Upcoming event

Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial

  • Christian Carrie,
  • Nicolas Magné,
  • Patricia Burban-Provost,
  • Paul Sargos,
  • Igor Latorzeff,
  • Jean-Léon Lagrange,
  • Stéphane Supiot,
  • Yazid Belkacemi,
  • Didier Peiffert,
  • Nedla Allouache,
  • Bernard M Dubray,
  • Stéphanie Servagi-Vernat,
  • Jean-Philippe Suchaud,
  • Gilles Crehange,
  • Stéphane Guerif,
  • Meryem Brihoum,
  • Nicolas Barbier,
  • Pierre Graff-Cailleaud,
  • Alain Ruffion,
  • Sophie Dussart,
  • Céline Ferlay,
  • Sylvie Chabaud

Publication: The Lancet Oncology, October 2019

DOI: https://doi.org/10.1016/S1470-2045(19)30486-3

Background

Radiotherapy is the standard salvage treatment after radical prostatectomy. To date, the role of androgen deprivation therapy has not been formally shown. In this follow-up study, we aimed to update the results of the GETUG-AFU 16 trial, which assessed the efficacy of radiotherapy plus androgen suppression versus radiotherapy alone.

Methods

GETUG-AFU 16 was an open-label, multicentre, phase 3, randomised, controlled trial that enrolled men (aged ≥18 years) with Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed adenocarcinoma of the prostate (but no previous androgen suppression or pelvic radiotherapy), stage pT2, T3, or T4a (bladder neck involvement only) and pN0 or pNx according to the tumour, node, metastasis (TNM) staging system, whose prostate-specific antigen (PSA) concentration increased from 0·1 ng/mL to between 0·2 ng/mL and 2·0 ng/mL after radical prostatectomy, without evidence of clinical disease. Patients were assigned through central randomisation (1:1) to short-term androgen suppression (subcutaneous injection of 10·8 mg goserelin on the first day of irradiation and 3 months later) plus radiotherapy (3D conformal radiotherapy or intensity modulated radiotherapy of 66 Gy in 33 fractions, 5 days a week for 7 weeks) or radiotherapy alone. Randomisation was stratified using a permuted block method (block sizes of two and four) according to investigational site, radiotherapy modality, and prognosis. The primary endpoint was progression-free survival in the intention-to-treat population. This post-hoc one-shot data collection done 4 years after last data cutoff included patients who were alive at the time of the primary analysis and updated long-term patient status by including dates for first local progression, metastatic disease diagnosis, or death (if any of these had occurred) or the date of the last tumour evaluation or last PSA measurement. Survival at 120 months was reported. Late serious adverse effects were assessed. This trial is registered on ClinicalTrials.govNCT00423475.

Findings

Between Oct 19, 2006, and March 30, 2010, 743 patients were randomly assigned, 374 to radiotherapy alone and 369 to radiotherapy plus goserelin. At the time of data cutoff (March 12, 2019), the median follow-up was 112 months (IQR 102–123). The 120-month progression-free survival was 64% (95% CI 58–69) for patients treated with radiotherapy plus goserelin and 49% (43–54) for patients treated with radiotherapy alone (hazard ratio 0·54, 0·43–0·68; stratified log-rank test p<0·0001). Two cases of secondary cancer occurred since the primary analysis, but were not considered to be treatment related. No treatment-related deaths occurred.

Interpretation

The 120-month progression-free survival confirmed the results from the primary analysis. Salvage radiotherapy combined with short-term androgen suppression significantly reduced risk of biochemical or clinical progression and death compared with salvage radiotherapy alone. The results of the GETUG-AFU 16 trial confirm the efficacy of androgen suppression plus radiotherapy as salvage treatment in patients with increasing PSA concentration after radical prostatectomy for prostate cancer.

When prostate cancer comes back after a radical prostatectomy (= an operation to remove prostate cancer), radiotherapy is the standard second attempt to treat prostate cancer with. However, another possible therapy is an antihormone treatment called androgen deprivation therapy. In this article, the authors describe the clinical trial they have conducted in which they assessed the impact of androgen deprivation therapy given simultaneously with radiotherapy on prostate cancer that has come back. The results were positive: patients who had received the combined treatment had better outcomes: they lived longer without the cancer getting worse, and they didn’t develop tumours in other parts of the body. Therefore, six months of androgen deprivation therapy simultaneous with radiotherapy should be considered the norm. The next step should be to identify patients who would benefit the most from this method in order to reduce the risks of overtreatment and the occurrence of negative effects linked to androgen deprivation therapy.

Expert's summary

The present publication reports the updated results after a 10-year follow-up in a cohort of 743 men randomly assigned (1:1 ratio) between salvage radiotherapy and salvage radiotherapy with goserelin. The pelvis was irradiated (46 Gy) in men (16% of the cohort) who did not undergo pelvic lymph node dissection. The primary endpoint was the progression-free survival defined by the time from randomisation to biological or clinical progression. Biological progression was defined by a PSA increase >0.5 ng/ml above the nadir. Metastasis-free survival was assessed as a secondary endpoint. Any metastatic event outside the prostatic bed was considered as a metastatic relapse, including nodal relapse. The 10-year progression rate was higher in the radiotherapy plus goserelin group compared with that reported in the radiotherapy group 64% versus 49%, respectively (p<0.001).

The 10-year metastasis-free survival rates were 75% and 69% in patients assigned to radiotherapy and to radiotherapy plus goserelin, respectively. The log-rank p value was 0.031 with a HR 0.73.

Sub-group analyses were performed. Progression-free survival was improved by concomitant goserelin in both low- and high-risk groups. Nevertheless, no difference in metastasis-free survival was reported between these two risk sub-groups as well as in sub-groups stratified by Gleason score, margins, PSA doubling time, seminal vesicle involvement. Mortality rate was 12% in the radiotherapy plus goserelin group versus 14% in the radiotherapy group (p=0.73).

Thus, the final analysis of this phase 3 trial confirmed the benefit from adding short-term ADT to salvage radiotherapy in the context of PSA recurrence after radical prostatectomy (as reported in the American RTOG trial). Advantages were seen in terms of progression-free survival and metastasis-free survival. However, the benefit was moderate regarding metastatic events. This could be explained by an insufficient follow-up with a low occurrence of events. Other limitations were the absence of centralized review for the baseline scans and the lack of systematic bone and CT scans during follow-up. Imaging was required at the time of recurrence but not regularly assessed thereafter. Metastatic events may have been underestimated. Sub-group analyses (all significantly negative) did not help us to identify patients who could benefit the most from this concomitant salvage strategy. A not negligible proportion of low-risk patients with favorable pathology could have been overtreated by the addition of short-term ADT. A pooled analysis incorporating patients from the RTOG and the AFU-GETUG trials might be relevant to improve the selection of ideal candidates for this combined strategy.