High-Dose Prostate Radiotherapy: Better Local Control, Not Survival

Geneva, Switzerland — For the first time in a randomized trial, dose-escalated radiation therapy for prostate cancer resulted in better local control at 10 years, but the results did not translate to better overall survival.

"We're very disappointed," Joos Lebesque, MD, told Medscape Medical News after presenting the study at the 2nd European Society for Radiotherapy & Oncology (ESTRO) Forum. "It's work of 20 years…. What we demonstrated is that local control is improved, biochemical control is improved, but unfortunately nothing is improved in survival," he said. Dr. Lebesque is a radiation oncologist at the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam.

"For the international radiation oncology community it is not such a nice message," he commented in an interview. "Twenty-five hundred patients have been randomized around the world, all based on this hypothesis, and now after 10 years of follow-up in all these trials the hypothesis is probably not true."

Co-moderator of the session, Mary Gospodarowicz, MD, medical director of the Princess Margaret Cancer Centre at the University Health Network in Toronto, Ontario, Canada, told Medscape Medical News that the results are "not unexpected because these days we use early hormonal interventions for people who develop local failure or biochemical progression, and then with lower- and intermediate-risk disease the patients can stay alive for many, many years."

Conducted at Dutch Hospitals

The phase 3 trial that Dr. Lebesque presented at the meeting enrolled 664 patients with prostate cancer (T1b-T4) from 4 Dutch hospitals between 1997 and 2003.

Patients were randomly assigned to receive either 78 Gy (n = 333) or 68 Gy (n = 331) of radiation therapy in 2 Gy per fraction using three-dimensional conformal radiation therapy.

"The hypothesis of all prostate cancer radiation dose-escalation trials has been that you get better local control and improved disease-specific and overall survival with a higher dose," said Dr. Lebesque.

The study found that freedom from biochemical/clinical failure was better in the higher-dose group according to American Society for Therapeutic Radiology and Oncology (ASTRO) criteria of 3 consecutive increases in prostate-specific antigen (PSA) level (45.9% vs 38.4%; P = .025) or Phoenix guidelines of nadir plus 2 μg/L (48.5% vs 43.1%; P = .045).

Local failure, one of the secondary endpoints, was observed significantly less in the higher-dose group ( 14 vs 27 events; P = .036). "This the first time after a follow-up of 9 years that we notice a difference in local failure," he noted.

However, "for the most important secondary endpoints [disease-specific survival and overall survival] there was no difference. This was a big disappointment for us."

Canadian trials in patients with locally advanced disease and 13 to 14 years of follow-up have shown some survival advantages for higher-dose radiation therapy, said Dr. Gospodarowicz. "For early-stage disease you need 20-year data to comment on overall survival," she said. "I think he needs a larger cohort of patients over a longer period of time," she told Medscape Medical News.

Dr. Lebesque acknowledged that longer follow-up would be more likely to reveal a survival difference, if there is one, and he suggested that the wide inclusion criteria may have obscured this potential trend.

"The selection of patients entering the trial was too wide. All patients could enter the trial. For low-risk patients you probably don't need dose escalation. For high-risk patients they may already have distant metastasis that are not visible but are there — so in the end you might have better local control but the distant metastasis are already present and give recurrence."

Indeed, a subgroup analysis of patients based on PSA levels below or above 10 μg/L showed a highly significant benefit to high-dose radiation therapy in patients with high PSA in terms of freedom from biochemical/clinical failure (41.7% vs 30% in the low-dose group; P = 0.008).

In contrast, patients with low PSA levels fared better overall, regardless of radiation therapy dose, in terms of freedom from biochemical/clinical failure (54.4% high dose and 52.6% low dose).

"In patients with a PSA of less than 10 μg/L there is no advantage at all for high-dose radiotherapy," Dr. Lebesque said.

<None of the speakers have disclosed any relevant financial relationships.

2nd European Society for Radiotherapy & Oncology (ESTRO) Forum Abstract OC-0048. Presented April 20, 2013.

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Cite this: High-Dose Prostate Radiotherapy: Better Local Control, Not Survival - Medscape - Apr 23, 2013.