FACTORS INFLUENCING THE DEVELOPMENT OF LUNG FIBROSIS AFTER CHEMORADIATION FOR SMALL-CELL CARCINOMA OF THE LUNG - EVIDENCE FOR INHERENT INTERINDIVIDUAL VARIATION

Purpose: Clinical observations often reveal individual differences in the severity of lung fibrosis after definitive radiation therapy for l ung cancer. Recent experimental studies suggest that the risk of devel oping lung fibrosis may be genetically controlled. The present study w as undertaken to examine the magnitude of individual variation in the incidence and severity of lung fibrosis in a well-defined patient popu lation treated by concurrent chemoradiation for limited sm;all-cell lu ng carcinomas (LSCLC). Materials and Methods: Between 1989 and 1994, 5 6 patients with LSCLC were enrolled in one of two controlled prospecti ve studies of concurrent chemotherapy and concomitant conventional (45 Gy in 25 fractions q.d. over 5 weeks) or accelerated (45 Gy in 30 fra ctions b.i.d. over 3 weeks) radiotherapy. Chemotherapy consisted of ci splatin and etoposide (PE) or PE plus ifosfamide and mesna (PIE). Of t he 56, a group of 25 patients who had serial computerized tomography ( CT) examinations of the chest and were deemed to have unequivocal radi ographic complete responses were selected for this study. The severity of lung fibrosis was recorded for each patient from the CT images usi ng an arbitrary scale (0 to 3) at 1 year after treatment. Radiographic fibrosis scores were recorded on 1-3 CT slices in 3 different dose-ar eas (20-30 Gy; 30-40 Gy; and >40 Gy) that were defined using the corre sponding CT slices from the patient's CT treatment plan. Of these pati ents, 23 (92%) had at least 2 slices scored; 11 patients had all 3 sli ces scored. Results: Among the clinical and treatment parameters inves tigated (including type of chemotherapy), only total dose and fraction ation schedule were identified as significant and independent determin ants of lung fibrosis, Radiographic fibrosis scores were higher in hig h-dose areas and among patients treated with the accelerated schedule. Using a fit of the proportional odds (PO) model based on the total do se and fractionation schedule, fibrosis score residuals were calculate d for each patient. The residual for each score is defined as the diff erence between the observed and expected score based on the dose and t reatment schedule received. Average residuals varied significantly amo ng patients (p = 0.005, Kruskal-Willis test), Using a modified version of the PO model, the coefficient of variation in patient heterogeneit y was estimated to be 10.1% (95% confidence interval: 6.2-14.9%). Incl usion of the heterogeneity factor, in addition to total dose and fract ionation schedule, improved the fit of the PO model to an extremely hi gh level of significance (p < 10(-7)). Conclusions: Our data indicate that the risk and severity of lung fibrosis analyzed radiographically on CT images increases with total dose and with the use of an accelera ted radiation schedule, for patients treated with chemoradiation for s mall-cell lung cancer. There was also demonstrable patient-to-patient heterogeneity, suggesting that the risk of lung fibrosis is strongly a ffected by inherent factors that vary among individuals. (C) 1998 Else vier Science Inc.