Novel cytoreductive treatments for de novo synchronous metastatic hormone-sensitive prostate cancer
File(s)
Author(s)
Connor, Martin
Type
Thesis
Abstract
Survival in patients with metastatic hormone-sensitive prostate cancer (mHSPC) has increased following the use of contemporary systemic therapy with traditional androgen deprivation therapy (ADT). However, systemic therapy in isolation does not target the primary tumour and typically results in the development of a castrate resistant state which restricts overall survival. In my thesis, I will assess the feasibility of performing novel local cytoreductive and metastasis directed treatment strategies in patients with de novo synchronous mHSPC to confer additional survival benefits.
The first part of my thesis I provide the pathobiological and clinical rationale of primary tumour cytoreduction, including an evaluation of introducing cytoreductive radical prostatectomy (cRP) and cytoreductive minimally invasive ablative therapies (MIAT). In addition, I systematically review the current evidence for both metastasis-directed therapy (surgery or stereotactic ablative radiation therapy [SABR]) and patient preferences’ for such innovative treatments in this disease setting. We explore how to identify suitable patients with non-curative disease, in a contemporary prostate cancer referral pathway.
This leads to the design and development of a phase II, randomised controlled trial, entitled “IP2-ATLANTA”, in the second part of this thesis. The completion of IP2-ATLANTA internal multicentre pilot enables us to report the acceptability, compliance and safety of using our novel cytoreductive interventions. By utilising serial research prostate biopsies and multi-parametric magnetic resonance imaging (mpMRI) of the prostate we report a detailed histopathological and radiological characterisation of the primary tumour and its response to ADT, with chemotherapy or androgen receptor signalling inhibitors (ARSIs). A dedicated embedded exploratory prospective, blinded, imaging response sub-study assess whether sequential [68Ga] PSMA-11 PET imaging can predict the presence or absence of residual prostate cancer in the prostate compared to paired mpMRI prostate imaging and prostate biopsy. In the final section, I confirm the safe technical surgical performance of cytoreductive MIAT (with or without metastasectomy), and report acceptable genitourinary and gastrointestinal toxicity in patient-reported outcome measures (PROMS) from the internal pilot RCT patients.
We confirm that most patients have a viable residual prostate tumour on which local cytoreduction can be targeted despite contemporary systemic therapy intensification. It is both safe and feasible to allocate patients with de novo synchronous mHSPC to cytoreductive MIAT, cRP or cytoreductive radiotherapy, with or without metastasis-directed interventions. The main stage component of IP2-ATLANTA will confirm treatment efficacy and superiority of any trial interventions against current standard of care.
The first part of my thesis I provide the pathobiological and clinical rationale of primary tumour cytoreduction, including an evaluation of introducing cytoreductive radical prostatectomy (cRP) and cytoreductive minimally invasive ablative therapies (MIAT). In addition, I systematically review the current evidence for both metastasis-directed therapy (surgery or stereotactic ablative radiation therapy [SABR]) and patient preferences’ for such innovative treatments in this disease setting. We explore how to identify suitable patients with non-curative disease, in a contemporary prostate cancer referral pathway.
This leads to the design and development of a phase II, randomised controlled trial, entitled “IP2-ATLANTA”, in the second part of this thesis. The completion of IP2-ATLANTA internal multicentre pilot enables us to report the acceptability, compliance and safety of using our novel cytoreductive interventions. By utilising serial research prostate biopsies and multi-parametric magnetic resonance imaging (mpMRI) of the prostate we report a detailed histopathological and radiological characterisation of the primary tumour and its response to ADT, with chemotherapy or androgen receptor signalling inhibitors (ARSIs). A dedicated embedded exploratory prospective, blinded, imaging response sub-study assess whether sequential [68Ga] PSMA-11 PET imaging can predict the presence or absence of residual prostate cancer in the prostate compared to paired mpMRI prostate imaging and prostate biopsy. In the final section, I confirm the safe technical surgical performance of cytoreductive MIAT (with or without metastasectomy), and report acceptable genitourinary and gastrointestinal toxicity in patient-reported outcome measures (PROMS) from the internal pilot RCT patients.
We confirm that most patients have a viable residual prostate tumour on which local cytoreduction can be targeted despite contemporary systemic therapy intensification. It is both safe and feasible to allocate patients with de novo synchronous mHSPC to cytoreductive MIAT, cRP or cytoreductive radiotherapy, with or without metastasis-directed interventions. The main stage component of IP2-ATLANTA will confirm treatment efficacy and superiority of any trial interventions against current standard of care.
Version
Open Access
Date Issued
2022-10-08
Date Awarded
01/06/2023
License URL
Advisor
Ahmed, Hashim
Winkler, Mathias
Sponsor
Wellcome Trust (London, England)
University College London Hospitals (Charity)
Grant Number
204998/Z/16/Z
P836724
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)