Combined alkylators and multiple-site irradiation for extensive small cell lung cancer: A Southwest Oncology Group study

The Southwest Oncology Group performed a study for patients with extensive small cell lung cancer in which two hypotheses were tested: (a) that combined alkylating agents for induction might improve the initial response rate; and (b) that multiple-site, involved-field consolidation with irradiation in patients with response to chemotherapy might further improve response quality and duration. A regimen of combined alkylating agents plus vincristine [carmustine, thiotepa, vincristine, and cyclophosphamide (BTOC)] was compared to our standard program of cyclophosphamide, doxorubicin, and vincristine (CAV). Patients with bone marrow metastases and/or disseminated bone metastases were randomized to BTOC or CAV as initial induction therapy, but received no multiple-field irradiation afterward. Among 189 such patients, the overall response rates were similar (48% to BTOC and 61% to CAV, with complete remission in 5% and 15%, respectively). Toxic effects were also comparable, with 23% sustaining life-threatening or fatal complications on BTOC and 16% on CAV. Median survival (5.9 and 7 months for BTOC and CAV, respectively) and overall survival were not different, and are superimposable upon our previously reported results with CAV alone. For patients with no evidence of bone marrow involvement and no metastases identified beyond the confines of ipsilateral hemithorax, liver, and brain, the plan of therapy consisted of induction chemotherapy (BTOC or CAV) every 3 weeks for three cycles, followed by multiple-field irradiation consolidation to sites of prior involvement. Among 239 such patients, response rates to therapy initiated with BTOC and CAV were also similar: 54% for BTOC and 62% for CAV, with complete response in 16% and 13%, respectively. However, the program of BTOC followed by multiple-site irradiation was associated with a higher incidence of severe or life-threatening thrombocytopenia (23% versus 8% for CAV), accounted for almost entirely by patients receiving hepatic irradiation after chemotherapy, among whom the incidence of this complication (grade 3 or 4) was 76% and 14%, respectively. Other toxic effects, including granulocytopenia were comparable. With the exception of thrombocytopenia in the cites subgroup, multiple-field irradiation consolidation proved feasible and tolerable, with improved quality of response evident after its initiation in 24% of 135 patients. However, a similar proportion developed disease progression during or shortly after radiation therapy, and the median survival of patients who received irradiation was only 9 months (7 months from the start of consolidation). Neither combined alkylating agents at doses equitoxic to CAV nor the use of multiple-site, involved-field irradiation as a consolidation measure can be recommended, based on the outcome of this study.