PROSTATE RT DOSE

SAN FRANCISCO — The results of a major clinical trial call into question the dose of radiation therapy (RT) most commonly used for the treatment of localized prostate cancer in the United States, according to a commentator here at the American Society for Radiation Oncology (ASTRO) 56th Annual Meeting.

The trial, known as Radiation Therapy Oncology Group (RTOG) 0126, compared high-dose RT (79.2 Gy) with standard-dose RT (70.2 Gy) in the treatment of more than 1500 men with intermediate-risk prostate cancer. This is the largest ever study, evaluating more than twice number of patients that other studies have analyzed.

The 79.2 Gy dose of RT, also known as dose-escalated RT, is actually the standard of care for these patients in the United States, said Danny Song, MD, from Johns Hopkins University in Baltimore. He was not involved with the trial and acted as a discussant during the meeting's plenary session.

After 10 years, there was no significant difference in overall survival between men in the high-dose group and men in the standard-dose group (66.7% vs 65.6%; hazard ratio [HR], 0.98;P = .87).

Furthermore, there was an increase in both gastrointestinal (GI) and genitourinary (GU) toxicity with the higher dose.

"The conundrum we face now is that high-dose radiation has already become standard of care in this country," said Dr. Song.

"I think it is safe to say that high-dose treatment should not be considered mandatory in patients with intermediate-risk prostate cancer, and may be overutilized," he added.

The trial was conducted at 104 centers in North America, and had a median follow-up of 7.0 years for all patients and 7.6 years for survivors.

All the men in the trial had intermediate-risk prostate cancer (T1b to T2b disease), with Gleason scores ranging from 2 to 7 and prostate-specific antigen (PSA) levels between 10 ng/mL and 20 ng/mL.

The results were made public early because the trial crossed a predetermined futility boundary, indicating that the hoped-for 23% reduction in the risk for death (HR, 0.77) would not be reached, said lead author and study chair Jeff Michalski, MD, from Washington University in St. Louis.

But there were bright spots in the results.

Dose escalation did improve local control and distant metastases-free and biochemical disease-free survivals, Dr. Michalski reported.

"These are important end points," said Dr. Song

Part of the problem with the trial is that "death due to prostate cancer was very uncommon," Dr. Michalski explained.

Death from prostate cancer occurred in only 3% of all patients and accounted for 13% of all deaths during the trial. Most causes of death were other cancers (22%) or other causes (46%).

In general, patients with prostate cancer "who do not have high-risk disease will most likely die of other causes," Dr. Song noted.

Five previous clinical trials have compared high- and standard-dose RT in localized prostate cancer patients, Dr. Song reported. Each reported significant improvements in freedom from biochemical failure, but none found a significant benefit in terms of overall or disease-specific survival, he said.

Freedom from Biochemical Failure and More Results

Of the 1532 men enrolled in the trial enrolled, 1499 were available for analysis: 748 in the high-dose group and 751 in the standard-dose group.

All of the men had negative lymph nodes and no metastases. None had received previous hormone therapy.

About one-third of the men received intensity-modulated radiation therapy (IMRT) and about two-thirds received 3-dimensional conformal radiation therapy (3D-CRT).

The high- and standard-dose groups were balanced in terms of Gleason score, PSA level, and tumor stage (T1 and T2), and median age in both groups was 71 years.

Dr. Michalski pointed out that the 10-year rate of biochemical failure was lower with high-dose than with standard-dose RT, whether the ASTRO definition was used (30% vs 45%; HR, 0.42; P < .0001), or the Phoenix definition (26% vs 43%; HR, 0.60; P < .0001).

Likewise, at 10 years, improvements in other secondary end points were better with high-dose than with standard-dose RT, including local progression (8% vs 4%; P = .0006) and distant metastasis (8% vs 5%;P = .26).

Acute adverse events were not significantly different between the 2 groups. However, there was a significant increase in late toxicities for both the GI and GU tracts in the high-dose group.

Table. Adverse Events

Grade of Toxicity	High-Dose RT, %	Standard-Dose RT, %	P Value
Acute Adverse Events
≥2 GI	2.4	2.8	.64
≥2 GU	11.1	12.8	.31
≥2 GI/GU	12.3	13.7	.42
10-Year Late Toxicities
≥2 GI	22.0	16.0	.006
≥2 GU	15.0	10.0	.001

Other trials, including RTOG 0621, have also found increased late toxicities for the GI and GU tracts with high-dose RT, Dr. Michalski added.

Who Can Be Treated With Lower-Dose RT?

After reviewing the medical literature on intermediate-risk disease and RT during his commentary, Dr. Song reported that a number of characteristics indicate whether patients will be good candidates for lower-dose radiotherapy (70 to 72 Gy).

He arrived at those characteristics by reviewing the evidence that suggests which patients are least likely to benefit from higher-dose RT. The unlikely beneficiaries of high-dose RT are patients of advanced age (older than 70 years) and those with favorable-risk disease (1 or 2 intermediate-risk factors), less than 50% of cores positive, a PSA velocity below 2 ng/mL per year, and comorbidities.

"Other patients may benefit from dose escalation, but there is no level 1 evidence of survival improvement," he summarized.

The study was supported by the ASTRO Radiation Oncology Institute and the National Cancer Institute. The authors have disclosed no relevant financial relationships. Dr. Song reports financial relationships with Augmenix, Bard, BrachySciences, GenomeDX, and sanofi-aventis.

American Society for Radiation Oncology (ASTRO) 56th Annual Meeting: Abstract LBA1. Presented September 15, 2014.