Comparative Healthcare Research Outcomes of Novel Surgery in prostate cancer (IP4-CHRONOS): A prospective, multi-centre therapeutic phase II parallel Randomised Control Trial

Abstract

Introduction: Focal therapy (FT) targets individual areas of cancer within the prostate, to confer oncological control with minimal side-effects. Early evidence demonstrates encouraging shortmedium-term outcomes. With no randomised controlled trials (RCT) comparing FT to radical therapies, Comparative Healthcare Research Outcomes of Novel Surgery in prostate cancer (CHRONOS) will compare the cancer control of these two treatment strategies.Patients and Methods: CHRONOS is a parallel phase II RCT for patients with clinically significant nonmetastatic prostate cancer. CHRONOS-A will randomise patients to either radical treatment or FT.CHRONOS-B is a multi-arm, multistage RCT comparing focal therapy alone to FT with neoadjuvant agents that might improve the current focal therapy outcomes. An internal pilot will determine the feasibility of randomisation and compliance to allocation, whilst the proposed definitive study will recruit and randomise 1190 patients into CHRONOS-A and 1260 patients into CHRONOS-B.Results: Primary outcome in CHRONOS-A is progression-free survival (the transition to salvage local or systemic therapy, development of metastases or prostate-cancer-related mortality) and in CHRONOS-B is failure-free survival (includes the above definition and recurrence of clinically significant prostate cancer after initial FT). Secondary outcomes include adverse events, health economics and continence, erectile and bowel function measured using validated questionnaires. CHRONOS is powered to assess non-inferiority of FT compared to radical therapy in CHRONOS-A, and superiority of neoadjuvant agents with FT in CHRONOS-B.Discussion: CHRONOS will assess the oncological outcomes after FT compared to radical therapy and determine whether neoadjuvant treatments might improve cancer control following one FT session.

Focal therapy for localized prostate cancer – Current status

“…For example, CHRONOS is a parallel phase II-controlled trial in men with newly diagnosed localized intermediate-high risk PCa. [ 44 ] In CHRONOS arm A patients will be randomized to whole-gland treatment (radical prostatectomy, radiotherapy, and brachytherapy) versus focal cancer treatment (HIFU and cryotherapy). On the other hand, patients who enroll in CHRONOS arm B, will be randomized to FT alone versus FT with neoadjuvant treatment, e.g., finasteride or bicalutamide.…”

A Systematic Review of Focal Ablative Therapy for Clinically Localised Prostate Cancer in Comparison with Standard Management Options: Limitations of the Available Evidence and Recommendations for Clinical Practice and Further Research

“…After screening, 22 studies were excluded: 16 were single-arm case series, four addressed salvage FT, one had an inappropriate comparator, and one had fewer than 50 patients per arm. Eight prospective comparative studies were eligible for inclusion; Table 4 summarises their baseline characteristics [40][41][42][43][44][45][46][47]. Seven are RCTs and one is a prospective NRCS.…”

“…Seven are RCTs and one is a prospective NRCS. Two large RCTs from the UK (PART, n = 800; and CHRONOS, n = 2450) are comparing FT with radical treatment (RP or EBRT or brachytherapy) [40,41] An RCT in China (n = 438) is comparing focal IRE to RP [42]. An RCT in Sweden (n = 250) is comparing HIFU to RP [43].…”

Feasibility of Comparative Health Research Outcome of Novel Surgery in prostate cancer (IP4-CHRONOS): statistical analysis plan for the randomised feasibility phase of the CHRONOS study

“…Our aim was to test the feasibility of two parallel RCTs within an overarching strategy that fits with existing patient and physician equipoise. The study protocol has been published [ 1 ] [International Standard Randomised Controlled Trial Number: ISRCTN17796995].…”