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•	Non-Hodgkin's lymphoma

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Non-Hodgkin's lymphoma

Highlights

Drug Approvals

• Rituximab (Rituxan) has received approval for three new non-Hodgkin’s lymphoma (NHL) treatments: First-line treatment for diffuse large B-cell, CD20-positive NHL in combination with CHOP chemotherapy; first-line treatment of previously untreated follicular NHL in combination with CVP chemotherapy; and treatment of low-grade NHL in patients who have stable disease or who have benefited from first-line treatment with CVP chemotherapy.
• Bortezomib (Velcade) has been approved for treatment of mantle cell lymphoma.
• Vorinostat (Zolinza) has been approved for treatment of cutaneous T-cell lymphoma.

Drug Warning

In 2006, the FDA updated rituximab’s warnings to include information on the risks for progressive multifocal leukoencephalopathy (PML), a rare and potentially deadly brain infection. As of February 2006, 23 cases of PML had been reported in patients with NHL who were treated with rituximab. In December 2006, the FDA reported 2 fatal cases of PML in patients with lupus who received rituximab. (Rituximab is currently approved only for NHL and rheumatoid arthritis, but is being investigated for other conditions.) The FDA advises that patients on rituximab therapy should immediately contact their doctors if they experience any of the following symptoms:

• Vision problems or unusual eye movements
• Confusion
• Dizziness or loss of balance
• Difficulty talking or walking

Investigational Drugs

Several vaccines are showing promise in late-stage clinical trials for treatment of NHL:

• The BioVaxID vaccine has shown good results in Phase II trials for follicular B-cell NHL and mantle cell lymphoma. It is currently in Phase III trials.
• The MyVax vaccine is currently in Phase III trials for treatment of follicular B-cell NHL.

NHL and Rheumatoid Arthritis

The inflammatory process of rheumatoid arthritis -- rather than its drug treatments -- may be the main reason why patients with this autoimmune condition are at increased risk for lymphoma. A 2006 study indicated that patients with severe and long-term rheumatoid arthritis are especially at risk.

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 and is discussed in another report. [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).

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.

Locations of Non-Hodgkin's Lymphomas

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.

Cells Affected in NHL

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.

Non-Hodgkin's Lymphomas Categories

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- 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 referred to as low-grade
• Aggressive (fast-growing), also referred to as intermediate- or high-grade

According to a 2002 report, half of new cases are now intermediate-grade lymphomas. Low-grade makes up 30% and high-grade 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.

Risk Factors

An estimated 58,870 Americans were diagnosed with non-Hodgkin's lymphomas in 2006 and about 18,840 people died of the disease. For the past 25 years, the incidence in NHL has increased continuously. Most of this increase has been observed in people over 65. There is some evidence that the rates are now stabilizing or even declining.

Part of the reason for the dramatic rise is AIDS, which increases the risk for high-grade lymphomas. However, even after eliminating changes in diagnosing NHLs and known causes such as AIDS, there remains a 40% higher incidence over the past 40 years. 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).

Gender, Age, and Ethnicity

The cancer can develop in people at all ages, including children, although it is most common in those between the 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.

A major 2000 study found that 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.

Family History

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.

Lifestyle Factors

Because of the rapid rise in NHL, investigators are looking for lifestyle factor that may contribute to this increase.

Body Weight, Shape, and Exercise. A 2002 study looked for any associations between lymphomas and body weight or shape or amounts of exercise. Overall, the researchers did not find any important relationships between non-Hodgkin's lymphomas and these lifestyle factors.

Dietary Factors. 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). Some have also found a higher risk with animal fats and 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), and in fact, 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. A 2002 study reported, for example, some reduced risk from wine drinking but not from beer or other spirits. A 2005 study found that alcoholic beverages were linked to a reduced risk of developing NHL, but that the amount of protection depended on the type of NHL.

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.

Infections

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 herpesvirus 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.

One study reported a lower risk for certain lymphomas in people with a history of receiving five or more different vaccines.

Disorders of the Immune System

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, in fact, be traced to AIDS. However, one 2002 study observed that AIDS is now declining in the U.S., but non-AIDS-related NHL continues to increase.
• Patients with a history of autoimmune diseases, including rheumatoid arthritis (RA), Hashimoto's thyroiditis, Crohn's disease, and Sjögren syndrome are at an increased risk for certain NHLs, such as marginal zone lymphomas. [See section: Other Conditions Associated with Non-Hodgkin's 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 allergy, which is an overactive response of the immune system and is the most common immune disorder.

Industrial Chemicals and Other Environmental Risk Factors

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.

Other Conditions Associated with Non-Hodgkin's Lymphomas

Autoimmune Diseases. Patients with autoimmune diseases may have increased risks for developing NHL. A 2005 review found that patients with Sjögren syndrome had 18.8 times more risk for NHL than healthy patients. Systemic lupus erythematosus increased risk by 7.4 times, and rheumatoid arthritis increased risk by 3.9 times. For patients with rheumatoid arthritis, the lymphoma risk appears highest for those with very severe and chronic forms of this autoimmune disease.

Tumor necrosis factor (TNF) blockers used to treat autoimmune conditions -- such as infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira) -- may also increase the risk for developing NHL. According to one study, lymphoma rates for patients who took infliximab for Crohn's disease or RA were six times higher than those found in the general public. However, several 2006 studies suggested that the inflammatory process of rheumatoid arthritis, rather than its drug treatments, is the main factor in increasing lymphoma risk.

Pregnancy and Childbirth. One study observed a higher risk for lymphomas in children with a low weight at birth or with mothers who were heavy smokers during pregnancy. (Breastfeeding for more than 6 months, on the other hand, may offer some protection.)

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.

Systemic and B Symptoms

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.

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 to be sure their swelling doesn't return.

Ruling Out Other Conditions

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.]

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. [See In-Depth Report #83: Hodgkin's disease or Report #86: Acute lymphocytic leukemia.]

Exposure to Chemicals. Exposure to industrial chemicals or 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.

Physical Examination

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 is sometimes indicative of 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

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.

Biopsy

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 only be performed 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 are indicative of 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

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.

Imaging Techniques

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. In one study, CT scans provided evidence of disease in 15% of sites that were considered normal on chest x-ray. A CT scan also is important in detecting lymphomas in the abdominal and pelvic areas if a chest x-ray is normal and lymphomas are still suspected.

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

Lymphangiography. Lymphangiography is an x-ray of the lymph glands and vessels after injection of a dye. It provides additional information on lower parts of the body and is a good complement to CT scans if the latter does not reveal abnormal lymph nodes but they are still suspected. On its own, however, lymphangiography misses cancer in 20% of cases. There is a slight risk that the dye will affect the lungs, so this test should not be used in patients with severe lung disease. Lymphangiography is not commonly used for staging non-Hodgkin's lymphomas.

Click the icon to see an image of a lymphangiogram.

Other Advanced Imaging Techniques. A number of advanced imaging techniques, including gallium scintigraphy and positron emission tomography (PET) are proving to be very helpful. Special PET imaging techniques known as FDG/PET scans may be more accurate than CT scans for staging lymphomas and more accurate than gallium scintigraphy in identifying the disease in the bone. They are also very accurate for evaluating the success of chemotherapy in patients who have been treated for lymphomas and for detecting relapsing lymphoma. Gallium scans are also useful for evaluating the success of chemotherapy.

Magnetic resonance imaging (MRI) may be used to detect the spread of the disease to the brain, spine, chest, pelvic, and abdomen. How additional tests such as MRI and PET scanning will impact the management of patients with lymphomas, however, is still unknown.

Click the icon to see an image of a MRI machine.

DNA Tests

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

Biologic markers, called biomarkers for short, are high levels of substances that are released by tumors and 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, when the cancer has spread, which reduces 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.

Outlook for Indolent (Low-Grade) Lymphomas

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%.

Outlook for Aggressive (Intermediate- to High-Grade) Lymphomas

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; and four or five factors pose the highest likelihood of poor survival.

Risk Factors for Central Nervous System Involvement

Lymphoma can spread to the central nervous system or it can appear there first, which is referred to as primary CNS lymphomas (PCNSL). It is a very serious event, 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. According to a 2002 study, the risk for CNS involvement in low-grade NHL is about 2.8%. Among patients with high-grade NHL, those with lymphoblastic and Burkitt's lymphoma are at high risk (nearly 25%) for recurrence in the central nervous system. For other patients with high-grade NHL, the 5-year risk was slightly over 5%, although having other factors increased this danger.

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.

Long-Term Complications of Treatments

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

General Approach for Treating Non-Hodgkin's Lymphoma

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.

Assessing Treatment Success

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.

Early Stage Lymphomas (Stage I and Stage II)

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 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, ranging 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

Advanced Stage Lymphomas (Stage III and IV)

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, C[M]OPP)
• 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 central nervous system in high-risk patients
• Clinical trials for patients at high risk for relapse that involve intensive chemotherapy, high dose chemotherapy, and bone marrow or stem cell transplantation

Relapsed or Refractory (Nonresponsive to Treatment) Non-Hodgkin's Lymphoma

Indolent-Lymphomas Relapses. Nearly all patients with indolent lymphomas relapse after initial treatment, with duration of remissions 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.

Preventing and Treating Lymphomas in the Central Nervous System

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 carries particular dangers for children.)

Chemotherapy Administration

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.

Effective Regimens and Drugs

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. 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.

Other Drugs

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. Doctors are finding 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.

Supportive Drugs

Granulocyte Colony-Stimulating Factor. Granulocyte colony-stimulating factor or G-CSF (lenograstim, filgrastim, sargramostim, nartograstim) regulates blood-cell growth. It is used to allow higher doses of chemotherapy. Doctors hope it might reduce infections and allow standard chemotherapy treatments and in elderly people, who otherwise could not withstand toxicities. Studies suggest it speeds up recovery after treatment but it is unclear if it reduces the rate of infection. Toxicities and infections are still common, even with the use of G-CSF.

Side Effects and Complications

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 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 side effects can also occur and may vary depending on the specific drugs used. They include the following:

• Neutropenia is a severe drop in white blood cells. Neutropenia increases the chance for infection from suppression of the immune system. White blood cell count may be improved with the addition of a drug called granulocyte colony-stimulating factor (filgrastim, pegfilgrastim, and lenograstim). There is no evidence that these drugs have any effect on survival or cancer recurrence.
• Anemia is a lack of red blood cells. Erythropoietin stimulates red blood cell production and can help reduce or prevent this side effect. It is available as epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). Aranesp persists longer in the blood than epoetin alfa and requires fewer injections.
• 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 also a danger, particularly with the use of cyclophosphamide.
• Some patients report osteoporosis and damage in bone cells, possibly related to corticosteroid treatments.
• 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. There is a 1 - 5% mortality rate from complications of chemotherapy and certain people may be at greater risk. A 2001 study suggested that the risk was highest in those who had low performance scores (are more debilitated than others) or have tests that show low levels of white blood cells.

Combinations of Chemotherapy and Radiation (Combined Modality)

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

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

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 are very variable. 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.

Other Biologic Drugs

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.

Investigational Biologic Therapies

Antisense Oligonucleotide. Oblimersen (G3139) is called an antisense oligonucleotide. It blocks BCL-2, a protein that is genetically overexpressed in some lymphomas and prevents apoptosis (a natural process by which all cells, including cancer cells, self-destruct). Studies suggest it may have some activity against mantle-cell lymphoma.

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 so help block their growth.

Vaccines. Lymphoma vaccines, which are still experimental, are therapeutic vaccines -- they 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 are showing promise in late-stage clinical trials. The MyVax vaccine uses a protein from the patient’s own tumor and combines it with a second protein that helps activate the immune system. It is currently being tested in a Phase III trial for follicular B-cell NHL. Another vaccine, BioVaxID, has also shown good results in clinical trials. In a Phase II trial for follicular B-cell NHL, the BioVaxID vaccine produced long-term clinical remission and an overall survival rate of more than 95 percent. In a Phase II trial for mantle cell lymphoma, the vaccine yielded an 89% survival rate. The vaccine is currently in Phase III trials for slow-growing follicular NHL.

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

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.

Collecting the Stem Cells

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 a 2002 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, so is the procedure discussed here.

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.

The Blood Stem Cell Collection Procedure.

• 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.

The Transplantation Procedure

• 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 and Success Rates

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 2000 and 2001 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%).

Side Effects and Complications

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 and can persist for several months after the transplant. Because the stem cell procedure is done more swiftly, the risk period is shorter than with bone marrow transplantation. 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.

Graft-versus-host disease (GVHD) is a serious attack by the patient's immune system triggered by the donated new marrow in allogeneic transplants. Acute GVHD occurs in over half of allogeneic transplants, usually within 90 days. Its severity ranges from very mild symptoms to a life-threatening condition (more often in older patients). In some cases, it can become chronic, which usually develops after the third month following the transplant but may not develop for a year or more. GVHD can causes gastrointestinal problems, severe skin reactions, hair loss, mouth and throat ulcers, and liver damage. Careful matching of the donor and preventive immunosuppressive drugs, such as corticosteroids, methotrexate, and cyclosporine, may reduce the risk. T-lymphocyte depletion is another approach for preventing GVHD, which involved reducing the number T cells infused with the stem cells.

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)
• 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 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.lymphomainfo.net -- Lymphoma Information Network
• www.cancer.gov/clinicaltrials -- Find clinical trials

References

Baecklund E, Iliadou A, Askling J, Ekbom A, Backlin C, Granath F, et al. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum. 2006 Mar;54(3):692-701.

Ferreri AJ, Ponzoni M, Guidoboni M, Resti AG, Politi LS, Cortelazzo S, et al. Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multicenter prospective trial. J Natl Cancer Inst. 2006 Oct 4;98(19):1375-82.

Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2006 Oct 20;24(30):4867-74.

Neelapu SS, Kwak LW, Kobrin CB, Reynolds CW, Janik JE, Dunleavy K, et al. Vaccine-induced tumor-specific immunity despite severe B-cell depletion in mantle cell lymphoma. Nat Med. 2005 Sep;11(9):986-91.

van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006 Nov 15;108(10):3295-301.

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