At the Pan Pacific Lymphoma Conference, held this year in Maui, Hawaii, Andreas Engert, MD, Chairman of the German Hodgkin Study Group, University Hospital of Cologne, Germany, led off the Hodgkin lymphoma section of the conference with a presentation on optimizing the use of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine [Matulane], prednisone) in Hodgkin lymphoma patients. The ASCO Post invited Prof. Engert to elaborate on the selection of patients for first-line BEACOPP.
Hodgkin lymphoma has become one of the most curable malignancies, due to substantial improvements in radiotherapy and the introduction of multiagent chemotherapy. Hodgkin lymphoma survivors constitute one of the largest groups of cancer survivors in Western countries. Depending on the choice and dose of treatment, these patients face some risk of treatment-related toxicities, including secondary neoplasia, organ damage, infertility, and psychosocial problems. Thus, there is an ongoing discussion on the best choice of treatment for these patients.
The combination chemotherapy ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) is regarded as standard of care for Hodgkin lymphoma patients in many countries. While this is not disputed for most early-stage patients, those in advanced stages have a poorer prognosis when treated with ABVD, with a reported failure-free survival at 5 years ranging from 63% to 66% in multicenter trials.1,2
In contrast, the more-recently developed multiagent regimen BEACOPP in its escalated-dose version (BEACOPPesc) has given more impressive results, with tumor control rates at 5 years of 87% and overall survival rates of 91%.3 Since BEACOPPesc is associated with more treatment-related toxicity, there is an ongoing discussion as to which patients should be treated with BEACOPPesc when diagnosed with Hodgkin lymphoma in advanced stages.
Escalated BEACOPP
The BEACOPP regimen was developed by the German Hodgkin Study Group (GHSG) to increase dose density of chemotherapy as compared with ABVD and other regimens used in advanced-stage Hodgkin lymphoma. The pivotal GHSG HD9 trial compared the alternating regimen COPP (cyclophosphamide, vincristine, procarbazine, prednisone)/ABVD with BEACOPP using baseline doses (BEACOPPbase) and escalated doses. This trial showed a significant advantage in terms of tumor control and overall survival for BEACOPPesc over both BEACOPPbase and COPP/ABVD at 5 years.3
These results were confirmed in the follow-up analysis at 10 years.4 BEACOPPesc was associated with higher hematologic toxicity compared with BEACOPPbase or COPP/ABVD and induced more infertility in both male and female patients. In addition, the rate of secondary acute myeloid leukemia (AML) was higher with BEACOPPesc.
The GHSG follow-up studies for patients with advanced-stage Hodgkin lymphoma thus focused on reducing intensity of treatment while maintaining efficacy. Although the GHSG HD12 trial failed to demonstrate that four cycles of BEACOPPesc followed by four cycles of BEACOPPbase were less toxic than eight cycles of BEACOPPesc, this trial gave a clear signal that additional radiotherapy might not be needed in the majority of patients.5
In the GHSG HD15 follow-up trial for this group of patients, the old standard of eight cycles of BEACOPPesc was thus compared with just six cycles of BEACOPPesc or eight cycles of BEACOPPbase (BEACOPP-14). Only responding patients with a persistent mass after chemotherapy measuring 2.5 cm or larger and positive on PET scan received additional radiotherapy. A total of 2,182 patients were enrolled between January 2003 and April 2008; 408 hospitals and practices in Germany, Czech Republic, Switzerland, The Netherlands, and Austria recruited and treated patients in the study.
The 5-year freedom from treatment failure rates were 84% for eight cycles of BEACOPPesc, 89.3% for six cycles of BEACOPPesc, and 85.4% for BEACOPP-14. The difference between eight and six cycles of BEACOPPesc was significant (P = .009). In addition, overall survival was better with six cycles compared with eight cycles of BEACOPPesc (95.3% vs 91.9%, P = .02). Importantly, six cycles of BEACOPPesc were also less toxic compared with eight cycles: the treatment-related mortality was 0.8% vs 2.1%, and mortality related to secondary neoplasia was 0.7% vs 1.8%. Overall, 0.3% of patients treated with six cycles of BEACOPPesc experienced secondary AML/myelodysplastic syndrome, compared with 2.7% of patients treated with eight cycles of BEACOPPesc.
Thus, six cycles of BEACOPPesc constitutes the new standard of care in most European countries, and this regimen has been incorporated in more-recently initiated studies by the European Organisation for Research and Treatment of Cancer (H11 trial) and the Groupe d’Etude des Lymphomes de l’Adulte (GELA)/Nordic group.
PET-driven Trials
The metabolic activity of tissue affected with Hodgkin lymphoma can be measured by PET. Initial retrospective studies such as the one by Hutchings and coworkers6 suggest that the metabolic activity as measured by PET after two cycles of ABVD has prognostic impact for Hodgkin lymphoma patients. Thus, most current clinical trials use PET in order to identify good- or poor-risk patients early in the course of treatment.
It is not surprising that most of the ongoing randomized clinical trials in patients with advanced-stage Hodgkin lymphoma are risk-adapted—ie, PET-negative patients receive less treatment, and PET-positive patients are being escalated. Possible designs include one or two initial cycles of BEACOPPesc followed by ABVD (Kairos Principle) in PET-negative patients, with PET-positive patients continuing on BEACOPPesc.
There are indications, however, that the capacity of PET to correctly predict outcome might have been overestimated in smaller retrospective studies. We still have to wait for the results of ongoing randomized trials in order to more precisely tailor treatment for advanced-stage Hodgkin lymphoma patients. In addition, a number of clinical risk factors and other biomarkers are being evaluated for their role in monitoring treatment outcome in this population.
Which Patients Are the Best Candidates for BEACOPP?
In the pivotal GHSG HD9 study, patients with an International Prognostic Index score of 2 to 3, constituting the largest cohort of advanced-stage Hodgkin lymphoma patients, were those with significant advantages in both tumor control and overall survival.3 More-recent retrospective analyses of the treatment-related mortality associated with BEACOPPesc show an overall mortality of 1.8% (64 of 3,565), which compares favorably with treatment-related mortality reported from more-recent randomized trials of ABVD regimens.7
BEACOPPesc is more toxic in patients aged over 40 years, particularly if they have a poorer performance status (Eastern Cooperative Oncology Group score of 2 or Karnofsky score < 80%). Thus, these patients are not good candidates for treatment with six cycles of BEACOPPesc. In addition, there are clear guidelines as to BEACOPPesc dose reductions based on the toxicity observed in prior cycles. Groups having no experience with this treatment need to follow these predefined guidelines for dose reduction of BEACOPPesc in order to avoid unnecessary toxicity.8 ■
Disclosure: Dr. Engert reported no potential conflicts of interest.
References
1. 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 21:607-614, 2003.
2. Gordon LI, Hong F, Fisher RI, et al: A randomized phase III trial of ABVD vs Stanford V ± radiation therapy in locally extensive and advanced stage Hodgkin’s lymphoma: An intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). 52nd ASH Annual Meeting. Abstract 415. Presented December 6, 2010.
3. Diehl V, Franklin J, Pfreundschuh M, et al: Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med 348:2386-2395, 2003.
4. 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 27:4548-4554, 2009.
5. Borchmann P, Haverkamp H, Diehl V, et al: Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin’s lymphoma: Final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol 29:4234-4242, 2011.
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 107:52-59, 2006.
7. Wongso D, et al: In preparation, 2012.
8. Engert A, Diehl V, Franklin J, et al: Escalated-dose BEACOPP in the treatment of patient with advanced-stage Hodgkin’s lymphoma: 10 years of follow-up of the GHSG HD9 Study. J Clin Oncol 27:4548-4544, 2009.
Dr. Engert is Professor of Internal Medicine, Hematology and Oncology, Department of Internal Medicine I, Cologne University Hospital, Cologne, Germany.
