Two-fraction Versus Five-fraction Stereotactic Radiotherapy for Localized Prostate Cancer

Following publication of multiple prospective clinical trials demonstrating the biochemical progression free survival (bPFS) benefits of high dose radiation for the curative treatment of localized prostate cancer, typical external beam radiotherapy (EBRT) courses ranged from 38-45 daily fractions delivered over 7.5-9 weeks. Over the past two decades, monumental advances in EBRT have been achieved, allowing significant shortening of the standard radiotherapy course. With diagnostic, imaging, and technological developments, the ability to deliver higher doses per fraction further expanded and an improved radiobiologic understanding of the response of prostate adenocarcinoma revealed that ultrahypofractionated regimen could take advantage of the comparatively low a/b ratio of prostate cancer cells. As a result of these two streams of development, stereotactic ablative radiation therapy (SABR) emerged as an accepted standard of care for definitive treatment in the low- and favorable intermediate-risk settings. At both the individual and systems levels, efficient delivery of patient care and prudent utilization of medical resources is at the forefront. Given the ubiquity of prostate cancer and high volumes of patients in treatment centers across the globe, there remains meaningful potential for substantial improvements in patient throughput and cost of care. Presently, the shortest treatment courses for low- and favorable intermediate-risk prostate cancer are radical prostatectomy and low-dose-rate (LDR) brachytherapy, which offer an excellent likelihood of cure but entail degrees of invasiveness that may not be appropriate, feasible, or desirable for all patients, and include additional costs associated with operating room facilities and anesthesia. Surgical patients typically require a brief inpatient hospital stay. A comparable radiation therapy treatment course could help address many of these concerns and offer effective and efficient patient care. A strong and mature precedent for a two-fraction course of high dose radiation can be found in the realm of high-dose-rate (HDR) brachytherapy. Under anesthesia, a radioactive source is programmed to traverse catheters that have been transperineally inserted into the prostate in order to produce a desired dose deposit. bPFS rates range between 91%-97% in the modern literature. While attempts were made to deliver single-fraction HDR brachytherapy (typical dose of 19 Gy), trials resulted in inferior oncologic outcomes, and to date, standard HDR treatment courses are comprised of two-fraction definitive treatment or single-fraction combined with EBRT. Radiobiologically, based on the particularly low a/b of prostate cancer cells and unique cell cycling, there is suggestion that at least two fractions are necessary for complete tumor eradication. There exists, to date, limited data on the safety and effectiveness of prostate SABR delivered in fewer than five fractions. A recent proof-of-concept study by Greco et al compared single-dose SABR of 24 Gy to 5 fractions of 9 Gy in favorable intermediate and unfavorable intermediate risk patients. The results demonstrated comparable four-year prostate specific antigen outcomes for favorable intermediate disease though inferior PFS for unfavorable intermediate disease. Objective and patient reported genitourinary and gastrointestinal toxicities were not significantly different, though one of the 15 patients in the single-fraction arm experienced delayed grade 3 urethral stenosis. Magli et al published acceptable 1-year toxicity outcomes for a novel three-fraction regimen of SABR for low- and favorable intermediate-risk patients, to a dose of 40 Gy. MRI based planning was utilized, gold fiducials and a hydrogel spacer were placed, and a catheter was inserted in the bladder for each fraction. They observed rates of 11.9% and 1.7% acute grade 2 and 3 urinary toxicity, respectively, and 8.5% acute grade 2 rectal toxicity, all of which resolved by 12 months. Alayed et al published safety and efficacy results of their prospective single-cohort study of low- and intermediate-risk patients undergoing a two-fraction SABR regimen to a dose of 26 Gy. On their sample of 30 patients, they reported no acute grade 3+ gastrointestinal or genitourinary toxicity, and one instance each in later follow up, comparable or even slightly better than that from five-fraction protocols. Multiple questions remain regarding the potential role for and safety of delivering SABR in fewer than five fractions. These include optimal patient selection, ideal dose fractionation, proper techniques to assure necessary avoidance of surrounding normal tissue, and how to balance dose to organs at risk with the accepted requirement of a planning target volume (PTV) to account for inevitable setup uncertainty. Importantly, recent endoscopic reports reveal notably high rates of rectal ulceration after dose-escalated SABR, and placement of a hydrogel spacer has been demonstrated to significantly reduce this risk. Placement of a resorbable hydrogel spacer to displace the rectum away from the high dose region, allowing for a posterior safety margin to account for potential intra-fractional motion, instead of a rectal balloon, is essential for accomplishing rectal sparing while facilitating additional assurance regarding treatment accuracy. In the context of modern dose escalation, and in lieu of a strong body of HDR-brachytherapy data supporting a two-fraction approach to ultra-high dose treatment with initial experiences of two-fraction SABR, direct comparison of a non-invasive and broadly generalizable two-fraction SABR regimen to the standard approach of five-fraction regimen is logical. Institutional studies have emerged in the recent years demonstrating evidence for safety of ultra-hypofractionated regimen in fewer than five fractions of SABR, and large-scale randomized data is much needed. Aided by the ability to achieve necessary rectal dose constraints through placement of a rectal hydrogel, this approach may serve as an appropriate balance between minimizing the number of treatments necessary while allowing for delivery of the higher dose needed to optimize likelihood of cure.