Kate Johnson

April 28, 2015

BARCELONA, Spain — Men with intermediate- or high-risk prostate cancer have double the chance of progression-free survival at 9 years if they are treated with brachytherapy in addition to external beam radiation therapy (EBRT), according to results of a randomized trial.

Brachytherapy, which involves the insertion of radiaotive seeds into the prostate, is generally used in low-risk and localized prostate cancer, but this trial shows benefits when combined with other therapies in high-risk disease.

The new results comes from the ASCENDE-RT (Androgen Suppression Combined With Elective Nodal and Dose Escalated Radiation Therapy) trial and were presented here at the European Society for Radiotherapy and Oncology (ESTRO) 3rd Forum.

This is "the first-ever randomized controlled trial of low-dose-rate prostate brachytherapy (LDR-PB) compared to any other form of radiation therapy in the curative management of prostate cancer," said lead investigator James Morris, MD, from the Department of Radiation Oncology, Vancouver Cancer Centre, British Columbia Cancer Agency (BCCA), in Canada.

"Prostate brachytherapy has now become the standard of care for all patients with high-risk prostate cancer at the BCCA," said Sree Rodda, MD, a research fellow of Dr Morris.

But "we do have to counsel the patients about the increased toxicity," she added, after giving a separate presentation showing a significant increase in both the cumulative incidence and prevalence of genitourinary (GU) toxicity in patients treated with brachytherapy compared with those treated with EBRT.

Approached for comment on the new findings, Andrew Loblaw, MD, professor in the Department of Radiation Oncology at the Institute of Health Policy, Management and Evaluation, University of Toronto, Canada, told Medscape Medical News: "We can safely conclude that for intermediate- and high-risk patients, brachytherapy plus EBRT is superior to EBRT alone in terms of long-term prostate-specific antigen [PSA] control."

Profound Difference in Biochemical-PFS

ASCENDE-RT included 398 high- or intermediate-risk prostate cancer patients (median age, 68 years), all of whom initially received 12 months of androgen deprivation therapy, followed by 46 Gy of EBRT to the whole pelvis in 23 fractions.

They were then randomly assigned to receive an additional boost of either dose-escalated EBRT, to 78 Gy (n = 200), or brachytherapy (LDR-PB), to 115 Gy (n = 198), delivered to the prostate via radioactive iodine "seeds."

The primary endpoint of the study was biochemical progression–free survival (b-PFS), defined as an increase in PSA level of 2 ng/mL or more above the nadir (lowest level attained after treatment).

The intent-to-treat analysis showed that the b-PFS was "quite profoundly different" (P = .001) between groups, said Dr Morris, with an advantage for brachytherapy at 5 years (88.7% vs 83.8% for EBRT), 7 years (86.2% vs 75.0%), and 9 years (88.3% vs 62.4%) (hazard ratio [HR], 0.49; P = .001).

"Treatment with LDR-PB boost resulted in a 50% reduction in biochemical recurrence compared to EBRT, with an absolute difference in b-PFS at 9 years of 20%," he reported. He added that "one of the most important things I can say is that there really is no difference at 5 years, so when we look at trials, we have to be very careful that we have reasonable follow-up."

Multivariate analysis showed that in addition to type of treatment, other strong predictors of b-PFS included percent positive cores (HR, 1.01; P = .006), clinical T3a stage vs T1-T2 stage (HR, 1.97; P = .004), initial PSA level (HR, 1.62; P = .01), and a Gleason sum of 8-10 vs 7 or less (HR, 1.38; P = .17).

At 9 years, overall survival was 77.9% in the brachytherapy group compared with 73.6% in the EBRT group. "This trial was not powered for overall survival, and clearly there is no statistically significant difference," said Dr Morris, "but the trend ― such as it is ― does favor brachytherapy. Also, the median survival has not yet been reached and is estimated at 13 years."

Dr Morris also presented the results using what he called the "surgical definition" of b-PFS (a PSA level > 0.2 ng/mL). "Using this definition, there's an extremely profound difference between the two treatment arms," he pointed out, showing a b-PFS of 31.5% in the EBRT group vs 82.2% in the brachytherapy group. "I'm not saying it's the right definition, but it's the one the surgeons care about, and that may be important," he noted.

But GU toxicity remains an issue that patients must be fully informed about, said Dr Rodda.

According to physician-scored toxicity that was prospectively assessed, there was no significant difference in gastrointestinal toxicity between the treatment groups, but overall, acute grade 2 GU toxicity was observed in 30% of the brachytherapy arm compared with 15.8% of the EBRT arm (P < .001), she reported.

At 5 years, the prevalence of grade 3 GU toxicity was 8.6% in the brachytherapy arm compared with 2.2% in the EBRT arm, and the cumulative incidence was 19% vs 5%, respectively (P < .0001).

The most common events were urethral strictures requiring dilatation, urinary retention requiring a procedure (transurethral resection/incision of the prostate), and severe urinary incontinence.

More modern brachytherapy techniques appear to have less urinary side effects, noted Dr Loblaw.

Commenting on the results, Philip Poortmans, MD, PhD, president of ESTRO, said the study "illustrates very nicely how the best results can be obtained by combining various treatment options instead of trying to get the most out of one single modality. Brachytherapy is an extremely efficient and safe radiation oncology modality, and this trial shows that it can have a wider field of applicability than simply in very localized and low-risk tumors when combined with other techniques ― in this case, androgen deprivation therapy and external bean radiation therapy."

The trial was funded privately by unrestricted grants from Oncura and Sanofi-Aventis, Canada. Dr Morris, Dr Rodda, Dr Loblaw, and Dr Poortmans have disclosed no relevant financial relationships.

European Society for Radiotherapy and Oncology (ESTRO) 3rd Forum: Abstract OC-0485, presented April 27, 2015; abstract PD-0047, presented April 25, 2015.


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