Focal RT Boost in High-Risk Prostate Cancer Cuts PSA Relapse - MedPage Today

An integrated focal boost of radiation improved biochemical disease-free survival (bDFS) without increasing toxicity in prostate cancer patients with mostly high-risk disease, a Dutch randomized trial showed.

With a median follow-up of 71 months, the 5-year bDFS rate significantly improved from 86% in the standard 77 Gy external-beam radiotherapy (EBRT) arm, to 93% with a focal boost up to 95 Gy, meeting the study's primary endpoint, reported Linda Kerkmeijer, MD, PhD, of Radboud University Medical Center Nijmegen, The Netherlands.

"FLAME is the first phase III trial to show that focal boosting improves 5-year biochemical disease-free survival, with relapse rates reducing from 14% to 7%," Kerkmeijer said during the virtual American Society for Radiation Oncology (ASTRO) annual meeting. "This was achieved without impacting toxicity or quality of life."

Local recurrences in prostate cancer most often occur at the primary tumor, she said, and while control of prostate-specific antigen (PSA) levels improves with increasing doses of radiation, EBRT trials have shown that whole-gland dose escalation increases toxicity.

"A potential solution may be focal-dose escalation," she said. "Increasing the dose to the microscopic intraprostatic lesion without increasing the dose to the organs at risk."

In the study, no differences were seen in late gastrointestinal (GI) grade ≥2 adverse events (AEs), with rates of 12% in the standard arm and 13% in the dose-escalation arm. Late GI grade ≥3 AEs were identical, at 1% in each arm. Late genitourinary (GU) grade ≥3 AEs were elevated in the dose-escalation arm (6% vs 4%), but this finding was not significant.

For patient-reported outcomes assessed using the EORTC QLQ-PR25 questionnaire, GU and GI quality of life were comparable in both groups, decreasing from baseline by 12 and 5 points, respectively, with both returning to normal within the first year, said Kerkmeijer. Among patients not taking hormonal therapy, sexual activity and functioning were also similar between arms, decreasing by fewer than 5 points.

Kerkmeijer noted that more than half of patients in the focal-boost group did not reach the target 95 Gy, as organs at risk were prioritized. This is important in interpreting the toxicity results, she said.

"Focal boosting will become the new standard of care for radiotherapy for intermediate- and especially high-risk prostate cancer," Kerkmeijer said, but cautioned that the FLAME trial used a conventional fractionation scheme. "Results of hypofractionated focal boost studies should be awaited first before routinely implementing this."

ASTRO discussant Alison Tree, MD, of the Royal Marsden and the Institute of Cancer Research in London, highlighted that bDFS has not been shown to be a surrogate for overall survival in prostate cancer. To date, only metastasis-free survival has been proven to predict overall survival.

"The endpoints that we should use in our trials, in my opinion, is not a solved problem," she said. "It depends on the cost of the intervention. Biochemical relapse-free survival may be a sensible endpoint if you are looking at something that doesn't come with a toxicity penalty."

Endpoints also have to be pragmatic, she said. "If it takes you 15 years to find your overall survival advantage, then technology would have moved on and your trial will have become obsolete."

Tree called the 93% bDFS rate "remarkable" considering the high-risk cohort included -- a third of patients had a Gleason score of 8 or above and 84% were high risk as classified by the European Association of Urology.

"Is this enough to change practice? Well certainly I think we're going to be moving in that direction," said Tree. "But as Dr. Kerkmeijer pointed out, this trial is only relevant to conventional fractionations, which most of us -- certainly in Europe -- are not giving any longer."

"However if you have an intervention like this which can improve biochemical relapse-free survival with no toxicity penalty, I would say you have a fairly low bar for actually doing it," she continued. "So is this a 'no penalty' way of improving biochemical relapse-free survival? Does this bring back PSA control as an endpoint? Let's watch this space."

FLAME was a phase III trial that randomized 571 patients with intermediate- and high-risk prostate cancer from 2009 to 2015 to either standard EBRT (77 Gy over 35 fractions) or EBRT with a focal boost up to 95 Gy. In the boost arm, gross tumor volume contouring was performed on multiparametric MRI. Baseline characteristics were well balanced, with 82% having International Society of Urological Pathology (ISUP) grade ≥2 tumors and two-thirds receiving adjuvant hormonal therapy.

Further details on the primary endpoint will be presented later this year at the 2020 European Society for Radiotherapy & Oncology (ESTRO) online congress, said Kerkmeijer.

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  Ian Ingram joined MedPage Today in 2018 as Deputy Managing Editor, and covers oncology for the site.

Disclosures

Funding for the study was provided by the Dutch Cancer Society and Stand Up Against Cancer Belgium.

Kerkmeijer reported having no disclosures.

Tree disclosed research funding from Elekta, Accuray, and Varian; honoraria or travel grants from Astellas, Janssen, Ferring, Bayer, Genesis Healthcare, and Elekta.