Sequential Versus Alternating Chemotherapy For High-Grade Non-Hodgkins-Lymphomas - A Randomized Multicenter Trial

In a multicentre phase III trial 146 previously untreated patients with high grade non-Hodgkin's lymphomas stage II-IV were randomized to receive either four cycles of CHOEP (cyclophosphamide 750 mg/m2 iv d 1, doxorubicin 50 mg/m2 iv d 1, vincristine 2 mg iv d 1, etoposide 100 mg/m2 iv d 3-5, prednisolone 100 mg po d 1-5) (treatment arm A), or four cycles of chemotherapy with hCHOP (cyclophosphamide 1200 mg/m2 iv d 1, doxorubicin 40 mg/m2 iv d 1 + 2, vincristine 2 mg iv d 1, prednisolone 100 mg po d 1-5) alternating with IVEP (ifosfamide 1500 mg/m2 iv d 1-5, vindesine 3 mg/m2 iv d 1, etoposide 120 mg/m2 iv d 3-5, prednisolone 100 mg po d 1-5) (treatment arm B). After four cycles of chemotherapy an involved field irradiation with a total dose of 35 Gy was given to all patients in complete or partial remission without persisting extranodal disease. A complete response (CR) was seen in 124/146 patients (86 per cent) with 87 per cent CR in arm A versus 83 per cent CR in arm B. During a median follow-up of 17 months (range 2-40) 30 patients relapsed (16 patients arm A, 14 patients arm B). The overall survival at 40 months is projected to be 71 per cent versus 70 per cent for arm A and B, respectively. Disease-free survival is projected to be 68 per cent in arm A and 59 per cent in arm B at 40 months. So far, the differences in CR, survival and disease-free survival are not statistically significant. Toxicity of all regimens was acceptable, however, with a significant morbidity and one treatment-related death in patients > 70 years after hCHOP. Main side effects were mild nausea/vomiting, leukopenia and fever/infection associated with leukopenia.In conclusion both treatment modalities produced high complete remission rates. A longer follow-up will be needed to exclude differences in over-all and disease-free survival.