The availability of increasing numbers of active agents has led to the development of a succession of regimens for use as alternative and second-line therapy following relapse from or refractoriness to MOPP (mechlorethamine/vincristine/procarbazine/prednisone) or its variants. ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) has been the most widely used and has been considered non-cross-resistant. Other programs containing the nitrosourea lomustine have been used with results similar to those with ABVD. A relatively small fraction of relapsed patients remain failure free at 5 years (about 20% to 30%) despite a 30% to 60% second-line complete response (CR) rate. The few randomized trials (Cancer and Leukemia Group B [CALGB], European Organization for Research and Treatment of Cancer) evaluable to assess the efficacy of alternating MOPP/ABVD compared with MOPP alone have shown a small but significant advantage in freedom from progression and/or survival favoring the complex regimens over MOPP. The CALGB trial (8251) included a third arm of ABVD alone. The ABVD and MOPP/ABVD arms had a higher CR rate and superior failure-free survival (FFS) than did MOPP, but have thus far shown no difference between ABVD and alternating MOPP/ABVD, suggesting that full doses of a single regimen are equivalent to the more complex multidrug regimen. The next step in the CALGB program was to attempt to improve ABVD. The substitution of etoposide, an active single agent, for dacarbazine and bleomycin in ABVD resulted in a new regimen, EVA (etoposide/vinblastine/doxorubicin). This program has already demonstrated a 66% response rate in MOPP-resistant/relapsed patients (CALGB 8751).(ABSTRACT TRUNCATED AT 250 WORDS)