SCHEDULE DEPENDENCY OF 21-DAY ORAL VERSUS 3-DAY INTRAVENOUS ETOPOSIDEIN COMBINATION WITH INTRAVENOUS CISPLATIN IN EXTENSIVE-STAGE SMALL-CELL LUNG-CANCER - A RANDOMIZED PHASE-III STUDY OF THE CANCER AND LEUKEMIA GROUP-B

Purpose: This was a randomized phase III study to test the schedule de pendency of etoposide given as a conventional 3-day intravenous (IV) r egimen versus a prolonged 21-day oral regimen for extensive-stage smal l-cell lung cancer (SCLC). Both regimens contained IV cisplatin. The o bjectives were to compare survival (primary end point) and to establis h response rates, failure-free survival, and toxicity (secondary end p oints). Patients and Methods: patients with untreated measurable or as sessable disease and normal organ function were eligible. Randomizatio n was stratified according to performance status 0 versus 1 or 2. Trea tment consisted of etoposide 130 mg/m(2)/d IV for 3 days and cisplatin 25 mg/m(2)/d IV for 3 days every 21 days for eight courses (schedule 1) versus etoposide 50 mg/m(2)/d orally for 21 days and cisplatin 33 m g/m(2)/d IV for 3 days every 28 days for six courses (schedule 2). In 1990, bioavailability of oral etoposide was assumed to be 50%, and the study was designed to deliver the same total doses of etoposide and c isplatin on both regimens over 24 weeks without the use of growth fact ors. Results: Between December 1990 and October 1993, 306 eligible pat ients were entered. Of these, 69% were male and 66% were greater than or equal to 60 years of age; 21% had a performance status of 0, 47% a performance status of I,and 32% a performance status of 2; 156 were ra ndomized to receive schedule 1 and 150 to receive schedule 2. Overall median survival estimates were 9.5 and 9.9 months (difference not sign ificant) for schedule 1 and schedule 2, respectively. The 95% confiden ce interval (CI) for overall survival, 8 to 11 months, was the same fo r both schedules, with 126 and 117 deaths on schedule 1 and 2, respect ively. Both schedules also resulted in the same median failure-free su rvival estimate of 7 months (95% CI, 6 to 8 months on either schedule) . Complete and partial responses were observed in 15% and 42% of patie nts on schedule 1 and 14% and 47% on schedule 2, respectively. The ove rall maximal hematologic toxicities grade 3 and 4 for leukocytes, neut rophils, platelets, and hemoglobin were, respectively, as follows: sch edule 1, 62%, 85%, 32%, and 32%; schedule 2, 83%, 83%, 52%, and 55%. L ethal toxicity due to neutropenia and infection occurred in 4% of pati ents on schedule 1 and 10% on schedule 2 (difference not statistically significant). Conclusion: The two schedules of etoposide in combinati on with cisplatin did not result in differences in treatment outcome w ith respect to tumor response and survival. However, a significantly g reater rate of severe or life-threatening hematologic toxicity was not ed on the 21-day oral etoposide treatment schedule. J Clin Oncol 13:18 71-1879. (C) 1995 by American Society of Clinical Oncology.