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© 2003 American Society for Clinical Oncology
Advanced Hodgkin’s Disease: ABVD Is Better, Yet Is Not Good Enough!University of Cologne, Cologne, Germany DURING THE last 60 years, Hodgkin’s disease (HD) has developed from being a fatal disease to being one of the most curable human cancers in adults. Despite remarkable clinical progress in the care and cure of HD, up to the end of the 1980s, little was known about the biology, etiology, and epidemiology of this rare tumor, which preferentially occurs in young adults. It was even debated until 1995 whether the pathognomonic Reed-Sternberg cell (RSC) was a polyclonal reactive cell or a truly monoclonal tumor cell.1 Since the introduction of the single-cell microdissection technique, it is known that the RSC is a monoclonal, preapoptotic, germinal center derived B lymphocyte2 that is inhibited to undergo programmed cell death by a number of constitutively expressed transcription factors like NFkB, Stat3, Notch1, and highly expressed cFlip molecules.3 The master switch that turns the normal B lymphocyte into a malignant cell, however, is unknown thus far. Many insights into the biologic behavior and the molecular changes within and around the tumor cell and its reactive microenvironment have been obtained from in vitro cell cultures and single-cell microdissection studies. From these sources, it seems that the tumor cells are fragile, radio- and chemosensitive, genetically unstable, and tend to regrow rapidly or develop early secondary resistance on re-exposure to cytotoxic agents. From studies with sequential biopsy material from the same patient, it is known that tumor cells, if not killed by the first therapeutic attack, progress, expand, and recur clonally, but mostly with additional multiple somatic mutations, leading to genetic diversity and phenotypic heterogeneity or even to a secondary non-Hodgkin’s lymphoma, arising from the same clonally related primary tumor cell that gave rise to Hodgkin’s lymphoma.4 Many of these biologic features of the RSCs explain the success in clinical research on HD, mainly in early stages of the disease. However, they also give hints for better understanding some of the negative results of clinical trials undertaken during the last three decades, especially in advanced and relapsing HD. Whereas tumors that were localized at diagnosis could already be controlled to a considerable degree by radiotherapy in the 1960s, advanced stages and bulky masses of HD were either refractory or relapsed after radiotherapy alone. Results of prospective multicenter trials using the traditional standard regimens of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP); doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); or alternating, sequential, or hybrid combinations of these two effective, non–cross-resistant drug regimens, mostly assisted by additive radiotherapy, have shown satisfactory complete remission rates of up to 80% to 90%. However, the failure-free survival (FFS) and overall survival (OS) rates at 5 years were only 65% to 70% and 75% to 85%, respectively. The pivotal Cancer and Leukemia Group B trial in advanced HD, which compared MOPP with ABVD and with alternating MOPP/ABVD (without additive radiotherapy), showed equal therapeutic results for ABVD and MOPP/ABVD as far as progression-free survival and OS were concerned.5 Both regimens were superior to MOPP. ABVD had less germ cell and hematopoietic stem-cell toxicity.6 A long-term follow-up of this study over 15 years has recently been published, demonstrating a 45% to 50% progression-free survival rate and a 65% OS rate for ABVD and MOPP/ABVD.7
Subsequently, large multicenter trials were started in the United States and Europe to compare a MOPP/ABV hybrid with alternating MOPP/ABVD and sequential MOPP As a conclusion to the sequence of these comparative trials, the article by Duggan et al10 in this issue of the Journal of Clinical Oncology addresses the important question of whether the inclusion of MOPP, given in the conventional setting and scheduling, adds therapeutic benefit to ABVD or merely enhances toxicity. The authors present a carefully designed, randomized Intergroup trial in which they compare ABVD with the MOPP/ABV hybrid in 856 adult patients with stage III or IV HD or after relapse from radiotherapy. Therapy was given for eight to 10 monthly cycles; radiotherapy and the use of prophylactic hematopoietic growth factors were not permitted. There was no statistical difference between the ABVD and the MOPP/ABV hybrid in terms of FFS and OS. After a median observation time of 5 years, FFS was 63% after ABVD and 66% after MOPP/ABV. OS was 82% after ABVD and 81% after MOPP/ABVD. There was, however, a significantly greater toxicity seen in the MOPP/ABV group, both during therapy and after completion of treatment. Increased toxicity was noted especially for objectively measurable parameters, such as hematologic and pulmonary toxicity, as well as subjective parameters pertaining to patient well-being, such as anorexia, fatigue, and hypotension. The total number of treatment-related deaths was 25 for MOPP/ABV and 15 for ABVD, which was not a significant difference. Fifty-six of 96 total deaths in the ABVD arm and 49 of 94 deaths in the MOPP/ABV arm were caused by progressive HD, accounting for more than 50% of the total deaths in each arm. After a median follow-up of 6 years, there have been 46 second malignancies reported: 18 for ABVD and 28 for MOPP/ABV, with 11 cases of acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) for MOPP/ABV and two for ABVD. The authors conclude the following from this study: "ABVD should be considered the standard regimen for the treatment of advanced [HD] and should be the regimen against which new treatments are evaluated." This conclusion is justified on the basis of acceptable short- and long-term toxicity after ABVD, again reported in this study. Furthermore, the low rate of AML/MDS after ABVD (the two cases in this arm received alkylating agents at relapse) again is in favor of ABVD. But the conclusion should be challenged on the basis of a 37% failure rate and 18% death rate after a median follow-up of 5 years, with 50% of these deaths owing to progressive HD. Furthermore, the data of the Cancer and Leukemia Group B trial, updated by Canellos and Niedzwiecki7 in 2002 after 15 years, show a FFS of 45% to 50% and an OS rate of 65% after ABVD, results that are not satisfactory considering the fact that HD is one of the most chemosensitive tumors in adults. The questions therefore remain: Which treatment is superior to ABVD, and which regimen or strategy should be studied in future trials against this gold standard? Having accepted this challenge, one must aim for higher cure rates than the anticipated 65% after ABVD without endangering the initial therapeutic win by a long-term loss caused by unwanted sequelae. There are three factors to consider when thinking about a better treatment for advanced HD: new drugs or drug combinations, dosage (including dose-intensity and total dose), and schedule. Except for etoposide and gemcitabine, there are no new drugs that likely could significantly add to the hitherto established regimens. Etoposide has been included in most of the third-line regimes like Stanford V (mechlorethanine, doxorubicin, vinblastine, vincristine, bleomysin, etoposide, prednisone, and granulocyte colony-stimulating factor), BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, Oncovin, procarbazine and prednisone), VAPEC-B (vincristine, doxorubicin, prednisone, etoposide, cyclophosphamide, and bleomycin), or ClVP/EVA (chorambucil, vinblastine, procarbazine, and prednisolone).11–13 Gemcitabine is active in salvage therapy14 and is now included in the first-line drug regimen consisting of vinblastine, prednisone, doxorubicin, and gemcitabine in a German Hodgkin’s Lymphoma Study Group (GHSG)-European Organization for Research and Treatment of Cancer trial, which will start in 2003. Dosage, dose-intensity, and total dose are decisive factors that are important when comparing similar drug regimens. It is difficult to predict the relative efficacy of chemotherapy regimens that use different drugs. Hasenclever et al15 proposed a theoretical framework as a first step to accomplish that task. Different drug doses in a regimen are assumed to be roughly additive on an efficacy scale when appropriately weighed. If the drug weights are known, a total chemotherapy dose may be derived. This total dose has to be further corrected for different treatment durations, assuming a typical regrowth kinetic for each lymphoma entity. The resulting quantity, the effective dose, is a reasonable first-order predictor of relative treatment efficacy. Hasenclever et al19 derived drug weight estimates from a model-based meta-analysis of all randomized chemotherapy trials in Hodgkin’s disease and provided an estimate of the slope of the effective dose/cure rate relationship. Applying the effective dose model and using the weights estimated from trials up to 1998, MOPP/ABVD, MOPP/ABV, and BEACOPP baseline are not predicted to be notably different from ABVD in cure rates (all within ± 5%) because their effective doses are similar. In this light, the result of the trial by Duggan et al10 is not surprising. However, Stanford V was predicted to be of reduced efficacy when given with less additional radiotherapy. This was recently confirmed by an Italian study.16 The effective dose model also predicted that early high-dose chemotherapy with stem-cell transplantation is not a promising option for improving the outcome in first-line therapy of advanced Hodgkin’s disease. The reason is simply that the total dose of high-dose therapy is roughly equal to two to three conventional cycles, so the effective doses are not sufficiently different. This was recently confirmed by two trials comparing high-dose chemotherapy and autologous stem-cell transplantation with conventional chemotherapy.17,18 However, the model predicted that a dose escalation of approximately 30% in conventional chemotherapy within the same treatment duration would translate into a relevant difference in freedom from progression of more than 10% in plateau.19 This has been confirmed in the escalated BEACOPP trial HD9 of the GHSG (Diehl et al, manuscript submitted for publication). In this trial, early progression rates were reduced from 10% (COPP/ABVD) to 2% (escalated BEACOPP). This indicates that there is a small group of patients with progressive disease, under standard treatment, that is possibly not resistant to cytotoxic drugs at the cell level, as previously thought, and that these tumors are kinetically resistant because of rapid regrowth during treatment intervals. For these patients, shortening of treatment intervals and giving the most cytotoxic drugs immediately at the onset of treatment may be an option. The GHSG recently developed a 14-day BEACOPP regimen given in baseline dosage with growth factor support.20 The results of a multicenter pilot study (37 centers) showed a FFS rate of 89% and an OS rate of 91% at a median observation time of 24 months, similar to the results of the BEACOPP escalated regimen. In the ongoing HD15 trial of the GHSG, this approach is compared with escalated BEACOPP in an attempt to achieve similar results with less total dose. The third factor to consider when attempting to improve conventional treatment principals is the scheduling of drugs. With cyclophosphamide, vincristine (Oncovine), procarbazine, prednisone (M[C]OPP)/ABVD, for example, M(C)OPP is administered first; the most active cytotoxic drug, doxorubicin, is administered only on days 29 and 43; and M(C)OPP is begun again on day 57, leaving ample time for the genetically unstable cells to produce resistance or at least offer sufficient opportunity for tumor regrowth. With the MOPP/ABV hybrid, drugs are administered on days 1 and 8, but doxorubicin is only administered on day 8 and recycles on day 29, again leaving a long intervening time for the most active drug. Stanford V reduces the total dose of active drugs and uses a continuous exposure over 3 months with an alternating schedule of hematotoxic and nonhematotoxic drugs,11 necessitating radiotherapy because of the reduced total dose according to the model of Hasenclever et al.19 The BEACOPP principle delivers the most cytotoxic drugs (doxorubicin, cyclophosphamide, and etoposide) on days 1 to 3 and recycles again on day 22, increasing dose intensity only by timeshift by approximately 25% and enabling by this schedule-change dose intensification with the support of hematopoietic growth factors. In the current issue, Duggan et al10 reported a FFS rate of 66% for MOPP/ABV and 63% for ABVD after 5 years. The corresponding numbers in the HD9 trial are 69% FFS for COPP/ABVD, 76% for baseline BEACOPP, and 87% for escalated BEACOPP. This 24% difference between ABVD and escalated BEACOPP means that one of five patients needs salvage therapy with an increased risk of secondary AML/MDS, as demonstrated in many prominent transplant centers.21,22 When deaths caused by AML/MDS and treatment-related toxicity after escalated BEACOPP are included in the analysis, there is still an OS superiority of escalated BEACOPP over COPP/ABVD of 8%, (91% v 83%; P = .002) after a median observation time of 5 years (Diehl et al, manuscript submitted for publication). Finally, is the International Prognostic Score (IPS) robust enough to tailor treatment at diagnosis for patients with advanced HD according to their risk for treatment failure?23 Important pivotal studies have started in which patients in advanced stages of HD with an IPS of 0 to 2 will be treated with ABVD or Stanford V (United States Intergroup trial) and patients with a higher IPS (> 3) will be treated with eight cycles of ABVD, four cycles of escalated BEACOPP, plus four cycles of baseline BEACOPP, without radiotherapy (European Organization for Research and Treatment of Cancer, National Cancer Institute of Canada, Nordic Scandinavian Group, and Australia). There is hope that these trials will tell us whether aiming at initial higher FFS rates is, for the long-term, more beneficial for the patient than hoping for cure at progression or relapse. The vision, however, is that in the near future we will be able to apply effective antibodies against HD-specific or associated targets, such as the CD30 molecule, after an initial tumor reduction by two to three courses of an effective drug combination, or use small molecules that turn back the master switch that transforms the normal B lymphocyte into a fragile but still aggressive RSC. REFERENCES 1. Diehl V, Mauch P, Harris NL: Hodgkin’s disease, in De Vita V (ed): Cancer: Principles and Practice of Oncology (vol 2). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 2339–2387
2. Kueppers R, Klein U, Hansmann ML, et al: Cellular origin of human B-cell lymphomas. N Engl J Med 341:1520–1529, 1999 3. Kueppers R: Molecular biology of Hodgkin’s lymphoma. Adv Cancer Res 84:277–312, 2002[Medline] 4. Thomas RK, Re D, Zander T, et al: Epidemiology and etiology of Hodgkin’s lymphoma. Ann Oncol 13:147–152, 2002 (suppl)[Medline] 5. 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 327:1478–1484, 1992[Abstract] 6. Viviani S, Ragni G, Santoro A, et al: Testicular dysfunction in Hodgkin’s disease before and after treatment. Eur J Cancer 27:1389–1392, 1991[Medline]
7. Canellos GP, Niedzwiecki D: Long-term follow-up of Hodgkin’s disease trial. N Engl J Med 346:1417–1418, 2002
8. Glick JH, Young ML, Harrington D, et al: MOPP/ABV hybrid chemotherapy for advanced Hodgkin’s disease significantly improves failure-free and overall survival: The 8-year results of the Intergroup trial. J Clin Oncol 16:19–26, 1998 9. Connors JM, Klimo P, Adams G, et al: Treatment of advanced Hodgkin’s disease with chemotherapy: Comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD—A report from the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 15:1638–1645, 1997[Abstract]
10. 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
11. Radford JA, Rohatiner AZ, Ryder WD, et al: ChlVPP/EVA hybrid versus the weekly VAPEC-B regimen for previously untreated Hodgkin’s disease. J Clin Oncol 20:2988–2994, 2002
12. Horning SJ, Hoppe RT, Breslin S, et al: Stanford V and radiotherapy for locally extensive and advanced Hodgkin’s disease: Mature results of a prospective clinical trial. J Clin Oncol 20:630–637, 2002
13. Diehl V, Franklin J, Hasenclever D, et al: BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin’s lymphoma: Interim report from a trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 16:3810–3821, 1998
14. Santoro A, Bredenfeld H, Devizzi L, et al: Gemcitabine in the treatment of refractory Hodgkin’s disease: Results of a multicenter phase II study. J Clin Oncol 18: 2615–2619, 2000 15. Hasenclever D, Brosteanu O, Gerike T, et al: Modelling of chemotherapy: The effective dose approach. Ann Hematol 80:89–94, 2001 (suppl) 16. Chisesi T, Federico M, Levis A, et al: ABVD versus Stanford V versus MEC in unfavourable Hodgkin’s lymphoma: Results of a randomised trial. Ann Oncol 13:102–106, 2002 (suppl)[Abstract] 17. Federico M, Carella AM, Brice P, et al: High dose therapy (HDT) and autologous stem cell transplantation (ASCT) versus conventional therapy for patients with advanced Hodgkin’s disease (HD) responding to initial therapy. Proc Am Soc Clin Oncol 21, 2002 (abstr 1050a) 18. Proctor SJ, Mackie M, Dawson A, et al: A population-based study of intensive multi-agent chemotherapy with or without autotransplant for the highest risk Hodgkin’s disease patients identified by the Scotland and Newcastle Lymphoma Group (SNLG) prognostic index: A Scotland and Newcastle Lymphoma Group study (SNLG HD III). Eur J Cancer 38:795–806, 2002[Medline]
19. Hasenclever D, Löffler M, Diehl V: Rationale for dose escalation of first line conventional chemotherapy in advanced Hodgkin’s disease. Ann Oncol 7:95–98, 1996 (suppl) 20. Sieber M, Franklin J, Bredenfeld H, et al: Promising results with a 14 day variant of the BEACOPP regimen in advanced Hodgkin lymphoma (HL): A pilot study of the German Hodgkin’s Lymphoma Study Group (GHSG). Blood 98:2848a, 2001 (abstr) 21. Park S, Brice P, Noguerra ME, et al: Myelodysplasias and leukemias after autologous stem cell transplantation for lymphoid malignancies. Bone Marrow Transplant 26:321–326, 2000[CrossRef][Medline]
22. Krishnan A, Bhatia S, Slovak ML, et al: Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: An assessment of risk factors. Blood 95:1588–1593, 2000
23. 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 339:1506–1514, 1998 This article has been cited by other articles:
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABVD. These multicenter trials demonstrated that the MOPP/ABV hybrid was as effective as alternating MOPP/ABVD, but more effective than sequential MOPP 
