Purpose of This PDQ Summary
General Information About Adult Hodgkin Lymphoma

Related Summaries Statistics

Cellular Classification of Adult Hodgkin Lymphoma
Stage Information for Adult Hodgkin Lymphoma
Treatment Option Overview

Radiation Therapy Second Malignancies Adverse Effects of Therapy

Early Favorable Hodgkin Lymphoma

Current Clinical Trials

Early Unfavorable Hodgkin Lymphoma

Current Clinical Trials

Advanced Favorable Hodgkin Lymphoma

Current Clinical Trials

Advanced Unfavorable Hodgkin Lymphoma

Current Clinical Trials

Recurrent Adult Hodgkin Lymphoma

Current Clinical Trials

Hodgkin Lymphoma During Pregnancy

Introduction Stage Information Treatment Option Overview

Get More Information From NCI
Changes to This Summary (04/29/2008)
More Information

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.

Back to Top

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.

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

• New cases: 8,220.
• Deaths: 1,350.

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.

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 (therapy for very young children requires special attention), sex, erythrocyte sedimentation rate, extent of abdominal involvement, hematocrit, and absolute number of nodal sites of involvement.[2,3]

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.[4-6]

References

1. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. Last accessed February 21, 2008. 
   
   
2. American Cancer Society.: Cancer Facts and Figures 2007. Atlanta, Ga: American Cancer Society, 2007. Also available online. Last accessed December 20, 2007. 
   
   
3. Cosset JM, Henry-Amar M, Meerwaldt JH, et al.: The EORTC trials for limited stage Hodgkin's disease. The EORTC Lymphoma Cooperative Group. Eur J Cancer 28A (11): 1847-50, 1992.  [PUBMED Abstract]
   
   
4. Mauch PM, Kalish LA, Marcus KC, et al.: Long-Term Survival in Hodgkin's Disease Cancer J Sci Am 1 (1): 33-42, 1995.  [PUBMED Abstract]
   
   
5. Aisenberg AC: Problems in Hodgkin's disease management. Blood 93 (3): 761-79, 1999.  [PUBMED Abstract]
   
   
6. Aleman BM, van den Belt-Dusebout AW, Klokman WJ, et al.: Long-term cause-specific mortality of patients treated for Hodgkin's disease. J Clin Oncol 21 (18): 3431-9, 2003.  [PUBMED Abstract]
   
   

Back to Top

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.[3-5] 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]

References

1. Lukes RJ, Craver LF, Hall TC, et al.: Report of the Nomenclature Committee. Cancer Res 26 (1): 1311, 1966. 
   
   
2. Harris NL: Hodgkin's lymphomas: classification, diagnosis, and grading. Semin Hematol 36 (3): 220-32, 1999.  [PUBMED Abstract]
   
   
3. von Wasielewski R, Mengel M, Fischer R, et al.: Classical Hodgkin's disease. Clinical impact of the immunophenotype. Am J Pathol 151 (4): 1123-30, 1997.  [PUBMED Abstract]
   
   
4. Bodis S, Kraus MD, Pinkus G, et al.: Clinical presentation and outcome in lymphocyte-predominant Hodgkin's disease. J Clin Oncol 15 (9): 3060-6, 1997.  [PUBMED Abstract]
   
   
5. Orlandi E, Lazzarino M, Brusamolino E, et al.: Nodular lymphocyte predominance Hodgkin's disease: long-term observation reveals a continuous pattern of recurrence. Leuk Lymphoma 26 (3-4): 359-68, 1997.  [PUBMED Abstract]
   
   
6. Shimabukuro-Vornhagen A, Haverkamp H, Engert A, et al.: Lymphocyte-rich classical Hodgkin's lymphoma: clinical presentation and treatment outcome in 100 patients treated within German Hodgkin's Study Group trials. J Clin Oncol 23 (24): 5739-45, 2005.  [PUBMED Abstract]
   
   
7. Diehl V, Sextro M, Franklin J, et al.: Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin's Disease. J Clin Oncol 17 (3): 776-83, 1999.  [PUBMED Abstract]
   
   
8. Aster JC: Lymphocyte-predominant Hodgkin's disease: how little therapy is enough? J Clin Oncol 17 (3): 744-6, 1999.  [PUBMED Abstract]
   
   
9. Pellegrino B, Terrier-Lacombe MJ, Oberlin O, et al.: Lymphocyte-predominant Hodgkin's lymphoma in children: therapeutic abstention after initial lymph node resection--a Study of the French Society of Pediatric Oncology. J Clin Oncol 21 (15): 2948-52, 2003.  [PUBMED Abstract]
   
   

Back to Top

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.[2-4] The use of PET scans to assess response and define the use or avoidance of further treatment is under clinical evaluation.[5-9] 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).[8] Only further prospective studies can assess whether these results can be replicated and can result in improved outcomes by altering the therapeutic strategy.

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.[10-13] The staging classification that is currently used for HL was adopted in 1971 at the Ann Arbor Conference [14] with some modifications 18 years later from the Cotswolds 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.

 [Note: 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.

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.[15] Other investigators use a measurement of the maximum width of the mediastinal mass divided by the maximum intrathoracic diameter.[16]

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:[17]

• 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 favorable: Clinical stage III or IV with zero to three adverse risk factors listed below. Patients with advanced favorable disease have a 60% to 80% freedom-from-progression at 5 years from treatment with first-line chemotherapy.[18][Level of evidence: 3iiiDiii]
• Advanced unfavorable: Clinical stage III or IV with four or more adverse risk factors listed below.[18] Patients with advanced unfavorable disease showed a 42% to 51% freedom-from-progression at 5 years from treatment with first-line chemotherapy.[18][Level of evidence: 3iiiDiii]. 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:[18]
  • 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.

References

1. Lister TA, Crowther D, Sutcliffe SB, et al.: Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 7 (11): 1630-6, 1989.  [PUBMED Abstract]
   
   
2. Jerusalem G, Beguin Y, Fassotte MF, et al.: Whole-body positron emission tomography using 18F-fluorodeoxyglucose compared to standard procedures for staging patients with Hodgkin's disease. Haematologica 86 (3): 266-73, 2001.  [PUBMED Abstract]
   
   
3. Naumann R, Beuthien-Baumann B, Reiss A, et al.: Substantial impact of FDG PET imaging on the therapy decision in patients with early-stage Hodgkin's lymphoma. Br J Cancer 90 (3): 620-5, 2004.  [PUBMED Abstract]
   
   
4. Munker R, Glass J, Griffeth LK, et al.: Contribution of PET imaging to the initial staging and prognosis of patients with Hodgkin's disease. Ann Oncol 15 (11): 1699-704, 2004.  [PUBMED Abstract]
   
   
5. Weihrauch MR, Re D, Scheidhauer K, et al.: Thoracic positron emission tomography using 18F-fluorodeoxyglucose for the evaluation of residual mediastinal Hodgkin disease. Blood 98 (10): 2930-4, 2001.  [PUBMED Abstract]
   
   
6. Hutchings M, Loft A, Hansen M, et al.: FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 107 (1): 52-9, 2006.  [PUBMED Abstract]
   
   
7. Dann EJ, Bar-Shalom R, Tamir A, et al.: Risk-adapted BEACOPP regimen can reduce the cumulative dose of chemotherapy for standard and high-risk Hodgkin lymphoma with no impairment of outcome. Blood 109 (3): 905-9, 2007.  [PUBMED Abstract]
   
   
8. Gallamini A, Hutchings M, Rigacci L, et al.: Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study. J Clin Oncol 25 (24): 3746-52, 2007.  [PUBMED Abstract]
   
   
9. Advani R, Maeda L, Lavori P, et al.: Impact of positive positron emission tomography on prediction of freedom from progression after Stanford V chemotherapy in Hodgkin's disease. J Clin Oncol 25 (25): 3902-7, 2007.  [PUBMED Abstract]
   
   
10. Urba WJ, Longo DL: Hodgkin's disease. N Engl J Med 326 (10): 678-87, 1992.  [PUBMED Abstract]
    
    
11. Sombeck MD, Mendenhall NP, Kaude JV, et al.: Correlation of lymphangiography, computed tomography, and laparotomy in the staging of Hodgkin's disease. Int J Radiat Oncol Biol Phys 25 (3): 425-9, 1993.  [PUBMED Abstract]
    
    
12. Mauch P, Larson D, Osteen R, et al.: Prognostic factors for positive surgical staging in patients with Hodgkin's disease. J Clin Oncol 8 (2): 257-65, 1990.  [PUBMED Abstract]
    
    
13. Dietrich PY, Henry-Amar M, Cosset JM, et al.: Second primary cancers in patients continuously disease-free from Hodgkin's disease: a protective role for the spleen? Blood 84 (4): 1209-15, 1994.  [PUBMED Abstract]
    
    
14. Carbone PP, Kaplan HS, Musshoff K, et al.: Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res 31 (11): 1860-1, 1971.  [PUBMED Abstract]
    
    
15. Bradley AJ, Carrington BM, Lawrance JA, et al.: Assessment and significance of mediastinal bulk in Hodgkin's disease: comparison between computed tomography and chest radiography. J Clin Oncol 17 (8): 2493-8, 1999.  [PUBMED Abstract]
    
    
16. Mauch P, Goodman R, Hellman S: The significance of mediastinal involvement in early stage Hodgkin's disease. Cancer 42 (3): 1039-45, 1978.  [PUBMED Abstract]
    
    
17. Jost LM, Stahel RA; ESMO Guidelines Task Force.: ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of Hodgkin's disease. Ann Oncol 16 (Suppl 1): i54-5, 2005.  [PUBMED Abstract]
    
    
18. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med 339 (21): 1506-14, 1998.  [PUBMED Abstract]
    
    

Back to Top

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

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.[2-5] 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.

Acute nonlymphocytic leukemia may occur in patients treated with combined modality therapy or with combination chemotherapy alone.[6-8] 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, colon and rectum, uterine cervix, head and neck, and mesothelioma.[7,10-15] 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%.[10,16] 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.[15]

Lung cancer is seen with increased frequency, even after chemotherapy alone, and the risk of this cancer is increased with cigarette smoking.[17-20] Breast cancer is seen with increased frequency after radiation therapy or combined modality therapy.[10,12,14,21-24] The risk appears greatest for women treated with radiation before age 30 years, and the incidence increases substantially after 15 years of follow-up.[10,13,25,26] 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.[27] 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.[28] 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.[22] Reaching menopause before age 36 years 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.[29-31] 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.[32]

A toxic effect that is primarily related to chemotherapy is infertility, usually after MOPP-containing or BEACOPP-containing regimens;[11,33,34] ABVD appears to spare long-term testicular and ovarian function.[34,35] Late complications primarily related to radiation therapy include hypothyroidism and cardiac disease, which may persist through to 25 years after first treatment.[36-41] 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).[37-39,41] 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.[38] 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.[41] 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.[42] Pulmonary toxic effects from bleomycin as used in ABVD are seen in older patients (especially those older than 40 years).[43] Avascular necrosis of bone has been observed in patients treated with chemotherapy and is most likely related to corticosteroid therapy.[44] Bacterial sepsis may occur rarely after splenectomy performed during staging laparotomy for HL;[45] 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.[46] Some investigators recommend reimmunization with all three vaccines 2 years after completion of treatment and with pneumococcal vaccine every 6 years thereafter.[47]

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.[48]

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.[49,50]

References

1. Advani RH, Horning SJ: Treatment of early-stage Hodgkin's disease. Semin Hematol 36 (3): 270-81, 1999.  [PUBMED Abstract]
   
   
2. Sears JD, Greven KM, Ferree CR, et al.: Definitive irradiation in the treatment of Hodgkin's disease. Analysis of outcome, prognostic factors, and long-term complications. Cancer 79 (1): 145-51, 1997.  [PUBMED Abstract]
   
   
3. Ng AK, Mauch PM: Radiation therapy in Hodgkin's lymphoma. Semin Hematol 36 (3): 290-302, 1999.  [PUBMED Abstract]
   
   
4. Dühmke E, Franklin J, Pfreundschuh M, et al.: Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin's disease: long-term results of a randomized trial of radiotherapy alone. J Clin Oncol 19 (11): 2905-14, 2001.  [PUBMED Abstract]
   
   
5. Mendenhall NP, Rodrigue LL, Moore-Higgs GJ, et al.: The optimal dose of radiation in Hodgkin's disease: an analysis of clinical and treatment factors affecting in-field disease control. Int J Radiat Oncol Biol Phys 44 (3): 551-61, 1999.  [PUBMED Abstract]
   
   
6. Valagussa P, Santoro A, Fossati-Bellani F, et al.: Second acute leukemia and other malignancies following treatment for Hodgkin's disease. J Clin Oncol 4 (6): 830-7, 1986.  [PUBMED Abstract]
   
   
7. Hancock SL, Hoppe RT: Long-Term Complications of Treatment and Causes of Mortality After Hodgkin's Disease. Semin Radiat Oncol 6 (3): 225-242, 1996.  [PUBMED Abstract]
   
   
8. van Leeuwen FE, Chorus AM, van den Belt-Dusebout AW, et al.: Leukemia risk following Hodgkin's disease: relation to cumulative dose of alkylating agents, treatment with teniposide combinations, number of episodes of chemotherapy, and bone marrow damage. J Clin Oncol 12 (5): 1063-73, 1994.  [PUBMED Abstract]
   
   
9. Schonfeld SJ, Gilbert ES, Dores GM, et al.: Acute myeloid leukemia following Hodgkin lymphoma: a population-based study of 35,511 patients. J Natl Cancer Inst 98 (3): 215-8, 2006.  [PUBMED Abstract]
   
   
10. Dores GM, Metayer C, Curtis RE, et al.: Second malignant neoplasms among long-term survivors of Hodgkin's disease: a population-based evaluation over 25 years. J Clin Oncol 20 (16): 3484-94, 2002.  [PUBMED Abstract]
    
    
11. Swerdlow AJ, Douglas AJ, Hudson GV, et al.: Risk of second primary cancers after Hodgkin's disease by type of treatment: analysis of 2846 patients in the British National Lymphoma Investigation. BMJ 304 (6835): 1137-43, 1992.  [PUBMED Abstract]
    
    
12. Yahalom J, Petrek JA, Biddinger PW, et al.: Breast cancer in patients irradiated for Hodgkin's disease: a clinical and pathologic analysis of 45 events in 37 patients. J Clin Oncol 10 (11): 1674-81, 1992.  [PUBMED Abstract]
    
    
13. Mauch PM, Kalish LA, Marcus KC, et al.: Second malignancies after treatment for laparotomy staged IA-IIIB Hodgkin's disease: long-term analysis of risk factors and outcome. Blood 87 (9): 3625-32, 1996.  [PUBMED Abstract]
    
    
14. Franklin J, Pluetschow A, Paus M, et al.: Second malignancy risk associated with treatment of Hodgkin's lymphoma: meta-analysis of the randomised trials. Ann Oncol 17 (12): 1749-60, 2006.  [PUBMED Abstract]
    
    
15. Hodgson DC, Gilbert ES, Dores GM, et al.: Long-term solid cancer risk among 5-year survivors of Hodgkin's lymphoma. J Clin Oncol 25 (12): 1489-97, 2007.  [PUBMED Abstract]
    
    
16. Bonadonna G, Viviani S, Bonfante V, et al.: Survival in Hodgkin's disease patients--report of 25 years of experience at the Milan Cancer Institute. Eur J Cancer 41 (7): 998-1006, 2005.  [PUBMED Abstract]
    
    
17. van Leeuwen FE, Klokman WJ, Stovall M, et al.: Roles of radiotherapy and smoking in lung cancer following Hodgkin's disease. J Natl Cancer Inst 87 (20): 1530-7, 1995.  [PUBMED Abstract]
    
    
18. Swerdlow AJ, Schoemaker MJ, Allerton R, et al.: Lung cancer after Hodgkin's disease: a nested case-control study of the relation to treatment. J Clin Oncol 19 (6): 1610-8, 2001.  [PUBMED Abstract]
    
    
19. Travis LB, Gospodarowicz M, Curtis RE, et al.: Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease. J Natl Cancer Inst 94 (3): 182-92, 2002.  [PUBMED Abstract]
    
    
20. Lorigan P, Radford J, Howell A, et al.: Lung cancer after treatment for Hodgkin's lymphoma: a systematic review. Lancet Oncol 6 (10): 773-9, 2005.  [PUBMED Abstract]
    
    
21. Cutuli B, Dhermain F, Borel C, et al.: Breast cancer in patients treated for Hodgkin's disease: clinical and pathological analysis of 76 cases in 63 patients. Eur J Cancer 33 (14): 2315-20, 1997.  [PUBMED Abstract]
    
    
22. van Leeuwen FE, Klokman WJ, Stovall M, et al.: Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin's disease. J Natl Cancer Inst 95 (13): 971-80, 2003.  [PUBMED Abstract]
    
    
23. Wahner-Roedler DL, Nelson DF, Croghan IT, et al.: Risk of breast cancer and breast cancer characteristics in women treated with supradiaphragmatic radiation for Hodgkin lymphoma: Mayo Clinic experience. Mayo Clin Proc 78 (6): 708-15, 2003.  [PUBMED Abstract]
    
    
24. Travis LB, Hill DA, Dores GM, et al.: Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 290 (4): 465-75, 2003.  [PUBMED Abstract]
    
    
25. Hancock SL, Tucker MA, Hoppe RT: Breast cancer after treatment of Hodgkin's disease. J Natl Cancer Inst 85 (1): 25-31, 1993.  [PUBMED Abstract]
    
    
26. Sankila R, Garwicz S, Olsen JH, et al.: Risk of subsequent malignant neoplasms among 1,641 Hodgkin's disease patients diagnosed in childhood and adolescence: a population-based cohort study in the five Nordic countries. Association of the Nordic Cancer Registries and the Nordic Society of Pediatric Hematology and Oncology. J Clin Oncol 14 (5): 1442-6, 1996.  [PUBMED Abstract]
    
    
27. Travis LB, Hill D, Dores GM, et al.: Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl Cancer Inst 97 (19): 1428-37, 2005.  [PUBMED Abstract]
    
    
28. Hill DA, Gilbert E, Dores GM, et al.: Breast cancer risk following radiotherapy for Hodgkin lymphoma: modification by other risk factors. Blood 106 (10): 3358-65, 2005.  [PUBMED Abstract]
    
    
29. Dietrich PY, Henry-Amar M, Cosset JM, et al.: Second primary cancers in patients continuously disease-free from Hodgkin's disease: a protective role for the spleen? Blood 84 (4): 1209-15, 1994.  [PUBMED Abstract]
    
    
30. van der Velden JW, van Putten WL, Guinee VF, et al.: Subsequent development of acute non-lymphocytic leukemia in patients treated for Hodgkin's disease. Int J Cancer 42 (2): 252-5, 1988.  [PUBMED Abstract]
    
    
31. Kaldor JM, Day NE, Clarke EA, et al.: Leukemia following Hodgkin's disease. N Engl J Med 322 (1): 7-13, 1990.  [PUBMED Abstract]
    
    
32. Lavoie JC, Connors JM, Phillips GL, et al.: High-dose chemotherapy and autologous stem cell transplantation for primary refractory or relapsed Hodgkin lymphoma: long-term outcome in the first 100 patients treated in Vancouver. Blood 106 (4): 1473-8, 2005.  [PUBMED Abstract]
    
    
33. Behringer K, Breuer K, Reineke T, et al.: Secondary amenorrhea after Hodgkin's lymphoma is influenced by age at treatment, stage of disease, chemotherapy regimen, and the use of oral contraceptives during therapy: a report from the German Hodgkin's Lymphoma Study Group. J Clin Oncol 23 (30): 7555-64, 2005.  [PUBMED Abstract]
    
    
34. van der Kaaij MA, Heutte N, Le Stang N, et al.: Gonadal function in males after chemotherapy for early-stage Hodgkin's lymphoma treated in four subsequent trials by the European Organisation for Research and Treatment of Cancer: EORTC Lymphoma Group and the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 25 (19): 2825-32, 2007.  [PUBMED Abstract]
    
    
35. Viviani S, Santoro A, Ragni G, et al.: Pre- and post-treatment testicular dysfunction in Hodgkin's disease (HD). [Abstract] Proceedings of the American Society of Clinical Oncology 7: A-877, 227, 1988. 
    
    
36. Tarbell NJ, Thompson L, Mauch P: Thoracic irradiation in Hodgkin's disease: disease control and long-term complications. Int J Radiat Oncol Biol Phys 18 (2): 275-81, 1990.  [PUBMED Abstract]
    
    
37. Reinders JG, Heijmen BJ, Olofsen-van Acht MJ, et al.: Ischemic heart disease after mantlefield irradiation for Hodgkin's disease in long-term follow-up. Radiother Oncol 51 (1): 35-42, 1999.  [PUBMED Abstract]
    
    
38. Hancock SL, Tucker MA, Hoppe RT: Factors affecting late mortality from heart disease after treatment of Hodgkin's disease. JAMA 270 (16): 1949-55, 1993.  [PUBMED Abstract]
    
    
39. Heidenreich PA, Schnittger I, Strauss HW, et al.: Screening for coronary artery disease after mediastinal irradiation for Hodgkin's disease. J Clin Oncol 25 (1): 43-9, 2007.  [PUBMED Abstract]
    
    
40. Dabaja B, Cox JD, Buchholz TA: Radiation therapy can still be used safely in combined modality approaches in patients with Hodgkin's lymphoma. J Clin Oncol 25 (1): 3-5, 2007.  [PUBMED Abstract]
    
    
41. Swerdlow AJ, Higgins CD, Smith P, et al.: Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study. J Natl Cancer Inst 99 (3): 206-14, 2007.  [PUBMED Abstract]
    
    
42. Horning SJ, Adhikari A, Rizk N, et al.: Effect of treatment for Hodgkin's disease on pulmonary function: results of a prospective study. J Clin Oncol 12 (2): 297-305, 1994.  [PUBMED Abstract]
    
    
43. Martin WG, Ristow KM, Habermann TM, et al.: Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin's lymphoma. J Clin Oncol 23 (30): 7614-20, 2005.  [PUBMED Abstract]
    
    
44. Prosnitz LR, Lawson JP, Friedlaender GE, et al.: Avascular necrosis of bone in Hodgkin's disease patients treated with combined modality therapy. Cancer 47 (12): 2793-7, 1981.  [PUBMED Abstract]
    
    
45. Schimpff SC, O'Connell MJ, Greene WH, et al.: Infections in 92 splenectomized patients with Hodgkin's disease. A clinical review. Am J Med 59 (5): 695-701, 1975.  [PUBMED Abstract]
    
    
46. Recommendations of the Advisory Committee on Immunization Practices (ACIP): use of vaccines and immune globulins for persons with altered immunocompetence. MMWR Recomm Rep 42 (RR-4): 1-18, 1993.  [PUBMED Abstract]
    
    
47. Molrine DC, George S, Tarbell N, et al.: Antibody responses to polysaccharide and polysaccharide-conjugate vaccines after treatment of Hodgkin disease. Ann Intern Med 123 (11): 828-34, 1995.  [PUBMED Abstract]
    
    
48. Loge JH, Abrahamsen AF, Ekeberg O, et al.: Hodgkin's disease survivors more fatigued than the general population. J Clin Oncol 17 (1): 253-61, 1999.  [PUBMED Abstract]
    
    
49. Ballova V, Rüffer JU, Haverkamp H, et al.: A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin's disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly). Ann Oncol 16 (1): 124-31, 2005.  [PUBMED Abstract]
    
    
50. Engert A, Ballova V, Haverkamp H, et al.: Hodgkin's lymphoma in elderly patients: a comprehensive retrospective analysis from the German Hodgkin's Study Group. J Clin Oncol 23 (22): 5052-60, 2005.  [PUBMED Abstract]
    
    

Back to Top

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 plus bleomycin plus vinblastine.
• ABVD: doxorubicin plus bleomycin plus vinblastine plus dacarbazine (1 cycle = 1 month of therapy).
• AV: doxorubicin plus vinblastine.
• AVD: doxorubicin plus vinblastine plus dacarbazine.
• MOPP-ABV: mechlorethamine plus vincristine plus procarbazine plus prednisone plus doxorubicin plus bleomycin plus vincristine.

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. A randomized prospective trial involving 542 patients with early favorable HL compared MOPP-ABV for three cycles plus involved-field radiation therapy (IF-XRT) with subtotal nodal radiation; with a median follow-up of 7.7 years, combined modality was favored in terms of 5-year event-free survival (98% vs. 74%, P < .001) and 10-year overall survival (97% vs. 92%, P = .001).[1][Level of evidence: 1iiA]The late mortality from solid tumors, especially in the lung, breast, gastrointestinal tract, and connective tissue, and from cardiovascular disease makes radiation therapy a less attractive option for the best-risk patients, who have the highest probability of cure and long-term survival.[2-6] 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 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).[7][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.[8][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.[9][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.[10] 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.[11][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.[12] Patients with nonbulky nodular sclerosing disease presenting in the anterior mediastinum only after clinical staging also do well with mantle radiation alone.[13]

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.[14]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References

1. Fermé C, Eghbali H, Meerwaldt JH, et al.: Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med 357 (19): 1916-27, 2007.  [PUBMED Abstract]
   
   
2. Dores GM, Metayer C, Curtis RE, et al.: Second malignant neoplasms among long-term survivors of Hodgkin's disease: a population-based evaluation over 25 years. J Clin Oncol 20 (16): 3484-94, 2002.  [PUBMED Abstract]
   
   
3. Reinders JG, Heijmen BJ, Olofsen-van Acht MJ, et al.: Ischemic heart disease after mantlefield irradiation for Hodgkin's disease in long-term follow-up. Radiother Oncol 51 (1): 35-42, 1999.  [PUBMED Abstract]
   
   
4. Longo DL: Radiation therapy in Hodgkin disease: why risk a Pyrrhic victory? J Natl Cancer Inst 97 (19): 1394-5, 2005.  [PUBMED Abstract]
   
   
5. Swerdlow AJ, Higgins CD, Smith P, et al.: Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study. J Natl Cancer Inst 99 (3): 206-14, 2007.  [PUBMED Abstract]
   
   
6. Engert A, Franklin J, Eich HT, et al.: Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin's lymphoma: final results of the GHSG HD7 trial. J Clin Oncol 25 (23): 3495-502, 2007.  [PUBMED Abstract]
   
   
7. Meyer RM, Gospodarowicz MK, Connors JM, et al.: Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol 23 (21): 4634-42, 2005.  [PUBMED Abstract]
   
   
8. Bonadonna G, Bonfante V, Viviani S, et al.: ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin's disease: long-term results. J Clin Oncol 22 (14): 2835-41, 2004.  [PUBMED Abstract]
   
   
9. Engert A, Pluetschow A, Eich H, et al.: Combined modality treatment of two or four cycles of ABVD followed by involved field radiotherapy in the treatment of patients with early stage Hodgkin's lymphoma: update interim analysis of the randomised HD10 study of the German Hodgkin Study Group. [Abstract] Blood 106: A-2673, 2005. 
   
   
10. Russell KJ, Hoppe RT, Colby TV, et al.: Lymphocyte predominant Hodgkin's disease: clinical presentation and results of treatment. Radiother Oncol 1 (3): 197-205, 1984.  [PUBMED Abstract]
    
    
11. Diehl V, Sextro M, Franklin J, et al.: Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin's Disease. J Clin Oncol 17 (3): 776-83, 1999.  [PUBMED Abstract]
    
    
12. Aster JC: Lymphocyte-predominant Hodgkin's disease: how little therapy is enough? J Clin Oncol 17 (3): 744-6, 1999.  [PUBMED Abstract]
    
    
13. Backstrand KH, Ng AK, Takvorian RW, et al.: Results of a prospective trial of mantle irradiation alone for selected patients with early-stage Hodgkin's disease. J Clin Oncol 19 (3): 736-41, 2001.  [PUBMED Abstract]
    
    
14. Landgren O, Axdorph U, Fears TR, et al.: A population-based cohort study on early-stage Hodgkin lymphoma treated with radiotherapy alone: with special reference to older patients. Ann Oncol 17 (8): 1290-5, 2006.  [PUBMED Abstract]
    
    

Back to Top

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

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.[2-6]

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).[7][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.[8][Level of evidence: 1iiDiii]

In a randomized study from the Milan Cancer Institute of patients with clinical early-stage Hodgkin lymphoma, 4 months of ABVD followed by either IF-XRT or EF-XRT showed similar OS and freedom-from-progression with 10 years' median follow-up, but the study had inadequate statistical power to determine noninferiority of IF-XRT versus EF-XRT.[9][Level of evidence: 1iiDii] Similarly, in a randomized study from the German Hodgkin Lymphoma Study Group (GHSG) of more than 1,000 patients with early unfavorable HL, 4 months of COPP plus ABVD followed by IF-XRT versus EF-XRT showed equivalent OS and freedom-from-treatment failure with 5 years' median follow-up.[10][Level of evidence: 1iiA] Another randomized study of 996 patients with early unfavorable HL also showed no difference in OS and event-free survival at 10 years comparing four to six cycles of MOPP-ABV plus IF-XRT versus the same chemotherapy plus subtotal nodal radiation therapy.[11][Level of evidence: 1iiA]

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.[12][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).[13][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.[7] 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.[14,15][Level of evidence: 3iiiDiii]

Treatment options:

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

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References

1. Tubiana M, Henry-Amar M, Carde P, et al.: Toward comprehensive management tailored to prognostic factors of patients with clinical stages I and II in Hodgkin's disease. The EORTC Lymphoma Group controlled clinical trials: 1964-1987. Blood 73 (1): 47-56, 1989.  [PUBMED Abstract]
   
   
2. Dores GM, Metayer C, Curtis RE, et al.: Second malignant neoplasms among long-term survivors of Hodgkin's disease: a population-based evaluation over 25 years. J Clin Oncol 20 (16): 3484-94, 2002.  [PUBMED Abstract]
   
   
3. Reinders JG, Heijmen BJ, Olofsen-van Acht MJ, et al.: Ischemic heart disease after mantlefield irradiation for Hodgkin's disease in long-term follow-up. Radiother Oncol 51 (1): 35-42, 1999.  [PUBMED Abstract]
   
   
4. Longo DL: Radiation therapy in Hodgkin disease: why risk a Pyrrhic victory? J Natl Cancer Inst 97 (19): 1394-5, 2005.  [PUBMED Abstract]
   
   
5. Swerdlow AJ, Higgins CD, Smith P, et al.: Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study. J Natl Cancer Inst 99 (3): 206-14, 2007.  [PUBMED Abstract]
   
   
6. Engert A, Franklin J, Eich HT, et al.: Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin's lymphoma: final results of the GHSG HD7 trial. J Clin Oncol 25 (23): 3495-502, 2007.  [PUBMED Abstract]
   
   
7. Meyer RM, Gospodarowicz MK, Connors JM, et al.: Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol 23 (21): 4634-42, 2005.  [PUBMED Abstract]
   
   
8. Press OW, LeBlanc M, Lichter AS, et al.: Phase III randomized intergroup trial of subtotal lymphoid irradiation versus doxorubicin, vinblastine, and subtotal lymphoid irradiation for stage IA to IIA Hodgkin's disease. J Clin Oncol 19 (22): 4238-44, 2001.  [PUBMED Abstract]
   
   
9. Bonadonna G, Bonfante V, Viviani S, et al.: ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin's disease: long-term results. J Clin Oncol 22 (14): 2835-41, 2004.  [PUBMED Abstract]
   
   
10. Engert A, Schiller P, Josting A, et al.: Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol 21 (19): 3601-8, 2003.  [PUBMED Abstract]
    
    
11. Fermé C, Eghbali H, Meerwaldt JH, et al.: Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med 357 (19): 1916-27, 2007.  [PUBMED Abstract]
    
    
12. Diehl V, Brillant C, Engert A, et al.: Recent interim analysis of the HD11 trial of the GHSG: intensification of chemotherapy and reduction of radiation dose in early unfavorable stage Hodgkin's lymphoma. [Abstract] Blood 106 (11): A-816, 2005. 
    
    
13. Noordijk EM, Thomas J, Fermé C, et al.: First results of the EORTC-GELA H9 randomized trials: the H9-F trial (comparing 3 radiation dose levels) and H9-U trial (comparing 3 chemotherapy schemes) in patients with favorable or unfavorable early stag