Dose rate modulation for the safe delivery of retreatment irradiation in recurrent glioma patients

In spite of the continued evolution of surgical and chemotherapeutic approaches tothe treatment of low and high-grade glioma patients, most patients recur, at which timetheir therapeutic options are limited. Most recently the conditional approval ofbevacizumab by the FDA for the recurrent glioblastoma patients has offered a significantimprovement in progression free survival. Efficacy, however, regarding overall survivalhas been limited. One unique approach to such recurrent glioma patients is the use ofdose rate modulated re-treatment irradiation. Radiotherapy (RT) delivered below standarddose-rates reduces normal tissue toxicity and can induce significant tumor regression insome tumor types including glioma. By reducing the effective dose-rate and increasingthe treatment time, it becomes possible for repair processes to be active duringirradiation. This reduction in dose-rate can result in a therapeutic advantage, as repair ofsub-lethal damage in normal neural tissues is greater for late complications than forneoplastic cells; further tumor cells (that have received prior RT) can accumulate in asensitive phase of the cell cycle, e.g., G2, thus leaving them at risk for radiation inducedkilling. In the chapter to follow, modeling for this approach, technological details, well asbiophysical basis for its application is summarized. The published peer reviewed clinical literature on the treatment of recurrent glioma patients using this technique is reviewed in detail: This literature, which encompasses relatively large treatment volumes, is consistent with the concept that fractionated reduced dose-rate external beam RT can achieve an improved therapeutic index. Also outlined are the current planned prospective clinical studies for evaluation this new approach in the context of cooperative group clinical trials in recurrent glioblastoma patients.