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Adult Hodgkin lymphoma is a type of cancer that develops in the lymph system, part of the body's immune system.
The lymph system is made up of the following:
Because lymph tissue is found throughout the body, Hodgkin lymphoma can begin in almost any part of the body and spread to almost any tissue or organ in the body.
Lymphomas are divided into two general types: Hodgkin lymphoma and non-Hodgkin lymphoma. This summary is about the treatment of adult Hodgkin lymphoma. (See the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)
Hodgkin lymphoma can occur in both adults and children; however, treatment for adults may be different than treatment for children. Hodgkin lymphoma may also occur in patients who have acquired immunodeficiency syndrome (AIDS); these patients require special treatment.
See the following PDQ summaries for more information:
Hodgkin lymphoma in pregnant women is the same as the disease in nonpregnant women of childbearing age. However, treatment is different for pregnant women. This summary includes information about treating Hodgkin lymphoma during pregnancy.
Most Hodgkin lymphomas are the classical type. The classical type is broken down into the following four subtypes:
Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn't mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors for adult Hodgkin lymphoma include the following:
Pregnancy is not a risk factor for Hodgkin lymphoma.
These and other signs and symptoms may be caused by adult Hodgkin lymphoma or by other conditions. Check with your doctor if any of the following do not go away:
The following tests and procedures may be used:
A pathologist views the tissue under a microscope to look for cancer cells, especially Reed-Sternberg cells. Reed-Sternberg cells are common in classical Hodgkin lymphoma.
The following test may be done on tissue that was removed:
The prognosis (chance of recovery) and treatment options depend on the following:
For Hodgkin lymphoma during pregnancy, treatment options also depend on:
Adult Hodgkin lymphoma can usually be cured if found and treated early.
The process used to find out if cancer has spread within the lymph system or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment. The following tests and procedures may be used in the staging process:
For pregnant women with Hodgkin lymphoma, staging tests that protect the fetus from the harms of radiation are used. These include:
Cancer can spread through tissue, the lymph system, and the blood:
Adult Hodgkin lymphoma may be described as follows:
Stage I is divided into stage I and stage IE.
Stage II is divided into stage II and stage IIE.
Stage III is divided into stage III, stage IIIE, stage IIIS, and stage IIIE,S.
In stage IV, the cancer:
Early favorable adult Hodgkin lymphoma is stage I or stage II, without risk factors.
Early unfavorable adult Hodgkin lymphoma is stage I or stage II with one or more of the following risk factors:
Advanced favorable adult Hodgkin lymphoma is stage III or stage IV with three or fewer of the following risk factors:
Advanced unfavorable Hodgkin lymphoma is stage III or stage IV with four or more of the following risk factors:
Recurrent adult Hodgkin lymphoma is cancer that has recurred (come back) after it has been treated. The cancer may come back in the lymph system or in other parts of the body.
Different types of treatment are available for patients with adult Hodgkin lymphoma. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
For pregnant women with Hodgkin lymphoma, treatment is carefully chosen to protect the fetus. Treatment decisions are based on the mother's wishes, the stage of the Hodgkin lymphoma, and the age of the fetus. The treatment plan may change as the signs and symptoms, cancer, and pregnancy change. Choosing the most appropriate cancer treatment is a decision that ideally involves the patient, family, and health care team.
Treatment will be overseen by a medical oncologist, a doctor who specializes in treating cancer. The medical oncologist may refer you to other health care providers who have experience and expertise in treating adult Hodgkin lymphoma and who specialize in certain areas of medicine. These may include the following specialists:
Treatment with chemotherapy and/or radiation therapy for Hodgkin lymphoma may increase the risk of second cancers and other health problems for many months or years after treatment. These late effects depend on the type of treatment and the patient's age when treated, and may include:
Regular follow-up by doctors who are expert in finding and treating late effects is important for the long-term health of patients treated for Hodgkin lymphoma.
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated. Combination chemotherapy is treatment with more than one anticancer drug.
When a pregnant woman is treated with chemotherapy for Hodgkin lymphoma, it isn't possible to protect the fetus from being exposed to the chemotherapy. Some chemotherapy regimens may cause birth defects if given in the first trimester. Vinblastine is an anticancer drug that has not been linked with birth defects when given in the second half of pregnancy.
See Drugs Approved for Hodgkin Lymphoma for more information.
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.
For a pregnant woman with Hodgkin lymphoma, radiation therapy should be postponed until after delivery, if possible, to avoid any risk to the fetus. If immediate treatment is needed, the woman may decide to continue the pregnancy and receive radiation therapy. However, lead used to shield the fetus may not protect it from scattered radiation that could possibly cause cancer in the future.
Laparotomy is a procedure in which an incision (cut) is made in the wall of the abdomen to check the inside of the abdomen for signs of disease. The size of the incision depends on the reason the laparotomy is being done. Sometimes organs are removed or tissue samples are taken and checked under a microscope for signs of disease. If cancer is found, the tissue or organ is removed during the laparotomy.
Watchful waiting is closely monitoring a patient's condition without giving any treatment unless signs or symptoms appear or change. Delivery may be induced when the fetus is 32 to 36 weeks old, so that the mother can begin treatment.
Steroids are hormones made naturally in the body by the adrenal glands and by reproductive organs. Some types of steroids are made in a laboratory. Certain steroid drugs have been found to help chemotherapy work better and help stop the growth of cancer cells. Steroids can also help the lungs of the fetus develop faster than normal. This is important when delivery is induced early.
This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied. Information about clinical trials is available from the NCI Web site.
High-dose chemotherapy and radiation therapy with stem cell transplant is a way of giving high doses of chemotherapy and radiation therapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After therapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body's blood cells. The use of lower-dose chemotherapy and radiation therapy with stem cell transplant is also being studied.
Monoclonal antibodytherapy is a cancer treatment that uses antibodies made in the laboratory, from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells.
For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.
Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.
Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.
Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's listing of clinical trials.
Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.
Treatment of early favorable Hodgkin lymphoma may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I adult Hodgkin lymphoma and stage II adult Hodgkin lymphoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
Treatment of early unfavorable Hodgkin lymphoma may include the following:
Treatment of advanced favorable Hodgkin lymphoma may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III adult Hodgkin lymphoma and stage IV adult Hodgkin lymphoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
Treatment of advanced unfavorable Hodgkin lymphoma may include the following:
Treatment of recurrentHodgkin lymphoma may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent adult Hodgkin lymphoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
When Hodgkin lymphoma is diagnosed in the first trimester of pregnancy, it does not necessarily mean that the woman will be advised to end the pregnancy. Each woman's treatment will depend on the stage of the lymphoma, how fast it is growing, and her wishes. For women who choose to continue the pregnancy, treatment of Hodgkin lymphoma during the first trimester of pregnancy may include the following:
When Hodgkin lymphoma is diagnosed in the second half of pregnancy, most women can delay treatment until after the baby is born. Treatment of Hodgkin lymphoma during the second half of pregnancy may include the following:
For more information from the National Cancer Institute about adult Hodgkin lymphoma, see the following:
For general cancer information and other resources from the National Cancer Institute, see the following:
This information is provided by the National Cancer Institute.
This information was last updated on April 23, 2014.
Estimated new cases and deaths from Hodgkin lymphoma in the United States in 2014:[1]
More than 75% of all newly diagnosed patients with adult Hodgkin lymphoma (HL) can be cured with combination chemotherapy and/or radiation therapy.[2] National mortality has fallen more rapidly for adult HL than for any other malignancy over the last 5 decades.[2]
Prognosis for a given patient depends on several factors. The most important
factors are the presence or absence of systemic symptoms, the stage of disease,
presence of large masses, and the quality and suitability of the treatment
administered. Other important factors are age, sex, erythrocyte sedimentation rate, extent of abdominal involvement, hematocrit, and absolute
number of nodal sites of involvement.[3][4][5]
HL is the main cause of death over the first 15 years after treatment. By
15 to 20 years after therapy, the cumulative mortality from a second malignancy
will exceed the cumulative mortality from HL.[6][7][8]
Other PDQ summaries containing information related to Hodgkin lymphoma include the following:
American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed May 21, 2014.
Brenner H, Gondos A, Pulte D: Ongoing improvement in long-term survival of patients with Hodgkin disease at all ages and recent catch-up of older patients. Blood 111 (6): 2977-83, 2008.
American Cancer Society: Cancer Facts and Figures 2007. Atlanta, Ga: American Cancer Society, 2007. Also available online. Last accessed October 7, 2013.
Cosset JM, Henry-Amar M, Meerwaldt JH, et al.: The EORTC trials for limited stage Hodgkin's disease. The EORTC Lymphoma Cooperative Group. Eur J Cancer 28A (11): 1847-50, 1992.
Evens AM, Helenowski I, Ramsdale E, et al.: A retrospective multicenter analysis of elderly Hodgkin lymphoma: outcomes and prognostic factors in the modern era. Blood 119 (3): 692-5, 2012.
Mauch PM, Kalish LA, Marcus KC, et al.: Long-Term Survival in Hodgkin's Disease Cancer J Sci Am 1 (1): 33-42, 1995.
Aisenberg AC: Problems in Hodgkin's disease management. Blood 93 (3): 761-79, 1999.
Aleman BM, van den Belt-Dusebout AW, Klokman WJ, et al.: Long-term cause-specific mortality of patients treated for Hodgkin's disease. J Clin Oncol 21 (18): 3431-9, 2003.
Pathologists currently use the World Health Organization (WHO) modification of
the Revised European-American Lymphoma (REAL) classification for the histologic
classification for adult Hodgkin lymphoma (HL).[1][2]
WHO/REAL classification
Among 10,019 patients who underwent central expert pathology review for the German Hodgkin Study Group, 84 patients (<1%) were identified as having lymphocyte-depleted classical HL.[3] These patients present with more advanced-stage HL and usually with B symptoms.
Nodular lymphocyte–predominant HL is a clinicopathologic entity
of B-cell origin that is distinct from classic HL.[4][5][6] The
typical immunophenotype for lymphocyte-predominant disease is CD15-, CD20+,
CD30-, CD45+, while the profile for classic HL is CD15+, CD20-,
CD30+, CD45-. Patients with lymphocyte-predominant disease have earlier-stage
disease, longer survival, and fewer treatment failures than those with classic
HL.[7] Despite a usually favorable prognosis, there is a tendency for histologic transformation to diffuse large B-cell lymphoma in around 10% of patients by 10 years.[8] Lymphocyte-predominant HL is usually
diagnosed in asymptomatic young males with cervical or inguinal lymph nodes
but usually without mediastinal involvement. Based on retrospective analyses spanning several decades and because of the rarity of this histology, limited-field radiation therapy is the most common treatment approach for patients with early-stage disease.[9][10][11]
The REAL Classification of
Lymphoid Neoplasms proposed separating nodular lymphocyte–predominant HL (CD15-, CD20+, CD30-) from lymphocyte-rich classical HL
(CD15+, CD20-, CD30+), on the basis of these immunophenotypic
differences.[2][12] The largest retrospective report of 426 cases showed no
significant difference in clinical response or outcome to standard therapies
for these two subgroups.[13][Level of evidence: 3iiiA] Of interest, with a median
follow-up of 7 to 8 years, more patients died of treatment-related toxic
effects (acute and long-term) than from Hodgkin recurrence. Limitation of
radiation dose and fields and avoidance of leukemogenic chemotherapeutic
agents, along with watchful waiting policies, should be investigated for these
subgroups.[14][15] For patients with advanced-stage nodular lymphocyte–predominant HL, chemotherapy regimens designed for non-HLs may be preferred, based on a retrospective review.[16][Level of evidence: 3iiiDii]
Lukes RJ, Craver LF, Hall TC, et al.: Report of the Nomenclature Committee. Cancer Res 26 (1): 1311, 1966.
Harris NL: Hodgkin's lymphomas: classification, diagnosis, and grading. Semin Hematol 36 (3): 220-32, 1999.
Klimm B, Franklin J, Stein H, et al.: Lymphocyte-depleted classical Hodgkin's lymphoma: a comprehensive analysis from the German Hodgkin study group. J Clin Oncol 29 (29): 3914-20, 2011.
von Wasielewski R, Mengel M, Fischer R, et al.: Classical Hodgkin's disease. Clinical impact of the immunophenotype. Am J Pathol 151 (4): 1123-30, 1997.
Bodis S, Kraus MD, Pinkus G, et al.: Clinical presentation and outcome in lymphocyte-predominant Hodgkin's disease. J Clin Oncol 15 (9): 3060-6, 1997.
Orlandi E, Lazzarino M, Brusamolino E, et al.: Nodular lymphocyte predominance Hodgkin's disease: long-term observation reveals a continuous pattern of recurrence. Leuk Lymphoma 26 (3-4): 359-68, 1997.
Nogová L, Reineke T, Brillant C, et al.: Lymphocyte-predominant and classical Hodgkin's lymphoma: a comprehensive analysis from the German Hodgkin Study Group. J Clin Oncol 26 (3): 434-9, 2008.
Al-Mansour M, Connors JM, Gascoyne RD, et al.: Transformation to aggressive lymphoma in nodular lymphocyte-predominant Hodgkin's lymphoma. J Clin Oncol 28 (5): 793-9, 2010.
Chen RC, Chin MS, Ng AK, et al.: Early-stage, lymphocyte-predominant Hodgkin's lymphoma: patient outcomes from a large, single-institution series with long follow-up. J Clin Oncol 28 (1): 136-41, 2010.
Nogová L, Reineke T, Eich HT, et al.: Extended field radiotherapy, combined modality treatment or involved field radiotherapy for patients with stage IA lymphocyte-predominant Hodgkin's lymphoma: a retrospective analysis from the German Hodgkin Study Group (GHSG). Ann Oncol 16 (10): 1683-7, 2005.
Wilder RB, Schlembach PJ, Jones D, et al.: European Organization for Research and Treatment of Cancer and Groupe d'Etude des Lymphomes de l'Adulte very favorable and favorable, lymphocyte-predominant Hodgkin disease. Cancer 94 (6): 1731-8, 2002.
Shimabukuro-Vornhagen A, Haverkamp H, Engert A, et al.: Lymphocyte-rich classical Hodgkin's lymphoma: clinical presentation and treatment outcome in 100 patients treated within German Hodgkin's Study Group trials. J Clin Oncol 23 (24): 5739-45, 2005.
Diehl V, Sextro M, Franklin J, et al.: Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin's Disease. J Clin Oncol 17 (3): 776-83, 1999.
Aster JC: Lymphocyte-predominant Hodgkin's disease: how little therapy is enough? J Clin Oncol 17 (3): 744-6, 1999.
Pellegrino B, Terrier-Lacombe MJ, Oberlin O, et al.: Lymphocyte-predominant Hodgkin's lymphoma in children: therapeutic abstention after initial lymph node resection--a Study of the French Society of Pediatric Oncology. J Clin Oncol 21 (15): 2948-52, 2003.
Canellos GP, Mauch P: What is the appropriate systemic chemotherapy for lymphocyte-predominant Hodgkin's lymphoma? J Clin Oncol 28 (1): e8, 2010.
Clinical staging
for patients with Hodgkin lymphoma (HL) includes a history, physical examination, laboratory studies (including
sedimentation rate), and thoracic and abdominal/pelvic computerized tomographic
(CT) scans.[1]
Positron emission tomography (PET) scans, usually combined with CT scans, have replaced gallium scans and lymphangiography for clinical staging.[2][3][4] A prospective, multinational study of 260 newly diagnosed patients with HL obtained PET scans at baseline and after two cycles (four doses) of ABVD (doxorubicin plus bleomycin plus vinblastine plus dacarbazine); with a median follow-up of 2.2 years, the 2-year progression-free survival was 12.8% with a positive PET scan after two cycles and 95% with a negative PET scan after two cycles (P < .0001).[5] In a prospective trial of BEACOPP-based therapy—which includes the drugs bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine sulfate, procarbazine, and prednisone— for previously untreated patients with advanced-stage HL, patients with residual abnormalities measuring 2.5 cm or more received a PET scan at the end of therapy.[6] A negative PET scan predicted no progression or relapse within 1 year for 94% of patients (confidence interval, 91%–97%). Whether consolidation with radiation therapy can be omitted for PET-negative patients must await overall survival data at 5 years. Only further prospective studies that compare a PET response–adapted strategy versus standard therapy without alteration can assess whether improved outcomes can be achieved by altering the therapeutic strategy based on PET scan results.[7][8]
Bone marrow involvement occurs in 5% of patients; biopsy may be indicated
in the presence of constitutional B symptoms or anemia, leukopenia, or
thrombocytopenia. In a retrospective review of 454 patients, no patients with a positive bone marrow biopsy had only stage I or II disease on PET-CT scans; omission of the bone marrow biopsy for PET-CT–designated early-stage patients did not change treatment selection.[9] Staging laparotomy is no longer recommended; it
should be considered only when the results will allow substantial reduction in
treatment. It should not be done in patients who require chemotherapy. If the laparotomy is required for treatment decisions, the risks
of potential morbidity should be considered.[10][11][12][13] The staging classification
that is currently used for HL was adopted in 1971 at the Ann
Arbor Conference [14] with some modifications 18 years later from the Cotswolds
Subclassification of stage
Stages I, II, III, and IV adult HL can be subclassified into A
and B categories: B for those with defined general symptoms and A for those
without B symptoms. The B designation is given to patients with any of the
following symptoms:
The most significant B symptoms are fevers and weight loss. Night
sweats alone do not confer an adverse prognosis. Pruritus as a systemic
symptom remains controversial and is not considered a B symptom in the Ann
Arbor staging system. (Refer to the PDQ summary on Pruritus for more information.) This symptom is hard to define quantitatively and
uniformly, but when it is recurrent, generalized, and otherwise unexplained, and
when it ebbs and flows parallel to disease activity, it may be the equivalent
of a B symptom.
The designation E is used when well-localized extranodal lymphoid malignancies
arise in or extend to tissues beyond, but near, the major lymphatic aggregates.
Stage IV refers to disease that is diffusely spread throughout an extranodal
site, such as the liver. If pathologic proof of involvement of one or more
extralymphatic sites has been documented, the symbol for the site of
involvement, followed by a plus sign (+), is listed.
N = nodes
H = liver
L = lung
M = bone marrow
S = spleen
P = pleura
O = bone
D = skin
Current practice is to assign a clinical stage (CS) based on the findings of
the clinical evaluation and a pathologic stage (PS) based on the findings of
invasive procedures.
For example, a patient who has disease in the chest and neck, systemic
symptoms, and a negative lymphangiogram might be found at laparotomy to have
involvement of the spleen, liver, and bone marrow. Thus, the precise stage of
such a patient would be CS IIB, PS IVB (S+)(H+)(M+).
The American Joint Committee on Cancer (AJCC) has designated staging using the Ann Arbor classification system to define adult Hodgkin lymphoma.[15]
Prognostic Groups
Involvement of a single lymphatic site (i.e., nodal region, Waldeyer ring, thymus or spleen) (I).
Localized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement (IE) (rare in Hodgkin lymphoma).
Involvement of ≥2 lymph node regions on the same side of the diaphragm (II).
Localized involvement of a single extralymphatic organ or site in association with regional lymph node involvement with or without involvement of other lymph node regions on the same side of the diaphragm (IIE).
The number of regions involved may be indicated by an arabic numeral, as in, for example, II3.
Involvement of lymph node regions on both sides of the diaphragm (III), which also may be accompanied by extralymphatic extension in association with adjacent lymph node involvement (IIIE) or by involvement of the spleen (IIIS) or both (IIIE, S).
Splenic involvement is designated by the letter S.
Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement.
Isolated extralymphatic organ involvement in the absence of adjacent regional lymph node involvement, but in conjunction with disease in distant site(s).
Stage IV includes any involvement of the liver or bone marrow, lungs (other than by direct extension from another site), or cerebrospinal fluid.
aReprinted with permission from AJCC: Hodgkin and non-Hodgkin lymphomas. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 607-11.
Massive mediastinal disease has been defined by the Cotswolds meeting as a
thoracic ratio of maximum transverse mass diameter of 33% or more of the internal transverse thoracic diameter measured at the T5/6
intervertebral disc level on chest radiography.[1] Some investigators have
designated a lymph node mass measuring 10 cm or more in greatest
dimension as massive disease.[16] Other investigators use a measurement of the
maximum width of the mediastinal mass divided by the maximum intrathoracic
Many investigators and many new clinical trials employ a clinical staging system that divides patients into four major groups that are also useful for the practicing physician:[18]
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 7 (11): 1630-6, 1989.
Jerusalem G, Beguin Y, Fassotte MF, et al.: Whole-body positron emission tomography using 18F-fluorodeoxyglucose compared to standard procedures for staging patients with Hodgkin's disease. Haematologica 86 (3): 266-73, 2001.
Naumann R, Beuthien-Baumann B, Reiss A, et al.: Substantial impact of FDG PET imaging on the therapy decision in patients with early-stage Hodgkin's lymphoma. Br J Cancer 90 (3): 620-5, 2004.
Munker R, Glass J, Griffeth LK, et al.: Contribution of PET imaging to the initial staging and prognosis of patients with Hodgkin's disease. Ann Oncol 15 (11): 1699-704, 2004.
Gallamini A, Hutchings M, Rigacci L, et al.: Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study. J Clin Oncol 25 (24): 3746-52, 2007.
Kobe C, Dietlein M, Franklin J, et al.: Positron emission tomography has a high negative predictive value for progression or early relapse for patients with residual disease after first-line chemotherapy in advanced-stage Hodgkin lymphoma. Blood 112 (10): 3989-94, 2008.
Terasawa T, Lau J, Bardet S, et al.: Fluorine-18-fluorodeoxyglucose positron emission tomography for interim response assessment of advanced-stage Hodgkin's lymphoma and diffuse large B-cell lymphoma: a systematic review. J Clin Oncol 27 (11): 1906-14, 2009.
Gallamini A, Kostakoglu L: Interim FDG-PET in Hodgkin lymphoma: a compass for a safe navigation in clinical trials? Blood 120 (25): 4913-20, 2012.
El-Galaly TC, d'Amore F, Mylam KJ, et al.: Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography-staged treatment-naive patients with Hodgkin lymphoma. J Clin Oncol 30 (36): 4508-14, 2012.
Urba WJ, Longo DL: Hodgkin's disease. N Engl J Med 326 (10): 678-87, 1992.
Sombeck MD, Mendenhall NP, Kaude JV, et al.: Correlation of lymphangiography, computed tomography, and laparotomy in the staging of Hodgkin's disease. Int J Radiat Oncol Biol Phys 25 (3): 425-9, 1993.
Mauch P, Larson D, Osteen R, et al.: Prognostic factors for positive surgical staging in patients with Hodgkin's disease. J Clin Oncol 8 (2): 257-65, 1990.
Dietrich PY, Henry-Amar M, Cosset JM, et al.: Second primary cancers in patients continuously disease-free from Hodgkin's disease: a protective role for the spleen? Blood 84 (4): 1209-15, 1994.
Carbone PP, Kaplan HS, Musshoff K, et al.: Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res 31 (11): 1860-1, 1971.
Hodgkin and non-Hodgkin lymphomas. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 607-11.
Bradley AJ, Carrington BM, Lawrance JA, et al.: Assessment and significance of mediastinal bulk in Hodgkin's disease: comparison between computed tomography and chest radiography. J Clin Oncol 17 (8): 2493-8, 1999.
Mauch P, Goodman R, Hellman S: The significance of mediastinal involvement in early stage Hodgkin's disease. Cancer 42 (3): 1039-45, 1978.
Jost LM, Stahel RA; ESMO Guidelines Task Force: ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of Hodgkin's disease. Ann Oncol 16 (Suppl 1): i54-5, 2005.
Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med 339 (21): 1506-14, 1998.
Drug combinations described in this section include the following:
After initial clinical staging for Hodgkin lymphoma (HL), patients with obvious stage III or IV disease,
bulky disease (defined as a 10 cm mass or mediastinal disease with a
transverse diameter exceeding 33% of the transthoracic diameter), or the
presence of B symptoms will require combination chemotherapy with or without
additional radiation therapy.
Patients with nonbulky
stage IA or IIA disease are considered to have clinical early-stage disease.
These patients are candidates for chemotherapy, combined modality therapy,
or radiation therapy alone.[1] Staging
laparotomy is no longer recommended because it may not alter management and does
not enhance ultimate outcome.[2] When chemotherapy alone or combined modality
therapy is applied, laparotomy is not required.
In adult HL, the appropriate dose of radiation alone is 25 Gy to 30 Gy to
clinically uninvolved sites and 35 Gy to 44 Gy to regions of initial
nodal involvement.[3][4][5][6] These recommendations are often modified in pediatric
or advanced-staged adult patients who also receive chemotherapy. Treatment is
usually delivered to the neck, chest, and axilla (mantle field) and then to an
abdominal field to treat para-aortic nodes and the spleen (splenic pedicle). In some patients, pelvic nodes are treated with
a third field. The three fields constitute total nodal radiation therapy. In some
cases, the pelvic and para-aortic nodes are treated in a single field called an
inverted Y. In patients with a favorable prognosis, treatment of the pelvic
lymph nodes is frequently omitted, since fertility can be preserved without
affecting relapse-free survival. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information on fertility.)
Acute nonlymphocytic leukemia may occur in patients treated with combined
modality therapy or with combination chemotherapy alone, especially with increasing exposure to alkylating agents.[7][8] At 10 years
following therapy with regimens containing MOPP, the risk of acute myelogenous leukemia
(AML) is approximately 3%, with the peak incidence occurring 5 to 9 years after
therapy. The risk of acute leukemia at 10 years following therapy with
ABVD appears to be less than 1%.[9] A population-based study of more than 35,000 survivors during a 30-year time span identified 217 patients who developed AML; the excess absolute risk is significantly higher (9.9 vs. 4.2 after 1984, P < .001) for older patients (i.e., >35 years at diagnosis) versus younger survivors.[10]
An increase in second solid tumors has also been observed,
especially cancers of the lung, breast, thyroid, bone/soft tissue, stomach, esophagus, colon and rectum, uterine cervix, head and neck, and mesothelioma.[7][11][12][13][14][15][16]
These tumors occur primarily after radiation therapy or with combined modality
treatment, and approximately 75% occur within radiation ports. At a 15-year
follow-up, the risk of second solid tumors is approximately 13%;[7][12] at a 20-year follow-up, the risk is approximately 17%;[17] and at a 25-year follow-up, the risk is approximately 22%.[11][18] In a cohort of 18,862 5-year survivors from 13 population-based registries, the younger patients had elevated risks for breast, colon, and rectal cancer for 10 to 25 years before the age when routine screening would be recommended in the general population.[16] Even with involved-field doses of 15 Gy to 25 Gy, sarcomas, breast cancers, and thyroid cancers occurred with similar incidence in young patients receiving higher-dose radiation.[17]
cancer is seen with increased frequency, even after chemotherapy alone, and the
risk of this cancer is increased with cigarette smoking.[19][20][21][22] In a retrospective Surveillance, Epidemiology, and End Results (SEER) analysis, stage-specific survival was decreased by 30% to 60% in HL survivors compared with patients with de novo non-small cell lung cancer.[23] Breast cancer
is seen with increased frequency after radiation therapy or combined modality
therapy.[11][13][15][24][25][26][27] The risk appears greatest for women treated with radiation
before age 30 years, and the incidence increases substantially after 15 years
of follow-up.[11][14][28][29][30] In two case control studies of 479 patients who developed breast cancer after therapy for HL, cumulative absolute risks for developing breast cancer were calculated as a function of radiation therapy dose and the use of chemotherapy.[31][32] With a 30-year to 40-year follow-up, cumulative absolute risks of breast cancer with exposure to radiation range from 8.5% to 39.6%, depending on the age at diagnosis. A family history of breast cancer or ovarian cancer does not confer a greater increased risk than that of radiation therapy for one of these cohorts.[33] These cohort studies show a continued increase in cumulative excess risk of breast cancer beyond 20 years of follow-up.[31][32]
In a nested case control study and subsequent cohort study, patients who received both chemotherapy and radiation therapy had a statistically significant lower risk of developing breast cancer than those treated with radiation therapy alone.[25][34] Reaching early menopause with less than 10 years of intact ovarian function appeared to account for the reduction in risk among patients who received combined modality therapy.[34] Reduction of radiation volume also decreased the risk of breast cancer after HL.[34] The risk of non-HL is also increased,
but this risk is not clearly related to type or extent of treatment.[12]
Several studies suggest that
splenic-field radiation therapy and splenectomy increase the risk of a
treatment-related second cancer.[35][36][37] Late effects after autologous stem cell transplantation that is given for failure of induction chemotherapy include second malignancies, hypothyroidism, hypogonadism, herpes zoster, depression, and cardiac disease.[38]
A toxic effect that is primarily related to chemotherapy is infertility,
usually after MOPP-containing or BEACOPP-containing regimens;[12][39][40][41] After six to eight cycles of BEACOPP, most men had testosterone levels within normal range; however, among women younger than 30 years, 82% recovered menses (mostly within 12 months), but only 45% of women older than 30 years recovered menses.[42] ABVD appears to spare long-term
testicular and ovarian function.[40][43][44]
Late complications primarily related to
radiation therapy include hypothyroidism and cardiac disease, which may persist through to 25 years after first treatment.[45][46][47][48][49][50] The absolute excess risk of fatal cardiovascular disease ranges from 11.9 to 48.9 per 10,000 patient years and is mostly attributable to fatal myocardial infarction (MI).[46][47][48][50] The use of subcarinal blocking did not reduce the incidence of fatal MI in a retrospective review, perhaps because of the exposure of the proximal coronary arteries to radiation.[47] In a cohort of 7,033 HL patients, MI mortality risk persisted through to 25 years after first treatment with supradiaphragmatic radiation therapy (dependent on the details of treatment planning), doxorubicin, or vincristine.[50] HL patients treated with mediastinal radiation compared with a normal-matched population have been reported to be at increased risk with the use of cardiac procedures.[51]
Impairment of
pulmonary function may occur as a result of mantle-field radiation therapy; this
impairment is not usually clinically evident, and recovery in pulmonary testing
often occurs after 2 to 3 years.[52] Pulmonary toxic effects from bleomycin as used in ABVD are seen in older patients (especially those older than 40 years).[53] Avascular necrosis of bone has
been observed in patients treated with chemotherapy and is most likely related
to corticosteroid therapy.[54]
Bacterial sepsis may occur rarely after
splenectomy performed during staging laparotomy for HL;[55] it
is much more frequent in children than in adults. The Advisory Committee on
Immunization Practices recommends that all patients with HL,
whether or not they have had a splenectomy, should be immunized with Haemophilusinfluenzae type b conjugate, meningococcal, and pneumococcal vaccines at least 1
week before treatment.[56] Some investigators recommend reimmunization with
all three vaccines 2 years after completion of treatment and with pneumococcal
vaccine every 6 years thereafter.[57]
Fatigue is a commonly reported symptom of patients who have completed
chemotherapy. In a case-control study design, a majority of HL
survivors reported significant fatigue lasting for more than 6 months after
therapy compared to age-matched controls.[58]
Patients older than 60 years with HL experience more treatment-related morbidity and mortality and typically receive a lower dose intensity of chemotherapy because of poorer tolerance of treatment than comparably staged younger patients.[59][60][61]
Armitage JO: Early-stage Hodgkin's lymphoma. N Engl J Med 363 (7): 653-62, 2010.
Advani RH, Horning SJ: Treatment of early-stage Hodgkin's disease. Semin Hematol 36 (3): 270-81, 1999.
Sears JD, Greven KM, Ferree CR, et al.: Definitive irradiation in the treatment of Hodgkin's disease. Analysis of outcome, prognostic factors, and long-term complications. Cancer 79 (1): 145-51, 1997.
Ng AK, Mauch PM: Radiation therapy in Hodgkin's lymphoma. Semin Hematol 36 (3): 290-302, 1999.
Dühmke E, Franklin J, Pfreundschuh M, et al.: Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin's disease: long-term results of a randomized trial of radiotherapy alone. J Clin Oncol 19 (11): 2905-14, 2001.
Mendenhall NP, Rodrigue LL, Moore-Higgs GJ, et al.: The optimal dose of radiation in Hodgkin's disease: an analysis of clinical and treatment factors affecting in-field disease control. Int J Radiat Oncol Biol Phys 44 (3): 551-61, 1999.
Swerdlow AJ, Higgins CD, Smith P, et al.: Second cancer risk after chemotherapy for Hodgkin's lymphoma: a collaborative British cohort study. J Clin Oncol 29 (31): 4096-104, 2011.
Koontz MZ, Horning SJ, Balise R, et al.: Risk of therapy-related secondary leukemia in Hodgkin lymphoma: the Stanford University experience over three generations of clinical trials. J Clin Oncol 31 (5): 592-8, 2013.
Valagussa P, Santoro A, Fossati-Bellani F, et al.: Second acute leukemia and other malignancies following treatment for Hodgkin's disease. J Clin Oncol 4 (6): 830-7, 1986.
Schonfeld SJ, Gilbert ES, Dores GM, et al.: Acute myeloid leukemia following Hodgkin lymphoma: a population-based study of 35,511 patients. J Natl Cancer Inst 98 (3): 215-8, 2006.
Dores GM, Metayer C, Curtis RE, et al.: Second malignant neoplasms among long-term survivors of Hodgkin's disease: a population-based evaluation over 25 years. J Clin Oncol 20 (16): 3484-94, 2002.
Swerdlow AJ, Douglas AJ, Hudson GV, et al.: Risk of second primary cancers after Hodgkin's disease by type of treatment: analysis of 2846 patients in the British National Lymphoma Investigation. BMJ 304 (6835): 1137-43, 1992.
Yahalom J, Petrek JA, Biddinger PW, et al.: Breast cancer in patients irradiated for Hodgkin's disease: a clinical and pathologic analysis of 45 events in 37 patients. J Clin Oncol 10 (11): 1674-81, 1992.
Mauch PM, Kalish LA, Marcus KC, et al.: Second malignancies after treatment for laparotomy staged IA-IIIB Hodgkin's disease: long-term analysis of risk factors and outcome. Blood 87 (9): 3625-32, 1996.
Franklin J, Pluetschow A, Paus M, et al.: Second malignancy risk associated with treatment of Hodgkin's lymphoma: meta-analysis of the randomised trials. Ann Oncol 17 (12): 1749-60, 2006.
Hodgson DC, Gilbert ES, Dores GM, et al.: Long-term solid cancer risk among 5-year survivors of Hodgkin's lymphoma. J Clin Oncol 25 (12): 1489-97, 2007.
O'Brien MM, Donaldson SS, Balise RR, et al.: Second malignant neoplasms in survivors of pediatric Hodgkin's lymphoma treated with low-dose radiation and chemotherapy. J Clin Oncol 28 (7): 1232-9, 2010.
Bonadonna G, Viviani S, Bonfante V, et al.: Survival in Hodgkin's disease patients--report of 25 years of experience at the Milan Cancer Institute. Eur J Cancer 41 (7): 998-1006, 2005.
van Leeuwen FE, Klokman WJ, Stovall M, et al.: Roles of radiotherapy and smoking in lung cancer following Hodgkin's disease. J Natl Cancer Inst 87 (20): 1530-7, 1995.
Swerdlow AJ, Schoemaker MJ, Allerton R, et al.: Lung cancer after Hodgkin's disease: a nested case-control study of the relation to treatment. J Clin Oncol 19 (6): 1610-8, 2001.
Travis LB, Gospodarowicz M, Curtis RE, et al.: Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease. J Natl Cancer Inst 94 (3): 182-92, 2002.
Lorigan P, Radford J, Howell A, et al.: Lung cancer after treatment for Hodgkin's lymphoma: a systematic review. Lancet Oncol 6 (10): 773-9, 2005.
Milano MT, Li H, Constine LS, et al.: Survival after second primary lung cancer: a population-based study of 187 Hodgkin lymphoma patients. Cancer 117 (24): 5538-47, 2011.
Cutuli B, Dhermain F, Borel C, et al.: Breast cancer in patients treated for Hodgkin's disease: clinical and pathological analysis of 76 cases in 63 patients. Eur J Cancer 33 (14): 2315-20, 1997.
van Leeuwen FE, Klokman WJ, Stovall M, et al.: Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin's disease. J Natl Cancer Inst 95 (13): 971-80, 2003.
Wahner-Roedler DL, Nelson DF, Croghan IT, et al.: Risk of breast cancer and breast cancer characteristics in women treated with supradiaphragmatic radiation for Hodgkin lymphoma: Mayo Clinic experience. Mayo Clin Proc 78 (6): 708-15, 2003.
Travis LB, Hill DA, Dores GM, et al.: Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 290 (4): 465-75, 2003.
Hancock SL, Tucker MA, Hoppe RT: Breast cancer after treatment of Hodgkin's disease. J Natl Cancer Inst 85 (1): 25-31, 1993.
Sankila R, Garwicz S, Olsen JH, et al.: Risk of subsequent malignant neoplasms among 1,641 Hodgkin's disease patients diagnosed in childhood and adolescence: a population-based cohort study in the five Nordic countries. Association of the Nordic Cancer Registries and the Nordic Society of Pediatric Hematology and Oncology. J Clin Oncol 14 (5): 1442-6, 1996.
Alm El-Din MA, Hughes KS, Finkelstein DM, et al.: Breast cancer after treatment of Hodgkin's lymphoma: risk factors that really matter. Int J Radiat Oncol Biol Phys 73 (1): 69-74, 2009.
Travis LB, Hill D, Dores GM, et al.: Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl Cancer Inst 97 (19): 1428-37, 2005.
Swerdlow AJ, Cooke R, Bates A, et al.: Breast cancer risk after supradiaphragmatic radiotherapy for Hodgkin's lymphoma in England and Wales: a National Cohort Study. J Clin Oncol 30 (22): 2745-52, 2012.
Hill DA, Gilbert E, Dores GM, et al.: Breast cancer risk following radiotherapy for Hodgkin lymphoma: modification by other risk factors. Blood 106 (10): 3358-65, 2005.
De Bruin ML, Sparidans J, van't Veer MB, et al.: Breast cancer risk in female survivors of Hodgkin's lymphoma: lower risk after smaller radiation volumes. J Clin Oncol 27 (26): 4239-46, 2009.
van der Velden JW, van Putten WL, Guinee VF, et al.: Subsequent development of acute non-lymphocytic leukemia in patients treated for Hodgkin's disease. Int J Cancer 42 (2): 252-5, 1988.
Kaldor JM, Day NE, Clarke EA, et al.: Leukemia following Hodgkin's disease. N Engl J Med 322 (1): 7-13, 1990.
Lavoie JC, Connors JM, Phillips GL, et al.: High-dose chemotherapy and autologous stem cell transplantation for primary refractory or relapsed Hodgkin lymphoma: long-term outcome in the first 100 patients treated in Vancouver. Blood 106 (4): 1473-8, 2005.
Behringer K, Breuer K, Reineke T, et al.: Secondary amenorrhea after Hodgkin's lymphoma is influenced by age at treatment, stage of disease, chemotherapy regimen, and the use of oral contraceptives during therapy: a report from the German Hodgkin's Lymphoma Study Group. J Clin Oncol 23 (30): 7555-64, 2005.
van der Kaaij MA, Heutte N, Le Stang N, et al.: Gonadal function in males after chemotherapy for early-stage Hodgkin's lymphoma treated in four subsequent trials by the European Organisation for Research and Treatment of Cancer: EORTC Lymphoma Group and the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 25 (19): 2825-32, 2007.
Scholz M, Engert A, Franklin J, et al.: Impact of first- and second-line treatment for Hodgkin's lymphoma on the incidence of AML/MDS and NHL--experience of the German Hodgkin's Lymphoma Study Group analyzed by a parametric model of carcinogenesis. Ann Oncol 22 (3): 681-8, 2011.
Behringer K, Mueller H, Goergen H, et al.: Gonadal function and fertility in survivors after Hodgkin lymphoma treatment within the German Hodgkin Study Group HD13 to HD15 trials. J Clin Oncol 31 (2): 231-9, 2013.
Viviani S, Santoro A, Ragni G, et al.: Pre- and post-treatment testicular dysfunction in Hodgkin's disease (HD). [Abstract] Proceedings of the American Society of Clinical Oncology 7: A-877, 227, 1988.
van der Kaaij MA, Heutte N, Meijnders P, et al.: Premature ovarian failure and fertility in long-term survivors of Hodgkin's lymphoma: a European Organisation for Research and Treatment of Cancer Lymphoma Group and Groupe d'Etude des Lymphomes de l'Adulte Cohort Study. J Clin Oncol 30 (3): 291-9, 2012.
Tarbell NJ, Thompson L, Mauch P: Thoracic irradiation in Hodgkin's disease: disease control and long-term complications. Int J Radiat Oncol Biol Phys 18 (2): 275-81, 1990.
Reinders JG, Heijmen BJ, Olofsen-van Acht MJ, et al.: Ischemic heart disease after mantlefield irradiation for Hodgkin's disease in long-term follow-up. Radiother Oncol 51 (1): 35-42, 1999.
Hancock SL, Tucker MA, Hoppe RT: Factors affecting late mortality from heart disease after treatment of Hodgkin's disease. JAMA 270 (16): 1949-55, 1993.
Heidenreich PA, Schnittger I, Strauss HW, et al.: Screening for coronary artery disease after mediastinal irradiation for Hodgkin's disease. J Clin Oncol 25 (1): 43-9, 2007.
Dabaja B, Cox JD, Buchholz TA: Radiation therapy can still be used safely in combined modality approaches in patients with Hodgkin's lymphoma. J Clin Oncol 25 (1): 3-5, 2007.
Swerdlow AJ, Higgins CD, Smith P, et al.: Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study. J Natl Cancer Inst 99 (3): 206-14, 2007.
Galper SL, Yu JB, Mauch PM, et al.: Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation. Blood 117 (2): 412-8, 2011.
Horning SJ, Adhikari A, Rizk N, et al.: Effect of treatment for Hodgkin's disease on pulmonary function: results of a prospective study. J Clin Oncol 12 (2): 297-305, 1994.
Martin WG, Ristow KM, Habermann TM, et al.: Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin's lymphoma. J Clin Oncol 23 (30): 7614-20, 2005.
Prosnitz LR, Lawson JP, Friedlaender GE, et al.: Avascular necrosis of bone in Hodgkin's disease patients treated with combined modality therapy. Cancer 47 (12): 2793-7, 1981.
Schimpff SC, O'Connell MJ, Greene WH, et al.: Infections in 92 splenectomized patients with Hodgkin's disease. A clinical review. Am J Med 59 (5): 695-701, 1975.
Recommendations of the Advisory Committee on Immunization Practices (ACIP): use of vaccines and immune globulins for persons with altered immunocompetence. MMWR Recomm Rep 42 (RR-4): 1-18, 1993.
Molrine DC, George S, Tarbell N, et al.: Antibody responses to polysaccharide and polysaccharide-conjugate vaccines after treatment of Hodgkin disease. Ann Intern Med 123 (11): 828-34, 1995.
Loge JH, Abrahamsen AF, Ekeberg O, et al.: Hodgkin's disease survivors more fatigued than the general population. J Clin Oncol 17 (1): 253-61, 1999.
Ballova V, Rüffer JU, Haverkamp H, et al.: A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin's disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly). Ann Oncol 16 (1): 124-31, 2005.
Engert A, Ballova V, Haverkamp H, et al.: Hodgkin's lymphoma in elderly patients: a comprehensive retrospective analysis from the German Hodgkin's Study Group. J Clin Oncol 23 (22): 5052-60, 2005.
Böll B, Görgen H, Fuchs M, et al.: ABVD in older patients with early-stage Hodgkin lymphoma treated within the German Hodgkin Study Group HD10 and HD11 trials. J Clin Oncol 31 (12): 1522-9, 2013.
Drug combinations described in this section include the following:
Patients are designated as having early favorable Hodgkin lymphoma (HL) if they have clinical stage I or stage II disease and no adverse risk factors. Adverse risk factors include the following:
Historically, radiation therapy alone had been the primary treatment for patients with early favorable HL, often after confirmatory negative staging laparotomy. A randomized, prospective trial involving 542 patients with early favorable HL compared MOPP-ABV for three cycles plus involved-field radiation therapy (IF-XRT) with subtotal nodal radiation; with a median follow-up of 7.7 years, combined modality was favored in terms of 5-year event-free survival (98% vs. 74%, P < .001) and 10-year overall survival (97% vs. 92%, P = .001).[1][Level of evidence: 1iiA] The late mortality from solid tumors, especially in the lung, breast, gastrointestinal tract, and connective tissue, and from cardiovascular disease makes radiation therapy a less attractive option for the best-risk patients, who have the highest probability of cure and long-term survival.[2][3][4][5][6] Recent clinical trials have focused on regimens with chemotherapy and IF-XRT or with chemotherapy alone.[7]
A randomized, prospective trial from the National Cancer Institute of Canada involving 123 patients with early favorable HL compared ABVD for four to six cycles to subtotal nodal radiation; with a median follow-up of 11.3 years, no difference was observed in event-free survival (89% vs. 86%; P = .64) or in overall survival (OS) (98% vs. 98%; P = 0.95).[8][Level of evidence: 1iiA]
In a randomized study from the Milan Cancer Institute of patients with clinical early-stage HL, 4 months of ABVD followed by either IF-XRT or extended-field radiation therapy (EF-XRT) showed similar OS and freedom-from-progression with a 10-year median follow-up, but the study had inadequate statistical power to determine noninferiority of IF-XRT versus EF-XRT.[9][Level of evidence: 1iiDii]
The German Hodgkin Lymphoma Study Group (GHSG) randomly assigned 1,190 patients with early favorable HL to the following:
With a 7.6-year median follow-up, no differences were observed in freedom-from-progression (97%) or OS (98%) for all four groups.[10][Level of evidence: 1iiA]
The ongoing GHSG study is comparing reduced chemotherapy schedules while maintaining IF-XRT at 30 Gy: two cycles of ABVD, two cycles of ABV, two cycles of AVD, or two cycles of AV.
A specialized approach to therapy can be taken when patients with nonbulky lymphocyte–predominant disease presenting in unilateral
high neck (above the thyroid notch) or epitrochlear locations require only
IF-XRT after clinical staging.[11] A retrospective report
of 426 cases of lymphocyte-predominant HL (including the
so-called nodular lymphocyte–predominant and lymphocyte-rich classical
subtypes) showed that more patients died of treatment-related toxicity (both
acute and long term) than from recurrence of HL.[12][Level of
evidence: 3iiiA] Limitation of radiation dose and radiation fields and avoidance of
leukemogenic chemotherapeutic agents, along with watchful waiting policies,
should be investigated for these subgroups.[13] Patients with nonbulky
nodular sclerosing disease presenting in the anterior mediastinum only after
clinical staging also do well with mantle radiation alone.[14]
Treatment options include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I adult Hodgkin lymphoma and stage II adult Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Fermé C, Eghbali H, Meerwaldt JH, et al.: Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med 357 (19): 1916-27, 2007.
Longo DL: Radiation therapy in Hodgkin disease: why risk a Pyrrhic victory? J Natl Cancer Inst 97 (19): 1394-5, 2005.
Engert A, Franklin J, Eich HT, et al.: Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin's lymphoma: final results of the GHSG HD7 trial. J Clin Oncol 25 (23): 3495-502, 2007.
Canellos GP, Abramson JS, Fisher DC, et al.: Treatment of favorable, limited-stage Hodgkin's lymphoma with chemotherapy without consolidation by radiation therapy. J Clin Oncol 28 (9): 1611-5, 2010.
Meyer RM, Gospodarowicz MK, Connors JM, et al.: ABVD alone versus radiation-based therapy in limited-stage Hodgkin's lymphoma. N Engl J Med 366 (5): 399-408, 2012.
Bonadonna G, Bonfante V, Viviani S, et al.: ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin's disease: long-term results. J Clin Oncol 22 (14): 2835-41, 2004.
Engert A, Plütschow A, Eich HT, et al.: Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma. N Engl J Med 363 (7): 640-52, 2010.
Russell KJ, Hoppe RT, Colby TV, et al.: Lymphocyte predominant Hodgkin's disease: clinical presentation and results of treatment. Radiother Oncol 1 (3): 197-205, 1984.
Backstrand KH, Ng AK, Takvorian RW, et al.: Results of a prospective trial of mantle irradiation alone for selected patients with early-stage Hodgkin's disease. J Clin Oncol 19 (3): 736-41, 2001.
Landgren O, Axdorph U, Fears TR, et al.: A population-based cohort study on early-stage Hodgkin lymphoma treated with radiotherapy alone: with special reference to older patients. Ann Oncol 17 (8): 1290-5, 2006.
Patients are designated as having early unfavorable Hodgkin lymphoma (HL) if they have clinical stage I or stage II disease and one or more of the following risk factors:
Patients with early unfavorable HL showed relapse rates over 30% at 5 years with radiation therapy alone, prompting evaluation of chemotherapy plus involved-field radiation therapy (IF-XRT) versus chemotherapy alone.[1] The late mortality from solid tumors, especially in the lung, breast, gastrointestinal tract, and connective tissue, and from cardiovascular disease makes radiation therapy a less attractive option unless therapeutic benefits exceed the long-term complications.[2][3][4][5][6]
A randomized, prospective trial from the National Cancer Institute of Canada (NCIC) involving 276 patients with early unfavorable HL compared ABVD for four to six cycles to ABVD for two cycles plus extended-field radiation therapy (EF-XRT); with a median follow-up of 11.3 years, the freedom-from-progression favored combined modality therapy (86% vs. 94%; P = .006), but the overall survival (OS) was better for ABVD alone (92% vs. 81%; P = .04).[7][Level of evidence: 1iiA] The trend toward a worse survival for the combined modality arm was attributed to excess secondary malignancies and cardiovascular deaths. In this trial, the extended-field radiation used higher doses and significantly larger exposure to body sites than are employed in current practice.
A randomized study from the Southwest Oncology Group of clinically staged
patients (no laparotomy) compared subtotal lymphoid radiation to 3 months of
AV followed by subtotal lymphoid radiation therapy; the
combined modality arm showed superior failure-free survival (94% vs. 81%; P < .001) but not OS at 3.3 years' median follow-up.[8][Level of evidence: 1iiDiii]
In a randomized study from the Milan Cancer Institute of patients with clinical early-stage
Hodgkin lymphoma, 4 months of ABVD followed
by either IF-XRT or EF-XRT showed
similar OS and freedom-from-progression with 10 years' median
follow-up, but the study had inadequate statistical power to determine noninferiority of IF-XRT versus EF-XRT.[9][Level of evidence: 1iiDii] Similarly, in a randomized study from the German Hodgkin Lymphoma Study Group (GHSG) of more than 1,000 patients with early unfavorable HL, 4 months of COPP plus ABVD followed by IF-XRT versus EF-XRT showed equivalent OS and freedom-from-treatment failure (FFTF) with 5 years' median follow-up.[10][Level of evidence: 1iiA] Another randomized study of 996 patients with early unfavorable HL also showed no difference in OS and event-free survival at 10 years comparing four to six cycles of MOPP-ABV plus IF-XRT versus the same chemotherapy plus subtotal nodal radiation therapy.[11][Level of evidence: 1iiA]
In the HD11 trial, the GHSG randomly assigned 1,395 patients with early unfavorable HL to:
With a 6.8 year median follow-up no differences were observed in OS (93%–96%) for all four groups.[12][13][Level of evidence: 1iiA] In the arms of the study with 30 Gy of IF-XRT, there was no difference in FFTF between BEACOPP and ABVD (P = .65), but a significant difference in favor of BEACOPP was seen for FFTF when 20 Gy of IF-XRT was used (P = .02).[13][Level of evidence: 1iiD]
In the HD14 trial, the GHSG randomly assigned 1,528 patients with early unfavorable HL to either four cycles of ABVD plus 30 Gy of IF-XRT or two cycles of escalated BEACOPP followed by two cycles of ABVD plus 30 Gy of IF-XRT. With a median follow-up of 43 months, no difference was observed in OS.[14][Level of evidence: 1iiA]
A prospective, randomized trial from the European Organization for Research and Treatment of Cancer and Groupe d'Etudes de Lymphomes de L'Adulte of 808 patients with early unfavorable HL compared:
With a 64-month median follow-up, in a preliminary report in abstract form, no differences were observed in event-free survival (89%–92%; P = .38) or OS (91%–96%; P = .98).[15][Level of evidence: 1iiA]
In summary, these randomized trials support the use of ABVD for four cycles with 20 Gy to 30 Gy IF-XRT. Could the radiation therapy be omitted to minimize late morbidity and mortality from secondary solid tumors and from cardiovascular disease?[16] The NCIC study is the only trial to address this question in patients with early unfavorable HL; although four to six cycles of ABVD alone has improved OS compared with a combined modality approach, the use of EF-XRT in the combined modality arm is excessive by current standards, and late effects will be magnified with these larger fields.[7] In addition, chemotherapy alone was 8% worse in freedom-from-progression compared to the combined modality approach.
How can we balance an improvement in freedom-from-progression using radiation therapy with chemotherapy against late morbidity and mortality from late effects?[16][17] Randomized studies with or without IF-XRT would be required, but no such studies are currently under way.[16] An indirect comparison for using ABVD alone is that the 94% OS seen for early unfavorable patients in the NCIC study [7] at 11 years is equivalent to the survival seen in the GHSG's HD6 [NCT00002561], HD10 [NCT01399931], and HD11 trials using combined modality therapy at 11 years.[18] A Cochrane meta-analysis of 1,245 patients in five randomized, clinical trials suggested improved survival for combined modality therapy versus chemotherapy alone (HR, 0.40; 95% CI, 0.27–0.61).[19] However, the NCIC study does demonstrate a 92% OS for ABVD alone at a median follow-up of 11.3 years. This would support the use of ABVD for patients with early unfavorable disease. Long-term follow-up, which would account for late toxicities and deaths from combined modality therapy, will not be forthcoming from these trials.[19]
Patients with bulky disease (≥10 cm) or massive mediastinal involvement were excluded from most of the aforementioned trials. Based on historical comparisons to chemotherapy or radiation therapy alone, these patients currently receive combined modality therapy.[20][21][Level of evidence: 3iiiDiii]
Tubiana M, Henry-Amar M, Carde P, et al.: Toward comprehensive management tailored to prognostic factors of patients with clinical stages I and II in Hodgkin's disease. The EORTC Lymphoma Group controlled clinical trials: 1964-1987. Blood 73 (1): 47-56, 1989.
Press OW, LeBlanc M, Lichter AS, et al.: Phase III randomized intergroup trial of subtotal lymphoid irradiation versus doxorubicin, vinblastine, and subtotal lymphoid irradiation for stage IA to IIA Hodgkin's disease. J Clin Oncol 19 (22): 4238-44, 2001.
Engert A, Schiller P, Josting A, et al.: Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol 21 (19): 3601-8, 2003.
Diehl V, Brillant C, Engert A, et al.: Recent interim analysis of the HD11 trial of the GHSG: intensification of chemotherapy and reduction of radiation dose in early unfavorable stage Hodgkin's lymphoma. [Abstract] Blood 106 (11): A-816, 2005.
Eich HT, Diehl V, Görgen H, et al.: Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol 28 (27): 4199-206, 2010.
von Tresckow B, Plütschow A, Fuchs M, et al.: Dose-intensification in early unfavorable Hodgkin's lymphoma: final analysis of the German hodgkin study group HD14 trial. J Clin Oncol 30 (9): 907-13, 2012.
Noordijk EM, Thomas J, Fermé C, et al.: First results of the EORTC-GELA H9 randomized trials: the H9-F trial (comparing 3 radiation dose levels) and H9-U trial (comparing 3 chemotherapy schemes) in patients with favorable or unfavorable early stage Hodgkin's lymphoma (HL) . [Abstract] J Clin Oncol 23 (Suppl 16): A-6505, 561s, 2005.
Bar Ad V, Paltiel O, Glatstein E: Radiotherapy for early-stage Hodgkin's lymphoma: a 21st century perspective and review of multiple randomized clinical trials. Int J Radiat Oncol Biol Phys 72 (5): 1472-9, 2008.
Meyer RM, Hoppe RT: Point/counterpoint: early-stage Hodgkin lymphoma and the role of radiation therapy. Blood 120 (23): 4488-95, 2012.
Herbst C, Rehan FA, Skoetz N, et al.: Chemotherapy alone versus chemotherapy plus radiotherapy for early stage Hodgkin lymphoma. Cochrane Database Syst Rev (2): CD007110, 2011.
Longo DL, Glatstein E, Duffey PL, et al.: Alternating MOPP and ABVD chemotherapy plus mantle-field radiation therapy in patients with massive mediastinal Hodgkin's disease. J Clin Oncol 15 (11): 3338-46, 1997.
Horning SJ, Hoppe RT, Breslin S, et al.: Stanford V and radiotherapy for locally extensive and advanced Hodgkin's disease: mature results of a prospective clinical trial. J Clin Oncol 20 (3): 630-7, 2002.
Patients are designated as having advanced favorable Hodgkin lymphoma (HL) if they have clinical stage III or stage IV disease and three or fewer risk factors on the International Prognostic Index for HL, which corresponds to a freedom-from-progression at greater than 80% at 5 years with combination chemotherapy.[1]
ABVD therapy for 6 to 8 months is as effective as 12 months of MOPP alternating
with ABVD, and both are superior to MOPP alone in terms of failure-free
survival (FFS) (50% vs. 36% with a 14-year median follow-up; P = .03).[2][3][Level of evidence: 1iiA] The Intergroup trial comparing ABVD with MOPP/ABV hybrid showed equivalent efficacy in FFS and overall
survival (OS), but increased toxic effects in the hybrid arm, especially from second
malignancies.[4][Level of evidence: 1iiA]
A prospective, randomized study, from the Medical Research Council (MRC) (MRC-UKLG-LY09), of 807 patients compared ABVD with two multidrug regimens also incorporating etoposide, chlorambucil, vincristine, and procarbazine. With 52 months' median follow-up, the 3-year event-free survival was 75% (confidence interval [CI], 71%–79%) for all three regimens, and 88% to 90% OS (CI, 84%–93%) for all three regimens, but there were significantly fewer toxic effects with ABVD.[5][Level of evidence: 1iiA]
A prospective, randomized study of 331 patients compared ABVD with escalated BEACOPP, along with a planned autologous stem cell transplantation after reinduction chemotherapy for relapsed or resistant disease. With 61 months' median follow-up, although 7-year freedom from first progression favored escalated BEACOPP (73% vs. 85%, P = .004), 7-year OS was not statistically different (84% vs. 89%, P = .39).[6][Level of evidence: 1iiA] Escalated BEACOPP is associated with increased rates of myelodysplasia and acute myelogenous leukemia (3%–4%).[7] Stanford V is an alternative drug combination with mandated radiation consolidation for most patients and survival rates comparable to those with ABVD.[8][9][10][Level of evidence: 1iiA]
A prospective, randomized trial of 307 patients with advanced-stage disease, including IIB disease and advanced-favorable Hodgkin lymphoma patients, compared ABVD, BEACOPP (four escalated courses plus two standard courses), and CEC.[11] With a median follow-up of 41 months, although progression-free survival favored BEACOPP over ABVD (78% vs. 68%, P = .038), there was no significant difference in OS.[11][Level of evidence: 1iiDiii] Further follow-up is required to assess rates of secondary malignancies with these regimens.
In a meta-analysis of 1,740 patients treated on 14 different trials, no improvement was observed in 10-years' OS for patients with advanced-stage
HL who received combined modality therapy versus chemotherapy
alone.[12][Level of evidence: 1iiA] Three prospective, randomized trials and a meta-analysis did not show a benefit in OS from the addition of consolidative radiation therapy to chemotherapy for patients with advanced-stage disease.[13][14][15][16] The lack of difference in OS
was attributed to a greater number of second malignancies and poorer response
and survival after relapse among patients who received combined modality
Proposed clinical trials will explore consolidation for patients with positive positron emission tomography testing after four cycles of ABVD.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III adult Hodgkin lymphoma and stage IV adult Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Moccia AA, Donaldson J, Chhanabhai M, et al.: International Prognostic Score in advanced-stage Hodgkin's lymphoma: altered utility in the modern era. J Clin Oncol 30 (27): 3383-8, 2012.
Canellos GP, Anderson JR, Propert KJ, et al.: Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327 (21): 1478-84, 1992.
Canellos GP, Niedzwiecki D: Long-term follow-up of Hodgkin's disease trial. N Engl J Med 346 (18): 1417-8, 2002.
Duggan DB, Petroni GR, Johnson JL, et al.: Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an intergroup trial. J Clin Oncol 21 (4): 607-14, 2003.
Johnson PW, Radford JA, Cullen MH, et al.: Comparison of ABVD and alternating or hybrid multidrug regimens for the treatment of advanced Hodgkin's lymphoma: results of the United Kingdom Lymphoma Group LY09 Trial (ISRCTN97144519). J Clin Oncol 23 (36): 9208-18, 2005.
Viviani S, Zinzani PL, Rambaldi A, et al.: ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned. N Engl J Med 365 (3): 203-12, 2011.
Hoskin PJ, Lowry L, Horwich A, et al.: Randomized comparison of the stanford V regimen and ABVD in the treatment of advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. J Clin Oncol 27 (32): 5390-6, 2009.
Gobbi PG, Levis A, Chisesi T, et al.: ABVD versus modified stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate- and advanced-stage Hodgkin's lymphoma: final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi. J Clin Oncol 23 (36): 9198-207, 2005.
Gordon LI, Hong F, Fisher RI, et al.: Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol 31 (6): 684-91, 2013.
Federico M, Luminari S, Iannitto E, et al.: ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin's lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol 27 (5): 805-11, 2009.
Loeffler M, Brosteanu O, Hasenclever D, et al.: Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin's disease. International Database on Hodgkin's Disease Overview Study Group. J Clin Oncol 16 (3): 818-29, 1998.
Fabian CJ, Mansfield CM, Dahlberg S, et al.: Low-dose involved field radiation after chemotherapy in advanced Hodgkin disease. A Southwest Oncology Group randomized study. Ann Intern Med 120 (11): 903-12, 1994.
Aleman BM, Raemaekers JM, Tirelli U, et al.: Involved-field radiotherapy for advanced Hodgkin's lymphoma. N Engl J Med 348 (24): 2396-406, 2003.
Fermé C, Mounier N, Casasnovas O, et al.: Long-term results and competing risk analysis of the H89 trial in patients with advanced-stage Hodgkin lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 107 (12): 4636-42, 2006.
Franklin JG, Paus MD, Pluetschow A, et al.: Chemotherapy, radiotherapy and combined modality for Hodgkin's disease, with emphasis on second cancer risk. Cochrane Database Syst Rev (4): CD003187, 2005.
Patients are designated as having advanced unfavorable Hodgkin lymphoma (HL) if they have clinical stage III or stage IV disease and four or more risk factors on the International Prognostic Index for HL, which corresponds to a freedom-from-progression at worse than 70% at 5 years with combination chemotherapy.[1]
ABVD therapy for 6 to 8 months is as effective as 12 months of MOPP alternating
with ABVD, and both are superior to MOPP alone in terms of failure-free survival (FFS) (50% vs. 36% with a 14-year median follow-up; P = .03).[2][3][Level of evidence: 1iiA] The Intergroup trial comparing ABVD with MOPP/ABV hybrid showed equivalent efficacy in FFS and overall
survival (OS), but increased toxic effects in the hybrid arm, especially from second
malignancies.[4][Level of evidence: 1iiA]
The German Hodgkin Study Group (GHSG HD9 trial) randomly assigned 1,201 patients with advanced-stage disease to COPP/ABVD, BEACOPP, or to escalated BEACOPP, with most patients receiving consolidative radiation therapy to sites of initial bulky disease (≥5 cm).[5] The 10-year OS rates from time of treatment were 75% for COPP/ABVD, 80% for BEACOPP, and 86% for escalated BEACOPP (P = .19 for the comparison of COPP/ABVD with BEACOPP, P = .005 for the comparison of BEACOPP with escalated BEACOPP, and P < .001 for the comparison of COPP/ABVD with increased-dose BEACOPP).[5][Level of evidence: 1iiA] The actuarial rate of secondary acute leukemias 10 years after diagnosis of HL was 0.4% for COPP/ABVD, 1.5% for BEACOPP, and 3.0% for escalated BEACOPP (P = .03).
In the GHSG HD15 trial, six cycles of escalated BEACOPP showed less toxicity and equivalent efficacy when compared with eight cycles of escalated BEACOPP or BEACOP delivered every 2 weeks.[6][Level of evidence: 1iiD]
A prospective, randomized trial of 307 patients with advanced-stage disease, including IIB disease and advanced-favorable HL patients, compared ABVD, BEACOPP (four escalated courses plus two standard courses), and CEC.[7] With a median follow-up of 41 months, although progression-free survival (PFS) favored BEACOPP over ABVD (78% vs. 68%, P = .038), there was no significant difference in OS.[7][Level of evidence: 1iiDiii]
A prospective, randomized study of 331 patients compared ABVD with escalated BEACOPP, along with a planned autologous stem cell transplantation after reinduction chemotherapy for relapsed or resistant disease. With 61 months' median follow-up, although 7-year freedom from first progression favored escalated BEACOPP (73% vs. 85%, P = .004), 7-year OS was not statistically different (84% vs. 89%, P = .39).[8][Level of evidence: 1iiA] Escalated BEACOPP is associated with increased rates of myelodysplasia and acute myelogenous leukemia (3%–4%).[9]
A Cochrane meta-analysis of randomized clinical trials comparing escalated BEACOPP and ABVD for early unfavorable HL or advanced-stage disease could identify no difference in OS.[10][Level of evidence: 1iiA]
Further follow-up is required to assess rates of secondary malignancies with these regimens. Stanford V is an alternative drug combination with mandated radiation therapy consolidation for most patients and survival rates comparable to those with ABVD.[11][12][Level of evidence: 1iiA]
Three prospective, randomized trials did not show a benefit
in OS from the addition of consolidative radiation therapy to
chemotherapy for patients with advanced-stage disease.[13][14][15][Level of evidence: 1iiA] In a meta-analysis
of 1,740 patients treated on 14 different trials, no improvement was observed in
10-years' OS for patients with advanced-stage HL who
received combined modality therapy versus chemotherapy alone.[16][Level of
evidence: 3iiiA] The German Hodgkin Lymphoma Study Group HD15 trial showed that a negative positive–emission tomographic (PET) scan after BEACOPP induction therapy was highly predictive for a good outcome even with omission of consolidative radiation therapy (negative predictive value for PET was 94% [95% confidence interval, 91%–97%]).[17] No survival advantage is known for the use of radiation consolidation for patients with massive mediastinal disease and advanced stage disease, though differences exist in sites of first relapse.[18]
Clinical trials are addressing the role of more intensive regimens for patients
with advanced-stage disease and poor prognostic factors. Early chemotherapy intensification resulting from an interim, PET-positive scan after two cycles of ABVD has also been proposed.[19] Controversy
exists about whether the optimal strategy should involve early dose intensification,
with subsequent risks of increased late toxic effects (such as leukemia) or
whether ABVD should be employed and patients who relapse be salvaged with
high-dose treatment and autografting. In a prospective, randomized trial of 163 patients with unfavorable advanced-stage disease who attained a complete or partial remission after four cycles of ABVD, no difference was observed in OS or FFS either with high-dose therapy with autologous stem cell transplant or with four more cycles of ABVD.[20][Level of evidence: 1iiA]
Engert A, Diehl V, Franklin J, et al.: Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin's lymphoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol 27 (27): 4548-54, 2009.
Engert A, Haverkamp H, Kobe C, et al.: Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet 379 (9828): 1791-9, 2012.
Bauer K, Skoetz N, Monsef I, et al.: Comparison of chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for patients with early unfavourable or advanced stage Hodgkin lymphoma. Cochrane Database Syst Rev (8): CD007941, 2011.
Chisesi T, Bellei M, Luminari S, et al.: Long-term follow-up analysis of HD9601 trial comparing ABVD versus Stanford V versus MOPP/EBV/CAD in patients with newly diagnosed advanced-stage Hodgkin's lymphoma: a study from the Intergruppo Italiano Linfomi. J Clin Oncol 29 (32): 4227-33, 2011.
Brice P, Colin P, Berger F, et al.: Advanced Hodgkin disease with large mediastinal involvement can be treated with eight cycles of chemotherapy alone after a major response to six cycles of chemotherapy: a study of 82 patients from the Groupes d'Etudes des Lymphomes de l'Adulte H89 trial. Cancer 92 (3): 453-9, 2001.
Gallamini A, Patti C, Viviani S, et al.: Early chemotherapy intensification with BEACOPP in advanced-stage Hodgkin lymphoma patients with a interim-PET positive after two ABVD courses. Br J Haematol 152 (5): 551-60, 2011.
Federico M, Bellei M, Brice P, et al.: High-dose therapy and autologous stem-cell transplantation versus conventional therapy for patients with advanced Hodgkin's lymphoma responding to front-line therapy. J Clin Oncol 21 (12): 2320-5, 2003.
Patients who experience a relapse after initial wide-field, high-dose radiation
therapy have a good prognosis. Combination chemotherapy results in 10-year
disease-free survival (DFS) and overall survival (OS) rates of 57% to 81% and 57% to 89%,
respectively.[1][2][3][4] For patients who experience a relapse after initial
combination chemotherapy, prognosis is determined more by the duration of the
first remission than by the specific induction or salvage combination
chemotherapy regimen. Patients whose initial remission after chemotherapy was
longer than 1 year (late relapse) have long-term survival with salvage
chemotherapy of 22% to 71%.[4][5][6][7][8][9] Patients whose initial remission after
chemotherapy was shorter than 1 year (early relapse) do much worse and have
long-term survival of 11% to 46%.[4][8][10]
Patients who relapse after initial
combination chemotherapy usually undergo reinduction with the same or another
chemotherapy regimen followed by high-dose chemotherapy and autologous bone
marrow or peripheral stem cell or allogeneic bone marrow rescue.[11][12][13][14][15] This
therapy has resulted in a 3- to 4-year DFS rate of 27% to
48%. Patients who are responsive to reinduction chemotherapy may have a better
Two randomized trials have compared aggressive conventional chemotherapy versus high-dose chemotherapy with autologous hematopoietic stem cell transplantation for relapsed chemosensitive Hodgkin lymphoma (HL). Both trials show improvement in freedom from treatment failure at 3 years for the transplantation arm (75% vs. 45% and 55% vs. 34%, respectively); but no difference was observed in OS.[16][17][Level of evidence: 1iiDii]
In two retrospective reviews of patients who
underwent autologous bone marrow transplantation (ABMT) for relapsed or refractory disease, a comparison was made of
those who received involved-field radiation therapy (IF-XRT) for residual masses after
high-dose therapy versus no further treatment.[18][19] Those who received
IF-XRT had improved progression-free survival. Normalization of 18F-fluorodeoxyglucose–positron emission tomography–computed tomography (FDG-PET-CT) scans after reinduction therapy predicted a much better outcome after stem cell transplantation, with an event-free survival rate of 80% versus 29% in one phase II trial.[20][Level of evidence: 3iiiDi] For patients at high risk of residual HL after stem cell transplant, a phase III study (the AETHERA trial [NCT01100502]) is evaluating the role of brentuximab vedotin.
The use of human
leukocyte antigen-matched sibling marrow (allogeneic transplantation) results
in a lower relapse rate, but the benefit may be offset by increased toxic
effects.[13][21][22] Reduced-intensity conditioning for allogeneic stem cell transplantation is also under clinical evaluation.[23][24][25][26][27]
Phase II trials support responses in relapsing patients using brentuximab vedotin (anti-tubulin agent attached to a CD30-specific monoclonal antibody) [28][29] and for bendamustine.[30][Level of evidence: 3iiiDiv] For patients with recurrent disease after ABMT, weekly
vinblastine therapy has provided palliation with minimal toxic
effects.[31][Level of evidence: 3iiiDiv]
Because of CD30 expression on malignant Reed-Sternberg cells of HL, but limited expression on normal cells, CD30 is a target for therapy. Brentuximab vedotin is a chimeric antibody directed against CD30, which is linked to the microtubule-disrupting agent, monomethyl auristatin E.[28][32][33] Response rates around 75% are seen with complete remissions around 30% to 50% and median progression-free survival of 4 to 8 months.[28][32][33][Level of evidence: 3iiiDiv]
For the small subgroup of patients with only limited nodal recurrence following
initial chemotherapy, radiation therapy with or without additional chemotherapy
may provide long-term survival for about 50% of these highly selected patients.[34][35]
Patients who do not respond to induction chemotherapy (about 10%–20% of all
presenting patients) have less than a 10% survival rate at 8 years.[8] For these
patients, high-dose chemotherapy and autologous bone marrow or peripheral stem
cell or allogeneic bone marrow rescue are under clinical evaluation.[13][14][36][37][38][39][40][41][42]
These trials have resulted in a 3- to
5-year DFS rate of 17% to 48%.[11][12][13][14][41]
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent adult Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Ng AK, Li S, Neuberg D, et al.: Comparison of MOPP versus ABVD as salvage therapy in patients who relapse after radiation therapy alone for Hodgkin's disease. Ann Oncol 15 (2): 270-5, 2004.
Specht L, Horwich A, Ashley S: Salvage of relapse of patients with Hodgkin's disease in clinical stages I or II who were staged with laparotomy and initially treated with radiotherapy alone. A report from the international database on Hodgkin's disease. Int J Radiat Oncol Biol Phys 30 (4): 805-11, 1994.
Horwich A, Specht L, Ashley S: Survival analysis of patients with clinical stages I or II Hodgkin's disease who have relapsed after initial treatment with radiotherapy alone. Eur J Cancer 33 (6): 848-53, 1997.
Josting A, Franklin J, May M, et al.: New prognostic score based on treatment outcome of patients with relapsed Hodgkin's lymphoma registered in the database of the German Hodgkin's lymphoma study group. J Clin Oncol 20 (1): 221-30, 2002.
Harker WG, Kushlan P, Rosenberg SA: Combination chemotherapy for advanced Hodgkin's disease after failure of MOPP: ABVD and B-CAVe. Ann Intern Med 101 (4): 440-6, 1984.
Tourani JM, Levy R, Colonna P, et al.: High-dose salvage chemotherapy without bone marrow transplantation for adult patients with refractory Hodgkin's disease. J Clin Oncol 10 (7): 1086-94, 1992.
Canellos GP, Petroni GR, Barcos M, et al.: Etoposide, vinblastine, and doxorubicin: an active regimen for the treatment of Hodgkin's disease in relapse following MOPP. Cancer and Leukemia Group B. J Clin Oncol 13 (8): 2005-11, 1995.
Bonfante V, Santoro A, Viviani S, et al.: Outcome of patients with Hodgkin's disease failing after primary MOPP-ABVD. J Clin Oncol 15 (2): 528-34, 1997.
Garcia-Carbonero R, Paz-Ares L, Arcediano A, et al.: Favorable prognosis after late relapse of Hodgkin's disease. Cancer 83 (3): 560-5, 1998.
Longo DL, Duffey PL, Young RC, et al.: Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin's disease after combination chemotherapy: the low probability for cure. J Clin Oncol 10 (2): 210-8, 1992.
Nademanee A, O'Donnell MR, Snyder DS, et al.: High-dose chemotherapy with or without total body irradiation followed by autologous bone marrow and/or peripheral blood stem cell transplantation for patients with relapsed and refractory Hodgkin's disease: results in 85 patients with analysis of prognostic factors. Blood 85 (5): 1381-90, 1995.
Horning SJ, Chao NJ, Negrin RS, et al.: High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin's disease: analysis of the Stanford University results and prognostic indices. Blood 89 (3): 801-13, 1997.
Akpek G, Ambinder RF, Piantadosi S, et al.: Long-term results of blood and marrow transplantation for Hodgkin's lymphoma. J Clin Oncol 19 (23): 4314-21, 2001.
Tarella C, Cuttica A, Vitolo U, et al.: High-dose sequential chemotherapy and peripheral blood progenitor cell autografting in patients with refractory and/or recurrent Hodgkin lymphoma: a multicenter study of the intergruppo Italiano Linfomi showing prolonged disease free survival in patients treated at first recurrence. Cancer 97 (11): 2748-59, 2003.
Holmberg L, Maloney DG: The role of autologous and allogeneic hematopoietic stem cell transplantation for Hodgkin lymphoma. J Natl Compr Canc Netw 9 (9): 1060-71, 2011.
Linch DC, Winfield D, Goldstone AH, et al.: Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet 341 (8852): 1051-4, 1993.
Schmitz N, Pfistner B, Sextro M, et al.: Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet 359 (9323): 2065-71, 2002.
Mundt AJ, Sibley G, Williams S, et al.: Patterns of failure following high-dose chemotherapy and autologous bone marrow transplantation with involved field radiotherapy for relapsed/refractory Hodgkin's disease. Int J Radiat Oncol Biol Phys 33 (2): 261-70, 1995.
Poen JC, Hoppe RT, Horning SJ: High-dose therapy and autologous bone marrow transplantation for relapsed/refractory Hodgkin's disease: the impact of involved field radiotherapy on patterns of failure and survival. Int J Radiat Oncol Biol Phys 36 (1): 3-12, 1996.
Moskowitz CH, Matasar MJ, Zelenetz AD, et al.: Normalization of pre-ASCT, FDG-PET imaging with second-line, non-cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma. Blood 119 (7): 1665-70, 2012.
Milpied N, Fielding AK, Pearce RM, et al.: Allogeneic bone marrow transplant is not better than autologous transplant for patients with relapsed Hodgkin's disease. European Group for Blood and Bone Marrow Transplantation. J Clin Oncol 14 (4): 1291-6, 1996.
Gajewski JL, Phillips GL, Sobocinski KA, et al.: Bone marrow transplants from HLA-identical siblings in advanced Hodgkin's disease. J Clin Oncol 14 (2): 572-8, 1996.
Sureda A, Robinson S, Canals C, et al.: Reduced-intensity conditioning compared with conventional allogeneic stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 26 (3): 455-62, 2008.
Thomson KJ, Peggs KS, Smith P, et al.: Superiority of reduced-intensity allogeneic transplantation over conventional treatment for relapse of Hodgkin's lymphoma following autologous stem cell transplantation. Bone Marrow Transplant 41 (9): 765-70, 2008.
Sarina B, Castagna L, Farina L, et al.: Allogeneic transplantation improves the overall and progression-free survival of Hodgkin lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability. Blood 115 (18): 3671-7, 2010.
Kuruvilla J, Pintilie M, Stewart D, et al.: Outcomes of reduced-intensity conditioning allo-SCT for Hodgkin's lymphoma: a national review by the Canadian Blood and Marrow Transplant Group. Bone Marrow Transplant 45 (7): 1253-5, 2010.
Peggs KS, Kayani I, Edwards N, et al.: Donor lymphocyte infusions modulate relapse risk in mixed chimeras and induce durable salvage in relapsed patients after T-cell-depleted allogeneic transplantation for Hodgkin's lymphoma. J Clin Oncol 29 (8): 971-8, 2011.
Younes A, Gopal AK, Smith SE, et al.: Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol 30 (18): 2183-9, 2012.
Chen R, Palmer JM, Thomas SH, et al.: Brentuximab vedotin enables successful reduced-intensity allogeneic hematopoietic cell transplantation in patients with relapsed or refractory Hodgkin lymphoma. Blood 119 (26): 6379-81, 2012.
Moskowitz AJ, Hamlin PA Jr, Perales MA, et al.: Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol 31 (4): 456-60, 2013.
Little R, Wittes RE, Longo DL, et al.: Vinblastine for recurrent Hodgkin's disease following autologous bone marrow transplant. J Clin Oncol 16 (2): 584-8, 1998.
Gopal AK, Ramchandren R, O'Connor OA, et al.: Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. Blood 120 (3): 560-8, 2012.
Younes A, Bartlett NL, Leonard JP, et al.: Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363 (19): 1812-21, 2010.
Uematsu M, Tarbell NJ, Silver B, et al.: Wide-field radiation therapy with or without chemotherapy for patients with Hodgkin disease in relapse after initial combination chemotherapy. Cancer 72 (1): 207-12, 1993.
Josting A, Nogová L, Franklin J, et al.: Salvage radiotherapy in patients with relapsed and refractory Hodgkin's lymphoma: a retrospective analysis from the German Hodgkin Lymphoma Study Group. J Clin Oncol 23 (7): 1522-9, 2005.
Marshall NA, DeVita VT Jr: Hodgkin's disease and transplantation: a room with a (nontransplanter's) view. Semin Oncol 26 (1): 67-73, 1999.
Lazarus HM, Rowlings PA, Zhang MJ, et al.: Autotransplants for Hodgkin's disease in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 17 (2): 534-45, 1999.
Fermé C, Mounier N, Diviné M, et al.: Intensive salvage therapy with high-dose chemotherapy for patients with advanced Hodgkin's disease in relapse or failure after initial chemotherapy: results of the Groupe d'Etudes des Lymphomes de l'Adulte H89 Trial. J Clin Oncol 20 (2): 467-75, 2002.
Sweetenham JW, Carella AM, Taghipour G, et al.: High-dose therapy and autologous stem-cell transplantation for adult patients with Hodgkin's disease who do not enter remission after induction chemotherapy: results in 175 patients reported to the European Group for Blood and Marrow Transplantation. Lymphoma Working Party. J Clin Oncol 17 (10): 3101-9, 1999.
Laurence AD, Goldstone AH: High-dose therapy with hematopoietic transplantation for Hodgkin's lymphoma. Semin Hematol 36 (3): 303-12, 1999.
Gopal AK, Metcalfe TL, Gooley TA, et al.: High-dose therapy and autologous stem cell transplantation for chemoresistant Hodgkin lymphoma: the Seattle experience. Cancer 113 (6): 1344-50, 2008.
Morschhauser F, Brice P, Fermé C, et al.: Risk-adapted salvage treatment with single or tandem autologous stem-cell transplantation for first relapse/refractory Hodgkin's lymphoma: results of the prospective multicenter H96 trial by the GELA/SFGM study group. J Clin Oncol 26 (36): 5980-7, 2008.
Since Hodgkin lymphoma affects primarily young adults, most oncologists will
eventually face the dilemma of how to provide therapy to a pregnant woman while
minimizing the risk to the fetus. Treatment choice must be individualized,
taking into consideration the mother's wishes, the severity and pace of the
Hodgkin lymphoma (HL), and the length of the remaining pregnancy. Since general
guidelines can never substitute for clinical judgment, oncologists should be
prepared to alter the initial plans when necessary.
To avoid exposure to ionizing
radiation, magnetic resonance imaging
is the preferred tool for staging evaluation.[1] The presenting stage, clinical behavior, prognosis, and histologic subtypes of HL during pregnancy do not differ from those of nonpregnant women during their childbearing years.[2] See the Stage Information for Adult Hodgkin Lymphoma section for more information.
HL that is diagnosed in the first trimester of pregnancy does not constitute an absolute indication for therapeutic abortion. Each patient must be looked at individually to take into account the stage and rapidity of growth of the lymphoma and the patient's wishes.[3] If the HL presents in
early stage above the diaphragm and appears to be growing slowly, patients can
be followed carefully with plans to induce delivery early and proceed with
definitive therapy.[4] Alternatively, these patients can receive radiation
therapy with proper shielding.[5][6][7][8] Investigators at M.D. Anderson reported no
congenital abnormalities in 16 babies delivered after the mothers had received
supradiaphragmatic radiation while shielding the uterus with five half-value
layers of lead.[9] Because of theoretical risks that the fetus might develop future malignancies from even minimal scattered radiation doses outside the radiation field, radiation therapy should be postponed, if possible, until after delivery.[10]
Chemotherapy that is administered in the first trimester has been
associated with congenital abnormalities in as many as 33% of infants.[11][12]
However, in one series, there were no adverse effects in 14 children of mothers
who received a combination of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or
a combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) during gestation, five
of whom began treatment during the first trimester.[13] Consequently, some
women may opt to continue the pregnancy and agree to radiation therapy or
chemotherapy if immediate treatment is required.
In the second half of pregnancy, most patients can be followed carefully
and can postpone therapy until induction of delivery at 32 to 36 weeks.[11][14][15] If
chemotherapy is mandatory prior to delivery, such as for patients with
symptomatic advanced stage disease, vinblastine alone (given at 6 mg/m² intravenously every 2 weeks until induction of delivery) may
be considered because it has never been associated with fetal abnormalities in the
second half of pregnancy.[14][15] Steroids are employed both for their
antitumor effect and for hastening fetal pulmonary maturity. As an
alternative, a short course of radiation therapy can be used prior to delivery in
cases of respiratory compromise caused by the rapidly enlarging mediastinal mass.
Combination chemotherapy with ABVD appears to be safe in the second half of
pregnancy.[13] If chemotherapy is required after the first trimester, many
clinicians prefer the combination of drugs over single-agent drugs or radiation
In one study, the 20-year survival rate of pregnant women with HL did not differ from the 20-year survival rate of nonpregnant women who were matched for similar stage of disease, age
at diagnosis, and calendric year of treatment.[16] The long-term effects on
progeny after chemotherapy in utero are unknown, though present evidence
tends to be reassuring.[12][13][14][15][16]
Nicklas AH, Baker ME: Imaging strategies in the pregnant cancer patient. Semin Oncol 27 (6): 623-32, 2000.
Gelb AB, van de Rijn M, Warnke RA, et al.: Pregnancy-associated lymphomas. A clinicopathologic study. Cancer 78 (2): 304-10, 1996.
Koren G, Weiner L, Lishner M, et al.: Cancer in pregnancy: identification of unanswered questions on maternal and fetal risks. Obstet Gynecol Surv 45 (8): 509-14, 1990.
Anselmo AP, Cavalieri E, Enrici RM, et al.: Hodgkin's disease during pregnancy: diagnostic and therapeutic management. Fetal Diagn Ther 14 (2): 102-5, 1999 Mar-Apr.
Mazonakis M, Varveris H, Fasoulaki M, et al.: Radiotherapy of Hodgkin's disease in early pregnancy: embryo dose measurements. Radiother Oncol 66 (3): 333-9, 2003.
Greskovich JF Jr, Macklis RM: Radiation therapy in pregnancy: risk calculation and risk minimization. Semin Oncol 27 (6): 633-45, 2000.
Fisher PM, Hancock BW: Hodgkin's disease in the pregnant patient. Br J Hosp Med 56 (10): 529-32, 1996 Nov 20-Dec 10.
Friedman E, Jones GW: Fetal outcome after maternal radiation treatment of supradiaphragmatic Hodgkin's disease. CMAJ 149 (9): 1281-3, 1993.
Woo SY, Fuller LM, Cundiff JH, et al.: Radiotherapy during pregnancy for clinical stages IA-IIA Hodgkin's disease. Int J Radiat Oncol Biol Phys 23 (2): 407-12, 1992.
Lishner M: Cancer in pregnancy. Ann Oncol 14 (Suppl 3): iii31-6, 2003.
Cardonick E, Iacobucci A: Use of chemotherapy during human pregnancy. Lancet Oncol 5 (5): 283-91, 2004.
Thomas PR, Biochem D, Peckham MJ: The investigation and management of Hodgkin's disease in the pregnant patient. Cancer 38 (3): 1443-51, 1976.
Avilés A, Díaz-Maqueo JC, Talavera A, et al.: Growth and development of children of mothers treated with chemotherapy during pregnancy: current status of 43 children. Am J Hematol 36 (4): 243-8, 1991.
Jacobs C, Donaldson SS, Rosenberg SA, et al.: Management of the pregnant patient with Hodgkin's disease. Ann Intern Med 95 (6): 669-75, 1981.
Nisce LZ, Tome MA, He S, et al.: Management of coexisting Hodgkin's disease and pregnancy. Am J Clin Oncol 9 (2): 146-51, 1986.
Lishner M, Zemlickis D, Degendorfer P, et al.: Maternal and foetal outcome following Hodgkin's disease in pregnancy. Br J Cancer 65 (1): 114-7, 1992.
This information was last updated on February 28, 2014.