Nearly 290,000 American men will be diagnosed with prostate cancer in 2023. Thankfully, the vast majority will be diagnosed with clinically localized disease and can be cured with either surgery or radiotherapy. Emerging clinical trial data have cemented stereotactic body radiotherapy (SBRT), a form of radiation in which ≤5 daily doses are delivered with high precision in generally five or fewer treatments, as a curative option for most men with localized prostate cancer. Because cure rates are so high, post-treatment quality of life (QOL) is often the major concern for patients with a new diagnosis of prostate cancer.
With respect to radiotherapy of any kind, including SBRT, the major QOL impacts can be categorized into one of three domains: genitourinary (GU), gastrointestinal (GI), and sexual. These domains can be impacted because the prostate is in close proximity to the bladder, urethra, rectum, and neurovascular structures that are related to normal urinary, bowel, and sexual function. As a result, due to the physics of dose-delivery, even with perfect precision, there will be a range of radiation dose impacting these normal structures (called organs-at-risk).
This intrinsic dose fall-off is compounded by the fact that, when any form of external beam radiotherapy is delivered, the existence of several basic uncertainties in targeting lead to physicians treating not just the prostate, but a margin around the prostate. The major contributor to this margin is motion. In fact, the prostate moves not just between treatments, but actually during treatments as well. Careful estimates have calculated that in a 3-minute timeframe – the time required to deliver modern SBRT on most gantry-mounted linear accelerators — the margin around the prostate that would need to be targeted to encompass the majority of positions the prostate could be in is approximately 3 mm in the superior-inferior and anterior-posterior dimensions and about 2 millimeters in the right-left dimension. Due to additional considerations (like minor differences in patient positioning and delineation of the target), recommended margins are typically on the order of 5 millimeters in each dimension. This means that the area intentionally receiving the prescription dose of radiation would be not just the prostate, but a 5 mm sphere around the prostate. Given the significant negative QOL impact that bowel toxicity can have, margins as narrow as 3 mm in the posterior direction (i.e., behind the prostate) have been accepted as well. The University of California, Los Angeles (UCLA) has been a bastion of SBRT for well over a decade, and our team settled on a margin of 4 mm around the prostate for routine SBRT.
In 2019, MRI-guided linear accelerators (MR-LINACs), a novel form of radiotherapy technology, became more widely available commercially. MR-LINACs offer several theoretical advantages in the context of prostate SBRT, where high accuracy and precision are required. First, MR-LINACs allow direct visualization of the prostate on the delivery platform. The resolution and contrast of standard CT images is suboptimal for visualization, which is why often metal fiducial markers are implanted into the prostate prior to radiotherapy. With MR-LINACs, these are not needed. Second, and perhaps most importantly, the MR-LINACs can monitor the position of the prostate with extremely high frequency (up to four times a second) and can automatically pause radiation delivery if the prostate moves out of a preset boundary. We acquired the MRIdian MR-LINAC from ViewRay, Inc. in late 2019, and it became readily apparent that we could confidently treat the prostate with much tighter margins than we had historically used, on the order of 2 mm.
But a question remained – would a reduction in these margins, from 4 mm (our standard with a CT-guided platform) to 2 mm (with the MR-LINAC) lead to improved outcomes for patients? It may seem self-evident that radiating a smaller volume of tissues will lead to lower toxicity, but the medical field is replete with “good ideas” that ultimately failed to achieve their potential. Thus, given our unique expertise in CT-guided SBRT, our experience with developing and running trials, and our commitment to demonstrating value, we launched the randomized MIRAGE trial (NCT04384770) to demonstrate whether the tightened margins afforded by the MR-LINAC reduced toxicity. Specifically, this trial, which ran from May 2020 to October 2021 and enrolled 156 patients, was designed to evaluate whether acute moderate grade or greater GU toxicity (i.e., grade ≥2) would be reduced as a result of the tighter margins.
The primary endpoint results of the trial, published in JAMA Oncology on January 12, 2023, found that this aggressive margin reduction did translate to reduced toxicity. Rates of grade ≥2 GU toxic effects were significantly lower with MRI vs. CT guidance (24.4% vs. 43.4%). Additionally, rates of grade ≥2 toxic effects were also significantly lower with MRI guidance vs. CT guidance (0.0% vs. 10.5%). The percentage of patients who self-reported a substantial increase in urinary symptoms increase was significantly greater with CT guidance at 1 month (19.4% vs 6.8%), as was the percentage of patients who noticed clinically significant impairments in bowel symptoms (50.0% vs. 25.0%).
In summary, the MIRAGE trial primary analysis demonstrates that the use of MRI guidance in the context of prostate SBRT leads to reduced physician-scored and patient-reported urinary and bowel toxicity. This advantage is attributable to MRI guidance allowing enhanced physical precision, with a 2 mm PTV margin around the prostate being targeted rather than a standard-of-care 4 mm PTV margin. Based on the positive results of the MIRAGE trial, we have changed our practice to offering MRI-guided SBRT as our preferred institutional standard of care.
Perhaps the biggest takeaway from the trial is that as we enter the era of precision medicine in oncology, our definition of precision can and should extend beyond the biological precision that comes from a deeper understanding of cancer physiology. Indeed, the MIRAGE trial has shown us that the benefits of physical precision are not illusory, but tangible.
Amar U. Kishan is a radiation oncologist.
