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Incidence and Mortality
Estimated new cases and deaths from Hodgkin lymphoma in the United States in 2014:
More than 75% of all newly diagnosed patients with adult Hodgkin lymphoma (HL) can be cured with combination chemotherapy and/or radiation therapy. National mortality has fallen more rapidly for adult HL than for any other malignancy over the last 5 decades.
Prognosis and Survival Factors
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:
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]
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. These patients present with more advanced-stage HL and usually with B symptoms.
Nodular Lymphocyte–Predominant HL
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. 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. 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.[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.[Level of evidence: 3iiiDii]
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.
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). 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. 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. 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  with some modifications 18 years later from the Cotswolds meeting.
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.
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.
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. Some investigators have designated a lymph node mass measuring 10 cm or more in greatest dimension as massive disease. Other investigators use a measurement of the maximum width of the mediastinal mass divided by the maximum intrathoracic diameter.
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:
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. Staging laparotomy is no longer recommended because it may not alter management and does not enhance ultimate outcome. 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%. 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.
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%; 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. 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.
Lung 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. 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. 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. Reduction of radiation volume also decreased the risk of breast cancer after HL. The risk of non-HL is also increased, but this risk is not clearly related to type or extent of treatment.
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.
Adverse Effects of Therapy
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. 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. 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. 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.
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. Pulmonary toxic effects from bleomycin as used in ABVD are seen in older patients (especially those older than 40 years). Avascular necrosis of bone has been observed in patients treated with chemotherapy and is most likely related to corticosteroid therapy.
Bacterial sepsis may occur rarely after splenectomy performed during staging laparotomy for HL; 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. Some investigators recommend reimmunization with all three vaccines 2 years after completion of treatment and with pneumococcal vaccine every 6 years thereafter.
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.
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]
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).[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.
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).[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.[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.[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. 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.[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. Patients with nonbulky nodular sclerosing disease presenting in the anterior mediastinum only after clinical staging also do well with mantle radiation alone.
Treatment options include the following:
Current Clinical Trials
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.
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. 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).[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.[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.[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.[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.[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).[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.[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).[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 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. 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. An indirect comparison for using ABVD alone is that the 94% OS seen for early unfavorable patients in the NCIC study  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. 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). 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.
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]
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.
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.[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.[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).[Level of evidence: 1iiA] Escalated BEACOPP is associated with increased rates of myelodysplasia and acute myelogenous leukemia (3%–4%). 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. 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.[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.[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 therapy.
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.
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.
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.[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). 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).[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.[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. 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.[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).[Level of evidence: 1iiA] Escalated BEACOPP is associated with increased rates of myelodysplasia and acute myelogenous leukemia (3%–4%).
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.[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.[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%]). 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.
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. 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.[Level of evidence: 1iiA]
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 prognosis.
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.[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.[Level of evidence: 3iiiDiv] For patients with recurrent disease after ABMT, weekly vinblastine therapy has provided palliation with minimal toxic effects.[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. 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.
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. 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. See the Stage Information for Adult Hodgkin Lymphoma section for more information.
Treatment Option Overview
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. 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. 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. 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.
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. 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. 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 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. The long-term effects on progeny after chemotherapy in utero are unknown, though present evidence tends to be reassuring.[12,13,14,15,16]
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 2014 (cited American Cancer Society as reference 1).
Stage Information for Adult Hodgkin Lymphoma
Revised text to state that positron emission tomography (PET) scans are usually combined with computed tomography (CT) scans for clinical staging. Also revised text to state that further prospective studies are needed to compare a PET response–adapted strategy versus standard therapy without alteration (cited Gallamini et al. as reference 8).
Added text to state that 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 (cited El-Galaly et al. as reference 9).
Revised text to state that increasing exposure to alkylating agents in combined modality treatments or chemotherapy treatments alone may be a secondary cause of acute nonlymphocytic leukemia (cited Koontz et al. as reference 8).
Added Böll et al. as reference 61.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult Hodgkin lymphoma. It 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.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Adult Hodgkin Lymphoma Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this 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.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Adult Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/adulthodgkins/HealthProfessional. Accessed <MM/DD/YYYY>.
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
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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 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.
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Last Revised: 2014-02-28
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