This phase II study was designed to improve the outcome of elderly patients with advanced aggressive non-Hodgkin's lymphomas (NHL's) by employing a novel chemotherapy regimen PEN (prednisone, oral etoposide and mitoxantrone), as initial treatment. Between July 1991 and September 1993, 43 patients (14 male, 29 female) aged 66-82 years (median 74) received 1-8 (median 4) courses of PEN (total 192) q28 days (prednisone 50 mg od x 14 days, oral etoposide 50 mg od x 14 days and mitoxantrone 8 mg/m2 i.v. day 1) in the ambulatory setting. Pathologies of patients' tumors classified by the Working Formulation (WF) included C = 4, D = 2, E = 1, F = 7, G = 25, H = 4. Eighteen patients (42%) had stage IV, 15 (35%) stage III, 9 (21%) stage II and 1 (2%) stage I disease. Nineteen patients (44%) had B symptoms, 7 (16%) primarily extranodal disease and 15 (35%) bone marrow involvement. Patients with congestive heart failure, current anti-failure medication or pretreatment Muga left ventricular ejection fraction (LVEF) of < 45% (median pretreatment 60%) were excluded from PEN. After a median follow-up of 8.5 months (range 1-30), 14 of 33 evaluable patients (42%) have achieved CR of their disease for 8+ months (range 4-19) and 6 (18%) PR for 6+ months (range 5-10), giving an overall response rate of 61%. Ten (30%) patients did not respond to PEN and 10 were not evaluable for response. Response to PEN was not predicted by any pretreatment characteristic.(ABSTRACT TRUNCATED AT 250 WORDS)