Stereotactic body radiotherapy (SBRT) is an established treatment for prostate cancer. It involves delivering large daily doses of precisely targeted radiation in five or fewer fractions, traditionally using either planar X-ray or cone-beam CT images to guide the radiation delivery.

The prostate is a highly mobile target and it’s essential to account for its motion during irradiation to maximize treatment effectiveness. This is typically achieved by creating a planning target volume (PTV) that includes a margin around the prostate to ensure adequate target dosing. However, the high-dose regions of the PTV often overlap portions of the bladder, rectum and other nearby structures, which can cause side effects such as urinary, bowel and sexual dysfunction.

The recent introduction of MRI-guided linacs could help minimize the risk of such toxicities. MRI-linacs offer high soft-tissue contrast and the ability to track intra-fraction prostate motion directly (rather than relying on fiducial markers) and control the beam in real time during treatment. These advantages should enable the use of significantly smaller margins around the prostate. To date, however, the theoretical advantages of MRI-guided radiotherapy for prostate SBRT have not been demonstrated in a randomized clinical trial.

The MIRAGE (MRI-guided stereotactic body radiotherapy for prostate cancer) trial aims to address this shortfall and determine whether MRI-guided radiotherapy offers an evident benefit for patients. The phase III randomized clinical trial, led by Amar Kishan and Michael Steinberg at the University of California, Los Angeles (UCLA), enrolled men receiving SBRT for localized prostate cancer. Between May 2020 and October 2021, the trial randomized 156 patients to receive SBRT with either CT guidance (77 patients) or MRI guidance using the MRIdian system (79 patients).

Patients were treated with 40 Gy in five fractions, using planning margins of 4 mm in the CT arm and 2 mm in the MRI arm. The researchers note that this 2 mm margin is narrower than used in any previous large study. They hoped to show that this aggressive margin reduction could reduce toxic effects following SBRT.

“MRI guidance offers several advantages over standard CT guidance, most notably the ability to dramatically reduce planning margins, providing more focused treatment with less injury to nearby normal tissues and organs,” says Kishan in a press statement. “MRI technology is more costly than CT, both in terms of upfront equipment expenses and longer treatment times, which is one reason our study set out to determine if MRI-guided technology offers tangible benefits for patients.”

Improved outcomes

The results of the trial, described in JAMA Oncology, revealed that MRI guidance led to fewer toxicities and better quality-of-life, as judged by both patients and the doctors treating them.

In 154 patients available for follow-up, the incidence of acute grade 2 or greater genitourinary (GU) toxic effects was significantly lower following MRI- than CT-guided SBRT: 24.4% in the MRI group versus 43.4% in the CT group. Patients in the MRI group also had fewer acute grade 2 or greater gastrointestinal toxic effects: 0.0% versus 10.5%, respectively. In a multivariate analysis accounting for all candidate variables, the MRI-guided arm remained associated with a 60% reduction in odds of grade 2 or greater GU toxicity.

After 100 patients reached 90 or more days post-treatment, the researchers conducted an interim analysis. At this time, the incidence of acute grade 2 or greater GU toxic effects was significantly reduced in men receiving MRI-guided SBRT compared with those receiving CT-guided SBRT (24 of 51 versus 11 of 49). They re-estimated the required sample size as 154 patients and, as 156 patients had already been treated, closed the trial for further accrual.

“This is the first large scale SBRT trial to use a dose of 40 Gy to the PTV, which we felt was an appropriate dose given the anticipated risk level of the cohort we would be treating. Because dose is associated closely with toxicity, we knew beforehand that the estimates of toxicity we used to power the trial might be underestimates,” Kishan tells Physics World. “Thus, we stipulated an interim analysis should occur after 100 patients were eligible for analysis in order for us to formally re-evaluate the power considerations for the trial.”

One unique aspect of the study was its inclusion of patient-reported outcomes. Significantly fewer patients receiving MRI-guided SBRT experienced large increases in urinary symptoms. Similarly, far more patients experienced a clinically notable decrease in bowel-related quality-of-life with CT guidance.

The researchers note that longer term follow-up is necessary to determine whether these benefits persist, whether differences in late urinary or bowel toxic effects occur and to evaluate differences in sexual outcomes. They plan to continue to monitor toxicity outcomes and perform an analysis of 2-year patient-reported outcomes.

“MRI-guided radiation has apparent theoretical benefits in this treatment scenario, and it was important to conduct a rigorous comparison,” says Steinberg. “Given the significance of the outcomes realized, we’ve evolved our prostate cancer treatment approach at UCLA to preferentially utilize MRI-guided SBRT.”

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