Long-Term Follow-Up Validates Noninferiority Between Radiation Regimens in Prostate Cancer

Vladimir Avkshtol, MD

Moderate hypofractionated intensity-modulated radiation therapy (H-IMRT) did not show biochemical and/or clinical disease failure (BCDF) rate superiority compared with conventionally fractioned IMRT (C-IMRT) for men with intermediate- and high-risk prostate adenocarcinoma, according to long-term results of a single-center, randomized prospective trial (NCT00062309) published in the Journal of Clinical Oncology.¹

At a 10-year follow-up, the cumulative incidence of BCDF was 25.9% with C-IMRT versus 30.6% with H-IMRT (HR, 1.31; 95% CI, 0.82-2.11; P = .25). These results confirm previously published 5-year results that demonstrated nonsuperiority between regimens.²

Additionally, rates of biochemical failure, local recurrence, prostate cancer—specific mortality (PCSM), and overall mortality were found to be similar between the C-IMRT and H-IMRT arms.

However, there was a 7.8% difference in incidence of distant metastasis noted between arms (95% CI, 0.7%-15.1%). The cumulative incidence was 14.3% with H-IMRT versus 6.4% with C-IMRT (P = .08).

“This study differs from other moderate hypofractionation randomized trials in multiple ways: its relatively large cohort size, the longest median follow-up to date, the contemporary dose-escalated control arm, the significant portion of patients with high-risk disease, the contemporary recommendations for ADT length, the contemporary treatment techniques, and the included lymph node radiation for high-risk disease,” lead study author Vladimir Avkshtol, MD, of UT Southwestern Medical Center, and co-investigators wrote.

In the C-IMRT arm, distant metastasis occurred before or at the time of BCDF in 81.8% of patients treated compared with 66.7% of patients in the H-IMRT arm (P = .44).

“One would expect to see significant differences in other disease outcome parameters in that situation as well,” Avkshtol and co-investigators continued. “Contemporary treatment techniques were used, and excellent compliance to androgen deprivation therapy (ADT) was seen in both groups. The increase in metastasis did not translate into a higher PCSM rate in the H-IMRT group, despite the long-term follow-up.”

The study enrolled 303 men with protocol-defined intermediate- or high-risk prostate adenocarcinoma who were then randomized to either C-IMRT (n = 152) at 76 Gy in 38 fractions at 2 Gy per fraction or H-IMRT (n = 151) at 70.2 Gy in 26 fractions at 2.7 Gy per fraction.

While 378 men were assessed for eligibility, 51 declined to participate and 7 did not meet inclusion criteria. Patients were considered ineligible if they had a prior history of ADT for >4 months before being randomized to a radiation regimen, an initial PSA of >80 mg/mL, prior pelvic radiotherapy, prior radical prostatectomy, or prior malignancy other than nonmetastatic skin cancers or early-stage small lymphocytic leukemia within the last 5 years.

Intermediate-risk was defined via protocol as a Gleason score of 7, pretreatment initial prostate-specific antigen (PSA) score between 10 and 20 ng/mL, or ≥3 biopsy cores with Gleason scores ≥5 and without any high-risk features. Conversely, high-risk was defined as a Gleason score between 8 and 10, a Gleason score of 7 in ≥4 cores, clinical T3 classification, or an initial PSA of ≥20 ng/mL.

Specifically, this 10-year update looked at redefined risk groups set by the National Comprehensive Cancer Network (NCCN). However, little variation in relative difference was found in the redefined groups upon arm analysis (HR, 1.36; 95% CI, 0.83-2.25).

In addition to the randomization, patients with intermediate-risk prostate cancer were given a median 4.2 months of ADT; those with high-risk prostate cancer were given a median 24.2 months of ADT. As such, no significant difference was found in median ADT use between arms (P = .56).

“In the subset analysis of patients who received ADT, the failure rate was identical between the 2 fractionation regimens,” Avkshtol and co-investigators wrote. “This also suggests that ADT usage negated some of the potential advantages of dose escalation.”

The median age of patients was 66.8 years old. There was an even patient balance noted between arms based on age, Gleason score, clinical T classification, initial PSA, ADT usage, and NCCN prostate risk group.

However, there was a higher proportion of African-American men in the C-IMRT arm (17.8%) compared with the H-IRMT arm (7.3%; P = .02). As such, ethnicity-adjusted hazard ratios and 95% confidence intervals were reported.

Additional results showed that the 10-year cumulative incidence of biochemical failure was 21.1% with C-IMRT versus 25.4% with H-IMRT (P = .26). Local recurrence rates were 4.7% and 4.0%, respectively (P = .82). Moreover, metastasis development was noted in 19.8%, 7.4%, and 3.6% of patients with high-, intermediate-, and low-risk disease, respectively.

In men treated with C-IMRT, cumulative incidence of all-cause mortality was 24.4% (95% CI, 17.2-32.2) compared with 33.2% (95% CI, 25.2-41.7) for men treated with H-IMRT (P = .12). While the cause of death was unknown in 31.9% of patients overall, 10-year PCSM was 4.4% in both the C-IMRT arm (95% CI, 1.5-8.3) and the H-IMRT arm (95% CI, 1.4-8.3).

The relative difference between arms regarding BCDF and treatment was not significantly impacted upon sensitivity analysis for additional age adjustment and ADT usage.

References

1. Avkshtol V, Ruth KJ, Ross EA, et al. Ten-year update of a randomized, prospective trial of conventional fractionated versus moderate hypofractionated radiation therapy for localized prostate cancer [published online March 2, 2020]. J Clin Oncol. doi: 10.1200/JCO.19.01485
2. Beckendorf V, Guerif S, Le Prise´ E, et al. 70 Gy versus 80 Gy in localized prostate cancer: 5-year results of GETUG 06 randomized trial. Int J Radiat Oncol Biol Phys. 2011;80:1056-1063. doi: 10.1016/j.ijrobp.2010.03.049