No Benefit from Combined Irradiation in Intermediate-Risk Prostate Cancer

Bradley R. Prestidge, MD

The addition of external-beam radiotherapy (EBRT) to interstitial brachytherapy failed to reduce prostate cancer progression compared to brachytherapy alone in men with intermediate-risk disease, interim data from a randomized trial showed.^1,2

The 5-year freedom from progression was 84.5% with combined-modality radiotherapy and 85.6% with prostate brachytherapy alone. The odds ratio (OR) for brachytherapy versus combined radiotherapy was 1.09 after a median follow-up of 7.7 years, a difference that did not achieve statistical significance for efficacy or meet the prespecified statistical value to stop the trial for futility.

Follow-up will continue until the data reach a cutoff for efficacy or futility, Bradley R. Prestidge, MD, a radiation oncologist at Bon Secours Cancer Institute and DePaul Medical Center, reported at the 2016 American Society for Radiation Oncology (ASTRO) Annual Meeting in Boston, Massachusetts.

“Among men with intermediate-risk prostate cancer, the addition of external-beam therapy to brachytherapy did not result in superior freedom from progression compared with brachytherapy alone at 5 years in this initial report,” Prestidge concluded. “Toxicity in both groups was limited, but there were fewer late effects, mostly genitourinary, noted in the brachytherapy-alone arm.”

The invited discussant for the presentation cautioned against extrapolating the data to all men with intermediate-risk prostate cancer. Recent clinical and biological evidence has demonstrated the existence of 2 types of intermediate-risk prostate cancer, said Michael J. Zelefsky, MD, chief of the Brachytherapy Service at Memorial Sloan Kettering Cancer Center.³

The two categories of favorable and unfavorable intermediate-risk disease exhibit distinctly different clinical behavior. Favorable intermediate-risk disease behaves like low-risk disease, whereas unfavorable intermediate-risk disease behaves more like high-risk prostate cancer. The RTOG 0232 study population described by Prestidge had characteristics more closely associated with favorable intermediate-risk disease.

“For favorable intermediate-risk disease, the addition of EBRT to brachytherapy doesn’t confer any biochemical control advantage for the patient,” said Zelefsky. “The addition of EBRT for such patients was associated with a higher late grade 3 urinary toxicity profile. Combining EBRT with brachytherapy for favorable intermediate-risk disease may constitute unnecessary overkill.”

RTOG (now NRG) 0232 tested the hypothesis that men with intermediate-risk prostate cancer would have a 10% improvement in failure from progression at 5 years if they received EBRT plus brachytherapy as compared with brachytherapy alone. Eligible patients had stage T1c/T2b prostate cancer associated with Gleason score £7 and PSA £20 ng/mL. Neoadjuvant hormonal therapy was permitted at the discretion of the treating physician.

Patients randomized to brachytherapy alone received a 125-Gy (Pd¹⁰³) or 145-Gy (I¹²⁵) total radiation dose. Patients randomized to combined-modality treatment received partial-pelvis EBRT at a total dose of 45 Gy, followed 2 to 4 weeks later by the same brachytherapy.

Of 588 patients randomized, 579 were included in the data analysis. Patients in the combined therapy arm received treatment in accordance with the protocol in 82% of cases, and an additional 15% received treatment that had acceptable variation. In the brachytherapy arm, 80% of patients received per-protocol treatment, and 17% received therapy with acceptable variation. In 2% to 3% of cases in each arm, treatment variation could not be evaluated.

The primary endpoint was freedom from progression (FFP), defined as the time from randomization to the first occurrence of biochemical failure, local progression, distant metastasis, or death from any cause. The secondary endpoint was biochemical failure, defined as the time to midway between the last non-rising PSA value and the first of 3 consecutive rises or the time to initiation of salvage hormone therapy.

Prestidge reported that 443 patients were evaluable for FFP at 5 years. The trial had a prespecified stopping point for futility ofP<.0001 for the between-group comparison of FFP. The report represented data from a fifth interim analysis. The OR of 1.09 for brachytherapy versus combined treatment was associated with aPvalue of .6188 for efficacy andP=.0006 for futility.

At the latest interim analysis, 34 FFP events had occurred in the EBRT arm and 32 in the brachytherapy arm. Analysis of events constituting first failure showed that biochemical failure was the first FFP event in 68% of cases in the combined-modality arm and 53% of cases in the brachytherapy group. Death from any cause accounted for 26% of FFP events in the EBRT arm and 44% of events in the brachytherapy arm.

In a multivariate analysis, only the combination of Gleason score <7 and PSA 10 to 20 ng/mL (versus Gleason &sup3;7 and PSA <10 ng/mL) emerged as a significant predictive factor (OR = 0.50,P=.046). Analysis of secondary endpoints showed no significant differences between treatment groups, including estimated 5-year overall survival of 95% in the EBRT group and 92% in the brachytherapy group (HR, 0.81,P=.41).

Analysis of adverse events showed that EBRT plus brachytherapy was associated with more late grade &sup3;2 adverse events (53% vs 37%,P= .0001) and late grade &sup3;3 adverse events (12% vs 7%,P=.039).

References:

1. Prestidge BR. Initial report of NRG Oncology/RTOG 0232. Presented at: 2016 ASTRO Annual Meeting; Boston, Massachusetts, September 22-25, 2016.
2. Prestige BR, Winter KA, Sanda MG, et al. A phase III study comparing combined external beam radiation and transperineal interstitial permanent brachytherapy with brachytherapy alone for selected patients with intermediate risk prostatic carcinoma. Presented at: 2016 ASTRO Annual Meeting; Boston, Massachusetts, September 22-25, 2016
3. Zelesky MJ. Commentary on initial report of NRG Oncology/RTOG: a phase 3 study comparing combined EBRT and BRT vs BRT alone for selected patients with intermediate risk prostate cancer. Presented at: 2016 ASTRO Annual Meeting; Boston, Massachusetts, September 22-25, 2016.