For patients with high-risk prostate cancer, external beam radiotherapy (EBRT) combined with long-term androgen deprivation therapy (ADT) is an established treatment approach. However, whether increasing the radiation dose provides additional long-term benefit when patients already receive prolonged ADT has remained uncertain.
The phase 3 GETUG-AFU 18 trial evaluated whether escalating the prostate radiation dose from 70 Gy to 80 Gy could improve outcomes in this setting. After a median follow-up approaching 10 years, the study reported improvements in progression-free survival (PFS), overall survival (OS), and prostate cancer-specific survival with the higher radiation dose, without an apparent increase in overall toxicity.
The study, titled “High-dose radiotherapy in patients with high-risk prostate cancers treated with long-term androgen deprivation therapy (GETUG AFU 18): a randomised, phase 3 trial,” was published in The Lancet Oncology.
Authors: Christophe Hennequin, Paul Sargos, Lise Roca, Marion Silva, Igor Latorzeff, Didier Peiffert, Salvatore Cozzi, Ahmed Benyoucef, Ali Hasbini, Stéphane Supiot, Philippe Ronchin, Thierry Wachter, David Azria, Nicolas Magne, Mallik Zibouche, Nicolas Vial, and Luc Cormier.
GETUG-AFU 18 Trial
GETUG-AFU 18 was a multicenter, open-label, randomized phase 3 trial conducted across 25 centers in France. The study enrolled 505 men with high-risk prostate cancer between April 2009 and January 2013. High-risk disease was defined by at least one of the following: PSA of 20 ng/mL or higher, Gleason score of at least 8, or clinical stage T3–T4. Patients were required to have no nodal or distant metastases on conventional staging with CT and bone scans.
Participants were randomly assigned 1:1 to receive either dose-escalated EBRT at 80 Gy or standard-dose EBRT at 70 Gy, together with long-term ADT.
A total of 250 patients were assigned to the 80 Gy group and 255 to the 70 Gy group. Radiation was delivered in conventional 2 Gy fractions: 80 Gy in 40 fractions over 8 weeks or 70 Gy in 35 fractions over 7 weeks. All patients were intended to receive ADT for up to 36 months. The median duration of ADT was approximately 33 months in both groups.
The primary endpoint was 5-year PFS, defined as the time from randomization to biochemical or clinical progression. Because considerably fewer events occurred than originally anticipated, the investigators also reported 10-year PFS in a post-hoc analysis.
Higher Radiation Dose Improved Long-Term PFS
At a median follow-up of 9.5 years, 92 progression events had occurred: 35 in the 80 Gy group and 57 in the 70 Gy group. At 5 years, PFS was:
- 91.4% with 80 Gy vs 88.1% with 70 Gy.
The difference became more pronounced with longer follow-up. At 10 years, PFS was:
- 83.6% vs 72.2%, respectively.
Dose escalation was associated with a lower risk of progression, with an adjusted hazard ratio of 0.56 (95% CI 0.40–0.78; p<0.0001). Median PFS was not reached in either treatment group.
Overall and Prostate Cancer-Specific Survival
A total of 120 deaths occurred during follow-up: 47 in the dose-escalation group and 73 in the control group. At 10 years, OS was 77.0% with 80 Gy compared with 65.9% with 70 Gy, corresponding to an HR of 0.61 (95% CI 0.44–0.85; p=0.0040).
Of the 120 deaths, 26 were attributed to prostate cancer: nine in the 80 Gy group and 17 in the 70 Gy group. Ten-year prostate cancer-specific survival was 95.6% with 80 Gy vs 90.0% with 70 Gy, with an HR of 0.48 (95% CI 0.27–0.83; p=0.0090).
Metastasis-free survival was evaluated post hoc. There were 18 metastatic progression events in the 80 Gy group and 24 in the 70 Gy group, with no significant difference between the groups (p=0.28).
Toxicity Was Similar Between Groups
Importantly, the improved disease outcomes with dose escalation were not accompanied by a clear increase in overall toxicity. Grade 3 or worse adverse events during the first 6 months were reported in 24% of patients receiving 80 Gy and 25% receiving 70 Gy.
The most frequent grade 3 or worse events were sexual disorders, occurring in 11% and 8% of patients, respectively, and bladder or urethral disorders, reported in 5% and 8%. Among patients evaluated at 5 years, late adverse events of any grade occurred in 70% of patients in the 80 Gy group and 73% in the 70 Gy group. Grade 3 or worse late toxicities occurred in 8% vs 7%, respectively.
The most common late grade 3 adverse event was bladder or urethral toxicity, reported in seven patients receiving 80 Gy and three receiving 70 Gy.
Serious adverse events occurred in 4% of patients in each group, and none were considered treatment related. There were no treatment-related deaths. The investigators also found no differences between the groups across the evaluated quality-of-life domains, although questionnaire completion was low at later follow-up.
Interpreting the Results
The findings suggest that increasing the prostate radiation dose from 70 Gy to 80 Gy can provide durable disease control when combined with long-term ADT in patients with high-risk prostate cancer.
The authors noted that GETUG-AFU 18 is, to their knowledge, the first randomized phase 3 trial to report improvements in prostate cancer-specific survival and OS with radiation dose escalation in this setting. However, several aspects of the study require caution when interpreting these findings.
The trial was designed more than a decade ago, before several developments that now influence prostate cancer staging and radiotherapy. CT and bone scans were used for staging, while the authors noted subsequent advances in imaging techniques, including PSMA imaging and MRI. Radiotherapy practices have also changed since the trial was designed.
There was an imbalance in the radiation techniques used between the treatment groups: 81% of patients receiving 80 Gy were treated with intensity-modulated radiotherapy (IMRT), compared with 59% in the 70 Gy group. Post-hoc sensitivity analyses adjusting for radiotherapy technique continued to show a benefit with dose escalation, and no significant interaction between dose and technique was identified.
Another important limitation was the unexpectedly low number of events. The study was designed to observe 197 progression events, but only 92 had occurred at the time of analysis. Although the PFS difference remained statistically significant in additional sensitivity analyses, the smaller-than-expected number of events reduced the statistical power of the trial.
The survival findings also require careful interpretation. The number of prostate cancer-related deaths was relatively small, and deaths unrelated to prostate cancer were more common in the control group. The authors therefore emphasized that additional studies are needed to confirm the apparent benefits in prostate cancer-specific survival and OS.
What Could Come Next?
Radiotherapy practice has evolved since GETUG-AFU 18 was designed, particularly with the adoption of moderate hypofractionation, IMRT, image-guided radiotherapy, and improved prostate cancer imaging.
The investigators noted that further studies are needed to determine the most effective hypofractionated schedule for this patient group, potentially using an equivalent dose close to 80 Gy.
The findings also raise questions about how radiation dose escalation should be integrated with newer systemic treatment strategies. The authors highlighted the growing role of androgen receptor pathway inhibitors in high-risk disease and suggested that future research should clarify how higher radiation doses can be positioned alongside these therapies.
Conclusion
After a median follow-up of 9.5 years, GETUG-AFU 18 showed that 80 Gy EBRT combined with long-term ADT improved PFS compared with 70 Gy in patients with high-risk prostate cancer.
The higher dose was also associated with better 10-year OS and prostate cancer-specific survival, while grade 3 or worse acute and late toxicity rates were similar between the groups.
At the same time, the unexpectedly low number of progression events, the low number of prostate cancer-related deaths, changes in radiotherapy practice since the trial was designed, and other methodological limitations mean that the survival findings should be interpreted cautiously.
The results support continued investigation of radiation dose escalation in high-risk prostate cancer, particularly within modern radiotherapy schedules and alongside contemporary systemic therapies.
The full article is available in The Lancet Oncology.