Pulsed Reduced Dose-Rate Radiotherapy: A Novel Re-Treatment Strategy in the Management of Large Volume Recurrent Glioma

Abstract

Radiotherapy delivered below standard dose-rates reduces normal tissue toxicity and can induce significant tumor regression in some tumor types. Early clinical studies suggested that fractionated reduced dose-rate external beam radiotherapy could achieve an improved therapeutic ratio. The factors and mechanisms that determine the response of normal cells and tumors to reduced dose-rate irradiation remain largely unknown. In conventional radiotherapy a dose of 2 Gy is delivered at a dose rate of 4–6 Gy/min, which means that the delivery of this dose requires only a few minutes. By reducing the effective dose-rate and increasing the treatment time, it becomes possible for repair processes to be active during irradiation. A reduced dose-rate can either be obtained by using a continuous reduced dose-rate irradiator, or by dividing the standard 2 Gy fractions into a number of equal sub-fractions that are delivered in a pulsed manner separated by a fixed time interval, allowing for repair during each sub-fraction. This is done by delivering treatment in a series of 0.2 Gy pulses separated by 3-minute time intervals, creating an apparent dose rate of 0.0667 Gy/min. We have termed this re-irradiation technique pulsed reduced dose-rate radiotherapy (PRDR). This pulsed approach will preferentially protect normal tissue and have almost the same effect in terms of tumor cell kill because repair capacity is greater in late responding normal tissues than tumors. Between January 1999 and March 2007, 99 patients with recurrent gliomas were re-irradiated using PRDR (mean dose 50 Gy) delivered in 1.8–2.0 Gy fractions. Prior to the initiation of PRDR, all patients had received conventional radiotherapy, 68 had multiple surgeries, 14 radiosurgery, 4 GliaSite brachytherapy and 78 received conventional chemotherapy and/or one or more experimental therapies. MRI-CT fusion with 3-dimensional planning was used for all patients. The treatment volume was the volume of the contrast-enhancing lesion and surrounding edema on pre-treatment MRI plus a 2 cm margin. Due to the complexities of MRI interpretation; overall survival at six months was used as the study end point. Thirty-one (31.3%) of these 99 heavily pretreated patients had an overall survival of six months or greater. There were no significant toxicities or treatment related deaths. The mean and median treatment volumes were 336 ccm and 388 ccm respectively, which is significantly larger than those reported previous re-irradiation series. Histological grading, time from initial diagnosis to the initiation of PLDR and KPS were the strongest predictors for overall survival. PRDR is a model-based methodology using reduced dose-rate external beam radiotherapy that is well tolerated and may be an effective treatment in patients with recurrent gliomas. Although the tendency is to minimize both total dose and treatment volume when re-irradiating brain tissue, our results suggest that the utilization PRDR may allow for the safe re-treatment of larger target volumes to higher doses potentially realizing a greater palliative benefit.