Abstract
Importance
The treatment of prostate cancer with radiotherapy is evolving. How quickly radiotherapy can be delivered, and the relative risks and benefits of such a treatment, is of significant public interest.
Objective
To determine whether stereotactic body radiotherapy (SBRT) was superior to moderately-hypofractionated intensity modulated radiation therapy (MH-IMRT) in terms of patient reported urinary irritative/obstructive and bowel quality of life (QOL) and disease-free survival (DFS).
Design, Setting, Participants
NRG-GU005 was a phase-3, international, open-label, randomized, controlled trial. The study was activated 11/16/2017 and closed to accrual on 6/8/2022. Date of last follow up was 10/13/2024. There were 121 centers in the United States, 13 in Canada, and 2 in Asia that accrued patients to the study.
Patients with localized prostate cancer, clinical stage T1-T2b with Gleason 3+4 (Grade group 2) and PSA < 20 ng/mL or Gleason 3+3 (Grade group 1) and PSA 10–20 ng/mL were eligible. Intended accrual of 692 patients provided reductions of 8% and 10% in minimal clinically important decline (MCID) frequency for urinary-irritative/obstructive and bowel domains of the Expanded Prostate cancer Index Composite 26-item (EPIC-26) at 2 years and >80% power to detect a hazard ratio of 0.62 in DFS.
Interventions
Patients were randomized 1:1 to receive SBRT (36.25 Gy in 5 fractions) or MH-IMRT (70 Gy in 28 fractions or 60 Gy in 20 fractions).
Main Outcomes and Measures
Primary outcomes were the frequency of a MCID in the urinary irritative/obstructive and bowel domains of the EPIC-26 at 2 years and DFS at 3 years.
Results
NRG-GU005 randomized 698 patients. Median follow-up was 3.2 years (min-max: 0–6.5). At 2 years, there were no significant difference in the urinary-irritative domain (35.4% vs. 33.7%, p=0.68). Urinary incontinence at 1- and 2-years post-treatment and sexual function at 1-year post-treatment favored SBRT. Fewer grade 3–4 genitourinary adverse events occurred in the SBRT vs MH-IMRT group (0.6 vs. 2.5%, p=.04). There were significantly fewer MCID with SBRT vs. MH-IMRT in the bowel domain (34.9% vs. 43.8%, p=0.034) At 3 years, DFS for MH-IMRT was 92.1% (95% confidence interval [CI]: 88.9–95.2) vs. 88.6% for SBRT (95% CI: 85.2–92.1) (one-sided log-rank p<0.0001).
Conclusions and Relevance
SBRT utilizing a modest dose prescription improved multiple QOL domains, but was not superior to MH-IMRT in terms of DFS and. The rate of PSA failure was not significantly improved in the SBRT vs. MH-IMRT arm.
Trial Registration:
Clinicaltrials.gov identifier: NCT03367702
Introduction
Prostate cancer is diagnosed in 1 in 8 men in the United States and is the most common non-skin cancer in men worldwide, with over 1.4 million new cases per year1. The United States has the highest prevalence of prostate cancer patients globally2. Radiation treatment is increasingly utilized relative to other treatments, and in particular, external beam radiotherapy (EBRT) has evolved to become the dominant form of radiotherapy treatment3. Technological advancements in the ability to deliver EBRT safely and effectively in few fractions, termed hypofractionation, has become widespread across cancer types, with great public interest4. As hundreds of thousands of men undergo prostate radiotherapy each year, how quickly a man can receive radiation treatment and the resultant toxicity of treatment is an issue that impacts not only patients and their caregiving teams, but entire healthcare systems5.
Due to this public interest, NRG Oncology embarked on a series of randomized studies to establish the safety and efficacy of shortened treatment courses for prostate cancer6–8. NRG-GU005 is the culmination of over two decades of effort and was launched to compare the most promising arms of these trials, specifically moderately hypofractionated intensity modulated radiation therapy (MH-IMRT) involving 20–28 daily treatments versus 5-treatment EBRT, also known as stereotactic body radiotherapy (SBRT). We hypothesized that SBRT would be superior to MH-IMRT in terms of quality of life (QoL) and disease-free survival (DFS) for patients with intermediate-risk prostate cancer.
Methods
Trial Design and Oversight
NRG-GU005 was a parallel phase III, open label, randomized, controlled trial. This study was reviewed and approved by the NCI’s Central Institutional Review Board. Written informed consent was provided by all patients. Enrolling sites were in the US, Canada, Europe, and Asia. NRG Oncology Statistics and Data Management handled randomization, treatment assignment, data collection, and analysis.
Patients
Patients with previously untreated, intermediate risk localized prostate cancer, defined as clinical stage T1-T2b with either Gleason 3+4 and PSA < 20 ng/ML, or Gleason 3+3 and PSA between 10 ng/mL and 20 ng/mL were eligible. Patients with prostate volume ≥ 70 cc or T3 disease on diagnostic MRI were excluded. Bone scan was required within 120 days and prostate MRI within 1 year prior to registration. Complete eligibility criteria are found in the protocol.
Treatment
IMRT or related techniques as well as image guidance were required for this study. For patients planned with CT, fiducial markers or implanted transponders were required but could be omitted for MRI only based planning and delivery platforms. Intra-fraction monitoring of prostate position (i.e. imaging during radiation delivery to confirm prostate location) was strongly recommended for all techniques.
For all patients, the gross tumor volume was defined as prostate alone, and clinical target volume included the gross tumor volume +/− 1 cm of the proximal seminal vesicles at the discretion of the treating radiation oncologist.
When the study was first designed, MH-IMRT was defined as 70 Gy in 28 fractions. Given expanding evidence supporting MH-IMRT using 60 Gy in 20 fractions this regimen was later allowed. For MH-IMRT, planning treatment volume included clinical tumor volume+ 8mm minimum expansion in all directions except posteriorly where 5mm was allowed. Maximum dose per protocol to the planning tumor volume was 77 Gy and 63 Gy for dose prescriptions of 70 and 60 Gy, respectively, while maintaining 98–99% coverage of the planning tumor volume. Maximum dose to 15% and 50% of the rectum was 70 Gy and 38 Gy, and maximum dose to 0.03cc and 50% of the bladder was 73.5 Gy and 38 Gy, respectively. There was no urethral constraint for MH-IMRT.
For SBRT, planning tumor volume included clinical tumor volume + 5mm minimum expansion in all directions except posteriorly and anteriorly where 3mm was allowed. Prescription dose was 36.25 Gy in 5 fractions, delivered 2–3 fractions per week, at least every other day, in fewer than 17 business days. Maximum dose to the planning tumor volume was 38.78 Gy, while maintaining 98% coverage of the planning tumor volume. Maximum dose to 0.03cc and 50% of the rectum were 38 Gy and 18 Gy, respectively. Maximum dose to 0.03cc and 50% of the bladder was 39 Gy and 15 Gy, respectively. For patients where the maximum dose within the planning tumor volume exceeded 38.78 Gy, urethral visualization and contouring was required, and maximum urethral dose (0.03cc) was limited to 38.78 Gy.
Radiation plans were reviewed centrally. Pre-treatment review was required for the first SBRT patient enrolled from each institution. Specific criteria are found in the protocol (Supplement).
Assessments
Baseline Expanded Prostate cancer Index Composite – 26 items (EPIC-26) surveys were completed within 60 days prior to registration. The EPIC-26 is a 5-domain (urinary incontinence, urinary irritative/obstructive, bowel, sexual, and hormonal), 26 question instrument that has been widely used to measure prostate cancer treatment-related QoL9,10. Adverse events (AEs) were graded with CTCAE version 5.
Primary Objectives
There were two co-primary objectives. The first primary objective was to determine whether SBRT can be shown to be superior to MH-IMRT in terms of GI and GU quality of life by having fewer patients that experience a minimal clinically important decline (MCID) in urinary irritative/obstructive and bowel HRQOL as measured by EPIC-26 at 24 months post completion of therapy. The second was to determine if SBRT (5 fractions of 7.25 Gy) is superior to MH-IMRT (28 fractions of 2.5 Gy or 20 fractions of 3 Gy) as measured by Disease Free Survival (DFS).
Secondary Objectives
There are two secondary objectives reported in this manuscript: First, to determine whether SBRT can be shown to be superior to MH-IMRT in terms of GI and GU quality of life by having fewer patients that experience a MCID in bowel and urinary irritative/obstructive HRQOL domains as measured by EPIC-26 at 24 months post completion of therapy. Second, to determine if SBRT (5 fractions of 7.25 Gy) is superior to MH-IMRT (28 fractions of 2.5 Gy or 20 fractions of 3 Gy) as measured by Disease Free Survival (DFS).
Two other secondary objectives are intended in this study related to MRI that are not reported in this manuscript and will be reported separately. Original MRI images were collected and reviewed to evaluate the presence or dominate lesions relative to positive biopsy sites, and repeat MRI’s were funded on study for PSA failures to determine if the initial dominate lesions were the site of recurrent disease to explore the potential benefits of a higher does to the dominate lesions.
Statistical analysis
Patients were stratified by risk group (defined by Gleason score and PSA) and use of rectal manipulation (rectal balloon and/or rectal spacing gel, or neither) and randomly assigned 1:1 using permuted blocks to receive SBRT or MH-IMRT. Patients were analyzed based on the arm to which they were randomized (intent-to-treat).
For the patient reported QoL endpoint, an absolute frequency of MCID for bowel and urinary irritative/obstructive domains was estimated to be 22.9% and 13.6% for MH-IMRT, and 12.9% and 5.6% for SBRT (i.e., an absolute reduction with SBRT of 10% and 8% for bowel and urinary domain MCID frequency, respectively). Using a 2-sided type I error of 0.05, and 1 interim futility analysis, as well as an assumed survey non-compliance of 25% and 10% rate of death and consent withdrawal, the target accrual was 692 patients.
The DFS endpoint was measured from the date of randomization to the date of first biochemical, local, regional, or distant failure, or death. Patients without events were censored at last known follow up. DFS and overall survival were estimated using the Kaplan-Meier method with between group differences tested using the stratified log-rank test. The cumulative incidence estimator was used to estimate time to event distributions for endpoints with competing risks using Gray’s test for between group differences11 DFS at 5 years was hypothesized to be 62% in the MH-IMRT group and 74.3% in the SBRT group, corresponding to a HR=0.62. Using a 2-sided type I error of 0.05 with a log-rank test and 1 interim futility analysis, 178 events from 692 patients provided 89% power assuming 13% loss to follow up and consent withdrawal. The futility analysis, occurring at 50% information, tested whether to reject the alternative hypothesis favoring SBRT at a one-sided type I error of 0.001.
Based on discussions with NCI personnel, the two co-primary endpoints were considered to address conceptually separate aspects of care and clinical outcomes. Each endpoint was analyzed with control of the endpoint-specific type I error risk at the traditional two-tailed .05; however, the studywise type I error risk was not controlled overall.
Longitudinal mixed effects models, adjusting for baseline domain score, treatment group, stratification factors, T-stage, age, and race were performed. Interactions between treatment group and time and treatment group and rectal manipulation were included only if significant at the 5% level. Differences in pretreatment characteristics by EPIC-26 completion status was assessed and those that were significantly different were included in models.
Overall survival was measured from the date of randomization to date of death. All other time-event measures were measured from the date of randomization to the event (biochemical, local, regional, distant failure) with death without an event considered a competing risk.
For all analyses, categorical and continuous variables were compared between groups using chi-square tests and t-test, respectively. The difference in EPIC domains was calculated as MH-IMRT – SBRT. Cox proportional hazards models (cause-specific models for endpoints with competing risks) assessed the effects of stratification factors and other covariates of interest, such as age, race, ethnicity, T stage, and ECOG performance status on outcomes. An interaction between rectal manipulation and treatment group was included only if significant at the 5% significance level.
Statistical analyses were conducted at NRG Oncology Statistics and Data Management Center using SAS v9.0.
Results
Randomization and Patient Characteristics
NRG-GU005 accrued from November 16, 2017 to June 8, 2022 with 698 patients randomized, 353 to SBRT and 345 to MH-IMRT (Figure 1). Two patients on the SBRT group were ineligible due to having higher risk disease.
Figure 1. Participant Randomization and Flow Through the Trial (Consolidated Standards of Reporting Trials – CONSORT Diagram).
MH-IMRT = moderately hypofractionated intensity modulated radiation therapy; SBRT = stereotactic body radiation therapy; PSA = prostate specifc antigen; EPIC = Expanded Prostate cancer Index Composite. *Patients were stratified by risk group (defined by Gleason score and PSA) and use of rectal manipulation (rectal balloon and/or rectal spacing gel, or neither).
Median age was 68 years (range 42–84) (Table 1). Most patients identified as White (80%), with 13% identifying as Black, and 3% as Asian. Most patients had Gleason score 3+4 and PSA < 10 ng/mL (73.5%), a T-stage of T1c (81.7%), and Zubrod performance status of 0 (88.1%). Most patients used rectal spacing alone (55.6%), 1.0% underwent rectal balloon alone, 3.2% underwent both, and 40.3% did not utilize a rectal device.
Table 1.
Patient and Tumor Characteristics for All Randomized Patients
| Patient or Tumor Characteristic | SBRT (n=353) |
MH-IMRT (n=345) |
|---|---|---|
|
| ||
| Age (years) | ||
| Median (Q1-Q3) | 69 (63 – 73) | 68 (64 – 73) |
| Race1 | ||
| American Indian or Alaska Native | 1 ( 0.3%) | 0 ( 0.0%) |
| Asian | 10 ( 2.8%) | 10 ( 2.9%) |
| Black or African American | 43 ( 12.2%) | 47 ( 13.6%) |
| White | 282 ( 79.9%) | 276 ( 80.0%) |
| More than one race | 0 ( 0.0%) | 2 ( 0.6%) |
| Unknown | 17 ( 4.8%) | 10 ( 2.9%) |
| Ethnicity1 | ||
| Hispanic or Latino | 6 ( 1.7%) | 13 ( 3.8%) |
| Not Hispanic or Latino | 335 ( 94.9%) | 322 ( 93.3%) |
| Unknown | 12 ( 3.4%) | 10 ( 2.9%) |
| Immediate relatives with cancer (patient-reported) | (n=331) | (n=320) |
| Immediate relatives with cancer reported | 214 (64.7%) | 210 (65.6%) |
| Patient-reported cardiovascular comorbidities | (n=331) | (n=320) |
| Comorbidities reported | 197 (59.5%) | 206 (64.4%) |
| Patient-reported diabetes | (n=331) | (n=320) |
| Diabetes reported | 60 (18.1%) | 50 (15.6%) |
| Charlson comorbidity score2 | ||
| Median (Q1-Q3) | 3 (2 – 3) | 3 (2 – 3) |
| Risk Group | ||
| Gleason score 7 (3+4) with PSA < 10 ng/ml | 256 ( 72.5%) | 257 ( 74.5%) |
| Gleason score 7 (3+4) with 10 ng/mL = PSA < 20 ng/mL | 74 ( 21.0%) | 72 ( 20.9%) |
| Gleason score 6 (3+3) 10 ng/mL < PSA < 20 ng/mL | 23 ( 6.5%) | 16 ( 4.6%) |
| Rectal Manipulation | ||
| SpaceOAR | 198 (56.1%) | 188 (54.5%) |
| None | 138 (39.1%) | 146 (42.3%) |
| SpaceOAR and rectal balloon | 15 (4.2%) | 8 (2.3%) |
| Rectal Balloon | 2 (0.6%) | 3 (0.9%) |
| Combined Gleason Score / Grade Group3 | ||
| Gleason 6 (3+3) / Grade Group 1 | 23 ( 6.5%) | 16 ( 4.6%) |
| Gleason 7 (3+4) / Grade Group 2 | 330 ( 93.5%) | 329 ( 95.4%) |
| T-Stage4 | ||
| T1 | 285 ( 80.7%) | 285 ( 82.6%) |
| T2 | 68 ( 19.3%) | 60 ( 17.4%) |
| N-Stage5 | ||
| N0 | 353 (100.0%) | 345 (100.0%) |
| Zubrod Performance Status6 | ||
| 0 | 318 ( 90.1%) | 297 ( 86.1%) |
| 1 | 35 ( 9.9%) | 48 ( 13.9%) |
| EPIC bowel domain6 | ||
| Median (Q1 - Q3) | 100.0 (95.8 – 100.0) | 100.0 (95.8 – 100.0) |
| EPIC urinary irritative/obstructive domain6 | ||
| Median (Q1 - Q3) | 93.8 (81.3 – 100.0) | 93.8 (81.3 – 100.0) |
| EPIC urinary incontinence domain6 | ||
| Median (Q1 - Q3) | 100.0 (87.5 – 100.0) | 100.0 (85.5 – 100.0) |
| Min - Max | 37.5 – 100.0 | 27.0 – 100.0 |
| Q1 - Q3 | 87.5 – 100.0 | 85.5 – 100.0 |
| EPIC sexual domain6 | ||
| Median (Q1 - Q3) | 62.5 (34.7 – 83.3) | 61.2 (34.7 – 83.3) |
| EPIC hormonal domain6 | ||
| Median (Q1 - Q3) | 100.0 (90.0 – 100.0) | 100.0 (90.0 – 100.0) |
SpaceOAR= FDA approved rectal spacer to create distance between the prostate and the Organ At Risk (ie rectum). No other competing devices were FDA approved and used during the trial.
MH-IMRT=moderately hypofractionated intensity modulated radiation therapy; SBRT=stereotactic body radiation therapy, PSA=prostate specific antigen; Q1=first quartile; Q3=third quartile.
Race and ethnicity were reported by the enrolling institution.
The Charlson modified comorbidity score is a measure of comorbid illnesses and age that predicts mortality. It determined by weighting comorbid medical conditions identified from a patient’s medical history and the patient’s age (see protocol appendix I). The score ranges from 0 (no comorbidities) to 37, with greater score meaning more a greater severity of total conditions and age.
Gleason score is the score assigned to the microscopic pattern of cells seen in the cancer histopathology, with higher score indicating more aggressive disease. The total Gleason score is the sum of two numbers, the first number indicating the most common pattern and the second number indicating the second most common pattern. The Gleason score can also be classified into a Grade grouping. Gleason score 6 (3+3) and 7 (3+4) mean the same thing as Grade group 1 and 2, respectively, indicating low and intermediate risk histopathology.
Zubrod (or Eastern Cooperative Oncology Group) Performance Status indicates a patient’s ability to perform activities of daily living. Zubrod 0 indicates normal activity, and a score of 1 indicates a patient who is ambulatory and able to care for oneself.
T-stage was collected using AJCC version 7. T1 indicates no findings on digital rectal exam but disease found via biopsy or transurethral resection of the prostate, T2 indicates palpable tumor on digital rectal exam.
N-stage was collected using AJCC version 7. N0 indicates no clinically involved lymph nodes.
Response options for each EPIC item form a Likert scale and the domain scores are transformed linearly to a 0–100 scale, with higher scores representing better health related quality of life. A domain score is the average of the transformed domain item scores.
Twenty-three patients did not receive study treatment (1 on the SBRT group and 22 on the MH-IMRT group) all due to patient withdrawal prior to start of treatment). Almost all patients on the SBRT group (96.6%) received 36.25 Gy in 5 fractions. On the MH-IMRT group, 70.6% received 28 fractions and 26.6% received 20 fractions. Few patients had RT delays (1.4% due to treatment related adverse events and 9.5% due to other reasons). Treatment was given per protocol or with acceptable variation in 97.7% and 97.2% of patients in the SBRT and MH-IMRT groups, respectively.
Primary Patient Reported Outcome (PRO) endpoints
At the time of the interim analysis, the corresponding co-primary HRQOL endpoint had reached the protocol specified time of analysis.
EPIC questionnaire compliance was 82% at 1 year and 84% at two years. Baseline EPIC was required at registration resulting in 100% compliance with scores similar between groups.
Table 2 represents a comparison of clinically meaningful patient reported declines in bowel, urinary, sexual, and hormonal quality of life. Regarding the co-primary PRO endpoint, at 2 years post treatment, there was no difference in the urinary irritative/obstructive domain (35.4% SBRT vs 33.7% MH-IMRT, mean difference of −1.7%, 95% CI: −9.7–6.3, p=0.68). However, at 2 years there were significantly fewer patients in the SBRT group as compared to the MH-IMRT group with a MCID in bowel domain (34.9% SBRT vs. 43.8% MH-IMRT, mean difference of 8.9%, 95% CI: 0.7–17.0, p=0.034 (Table 3).
Table 2.
Proportion of patients with a minimal clinically meaningful decline in EPIC domain scores
| EPIC Domain Score1 | MCID decline in domain | SBRT n/N (%) | MH-IMRT n/N (%) | Unadjusted Difference2 (95% CI) | p-value3 |
|---|---|---|---|---|---|
|
Primary endpoints | |||||
| Bowel at 2 years | 4 | 101/353 (34.9%) | 113/345 (43.8%) | 8.9% (0.7%, 17.0%) |
0.034 |
| Urinary irritative/obstructive at 2 years | 5 | 102/353 (35.4%) | 102/345 (41.1%) | −1.7% (−9.7%, 6.3%) |
0.68 |
|
Secondary endpoints | |||||
| Bowel at 1 year | 4 | 98/353 (33.1%) | 117/345 (45.9%) | 12.8% (4.6%, 20.9%) |
0.0022 |
| Urinary irritative/obstructive at 1 year | 5 | 105/353 (36.1%) | 94/345 (37.3%) | 1.2% (−6.9%, 9.3%) |
0.77 |
| Urinary incontinence at 1 year | 6 | 80/353 (29.9%) | 87/345 (34.5%) | 7.6% (−0.2%, 15.3%) |
054 |
| Urinary incontinence at 2 years | 6 | 75/353 (25.9%) | 90/345 (34.7%) | 8.9% (1.2%, 16.6%) |
0.023 |
| Sexual at 1 year | 10 | 94/353 (34.3%) | 107/345 (43.9%) | 9.5% (1.2%, 17.9%) |
0.026 |
| Sexual at 2 years | 10 | 116/353 (43.0%) | 102/345 (41.1%) | −1.8% (−10%, 6.7%) |
0.67 |
| Hormonal at 1 year | 4 | 73/353 (26.0%) | 82/345 (32.7%)) | 6.7% (−1.1%, 14.4%) |
0.090 |
| Hormonal at 2 years | 4 | 84/353 (30.2%) | 82/345 (32.0%) | 1.8% (−6.0%, 9.7%) |
0.65 |
EPIC=Expanded Prostate cancer Index Composite, MH-IMRT=moderately hypofractionated intensity-modulated radiation therapy, SBRT=stereotactic body radiation therapy, MCID=minimally clinically important difference.
The MCID proportion is calculated as the proportion of patients with a decline from baseline to 1 or 2 years that is ≥ the domain’s prespecified MCID.
Response options for each EPIC item form a Likert scale and the domain scores are transformed linearly to a 0–100 scale, with higher scores representing better health related quality of life. A domain score is the average of the transformed domain item scores.
Difference calculated as MH-IMRT – SBRT. A positive difference favors the SBRT group.
t-test p-value
Table 3.
Biochemical Failure/Disease-Free Survival/Overall survival endpoint table
| Endpoint | SBRT rate (%) (CI)1 n=353 | MH-IMRT rate (%) (CI)1 n=345 | Unadjusted hazard ratio (CI) | p-value | Adjusted hazard ratio (CI)4 | p-value |
|---|---|---|---|---|---|---|
|
Primary co-endpoint | ||||||
| Disease free survival at 2 years | 91.4% (88.4–94.3) |
95.9% (93.8–98.1) |
1.38 (0.91–2.09) |
0.132 <0.00013 |
1.41 (0.92–2.15) |
0.114 |
| Disease free survival at 5 years | 77.5% (71.0–84.0) |
81.8% (75.3–88.2) |
||||
|
Secondary endpoints | ||||||
| Biochemical failure at 2 years | 6.3% (4.1–9.2) |
1.9% (0.8–3.8) |
1.82 (1.03–3.33) |
0.0345 | 1.82 (1.01–3.27) |
0.0464 |
| Biochemical failure at 5 years | 12.3% (8.1–17.4) |
7.7% (4.2–12.6) |
||||
| Overall survival at 2 years | 98.6% (96.6–99.4) |
97.8% (95.5–99.0) |
1.21 (0.54–2.33) |
0.662 | 1.15 (0.55–2.41 |
0.704 |
| Overall survival at 5 years | 91.1% (84.7–94.8) |
94.5% (90.5–96.9) |
||||
CI=confidence interval
Survival estimates are based on Kaplan Meier curves and therefore include CIs.
Stratified log-rank test p-value
p-value for futility
p-value from Cox proportional hazards model adjusted for age, race, risk group, rectal manipulation, and t-stage
Gray’s test p-value.
Due to the small number of observed events, distant metastases, local and reginal failure were not analyzed.
DFS
Through October 11, 2024, 91 DFS events were reported triggering an interim analysis. The DFS hypothesis (superiority of SBRT) was rejected (p<0.0001; hazard ratio (HR; SBRT/MH-IMRT)=1.38, 95% CI: 0.91–2.09). Thus, the co-primary endpoint of DFS was released for early reporting by the NRG Oncology Data Monitoring Committee.
The three-year DFS rate in the MH-IMRT group was 92.1% (95% confidence interval [CI]: 88.9–95.2) and in the SBRT group was 88.6% (95% CI: 85.2–92.1) (Table 3, Figure 2a). After covariate adjustment, there was no significant between group difference in DFS (HR=1.40, 95% CI: 0.91–2.13, p=0.12) (Supplemental Table 1).
Figure 2. A) Disease free survival by treatment group. 3) Overall survival by treatment group.
MH-IMRT = moderately hypofractionated intensity modulated radiation therapy; SBRT = stereotactic body radiation therapy.
Secondary PRO Endpoints
As a secondary PRO endpoint, there were significantly fewer patients in the SBRT group who had a decline in the sexual domain at 1 year (34.3% vs. 43.9%, mean difference of 9.5%, 95% CI: 1.2–17.9, p=0.026), bowel domain at 1 year (33.1% vs. 45.9%, mean difference of 12.8%, 95% CI: 4.6–20.9, p=0.002), and urinary incontinence domain at 2 years (25.9% vs. 34.7%, mean difference of 8.9%, 95% CI: 1.2–16.6, p=0.023). All other domains were not statistically different.
Analysis of longitudinal bowel domain scores showed a significant treatment effect in favor of SBRT (least square [LS] mean=2.68 [95% CI: 1.02, 4.34] p=0.0016). Not using a rectal balloon or spacer resulted in worse bowel scores (LS mean=-2.81 [95% CI: −4.49, −1.13], p=0.0011). SBRT had better urinary incontinence scores (LS mean=2.91 [95% CI: 0.85, 4.97], p=0.0058). There were no significant between group differences for EPIC urinary irritative/obstructive domain, EPIC sexual domain (Supplemental Figure 2) or EPIC hormonal domain scores across time (Supplemental Figures 1–5). The interaction between rectal manipulation and treatment group was not significant in any of the EPIC models and thus was removed from the models.
Secondary Clinical Endpoints: Overall Survival, biochemical Disease Free Survival (bDFS), Local Failure
There was no difference in overall survival between groups (p=0.62) (Table 3, Figure 2b), which persisted in the adjusted analysis (HR=1.15, 95% CI: 0.55–2.41, p=0.70) (Supplemental Table 2).
The rate of biochemical Disease Free Survival (bDFS) failure by prostate specific antigen (PSA) testing was significantly higher in the SBRT vs. MH-IMRT group (7.8% vs. 4.2% at 3 years; p=0.037; adjusted HR=1.82, 95% CI: 1.01–3.27, p=0.046) (Supplemental Table 3). Age and t-stage were also significantly associated with biochemical failure.
There was no difference in local failure between the SBRT and MH-IMRT groups (1.2% vs. 1.0% at 3 years, p=0.97). Due to the small number of events (8 in the SBRT group and 7 in the IMRT group), no further analyses were conducted.
Similarly, due to the small number of events for regional (4 and 2 in the SBRT and MH-IMRT groups, respectively) and distant failure (4 in each group), those endpoints were not analyzed.
AEs
Fewer grade 3–4 genitourinary adverse events occurred in the SBRT group as compared to the MH-IMRT group (0.6% vs. 2.5, p=0.040) (Supplemental Table 4). Fewer patients in the SBRT group as compared to the MH-IMRT group reported any grade, any attribution toxicity for rectal hemorrhage (10.5% vs. 17.3%, p=0.010) and fatigue (39.2% vs. 50.8%, p=0.0025).
Discussion
In this randomized phase III study of 698 patients, we found that while SBRT was associated with a lower impact on bowel-related quality of life compared to MH-IMRT in patients with intermediate-risk prostate cancer, that SBRT was not superior to MH-IMRT in terms of urinary irritative/obstructive related quality of life or DFS. Our study has immediate impact on patients and physicians considering a shorter course of radiotherapy for localized prostate cancer. Furthermore, there are several important insights drawn when this study is placed in the context of prior randomized studies investigating SBRT for prostate cancer. The DFS is numerically worse for SBRT (vs. MH-IMRT), and so it remains possible that improved freedom from adverse quality of life effects may come at the price of worse DFS should this difference become statistically significant with further follow up.
It is important to remember that when this trial was designed in 2016, no randomized trials on prostate SBRT had been reported. SBRT was inherently desirable from a patient convenience standpoint given that treatment is delivered in 5 sessions over 2 weeks, compared to treatment delivered daily over 4 to 6 weeks. However, it there were concerns regarding some reports showing high levels of adverse events from this faster form of treatment. NRG-GU005 began enrollment in 2017, and in 2019 multiple informative studies on prostate SBRT were reported. Perhaps the most informative comparison is the PACE-B study which found that SBRT had non-inferior PSA and disease control compared to both MH-IMRT and standard IMRT, at the cost of increased acute GU toxicity5, using a slightly higher dose of radiation than recommended in GU005.
The collective results provide many important lessons. First, PACE-B prescribed and allowed a roughly 15% higher radiation dose compared to NRG-GU005. Likely from this higher radiation dose, PACE-B demonstrated numerically superior post-treatment PSA control to MH-IMRT, whereas NRG-GU005 demonstrated inferior post-treatment PSA control to MH-IMRT. However, improvement in PSA control this came at the expense of the higher doses of SBRT in PACE-B showing an increased number of urinary adverse events and reduction in quality of life, whereas the lower radiation dose used for SBRT in NRG-GU005 had either similar or improved quality of life in multiple domains.
It is notable that SBRT technique uses smaller margins of expansion from the prostate. These smaller margins are allowable because of the greater precision allowed by the use of more rigorous imaging and prostate tracking during treatment for SBRT in comparison to standard non-SBRT radiation technique (as used in MH-IMRT)12. The margins used in our study were defined by prior studies (RTOG 0415 and RTOG 0938), and considered standard by NRG. It is possible that smaller margins may be used in the future for both SBRT and MH-IMRT with innovations in intra-treatment tracking such as MRI guidance. Other factors, including the abutment of grossly visible disease on MRI to the target margin, are currently being investigated to determine their impact on cancer control outcomes when applying SBRT techniques to radiation delivery.
It is therefore possible that the lower PSA control with SBRT as compared to IMRT may be explained by a lower biologically effective dose of radiation than expected due to prostate cancer biology or marginal missing of prostate cancer due to smaller radiation treatment volumes in the SBRT group. Similarly, these factors (lower biologically effective dose and smaller margins) may also be the reason for the reduced impact on bowel-related quality of life with SBRT.
Our study was unique compared to PACE-B and HYPO-RT-PC due to the utilization and stratification of patients by rectal manipulation, which largely was via rectal spacing. As a result, rectal spacing use was balanced between the MH-IMRT and SBRT groups. We found that rectal spacing was a significant factor associated with improved patient reported bowel function in a longitudinal analysis of bowel domain scores, favoring rectal spacing and its association with improved QoL. Given the overall low impact on bowel quality of life, we do not believe that these data would mandate use of a rectal spacer for all patients, but may show benefit in select patients as desired.
As we were unable to show superiority of SBRT with regards to disease control, it is also possible that with further follow up SBRT may provide worse disease control in the future, as reflected in the worse PSA control seen at 3 years. It is possible that future modifications to SBRT (by increasing radiation dose to tumor nodules) that do not significantly increase toxicity may be needed. Given the likely subtle differences in disease control and quality of life with each refinement in technique, large randomized studies are needed for definitive evaluation. We recommend that patients who would be included within the NRG-GU005 patient population but with a higher risk of local disease recurrence due to measurably large tumor burden, unfavorable clinical features, or genomic risk, may benefit from SBRT techniques that utilize higher radiation doses than allowed on NRG-GU005. At the same time, patients who prioritize convenience and quality of life over a small difference in PSA control may prefer SBRT over MH-IMRT.
A strength of our study was the assignment of patient reported QoL as a co-primary endpoint. Given the overall favorable prognosis of intermediate-risk prostate cancer, patients often co-prioritize QoL and convenience of therapy. Our study is representative of this modern focus, and our finding of improved patient reported outcomes at 2 years will likely be influential to patients seeking to maximize their QoL and convenience. Shared-decision making will be valuable when selecting not only the number of fractions, but also the various dose/fraction schedules to optimize treatment outcomes that are most important to each individual patient.
Limitations
Our randomized study is limited by several factors. First, it was designed to test the superiority (not the non-inferiority) of SBRT compared to MH-IMRT, with regards to DFS. Though we can say that SBRT is not superior to MH-IMRT, this study design does not allow us to state whether our protocol-defined SBRT is non-inferior to MH-IMRT. Second, we did not explore focal radiation dose escalation. As noted previously, the protocol defined SBRT in our study prioritized dose uniformity and reduction of potential toxicity compared to other studies that mandated higher doses to prostate tissue. Since the inception of this trial, growing bodies of evidence support the potential role of focal or microboosts to the dominant intraprostatic lesion (DIL). This may be a method to balance toxicity from dose-escalated whole gland treatment with efficacy of treatment of the whole gland and dose-escalation to the DIL. Third, the higher rate of benign PSA bounce documented for SBRT may impact the DFS and biochemical endpoints13–15. Fourth, the study is limited by the lack of quality of life and toxicity data beyond 2 years. It is possible that there may be further changes with longer follow up. However, compliance to patient reported quality of life data collection will also likely decline with time. Fifth, the study was not designed to distinguish between a benign PSA bounce and true PSA failure. Further study and follow up are needed to assess the impact of the benign PSA bounce phenomenon. As mentioned above, there was no correction for the co-primary endpoints of DFS and QoL. To prevent the possibility of an increased type I error, both co-primary endpoints were required to be significant to have a positive study which was not met.
Despite these limitations, our study provides an important advance in the understanding of the radiotherapeutic treatment of prostate cancer. SBRT is more convenient and less expensive than a conventionally fractioned radiation16,17. While SBRT requires fewer treatments, it is a more complex technology, staff effort, and physician oversight18. Recently proposed legislation in the US attempts to provide reimbursement regardless of treatment fractionation, encouraging physicians to choose the treatment they believe is best without potentially conflicting reimbursement incentives19.
Conclusions
Although we found the use of SBRT was superior to MH-IMRT with regards to patient reported bowel quality of life, it was not superior for urinary irritative/obstructive related quality of life at 2 years nor DFS. We additionally found that secondary endpoints showed that declines in urinary incontinence and sexual function by EPIC-26 favored SBRT over MH-IMRT. Rectal spacing appeared to improve bowel related quality of life in both cohorts. Further investigation into differences in SBRT technique for the treatment of prostate cancer should be an area of future research.
Supplementary Material
Key Points.
Question
Is stereotactic body radiation therapy (SBRT) superior in efficacy and patient-reported health-related quality of life to moderately hypofractionated intensity modulated radiation therapy (MH-IMRT) in patients with favorable intermediate risk prostate cancer?
Findings
There was no difference in the number of patients with minimal clinically important declines in urinary irritative/obstructive quality of life between SBRT and MH-IMRT at two years (35.4% vs. 33.7%). Fewer patients in the SBRT group as compared to the MH-IMRT group had minimal clinically important declines in bowel related quality of life (34.9% vs. 43.8%). At three years after treatment, SBRT was not superior to MH-IMRT in terms of disease-free survival (88.6% for SBRT vs. 92.1% for MH-IMRT).
Meaning
SBRT did not result in improved urinary irritative/obstructive-related quality of life compared to MH-IMRT at 2 years, but did improve bowel-related quality of life. SBRT was not superior to MH-IMRT in terms of cancer control at 3 years.
Acknowledgments:
Dr. Rodney J Ellis and NRG Oncology would like to thank the following accrual institutions who have been part of our mission to improve the lives of patients with cancer by conducting practice-changing multi-institutional clinical and translational research:
Adams Cancer Center
Allan Blair Cancer Centre
Alta Bates Summit Medical Center-Herrick Campus
Arizona Breast Cancer Specialists-Scottsdale
Arizona Center for Cancer Care-Peoria
Arizona Oncology Associates-West Orange Grove
Ascension All Saints Hospital
Ascension All Saints Hospital
Ascension Columbia Saint Mary’s Hospital - Milwaukee
Ascension Columbia Saint Mary’s Hospital Ozaukee
Ascension Southeast Wisconsin Hospital - Elmbrook Campus
Asplundh Cancer Pavilion
Aurora BayCare Medical Center
Aurora Saint Luke’s Medical Center
Beacon Hospital
Beaumont Hospital - Dearborn
Beaumont Hospital - Farmington Hills
Billings Clinic Cancer Center
Bon Secours Cancer Institute at Reynolds Crossing
Boston Medical Center
Case Western Reserve University
Centre De Sante Et De Services Sociaux De Chicoutimi
Centre Hospitalier Universitaire de Sherbrooke-Fleurimont
CHU de Quebec-ĽHotel-Dieu de Quebec (HDQ)
CHUM - Centre Hospitalier de l’Universite de Montreal
CIUSSSEMTL-Hospital Maisonneuve-Rosemont
Cleveland Clinic Cancer Center Mansfield
Community Medical Center
Cross Cancer Institute
Crossroads Cancer Center
Dartmouth Cancer Center - North
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
Decatur Memorial Hospital
Deke Slayton Cancer Center
Drexel Town Square Health Center
Duke Raleigh Hospital
Duke University Medical Center
Durham VA Medical Center
East Jefferson General Hospital
Edward Hines Jr VA Hospital
Emory University Hospital/Winship Cancer Institute
Exeter Hospital
Geauga Hospital
Geisinger Medical Center
Geisinger Medical Oncology-Lewisburg
GenesisCare USA - Clarkston
GenesisCare USA - Farmington Hills
GenesisCare USA - Farmington Hills
GenesisCare USA - Lakewood Ranch
GenesisCare USA - Macomb
GenesisCare USA - Madison Heights
GenesisCare USA - Troy
GenesisCare USA - Troy
Grady Health System
Gundersen Lutheran Medical Center
Helen F Graham Cancer Center
Highland Hospital
John Fitzgerald Kennedy Medical Center
Juravinski Cancer Centre at Hamilton Health Sciences
Kaiser Permanente-Anaheim
Kantonsspital Aarau
Lankenau Medical Center
Legacy Good Samaritan Hospital and Medical Center
Legacy Mount Hood Medical Center
Lehigh Valley Hospital-Cedar Crest
Lewis and Faye Manderson Cancer Center
Lewis Cancer and Research Pavilion at Saint Joseph’s/Candler
Los Angeles County-USC Medical Center
Lovelace Radiation Oncology
Loyola University Medical Center
LSU Healthcare Network / Metairie Multi-Specialty Clinic
Luminis Health Anne Arundel Medical Center
Marin General Hospital
Mary Imogene Bassett Hospital
Mass General/North Shore Cancer Center
Massachusetts General Hospital Cancer Center
McLaren Cancer Institute-Clarkston
McLaren Cancer Institute-Flint
McLaren Cancer Institute-Macomb
McLaren-Port Huron
Medical College of Wisconsin
Medical University of South Carolina
Memorial Medical Center
Midwestern Regional Medical Center
New Mexico Oncology Hematology Consultants
New York-Presbyterian/Brooklyn Methodist Hospital
Novant Health Cancer Institute Radiation Oncology - Wilmington
OSF Saint Francis Medical Center
Ottawa Hospital and Cancer Center-General Campus
Pamela Youde Nethersole Eastern Hospital
Penn State Milton S Hershey Medical Center
Penn State Milton S Hershey Medical Center
ProMedica Flower Hospital
Providence Saint Mary Regional Cancer Center
Reading Hospital
Regions Hospital
Rohnert Park Cancer Center
Saint Francis Medical Center
Saint James Community Hospital and Cancer Treatment Center
Saskatoon Cancer Centre
Scotland Memorial Hospital-Laurinburg Cancer Center
Self Regional Healthcare
Siteman Cancer Center at Saint Peters Hospital
Siteman Cancer Center at West County Hospital
Siteman Cancer Center-South County
Stanford Cancer Institute Palo Alto
State University of New York Upstate Medical University
Tata Memorial Hospital
Texas Oncology-McKinney
The James Graham Brown Cancer Center at University of Louisville
The Research Institute of the McGill University Health Centre (MUHC)
Thomas Jefferson University Hospital
Thompson Cancer Survival Center
TidalHealth Richard A Henson Cancer Institute
Trinity Health Saint Joseph Mercy Hospital Ann Arbor
Tulane University Health Sciences Center
UCHealth Memorial Hospital Central
UM Baltimore Washington Medical Center/Tate Cancer Center
University of Arkansas for Medical Sciences
University of California Davis Comprehensive Cancer Center
University of Kansas Cancer Center
University of Maryland Shore Medical Center at Easton
University of Maryland/Greenebaum Cancer Center
University of Michigan Comprehensive Cancer Center
University of Nebraska Medical Center
University of New Mexico Cancer Center
University of Oklahoma Health Sciences Center
University of Rochester
University of Vermont Medical Center
USC / Norris Comprehensive Cancer Center
Valley View Hospital Cancer Center
Vince Lombardi Cancer Clinic-Two Rivers
Virginia Mason Medical Center
Washington University School of Medicine
Wayne State University/Karmanos Cancer Institute
Weisberg Cancer Treatment Center
WellSpan Health-York Cancer Center
West Virginia University Healthcare
Yale University
Zablocki Veterans Administration Medical Center
Funding:
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U24CA180803 (IROC), CTEP. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Acquisition:
Agree to be accountable for all aspects of the work, which includes ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: ABS, FA, AA, YA, AMM, HA, HB, TBC, GMC, NB, ID, GD, RD, CD, JE, AE-G, RJE, JF, SF, FYF, JAF, AJF, DJG, RLGIII, TG, AEH, KS, NK, AAK, NL-C, JM, SM, DTM, A-GM, AM, CM, JAM, JMM, LTM, SCM, JWN, AAO, JRO, ANP, JAP, JDP, KP, MAP, RP, SLP, WHP, A.Raben, A.Rewari, LR, OR, AAS, CS, DES, HMS, JWS, MWS, SRS, TMS, AT, NU, PV, RV, REW, PYW, HY, JBY, HZ
Footnotes
Combined COIs:
Drs__A. Shah, Alite, Amjad, An, Ashamalla, Bahshaw, Cescon, Clark, Delouya, Dess, Driscoll, El-Gayed, Ellis, Famoso, Faria, Feng, Forquer, Gunter, Hirsch, K. Shah, Kapadia, Konski, Lester-Coll, Mansueti, Maraboyina, Marshall, Martinez, Ménard, Michalski, Nelson, Olsen, Onitilo, Pablo, Panwala, Patel, Paulus, Pinover, Proper, A. Rabin, A. Rewari, Riesterer, Rosenberg, Schroeder, Shelton, Shideman, Silva, Solanki, Straza, Tetreault-Laflamme, Valicenti, Vavassis, Wu, Yoon and Zhang have nothing to disclose.
Dr. Daboul declares in the last 36 months WVU was an active site for this trial. We accrued a patient in it. I reviewed the manuscript. I am the NRG PI at WVU who reviews the protocol or any adverse event related to it.
Dr Dayes declares in the last 36 months Participation on a Data Safety Monitoring Board or Advisory Board in the past 36 months, AbbVie, small personal honorarium for a one-time advisory board.
Dr. Efstathiou, declares in the last 36 months Consulting fees received in the past 36 months, Blue Earth Diagnostics, Boston Scientific, MDxHealth, AstraZeneca, Lantheus, Astellas/Pfizer, Clarity, Angiodynamics, Janssen/Johnson & Johnson, Bioprotect, Gilead, Myovant, payments made to me. Payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events in the past 36 months, IBA, Elekta, payments made to me. Leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid in the past 36 months, Board member: Radiation Oncology Institute (ROI), American College of Radiation Oncology (ACRO), Massachusetts Prostate Cancer Coalition (MPCC); Co-Chair: NCI GUSC, unpaid.
Dr. Frazier declares in the last 36 months since the initial planning of the work all support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.), I participated in review of the documents related this manuscript. I participated in trial enrollment and data review, I received no payments regarding this trial. I am not aware of payments made to the institution.
Dr. Gladstone declares in the last 36 months since the initial planning of the work all support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.), NCI / NIH Cancer Center Core Grant, P30CA023108.
Dr. Grubb declares in the last 36 months support for attending meetings and/or travel in the past 36 months, Alliance for Clinical Trials in Oncology, funded travel as part of leadership of GU committee. Leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid in the past 36 months, Alliance for Clinical Trials in Oncology, Early Prostate Cancer Cadre Leader - no payments other than funding for travel to biannual meetings.
Dr. Martin declares in the last 36 months grants or contracts from any entity (if not indicated in item above) the past 36 months, TerSera Inc., Financial support to the institution for an investigator initiated protocol : (NCT05820633). Support for attending meetings and/or travel in the past 36 months, TerSera Inc., Travel support for ESTRO-25 : presentation of interim analysis of the study NCT05820633.
Dr. Miccio declares in the last 36 months grants or contracts from any entity (if not indicated in item above) the past 36 months, Boston Scientific, Boston Scientific provided payment to my institution for an investigator initiated study using rectal spacer to help with image guided radiotherapy.
Dr. Mihai declares in the last 36 months Payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events for Vision RT speaker with Specifications/Comments of to me; Support for attending meetings and/or travel from Beacon Hospital, Vision RT with Specifications/Comments of to me; Leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid from Beacon Hospital – Director of Oncology Research with Specifications/Comments of no payment.
Dr. Miyawaki declares in the last 36 months Since the initial planning of the work all support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) from UCSF Cooperative Group Affiliate with Specifications/Comments of Principle investigator of study at Marin Cancer Care/Marin Health site.
Dr. Morgan declares in the last 36 months Grants or contracts from any entity from Knight Therapeutics Inc. with Specifications/Comments of Research grant to my institution; Leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid Co-Chair, Genitourinary Radiation Oncologists of Canada.
Dr. Pennington declares in the last 36 months since the initial planning of the work all support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) from NIH grant 5UG1CA189858 with Specifications/Comments of This grant supports SCOR NCORP, my institution.
Dr. Pugh declares in the last 36 months since the initial planning of the work all support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) from Grant from NCI with Specifications/Comments of Payments made to my institution.
Dr. Sandler declares in the last 36 months Leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid from ASTRO with Specifications/Comments of Member, Board of Directors.
Dr. Spratt declares in the last 36 months Consulting fees received from Boston Scientific with Specifications/Comments of SpaceOAR gel; Leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid from Chair of NCCN Prostate Cancer Guidelines.
Dr. Usmani declares in the last 36 months Grants or contracts from Alberta Innovates Health Solutions; Movember; Kaye Competition; Ontario Institute in Cancer Research; New Frontiers in Research Fund; Alberta Cancer Foundation; Astra Zene; with Specifications/Comments of Research grants paid to University of Alberta; Payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events from Astellas with Specifications/Comments of Honorarium for Advisory Board participation paid to myself; Patents planned, issued, or pending for US patent applications pending: 1 - Theranostic radiophotodynamic therapy nanoparticles. 2 - Hand-held device and computer-implemented system and method for assisted steering with Specifications/Comments of Unpaid; Participation on a Data Safety Monitoring Board or Advisory Board for Ottawa Hospital Research Institute with Specifications/Comments of Unpaid; Leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid for Alberta Health Services - Radiation Medicine Operations Committee Co-Chair with Specifications/Comments of Unpaid.
Dr. Wallace declares in the last 36 months Consulting fees received from Radiology Support Devices, Gardena CA with Specifications/Comments of Direct consulting post-retirement 01/03/25: engineering consulting, Radiol & MR equiv materials and robotic device devel RadOnc QA, unrelated to subject of the NRG work.
Dr. Yu declares in the last 36 months Grants or contracts from Pfizer/Myovant with Specifications/Comments of Payment to my institution; Consulting fees received from Boston Scientific with Specifications/Comments of Consulting fees to me;
NRG-GU005 Collaborative Authors:
Fiori Alite, MD, Yi An, MD, Hani Ashamalla, MD, Hilary Bagshaw, MD, Grant M Clark, MD, Nour Daboul, MD, Ian Dayes, MD, Robert Dess, MD, Collin Driscoll, MD, Jason Efstathiou, MD, Justin Famoso, MD, Sergio Faria, MD, Jeffrey Forquer, MD, Tyler Gunter, MD, Ariel E Hirsch, MD, Nataniel Lester-Coll, MD, John Mansueti, MD, Sanjay Maraboyina, MD, Andre-Guy Martin, MD, Lloyd Miyawaki, MD, John W Nelson, MD, Jeffrey Olsen, MD, Adedayo Onitilo, MD, PhD, John A Pablo, MD, Kathryn V Panwala, MD, Wayne Pinover, DO, Michelle Proper, MD, Adam Raben, MD, Amar Rewari, MD, Oliver Riesterer, MD, Lewis Rosenberg, MD, PhD, Amit Shah, MD, Karan Shah, MD, Joseph W Shelton, MD, Charles Shideman, MD, Scott R Silva, MD, PhD, Audrey Tetreault-Laflamme, FRCPC, Nawaid Usmani, MD, Richard Valicenti, MD, Peter Vavassis, MD, Philip Yuguang WU, FRCR, Hong Zhang, MD, PhD
References
- 1.Raychaudhuri R, Lin DW, Montgomery RB. Prostate Cancer: A Review. JAMA 2025;333(16):1433–46. [DOI] [PubMed] [Google Scholar]
- 2.Zhao X, Liu S, Zou Z, Liang C. Global, regional, and national prevalence of prostate cancer from 1990 to 2021: a trend and health inequality analyses. Front Public Health 2025;13:1595159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Yu JB, Sun Y, Jia AY, et al. Increasing Use of Shorter-Course Radiotherapy for Prostate Cancer. JAMA Oncol 2023;9(12):1696–701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Kolata G Popular Prostate Cancer Therapy Is Short, Intense and Unproven [Internet]. The New York Times. 2017;Available from: https://www.nytimes.com/2017/03/20/health/prostate-cancer-sbrt-radiation-therapy.html Accessed March 20, 2025 [Google Scholar]
- 5.Timmerman RD, Herman J, Cho LC. Emergence of Stereotactic Body Radiation Therapy and Its Impact on Current and Future Clinical Practice. Journal of Clinical Oncology 2014;32(26):2847. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Lee WR, Dignam JJ, Amin MB, et al. Randomized Phase III Noninferiority Study Comparing Two Radiotherapy Fractionation Schedules in Patients With Low-Risk Prostate Cancer. J Clin Oncol 2016;34(20):2325–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Lee WR, Dignam JJ, Amin MB, et al. Long-Term Analysis of NRG Oncology RTOG 0415: A Randomized Phase III Noninferiority Study Comparing Two Fractionation Schedules in Patients With Low-Risk Prostate Cancer. J Clin Oncol 2024;42(20):2377–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Lukka HR, Pugh SL, Bruner DW, et al. Patient Reported Outcomes in NRG Oncology RTOG 0938, Evaluating Two Ultrahypofractionated Regimens for Prostate Cancer. Int J Radiat Oncol Biol Phys 2018;102(2):287–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Szymanski KM, Wei JT, Dunn RL, Sanda MG. Development and Validation of an Abbreviated Version of the Expanded Prostate Cancer Index Composite Instrument (EPIC-26) for Measuring Health-Related Quality of Life Among Prostate Cancer Survivors. Urology 2010;76(5):1245–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Einstein DJ, Patil D, Chipman J, et al. Expanded Prostate Cancer Index Composite-26 (EPIC-26) Online: Validation of an Internet-Based Instrument for Assessment of Health-Related Quality of Life After Treatment for Localized Prostate Cancer. Urology 2019;127:53–60. [DOI] [PubMed] [Google Scholar]
- 11.Gray RJ. A Class of K-Sample Tests for Comparing the Cumulative Incidence of a Competing Risk. The Annals of Statistics 1988;16(3):1141–54. [Google Scholar]
- 12.Shimomura A, Wu T, Rusu I, et al. Monitoring Intrafraction Motion of the Prostate During Radiation Therapy: Suggested Practice Points From a Focused Review. Pract Radiat Oncol 2024;14(2):146–53. [DOI] [PubMed] [Google Scholar]
- 13.Jiang NY, Dang AT, Yuan Y, et al. Multi-Institutional Analysis of Prostate-Specific Antigen Kinetics After Stereotactic Body Radiation Therapy. Int J Radiat Oncol Biol Phys 2019;105(3):628–36. [DOI] [PubMed] [Google Scholar]
- 14.Dejonckheere CS, Caglayan L, Glasmacher AR, et al. Prostate-specific antigen kinetics after stereotactic body radiotherapy for localized prostate cancer: A scoping review and meta-analysis. Radiother Oncol 2025;202:110642. [DOI] [PubMed] [Google Scholar]
- 15.Chen LN, Suy S, Uhm S, et al. Stereotactic Body Radiation Therapy (SBRT) for clinically localized prostate cancer: the Georgetown University experience. Radiat Oncol 2013;8:58. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Yu JB, Cramer LD, Herrin J, Soulos PR, Potosky AL, Gross CP. Stereotactic body radiation therapy versus intensity-modulated radiation therapy for prostate cancer: comparison of toxicity. J Clin Oncol 2014;32(12):1195–201. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Pan HY, Jiang J, Hoffman KE, et al. Comparative Toxicities and Cost of Intensity-Modulated Radiotherapy, Proton Radiation, and Stereotactic Body Radiotherapy Among Younger Men With Prostate Cancer. J Clin Oncol 2018;36(18):1823–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Mahase SS, D’Angelo D, Kang J, Hu JC, Barbieri CE, Nagar H. Trends in the Use of Stereotactic Body Radiotherapy for Treatment of Prostate Cancer in the United States. JAMA Network Open 2020;3(2):e1920471. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Yashar CM, Hubbard A, Chollet-Lipscomb C. ROCR: Modernizing Radiation Oncology Payment to Embrace Innovation and Better Care. Semin Radiat Oncol 2024;34(4):474–6. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.