A new approach to dose escalation in non-small-cell lung cancer

Purpose: To describe the radiobiological rationale for dose-per-fraction es calation in non-small-cell lung cancer (NSC-LC) and to devise a novel Phase I scheme to implement this strategy using advanced radiotherapy delivery t echnologies. Methods and Materials: The data from previous dose escalation trials in NSC LC are reanalyzed to establish a dose-response relationship in this disease . We also use data relating prolongation in treatment time to survival to c ompute the potential doubling time for lung tumors. On the basis of these r esults, and using a Bayesian model to determine the probability of pneumoni tis as a function of mean normalized lung dose, a dose-per-fraction escalat ion strategy is developed. Results: Standard approaches to dose escalation using 2 Gy per fraction, fi ve fractions per week, require doses in excess of 85 Gy to achieve 50% long -term control rate. This is partly because NSCLCs repopulate rapidly, with a 1.6% per day loss in survival from prolongation in overall treatment time beyond 6 weeks, and a cell doubling time of only 2.5 to 3.3 days. A dose-p er-fraction escalation strategy, with a constant number of fractions, 25, a nd overall time, 5 weeks, is projected to produce tumor control rates predi cted to be 10%-15% better than 2 Gy per fraction dose escalation, with equi valent late effects. This Phase I clinical study is divided into three part s. Step 1 examines the feasibility of the maximum breath-holding technique and junctioning of tomotherapy slices. Step 2 treats 10 patients with 30 fr actions of 2 Gy over 6 weeks and then reduces duration to 5 weeks using few er but larger fractions in 10 patients. Step 3 will consist of a dose-per-f raction escalation study on roughly 50 patients, maintaining 25 fractions i n 5 weeks. Bayesian methodology (a modification of the Continual Reassessme nt Method) will be used in Step 3 to allow consistent and efficient escalat ion within five volume bins. Conclusions: A dose-per-fraction escalation approach in NSCLC should yield superior outcomes, compared to standard dose escalation approaches using a fixed dose per fraction, for a given level of pneumonitis and late toxicity . Highly conformal radiotherapy techniques, such as intensity modulated rad iotherapy (IMRT) and helical tomotherapy with its adaptive capabilities, wi lt be necessary to achieve significant dose-per-fraction escalation without unacceptable lung and esophageal morbidity. (C) 2001 Elsevier Science Inc.