A modest increase in radiotherapy dose may improve survival outcomes among men on long-term androgen deprivation therapy (ADT) for high-risk, localized prostate cancer, according to a randomized trial.

The study, of 505 patients, found that giving radiotherapy at a total dose of 80 Gy improved biochemical or clinical progression-free survival from 88.1% to 91.4% at 5 years vs the conventional dose of 70 Gy. At 10 years, that advantage widened to 83.6% vs 72.2% — with no increase in short- or long-term toxicity.

Men on the higher-dose regimen also had better 10-year prostate cancer-specific survival (95.6% vs 90%) and overall survival (77% vs 65.9%).

The results are the first to show that radiotherapy at 80 Gy may improve all of those survival outcomes in men with high-risk disease, according to the investigators, led by Christophe Hennequin, MD, PhD, of Saint-Louis Hospital and Paris Cité University in Paris, France.

Long-term ADT with radiation dose escalation “might be the optimal treatment for patients with high-risk prostate cancer,” they reported in Lancet Oncology.

However, an accompanying editorial sounded some cautionary notes.

The trial does provide “convincing evidence” of a progression-free survival benefit with higher-dose radiotherapy, wrote Tyler Seibert, MD, PhD, a radiation oncologist at the University of California, San Diego.

But he also stressed that the prostate-specific and overall survival results, both of which were secondary outcomes, are inconclusive and may, in fact, reflect residual confounding.

The trial, dubbed GETUG AFU 18, enrolled patients at 25 centers in France from 2009 to 2013. All had a prostate-specific antigen of at least 20 ng/mL, Gleason scores of 8 or higher, and cT3-cT4 tumors; they were randomized evenly between the two treatment groups.

ADT included luteinizing hormone-releasing hormone agonists for a median duration of over 33 months in both groups. External beam radiotherapy was delivered in five 2 Gy fractions per week, for a total of 7 weeks in the 70 Gy group and 8 weeks in the 80 Gy group. Investigators had a choice of intensity-modulated radiotherapy or three-dimensional-RT, targeting the prostate, pelvic lymph nodes, and seminal vesicles.

Overall, the higher-dose regimen did not increase the risk for adverse events: About one-quarter of patients in both groups had grade 3 or worse toxicity at 6 months, which most often included sexual, bladder, or urethra problems. The rate of grade 3 or higher toxicity at 5 years was less than 10% in each group, with bladder and urethra disorders being the most common.

But while the safety data were reassuring, Seibert highlighted issues in interpreting the cancer-specific and overall survival findings.

The number of deaths in the trial was lower than expected, and more men died from reasons other than prostate cancer in the control group: 73 vs 47. It’s unclear why, Seibert noted, but the results skewed overall survival in favor of the 80 Gy group.

Among those men, the hazard ratio for non-prostate-cancer deaths was 0.64 — which Seibert called “a perplexing outcome given the implausibility that increasing the radiotherapy dose to the prostate would prevent non-prostate-cancer deaths.”

Similarly, there were fewer prostate cancer-specific deaths than expected: 9 in the 80 Gy group vs 17 in the 70 Gy group.

With only eight excess deaths from prostate cancer in the 70 Gy group, even small treatment imbalances might have affected the results, Seibert wrote. He noted that three patients in the 70 Gy group did not receive ADT, whereas four did not receive radiotherapy — compared with zero and two, respectively, in the 80 Gy group.

Overall, Seibert wrote, “the logical conclusion is that there was residual confounding despite the randomized design — an unfortunate reminder that randomized trials can have spurious results, especially for secondary outcomes that are underpowered.”

The investigators had similar concerns, writing that “given the low number of events, further research is needed to consolidate and confirm the benefit [of] dose escalation in prostate cancer-specific survival and overall survival.”

At the same time, those low event numbers are “great news for patients,” Seibert pointed out. Even for those with high-risk disease, he wrote, outcomes with radiotherapy and ADT are now “excellent,” likely due to improved diagnostic and staging tools.

Seibert also underscored another positive: The apparent safety of higher-dose radiation in this study supports ongoing trials to see whether dose escalation can offset the need for extended ADT, which could improve patients’ quality of life.

The investigators agreed and pointed to some key open questions. Their trial did not, for example, include use of androgen receptor pathway inhibitors or hypofractionated radiation, which are common in current practice. Further work is needed to understand how they fit in with the findings, the researchers said.

The trial was funded by the French National Cancer Institute and AstraZeneca. Hennequin disclosed receiving advisor fees from Astellas, Bayer, Ipsen, and Janssen. Seibert reported having financial relationships with GE HealthCare, Blue Earth Diagnostics, Janssen, Precision Pro, and others. He also reported receiving honoraria/consulting fees from WebMD.

M. Alexander Otto is a physician assistant and award-winning journalist. He is also an MIT science journalism fellow. Email: aotto@medscape.net.