Magnetic Resonance Imaging-Guided vs. Computed Tomography-Guided Stereotactic Body Radiotherapy for Prostate Cancer (MIRAGE): Primary Endpoint Analysis of a Phase III Randomized Trial

Abstract

<h3>Purpose/Objective(s)</h3> Magnetic resonance imaging (MRI) guidance offers multiple potential advantages over computed tomography (CT) guidance in the context of stereotactic body radiotherapy (SBRT) for intact prostate cancer. Herein we report the outcomes of a phase III randomized trial comparing acute grade ≥2 genitourinary (GU) toxicity after MRI- vs. CT-guided prostate SBRT. <h3>Materials/Methods</h3> Following stratification based on IPSS (≤15 or >15) and prostate volume (≤50 or >50 mL), patients were randomized to receive SBRT with CT- vs. MRI-guidance. Planning margins of 4 mm (CT-arm) and 2 mm (MRI-arm) were placed around the prostate and proximal seminal vesicles, and this volume received 40 Gy in five fractions. Elective nodal radiotherapy and rectal spacers were allowed per physician discretion. The primary endpoint was the incidence of acute (i.e., within 90 days of SBRT completion) grade ≥2 GU physician-reported toxicity (by CTCAE version 4.03). The trial had a superiority design, hypothesizing that 154 patients would provide 89% power to detect a 14% reduction in acute grade ≥2 GU toxicity with MRI-guidance with a one-sided significance level of 0.025. Changes in patient-reported outcomes were compared using a chi-square test with the same significance level. <h3>Results</h3> Between May 2020 and October 2021, 156 patients (n=77 CT and n=79 MRI) were randomized. 81% of patients had NCCN unfavorable intermediate-, high, or very high-risk disease, 44% had placement of a spacer and 27% had nodal radiation. Rates of acute grade ≥2 GU toxicity were significantly lower with MRI- vs. CT-guidance (24.4% [95%CI 15.4-35.4%] vs. 43.4% [95%CI 32.1-55.3%], p=0.01). Rates of acute grade ≥2 GI toxicity were also significantly lower with MRI-guidance (0.0% [95% CI 0-4.6%] vs. 10.5% [4.7-19.7%], p=0.003). On multivariable analysis adjusting for trial arm, age, IPSS, gland volume, spacer use, lymph node radiation, and use of a simultaneous integrated boost dose to gross disease, trial arm remained associated with a 60% reduction in odds of grade ≥2 GU toxicity (odds ratio 0.40 [95%CI 0.19-0.84], p=0.02). MRI-guidance was associated with a significantly smaller proportion of patients with a ≥15-point increase in IPSS approached (6.8% vs. 19.4%, p=0.011). MRI-guidance was associated with a significantly reduced proportion of patients with a clinically significant (>12 point) significant decrease in EPIC-26 bowel scores (25.0% vs. 50.0%, p=0.0013). <h3>Conclusion</h3> MRI-guidance significantly reduced acute grade ≥2 GU and GI toxicity. Patient-reported outcomes were also improved at 1 month with MRI-guidance, and trial arm was a significant predictor of lower odds of moderate GU toxicity after adjusting for other important covariates. Differences in late toxicity will take years to manifest, but in the interim, these data strongly suggest that MRI-guided prostate SBRT affords significantly reduced toxicity compared with CT-guided SBRT.