ASTRO 2022: MRI-Guided vs. Computed Tomography-Guided Stereotactic Body Radiotherapy for Prostate Cancer (MIRAGE): Primary Endpoint Analysis of a Phase III Randomized Trial

(UroToday.com) The 2022 American Society for Radiation Oncology (ASTRO) Annual Meeting held in San Antonio, TX between October 23rd and 26th, 2022 was host to a State of the Art session for the selection and treatment of localized prostate cancer. Dr. Amar Kishan presented the primary endpoint analysis of MIRAGE: a phase III randomized trial of MRI-guided versus CT-guided stereotactic body radiotherapy for prostate cancer.

 

Dr. Kishan began his presentation by highlighting the potential benefits of MRI-guided prostate radiotherapy:

  1. Reduced planning target volume (PTV) margins: highly precise intrafraction monitoring, less uncertainty in contouring by bypassing MRI-CT fusion
  2. Better ability to visualize the urethra on simulation images
  3. No need for fiducial or X-ray dose from image-guided radiotherapy (IGRT)
  4. Ability to perform online-adaptive radiotherapy

 

The PTV accounts for possible uncertainties in beam alignment, patient positioning, organ motion, and organ deformation. In the context of prostate SBRT, the major contributor to the PTV is prostate motion. The margin for motion is estimated to be at least 3 mm in the anteroposterior and the S/I dimensions with volumetric modulated arc therapy (VMAT). Setup uncertainties can persist due to the intrinsic nature of treatment, but also due to residual error introduced by an MRI-CT fusion.

 

As such the study hypothesis was that aggressive margin reduction from 4 to 2 mm using MR-guided radiotherapy technology would reduce acute grade 2+ GU toxicity from 29% to 14%. An estimated sample size of 300 patients would have a power of 83.7% to detect this difference using a one-sided z-test at a p-value threshold of 0.025. An interim analysis was stipulated after 100 patients were eligible. The Pocock alpha-spending function was used to divide the alpha allowance between the interim and final analyses.

 

With regards to treatment volumes and parameters, high-dose CTV to the prostate and proximal 1 cm of the seminal vesicle was performed with a 2 mm margin (MRI-guided) or 4 mm margin (CT-guided) at a dose of 40 Gy. ADT (including 2nd generation agents), pelvic nodal radiotherapy, hydrogel placement, and boosting dominant nodules was allowed per investigator discretion, as detailed below:

 

ASTRO 2022  Amar U. Kishan_0 

 

Next, Dr. Kishan detailed the IGRT and planning details for each arm:

 

ASTRO 2022  Amar U. Kishan_01 

 

The study CONSORT diagram is demonstrated below, with 178 patients initially randomized. Two patients (1 in each arm) unfortunately passed away from COVID-related pneumonitis and were not evaluable for study purposes.

 

ASTRO 2022  Amar U. Kishan_02 

 

 

Baseline patient characteristics are demonstrated below. Of note, more than 80% of patients in each arm had either unfavorable intermediate-, high-, or very high-risk prostate cancer. ADT was used in in about 70% of patients, nodal radiation in about 25%, and GTV boost also in about 25% of patients.

 

ASTRO 2022  Amar U. Kishan_03 

 

Results of the primary outcome demonstrated that acute grade 2+ GU toxicity was significantly lower in the MRI-guided group (24.4% versus 43.4%, p=0.01). The majority of this difference was driven by urinary frequency and retention adverse events. Notably, the rate of acute grade 2+ GI toxicity was also significantly lower in the MR-guided arm (0% versus 10.5%, p=0.003). The majority of these differences were driven by increased diarrhea and proctitis in the CT-guided arm. Multivariable analysis adjusting for key factors including IPSS, gland volume, and spacer use demonstrated that the MR-guided treatment arm remained associated with a 60% reduction in the odds of grade 2+ GU toxicity (OR: 0.40, 95% CI: 0.19 – 0.84).

 

ASTRO 2022  Amar U. Kishan_04 

Patient reported outcomes evaluated using the EPIC-26 and IPSS questionnaires demonstrated the following:

  • Improved urinary incontinence score at 1 month in the MR-guided arm (p=0.01)
  • A significantly smaller percentage of patients with a 15+ increase in IPSS score in the MR-guided arm (6.8% versus 19.4%, p=0.01)
  • Improved bowel domain score at 1 month in the MR-guided arm (p=0.0003)
  • A significantly reduced percentage of patients with a clinically significant (12+ point) decrease in EPIC-26 bowel scores in the MR-guided arm (25% versus 50%, p=0.001)

ASTRO 2022  Amar U. Kishan_05 

Dr. Kishan concluded his presentation as follows:

  • Aggressive margin reduction with MR-guidance leads to a significant reduction in acute physician-scored GU toxicity (study met its primary endpoint)
  • MR-guided SBRT also significantly reduces acute physician-scored GI toxicity and leads to lower percentages of patients experiencing a large increase in IPSS scores and clinically meaningful decrement in EPIC bowel scores
  • Strengths included the randomized nature of the study
  • Limitations include the lack of blinding with respect to primary outcome and the uncertain long-term significance of differences in acute toxicity



Presented by: Dr. Amar U. Kishan, MD, Associate Professor, Department of Radiation Oncology, University of California, Los Angeles, CA 

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2022 American Society of Radiation Oncology (ASTRO) Annual Hybrid Meeting, San Antonio, TX, Sat, Oct 22 – Wed, Oct 26, 2022.

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