Sequential versus alternating chemotherapy for high grade non‐hodgkin's lymphomas: A randomized multicentre 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.