Early Unfavorable HL
Drug combinations described in this section include the following:
- ABVD: doxorubicin, bleomycin, vinblastine, and dacarbazine (1 cycle = 1 month of therapy).
- AV: doxorubicin and vinblastine.
- BEACOPP: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone.
- COPP/ABVD: cyclophosphamide, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine.
- MOPP/ABV: mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and 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 mm/h.
Patients with early unfavorable HL showed relapse rates greater than 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.[2-6]
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 with 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 with 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 HL, 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:
- 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 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:
- 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).[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 with 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]
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.
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- 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]
- Meyer RM, Gospodarowicz MK, Connors JM, et al.: ABVD alone versus radiation-based therapy in limited-stage Hodgkin's lymphoma. N Engl J Med 366 (5): 399-408, 2012. [PUBMED Abstract]
- 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]
- 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]
- 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]
- 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]
- Diehl V, Brillant C, Engert A, et al.: Recent interim analysis of the HD11 trial of the GHSG: intensification of chemotherapy and reduction of radiation dose in early unfavorable stage Hodgkin's lymphoma. [Abstract] Blood 106 (11): A-816, 2005.
- Eich HT, Diehl V, Görgen H, et al.: Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol 28 (27): 4199-206, 2010. [PUBMED Abstract]
- von Tresckow B, Plütschow A, Fuchs M, et al.: Dose-intensification in early unfavorable Hodgkin's lymphoma: final analysis of the German hodgkin study group HD14 trial. J Clin Oncol 30 (9): 907-13, 2012. [PUBMED Abstract]
- Noordijk EM, Thomas J, Fermé C, et al.: First results of the EORTC-GELA H9 randomized trials: the H9-F trial (comparing 3 radiation dose levels) and H9-U trial (comparing 3 chemotherapy schemes) in patients with favorable or unfavorable early stage Hodgkin's lymphoma (HL) . [Abstract] J Clin Oncol 23 (Suppl 16): A-6505, 561s, 2005.
- Canellos GP, Abramson JS, Fisher DC, et al.: Treatment of favorable, limited-stage Hodgkin's lymphoma with chemotherapy without consolidation by radiation therapy. J Clin Oncol 28 (9): 1611-5, 2010. [PUBMED Abstract]
- Bar Ad V, Paltiel O, Glatstein E: Radiotherapy for early-stage Hodgkin's lymphoma: a 21st century perspective and review of multiple randomized clinical trials. Int J Radiat Oncol Biol Phys 72 (5): 1472-9, 2008. [PUBMED Abstract]
- Meyer RM, Hoppe RT: Point/counterpoint: early-stage Hodgkin lymphoma and the role of radiation therapy. Blood 120 (23): 4488-95, 2012. [PUBMED Abstract]
- Herbst C, Rehan FA, Skoetz N, et al.: Chemotherapy alone versus chemotherapy plus radiotherapy for early stage Hodgkin lymphoma. Cochrane Database Syst Rev (2): CD007110, 2011. [PUBMED Abstract]
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