Dose-escalation of CHOP in non-Hodgkin's lymphoma

Background: CHOP is considered to be the gold standard for patients with hi stologically aggressive non-Hodgkin's lymphoma both in limited and advanced stages. In order to determine the maximum tolerable dose of an intensified CHOP regimen, a dose-escalation study of CHOP (cyclophosphamide, doxorubic in, vincristine, and prednisone) in patients with non-Hodgkin's lymphoma (N HL) was started. Patients and methods: With an increased fixed dose of doxorubicin at 75 mg/ m(2) instead of 50 mg/m(2) on day 1 and standard doses of vincristine (1.4 mg/m(2) on day 1) and prednisone (100 mg day 1 through 5), cyclophosphamide dose was escalated by increments of 250 mg/m(2) in consecutive cohorts of at least three patients starting from 1000 mg/m(2). Granulocyte-colony stim ulating factor (G-CSF) support was added to the regimen starting from the d ose-level inducing grade 4 neutropenia lasting more than five days in two p atients. Dose limiting toxicity was defined as either the dose inducing gra de 4 neutropenia lasting more than seven days despite the use of G-CSF, or grade 3-4 thrombocytopenia lasting more than seven days, or any grade 4 non -hematological toxicity other than alopecia. The dose-level below the one i nducing dose-limiting toxicity was defined as maximum tolerable dose. All p atients were treated on an outpatient basis. Dose-intensity parameters for single agent doxorubicin and cyclophosphamide as well as for the whole regi men were evaluated. Results: Eighty-seven patients are evaluable over a four-year study period. At 1750 mg/m(2) dose-level, G-CSF was added to the regimen according to de scribed criteria. At the cyclophosphamide dose of 3000 mg/m(2), dose-limiti ng hematological toxicity occurred in two patients, with one grade 4 thromb ocytopenia and neutropenia and one grade 4 neutropenia lasting more than se ven days. Thus, cyclophosphamide dose of 2750 mg/m(2) was defined as maximu m tolerable dose. Conclusions: CHOP intensification of approximately 1.8 times that of the st andard regimen is feasible and safely administered on an outpatient basis w ith G-CSF support. Further investigation on the role of dose-intensity in t he outcome of NHL should focus on the comparison of intensified CHOP regime n and standard CHOP or high-dose chemotherapy.