A RANDOMIZED, CONTROLLED PHASE-III STUDY OF CYCLOPHOSPHAMIDE, DOXORUBICIN, AND VINCRISTINE WITH ETOPOSIDE (CAV-E) OR TENIPOSIDE (CAV-T), FOLLOWED BY RECOMBINANT INTERFERON-ALPHA MAINTENANCE THERAPY OR OBSERVATION, IN SMALL-CELL LUNG-CARCINOMA PATIENTS WITH COMPLETE RESPONSES

BAGKGROUND. Studies of chemotherapy for patients with small cell lung carcinoma (SCLC) have shown that teniposide (T) may have higher activi ty than etoposide (E). In this randomized, controlled Phase III study, the authors compared cyclophosphamide, doxorubicin, and vincristine ( CAV) with E and CAV with T as induction treatments for patients with S CLC. A second objective of the study was to study patients who had ach ieved complete response (CR). They were considered for a second random ization to maintenance therapy, in which they would receive either rec ombinant interferon-alpha (rIFN-alpha) or no treatment. METHODS, From Tune 1990 to December 1995, 140 untreated SCLC patients were enrolled in this study. Patients were stratified by either limited disease (LD) or extensive disease (ED) and randomized to one of two treatment arms . The schedules for both arms included cyclophosphamide 1000 mg/m(2) a dministered intravenously (i.v.), doxorubicin 50 mg/m(2) i.v., and vin cristine 2 mg i.v. on Day 1. Arm A (CAV-E) involved the addition of E 100 mg/m(2) i.v. on Days 2, 3, and 4; Arm B (CAV-T) involved the addit ion of T 60 mg/m(2) i.v. on Days 2, 3, and 4. Courses were repeated ev ery 3 weeks. After 3 courses, patients with LD received chest radiothe rapy and 2 additional consolidation courses, whereas patients with ED received 5 consecutive courses only. Patients with CR were considered for the second randomization, which consisted of either maintenance th erapy with intramuscular (i.m.) rIFN-alpha-2b, 3 M.U., once a day for 9 months (IFN-alpha arm) or no therapy (control arm). RESULTS. At 5 ye ars from start-up (3-year median observation time and 90% death rate), the study was closed. Results were as follows: 140 patients (71 in Ar m A and 69 in Arm B) were eligible for survival analysis; 131 were eva luable for response and toxicity (66 in Arm A and 65 in Arm B), wherea s 9 were not (6 early deaths and 3 with protocol violations). Among ev aluable patients, 68 showed LD (35 assigned to Arm A and 33 to Arm B); the responses to treatment were 28.5% (10/35) CR and 51% (18/35) part ial response (PR) to CAV-E, and 39% (13/33) CR and 39% PR (13/33) to C AV-T. Sixty-three patients showed ED (31 assigned to Arm A and 32 to A rm B); their responses were 22.5% (7/31) CR and 52% (16/31) PR to CAV- E, and 12.5% (4/32) CR and 50% (16/32) PR to CAV-T. Drug-related toxic ity was WHO Grade 3-4 myelosuppression in 20% of 292 CAV-E courses and in 27% of 252 CAV-T courses. There were 6 toxic deaths, 1 in Arm A an d 5 in Arm B (chi-square = 2.86); 2 patients in Arm A discontinued the rapy due to persistent leukopenia and thrombocytopenia. No other remar kable toxicities were observed. Actuarial median survival (MS) was 13. 7 months (range, 1.0-62.5 months) for patients with LD receiving CAV-E (Arm A) and 15.2 months (range, 0.5-68.2 months) for those receiving CAV-T (Arm B) (chi-square = 0.89); in patients with ED it was 10.5 mon ths (range, 0.6-30.4 months) and 8.2 months (range, 0.2-24.8 months), respectively (chi-square = 3.42). Overall, MS was 12 months (range, 0. 6-62.5 months) in Arm A and 10 months (range, 0.2-68.2 months) in Arm B (chi square = 0.059). Thirty-nine patients with CR (27.8%) were cand idates for the second randomization. Among them, 26 patients (18.5%) c omplied with the program and were randomized as follows: 14 were assig ned to the IFN-alpha arm and 12 Co the control arm. Starting from the second randomization, median time to progression was 12 months (range, 3-51 months) for patients in the IFN-alpha arm versus 7 months (range , 1-59 months) for patients in the control arm (chi-square = 0.12). MS was 15 months (range, 5-52.3 months) versus 9 months (range, 2-60.5 m onths) (chi-square = 0.13). CONCLUSIONS, This study did not show a wid e difference inactivity and toxicity between CAV-E and CAV-T. The numb er of patients who entered the second randomization was too small to r each the second study endpoint. (C) 1997 American Cancer Society.