Phase III randomised trial of high dose Cyclophosphamide, Epirubicin, Vincristine and Prednisolone (CEOP) chemotherapy regimen & Filgrastim versus standard dose CEOP chemotherapy regimen in patients with non-Hodgkin’s lymphoma

INTERVENTION: HIGH DOSE CEOP. One cycle consisted of: Cyclophosphamide 1500mg/m2 intravenously Day 1 Epirubicin 150mg/m2 intravenously Day 1 Vincristine (max 2.0 mg) 1.4 mg/m2 intravenouslyDay 1 Prednisolone 100mg/D orally Days 1‐5 Filgrastim 5 microg/kg/D subcutaneously Days 2 until absolute neutrophil count (ANC) >10X 109/L (max. 14 days) The above regimen was repeated every 3 weeks for 6 to 8 cycles depending on when the patient achieved complete response (CR). Patients were then assessed 3 months following completion of treatment and then at the clinician's discretion or upon request from the Trial Centre. All patients were followed up for a minimum of 10 years. CONDITION: Non‐Hodgkin Lymphoma PRIMARY OUTCOME: The primary endpoint was overall survival (OS) 5 years after randomisation, analysed by intention‐to‐treat analysis including all eligible randomised patients. The reverse Kaplan‐Meier method was used to calculate the estimated median duration of follow‐up. OS was measured from the date of randomisation, to the date of death (no matter what the cause). Survival proportions were estimated using the Kaplan‐Meier product‐limit method. Hazard ratios (HR) were estimated using the Cox proportional hazards model, stratified by the International Prognostic Index (IPI), including a stratum for patients with unknown IPI. SECONDARY OUTCOME: Progression‐free survival (PFS) 5 years after randomisation, analysed by intention‐to‐treat analysis including all eligible randomised patients. Survival proportions were estimated using the Kaplan‐Meier product‐limit method. Hazard ratios (HR) were estimated using the Cox proportional hazards model, stratified by the IPI, including a stratum for patients with unknown IPI. Quality of life (QoL) was measured using the European Organization for the Research and Treatment of Cancer (EORTC) QLQ‐C308 version 1 questionnaire and scored accordingly. Quality of life scores were compared using t‐tests. Response rate. Response rates were compared using an exact test for stratified 2x2 tables, with strata based on the International Prognostic Index (IPI). Time to progression 5 years after randomisation, analysed by intention‐to‐treat analysis including all eligible randomised patients. Survival proportions were estimated using the Kaplan‐Meier product‐limit method. Hazard ratios (HR) were estimated using the Cox proportional hazards model, stratified by the IPI, including a stratum for patients with unknown IPI. Toxicity was analysed by intention‐to‐treat analysis including all eligible randomised patients. . Toxicity grades were compared using the exact version of the Wilcoxon‐Mann‐Whitney test comparing two ordered multinomial distributions and the incidence of grade 3 or 4 toxicities and other binary endpoints were compared using Fisher’s exact test. Non‐censored continuous variables were compared using the exact version of the Wilcoxon‐Mann‐Whitney test. INCLUSION CRITERIA: 1. Patients with non‐Hodgkin’s lymphoma of the following histological types: ‐Follicular large cell (Group D). ‐Diffuse mixed small cleaved and large cell (Group F). ‐Diffuse large cell (Group G). ‐Large cell immunoblastic (Group H). 2. Ann Arbor Stage I with bulky disease (tumour mass >=10cm in largest diameter), II, III or IV. 3. Age >=16 years. 4. Measurable or evaluable disease. 5. Absolute neutrophil count >1.5 x 109/L, platelet count >75 x 109/L, unless cytopenia is due to bone marrow infiltration. 6. Adequate renal function (creatinine less than twice upper limit of normal); adequate hepatic function (bilirubin less than twice upper limit of normal). 7. ECOG performance status 0‐3. 8. Accessible for treatment and follow‐up. 9. Informed consent in accordance with institutional ethical guidelines.