Dose-escalated CHOEP for the treatment of young patients with aggressive non-Hodgkin's lymphoma:: I.: A randomized dose escalation and feasibility study with bi- and tri-weekly regimens

Background: To determine the maximum tolerated dose of a bi- and tri-weekly combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone plus etoposide (CHOEP) regimen without stem-cell support. Patients and methods: Randomized phase I/II multicenter four-level (cyclophosphamide: 1000-1200-1400-1600 mg/m(2); doxorubicin: 55-60-65-70 mg/m(2); etoposide: 375-450-525-600 mg/m(2)) dose escalation study with CHOEP-14 and CHOEP-21 in young patients (18-60 years) with newly diagnosed aggressive non-Hodgkin's lymphoma. Dose-limiting toxicity was defined as thrombocytopenia < 80 000/mm(3) and leukocytopenia < 2500/mm(3) on days 16 (CHOEP-14) and 23 (CHOEP-21) or prolonged (> 4 days) leukocytopenia (< 1000/mm(3)) or thrombocytopenia (< 20 000/mm(3)). Results: One hundred and thirty-nine patients (high-CHOEP-14: 47, high-CHOEP-21: 92) were randomly allocated to the study. Maximal tolerated dose was level 2 for CHOEP-14 and level 4 for CHOEP-21. With a less favorable profile of patients in CHOEP-14, 4-year event-free survival was 47.9% after high-CHOEP-14 and 66.2% after high-CHOEP-21, 4-year overall survival 62.1% after high-CHOEP-14 and 73.4% after high-CHOEP-21, respectively. Conclusion: Significant dose escalations of CHOEP are possible with granulocyte colony-stimulating factor support, with different chemotherapy models favoring the maximally escalated bi- or tri-weekly regimen, respectively. Because a higher total dose can be achieved with six cycles of the tri-weekly compared with the biweekly regimen, CHOEP-21 at dose escalation level 3 was chosen for a nationwide randomized comparison with baseline CHOEP-21 in a subsequent phase III trial.