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© 2002 American Society for Clinical Oncology
New Treatments for Advanced Hodgkin’s Disease: An Uphill Fight Beginning Close to the TopDana-Farber Cancer Institute, Boston, MA NO OTHER HUMAN malignancy has attracted more biologic and therapeutic attention than Hodgkin’s disease. It was the first "shot in the arm" for adult medical oncology with the early success of combination chemotherapy with nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP).1 This regimen was the prototypic model for treatment of non-Hodgkin’s lymphoma and other solid tumors. The principle of combining individually active cytotoxic agents in a cyclical schedule continues to be the basis for the chemotherapy treatment of many tumors. The regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) has replaced MOPP as the standard chemotherapy program for Hodgkin’s disease, primarily because of its relative freedom from the long-term bone marrow and germ cell toxicity of the alkylating agents in the MOPP program. Most chemotherapy regimens are administered over several days, with an intervening period of several weeks between treatments to allow for hematologic recovery. The ABVD regimen was designed as an every-2-weeks regimen, narrowing the interval of time between injections. Whether this is a factor in its efficacy is unknown.2 Although the prospective trial comparing ABVD with MOPP showed an advantage in relapse-free survival for ABVD, the dosing of nitrogen mustard was reduced because of cumulative bone marrow toxicity.3 However, there was no (and continues to be no) statistically significant difference in overall survival, reflecting the ability to salvage relapse with secondary therapy. The fact that ABVD was originally used as an active salvage regimen after relapse from MOPP and vice versa speaks to the broad sensitivity of Hodgkin’s disease cells to a variety of cytotoxic agents.3,4 The survival of any treated cohort of patients with Hodgkin’s disease is a function of the stage, total quantity of disease, its impact on the host, and the toxicity of the therapy. A number of clinical prognostic factors have been identified to have an independent influence on the outcome after cytotoxic chemotherapy. These include age more than 45 years, male sex, stage IV disease, serum albumin less than 4 g%, hemoglobin less than 10.5 g%, leukocytosis more than 15,000/mm3, and absolute lymphocyte count less than 600/mm3.5 Other less obvious factors are the unconscious selection of patients by single institutions, patterns of referral, and experience in the management of malignant disease, including Hodgkin’s disease. These latter factors also may contribute to small statistical differences among various series using the same regimen and, more than likely, explains the less favorable results when certain chemotherapy regimens are tested in cooperative group settings, as opposed to single institutions from which they were generated. There are a number of examples of this in lymphoma therapy.6 The above may have some bearing on the interpretation of the phase II therapeutic trial known as Stanford V and radiotherapy in the current issue of the Journal of Clinical Oncology. Horning et al7 present a carefully studied population of 142 patients with advanced Hodgkin’s disease, which also includes locally advanced disease in 32% of the treated patients. Overall, 71% had zero to two negative prognostic factors which, according to the previously mentioned International Prognostic Index, would predict for quite a favorable outcome after chemotherapy. The series of Hasenclever et al5 had 58% of their 1,618 patients in the zero to two negative prognostic factor group, with progression-free survival between 75% and 80%. Therapeutic innovation in the treatment of advanced Hodgkin’s disease has followed two general paths. The first is the use of dose intensification with multiple agents with its attendant risk of toxicity or, second, an alteration in drug scheduling with the goal of offering continuous exposure to active drugs on a weekly basis for a total treatment duration of 3 months. This was the principle of Stanford V. It is reminiscent of the regimen known as MACOP-B (methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin), which was a 3-month weekly regimen for the treatment of large-cell lymphoma developed by the Vancouver group.8 The Stanford V scheme anticipates that the total dose of drugs, and thus cumulative toxicity, could be reduced. For example, the total dose of doxorubicin is 150 mg/m2, as opposed to 300 mg/m2 in six cycles of ABVD. The regimen contains seven agents, including prednisone. All of the agents have known anti-Hodgkin’s activity, but one can question whether three isolated injections of nitrogen mustard over 3 months add significantly to the regimen. The more intensive use of the vinca alkaloids is noted with vinblastine alternating with vincristine given on a weekly basis for 3 months. The alternate-day prednisone for 3 months and weekly chemotherapy have the potential for to secondary infection, thus prophylactic trimethoprim/sulfamethoxazole, ranitidine, and acyclovir were also given. Twenty-five percent of the series required hospitalization because of toxicity. PACE-BOM (oral prednisolone, intravenous doxorubicin, cyclophosphamide, and etoposide alternating weekly with intravenous bleomycin, vincristine, and methotrexate) is a 12-week regimen similar in many ways to Stanford V. It has been used in the United Kingdom with some difference in schedule, and it includes methotrexate. The 5-year overall survival rate was 90%, with a failure-free survival rate of 64%, far less than the 89% of the Stanford V series.9 This may reflect an intrinsic feature of the Stanford V program, because multisite radiation therapy was used in 90% of patients by the very experienced Stanford radiation oncology team. Relatively little radiation was used with PACE-BOM. The 5-year freedom-from-first-progression rate for ABVD alone for stage III/IV disease without radiation therapy in two consecutive Cancer and Leukemia Group B and Intergroup trials with a total of 548 patients was 61% to 63%.3,10 It is difficult to assess whether Stanford V is by itself a potent cytotoxic regimen for Hodgkin’s disease or a regimen that facilitates the reduction of tumor volume to a point where consolidative radiation effectively eliminates residual disease. The role of radiation therapy in the management of advanced Hodgkin’s disease is not without a rising level of concern. Secondary in-the-field malignancies have appeared more than 20 years in 20% to 25% of patients.11 They include both carcinomas and sarcomas. Breast carcinoma was a special hazard in young women.12 Some prospective randomized trials and one meta-analysis suggest that the addition of radiation offers no significant impact on overall survival.13-16 It is understandable that progression-free survival may be prolonged because of irradiation to bulky nodal sites, but that may not translate into ultimate survival advantage. The use of combined chemotherapy and radiation therapy to sites of initial nodal involvement indeed has a long history pioneered by the Stanford group 30 years ago. A recent series from the Milan (National Cancer Institute) group, which had pioneered ABVD, is the etoposide, epirubicin, bleomycin, cyclophosphamide and prednisolone regimen (VEBEP). Eight cycles every 21 days of this treatment plus irradiation to nodal sites resulted in 78% freedom from progression at 6 years.17 A prior series from the same institution using MOPP-ABVD hybrid, or alternating MOPP-ABVD with similar radiation, had a 66% freedom-from-progression rate with longer follow-up (91 months of median follow-up).18 The median follow-up of the Stanford V series is 5.4 years so that further relapses may yet occur, especially in the stage III/IV cohort of patients. Whether the recent techniques of lower doses and small fields will reduce that risk of second malignancy is unknown. Thus it may not be an advantage to have a program that requires complementary radiation therapy to achieve the excellent early results when the long-term toxicity remains uncertain. The other approach is a more intensive combination chemotherapy using a conventional schedule with multiple agents. The regimen of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) introduced by the German Hodgkin Group is a recent example of such a regimen. This relies more on cytotoxic chemotherapy, but radiation to bulky sites was also included in 70% of patients in the initial prospective trial, which compared eight cycles of BEACOPP with eight cycles of escalated BEACOPP, with four courses of cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/ABVD as a standard.19 The failure-free survival rate at 40 months’ median follow-up was 79% for BEACOPP but was even higher (at 89%) after eight cycles of a dose-escalated version. An updated analysis at 60 months showed a failure-free rate of 87% compared with 76% for nonescalated BEACOPP and 69% for COPP/ABVD, with survival rates of 91%, 88% and 83%, respectively (V. Diehl, personal communication, October 2001). There was a significantly higher overall grade 3/4 hematologic toxicity for the escalated BEACOPP, and it was associated with myelodysplastic syndrome/leukemia in nine of 466 patients, with relatively short follow-up. It is, however, an interesting and relatively well-evaluated program, which is now being compared with standard therapy, ABVD. It is clear that these newer regimens are not ready for general use in community practice. Ultimately, they need to be compared with the standard ABVD. This regimen has thus far been compared with MOPP alone, 12 months of MOPP alternating with ABVD, and 6 to 8 months of MOPP-ABV hybrid.3,10 In all instances, it has been found to be equivalent in overall survival without the accompanying toxicity related to alkylating agents. If any new regimen has an increased risk of more life-threatening toxicity, such as sepsis and myelodysplastic syndrome/leukemia or long-term radiation-induced second solid tumors, then a higher freedom-from-progression rate has to be balanced against the toxicity. A possibly higher relapse rate that is still salvageable might allow 60% to 70% of patients in stage III/IV to be cured without the above risks. In long-term follow-up, the overall survival rate may be the same. Despite the issues raised in the interpretation of this important series, Stanford V/radiotherapy clearly represents an effective approach to the treatment of advanced Hodgkin’s disease. It is in fact the subject of a current Intergroup prospective comparison with conventional ABVD with or without radiation to bulk disease. The detailed analysis of the data in Stanford V (plus radiotherapy) as presented in the article is a continuing reminder of the productivity of the multidisciplinary team at Stanford that in times past pioneered many new approaches to Hodgkin’s disease. REFERENCES 1. DeVita VT Jr, Simon RM, Hubbard SM, et al: Curability of advanced Hodgkin’s disease with chemotherapy. Ann Intern Med 92: 587-595, 1980 2. Bonadonna G, Santoro A: ABVD chemotherapy in the treatment of Hodgkin’s disease. Cancer Treat Rev 9: 21-35, 1982[Medline] 3. 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] 4. Santoro A, Bonfante V, Bonadonna G: Salvage chemotherapy with ABVD in MOPP-resistant Hodgkin’s disease. Ann Intern Med 96: 139-143, 1982
5.
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
6.
Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328: 1002-1006, 1993
7.
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 8. Klimo P, Connors JM: MACOP-B chemotherapy for the treatment of diffuse large-cell lymphoma. Ann Intern Med 102: 596-602, 1985
9.
Simmonds PD, Mead GM, Sweetenham JW, et al: PACE BOM chemotherapy: A 12-week regimen for advanced Hodgkin’s disease. Ann Oncol 8: 259-266, 1997 10. Duggan D, Petroni G, Johnson J, et al: MOPP/ABV versus ABVD for advanced Hodgkin’s disease: A preliminary report of CALGB 8952 (with SWOG, ECOG, and NCIC). Proc Am Soc Clin Oncol 16: 12, 1997a (abstr 43) 11. van Leeuwen FE, Klokman WJ, Hagenbeek A, et al: Second cancer risk following Hodgkin’s disease: A 20-year follow-up study. J Clin Oncol 12: 312-325, 1994[Abstract] 12. 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: 2315-2320, 1997
13.
Ferme C, Sebban C, Hennequin C, et al: Comparison of chemotherapy to radiotherapy as consolidation of complete or good partial response after six cycles of chemotherapy for patients with advanced Hodgkin’s disease: Results of the Group d’études des Lymphomes de l’Adulte H89 trial. Blood 95: 2246-2252, 2000
14.
Diehl V, Loeffler M, Pfreundschuh M, et al: Further chemotherapy versus low-dose involved-field radiotherapy as consolidation of complete remission after six cycles of alternating chemotherapy in patients with advanced Hodgkin’s disease. Ann Oncol 6: 901-910, 1995
15.
Fabian CJ, Mansfield CM, Dahlberg S, et al: Low-dose involved field radiation after chemotherapy in advanced Hodgkin disease. Ann Intern Med 120: 903-912, 1994 16. Loeffler M, Brosteanu O, Hasenclever D, et al: Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin’s disease. J Clin Oncol 16: 818-829, 1998[Abstract] 17. Viviani S, Bonfante V, Santoro A, et al: Long-term results of an intensive regimen: VABEP plus involved-field radiotherapy in advanced Hodgkin’s disease. Cancer J Sci Am 5: 275-282, 1999[Medline]
18.
Bonfante V, Santoro A, Viviani S, et al: Outcome of patients with Hodgkin’s disease failing after primary MOPP-ABVD. J Clin Oncol 15: 528-534, 1997
19.
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
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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