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.

Background: Studies of chemotherapy for patients with small cell lung carcinoma (SCLC) have shown that teniposide (T) may have higher activity 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 SCLC. A second objective of the study was to study patients who had achieved complete response (CR). They were considered for a second randomization to maintenance therapy, in which they would receive either recombinant interferon-alpha (rIFN-alpha) or no treatment.

Methods: From June 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/m2 administered intravenously (i.v.), doxorubicin 50 mg/m2 i.v., and vincristine 2 mg i.v. on Day 1. Arm A (CAV-E) involved the addition of E 100 mg/m2 i.v. on Days 2, 3, and 4; Arm B (CAV-T) involved the addition of T 60 mg/m2 i.v. on Days 2, 3, and 4. Courses were repeated every 3 weeks. After 3 courses, patients with LD received chest radiotherapy 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 therapy 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 years from start-up (3-year median observation time and 90% death rate), the study was closed. Results were as follows: 140 patients (71 in Arm A and 69 in Arm B) were eligible for survival analysis; 131 were evaluable for response and toxicity (66 in Arm A and 65 in Arm B), whereas 9 were not (6 early deaths and 3 with protocol violations). Among evaluable 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) partial response (PR) to CAV-E, and 39% (13/33) CR and 39% PR (13/33) to CAV-T. Sixty-three patients showed ED (31 assigned to Arm A and 32 to Arm 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 toxicity 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 and 5 in Arm B (chi-square = 2.86); 2 patients in Arm A discontinued therapy due to persistent leukopenia and thrombocytopenia. No other remarkable 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 months (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 candidates for the second randomization. Among them, 26 patients (18.5%) complied with the program and were randomized as follows: 14 were assigned to the IFN-alpha arm and 12 to 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 months) (chi-square = 0.13).

Conclusions: This study did not show a wide difference in activity and toxicity between CAV-E and CAV-T. The number of patients who entered the second randomization was too small to reach the second study endpoint.