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

To describe the radiobiological rationale for dose-per-fraction escalation in non-small-cell lung cancer (NSCLC) and to devise a novel Phase I scheme to implement this strategy using advanced radiotherapy delivery technologies.

The data from previous dose escalation trials in NSCLC are reanalyzed to establish a dose-response relationship in this disease. We also use data relating prolongation in treatment time to survival to compute the potential doubling time for lung tumors. On the basis of these results, and using a Bayesian model to determine the probability of pneumonitis as a function of mean normalized lung dose, a dose-per-fraction escalation strategy is developed.

Standard approaches to dose escalation using 2 Gy per fraction, five 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-per-fraction escalation strategy, with a constant number of fractions, 25, and overall time, 5 weeks, is projected to produce tumor control rates predicted to be 10%-15% better than 2 Gy per fraction dose escalation, with equivalent late effects. This Phase I clinical study is divided into three parts. Step 1 examines the feasibility of the maximum breath-holding technique and junctioning of tomotherapy slices. Step 2 treats 10 patients with 30 fractions of 2 Gy over 6 weeks and then reduces duration to 5 weeks using fewer but larger fractions in 10 patients. Step 3 will consist of a dose-per-fraction escalation study on roughly 50 patients, maintaining 25 fractions in 5 weeks. Bayesian methodology (a modification of the Continual Reassessment Method) will be used in Step 3 to allow consistent and efficient escalation within five volume bins.

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 radiotherapy (IMRT) and helical tomotherapy with its adaptive capabilities, will be necessary to achieve significant dose-per-fraction escalation without unacceptable lung and esophageal morbidity.