VP-16-213 in the treatment of stage III and IV diffuse large cell lymphoma

Between 1975 and 1979, 81 consecutive patients with clinical Stage III or IV diffuse large cell lymphoma were randomized to prospectively receive the epipodophyllotoxin VP-16-213 as a single agent (Group 1: n = 25), or an equivalent quantity of the same drug combined with either cyclophosphamide (Group 2: n = 24), or doxorubicin (Group 3: n = 32). In previously untreated patients complete remission rates were 55% for Group 1, 29% for Group 2, and 62% for Group 3, with further partial remission in 22%, 12%, and 13%, and overall median survival for the three groups being 19 months, 5 months, and 19 months, respectively. There was no difference between Group 1 and Group 3, whereas the cyclophosphamide-containing regimen (Group 2) was clearly inferior (P less than 0.01). Survival was adversely affected by failure to achieve complete remission, prior chemotherapy, and the presence of high bulk disease. No statistically significant correlation could be demonstrated between survival and histologic subtype, differences between Stage III and IV disease, and invasion of either the bone marrow or gastrointestinal tract. The epipodophyllotoxin VP-16-213 is an active agent in patients with advanced stages of diffuse large cell lymphoma. The inferior results obtained when combined with cyclophosphamide remain unexplained. The inclusion of previously treated patients in the series suggested a superiority for combining the epipodophyllotoxin VP-16-213 with doxorubicin, since a higher percentage achieved complete remission, median duration of survival was longer, and a great number of individuals remain disease-free. When re-analysed excluding previously treated patients, these differences are no longer evident and the combination is not statistically superior to the epipodophyllotoxin alone.