Hodgkin's disease

Hodgkin's Disease

Hodgkin's disease is a lymphoma, a cancer of the lymphatic system. Hodgkin's disease and non-Hodgkin's lymphoma are the two types of lymphomas. Hodgkin's disease is distinguished by the presence of large abnormal cells, called Reed-Sternberg cells. The disease is less common than non-Hodgkin's lymphoma.

Hodgkin's disease is classified into two main types:

• Classical Hodgkin's lymphoma, which includes nodular sclerosis and mixed cellularity, the two most common subtypes
• Nodular lymphocyte-predominant Hodgkin's disease, which affects about 5% of patients

Prognosis

Hodgkin's disease is considered one of the most curable forms of cancer, especially if it is diagnosed and treated early. Five-year survival rates for patients diagnosed with stage I or stage II Hodgkin's disease are 90 - 95%. Many patients with late-stage Hodgkin's disease also have good odds for survival.

Risk Factors

Hodgkin's disease occurs most often in people ages 15 - 40 (especially in their 20s), and in people over age 55. About 10 - 15% of Hodgkin's disease cases are diagnosed in children and teenagers. It is slightly more common in males than in females.

Certain types of viral infections may increase the risk of Hodgkin's disease. Infectious mononucleosis, which is caused by the Epstein-Barr virus, is associated with increased risk as is infection with the human immunodeficiency virus (HIV).

Treatment

Chemotherapy and radiation are the main treatments for Hodgkin's disease. Patients who have relapsed may be treated with autologous stem cell transplantation.

Preventing Infection after Cancer Treatment

Both chemotherapy and stem cell transplants increase the risk for serious infections. Patients must take precautions to avoid exposure to germs. Ways to prevent infection include:

• Practice good hygiene, including regular handwashing and dental care (brushing, flossing).
• Avoid crowds, especially during cold and flu season.
• Eat only well-cooked foods (no raw fruits or vegetables).
• Boil tap water before drinking it.
• Do not keep fresh flowers or plants in your house as they may carry mold.

Hodgkin's disease is a type of lymphoma. Lymphomas are cancers of the lymphatic system. They are generally subdivided into two groups: Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). NHL is discussed in another report. [For more information, see In-Depth Report #84: Non-Hodgkin's lymphomas.] Hodgkin's disease is also called Hodgkin's lymphoma.

Hodgkin's disease is marked by the presence of abnormal large cells called Reed-Sternberg cells. Reed-Sternberg cells are derived from B cell lymphocytes (white blood cells). Reed-Sternberg cells are specific to Hodgkin's disease. They are not found in non-Hodgkin's lymphoma.

Most often HD starts in B cell lymphocytes located in lymph nodes in the neck area, although any lymph node may be the site of initial disease.

Click the icon to see an image of the lymph nodes in the head and neck.

Types of Hodgkin's Disease

There are two major types of Hodgkin's disease: Classical Hodgkin's lymphoma and nodular lymphocyte-predominant Hodgkin's disease.

Classical Hodgkin's Lymphoma. Classical Hodgkin's lymphoma accounts for about 95% of Hodgkin's disease cases. It has four major subtypes:

• Nodular Sclerosis. Nodular sclerosis is the most common subtype, representing about 60 - 80% of HD cases. Younger patients are more likely to have this type. The nodes first affected are often those located in the center of the chest (the mediastinum) or the neck.
• Mixed Cellularity. Mixed cellularity is the next most common HD form, occurring in about 15 - 30% of patients, mostly in older adults. Mixed cellularity refers to the presence of Reed-Sternberg cells and other cell types.
• Lymphocyte Rich. The lymphocyte-rich subtype accounts for about 5% of all HD cases. It tends to affect men more than women.
• Lymphocyte Depleted. The lymphocyte-depleted subtype is the least common type of HD, occurring in only about 1% of cases. It is usually seen in older people and patients infected with HIV. It is also more common in less developed countries. The cancer tends to be diagnosed when it is widespread, affecting the spleen, bone marrow, and liver as well as abdominal lymph nodes.

Nodular Lymphocyte-Predominant Hodgkin's Disease. Nodular lymphocyte-predominant Hodgkin's disease occurs in about 5% of patients. It is distinct from classical Hodgkin's lymphoma. The cells look like and are referred to as 'popcorn' cells, which are variants of Reed-Sternberg cells. This type of HD typically affects younger patients and usually originates in the neck lymph nodesThis type of HD is sometimes confused with non-Hodgkin's lymphoma (NHL). In fact, there is a 3 - 5% risk that nodular lymphocyte-predominant Hodgkin's disease can transform into diffuse large B-cell NHL.

The Lymphatic System

Lymphomas 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, which are important cells involved in defending the body against infections. This system also restores 60% of the fluid that leaks out from blood capillaries back into circulation. Its ducts provide transportation for fats, proteins, and other substances collected from the body's tissues.

Lymphocytes. The lymphatic system helps produce and transport lymphocytes, white blood cells that are a primary component of the immune system. Some lymphocytes produce antibodies that can target and attack specific foreign substances (antigens).

• Lymphocytes develop in the bone marrow or thymus gland. They are categorized as either B cells (bone marrow-derived cells) or T cells (thymus gland-derived cells).
• Lymphatic vessels begin as tiny tubes. They lead to larger lymphatic ducts and branches, and drain into two ducts in the neck, where the fluid re-enters the bloodstream.
• Along the way, the fluid passes through lymph nodes, which are 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.
• Both leukemia and lymphomas (Hodgkin's disease and non-Hodgkin's lymphomas) are cancers of lymphocytes. The difference is that leukemia starts in the bone marrow while lymphomas originate in lymph nodes and then spread to the bone marrow or other organs.

Lymph Nodes. In a lymph node, lymphocytes typically receive their initial exposure to foreign substances, such as bacteria. This exposure prompts 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 clustered throughout the body. 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 lymphatic organs. They are 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.

Spread of Cancer. 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 may then 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.

Click the icon to see an image of an antibody.

Click the icon to see an image of the immune system structures.

Hodgkin's disease is less common than non-Hodgkin's lymphoma. It accounts for about 11.5% of all lymphomas. According to the American Cancer Society, about 8,200 new cases of Hodgkin's disease (HD) are diagnosed in the United States each year. The exact causes of Hodgkin's disease are unknown. Research indicates that the malignant process leading to Hodgkin's disease may be triggered by a combination of environmental and genetic factors along with a susceptible immune system.

Age and Gender

Hodgkin's disease occurs most often in people ages 15 - 40 (especially in their 20s), and in people over age 55. About 10 - 15% of Hodgkin's disease cases are diagnosed in children and teenagers.

Hodgkin's disease is slightly more common among males than females. Women who get Hodgkin's disease appear to have a slightly lower risk for relapse after treatment than men.

Viral Infection

Infectious mononucleosis ('mono'), which is caused by the Epstein-Barr virus (EBV), is strongly linked with increased risk for Hodgkin's disease. Research suggests that the virus activates some pathway within the lymphocyte cell that leads to cell proliferation. However, only 1 in 1,000 patients with mononucleosis develops Hodgkin's disease. The Epstein-Barr virus itself is present in 90% of the population and, in the great majority of these cases, causes a mild infection or none at all. Very few people who have had mononucleosis go on to develop HD. Other factors must be present to trigger the malignancy.

People infected with the human immunodeficiency virus (HIV), which weakens the immune system, are also at increased risk of developing Hodgkin's disease.

Family

Hodgkin's disease runs in families in about 5% of cases. Siblings of patients have a three times higher risk than the general population.

Symptoms of Hodgkin's disease may include:

• Swollen (but painless) lymph nodes in the neck, armpits, or groin
• Pain in lymph nodes after drinking alcohol
• Itching throughout body (pruritis)
• Persistent fatigue
• Coughing, difficulty breathing, or chest pain may indicate that swollen lymph nodes in the chest are pressing on the windpipe
• Unexplained weight loss of more than 10% in previous 6 months
• Persistent fever
• Drenching night sweats

The last three symptoms (weight loss, fever, and night sweats) are classified as 'B symptoms.' B symptoms may be used in staging Hodgkin's disease and can indicate that more aggressive treatment will be required.

Sometimes patients with Hodgkin's disease do not experience any symptoms, or symptoms may not appear until the cancer is very advanced. Enlarged lymph nodes can also be caused by many noncancerous conditions, such as infections.

The doctor will take a medical history and perform a physical examination. If these simple procedures point to Hodgkin's disease, a number of additional tests may be needed to either rule out other diseases or confirm HD and determine the extent of the cancer.

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 (including Hodgkin's). Soft nodes suggest infection or inflammatory conditions.

Blood Tests

Blood tests are performed to measure white and red blood cells, blood protein levels, the uric acid level, blood proteins, and the liver's function. Another blood test is the erythrocyte sedimentation rate (ESR), which is sometimes elevated in Hodgkin's disease (although it is not specific for this condition).

Click the icon to see an image of the formed elements of blood.

Imaging Techniques

Chest X-Ray. A chest x-ray shows the lymph nodes in the chest and neck area, where Hodgkin's disease usually starts. It a useful step for detection of 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.

Positron Emission Tomography (PET). PET scans combined with CT scans can help doctors clarify the location of the cancer. PET scans can also provide information on whether or not an enlarged lymph node is benign or cancerous and 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.

Biopsy

A biopsy of the suspicious lymph node is the most definitive way to diagnose Hodgkin's disease. The lymph node sample will be examined by a pathologist for the presence of Reed-Sternberg cells or other abnormal features.

The type of biopsy performed depends in part on the location and accessibility of the lymph node. The doctor may surgically remove the entire lymph node (excisional biopsy) or a small part of it (incisional biopsy). In some cases, the doctor may use fine needle aspiration to withdraw a small amount of tissue from the lymph node. Biopsies of bone marrow may also be performed in patients with existing Hodgkin's disease if the doctor suspects that it may have spread to the marrow.

Hodgkin's disease is considered one of the most curable forms of cancer, especially if it is diagnosed and treated early. Unlike other cancers, Hodgkin's disease is even potentially curable in late stages Five-year survival rates for patients diagnosed with stage I or stage II Hodgkin's disease are 90 - 95%. With advances in treatment, recent studies have indicated that even patients with advanced Hodgkin's disease have 5-year survival rates of 90%, although it is not yet certain if their cancer will return. Patients who survive 15 years after treatment are more likely to later die from other causes than Hodgkin's disease.

Survival rates are poorest for:

• Those who relapse within a year of treatment
• Patients who do not respond to the first-line therapy and have signs of disease progression

Factors that Influence Prognosis

The International Prognostic Factors Project on Advanced Hodgkin's Disease uses seven factors to help determine which patients with advanced Hodgkin's disease have a more serious prognosis and could benefit from more aggressive chemotherapy. These factors are also used to predict success in patients with relapsed or persistent HD who are undergoing stem cell transplantation.

The more of these factors that are met, the worse the outlook and the more likely the patient needs to be treated aggressively:

• Being male
• Age of 45 years or older
• Stage IV disease
• Low blood albumin level (less than 4g/dL; albumin is a type of protein.)
• Low hemoglobin level (less than 10.5g/dL; hemoglobin is the oxygen-carrying component of red blood cells)
• High white blood cell count (more than 15,000)
• Low lymphocyte count (less than 600)

Long-Term Effects of Treatments

The good news about Hodgkin's disease is that treatment can cure the disease. The bad news is that survivors face a higher than average risk for long-term complications of these treatments, some very serious.

Many patients may experience chronic fatigue that could persist for years. The most serious complications are secondary cancers and heart disease, which occur over the 2 - 3 decades following treatments. Secondary cancers include non-Hodgkin's lymphoma, leukemia, melanoma, stomach and lung cancers, and breast and uterine cancers. Heart disease complications include coronary artery disease, stroke, heart valve problems, and cardiomyopathy (weakening of the heart muscle). Thyroid disorders are also a potential complication. Combinations of radiation and chemotherapies are especially associated with these problems.

Studies of adult survivors of various childhood cancers have found that, 30 years after treatment, patients with Hodgkin's disease have among the highest risk of developing serious health problems. Female survivors have a significantly greater risk than male survivors. In particular, women who received chest radiation are at very high risk for developing breast cancer.

Patients with Hodgkin's disease should get a written record of the treatments they received as children, and the potential risks of these treatments. These records can help the doctors who later oversee their care monitor for potential health problems. Survivors of Hodgkin's disease should receive regular screening tests for cancer and heart disease. They may need to get these tests at a younger age than most patients. In particular, patients who were treated with chest radiation should get blood tests every 5 years to measure their cholesterol levels. Female patients who received chest radiation should get early and frequent mammograms.

Treatment options depend on:

• Type of Hodgkin's disease
• Tumor stage, size, and location
• Patient's age and overall health status
• Presence or absence of 'B symptoms' (weight loss, persistent fever, night sweats)

Certain factors may determine whether more intensive treatment is required. For example, the presence of B symptoms and 'bulky' (large mass) tumors are treated usually indicates a more aggressive treatment approach.

Chemotherapy, radiation, or both (chemoradiation) are the main treatments for Hodgkin's disease. Stem cell transplantation may be recommended for patients whose cancer has recurred.

Staging

Hodgkin's disease is staged (I through IV) to determine to how far the cancer has spread. Staging is the primary method for determining both treatment options and prognosis.

Stage I. Disease is limited to a single node region (I) or has involved one neighboring area or a single nearby organ.

Stage II. Disease is limited to two or more lymph nodes on the same side of (above or below) the diaphragm or extends locally from the lymph node into a nearby organ.

Stage III. Disease is in lymph nodes on both sides of the diaphragm or has spread to nearby organs, the spleen, or both.

Stage IV. Disease has become widespread involving organs outside the lymph system, such as liver, lung, or bone marrow.

Treatment Options by Stage

Early Stages (I or II). For disease in stages I or II, the following treatments may be used:

• Treatment in Adults. Doctors usually recommend radiation first for adults with HD. It provides excellent remission rates, although studies have reported a number of serious long-term complications in some patients. Selected patients in early stages may also be candidates for radiation limited only to areas above the diaphragm (called the mantle field), which can also have excellent results although still pose a considerable risk for late serious complications.
• Treatment in Children. Chemotherapy and low-dose radiation is the standard treatment for most children and adolescents who have not reached full growth. Specific chemotherapy combinations have been developed to reduce the risks for infertility, leukemia, and toxic effects on the heart and lungs.

Later Stages. For stage III disease, chemotherapy, often with radiation, is a standard treatment. For stage IV disease, chemotherapy alone is generally recommended. The latest chemotherapy regimens are achieving survival rates that reach 90%.

Relapse. Relapse after treatment occurs in 20 - 35% of patients. Treatments for relapse include chemotherapy, radiation, and bone marrow or blood stem cell transplantation. Many patients respond favorably to such treatments, although another relapse is still possible.

Preparing for Side Effects before Treatment

Preventing Infection. Both the disease and some of the treatments suppress the immune system, increasing the risk for infections. Widespread, life-threatening infection is a particular danger if the spleen has been removed and both radiation and chemotherapy are administered. At least a week before any treatment, patients are often vaccinated against three bacteria: pneumococcus, meningococci, and Haemophilus influenza.

Preserving Fertility. People who may wish to have children in the future should discuss the possibility for receiving treatments that may lessen the risk for infertility. Men with Hodgkin's disease may want to consider sperm freezing and assisted reproductive techniques. Women should ask their doctors about the possibility for preserving fertility by taking hormonal drugs called GnRH analogs before and during chemotherapy.

[For more information on fertility preservation treatments, see In-Depth Report #67: Male infertility and In-Depth Report #22: Female infertility.]

Monitoring after Treatment

Periodic examination for recurrent Hodgkin's disease is necessary for years after treatment, since relapse is not uncommon, even after treatment for early stages, and can occur a decade or more after treatment. Imaging tests of the abdomen are useful for detecting relapsed disease. Relapse is more likely to occur in early-stage disease, probably because limited radiation normally used in such cases did not destroy all malignancies. Patients who had large tumors in the chest are also at higher risk for recurrence. Patients also need to be monitored for long-term effects of the treatments themselves. Conditions to watch for include inflammation in the lungs and thyroid disease from radiation in the chest and heart disease and cancers from combined treatments, chemotherapy and blood stem cell transplantation.

Treatment of Pregnant Women

Because Hodgkin's disease often occurs in young adults, treatment for pregnant women is of particular concern. Therapy must be effective enough to protect the mother without hurting the fetus. Chemotherapy is rarely used early in the term, because it poses a risk for birth defects. Treatment choice must be individualized, taking into consideration the mother's wishes, the severity and pace of the disease, and the length of the remaining pregnancy. The treatment plan may need to be changed as the pregnancy progresses. If the disease develops in the second half of the pregnancy, it may be possible to postpone chemotherapy or radiation therapy until after an early induced delivery.

Treatment is guided by the stage of the disease and usually relies on the location and extent of the disease. Treatment may vary within a stage, depending on whether it is categorized as either A or B. (Systemic symptoms are absent in "A" and present in "B.?) The presence of B symptoms increases the risk of relapse, and so may require more aggressive treatments for that stage.

Early Stages (I or II). For disease in stages I or II, the following treatments may be used:

• Treatment in Adults. Doctors usually recommend radiation first for adults with HD. It provides excellent remission rates, although studies have reported a number of serious long-term complications in some patients. Selected patients in early stages may also be candidates for radiation limited only to areas above the diaphragm (called the mantle field), which can also have excellent results although still pose a considerable risk for late serious complications.
• Treatment in Children. Chemotherapy and low-dose radiation is the standard treatment for most children and adolescents who have not reached full growth. Specific chemotherapy combinations have been developed to reduce the risks for infertility, leukemia, and toxic effects on the heart and lungs. Researchers are studying the use of chemotherapy alone in this group.

Later Stages. For stage III disease, chemotherapy, often with radiation, is a standard treatment. For stage IV disease, chemotherapy alone is generally recommended. The latest chemotherapy regimens are achieving survival rates that reach 90%.

Relapse. Relapse after treatment occurs in 20 - 35% of patients. Treatments for relapse include chemotherapy, radiation, and bone marrow or blood stem cell transplantation. Many patients respond favorably to such treatments, although another relapse is still possible.

Click the icon to see an illustrated series detailing bone marrow transplant surgery.

Stage I Hodgkin's Disease

Disease is limited to a single node region (I) or has involved one neighboring area or a single nearby organ (IE). The standard treatment for stage I disease is usually radiation for adult patients who have determined the stage using pathologic staging with laparotomy. Chemotherapy with low-dose radiation is now the standard approach for children and adolescents. Cure rates can be greater than 90%.

Stage IA. Treatments depend on location. For a malignancy above the diaphragm, which does not involve a large part of the chest, the following may be used:

• Radiation therapy to the mantle field (chest, neck, and arm pits) and to the lymph nodes in the upper abdomen and spleen
• Radiation therapy to a mantle field in certain patients -- best candidates are females with nodular sclerosis or lymphocyte predominant cell types, who are no older than 40 years, have no "B" symptoms, and have erythrocyte sedimentation rate (ESR) levels less than 50
• Radiation therapy to a mantle field, the lymph nodes in the upper abdomen, and the spleen (subtotal node irradiation)
• Chemotherapy alone is under investigation

If the malignancy is bulky, above the diaphragm, and involves a large part of the chest, chemotherapy plus radiation therapy is commonly used.

If the malignancy is below the diaphragm, treatment includes chemotherapy with or without radiation. Radiation therapy may be directed to the lymph nodes in the upper abdomen and pelvis, and sometimes the spleen or groin. Total nodal irradiation is an option which includes these regions plus the mantle field.

Stage IB. Treatments depend on location. For a malignancy above the diaphragm, which does not involve a large part of the chest, the following may be used:

• Chemotherapy plus radiation therapy to a mantle field (in patients who have severe symptoms and did not undergo laparotomy to determine the extent of the disease below the diaphragm)
• Radiation therapy to the mantle field and to the lymph nodes in the upper abdomen is sometimes considered, but relapse rate can be high if significant B symptoms are present
• Chemotherapy alone under investigation for children

If the malignancy is bulky, above the diaphragm, and involves a large part of the chest, chemotherapy plus radiation therapy is commonly used.

If the malignancy is below the diaphragm, treatment includes chemotherapy with or without radiation to the upper abdomen and pelvis, to the areas that contain cancer, or to the spleen. Total nodal irradiation or radiation to lymph nodes in the upper abdomen and pelvis is another option.

Stage II Hodgkin's Disease

Disease is limited to two or more lymph nodes on the same side of the diaphragm (II) or involvement of a single neighboring organ or area and one or more nearby lymph nodes; other lymph nodes on the same side of the diaphragm may be involved (IIE).

There are few differences between treatments for stage IIA and IIB, and the approach for both depends on the extent and location of the disease:

Non-bulky disease:

• Radiation alone for adult and possibly adolescent (especially male) patients
• Chemotherapy with low-dose radiation is used for children

For a malignancy above the diaphragm, which does not involve a large part of the chest, the following may be used:

• Radiation therapy to a mantle field and to the lymph nodes in the upper abdomen
• Radiation therapy to a mantle field only (See Stage I Hodgkin's Disease section above)

Chemotherapy alone or with radiation therapy (combined modality) is being evaluated for those with non-bulky stage IIA. Also under investigation is radiation therapy to a mantle field only in patients with lymphocyte predominant cell types, who are no older than 40 years.

If the malignancy is above the diaphragm and does involve a large part of the chest, chemotherapy plus radiation therapy to a mantle field is the common approach.

If the malignancy is below the diaphragm, treatment includes chemotherapy with or without radiation to the upper abdomen and pelvis, and possibly the spleen. Total nodal irradiation is another option.

Stage III Hodgkin's Disease

Disease is in lymph nodes on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an associated organ or site outside the lymph node (IIIE), by involvement of the spleen (IIIS), or by both (IIIE+S). In addition, stage III may be further categorized by the extent of its spread into the spleen or where it has spread in the abdominal area. Survival rates in some cases can be as high as 90%.

Stage IIIA. Chemotherapy is the most common treatment approach for most adults and children. Radiation may be added under certain circumstances, especially to provide localized treatment of bulky areas. (Radiation does not appear to offer any survival advantage for patients whose disease is in complete remission after chemotherapy.)

For a malignancy above the diaphragm, which does not involve a large part of the chest, the following may be used:

• Chemotherapy alone
• Chemotherapy with radiation therapy (combined modality)
• Total or subtotal nodal radiation therapy alone -- for adults if disease is only in the upper abdomen and fewer than five nodes in the spleen are affected

If the malignancy involves a large part of the chest, the following may be used:

• Standard chemotherapy alone
• Chemotherapy plus radiation therapy (combined modality)
• Investigative treatments

Stage IIIB. Chemotherapy alone is the standard treatment for most adults and children. Radiation is often added to treat areas of bulky tumor.

Stage IV Hodgkin's Disease

Disease has spread to organs outside the lymph system, such as liver, lung, or bone marrow. Even in this population, high long-term survival rates of over 85% are possible, including in children.

Treatment may include:

• Chemotherapy alone
• Chemotherapy with limited radiation to places of bulky disease
• A clinical trial of investigational chemotherapy regimens or of stem-cell transplantation

Click the icon to see an image of liver involvement in Hodgkin's disease.

Relapsed or Refractory Hodgkin's Disease

When disease recurs or persists after initial treatment either in the same area or in another part of the body, the next round of therapy depends on where the disease returns and the previous treatment used.

• If the previous treatment was radiation therapy without chemotherapy, salvage chemotherapy is the usual choice.
• If the patient was previously treated with chemotherapy, the choice may be radiation therapy to the lymph nodes with or without salvage chemotherapy.
• In some patients, if the disease has persisted or if relapse has occurred after chemotherapy with or without radiation, high-dose chemotherapy and stem cell transplantation may be given.

High-dose radiation therapy, which shrinks the tumors, has been used for more than 50 years for treating Hodgkin's disease. High-dose radiation is generally reserved for adults. Radiation treatments are highly toxic for children and appear to add little benefit. In such young age groups radiation is mostly used if there are large areas of disease in the chest; otherwise, chemotherapy with possibly low-dose radiation is the best option with excellent survival rates.

Radiation Target

Radiation is directed to specific areas depending on the location of the disease:

• If HD is above the diaphragm, 'extended field radiation? is delivered to the neck, chest, and under arms (called the mantle field). Extended-field radiation is sometimes expanded to include lymph nodes in the upper abdomen.
• If cancer is below the diaphragm, an "inverted Y" field is sometimes used, in which radiation is directed at lymph nodes in the upper abdomen, spleen, and pelvis.
• Inverted Y-field radiation therapy combined with mantle-field radiation is called 'total nodal radiation.?
• "Involved field radiation" targets only lymph node regions that are known to have cancer. By contrast, extended-field radiation targets lymph node regions with cancer as well as adjacent, uninvolved lymph node regions. Involved-field radiation is usually given after several rounds of chemotherapy.

A 2006 study indicated that radiation therapy alone, without chemotherapy, may help older patients with early-stage Hodgkin's disease. If chemotherapy is given, another 2006 study suggested that involved-field is a better option than extended-field radiation for elderly adults with early-stage unfavorable Hodgkin's lymphoma.

In general, recent research suggests that extended-field radiation adds little survival advantage and carries a greater risk of serious side effects. Involved-field radiation is now becoming the preferred method. Some researchers recommend that involved-field radiation therapy plus chemotherapy should become the standard treatment for patients with early-stage Hodgkin's disease who have a good prognosis. More research is needed before standard practice guidelines can be implemented.

Radiation Treatment Approaches

It is very important that radiation treatments cover the entire diseased area and that the radiation therapy be powerful enough to destroy the malignant cells' capacity to grow and divide. Unfortunately, this means that normal cells are also affected, which can cause serious side effects. Different approaches may be used to prevent complications.

• 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.
• Long-term complications generally occur at higher radiation doses (over 35 Gy). Investigators are studying the doses as low as 20 Gy (in children). Studies indicate that radiation alone in doses under 35 Gy can control the disease as well as higher doses in most stage I and II patients, although some patients may require more aggressive treatment.
• To protect ovaries, a technique called ovarian transposition may sometimes be performed. The procedure uses a laparoscope (a thin tube containing tiny instruments and cameras) that 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.

Complications of Radiation

Infections. Infections may be a particular problem with radiation combined with chemotherapy. All patients should be vaccinated against pneumonia and influenza.

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.

Click the icon to see an image of the lungs.

Infertility. Radiation therapy to the pelvic area can adversely affect later fertility in women and men. Such negative effects may be worse in women; sperm usually recover within 5 years.

Heart Disease and Stroke. Radiation is associated with a future risk of heart disease, which includes atherosclerosis (hardening of the arteries) and diseases of the heart valves. Lower doses pose less risk. Recent research suggests that adults who survived childhood Hodgkin's disease have a four times higher risk of having a stroke than healthy patients.

Fatigue. Fatigue is significant and chronic in many survivors. It is more highly associated with intensive chemotherapy, but it also may be a late response to radiation treatment.

Secondary Cancers. Second cancers (such as breast, stomach, lung, melanoma) may develop later in areas within or at the edge of the radiation area. Thyroid, respiratory tract, and digestive tract secondary cancers may affect patients who were treated as children. The risks are twice as high with treatments that are combined with chemotherapy.

Lung cancer in survivors is highly associated with smoking after treatment, and no survivor should smoke. The risk for breast cancer increases significantly in young women after treatment, particularly with high radiation doses and combined chemotherapy and radiation. The risk can persist for 25 years or more after radiotherapy, and lifetime monitoring (including frequent mammograms) is essential.

Thyroid Disorders. Hypothyroidism (underactive thyroid) occurs in a number of patients treated with radiation treatments. There is also a 5% chance for hyperthyroidism (overactive thyroid).

Click the icon to see an image of hypothyroidism.

Click the icon to see an image of hyperthyroidism.

Impaired Growth in Children. Children and adolescents are at special risk for impaired bone growth.

Chemotherapy uses drugs to kill cancer cells. The drugs are called cytotoxic medications. Chemotherapy is referred to as body-wide, or systemic, therapy because the drugs travel throughout the entire body.

Cytotoxic drugs may be taken by mouth or given by injection. Treatment may be administered at a medical center, doctor's office, or even a patient's home. Some patients receiving chemotherapy may need to remain in the hospital for several days so the effects of the drug can be monitored.

Patients may receive 4 - 8 cycles of chemotherapy, depending on the stage. A cycle is usually 28 days and consists of several doses of drug administration followed by a period of rest.

Specific Drugs and Drug Combinations Used in Hodgkin's Disease

The standard chemotherapy regimens for Hodgkin's disease are ABVD and Stanford V.

ABVD consists of a 4-drug combination:

• Doxorubicin (Adriamycin)
• Bleomycin
• Vinblastine
• Dacarbazine

Stanford V consists of a 7-drug combination:

• Doxorubicin (Adriamycin)
• Mechlorethamine (nitrogen mustard)
• Vincristine
• Vinblastine
• Bleomycin
• Etoposide
• Prednisone

BEACOPP (bleomycin, etoposide, Adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) is a chemotherapy regimen reserved for high-risk patients. This regimen is proving to be extremely effective, particularly in advanced stages, with studies reporting remission rates of over 95% in patients with advanced Hodgkin's. However, this regimen also increases the risk for developing secondary cancers such as leukemia. Patients who are treated with BEACOPP should receive long-term follow-up care to monitor for side effects from this therapy.

Side Effects and Complications

Side effects and complications of any chemotherapeutic regimen are common, are more severe with higher doses, and increase over the course of treatment, though some trials suggest that toxicities can be reduced by administering the drugs for shorter duration without loss of cancer-killing effects.

Common Side Effects. Common side effects include the following:

• Nausea and vomiting -- drugs known as serotonin antagonists, including 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 1 or 2 days a month.

Serious Side Effects. Serious 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 only treat 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.
• Infection. Patients must take precautions against infections (see "Infection Prevention" in Transplant section).
• Liver and kidney damage
• Abnormal blood clotting (thrombocytopenia)
• Allergic reaction

Long-Term Complications.

• Fatigue and general aches and pains are called somatic symptoms. Fatigue is especially common after chemotherapy and can even last for years.
• Many women stop menstruating after chemotherapy. The risk for infertility is highest for women with advanced stage Hodgkin's disease who are treated after age 30. Studies indicate that the risk for infertility is higher with BEACOPP than with ABVD. Researchers are studying whether taking oral contraceptives during chemotherapy can reduce the risk.
• Bone thinning (osteoporosis) may be related to steroid treatments such as prednisone.
• Heart failure may occur with the use of anthracyclines (such as doxorubicin).
• Bleomycin (Blenoxane), an antibiotic, is particularly toxic to the lungs. Vinblastine may also pose a risk when used in combination with radiation therapy.

In general, these serious late side effects are dependent on the cumulative drug dose and rate of administration.

Combinations of Chemotherapy and Radiation (Combined Modality)

Regimens. Chemotherapy (usually ABVD) plus radiation, referred to as combined modality, is a common treatment approach for patients with more advanced-stage disease and for those who have early-stage bulky (large mass) disease.

Chemotherapy with low-dose radiation is being used in children with excellent results, even for late stage cancer. In one study, 82% of the children were still disease free at 5 years. Some chemotherapy drugs or high doses of radiation may be more deleterious to a boy's future fertility than to a girl's. A gender-specific combined regimen for pediatric Hodgkin's reduces the amount of radiation given to boys and also substitutes etoposide for procarbazine in the chemotherapy mixture (procarbazine, vincristine, prednisone, and doxorubicin).

Side Effects and Long-Term Complications. Side effects of combination treatments can be very serious. Examples include:

• Combined modality poses a higher risk for secondary cancers than the use or radiation or chemotherapy alone. They include breast, lung, thyroid, melanoma, and gastrointestinal cancers, which usually develop in near or in the areas treated with radiation. Of note, the risk for breast cancer is lower when chemotherapies using alkylated drugs or radiation treatments damage the ovaries, suggesting that hormone stimulation plays a role in this higher risk. Newer drugs used in combined modalities may reduce the risk, at least for breast cancer.
• ABVD and other regimens containing bleomycin increase the risk for severe effects on the lungs when used before or after mantle-field radiation. EVA (etoposide, vinblastine, and doxorubicin) is considered to be an effective substitute in patients with lung disease for whom bleomycin and radiation present an unacceptable risk.

Patients with relapsed or progressive HD are often treated with high-dose chemotherapy followed by stem cell transplantation procedures. (Transplantation does not appear to offer an advantage compared to standard chemotherapy as initial treatment for patients with high-risk advanced HD.)

This treatment involves removal and replacement of stem cells, which are produced in the bone marrow. This allows the patient to receive high-dose chemotherapy without destroying these important cells. 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.

For Hodgkin's disease, the most common type of transplant is an autologous procedure, using the patient's own cells. An allogeneic transplant, using cells from a donor, is more risky for patients with Hodgkin's disease and is generally used only when an autologous transplant has failed. (This section provides information pertinent to autologous procedures. Detailed information on allogeneic transplants, including such complications as graft-versus-host-disease, can be found in In-Depth Report #84: Non-Hodgkin's Lymphoma.)

Transplantation Procedure

Stem cells must first be collected in one of the following ways:

• Directly from blood (peripheral blood stem cell transplantation)
• From bone marrow (bone marrow transplantation)

Click the icon to see an illustrated series detailing bone marrow transplant surgery.

Stem cells are collected several weeks before the procedure. They are frozen and stored while the patient undergoes high-dose chemotherapy. Some patients receive high-dose whole body radiation therapy along with chemotherapy.

After the patient completes the pre-transplant therapy, the frozen cells are thawed and then infused into the patient. Within a few weeks, these cells start to generate new white blood cells and then new red blood cells.

Infection

The risk for infection greatest during the first 6 weeks following the transplant. During this period, a patient usually remains in isolation and receives antibiotics and intravenous nutrition. It takes 6 - 12 months post-transplant for a patient's immune system to fully recover.

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 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.
• 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.

Other Side Effects and Complications

Common side effects of stem cell transplants 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%.

There is a small long-term risk for leukemia after transplantation in young people. Chemotherapy itself increases the risk of secondary cancers. Recent studies suggest that transplantation after chemotherapy does not add any additional risks. In addition, use of newer chemotherapeutic drugs may not pose as high a danger as older treatments.

Other serious potential 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)

Investigational approaches to Hodgkin's disease include immunotherapies, which are drugs that take advantage of the patients' own immune factors to attack the disease.

One important approach uses genetically designed immune factors called monoclonal antibodies (MAb) that recognize and attack specific molecules found on the surface of cells associated with HD.

Rituximab (Rituxan) was the first monoclonal antibody to be approved for any cancer. It is an unconjugated MAb that targets the CD-20 antigen, which is found on most B-cell lymphomas and normal mature B cells (although not stem cells). It is used in non-Hodgkin's lymphomas, but it may have benefits for some patients with Hodgkin's disease as well.

• www.cancer.gov -- National Cancer Institute
• www.cancer.org -- American Cancer Society
• www.lymphoma.org -- Lymphoma Research Foundation
• www.leukemia.org -- Leukemia and Lymphoma Society
• www.canceradvocacy.org -- National Coalition for Cancer Survivorship
• www.asco.org -- American Society of Clinical Oncology
• www.plwc.org -- People Living with Cancer
• www.marrow.org -- National Marrow Donor Program
• www.oncolink.org -- Cancer information
• www.lymphomainfo.net -- Lymphoma Information Network
• www.cancer.gov/clinicaltrials -- Find clinical trials

Fermé C, Eghbali H, Meerwaldt JH, et al. Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med. 2007 Nov 8;357(19):1916-27.

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: Hodgkin Disease / Lymphoma. V.1.2007.