Elsevier

The Lancet Oncology

Volume 17, Issue 6, June 2016, Pages 727-737
The Lancet Oncology

Articles
Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial

https://doi.org/10.1016/S1470-2045(16)00107-8Get rights and content

Summary

Background

Androgen-deprivation therapy is offered to men with prostate cancer who have a rising prostate-specific antigen after curative therapy (PSA relapse) or who are considered not suitable for curative treatment; however, the optimal timing for its introduction is uncertain. We aimed to assess whether immediate androgen-deprivation therapy improves overall survival compared with delayed therapy.

Methods

In this randomised, multicentre, phase 3, non-blinded trial, we recruited men through 29 oncology centres in Australia, New Zealand, and Canada. Men with prostate cancer were eligible if they had a PSA relapse after previous attempted curative therapy (radiotherapy or surgery, with or without postoperative radiotherapy) or if they were not considered suitable for curative treatment (because of age, comorbidity, or locally advanced disease). We used a database-embedded, dynamically balanced, randomisation algorithm, coordinated by the Cancer Council Victoria, to randomly assign participants (1:1) to immediate androgen-deprivation therapy (immediate therapy arm) or to delayed androgen-deprivation therapy (delayed therapy arm) with a recommended interval of at least 2 years unless clinically contraindicated. Randomisation for participants with PSA relapse was stratified by type of previous therapy, relapse-free interval, and PSA doubling time; randomisation for those with non-curative disease was stratified by metastatic status; and randomisation in both groups was stratified by planned treatment schedule (continuous or intermittent) and treatment centre. Clinicians could prescribe any form and schedule of androgen-deprivation therapy and group assignment was not masked. The primary outcome was overall survival in the intention-to-treat population. The trial closed to accrual in 2012 after review by the independent data monitoring committee, but data collection continued for 18 months until Feb 26, 2014. It is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12606000301561) and ClinicalTrials.gov (NCT00110162).

Findings

Between Sept 3, 2004, and July 13, 2012, we recruited 293 men (261 with PSA relapse and 32 with non-curable disease). We randomly assigned 142 men to the immediate therapy arm and 151 to the delayed therapy arm. Median follow-up was 5 years (IQR 3·3–6·2) from the date of randomisation. 16 (11%) men died in the immediate therapy arm and 30 (20%) died in the delayed therapy arm. 5-year overall survival was 86·4% (95% CI 78·5–91·5) in the delayed therapy arm versus 91·2% (84·2–95·2) in the immediate therapy arm (log-rank p=0·047). After Cox regression, the unadjusted HR for overall survival for immediate versus delayed arm assignment was 0·55 (95% CI 0·30–1·00; p=0·050). 23 patients had grade 3 treatment-related adverse events. 105 (36%) men had adverse events requiring hospital admission; none of these events were attributable to treatment or differed between treatment-timing groups. The most common serious adverse events were cardiovascular, which occurred in nine (6%) patients in the delayed therapy arm and 13 (9%) in the immediate therapy arm.

Interpretation

Immediate receipt of androgen-deprivation therapy significantly improved overall survival compared with delayed intervention in men with PSA-relapsed or non-curable prostate cancer. The results provide benchmark evidence of survival rates and morbidity to discuss with men when considering their treatment options.

Funding

Australian National Health and Medical Research Council and Cancer Councils, The Royal Australian and New Zealand College of Radiologists, Mayne Pharma Australia.

Introduction

The question of when to start androgen-deprivation therapy in men with incurable prostate cancer has vexed clinicians for many years. Prostate cancer has a long natural history with many deaths being attributed to other causes, and treatment has substantial costs, side-effects, and inconvenience. Several trials1, 2, 3 have sought to assess the best timing for androgen-deprivation therapy in men with established metastatic or locally advanced disease. Findings suggest that survival is improved with early intervention, compared with waiting for the development of, or increasing, symptoms or disease progression.1, 2, 3 The decision of the optimal timing for intervention is more difficult when men are asymptomatic, either at the time of diagnosis when curative strategies are not appropriate or at relapse after failed curative therapy when the only sign of any disease activity is a rising prostate-specific antigen (PSA). Although prolonged survival after curative therapies for prostate cancer is expected,4, 5, 6 a detectable PSA in an asymptomatic patient is an important clinical issue. Review of the available evidence7 in 2006 to update the American Society of Clinical Oncology (ASCO) management guidelines could not find sufficient evidence to establish the optimum timing of androgen-deprivation therapy in these men.

Research in context

Evidence before this study

When this study was conceived in 2003, there was no evidence to guide clinical decision making for the timing of intervention with androgen-deprivation therapy for men with prostate cancer who have a rising prostate-specific antigen (PSA) after unsuccessful curative therapy. For asymptomatic men with overt disease who are not considered for curative treatment, three randomised phase 3 trials were either completed or closed to accrual with data maturing, which were identified through the programmes of recognised collaborative trial groups. We surmised that there was insufficient published evidence available to support a systematic literature review. The MRC-UK trial of men with established locally advanced or metastatic disease suggested a benefit from early rather than delayed intervention, but the men given delayed intervention were perhaps not optimally managed. The two studies subsequently reported from the European Organisation for Research and Treatment of Cancer (EORTC 30891 and 30846) for men with loco-regional disease showed an inconclusive result for 30846, but 30891 suggested a benefit to early intervention.

Added value of this study

To our knowledge this is the first randomised trial to provide evidence of the impact of the timing of androgen-deprivation therapy in men with prostate cancer with a PSA relapse. It provides a benchmark for the survival rates of men diagnosed with this disease stage, which was not previously available, and indicates the effects on survival, disease progression, development of complications, toxicity of treatment, and quality of life. We plan to combine these data for men with PSA-relapse with the parallel Canadian ELAAT study to increase the strength of the evidence. The small number of men in the overt disease group of our trial precluded useful analysis of treatment-timing to add evidence to the three previous studies.

Implications of all the available evidence

Results from our randomised trial, combined with the evidence from other studies, add weight to the concept that early intervention in incurable disease, whether occult or overt, improves survival. We provide evidence to guide discussions with men with a PSA relapse as to their preferred treatment approach, with benchmarks for survival rates, morbidity rates, and quality of life for both immediate and delayed strategies.

The TOAD (Timing Of Androgen Deprivation) trial was developed in 2003, as a collaboration between the Cooperative Oncology Group of the Cancer Council Victoria (CCV), the Trans Tasman Radiation Oncology Group (TROG), and the Urological Society of Australia and New Zealand (USANZ). Androgen-deprivation therapy was known to affect quality of life in terms of reduced energy and poorer sexual and urinary function.8 TOAD was therefore designed to provide evidence about the effect of immediate versus delayed intervention on the trade-offs between overall survival, toxicity, and quality of life. The trial mainly aimed to assess men with a PSA relapse after definitive therapy (radical prostatectomy with or without postoperative radiotherapy or curative radiotherapy alone) but who had no overt clinical disease. There was also interest in newly diagnosed asymptomatic men who were considered unsuitable for curative treatment. Therefore, we aimed to assess whether early intervention with androgen-deprivation therapy in either of these patient populations would improve overall survival, while maintaining an acceptable quality of life, when compared to delayed intervention.

Section snippets

Study design and participants

The TOAD trial is a randomised, multicentre, phase 3 trial done in 29 public and private cancer centres across Australia, New Zealand, and Canada (appendix). Men were recruited by their medical specialists after confirming that they met the relevant eligibility criteria.

Eligible participants had a histologically confirmed diagnosis of adenocarcinoma of the prostate. We specified no age limit for eligibility, but we excluded men with substantial medical comorbidities that reduced life expectancy

Results

Between Sept 3, 2004 and July 13, 2012, we recruited 293 men with prostate cancer. 261 men were recruited according to the PSA-relapse protocol (group one) and 32 were recruited according to the non-curable disease protocol (group two; table 1, figure 1). The trial closed in mid-2012 after review of accrual by the independent data monitoring committee. The close date for follow-up data to be included in the analysis was Feb 26, 2014, allowing a minimum of 18 months of data collection after

Discussion

Overall survival was significantly longer in the immediate androgen-deprivation therapy arm compared with the delayed therapy arm. Our trial also demonstrated a significant benefit to early intervention for most outcomes, except for cause-specific mortality where the number of events was low. Global quality of life did deteriorate more in the immediate therapy arm than in the delayed therapy arm over the first 2 years by a small but clinically notable amount, but men assigned to the immediate

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Rodney A Syme is retired

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