Advanced Unfavorable HL
Drug combinations described in this section include the following:
- ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine.
- BEACOPP: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone.
- CEC: cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, and bleomycin.
- COPP/ABVD: cyclophosphamide, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine.
- MOPP: mechlorethamine, vincristine, procarbazine, and prednisone.
- MOPP alternating with ABVD: mechlorethamine, vincristine, procarbazine, prednisone alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine.
- MOPP/ABV hybrid: mechlorethamine, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, and vinblastine.
- Stanford V: doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone.
Patients are designated as having advanced unfavorable Hodgkin lymphoma (HL) if they have clinical stage III or stage IV disease and four or more risk factors on the International Prognostic Index for HL, which corresponds to a freedom-from-progression at worse than 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.[13-15][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]
Treatment options include the following:
- ABVD for six to eight cycles.
- BEACOPP (increased dose).
Current Clinical Trials
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.
General information about clinical trials is also available from the NCI Web site.
- Moccia AA, Donaldson J, Chhanabhai M, et al.: International Prognostic Score in advanced-stage Hodgkin's lymphoma: altered utility in the modern era. J Clin Oncol 30 (27): 3383-8, 2012. [PUBMED Abstract]
- Canellos GP, Anderson JR, Propert KJ, et al.: Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327 (21): 1478-84, 1992. [PUBMED Abstract]
- Canellos GP, Niedzwiecki D: Long-term follow-up of Hodgkin's disease trial. N Engl J Med 346 (18): 1417-8, 2002. [PUBMED Abstract]
- Duggan DB, Petroni GR, Johnson JL, et al.: Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an intergroup trial. J Clin Oncol 21 (4): 607-14, 2003. [PUBMED Abstract]
- Engert A, Diehl V, Franklin J, et al.: Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin's lymphoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol 27 (27): 4548-54, 2009. [PUBMED Abstract]
- Engert A, Haverkamp H, Kobe C, et al.: Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet 379 (9828): 1791-9, 2012. [PUBMED Abstract]
- Federico M, Luminari S, Iannitto E, et al.: ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin's lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol 27 (5): 805-11, 2009. [PUBMED Abstract]
- Viviani S, Zinzani PL, Rambaldi A, et al.: ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned. N Engl J Med 365 (3): 203-12, 2011. [PUBMED Abstract]
- Scholz M, Engert A, Franklin J, et al.: Impact of first- and second-line treatment for Hodgkin's lymphoma on the incidence of AML/MDS and NHL--experience of the German Hodgkin's Lymphoma Study Group analyzed by a parametric model of carcinogenesis. Ann Oncol 22 (3): 681-8, 2011. [PUBMED Abstract]
- Bauer K, Skoetz N, Monsef I, et al.: Comparison of chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for patients with early unfavourable or advanced stage Hodgkin lymphoma. Cochrane Database Syst Rev (8): CD007941, 2011. [PUBMED Abstract]
- Hoskin PJ, Lowry L, Horwich A, et al.: Randomized comparison of the stanford V regimen and ABVD in the treatment of advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. J Clin Oncol 27 (32): 5390-6, 2009. [PUBMED Abstract]
- Chisesi T, Bellei M, Luminari S, et al.: Long-term follow-up analysis of HD9601 trial comparing ABVD versus Stanford V versus MOPP/EBV/CAD in patients with newly diagnosed advanced-stage Hodgkin's lymphoma: a study from the Intergruppo Italiano Linfomi. J Clin Oncol 29 (32): 4227-33, 2011. [PUBMED Abstract]
- Fabian CJ, Mansfield CM, Dahlberg S, et al.: Low-dose involved field radiation after chemotherapy in advanced Hodgkin disease. A Southwest Oncology Group randomized study. Ann Intern Med 120 (11): 903-12, 1994. [PUBMED Abstract]
- Aleman BM, Raemaekers JM, Tirelli U, et al.: Involved-field radiotherapy for advanced Hodgkin's lymphoma. N Engl J Med 348 (24): 2396-406, 2003. [PUBMED Abstract]
- Fermé C, Mounier N, Casasnovas O, et al.: Long-term results and competing risk analysis of the H89 trial in patients with advanced-stage Hodgkin lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 107 (12): 4636-42, 2006. [PUBMED Abstract]
- Loeffler M, Brosteanu O, Hasenclever D, et al.: Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin's disease. International Database on Hodgkin's Disease Overview Study Group. J Clin Oncol 16 (3): 818-29, 1998. [PUBMED Abstract]
- Kobe C, Dietlein M, Franklin J, et al.: Positron emission tomography has a high negative predictive value for progression or early relapse for patients with residual disease after first-line chemotherapy in advanced-stage Hodgkin lymphoma. Blood 112 (10): 3989-94, 2008. [PUBMED Abstract]
- Brice P, Colin P, Berger F, et al.: Advanced Hodgkin disease with large mediastinal involvement can be treated with eight cycles of chemotherapy alone after a major response to six cycles of chemotherapy: a study of 82 patients from the Groupes d'Etudes des Lymphomes de l'Adulte H89 trial. Cancer 92 (3): 453-9, 2001. [PUBMED Abstract]
- Gallamini A, Patti C, Viviani S, et al.: Early chemotherapy intensification with BEACOPP in advanced-stage Hodgkin lymphoma patients with a interim-PET positive after two ABVD courses. Br J Haematol 152 (5): 551-60, 2011. [PUBMED Abstract]
- Federico M, Bellei M, Brice P, et al.: High-dose therapy and autologous stem-cell transplantation versus conventional therapy for patients with advanced Hodgkin's lymphoma responding to front-line therapy. J Clin Oncol 21 (12): 2320-5, 2003. [PUBMED Abstract]