Risk stratification in the management of localised prostate cancer treated with radical radiotherapy

Abstract

The National Cancer Institute defines precision medicine as ‘a form of medicine that uses information about a person’s genes, proteins, and environment to prevent, diagnose, and treat disease’. When applied to radiation oncology, it may be considered from two separate but interlinked perspectives; namely, physical- and imaging-based (arguably the more advanced of the two) and biology-based ‘radiogenomics’. The work reported here investigates both aspects of this topic in the context of localised prostate cancer, the management of which has changed greatly in recent years. Radical radiotherapy and radical prostatectomy remain the cornerstones of treatment but have now been joined by active surveillance, dose escalation (via multiple strategies), systemic approaches using androgen deprivation and up-front chemotherapy in addition to adjuvant androgen deprivation therapies and radiotherapy in the post-prostatectomy setting. In contrast to other tumour sites, however, commonly employed methods of risk stratification have not changed significantly and certainly have not kept pace with these advances in management.

The hypothesis that underpins this work is that precision medicine will transform prostate cancer therapy. At a population level, improved patient selection using novel prognostic or predictive biomarkers will allow greater individualisation of treatment for men with localised prostate cancer. At an individual level, advances in radiotherapy will enable more precise and accurate tumour targeting improving the therapeutic ratio.

A large clinically annotated database of Northern Irish men treated with radical radiotherapy for localised prostate cancer was generated which served as a resource to facilitate biomarker investigation in multiple settings. Whole-transcriptome analysis of diagnostic prostate tissue was carried out and a novel 70-gene Metastatic Assay, that had previously proven prognostic for biochemical failure-free and metastasis-free survival in surgical patients was, for the first time, shown to be prognostic for the same outcomes in men treated with radical radiotherapy. Neither pre-radiotherapy PSA nadir nor neutrophil-lymphocyte ratio, both clinical biomarkers which had previously shown promise, were found to be prognostic for any outcome of interest in this patient group. The choice of androgen deprivation therapy subtype was prognostic for biochemical failure, with poorer outcomes in the group treated with anti-androgen monotherapy, but, interestingly, was not prognostic for metastatic disease, prostate-cancer specific survival or overall survival.

The SPORT High-Risk Trial, a randomised feasibility study designed to investigate the addition of elective pelvic nodal stereotactic radiotherapy (SABR) to prostate SABR in men with unfavourable intermediate- and high-risk localised prostate cancer, was designed and developed as part of this work. The development of a novel composite volume margin derivation approach is presented here. This method permits the derivation of planning margins for two or more separate CTVs treated using a single isocentre, independent of the assumptions of conventional margin recipes, and was undertaken to provide necessary planning data prior to the opening of the SPORT trial. Early results from this trial are also reported here and, to date, do not demonstrate any evidence of excessive or unexpected toxicity.

The management of prostate cancer is evolving more rapidly than ever before; the continued development of precision medicine – in all its aspects – is essential to truly allow individualisation of treatment at all stages.

Date of Award	Jul 2021
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Queen's University Belfast
Supervisor	Suneil Jain (Supervisor), Joe O'Sullivan (Supervisor) & David Waugh (Supervisor)