Exploiting biological and physical determinants of radiotherapy toxicity to individualise treatment.

Abstract

The recent advances in radiation delivery can improve tumour control probability and reduce treatment related toxicity. The use of intensity-modulated radiotherapy (IMRT) in particular can reduce normal tissue toxicity, an objective in its own right, and can allow safe dose escalation in selected cases. Ideally IMRT should be combined with image guidance to verify the position of the target, since patients, target and organs at risk can move day-to-day. Daily image guidance scans can be used to identify the position of normal tissue structures, and potentially to compute the daily delivered dose. Fundamentally, it is still the tolerance of the normal tissues which limits radiotherapy dose and therefore tumour control. However, the dose response relationships for both tumour and normal tissues are relatively steep, meaning that small dose differences can translate into clinically relevant improvements. Differences exist between individuals in the severity of toxicity experienced for a given dose of radiotherapy. Some of this difference may be the result of differences between the planned dose and the accumulated dose (DA). However, some may be due to intrinsic differences in radiosensitivity of the normal tissues between individuals. This field has been developing rapidly, with the demonstration of definite associations between genetic polymorphisms and variation in toxicity recently described. It might be possible to identify more resistant patients who would be suitable for dose escalation, as well as more sensitive patients for whom toxicity could be reduced or avoided. Daily differences in delivered dose have been investigated within the VoxTox research programme, using the rectum as an example organ at risk. In prostate cancer patients receiving curative radiotherapy, considerable daily variation in rectal position and dose can be demonstrated, although the median position matches the planning scan well. Overall, in 10 patients, the mean difference between planned and accumulated rectal equivalent uniform doses (EUDs) was -2.7 Gy (5%), and a dose reduction was seen in 7/10 cases. If dose escalation were performed to take rectal dose back to the planned level, this should increase the mean tumour control probability (TCP) (as biochemical progression-free survival) by 5%. Combining radiogenomics with individual estimates of DA might identify almost half of patients undergoing radical radiotherapy who might benefit from either dose escalation, suggesting improved tumour cure, or reduced toxicity, or both.