A New Gold Standard in Advanced Hodgkin’s Disease?

LUGANO, Switzerland—Dose-escalated BEACOPP chemotherapy (bleomycin, etoposide, Adriamycin [doxorubicin], cyclophosphamide, Oncovin [vincristine], procarbazine, and prednisone) with growth factor support boosts survival in patients with advanced Hodgkin’s disease, according to the fourth interim analysis of the German Hodgkin’s Lymphoma Study Group’s (GHSG) HD9 trial.

“We all made a mistake in using MOPP-ABVD[mechlorethamine, Oncovin, procarbazine, and prednisone plus Adriamycin, bleomycin, vindesine, and dacarbazine] or COPP-ABVD as a gold standard for 20 years,” Dr. Volker Diehl, of the University of Cologne, reported at the VII International Conference on Malignant Lymphoma.

Those regimens, he said, “allowed the malignant cells to develop resistance because we used doxorubicin only on days 29 and 43, yielding 3-year disease-free survival rates of only 55% to 60%.” The 21-day BEACOPP regimen, Dr. Diehl said, addresses these shortcomings through dose intensification and the substitution of etoposide for vinblastine and dacarbazine.

GHSG investigators at more than 350 centers enrolled more than 1,300 previously untreated patients with either stage IIB-IIIA disease associated with risk factors or stage IIIB-IV disease. HD9 study participants were randomized to four cycles of COPP plus ABVD, or eight cycles of a standard BEACOPP regimen, or eight cycles of dose-escalated BEACOPP.

In the dose-escalated regimen, the doses of cyclophosphamide, etoposide, and doxorubicin were increased by 192%, 200%, and 140%, respectively, and G-CSF (Neupogen) was administered starting on day 8 to bolster the leukocyte count. After completing chemotherapy, patients received radiotherapy for bulky and residual disease.

Significantly inferior results among patients receiving COPP-ABVD forced the premature termination of this study arm, Dr. Diehl noted. The complete remission rate reached 83% in the COPP-ABVD group, 88% in patients assigned to standard BEACOPP, and 96% in those treated with dose-escalated BEACOPP. The proportions of patients with progressive disease were 12% with COPP-ABVD, 8% with standard BEACOPP, and only 2% with escalated BEACOPP.

Dr. Diehl reported 3-year freedom from failure rates of 69% with COPP-ABVD, 79% with standard BEACOPP, and 88% with escalated BEACOPP. Overall 3-year survival was 86% in the COPP-ABVD arm, 90% with standard BEACOPP, and 91% with escalated BEACOPP.

The gains afforded by the more aggressive BEACOPP regimen were not without their price. Leukopenia, thrombocytopenia, and anemia (but not infection) were significantly more common with dose-escalated BEACOPP than with the other two study regimens. Nevertheless, the higher incidence of side effects did not translate into greater treatment-related mortality.

“When you calculate the long-term benefit of escalated BEACOPP vs standard BEACOPP, taking into account the loss of benefit through toxicity from primary and salvage treatment and from secondary malignancies, you still come up with an advantage of 5.7% for dose escalation,” Dr. Diehl said. On the basis of known prognostic factors, the GHSG was unable to define a high-risk group that would benefit particularly from intensive BEACOPP therapy.

“We think the possible mechanisms for better results are time intensification, dose intensification, and the addition of etoposide,” Dr. Diehl said. He also suggested the possibility of synergism among cyclophosphamide, etoposide, and doxorubicin given during the first 3 days of each cycle.

The Next Step

The next step for the GHSG is trial HD12, which is attempting to determine whether eight courses of dose-escalated BEACOPP followed by radiotherapy (as used in HD9) might represent overtreat-ment. HD12 enrollees are being randomized to either eight courses of escalated BEACOPP or four courses of escalated BEACOPP followed by four courses of standard BEACOPP. A second randomization will assign patients who have completed chemotherapy to receive 30 Gy of irradiation or no further treatment.

“We hopefully will have less acute and long-term toxicity,” Dr. Diehl said, adding that HD12 has already recruited 200 patients in the past 6 months.

Still another GHSG strategy is to assess the impact of compressing the escalated BEACOPP regimen into a 14-day cycle. A pilot study involving 98 patients has shown that the efficacy and toxicity of the 14-day regimen are exactly intermediate between 21-day standard BEACOPP and 21-day dose-escalated BEACOPP.