Clinical Investigation
Patient Reported Outcomes in NRG Oncology RTOG 0938, Evaluating Two Ultrahypofractionated Regimens for Prostate Cancer

https://doi.org/10.1016/j.ijrobp.2018.06.008Get rights and content

Purpose

There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores.

Methods and Materials

NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions (7.25 Gy in 2 weeks) or 12 fractions (4.3 Gy in 2.5 weeks). The co-primary endpoints were the proportion of patients with a change in EPIC-50 bowel score at 1 year (baseline to 1 year) >5 points and in EPIC-50 urinary score >2 points tested with a 1-sample binomial test.

Results

The study enrolled 127 patients to 5 fractions (121 analyzed) and 128 patients to 12 fractions (125 analyzed). Median follow-up for all patients at the time of analysis was 3.8 years. The 1-year frequency for >5 point change in bowel score were 29.8% (P < .001) and 28.4% (P < .001) for 5 and 12 fractions, respectively. The 1-year frequencies for >2 point change in urinary score were 45.7% (P < .001) and 42.2% (P < .001) for 5 and 12 fractions, respectively. For 5 fractions, 32.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥11 points (P = .34); for 12 fractions, 30.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥ 11 points (P = .20). Disease-free survival at 2 years is 99.2% (95% confidence interval: 97.5-100) in the 5-fraction arm and 97.5% (95% confidence interval: 94.6-100) in the 12-fraction arm. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity.

Conclusions

This study confirms that, based on changes in bowel and urinary domains and toxicity (acute and late), the 5- and 12-fraction regimens are well tolerated. These ultrahypofractionated approaches need to be compared with current standard radiation therapy regimens.

Introduction

Radiation therapy over 7.5 to 9 weeks is a common treatment option in the management of localized prostate cancer. Randomized clinical trials (RCTs) have confirmed that higher doses (2 Gy fractions) and high-precision radiation therapy techniques result in improved control of prostate-specific antigen (PSA) 1, 2, 3. There is considerable interest in treating patients with localized prostate cancer with hypofractionated regimens (HypoRT). Hypofractionation offers the advantage of fewer fractions being more convenient for patients and an economic benefit because more patients could be treated with the available resources. Subsequently, the possibility that hypofractionation may confer a therapeutic advantage was raised because of the low α/β ratio (1/4) of prostate cancer 4, 5, 6, 7, 8, 9, 10 relative to late tissue. Some clinicians use the term moderate HypoRT in reference to radiation therapy treatments in 20 to 28 fractions using 2.5 to 3 Gy fractions. To date, similar efficacy and toxicity data are available from 3 RCTs using moderate HypoRT 11, 12, 13. One of these studies showed slightly higher late grade 2 gastrointestinal and genitourinary toxicity (11).

Recently, investigators have evaluated shorter HypoRT (5-12 fractions) and have considered ultrahypofractionated regimens (UHRT). The reported UHRT results suggest that the acute and late side effects are acceptable, although the toxicity and efficacy outcomes of these regimens have not been compared with those of standard radiation therapy regimens (SRT) in an RCT 14, 15, 16, 17, 18, 19. The availability of modern high-precision radiation therapy techniques enables UHRT to be given with a low incidence of acute and late side effects.

Patient-reported outcomes (PROs) using the Expanded Prostate Index-Cancer (EPIC-50) bowel and urinary scores have been reported by several investigators 20, 21, 22. The 50-item EPIC questionnaire is a robust validated prostate cancer patient-reported (PRO) questionnaire (22). Throughout this article, the term EPIC refers to the utilization of the EPIC-50 quality of life instrument. Some case series have reported on PROs using UHRT 23, 24, 25, 26; this moderately sized multi-institution study collected PRO data prospectively as per the study protocol. Based on published data, rectal and bladder scores decline during and for a few weeks after radiation therapy, but by 1 to 2 years, the scores return to near pretreatment levels. This study assessing bowel and urinary PROs was undertaken as a prelude to an RCT comparing UHRT (5-12 fractions) with SRT. If UHRT are found to be noninferior for important efficacy and toxicity endpoints, PROs become an important and relevant endpoint in determining whether UHRT will be used in clinical practice.

Section snippets

Randomization and masking

NRG Oncology's RTOG 0938 (ClinicalTrials.gov #NCT01434290) is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk localized prostate cancer in which each arm was compared with a historical control. Patients were randomized by the NRG Oncology Statistics and Data Management Center using an automated permuted block randomization scheme to receive UHRT to a dose of 36.25 Gy (5 fractions of 7.25 Gy in 2 weeks) or 51.6 Gy (12 fractions of 4.3 Gy in 2.5 weeks) (27)

Results

From September 2011 to February 2014, 255 patients were randomized, with 127 patients on the 5-fraction arm of the study and 128 patients on the 12-fraction arm (Fig. 1), from 52 NRG Oncology members. Nine patients were found ineligible (7 with baseline PSA and 2 with history and physical examination out of the time window), and 6 patients did not receive protocol treatment. As a result, 119 and 121 patients were analyzable for the 5- and 12-fraction arms, respectively. The patient

Discussion

Although patients with National Comprehensive Cancer Network low-risk prostate cancer now often choose to undergo active surveillance, some choose to be treated. Treatment of localized prostate cancer using modern high-precision techniques to a dose of 76 to 79.2 Gy over 7.5 to 9 weeks is now established 1, 2, 3. Recently presented RCT data using moderate HypoRT have shown bNED (no evidence of biochemical failure) rates and toxicity outcomes comparable to those with SRT (7.5-8 weeks) 11, 12, 13

Conclusions

The 5- and 12-fraction UHRTs in this study are well tolerated. The bowel, urinary, and sexual PROs are comparable to those for SRT. The acute and late toxicity rates for the 5-fraction and 12-fraction regimens were low, but longer follow-up is required. Ongoing and maturing randomized trials are comparing UHRT to moderate HypoRT and conventional fractionation regimens, and we await their mature results.

References (34)

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This project was supported by the National Cancer Institute, grant nos. UG1CA189867 (National Cancer Institute Community Oncology Research Program), U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology Statistics and Data Management Center), and U24CA180803 (Imaging and Radiation Oncology Core).

Conflict of interest: none.

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