Elsevier

The Lancet Oncology

Volume 21, Issue 10, October 2020, Pages 1331-1340
The Lancet Oncology

Articles
Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial

https://doi.org/10.1016/S1470-2045(20)30456-3Get rights and content

Summary

Background

Adjuvant radiotherapy has been shown to halve the risk of biochemical progression for patients with high-risk disease after radical prostatectomy. Early salvage radiotherapy could result in similar biochemical control with lower treatment toxicity. We aimed to compare biochemical progression between patients given adjuvant radiotherapy and those given salvage radiotherapy.

Methods

We did a phase 3, randomised, controlled, non-inferiority trial across 32 oncology centres in Australia and New Zealand. Eligible patients were aged at least 18 years and had undergone a radical prostatectomy for adenocarcinoma of the prostate with pathological staging showing high-risk features defined as positive surgical margins, extraprostatic extension, or seminal vesicle invasion; had an Eastern Cooperative Oncology Group performance status of 0–1, and had a postoperative prostate-specific antigen (PSA) concentration of 0·10 ng/mL or less. Patients were randomly assigned (1:1) using a minimisation technique via an internet-based, independently generated allocation to either adjuvant radiotherapy within 6 months of radical prostatectomy or early salvage radiotherapy triggered by a PSA of 0·20 ng/mL or more. Allocation sequence was concealed from investigators and patients, but treatment assignment for individual randomisations was not masked. Patients were stratified by radiotherapy centre, preoperative PSA, Gleason score, surgical margin status, and seminal vesicle invasion status. Radiotherapy in both groups was 64 Gy in 32 fractions to the prostate bed without androgen deprivation therapy with real-time review of plan quality on all cases before treatment. The primary endpoint was freedom from biochemical progression. Salvage radiotherapy would be deemed non-inferior to adjuvant radiotherapy if freedom from biochemical progression at 5 years was within 10% of that for adjuvant radiotherapy with a hazard ratio (HR) for salvage radiotherapy versus adjuvant radiotherapy of 1·48. The primary analysis was done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT00860652.

Findings

Between March 27, 2009, and Dec 31, 2015, 333 patients were randomly assigned (166 to adjuvant radiotherapy; 167 to salvage radiotherapy). Median follow-up was 6·1 years (IQR 4·3–7·5). An independent data monitoring committee recommended premature closure of enrolment because of unexpectedly low event rates. 84 (50%) patients in the salvage radiotherapy group had radiotherapy triggered by a PSA of 0·20 ng/mL or more. 5-year freedom from biochemical progression was 86% (95% CI 81–92) in the adjuvant radiotherapy group versus 87% (82–93) in the salvage radiotherapy group (stratified HR 1·12, 95% CI 0·65–1·90; pnon-inferiority=0·15). The grade 2 or worse genitourinary toxicity rate was lower in the salvage radiotherapy group (90 [54%] of 167) than in the adjuvant radiotherapy group (116 [70%] of 166). The grade 2 or worse gastrointestinal toxicity rate was similar between the salvage radiotherapy group (16 [10%]) and the adjuvant radiotherapy group (24 [14%]).

Interpretation

Salvage radiotherapy did not meet trial specified criteria for non-inferiority. However, these data support the use of salvage radiotherapy as it results in similar biochemical control to adjuvant radiotherapy, spares around half of men from pelvic radiation, and is associated with significantly lower genitourinary toxicity.

Funding

New Zealand Health Research Council, Australian National Health Medical Research Council, Cancer Council Victoria, Cancer Council NSW, Auckland Hospital Charitable Trust, Trans-Tasman Radiation Oncology Group Seed Funding, Cancer Research Trust New Zealand, Royal Australian and New Zealand College of Radiologists, Cancer Institute NSW, Prostate Cancer Foundation Australia, and Cancer Australia.

Introduction

Radical prostatectomy is the most frequently used treatment modality for men with clinically localised prostate cancer.1 Historically, a third of patients develop recurrent disease,2 although with better selection and contemporary surgical techniques the proportion might be closer to 20%.3 The risk of recurrence is greater among men with high-risk features, including extraprostatic extension, seminal vesicle invasion, and positive surgical margins.4

Research in context

Evidence before this study

When this study was under development in 2007, the use of adjuvant radiotherapy to the prostate bed after radical prostatectomy had been shown to halve the risk of biochemical progression when compared with observation for men with prostate cancer with high-risk features. Results of three randomised trials initiated between 1988 and 1996 supported the use of adjuvant radiotherapy (ARO 96-02/AUO AP 09/95; EORTC trial 2291; SWOG8794), with one of these studies also showing improved metastasis-free survival and overall survival. Despite this evidence, adjuvant radiotherapy has not been widely adopted due to concerns over perceived toxicity. A potential limitation of these three randomised trials is that there was no standard management for patients on observation who developed relapse. Salvage radiotherapy was given intermittently and at varying lengths of time after relapse, with some patients having documented locoregional progression before treatment. The results of the three studies were used to generate American and European guidelines, which recommend that such men be referred for consideration of adjuvant radiotherapy. Due to this broad acknowledgment of the three studies in the field of post-prostatectomy prostate cancer management, a systematic review was not done before the development of the RAVES trial. The recommendation to routinely administer adjuvant radiotherapy comes at the potential cost of increased morbidity. There is the possibility that observing these patients and delivering salvage radiotherapy when prostate-specific antigen (PSA) first starts to rise could have similar efficacy.

Added value of this study

This study confirmed that men with high-risk features have a rising PSA in more than 50% of cases following surgery when observed. Our results have shown similar high rates of disease-free survival at 5 years for both the early salvage and adjuvant radiotherapy groups. This outcome has been achieved with relatively modest radiation doses in the salvage radiotherapy group by treating relapse very early as soon as the PSA reaches 0·20 ng/mL. The study also documented an increase in genitourinary morbidity when radiotherapy is given to all patients in an adjuvant setting.

Implications of all the available evidence

These results are being released concurrently with the RADICALS and GETUG-17 trials, along with a pre-planned meta-analysis of all three trials. These trials have concordant results suggesting that adjuvant radiotherapy does not improve event-free survival in men with high-risk features following radical prostatectomy. It now appears preferable to wait until the cancer recurs, heralded by a PSA rising to 0·20 ng/mL, before commencing radiotherapy, which would spare many men from potential radiotherapy-related side-effects.

Three randomised controlled trials have reported a halving of biochemical progression with the use of adjuvant radiotherapy compared with surgery alone in patients with high-risk features following radical prostatectomy.5, 6, 7 One of these trials also showed an improvement in metastasis-free survival and overall survival.7 Although these trials have shown a benefit of adjuvant radiotherapy over observation, subsequent use of adjuvant radiotherapy has been uncommon,8 in part due to clinician concerns about radiation-related toxicities and the possibility that early salvage radiotherapy to the prostate bed might provide equivalent control to adjuvant radiotherapy.9

The primary aim of the RAVES trial was to test the hypothesis that for patients with pT3 disease (ie, extraprostatic extension with or without seminal vesicle involvement) or positive margins following radical prostatectomy, observation with early salvage radiotherapy is non-inferior to standard treatment of adjuvant radiotherapy with respect to biochemical progression.

Section snippets

Study design and participants

This phase 3, randomised, controlled, non-inferiority trial (RAVES) was done in 32 oncology centres across Australia and New Zealand, and led by the Trans-Tasman Radiation Oncology Group (TROG) in collaboration with the Urological Society of Australia and New Zealand, and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (appendix p 5).

Eligible patients were aged at least 18 years and had undergone a radical prostatectomy for adenocarcinoma of the prostate with

Results

Between March 27, 2009, and Dec 31, 2015, 333 patients were randomly assigned to treatment (166 to adjuvant radiotherapy; 167 to salvage radiotherapy; figure 1). 26 patients did not complete study follow-up due to withdrawal, loss to follow-up, or death. Median follow-up was 6·1 years (IQR 4·3–7·5). Demographics and baseline features are shown in the table.

84 (50%) patients in the salvage radiotherapy group had a PSA of 0·20 ng/mL or more to trigger radiotherapy (one patient requested salvage

Discussion

The RAVES trial shows similar biochemical control rates between adjuvant radiotherapy and early salvage radiotherapy with 5-year freedom from biochemical progression of 86% in the adjuvant radiotherapy group compared with 87% in the salvage radiotherapy group. Although the study was underpowered for non-inferiority, these findings support our hypothesis that salvage radiotherapy does not have a freedom from biochemical progression rate that is more than 10% inferior to adjuvant radiotherapy.

Data sharing

Secondary analyses of these trial data are encouraged, subject to review by the TROG scientific committee. Once all planned analyses have been completed, de-identified individual participant data and a data dictionary will be made available to the scientific community upon formal application once publication of primary and secondary analyses are complete. All applications will be reviewed per the Trans-Tasman Radiation Oncology Group's policy statement on Undertaking Secondary Analyses on TROG

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