Immediate versus deferred initiation of androgen deprivation therapy in prostate cancer patients with PSA-only relapse. An observational follow-up study

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Abstract

Background

The optimal timing to start androgen deprivation therapy (ADT) in prostate cancer patients with rising prostate-specific antigen (PSA) as the only sign of relapse is unknown.

Methods

We identified men with prostate cancer in the Cancer of the Prostate Strategic Urologic Research Endeavour (CaPSURE) study who would have been eligible (⩽ cT3aN0M0, primary radical prostatectomy or radiotherapy, PSA relapse as the only evidence of recurrence) for a randomised trial comparing ‘immediate’ versus ‘deferred’ ADT initiation. We emulated such trial by assigning patients to the ‘immediate’ strategy if they initiated ADT within 3 months of PSA relapse and to the ‘deferred’ strategy if they initiated ADT when they presented with metastasis, symptoms or a short PSA doubling time. We censored patients when they deviated from the assigned strategy and adjusted for this censoring via inverse probability weighting.

Results

Of 2096 eligible patients (median age 69, interquartile range 63–75 years), 88% were white, 35% had a Gleason score ⩾7, 69% were treated with radical prostatectomy and 31% received radiotherapy only as primary treatment. The mean time from primary treatment to PSA relapse was 37.4 (standard deviation [SD] 34.2) months. Mean follow-up from primary treatment was 91.4 (SD 48.4) months. The adjusted mortality hazard ratio for immediate versus deferred ADT was 0.91 (95% confidence interval (CI), 0.52–1.60), which would be translated into a similar 5-year survival (difference between groups: −2.0% (95% CI: −10.0 to 5.9%).

Conclusion

Our analysis suggests that prostate cancer patients undergoing immediate ADT initiation within three months after PSA-only relapse had similar survival to those who deferred ADT initiation within 3 months after clinical progression.

Introduction

Androgen deprivation therapy (ADT) is the first line of therapy for advanced prostate cancer [1]. However, the optimal timing to administer ADT is unknown in patients diagnosed with localised disease and treated with curative intention that later present a prostate-specific antigen (PSA)-only relapse (no symptoms, no detectable metastasis) [2]. Specifically, there are no published randomised trials of immediate versus deferred ADT initiation in this subset of patients [3]. The American Society of Clinical Oncology guidelines state that ‘the Panel cannot make a strong recommendation for the early use of ADT’, and that ‘the critical issue is to determine whether there is benefit and how large it is for starting ADT while patients are asymptomatic’ [4].

Randomised controlled trials have shown that castration of asymptomatic patients not suitable for curative treatment resulted in longer time to disease progression [5], [6] and lower prostate cancer mortality [4], [7] as compared with castration at symptom onset. On the other hand, deferring ADT until overt progression (metastases or symptoms) may preserve quality of life [6], [8], [9] and cognitive function [10] for a longer period.

An intermediate strategy for patients with PSA-only relapse would be to use PSA levels and clinical events to decide the timing of ADT initiation. The National Comprehensive Cancer Network considers asymptomatic patients with rising PSA level as a ‘therapeutic dilemma regarding the role of ADT’ [11]. Given the strong association of PSA dynamics (i.e. PSA doubling time) with disease progression and prognosis [12], [13], [14], PSA evolution and clinical events-based initiation may provide the optimal balance between deferring ADT for patients who do not need it and starting ADT immediately in patients with an aggressive disease. Results from an ongoing phase III clinical trial that uses PSA and clinical events-based ADT initiation are not yet available [ClinicalTrials.gov identifier: NCT00110162].

Here we used observational data from a prospective study to emulate this trial. Because, PSA was both a time-varying confounder (it affects timing of treatment, it is associated with survival through biological aggressiveness of the tumour and other unmeasured variables) and was itself affected by prior therapy, we used statistical methods designed to appropriately adjust for time-varying confounders that are affected by prior treatment. [15], [16]) Our goal was to provide a preliminary answer to the question ‘when to start ADT therapy in PSA-only relapsed patients’.

Section snippets

Study population

CaPSURE is a prostate cancer registry study of over 14,000 men with biopsy-proven prostate adenocarcinoma enrolled consecutively from over 45 community-based clinics, three academic institutions and three Veterans Administration hospitals since 1995 [17]. Urologists ascertain clinical data at baseline and subsequent clinic visits. Baseline recorded variables include results of biopsy of the prostate and clinical TNM staging, complete pathology report of the surgical specimen, medical history

Results

Of 9344 patients staged ⩽cT3aN0M0 with PSA determinations and imaging tests after primary treatment, 5351 underwent radical prostatectomy (with or without additional external beam radiotherapy) and 2368 received external beam radiotherapy and/or brachytherapy as their primary treatment. Of these, 2096 patients who never underwent orchiectomy (1437 treated primarily with radical prostatectomy) were eligible for our analysis. See Fig. 1 for a detailed flowchart that shows patients assigned to

Discussion

Our study suggests little or no survival benefit of immediate ADT initiation compared with deferred ADT initiation (at clinical progression) among prostate cancer patients with PSA-only relapse. No survival comparisons between ADT initiation strategies guided by PSA and clinical events have been previously reported for patients with biochemical-only relapse. Therefore our study provides at least a first approximation to answer the ‘when to start ADT’ question in these patients.

Two randomised

Funding

This work was partly funded by NIH grant (P01-CA134294). XGA is a 2012–13 CaPSURE scholar and also a recipient of an ‘ASISA Fellowship’ and a SEOM (Sociedad Española de Oncología Médica) grant. CaPSURE is supported in part by an independent, educational grant from Abbott.

Role of the funding source

The funding sources did not have any involvement in the study design, collection, analysis and interpretation of data, writing of the report or in the decision to submit the article for publication.

Conflict of interest statement

None declared.

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