterol and formoterol products emphasize that these medicines can increase the risk of severe asthma episodes. Long-acting beta2-agonists require up to 20 minutes to achieve effectiveness, and there is a danger of overdose if a patient is not aware of this delay and takes additional doses to achieve faster relief. The FDA recommends that patients:

Use long-acting beta2-agonists only if other medicines (such as steroids) have not helped control asthma.
Use a short-acting bronchodilator, not a long-acting beta2-agonist, to treat sudden wheezing.
Do not use long-acting beta2-agonists to treat wheezing that is getting worse. Call your doctor if this situation occurs.
Do not stop using any asthma medicines without first talking to your doctor.

Cromolyn sodium (Intal) is both an anti-inflammatory drug and has antihistamine properties that block asthma triggers such as allergens, cold, or exercise. Cromolyn has been the anti-inflammatory drug of choice for prevention of asthma attacks in children over age 4 with chronic moderate asthma. It is not as effective as inhaled corticosteroids, however, for reducing hospitalization rates, improving symptoms, and reducing the use of beta2-agonists in children with persistent asthma. Still, cromolyn has a well-known long-term safety record, while the long-term adverse effects of corticosteroids in children are still not fully known. Many children who need asthma maintenance therapy will still do well on cromolyn. (It may not provide any real benefit for children under age 4.)

Nedocromil (Tilade) is similar to cromolyn and needs to be taken only once a day. It also prevents asthmatic reactions to cold and exercise. It is not used in very young children. A cromolyn nasal spray called Nasalcrom has been approved for over-the-counter purchase, but only to relieve nasal congestion caused by allergies. Patients should not use it for self-medication without the advice of a doctor.

Side Effects. Side effects of cromolyn include nasal congestion, coughing, sneezing, wheezing, nausea, nosebleeds, and dry throat. Nedocromil has an unpleasant taste, and some people have complained of nausea, headache, and spasms in the airways, but no serious side effects have been reported.

Leukotriene-antagonists (also called anti-leukotrienes or leukotriene modifiers) are oral medications that block leukotrienes. Leukotrienes are powerful immune system factors that, in excess, produce a battery of damaging chemicals that can cause inflammation and spasms in the airways of people with asthma. As with other anti-inflammatory drugs, leukotrienes are used for prevention and not for treating acute asthma attacks.

Leukotriene-antagonists include zafirlukast (Accolate), montelukast (Singulair), zileuton (Ziflo), and pranlukast (Ultair, Onon). These drugs are proving helpful for long-term prevention of asthma, including exercise-induced asthma and aspirin (or NSAID) -induced asthma. However, most studies to date have reported better success with inhaled corticosteroids than with the leukotriene-antagonists. A 2006 study of children with mild-to-moderate persistent asthma indicated that the corticosteroid fluticasone worked better than the leukotriene-antagonist montelukast in controlling symptoms. Nevertheless, some studies suggest that montelukast, which comes in a chewable tablet, may be particularly useful for managing asthma in small children (ages 2 - 5), since they have trouble with inhaled steroids.

Side Effects and Complications. Gastrointestinal distress is the most common side effect of leukotriene-antagonists. Very few other side effects have been reported. In general, these drugs appear to be safe and well-tolerated.

Of some concern are reports of Churg-Strauss syndrome in a few people taking zafirlukast or montelukast. Churg-Strauss syndrome is very rare, but it causes blood vessel inflammation in the lungs and can be life threatening. Oral steroids quickly resolve the problem. In fact, usually the syndrome has occurred in patients who were tapering off steroids and changing over to the leukotriene-antagonists. Some experts believe that, in such cases, the steroids may simply have masked the presence of the disorder, which then developed when the steroid drugs were withdrawn. Symptoms include severe sinusitis, flu-like symptoms, rash, and numbness in the hands and feet.

Other concerns are indications of liver injury in patients taking zileuton and zafirlukast when taken at higher than standard doses. No adverse effects on the liver have been reported to date with montelukast.

Theophylline (Theo-Dur, Theolair, Slo-Phyllin, Slo-bid, Constant-T, Respbid) is a mild-to-moderate bronchodilator that has been used to treat childhood asthma for more than 30 years. It is useful for treating nocturnal asthma and may also have anti-inflammatory qualities even in low doses.

Available in tablet, liquid, and injectable forms, some theophylline sustained-release tablets and capsules have a long duration of action and can therefore be taken once or twice a day with good results.

Side effects may include changes in behavior, mood, and memory. If theophylline is not taken exactly as prescribed, an overdose can easily occur. Toxicity can cause nausea, vomiting, headache, insomnia, and, in rare cases, disturbances in heart rhythm and convulsions. Contact a doctor immediately if any of these side effects occur.

The risks for these adverse effects are small if the drug is taken exactly as prescribed but the following precautions should be noted:

Infants tend to metabolize the drug extremely slowly and, therefore, should receive very low doses.
By the time children reach age 1, however, they metabolize the drug faster than adults. There is a risk, therefore, of toxic effects.
Fever and certain antibiotics may slow down the rate at which theophylline is eliminated from the body. In such cases, the doctor may want to reduce the dosage of theophylline.

If a child is taking theophylline on an ongoing basis, the doctor should monitor the drug level at the start of therapy and at regular intervals thereafter.

Omalizumab (Xolair) is FDA-approved for patients age 12 and older who have moderate-to-severe persistent asthma related to allergies. The first drug of this type to be approved for asthma, omalizumab is a monoclonal antibody (MAb), a genetically developed drug designed to attack very specific targets. Omalizumab is administered by injection every 2 - 4 weeks. It is used only to treat patients whose symptoms are not controlled by inhaled corticosteroids.

Omalizumab prevents the antibody immunoglobulin E (IgE) from triggering the inflammatory events that lead to asthmatic attacks. Studies have shown excellent benefits of the drug, including a reduced need for corticosteroids, fewer hospitalizations, and significant symptomatic improvements.

However, about 1 in 1,000 patients who take omalizumab develop anaphylaxis (a life-threatening allergic reaction). In 2007 the FDA requested the manufacturers of omalizumab to put a “boxed warning” on the medicine’s label emphasizing the drug’s risk for anaphylaxis. The boxed warning notes that patients can develop anaphylaxis after any dose of omalizumab, even if they had no reaction to a first dose. Anaphylaxis may occur up to 24 hours after the dose is given.

The FDA recommends that healthcare providers observe patients for at least 2 hours after an injection. Patients should also carry emergency self-treatment for anaphylaxis (such as an Epi-Pen) and know how to administer it. With an Epi-Pen, or similar auto-injector device, patients can quickly give themselves a life-saving dose of epinephrine.

Anaphylaxis symptoms include:

Difficulty breathing
Chest tightness
Dizziness
Fainting
Itching and hives
Swelling of the mouth and throat

[See In-Depth Report #4: Asthma in adults.]

Other Treatments

Alternative therapies are widely used by children, adolescents, and adults with asthma. In one study, nearly half of asthma or allergy sufferers resorted to alternative treatments. To date, however, evidence does not support most alternative therapies, including high-dose vitamins, urine injections, homeopathic remedies, and most herbal remedies.

Relaxation and Stress-Reduction Techniques. Patients report benefits from many stress reduction and physical techniques, such as acupuncture, hypnosis, breathing relaxation techniques, the Alexander technique, massage therapy, and meditation practices. There have been very few well-conducted studies supporting their use, however.

Acupuncture, hypnosis, and biofeedback are alternative ways to control pain. Acupuncture involves the insertion of tiny sterile needles, slightly thicker than a human hair, at specific points on the body.

Breathing Exercises. Some studies have suggested that breathing exercises or training may be helpful. A number of different methods are available. One example is the Buteyko breathing method, an experimental approach designed to increase levels of carbon dioxide in the body. To do this, patients are trained to reduce their volume of breath and to avoid hyperventilation (over-breathing). Some studies report that patients using this method reduce their use of medications and improve their quality of life. The system originated in Australia and is not yet widely available in the U.S.

Probiotics. Probiotics are beneficial bacteria that may possibly help protect against allergies and asthma. Antibiotic overuse and modern hygiene may specifically be reducing these helpful organisms. Look for probiotics in active yogurt cultures and in supplements, which are being studied for protection.

Herbal Remedies. Butterbur (also known as Petasites hybridus, butter dock, blatterdock, bog rhubarb, and exwort), is a traditional herbal remedy used for seasonal allergies and asthma. In a 2002 study, it was as effective and less sedating than a commonly prescribed antihistamine for treating seasonal allergies over a 2-week period. However, little research exists on its effect on asthma. Overall, there is scant evidence supporting the benefits of herbs and nutritional supplements for asthma control.

Managing Asthma

The more allergies a child has, the more severe the asthma. Making lifestyle changes to reduce allergy attacks and other triggers is extremely important.

House dust is a reservoir for pollen and dust mites. Some experts believe that reducing household allergens and pollutants in the home could reduce asthma in children by 40%.

Controlling for Dust. Spray furniture polish is very effective for reducing both dust and allergens. Air cleaners, filters for air conditioners, and vacuum cleaners with High Efficiency Particular Air (HEPA) filters can help remove particles and small allergens found indoors. Neither vacuuming nor the use of anti-mite carpet shampoo, however, is effective in removing mites in house dust. Vacuuming actually stirs up both mites and cat allergens. If possible, avoid carpets and rugs.

Click the icon to see an image of a HEPA air filter.

Bedding and Curtains. Many experts recommend reducing exposure to dust mites by enclosing mattresses and pillows in semipermeable coverings. (Vinyl mattress covers limit airflow and may also worsen, or even cause, asthma in children. Synthetic pillows may pose a significantly higher risk for severe asthma attacks in children than feather or no pillows.) However, several 2005 studies suggested that such covers do not prevent asthma or allergies. Replace curtains with shades or blinds, and wash bedding using the highest temperature setting.

Click the icon to see an image of dust mite prevention.

One study found that children sleeping in bottom bunk beds are significantly more likely to develop asthma than siblings occupying the upper bunks. Families with children who have asthma or allergies should avoid bunk beds or be sure that children with asthma sleep in the top bunk. Even with standard beds, it may be useful to have them sleep as high off the floor as possible.

Exterminating Pests (Cockroaches and Mice). Use professional exterminators to eliminate cockroaches. (One study reported that ridding a home of cockroaches and cleaning the house using standard housecleaning techniques failed to eliminate the cockroach allergens themselves.) Exterminate mice, and attempt to remove all dust, which might contain mouse urine and dander.

Reducing Humidity in the House. Although warm, moist air from vaporizers can greatly ease and moderate asthma attacks, living in a damp house is counterproductive. Dust mites thrive in humidity and damp houses increase the risk for mold, so on-going humidifiers can be unhelpful. If they are used, humidity levels should not exceed 40%, and humidifier should be cleaned daily with a vinegar solution.

Controlling Pets. People with asthma who already have pets and are not allergic to them probably have a low risk for developing such allergies later on. When children are exposed to more than one dog or cat during their first year, they have a much lower risk for allergies and asthma.

For children who have an existing allergy to pets, however, the pets should be given away or kept outside. If this isn't possible, they should at least be confined to carpet-free areas outside the bedroom. Cats harbor significant allergens, which can even be carried on clothing; dogs usually present fewer problems. Washing animals once a week can reduce allergens. Dry shampoos, such as Allerpet, are now available for both cats and dogs to remove allergens from skin and fur and are easier to administer than wet shampoos.

Many of the same substances trigger both allergies and asthma. Common allergens include pollen, dust mites, mold and pet dander. Other asthma triggers include irritants like smoke, pollution, fumes, cleaning chemicals, and sprays. Asthma symptoms can be substantially reduced by avoiding exposure to known allergens and respiratory irritants.

Preventing Exposure to Cigarette and Cooking Smoke. Parents who smoke are strongly urged to quit. Studies indicate that exposure to second-hand smoke in the home increases the risk for asthma and asthma-related emergency room visits in children. Even smoky cooking can worsen asthma.

Parental smoking has been shown to increase the airway responsiveness of infants as early as the first 2 - 10 weeks of life. This extends even to the fetus of pregnant women who smoke. Such mothers tend to have babies born at a low birth weight, which affects lung function and increases babies' risks for asthma.

Avoiding Outdoor Allergens. The following are some recommendations for avoiding allergens outside:

Avoid scheduling camping and hiking trips during times of high pollen count (generally, May and June for grass pollen and mid-August to October for ragweed).
Patients should avoid strenuous activity when ozone levels are highest, which usually occur in early afternoon, particularly on hot hazy summer days. Levels are lowest in early morning and at dusk.
Asthma attacks are often higher during thunderstorms. Some evidence points to a build-up of ozone that accompanies such storms. Other evidence suggests that the changing airflow patterns bring a sudden downdraft of air containing concentrations of pollens, small particles and allergens.
Patients who are allergic to mold should avoid barns, hay, raking leaves, and mowing grass.
Exposure to automobile fumes may worsen asthma. Fungi in car air conditioners can also be a problem.

Reducing Exposure to Air Pollution. Children breathe faster than adults, taking in more pollutants, and therefore are particularly susceptible to soot and other small particles in the air. A 2001 study found an association between higher rates of asthma and other health problems in children who were exposed to high levels of specific pollutants (particularly sulfur dioxide and nitrogen dioxide). Diesel fuel exhaust has also been associated with worsening asthma in children.

Some experts point out that asthma rates in North America have increased over recent years while the prevalence of many common air pollutants have declined. So pollution is unlikely to be a primary cause of asthma. Regardless of whether pollution is an important cause of asthma, evidence strongly suggests that it can affect existing asthma.

Patients with asthma and chronic allergic rhinitis may require daily medications. Patients with severe seasonal allergies may be advised to start medications a few weeks before the pollen season, and to continue it until the season is over.

Immunotherapy ("allergy shots") may help reduce asthma symptoms, and the use of asthma medications, in patients with known allergies. They may also help prevent the development of asthma in children with allergies. Immunotherapy poses some risk for severe allergic reactions, especially for children with poorly controlled asthma, so it is important that the doctor carefully evaluates the child’s asthma condition.

[See In-Depth Report #77: Allergic rhinitis.]

Weight Loss. Children who are both asthmatic and overweight may reduce asthma symptoms simply with weight loss.

Fruits, Vegetables, and Whole Grains. Healthy foods are important for lung function. Specific foods that may be important for healthy lungs contain antioxidants (deep green and yellow-orange fruits and vegetables), selenium (fish, red meat, grains, eggs, chicken, liver, garlic), plant chemicals called flavonoids (apples, onions), and magnesium (green leafy vegetables, nuts, whole grains, milk, and meats).

Fish Oil. Omega-3 fatty acids, found in cold water oily fish and in supplements (preferably DHA-EPA, the important compounds in fish oil) have anti-inflammatory effects. Some evidence suggests they may be helpful for people with asthma.

Caffeine. Caffeine has properties that are similar to the asthma drug theophylline. A major analysis of studies reported that caffeine improved lung function for up to 4 hours after consumption. Although tea and coffee are the major sources of caffeine, some sodas contain it and should be avoided when children have an asthma attack. (People who are going to have their lung function tested should avoid drinking coffee, tea, or other caffeinated beverages for at least 4 hours beforehand.)

Food Allergies. Although about 70% of people with asthma believe their symptoms are aggravated by food allergies, studies indicate that this belief may be true in only 5% of cases. If young children show signs of or test positive for food allergies, however, parents should be extra cautious in preventing exposure to any asthma trigger. Some doctors now counsel all children with asthma to avoid nuts entirely, and, of course, children who experience reactions to any foods should avoid them.

Chemicals that may pose some risk for an allergic reaction are monosodium glutamate, or MSG (found in some canned soups, cheese, and certain vegetables), and sulfites (preservatives in foods, such as frozen potatoes and tuna). Contrary to what many believe, dairy products do not appear to worsen asthma symptoms in people who are not already allergic to them.

Asthma is no reason to avoid exercise. Historically, about 10% of Olympic athletes have asthma. Some studies indicate that long-term exercise may help control asthma and reduce hospitalization.

Encourage children with asthma to swim and play sports, such as baseball, that will present less difficulty for them. Intense activities lasting less than 2 minutes, such as sprinting or competitive swimming, may cause fewer problems than longer-lasting exercises.

Young people who enjoy running should probably choose an indoor track to avoid pollutants. Swimming is excellent for people with asthma. Yoga practice, which uses both stretching, breathing, and meditation techniques, may have particular benefits. One study reported that two-thirds of patients who practiced yoga regularly were able to reduce or stop taking their asthma medications.

Patients should consult their doctors before starting any exercise program. Exercise-induced asthma is a limited condition that has specific recommendations.

People with asthma should try to minimize their risk for respiratory tract infections. Washing hands is a very simple but effective preventive measure.

Patients with asthma should ask their doctor about getting the influenza ("flu") vaccine and also whether they should receive the vaccination against pneumococcal pneumonia.

Zanamivir, a new drug used for treating influenza, is considered safe for patients with asthma 12 years of age or older. In one study, patients with asthma treated with zanamivir experienced fewer flu symptoms, and their lung function improved.

People with asthma have no higher rate of anxiety or depression than the general population. However, such emotions interact with the effects of asthma and its treatments in important ways:

Negative emotions can discourage compliance with medication and the ability to cope.
Poor control of asthma symptoms, in turn, increases the risk for negative emotions.
Stress and depression have been associated with more severe symptoms and even an increased risk of fatal asthma attacks.

Some evidence suggests that stress reduction techniques, a positive attitude, and relaxation techniques may be very helpful in the long-term management of asthma.

Resources

www.lungusa.org -- The American Lung Association
www.acaai.org -- American College of Allergy, Asthma & Immunology
www.aaaai.org -- American Academy of Allergy, Asthma, and Immunology
www.nhlbi.nih.gov -- National Heart, Lung, and Blood Institute
www.asthma-carenet.org -- Childhood Asthma Research and Education Network
www.njc.org -- National Jewish Center for Immunology and Respiratory Medicine
www.aafa.org -- Asthma and Allergy Foundation of America
www.aanma.org -- Allergy and Asthma Network, Mothers of Asthmatics

References

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Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med. 2006 May 11;354(19):1998-2005.

Cates CJ, Crilly JA, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD000052.

Douwes J, van Strien R, Doekes G, Smit J, Kerkhof M, Gerritsen J, et al. Does early indoor microbial exposure reduce the risk of asthma? The Prevention and Incidence of Asthma and Mite Allergy birth cohort study. J Allergy Clin Immunol. 2006 May;117(5):1067-73.

Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006 May 11;354(19):1985-97.

Haland G, Carlsen KC, Sandvik L, Devulapalli CS, Munthe-Kaas MC, Pettersen M, et al. Reduced lung function at birth and the risk of asthma at 10 years of age. N Engl J Med. 2006 Oct 19;355(16):1682-9.

Marks GB, Mihrshahi S, Kemp AS, Tovey ER, Webb K, Almqvist C, et al. Prevention of asthma during the first 5 years of life: a randomized controlled trial. J Allergy Clin Immunol. 2006 Jul;118(1):53-61.

National Asthma Education and Prevention Program Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics -- 2002. Rockville, MD. National Heart, Lung, and Blood Institute, US Dept of Health and Human Services; 2003. NIH publications 02-5074.

O'Byrne PM, Pedersen S, Busse WW, Tan WC, Chen YZ, Ohlsson SV, et al. Effects of early intervention with inhaled budesonide on lung function in newly diagnosed asthma. Chest. 2006 Jun;129(6):1478-85.

Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med. 2006 Jun 20;144(12):904-12.

Schuh S, Dick PT, Stephens D, Hartley M, Khaikin S, Rodrigues L, Coates AL. High-dose inhaled fluticasone does not replace oral prednisolone in children with mild to moderate acute asthma. Pediatrics. 2006 Aug;118(2):644-50.

Sorkness CA, Lemanske RF Jr, Mauger DT, Boehmer SJ, Chinchilli VM, Martinez FD, et al. Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial. J Allergy Clin Immunol. 2007 Jan;119(1):64-72.

Review Date:
3/26/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

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