Hypofractionation Noninferior to Conventional Radiotherapy for Low-Risk Prostate Cancer


Hypofractionated radiotherapy was noninferior to conventional radiotherapy in patients with low-risk prostate cancer.

Hypofractionation Noninferior to Conventional Radiotherapy for Low-Risk Prostate Cancer

Hypofractionation Noninferior to Conventional Radiotherapy for Low-Risk Prostate Cancer

Analysis of disease-free survival (DFS) in low-risk prostate cancer revealed no significant difference between hypofractionated and conventional radiotherapy, suggesting noninferiority of the hypofractionated approach, according to findings from a long-term analysis of the phase 3 noninferiority RTOG 0415 study (NCT00331773) published in the Journal of Clinical Oncology.1

At a median follow-up of 12.8 years in surviving patients, patients treated with conventional fractionation radiotherapy of 73.8 Gy in 41 fractions (n = 542) experienced an estimated 12-year DFS rate of 56.1% (95% CI, 51.5%-60.5%) vs 61.8% (95% CI, 57.2%-66.0%) in patients treated with hypofractionation radiotherapy of 70 Gy in 28 fractions (n = 550; HR, 0.85; 95% CI, 0.71-1.03; P < .001); investigators noted that the hazard ratio confirmed noninferiority of hypofractionation. Additionally, the 12-year cumulative incidence of biochemical failure was 17.0% (95% CI, 13.8%-20.5%) compared with 9.9% (95% CI, 7.5%-12.6%), respectively (HR, 0.55; 95% CI, 0.39-0.78; two-sided P < .001), and the protocol-specified noninferiority criterion was met.

“In the initial report, there was no difference in biochemical failure according to assigned arm, but the median follow-up was 5.8 years,” W. Robert Lee, MD, MEd, MS, a radiation oncologist at Duke Cancer Center in Durham, North Carolina, and coauthors wrote. “The updated cumulative incidence estimate plots for biochemical failure show a separation starting 5 years after treatment with a 44% relative risk reduction of biochemical failure over more extended follow-up. This delay in the separation of the curves is expected given that participants had low-risk disease, and the most likely pattern of tumor recurrence is local.”

RTOG 0415 was a randomized, multicenter, parallel-group study initially reported in 2016 that demonstrated the efficacy of moderate hypofractionation was noninferior to conventional fractionation in patients with low-risk prostate cancer; a modest increase in grade 2 adverse effects (AEs) was also seen. Adult patients enrolled had clinical stage T1b-T2c prostate adenocarcinoma, a Gleason score of 2-6, and a prostate-specific antigen (PSA) level of less than 10. Further, patients could not have received androgen deprivation therapy or have regional lymph node involvement.2,3

The trial stratified patients by PSA level (less than 4 ng/mL vs 4-10 ng/mL), Gleason score (2-4 vs 5-6), and radiation modality (3D conformal radiotherapy vs intensity-modulated radiotherapy). The primary end point was DFS, and biochemical failure represented a key secondary end point.1

Baseline characteristics were generally well balanced between the 2 arms. In the overall population (n = 1092), the median age was 67 years and the median pretreatment PSA level was 5.4 ng/mL. Most patients had a Zubrod performance status of 0 (92.6%), a PSA level of 4-10 ng/mL (80.0%), a Gleason score of 5-6 (99.8%), T1 stage disease (78.1%), and received intensity-modulated radiotherapy (79.1%).2

Additional data revealed that the cumulative incidence of local progression at 12 years was 4.7% (95% CI, 3.0%-6.9%) in the conventional fractionation radiotherapy arm vs 0.6% (95% CI, 0.2%-1.7%) in the hypofractionation radiotherapy arm, meeting the noninferiority criterion (HR, 0.17; 95% CI, 0.06-0.48). The 12-year cumulative incidence of distant metastases was 1.6% (95% CI, 0.8%-3.0%) vs 1.7% (95% CI, 0.8%-3.2%), respectively (HR, 1.10; 95% CI, 0.42-2.85); no noninferiority criteria was specified for this end point.1

Further, the estimated 12-year overall survival (OS) rates were 68.7% (95% CI, 64.3%-72.7%) in the conventional radiotherapy arm compared with 69.9% (95% CI, 65.5%-73.9%) in the hypofractionation radiotherapy arm. Investigators noted that the protocol-specified non-inferiority criteria was met for OS with a HR of 1.01 (95% CI, 0.82-1.24) observed.

In the safety population, most patients who received conventional radiotherapy (n = 533; 64.2%) and hypofractionation radiotherapy (n = 542; 52.6%) did not experienced a late gastrointestinal AE; grade 1 (20.5% vs 23.6%) and 2 (12.2% vs 19.4%) late gastrointestinal AEs occurred, and the rate of grade 3 late gastrointestinal AEs was 3.0% in the conventional arm vs 4.4% in the hypofractionation arm (RR, 1.39; 95% CI, 0.75-2.55). Late grade genitourinary AEs occurred most frequently at grades 1 (29.3% vs 27.1%) and 2 (23.5% vs 29.2%), respectively. Grade 3 genitourinary AEs occurred in 3.0% vs 4.2% of patients (RR, 1.26; 95% CI, 0.69-2.30), and 2 patients in the conventional arm also experienced a grade 4 genitourinary AE.

“[This] current update confirms noninferiority of the primary DFS end point. To our knowledge, for the first time, however, there is strong evidence that moderate hypo- fractionation results in improved efficacy as measured by lesser long-term incidence of biochemical failure,” Lee and coauthors noted.


  1. 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. Published online May 17, 2024. doi:10.1200/JCO.23.02445
  2. 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:10.1200/JCO.2016.67.0448
  3. Radiation therapy in treating patients with stage II prostate cancer. ClinicalTrials.gov. Updated January 18, 2023. Accessed June 10, 2024. https://www.clinicaltrials.gov/study/NCT00331773
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