Determinants of lung fibrosis after chemo radiation for small cell carcinoma of the lung: evidence for inherent interindividual variation

Purpose: Clinical observations often reveal discernible individual differences in the severity of lung fibrosis after definitive radiation therapy for lung cancer. Recent experimental studies also suggest that the risk of developing lung fibrosis may be genetically controlled. This study was undertaken to examine the magnitude of individual variation in the incidence and severity of lung fibrosis in a well defined patient population treated by combined chemo radiation for limited small cell lung carcinomas (LSCLC). Materials and Methods: Between 1989 and 1994, 56 patients with LSCLC were enrolled on one of two controlled protocols of combined chemotherapy and concomitant conventional (45 Gy in 25 fractions q.d. over 5 weeks) or accelerated radiotherapy (45 Gy in 30 fractions b.i.d. over 3 weeks). Chemotherapy consisted of cis-platin and etoposide (PE) or PE with ifosfamide and Mesna. Among those patients, 25 patients who had serial computerized tomography (CT) examinations of the chest and were deemed to have unequivocal radiographic complete responses were selected for the study. The severity of lung fibrosis was recorded for each patient on the CT images using an arbitrary scale (0 to 3) at 1 year after treatment. Radiographic fibrosis scores were recorded on 1-3 CT slices in three different dose-areas (20-25 Gy; 30-35 Gy; and 40-45 Gy) that were defined using the corresponding CT slices from the patient's CT plan. Twenty three patients (92%) had at least 2 slices scored; 11 patients had all 3 slices scored. Results: Among all clinical and treatment parameters examined including type of chemotherapy, only total dose and fractionation schedule were identified as significant and independent determinants of lung fibrosis. Radiographic fibrosis scores were higher in high dose areas and in patients treated with the accelerated schedule. Using a fit of the proportional odds (PO) model based on the total dose and fractionation schedule, fibrosis score residuals were calculated for each patient. Residual for each score is defined as the difference between the observed and expected score based on the dose and treatment schedule received. Individual score residuals were very consistent within the same patients, but showed significant interindividual variation (p = 0.005, Kruskal-Willis test). Using maximum likelihood analysis, the coefficient of variation in patient heterogeneity was 15.3% (95% confidence interval: 8.3 - 22.3%). Inclusion of the calculated heterogeneity factor in addition to total dose and fractionation improved the fit of the PO model to an extremely high 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 accelerated radiation schedule. There was also a demonstrable patient-to-patient heterogeneity suggesting that this risk is strongly affected by inherent factors that vary among individuals