Hypofractionation is Noninferior to Conventional Fractionation Radiotherapy in Low-Risk Prostate Cancer

The efficacy of hypofractionation radiotherapy was noninferior to that of conventional fractionation radiotherapy in terms of disease-free survival (DFS) in patients with low-risk prostate cancer, 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.

References

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