External beam radiotherapy for painful osseous metastases: Pooled data dose response analysis

Purpose: Although the effectiveness of external beam irradiation in palliat ion of pain from osseous metastases is well established, the optimal fracti onation schedule has not been determined. Clinical studies to date have fai led to demonstrate an advantage for higher doses. To further address this i ssue, we conducted a pooled dose response analysis using data from publishe d Phase III clinical trials. Methods and Materials: Complete response (CR) was used as an endpoint becau se it was felt to be least susceptible to inconsistencies in assessment. Th e biological effective dose (BED) was calculated for each schedule using th e linear-quadratic model and an alpha/beta of 10. Using SAS version 6.12, t he data were fitted using a weighted linear regression, a logistic model, a nd the spline technique. Finally, BED was categorized, and odds ratios for each level were calculated. Results: CR was assessed early and late in 383 and 1,007 patients, respecti vely. Linear regression on the early-response data yielded a poor fit and a nonsignificant dose coefficient. With the late-response data, there was an excellent fit (R-square = 0.842) and a highly significant dose coefficient (p = 0.0002). Fitting early CR to a logistic model, we could not establish a significant dose response relationship. However, with the late-response data there was an excellent fit and the dose coefficient was significantly different from zero (0.017 +/- 0.00524; p = 0.0012). Application of the spl ine technique or removal of an outlier resulted in an improved fit (p = 0.0 48 and p = 0.0001, respectively). Using BED of < 14.4 Gy as a reference lev el, the odds ratios for late CR were 2.293.32 (BED of 19.5-51.4 Gy, respect ively). Conclusion: Our results demonstrate a clear dose-response for pain relief. Further testing of high intensity regiments is warranted. (C) 1999 Elsevier Science Inc.