Staging and treatment for Hodgkin's disease

DEFINITION — Hodgkin's disease, also known as Hodgkin's lymphoma, is one of two common types of cancer of the body's lymphatic system. The lymphatic system is a network of lymph nodes and interconnecting lymph vessels (show figure 1). Lymph nodes are small, pea-shaped organs that make and store lymphocytes, a type of white blood cell that fights infection. Lymph vessels are similar to blood vessels, and carry a watery fluid (lymphatic fluid) that contains lymphocytes. The thymus, spleen, and bone marrow are other organs in the lymphatic system.

In Hodgkin's lympoma, a cancerous tumor develops in a lymph node, usually in the neck or chest. If Hodgkin's lympoma spreads, its pattern is to first spread to adjacent lymph nodes, and then to the spleen, liver, or bone marrow. As it progresses, Hodgkin's lympoma may affects the body's ability to fight infection.

Fortunately, Hodgkin's disease is one of the most treatable forms of cancer. About 75 percent of patients diagnosed with Hodgkin's disease can be cured with treatment. Over 90 percent are expected to live at least 10 years following diagnosis and treatment.

The following discussion will review the staging and treatment for Hodgkin's lympoma. Issues regarding the risk factors and diagnosis of the disease are discussed in a separate topic review. (See "Patient information: Features and diagnosis of Hodgkin's disease").

STAGING — One of the reasons that Hodgkin's lympoma treatment is successful is the ability to carefully plan treatment based upon a patient's stage of illness. Staging involves dividing patients with Hodgkin's lympoma into groups (stages) based upon criteria at the time of diagnosis. Treatment decisions are based in large part on the stage of disease that is found.

The following are terms used in the staging criteria: Lymph node regions: An area of lymph nodes and the surrounding tissue. Examples include the cervical nodes in the neck (show figure 2), the axillary nodes in the armpit, the inguinal nodes in the groin, or the mediastinal nodes in the chest (show figure 3). Lymph structures: Organs or structures that are part of the lymphatic system, such as the lymph nodes, spleen, and thymus gland. Diaphragm: A large muscle that separates the chest cavity from the abdominal cavity.

Stage I — Only one lymph node region is involved, or only one lymph structure is involved.

Stage II — Two or more lymph node regions or lymph node structures on the same side of the diaphragm are involved.

Stage III — Lymph node regions or structures on both sides of the diaphragm are involved.

Stage IV — There is widespread involvement of a number of organs or tissues other than lymph node regions or structures, such as the liver, lung, or bone marrow.

Subclassifications — Additional criteria help clinicians further identify subgroups within each stage, as follows: A or B — The letter "A," as in stage IIA, means that symptoms of unexplained fever, night sweats, or weight loss (at least 10 percent of the body weight) were NOT present during the six months prior to diagnosis. The letter "B," as in stage IIIB, means that these symptoms were present. These symptoms are therefore referred to as "B symptoms". E — The presence of local spread of the disease from one nodal area or structure to surrounding or extranodal tissue in the same area of the body is indicated by the letter "e," as in stage IIe. S — Involvement of the spleen is designated by the letter "s", as in stage IIIs. X — The presence of "bulky disease," referring to larger masses of cancerous tissue, is indicated by the letter x.

For example, a patient with Hodgkin's disease involving lymph nodes in the neck, mediastinum, and groin (ie, involvement above and below the diaphragm) who also has symptoms of fever, night sweats, and weight loss (ie, systemic symptoms), would be in stage IIIB.

DETERMINING STAGE — A number of tests are used in the process of disease staging. However, not all patients will require every test.

History and physical exam — A careful history and physical examination will help determine whether symptoms related to Hodgkin's disease have been present (eg, fever, night sweats, weight loss). The physical exam may reveal swollen lymph nodes in various locations (show figure 1).

Diagnostic tests — A number of diagnostic tests are available to help determine which areas of the body have been affected by Hodgkin's disease. Tests that may be done include: Chest X-ray CT scan of the chest, abdomen, and pelvic area Blood tests Bone marrow biopsy: Removal of tissue from the bone marrow, the spongy area in the middle of large bones, for analysis. This is done for persons with stage IIB and higher. PET scan: This test uses a small amount of a radioactive substance, which is injected into a vein; the radioactive substance is absorbed by the cancer cells and can be viewed with a special camera.

Staging laparotomy — In the past, surgery was done in order to directly visualize and take samples from areas in the abdomen in order to determine the stage of the Hodgkin's disease. The operation, called a staging laparotomy, is now rarely done because there are other procedures that do not require a surgical procedure.

However, staging laparotomy may still be offered to patients who have early stage Hodgkin's disease with a good prognosis. Staging laparotomy provides reassurance that the disease is not widespread and allows patients the option of avoiding some of the risks and side effects associated with more extensive treatment.

TREATMENT — The mainstays of treatment for Hodgkin's lympoma are chemotherapy and radiation. Chemotherapy uses strong medicines to kill cancer cells while radiation therapy uses high-energy particles (gamma rays) to slow or stop the growth of cancer cells. Decisions about whether to use chemotherapy, radiation, or both depend upon several factors, including the stage of the disease and the presence or absence of large tumor masses.

Radiation therapy — Radiation therapy is administered to the region of affected lymph nodes with a carefully focused beam of radiation; this is called involved field radiation. Radiation therapy must be given in small daily doses over a period of weeks in order to minimize the side effects; the number of weeks depends upon the amount of radiation to be administered.

Side effects — During radiation treatment, some patients develop skin changes in the area that was treated, similar to a sunburn. These changes fade over time. Other side effects can include fatigue, and nausea.

Some forms of radiation therapy increase the risk of developing cancer in areas that have received incidental radiation (such as to the lungs and breast tissue) years after therapy is completed. Women under 30 are at increased risk of breast cancer, and smokers have an increased risk of lung cancer (beyond the already increased risk of lung cancer from smoking). A patient and his or her healthcare provider should discuss these issues when deciding upon a treatment plan.

Chemotherapy — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. Chemotherapy works by interfering with the ability of rapidly growing cells (like cancer cells) to divide or multiply. Because most of an adult's normal cells are not actively dividing or multiplying, they are not affected by chemotherapy. However, the bone marrow (where the blood cells are produced), the hair follicles, and the lining of the gastrointestinal (GI) tract are all growing. The side effects of chemotherapy drugs are related to effects on these and other normal tissues.

Modern chemotherapy typically involves a combination of two or more drugs; these combinations are referred to as regimens. Most drugs are given intravenously (IV) rather than by mouth. They are not usually taken daily, but periodically, in cycles. A cycle of chemotherapy refers to the time it takes to give the drugs and the time required for the body to recover. For example, a typical chemotherapy regimen is a one hour IV infusion of two or more different chemotherapy medications given once every three to four weeks. This three week period is one cycle of therapy. If this regimen were repeated for a total of three or four cycles, it would take up to four months to complete.

Chemotherapy regimens are identified by their initials and include: ABVD — ABVD includes Adriamycin® (doxorubicin), bleomycin, vinblastine, and dacarbazine, and is the most commonly used chemotherapy regimen. Stanford V — Stanford V includes Adriamycin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone. BEACOPP — BEACOPP includes bleomycin, etoposide, Adriamycin, cyclophosphamide, Oncovin®, procarbazine, and prednisone. This regimen is more commonly used in Europe. MOPP — MOPP includes mechlorethamine, Oncovin® (vincristine), procarbazine, and prednisone, and was one of the first chemotherapy regimens to be used for Hodgkin's lymphoma. It is no longer recommended for most patients due to its serious toxic side effects.

These regimens have been created to maximize effectiveness and minimize short-term and long-term side effects; as new medications and combinations are developed, it is hoped that survival will continue to improve as life-threatening and long-term complications diminish.

Side effects — The type and severity of side effects depends upon the type, combination, and dose of chemotherapy medication used. The most common treatment-related side effects include hair loss, nausea, vomiting, fatigue, loss of appetite, increased risk of infections, and becoming bruised or bleeding easily. Many of these side effects can be prevented or treated with other medications, such as those used for nausea and vomiting.

Long-term side effects of chemotherapy include infertility; in one study, 36 percent of men and 20 percent of women were infertile after undergoing ABVD [4]. This is an improvement over MOPP therapy, which caused 97 percent of men to become infertile. However, men and women who would like to have children after treatment should consider sperm or egg banking before chemotherapy begins.

A long-term side effect of bleomycin is damage to the lungs; this risk is highest in children and those who have radiation therapy to the mediastinum (mid-chest).

Stage I or II — For patients with Stage I or II disease, additional criteria are used to define the extent of disease. Criteria include: the presence of a large mass in the chest, the number of lymph node regions are affected by Hodgkin's lympoma, the age of the patient, the presence of B symptoms, and a specific abnormality in the erythrocyte sedimentation rate (a blood test).

Persons without these criteria are referred to as having favorable disease, while those with these characteristics are referred to as having unfavorable disease.

Favorable disease — A number of choices are available for patients with stage I or II disease with a favorable designation. As noted above, some of these patients may undergo staging laparotomy in order to be sure that the disease has not spread. If spread is not found, a patient may be treated with only radiation to the affected area.

Treatment choices include chemotherapy and radiation or radiation alone. The use of chemotherapy along with radiation is associated with a lower relapse rate, but potentially higher toxicity. Radiation or chemotherapy alone carry a higher risk of relapse, but patients who do relapse may be easier to treat than those who relapse following chemotherapy plus radiation.

A patient should discuss these options with their clinician because the patient's preferences (risk of recurrence of disease versus possible toxic effects of treatment) are an important part of the decision-making process. The treatment of early stage Hodgkin's disease has become so successful that at 15 to 20 years posttreatment, the overall mortality rate from causes other than Hodgkin's disease may be higher than that seen from Hodgkin's disease (show figure 4).

Unfavorable disease — Patients at Stage I or II with an unfavorable designation are generally treated with chemotherapy and radiation. Combination therapy allows approximately 80 to 85 percent of patients with unfavorable Hodgkin's lympoma to be alive and without disease relapse 10 years after treatment.

Stage III and IV — The primary treatment for patients with stage III and IV Hodgkin's lympoma is chemotherapy. Radiation therapy may be added if there are large masses that remain after chemotherapy or areas that do not show a complete response to chemotherapy.

Most patients will receive the ABVD regimen. With this, 60 to 70 percent of patients will be alive and free of disease at five years. ABVD is much less likely to cause severe bone marrow suppression (called myelosuppression, which can lead to very low white and red blood cell and platelet counts), acute leukemia, or sterility compared to treatment regimens, such as MOPP. ABVD alone is the treatment of choice for most patients with advanced disease, although Stanford V and BEACOPP combined with involved field radiotherapy are reasonable alternatives for some patients.

Bone marrow transplantation — Bone marrow transplantation (also called hematopoietic cell transplantation) may be offered to some patients who have recurrent Hodgkin's lympoma, or Hodgkin's lympoma that is resistant to other forms of treatment. This includes patients whose disease relapses following initial treatment. A separate topic review is available about bone marrow transplantation. (See "Patient information: Overview of bone marrow transplantation").

CLINICAL TRIALS — Many patients with Hodgkin's disease will be asked about enrolling in a clinical (research) trial. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask your healthcare provider for more information, or read about clinical trials at: National Cancer Institute

(www.cancer.gov/clinicaltrials/)
National Library of Medicine

(http: clinicaltrials.gov/)


WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
CancerNet, from the National Cancer Institute

(www.cancer.gov)
American Cancer Society

(www.cancer.org)
The Leukemia & Lymphoma Society

(www.leukemia-lymphoma.org)
Cure for Lymphoma Foundation

(www.cfl.org)
Lymphoma Research Foundation of America

(www.lymphoma.org)
National Marrow Donor Program

(www.marrow.org)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)


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Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Lister, TA, Crowther, D, Sutcliffe, SB, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 1989; 7:1630.
2. Henry-Amar, M, Somers, R. Survival outcome after Hodgkin's disease: A report from the international data base on Hodgkin's disease. Semin Oncol 1990; 17:758.
3. Advani, RH, Horning, SJ. Treatment of early-stage Hodgkin's disease. Semin Hematol 1999; 36:270.
4. Viviani, S, Santoro, A, Ragni, G, et al. Gonadal toxicity after combination chemotherapy for Hodgkin's disease. Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol 1985; 21:601.