Hypofractionated radiotherapy to the prostate bed proved to be noninferior to conventionally fractionated radiotherapy after prostatectomy regarding gastrointestinal and genitourinary side effects, according to the results of the phase III NRG Oncology GU003 trial, presented at the 2021 American Society for Radiation Oncology (ASTRO) Annual Meeting.1 This large, multi-institutional, National Cancer Institute (NCI)-funded trial showed that at the end of treatment, patient-reported outcome scores were similar between treatment arms for genitourinary adverse events at all time points. However, gastrointestinal events were more frequent at the end of treatment with hypofractionation than conventional fractionation, but they resolved by 6 months.
Mark K. Buyyounouski, MD, MS
“Hypofractionation was associated with greater patient-reported gastrointestinal toxicity at the end of treatment, but patients recovered within 6 months, with no worsening thereafter. Hypofractionation is noninferior to conventional radiotherapy in terms of patient-reported gastrointestinal or genitourinary toxicity at 2 years and is a new acceptable practice standard for patients receiving radiotherapy after prostatectomy,” said lead author Mark K. Buyyounouski, MD, MS, Professor of Radiation Oncology and Director of Genitourinary Cancers, Department of Radiation Oncology, Stanford University’s School of Medicine, California.
“Hypofractionation—delivering radiation therapy with fewer treatments—is a win when it comes to reducing the burden of prostate cancer on society. For patients, fewer treatments equate to a shorter time commitment, which increases access to a potentially curative treatment, reduces expenses for travel and co-pays, and involves less time away from work and other responsibilities. For providers, hypofractionation can improve productivity and increase the overall capacity for all patients. For payers, fewer treatments mean fewer expenses,” he explained.
Background and Study Themes
Prostate cancer is the second most common cancer in men in the United States. In many cases, the disease is treatable, with 10-year survival rates at about 98%. Quality of life becomes an important consideration in treating prostate cancer, so a shorter course of radiotherapy that is equally effective with no decrement in quality of life is of interest.
Dr. Buyyounouski commented on the study’s three major themes:
Postprostatectomy radiotherapy: “This is a well-established, albeit underutilized, standard for biochemical recurrence after prostatectomy and sometimes for patients with adverse features.”
Hypofractionation: “This is a well-accepted practice standard for intact prostate cancer based on noninferiority trials that may also be acceptable after surgery.”
Quality of life: “This may be impacted by hypofractionation and is a determinant of an acceptable practice standard. Any new practice should preserve quality of life.”
A total of 93 institutions participated in this NCI-funded trial, which is reportedly the first randomized trial of hypofractionated radiation therapy in the post-prostatectomy space. Patients were enrolled if they had an undetectable prostate-specific antigen (PSA) level (ie, < 0.1 ng/mL), provided they had adverse features, including extracapsular extension or positive surgical margins. Metastasis was an exclusion criterion.
Patients (n = 294) were randomly assigned 1:1 to receive conventionally fractionated postoperative radiotherapy directed to the prostate bed at 1.8 Gy × 37 fractions (total of 66.6 Gy) vs hypofractionated postoperative radiotherapy directed to the prostate bed at 2.5 Gy × 25 fractions (total of 62.5 Gy). Stratification factors included baseline gastrointestinal and genitourinary function as well as receipt (or not) of adjuvant hormonal therapy for up to 6 months.
The primary endpoint was a change in Expanded Prostate Cancer Index Composite (EPIC) score measured at 2 years. (See Sidebar for more on this patient-reported outcome measure.) “The trial is unique in its use of patient-reported outcomes as the primary endpoint. The ideal way of measuring quality of life is by asking patients themselves,” Dr. Buyyounouski said.
Several radiation techniques were acceptable, he noted, provided they were image-guided. Also, the age of patients varied. At baseline, there was a wide distribution of pretreatment bowel and urinary tract function. A total of 23% of the study population received hormonal therapy; 93% had a PSA level < 0.5 ng/mL; 54% had extraprostatic extension; and 21% had a pathologic nodal evaluation.
According to physician-reported toxicity, there were no grade 4 or 5 adverse events and no difference in grade 3 adverse events related to treatment. Six cases of grade 3 cystitis were reported by physicians. However, according to Dr. Buyyounouski, “this was poorly correlated with patient-reported outcomes, where five of the six patients said cystitis was ‘a very small or small bother.’”
Mean EPIC genitourinary domain scores over time had “essentially superimposable curves over time” for the two treatment arms. The EPIC genitourinary change score at any time compared with baseline was no different between treatment arms at 6, 12, and 24 months after treatment.
The Expanded Prostate Cancer Index Composite (EPIC) score is based on a validated questionnaire used to evaluate patient function and symptoms after prostate cancer treatment. Based on the original UCLA–Prostate Cancer Index (PCI), the expanded version was developed by a host of experts as well as patients to include concerns related to brachytherapy, external-beam radiation therapy, radical prostatectomy, and androgen deprivation. Specific domains, such as urinary incontinence, urinary irritation, bowel habits, sexual function, and hormonal domains, were added to achieve bother scales for each health-related quality-of-life domain. Scores range from 0 to 100, with higher scores reflecting more adequate function or fewer symptoms than lower scores.
Source: Michigan Medicine (medicine.umich.edu/dept/urology/research/epic).
The mean EPIC gastrointestinal domain scores were significantly different for conventionally fractionated and hypofractionated radiation therapies at the end of treatment, with hypofractionation associated with lower scores (P < .001). However, this difference favoring conventional fractionation seemed to disappear by 6 months, with no further decline throughout the study. At the completion of treatment, gastrointestinal change scores were clinically significant favoring conventional fractionation (P = .0011), but they were no different at 6 to 24 months.
“At a median follow-up of 2.1 years, there was no signal of worse time to disease progression with hypofractionated radiation treatment,” Dr. Buyyounouski stated.
DISCLOSURE: Dr. Buyyounouski has received honoraria from Elsevier and Wolters Kluwer; and has received research grants from Varian.
1. Buyyounouski MK, et al: Primary endpoint analysis of a randomized phase III trial of hypofractionated vs conventional post-prostatectomy radiotherapy. 2021 ASTRO Annual Meeting. Abstract 3. Presented October 25, 2021.
Sophia C. Kamran, MD
Sophia C. Kamran, MD, Assistant Professor of Radiation Oncology at Massachusetts General Hospital, commented on the NRG Oncology GU003 study at a press conference where this abstract was discussed. Dr. Kamran was not involved in this trial. “This is a potentially...