Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial

Summary

Background

How best to treat rising prostate-specific antigen (PSA) concentration after radical prostatectomy is an urgent clinical question. Salvage radiotherapy delays the need for more aggressive treatment such as long-term androgen suppression, but fewer than half of patients benefit from it. We aimed to establish the effect of adding short-term androgen suppression at the time of salvage radiotherapy on biochemical outcome and overall survival in men with rising PSA following radical prostatectomy.

Methods

This open-label, multicentre, phase 3, randomised controlled trial, was done in 43 French study centres. We enrolled men (aged ≥18 years) who had received previous treatment for a histologically confirmed adenocarcinoma of the prostate (but no previous androgen deprivation therapy or pelvic radiotherapy), and who had stage pT2, pT3, or pT4a (bladder neck involvement only) in patients who had rising PSA of 0·2 to less than 2·0 μg/L following radical prostatectomy, without evidence of clinical disease. Patients were randomly assigned (1:1) centrally via an interactive web response system to standard salvage radiotherapy (three-dimensional [3D] conformal radiotherapy or intensity modulated radiotherapy, of 66 Gy in 33 fractions 5 days a week for 7 weeks) or radiotherapy plus short-term androgen suppression using 10·8 mg goserelin by subcutaneous injection on the first day of irradiation and 3 months later. Randomisation was stratified using a permuted block method according to investigational site, radiotherapy modality, and prognosis. The primary endpoint was progression-free survival, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00423475.

Findings

Between Oct 19, 2006, and March 30, 2010, 743 patients were randomly assigned, 374 to radiotherapy alone and 369 to radiotherapy plus goserelin. Patients assigned to radiotherapy plus goserelin were significantly more likely than patients in the radiotherapy alone group to be free of biochemical progression or clinical progression at 5 years (80% [95% CI 75–84] vs 62% [57–67]; hazard ratio [HR] 0·50, 95% CI 0·38–0·66; p<0·0001). No additional late adverse events occurred in patients receiving short-term androgen suppression compared with those who received radiotherapy alone. The most frequently occuring acute adverse events related to goserelin were hot flushes, sweating, or both (30 [8%] of 366 patients had a grade 2 or worse event; 30 patients [8%] had hot flushes and five patients [1%] had sweating in the radiotherapy plus goserelin group vs none of 372 patients in the radiotherapy alone group). Three (8%) of 366 patients had grade 3 or worse hot flushes and one patient had grade 3 or worse sweating in the radiotherapy plus goserelin group versus none of 372 patients in the radiotherapy alone group. The most common late adverse events of grade 3 or worse were genitourinary events (29 [8%] in the radiotherapy alone group vs 26 [7%] in the radiotherapy plus goserelin group) and sexual disorders (20 [5%] vs 30 [8%]). No treatment-related deaths occurred.

Interpretation

Adding short-term androgen suppression to salvage radiotherapy benefits men who have had radical prostatectomy and whose PSA rises after a postsurgical period when it is undetectable. Radiotherapy combined with short-term androgen suppression could be considered as a reasonable option in this population.

Funding

French Ministry of Health, AstraZeneca, and La Ligue Contre le Cancer.

Introduction

After radical prostatectomy a third of patients relapse with a rise in serum prostate-specific antigen (PSA) concentration without evidence of clinical or radiographic disease and, in the absence of salvage treatment, develop distant metastases.¹ Antonarakis and colleagues² reported metastasis-free survival rates of 67% at 5 years and 48% at 10 years in patients with PSA recurrence after radical prostatectomy without salvage treatment.

The standard treatment for most patients with biochemical recurrence after radical prostatectomy is salvage radiotherapy. Boorjian and colleagues³ reported a decrease in the risk of distant metastasis of 75% with salvage therapy and a 20% reduction in the need of androgen ablation therapy compared with no salvage therapy in 2657 patients with PSA relapse after radical prostatectomy. However, fewer than 50% of patients are thought to be free of biochemical relapse 5 years after salvage radiotherapy alone.4, 5, 6, 7, 8, 9 Salvage radiotherapy delays the need for chronic, non-curative treatment, such as long-term androgen suppression, and is the only potentially curative treatment. Suggested risk factors for biochemical relapse following salvage radiotherapy after radical prostatectomy are time to relapse after surgery, PSA doubling time, PSA concentration at the time of salvage radiotherapy, Gleason score greater than 7, and positive surgical margins or seminal vesicle involvement.8, 9, 10 Without treatment, risk of prostate cancer death at 10 years is estimated to be 99% for these high-risk subgroups, but retrospective data suggest an improvement in biochemical outcomes if short-term androgen suppression is added to salvage radiotherapy.¹¹ This combined modality approach has proved efficacious in randomised studies of patients with locally advanced prostate cancer who received radiotherapy. Results of the RTOG 9601 trial¹² showed a benefit for overall survival when 2 years of bicalutamide was combined with salvage radiotherapy. However, in this trial,¹² patients with persistently raised or recurrent PSA concentrations were included, and the benefit seemed to be higher for patients with a PSA concentration of greater than 1·5 μg/L than for those with a lower PSA concentration.

Research in context

Evidence before this study

We searched PubMed using the terms “randomised trial”, “rising PSA”, “radical prostatectomy”, and “salvage radiation therapy” for articles published between Jan 1, 1995, and Dec 31, 2015. We took into account the consensus statement on radiation therapy of prostate cancer published in the Journal of Clinical Oncology (1999), the prescribing recommendations from the International Commission on Radiation Units (1993), the European Organisation for Research and Treatment of Cancer QLQ-C30 scoring manual, and the RTOG 9601 protocol even though this trial allowed the inclusion of patients with persistent PSA after radical prostatectomy. We found no randomised trials comparing hormone therapy and radiotherapy versus radiotherapy alone in patients with rising PSA concentrations after radical prostatectomy, that had excluded patients with sustained elevated PSA concentrations after surgery.

Added value of this study

Our study showed that progression-free survival was improved when goserelin treatment was added to salvage radiotherapy compared with salvage radiotherapy alone. Although no effect on overall survival has been found to date, combined treatment should be considered a reasonable option.

Implications of all the available evidence

Short-term androgen suppression combined with salvage radiotherapy should be considered as a reasonable treatment option, especially for high-risk patients. The improvement in progression-free survival could allow postponement of more aggressive treatment, such as long-term androgen suppression, and thus prevent a deleterious effect on quality of life and cardiovascular status. Comparison of this combined treatment with salvage radiotherapy plus abiraterone could be explored.

We did a phase 3 trial (GETUG-AFU 16) to investigate whether the addition of short-term androgen suppression to salvage radiotherapy in men with rising PSA concentrations after radical prostatectomy would improve biochemical outcome and overall survival without jeopardising quality of life. To our knowledge, this is the first prospective controlled study of short-term androgen suppression combined with salvage radiotherapy in this clinical setting.