VEBEP: The Milan Approach to Increasing Cure Rates in Advanced Hodgkin’s Disease

ABSTRACT & COMMENTARY

Synopsis: The overall cure rates in Hodgkin’s disease are relatively high, but there remain approximately 35% with advanced disease who progress despite aggressive therapy. Thus, there remains a need for still more effective regimens. In this report from the University of Milan, the phase II experience with the VEBEP regimen, followed by involved field radiation, is reported. Complete remission rate was 94% and freedom from progression and survival at six years were 78% and 82% respectively for the 73 patients with advanced Hodgkin’s disease entered on study, toxicity was manageable and patient compliance was high. Viviani and colleagues suggest that this approach may be superior to the current "gold standard" ABVD and should be compared directly in a randomized trial.

Source: Viviani S, et al. Cancer J Sci Am 1999;5: 275-282.

With more than 30 years of experience with combination chemotherapy for Hodgkin’s disease, there remains a desire to improve both efficacy and safety of the treatment programs. For patients presenting with advanced disease, despite current approaches, relapses occur in as many as 30% to 35%.1 In this context, the Milan group reports its phase II experience with the VEBEP combination (etoposide 120 mg/m2 IV; epirubicin 40 mg/m2 IV on days 1 and 2; bleomycin 10 mg/m2 IV on day 1; cyclophosphamide 500 mg/m2 IV on days 1 and 2; and prednisilone 50 mg/PO on days 1-7). Patients with newly diagnosed stage IIB, III (A and B), and IV (A and B) Hodgkin’s disease, or those who were relapsing after primary subtotal or total nodal irradiation were treated with this combination for a total of eight 21- day cycles followed by radiotherapy (30-36 Gy) to nodal site or sites of pretreatment disease. The median duration of follow-up was 68 months.

The complete remission rate was 94% and at six years, the freedom-from-progression and overall survival were 78% and 82%, respectively. Treatment compliance was excellent, with no patients refusing to complete the entire program. Grade 3 and 4 neutropenia were common (12% and 85%, respectively) but recovery was prompt and most completed the full eight cycles without delays. Growth factor therapy was not required and infectious complications occurred in only 8% of the cycles administered. There was one septic death during chemotherapy-induced marrow aplasia. Grade 3 thrombocytopenia occurred in 1% of cycles administered and there were no clinically evident cardiac or lung toxicities clearly attributable to epirubicin, bleomycin, or radiation therapy. Hypothyroidism was detected in 38% of the cases and gonadal damage was evident in the large majority of males but this was reversible in half of the cases. There were no cases of leukemia observed during this study period.

Viviani and colleagues conclude that VEBED followed by involved-field radiotherapy is an effective treatment approach for advanced Hodgkin’s disease with acceptable rates of acute and chronic toxicities. They urged a comparison of this regimen with the standard ABVD or MOPP/ABVD combinations currently in wide use.

COMMENT By William B. Ershler, MD

In the more than 30 years since the introduction of MOPP chemotherapy for Hodgkin’s disease, there has been a challenge to improve the success rate, either by enhancing efficacy or by maintaining efficacy but reducing toxicity. Thus, ABVD and other combinations have gradually replaced MOPP as first-line approaches.2 In this report from the Milan group, phase II data are presented that would suggest that a new, intensive regimen is both better tolerated and more efficacious than the current gold standard, ABVD.

There are, of course, a few caveats. These are phase II data, and subject to the typical biases encountered, including those related to patient selection. With the data presented, however, it is hard to argue with the call by Viviani et al for a direct comparison in a randomized study with more established regimens such as ABVD. For stages III and IV, VEBEP appears to produce more durable complete remissions at less toxicity than observed with the ABVD-treated patients treated on the CALGB protocols.2 As Viviani et al suggest, there needs to be a direct comparison with other regimens using appropriate clinical trial methodology.

Another third generation regimen for Hodgkin’s disease (Stanford V: Doxorubicin 25 mg/m2 IV days 1,15; Vinblastine 6 mg/m2 IV days 1,15; Nitrogen Mustard 6 mg/m2 IV day 1; Vincristine 1.4 mg/m2 IV days 8, 22; Bleomycin 5 mg/m2 IV days 8, 22; etoposide 60 mg/m2 IV days 15, 16; and Prednisone 40 mg/m2 PO every other day for 12 weeks)3,4 has been shown to produce impressive response rates and has the advantage, despite its intensity, of a short treatment program (3 28-day cycles). This regimen is to be compared with ABVD in an NCI-sponsored trial soon to be undertaken.

Finally, the contribution of consolidative radiotherapy in VEPEB and the other third generation programs (including Stanford V) needs further evaluation. Overall survival in these studies will be the outcome of relevance.

References

1. Viviani S, et al. J Clin Oncol 1996;14:1421-1430.

2. Cannellos GP, et al. N Engl J Med 1992;327: 1478-1484.

3. Bartlett NL, et al. J Clin Oncol 1995;13:1080-1088.

4. Horning SJ, et al. Ann Oncol 1996;4:105-108.

For the treatment of patients with advanced (stage III or IV) Hodgkin’s disease, which one of the following statements about the VEBEP regimen is true?

a. It has been established to be more effective than MOPP, ABVD, or MOPP/ABVD hybrids.

b. It has been established to be less toxic than MOPP, ABVD, or MOPP/ABVD hybrids.

c. It has been established to be both more effective and less toxic than MOPP, ABVD, or MOPP/ABVD hybrids.

d. It has been shown to have high response rates and relatively low toxicity profiles in phase II trials.