Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult Hodgkin lymphoma. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

• Prognostic factors.
• Cellular classification.
• Staging.
• Pregnancy-related considerations.
• Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

General Information About Adult Hodgkin Lymphoma

Related Summaries

Other PDQ summaries containing information related to Hodgkin lymphoma include:

• AIDS-Related Lymphoma Treatment
• Childhood Hodgkin Lymphoma Treatment

Statistics

Note: Estimated new cases and deaths from Hodgkin lymphoma in the United States in 2008: ^[1]

• New cases: 8,220.
• Deaths: 1,350.

Cellular Classification of Adult Hodgkin Lymphoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

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

• Classical HL.
  • Nodular sclerosis HL.
  • Mixed-cellularity HL.
  • Lymphocyte depletion HL.
  • Lymphocyte-rich classical HL.
• Nodular lymphocyte–predominant HL.

Nodular lymphocyte–predominant HL is a clinicopathologic entity of B-cell origin that is distinct from classic HL.^[3][4][5] 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. Lymphocyte-predominant HL is usually diagnosed in asymptomatic young males with cervical or inguinal lymph nodes but usually without mediastinal involvement.

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][6] The largest retrospective report of 426 cases showed no significant difference in clinical response or outcome to standard therapies for these two subgroups.^[7][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.^[8][9]

Stage Information for Adult Hodgkin Lymphoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

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, sometimes combined with CT scans, have replaced gallium scans and lymphangiography for clinical staging.^[2][3][4] The use of PET scans to assess response and define the use or avoidance of further treatment is under clinical evaluation.^[5][6]Bone marrow involvement occurs in 5% of patients; biopsy is indicated in the presence of constitutional B symptoms or anemia, leukopenia, or thrombocytopenia. 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.^{[7][8][9][10]} The staging classification that is currently used for HL was adopted in 1971 at the Ann Arbor Conference^[11] with some modifications 18 years later from the Cotswolds meeting.^[1]

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:

• Unexplained loss of more than 10% of body weight in the 6 months before diagnosis.
• Unexplained fever with temperatures above 38°C.
• Drenching night sweats.

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. 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.

Sites are identified by the following notations:

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+).

Stage I

Stage I adult HL is characterized by the involvement of a single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE).

Stage II

Stage II adult HL is characterized by the involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ or site and its regional lymph node(s) with or without involvement of other lymph node regions on the same side of the diaphragm (IIE). Note: The number of lymph node regions involved may be indicated by a subscript.

Stage III

Stage III adult HL is characterized by the involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an associated extralymphatic organ or site (IIIE), by involvement of the spleen (IIIS), or by involvement of both (IIIE + S). Stage III disease may be subdivided by anatomic distribution of abdominal involvement or by extent of splenic involvement. Stage III(1) indicates involvement that is limited to the upper abdomen above the renal vein. Stage III(2) indicates involvement of pelvic and/or para-aortic nodes. Five or more visible splenic nodules on a cut section constitutes extensive splenic involvement. Zero to four nodules is classified as minimal splenic disease.

Stage IV

Stage IV adult HL is characterized by disseminated (multifocal) involvement of one or more extralymphatic organs, with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement.

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.^[12] Other investigators use a measurement of the maximum width of the mediastinal mass divided by the maximum intrathoracic diameter.^[13]

Many investigators and many new clinical trials employ a clinical staging system that divides patients into three major groups that are also useful for the practicing physician:^[14]

• Early favorable: Clinical stage I or II without any risk factors.
• Early unfavorable: Clinical stage I or II with one or more of the following risk factors:
  • Large mediastinal mass (>33% of the thoracic width on the CXR, ≥10 cm on CT scan).
  • Extranodal involvement.
  • Elevated ESR (>30 mm/hr for B stage, >50 mm/hr for A stage).
  • Three or more lymph node areas' involvement.
  • B symptoms.
• Advanced: Clinical stage III or IV. For patients with advanced-stage HL, the International Prognostic Factors Project has developed an International Prognostic Index with a prognostic score that is based on seven adverse factors:^[15]
  • Albumin level of less than 4.0 g/dL.
  • Hemoglobin level of less than 10.5 g/dL.
  • Male sex.
  • Age of 45 years or older.
  • Stage IV disease.
  • White blood cell (WBC) count of at least 15,000/mm³.
  • Absolute lymphocytic count of less than 600/mm³ or a lymphocyte count that was less than 8% of the total WBC count.

Patients with advanced favorable disease, with zero to three adverse risk factors, have a 60% to 80% freedom-from-progression at 5 years with first-line chemotherapy.^[15][Level of evidence: 3iiiDiii]

Even the patients at the very highest risk, with advanced unfavorable disease and four to seven adverse factors, showed a 42% to 51% freedom-from-progression at 5 years with first-line therapy.^[15][Level of evidence: 3iiiDiii]

Treatment Option Overview

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Drug combinations described in this section:

• ABVD: doxorubicin + bleomycin + vinblastine + dacarbazine.
• BEACOPP: bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone.
• MOPP: mechlorethamine + vincristine + procarbazine + prednisone.

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. Staging laparotomy is no longer recommended because it may not alter management and does not enhance ultimate outcome.^[1] When chemotherapy alone or combined modality therapy is applied, laparotomy is not required.

Radiation Therapy

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.^[2][3][4][5] 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.

Second Malignancies

Acute nonlymphocytic leukemia may occur in patients treated with combined modality therapy or with combination chemotherapy alone.^[6][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%.^[6] 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., older than 35 years at diagnosis) versus younger survivors.^[9]

An increase in second solid tumors has also been observed, especially cancers of the lung, breast, thyroid, bone/soft tissue, stomach, esophagus, uterine cervix, and head and neck.^{[7][10][11][12][13][14]} 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][11] and at a 25-year follow-up the risk is approximately 22%.^[10][15]

Lung cancer is seen with increased frequency, even after chemotherapy alone, and the risk of this cancer is increased with cigarette smoking.^{[16][17][18][19]} Breast cancer is seen with increased frequency after radiation therapy or combined modality therapy.^{[10][12][14][20][21][22][23]} The risk appears greatest for women treated with radiation before age 30 years, and the incidence increases substantially after 15 years of follow-up.^{[10][13][24][25]} In a case control study of 106 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.^[26] With a 30-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 this cohort.^[27] In a nested case control 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.^[21] Reaching menopause before age 36 appeared to account for the reduction in risk among patients who received combined modality therapy. The risk of non-Hodgkin lymphoma is also increased, but this risk is not clearly related to type or extent of treatment.^[11]

Several studies suggest that splenic-field radiation therapy and splenectomy increase the risk of a treatment-related second cancer.^[28][29][30] 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.^[31]

Adverse Effects of Therapy

A toxic effect that is primarily related to chemotherapy is infertility, usually after MOPP-containing or BEACOPP-containing regimens;^[11][32] ABVD appears to spare long-term testicular and ovarian function.^[33] Late complications primarily related to radiation therapy include hypothyroidism and cardiac disease.^{[34][35][36][37][38]} The absolute excess risk of fatal cardiovascular disease ranges from 11.9 to 48.9 per 10,000 patient years, mostly attributable to fatal myocardial infarction (MI).^[35][36][37] 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.^[36] 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.^[39] Pulmonary toxic effects from bleomycin as used in ABVD are seen in older patients (especially those older than 40 years).^[40] Avascular necrosis of bone has been observed in patients treated with chemotherapy and is most likely related to corticosteroid therapy.^[41] Bacterial sepsis may occur rarely after splenectomy performed during staging laparotomy for HL;^[42] 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 Haemophilus influenzae type b conjugate, meningococcal, and pneumococcal vaccines at least 1 week before treatment.^[43] Some investigators recommend reimmunization with all three vaccines 2 years after completion of treatment and with pneumococcal vaccine every 6 years thereafter.^[44]

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.^[45]

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.^[46][47]

Hodgkin Lymphoma During Pregnancy

Introduction

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, 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.

Stage Information

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 Hodgkin lymphoma during pregnancy do not differ from those of nonpregnant women during their childbearing years.^[2] See the Stage Information section for more information.

Treatment Option Overview

Hodgkin lymphoma 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 Hodgkin lymphoma 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, plus bleomycin, plus 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 therapy.

In one study, the 20-year survival rate of pregnant women with Hodgkin lymphoma 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]}

Early Favorable Hodgkin Lymphoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Drug combinations described in this section:

• ABV: doxorubicin + bleomycin + vinblastine.
• ABVD: doxorubicin + bleomycin + vinblastine + dacarbazine (1 cycle = 1 month of therapy).
• AV: doxorubicin + vinblastine.
• AVD: doxorubicin + vinblastine + dacarbazine.

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:

• B symptoms (fever ≥38°C, soaking night sweats, weight loss ≥10% within 6 months).
• Extranodal disease.
• Bulky disease (≥10 cm or >33% of the chest diameter on chest x-ray).
• Three or more sites of nodal involvement.
• Sedimentation rate of 50 or more.

Historically, radiation therapy alone had been the primary treatment for patients with early favorable HL, often after confirmatory negative staging laparotomy. 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.^[1][2][3] Recent clinical trials have focused on regimens with chemotherapy and involved-field radiation therapy (IF-XRT) or with chemotherapy alone.

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 4.2 years, no difference was observed in event-free survival (88% vs. 87%; P = .60) or in overall survival (OS) (97% vs. 100%; P = .30).^[4][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 (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.^[5][Level of evidence: 1iiDii]

The German Hodgkin Lymphoma Study Group (GHSG) randomly assigned 1,131 patients with early favorable HL to:

• Two cycles of ABVD plus 30 Gy of IF-XRT.
• Two cycles of ABVD plus 20 Gy of IF-XRT.
• Four cycles of ABVD plus 30 Gy of IF-XRT.
• Four cycles of ABVD plus 20 Gy of IF-XRT.

With a 3-year median follow-up, in a preliminary report in abstract form, no differences were observed in freedom-from-progression (97%) or OS (98%) for all four groups.^[6][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.^[7] 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.^[8][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.^[9] Patients with nonbulky nodular sclerosing disease presenting in the anterior mediastinum only after clinical staging also do well with mantle radiation alone.^[10]

Treatment options:

• ABVD for four to six cycles.
• ABVD for two cycles plus IF-XRT (20 Gy or 30 Gy).
• Radiation therapy alone in special circumstances.^[11]

References

Early Unfavorable Hodgkin Lymphoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Drug combinations described in this section:

• ABVD: doxorubicin + bleomycin + vinblastine + dacarbazine (1 cycle = 1 month of therapy).
• AV: doxorubicin + vinblastine.
• BEACOPP: bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone.
• COPP/ABVD: cyclophosphamide + vincristine + procarbazine + prednisone/doxorubicin + bleomycin + vinblastine + dacarbazine.

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:

• B symptoms (fever ≥38°C, soaking night sweats, weight loss ≥10% within 6 months).
• Extranodal disease.
• Bulky disease (≥10 cm or >33% of the chest diameter on chest x-ray).
• Three or more sites of nodal involvement.
• Sedimentation rate of 50 or more.

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]

A randomized prospective trial from the National Cancer Institute of Canada 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 4.2 years, the freedom-from-progression favored combined modality therapy (95% vs. 88%; P = .004), with no difference in overall survival (OS).^[5][Level of evidence: 1iiDiii]

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.^[6][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.^[7][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 with 5 years' median follow-up.^[8][Level of evidence: 1iiA]

The GHSG randomly assigned 1,051 patients with early unfavorable HL to:

• Four cycles of ABVD plus 30 Gy of IF-XRT.
• Four cycles of ABVD plus 20 Gy of IF-XRT.
• Four cycles of BEACOPP plus 30 Gy of IF-XRT.
• Four cycles of BEACOPP plus 20 Gy of IF-XRT.

With a 40-month median follow-up, in a preliminary report in abstract form, no differences were observed in freedom-from-treatment failure (87%–90%) or in OS (96%–97%) for all four groups.^[9][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:

• Four cycles of ABVD plus 30 Gy of IF-XRT.
• Six cycles of ABVD plus 30 Gy of IF-XRT.
• Four cycles of BEACOPP plus 30 Gy of IF-XRT.

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).^[10][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? 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 no worse 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.^[5] In addition, chemotherapy alone was 7% 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? Randomized studies with or without IF-XRT would be required, but no such studies are currently under way.

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.^[11][12][Level of evidence: 3iiiDiii]

Treatment options:

• Four cycles of ABVD plus IF-XRT (20 Gy–30 Gy).
• Four to six cycles of ABVD.

References

Advanced Favorable Hodgkin Lymphoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Drug combinations described in this section:

• ABVD: doxorubicin + bleomycin + vinblastine + dacarbazine.
• MOPP: mechlorethamine + vincristine + procarbazine + prednisone.
• MOPP/ABV hybrid: mechlorethamine + vincristine + procarbazine + prednisone/doxorubicin + bleomycin + vinblastine.
• Stanford V: doxorubicin + vinblastine + mechlorethamine + etoposide + vincristine + bleomycin + prednisone.
• MOPPEBVCAD: mechlorethamine + vincristine + procarbazine + prednisone + epidoxorubicin + bleomycin + vinblastine + lomustine + doxorubicin + vindesine.

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 60% 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 (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] Stanford V is an alternative drug combination currently under clinical evaluation (ECOG-2496)).^[6] A prospective randomized trial of 355 patients compared Stanford V to ABVD and a variation of MOPP/ABV (MOPPEBVCAD).^[7] With a median follow-up of 5.1 years, the FFS was worse for patients on Stanford V compared with those on the other regimens (54% vs. 78% and 81% at 5 years; P < .01).^[7][Level of evidence: 1iiDiii]

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.^[8][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.^{[9][10][11][12]} 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 therapy.

Proposed clinical trials will explore consolidation for patients with positive positron emission tomography testing after four cycles of ABVD.

Treatment options:

• ABVD for six to eight cycles.
• ABVD for six to eight cycles + IF-XRT for some patients with bulky disease.

References

Advanced Unfavorable Hodgkin Lymphoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Drug combinations described in this section:

• ABVD: doxorubicin + bleomycin + vinblastine + dacarbazine.
• BEACOPP: bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone.
• COPP/ABVD: cyclophosphamide + vincristine + procarbazine + prednisone/doxorubicin + bleomycin + vinblastine + dacarbazine.
• MOPP: mechlorethamine + vincristine + procarbazine + prednisone.
• MOPP alternating with ABVD: mechlorethamine + vincristine + procarbazine + prednisone alternating with doxorubicin + bleomycin + vinblastine + dacarbazine.
• MOPP/ABV hybrid: mechlorethamine + vincristine + procarbazine + prednisone/doxorubicin + bleomycin + vinblastine.
• Stanford V: doxorubicin + vinblastine + mechlorethamine + etoposide + vincristine + bleomycin + prednisone.

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 50% 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 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 Lymphoma Study Group randomly assigned 1,201 patients with advanced-stage disease to COPP/ABVD, BEACOPP, or to increased-dose BEACOPP, with most patients receiving consolidative radiation therapy to sites of initial bulky disease (≥5 cm).^[5] The 5-year OS was 83% for COPP/ABVD, 88% for BEACOPP, and 91% for increased-dose BEACOPP (P = .16 for the comparison of COPP/ABVD with BEACOPP, P = .06 for the comparison of BEACOPP with increased-dose BEACOPP, and P = .002 for the comparison of COPP/ABVD with increased-dose BEACOPP).^[5][Level of evidence: 1iiA] The actuarial rate of secondary acute leukemias 5 years after diagnosis of HL was 0.4% for COPP/ABVD, 0.6% for BEACOPP, and 2.5% for increased-dose BEACOPP (P = .03). Stanford V is an alternative drug combination currently under clinical evaluation (ECOG-2496; EORTC-20012).^[6]

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.^[7][8][9][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.^[10][Level of evidence: 3iiiA] No survival advantage is known for the use of radiation consolidation for patients with massive mediastinal disease and advanced stage, though differences exist in sites of first relapse.^[11]

Clinical trials are addressing the role of more intensive regimens for patients with advanced-stage disease and poor prognostic factors. 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.^[12][Level of evidence: 1iiA]

Treatment options:

• ABVD for six to eight cycles.
• BEACOPP (increased dose).

References

Recurrent Adult Hodgkin Lymphoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

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]} 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 prognosis. Two randomized trials have compared aggressive conventional chemotherapy versus high-dose chemotherapy with autologous hematopoietic stem cell transplantation for relapsed chemosensitive 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.^[15][16][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.^[17][18] Those who received IF-XRT had improved progression-free survival. 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][19][20] For patients with recurrent disease after ABMT, weekly vinblastine therapy has provided palliation with minimal toxic effects.^[21][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.^[22][23]

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][24][25][26][27][28]} These trials have resulted in a 3- to 4-year DFS rate of 27% to 48%.^{[11][12][13][14]}

Information about ongoing clinical trials is available from the NCI Web site.

References

Get More Information From NCI

Call 1-800-4-CANCER

For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. Deaf and hard-of-hearing callers with TTY equipment may call 1-800-332-8615. The call is free and a trained Cancer Information Specialist is available to answer your questions.

Chat online

The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 9:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.

Write to us

For more information from the NCI, please write to this address:

• NCI Public Inquiries Office
• Suite 3036A
• 6116 Executive Boulevard, MSC8322
• Bethesda, MD 20892-8322

Search the NCI Web site

The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use our “Best Bets” search box in the upper right hand corner of each Web page. The results that are most closely related to your search term will be listed as Best Bets at the top of the list of search results.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237), TTY at 1-800-332-8615.

Changes to This Summary (03/03/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information About Adult Hodgkin Lymphoma

Updated statistics with estimated new cases and deaths for 2008 (cited American Cancer Society).