Reduced dose posterior to prostate correlates with increased PSA progression in voxel-based analysis of 3 randomised phase 3 trials

Purpose Reducing margins during treatment planning to decrease dose to healthy organs surrounding the prostate can risk inadequate treatment of subclinical disease. This study aimed to investigate whether lack of dose to subclinical disease is associated with increased disease progression by utilizing high-quality prostate radiotherapy clinical trial data to identify anatomically-localised regions where dose variation is associated with PSA progression (PSAP). Methods and Materials Planned dose distributions for 683 patients of the ‘Trial-A’s name’ were deformably registered onto a single exemplar computed tomography (CT) dataset. These were divided into high-risk and intermediate-risk sub-groups for analysis. Three independent voxel-based statistical tests, utilizing permutation testing, Cox regression modelling and LASSO feature selection, were applied to identify regions where dose variation was associated with PSAP. Results from the intermediate-risk ‘Trial-A’ sub-group were externally validated by registering dose distributions from ‘Trial-B’ (n=388) and ‘Trial-C’ (n=253) trials onto the same exemplar and repeating the tests on each of these data sets. Results Voxel-based Cox regression revealed regions where reduced dose was correlated with increased PSA progression. Reduced dose in regions associated with coverage at the posterior prostate, in the immediate periphery of the posterior prostate and in regions corresponding to the posterior oblique beams or posterior lateral beam boundary, was associated with increased PSAP for ‘Trial-A’ and ‘Trial-B’ patients, but not for ‘Trial-C’ patients. Reduced dose to the seminal vesicles (SV) region was also associated with increased PSAP for ‘Trial-A’ intermediate-risk patients. Conclusions Ensuring adequate dose coverage at the posterior prostate and immediately surrounding posterior region (including the SV), where aggressive cancer spread may be occurring, may improve tumour control. It is recommended that particular care is taken when defining margins at the prostate posterior, acknowledging the trade-off between quality of life due to rectal dose and the preferences of clinicians and patients.