Hypofractionation is the Preferred Treatment Type of Radiation therapy for Intact Prostate Cancer: Is it Now Also for Post-prostatectomy RT Based on NRG GU003?

Presenting author:
Mark K. Buyyounouski, MD, MS

By Daniel E. Spratt, MD, Chairman and Vincent K Smith Professor, Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, Ohio

Both ASTRO and NCCN acknowledge that moderately hypofractionated radiation therapy (RT) is preferred over conventionally fractionated RT for men with localized prostate cancer. This is based on multiple large phase III non-inferiority trials demonstrating comparable tumor control with no meaningful negative effect on long-term toxicity or quality of life (QOL) when using the 20-fraction regimen. The rationale was motivated in part by the desire for patient convenience and to reduce costs, but also the lower alpha/beta ratio of prostate cancer to improve the therapeutic ratio.

Post-prostatectomy there are divergent practice patterns around the world.  In the United States, most use 37-39 fractions at 1.8 Gy/fx to 66.6-70.2 Gy; in Canada and many other countries, they deliver 33-34 fractions at 2 Gy/fraction to 66-68 Gy; and in the United Kingdom (UK) many have already adopted a moderate hypofractionated schedule of 52.5 Gy in 20 fractions. In fact, the UK regimen was used on the landmark RADICALS trial as an acceptable method of RT delivery. To date there have been numerous phase I and II trials of moderate hypofractionation and even ultra-hypofractionation in as few as five treatments post-radical prostatectomy (RP). Generally, these single arm trials demonstrate expected tumor control and side effect profiles for patients receiving post-RP RT. However, no randomized trial testing post-RP hypofractionated RT has been reported to date. Hence, the NRG GU003 phase III randomized trial was conducted, which randomized men to 66.6 Gy in 37 fractions versus 62.5 Gy in 25 fractions.

This was a unique phase III trial, as its co-primary endpoints were patient-reported genitourinary (GU) and gastrointestinal (GI) QOL, but also we’re at only two years post-treatment. The trial was one of the fastest accruing trials in NRG Oncology’s history with 296 patients randomized in just one year.  There was reasonable compliance to the EPIC QOL inventory with 73% compliance at two years. The trial was positive with non-inferiority between the two RT regimens. There were no clinically or statistically significant differences in two-year QOL in GU or GI domains and no differences in biochemical or local failure.

ADT was allowed on this trial at the discretion of the treating physician, but nodal RT was not permitted.  Given recent results showing the benefit of nodal RT for men with pre-salvage RT PSAs ≥0.4 ng/mL based on RTOG 0534, some may question if the results of NRG GU003 apply to those receiving nodal RT.  Absolutely they should. Nodal RT is commonly delivered in 1.8 Gy x 25 fractions, and thus the addition of nodal RT would remain conventionally fractionated and should not deter the use of moderate hypofractionation post-RP. 

The biggest question that will challenge the GU community is if the primary endpoint of two-year QOL is sufficient to change practice. At ASTRO this year, a large meta-analysis of 29 prostate cancer randomized trials tested whether any new information was gained from long-term follow-up in trials that changed RT dose, fractionation or field size. A clear and resounding no! Although toxicity continues to happen with longer-term follow-up, Elizabeth Jaworski, MD, demonstrated beyond three years the relative risk of toxicity in fact decreased over time between treatment arms, suggesting that if anything the relative toxicity change lessens and not widens with greater follow-up.

Future trials through NRG Oncology are planned to test if ultra-hypofractionation is a safe and effective method post-RP. Ongoing trials using MR-linac technology are already underway and may allow safe and convenient ultra-hypofractionation post-RP. Until then, I look forward to adopting the RADICALS 20-fraction regimen or the 25-fraction regimen used on NRG GU003 into my routine practice.

Abstract 3 - Primary Endpoint Analysis of a Randomized Phase III Trial of Hypofractionated versus Conventional Post-Prostatectomy Radiotherapy: NRG Oncology GU003 was presented on October 25, 2021, during the Plenary session.

Published October 26, 2021

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