Patterns of failure following loco-regional radiotherapy in the treatment of limited stage small cell lung cancer

PURPOSE: The probability of treatment resistant cells developing in a tumor, such as small cell lung cancer (SCLC) which has a rapid cell cycle time, is a function of the number of tumor cells present and of time. Theoretically, the development of resistance to chemotherapy and radiotherapy should be minimized by using all treatment modalities early in the treatment program. METHODS AND MATERIALS: The importance of the timing of loco-regional radiotherapy was assessed in a multi-institution randomized study. Three hundred and eight patients with limited small cell lung cancer (LSCLC) were given three cycles of cyclophosphamide, doxorubicin and vincristine alternating with three cycles of etoposide and cisplatin. In addition, patients were randomized to receive locoregional radiotherapy: 40 Gy in 15 fractions in 3 weeks with treatment planning techniques to limit the spinal cord dose to be < or = 35 Gy either with the first cycle (early) or with the sixth cycle of chemotherapy (late). Responding patients received prophylactic brain irradiation (25 Gy in 10 fractions in 2 weeks) after completion of locoregional radiotherapy and chemotherapy. RESULTS: 96% of the 155 eligible patients allocated to the "early" arm and 87% of the 153 allocated to the "late" arm received locoregional radiotherapy; 26 patients did not receive locoregional radiotherapy. The mean field sizes were similar in both arms. The mean radiation doses were significantly less in the "early" arm (p = 0.0319 Wilcoxon rank sum test). Any differences in the frequency of toxicities were minor. All patients have been followed for at least 2 years and the median follow up is 4 years. 64% had a complete response in the "early" arm compared with 56% in the "late" arm (p = 0.137). Survival was measured from the start of chemotherapy. There was a significant improvement in survival in the "early" arm; median survival was 21.2 months compared with 16.0 months in the "late" arm (p = .008 log rank test). Survival at 2, 3, and 4 years was 40%, 32%, and 25%, respectively, for the "early" arm and 33%, 22%, and 15% for the "late" arm. There were 232 (75%) recurrences among those patients whose disease recurred. The proportion who had local recurrence within the radiation field was 41% and 39% for "early" and "late" treatment arms respectively. The proportion of brain metastases in the "late" arm (28%) was significantly higher than in the "early" arm (18%) p = .0425 Fishers' exact test. CONCLUSION: We conclude that early administration of locoregional radiotherapy in a combined modality treatment is superior to late consolidative locoregional radiotherapy in limited small cell lung cancer.