Amar Kishan, MD

GU Oncology Now

In an interview with GU Oncology Now, Amar Kishan, MD, Vice-Chair of Clinical and Translational Research and Chief of the Genitourinary Oncology Service for the Department of Radiation Oncology at the David Geffen School of Medicine at UCLA and the UCLA Jonsson Comprehensive Cancer Center in California, gives an overview of the MIRAGE trial that compared the safety and efficacy of magnetic resonance imaging (MRI)-guided and computed tomography (CT)-guided stereotactic body radiation therapy (SBRT) for prostate cancer.Can you give a brief overview of the MIRAGE trial and what its results were?Dr. Kishan: The MIRAGE trial was a single-center phase three randomized trial comparing CT-guided SBRT, which is a standard of care approach, versus MRI-guided SBRT for prostate cancer. In a little bit more detail, SBRT is a type of radiation for prostate cancer where a high dose is delivered per day with extreme accuracy and precision in order to complete the radiation course in just five treatments as opposed to some of the older and longer courses of radiation. Historically, this has been delivered with CT or X-ray guided devices, so that was kind of the standard arm.More recently, we have these MRI-guided radiation delivery platforms, and so on the MIRAGE trial we wanted to see whether there would be a benefit to the patient by using the MRI-guided device. It&rsquo;s more expensive, it&rsquo;s a little bit slower to do the delivery, but it has numerous theoretical advantages and we wanted to test that.What did we find? Well, the primary endpoint was physician-scored moderate genitourinary toxicity. What does that mean? That means urinary side effects like needing to urinate more frequently, needing a medication to control urinary frequency, urgency or pain with urination, and we found a significant reduction with the use of the MRI-guided device. Specifically, the rate of toxicity reduced from about 43.4% with CT-guided SBRT, to 24.4% with MRI-guided SBRT. We also looked at bowel toxicity or gastrointestinal toxicity, which is things like diarrhea, pain in the rectum, urgency to defecate. That was reduced from 10.5% in the CT-guided arm to 0%; no events in the MRI-guided arm.We looked at a number of patient-reported outcomes as well; what does the patient feel in terms of their symptoms? Are they reporting more urinary toxicity and bowel toxicity? We gave them questionnaires to fill out and to boil it down, we did see significant improvements there as well. The proportion of patients that reported a significant increase in their urinary symptoms dropped from 19.4% to 6.8%, and the proportion of patients that reported some noticeable change in bowel symptoms dropped from 50% to 25%.So, the takeaway, one-sentence summary would be that MRI guidance allowed a significant reduction in patient-reported and physician-scored urinary and bowel toxicity in the context of prostate SBRT. Now, the reason we see this benefit is likely because the MRI-guided device allows a lot more precision. We felt comfortable basically treating a much smaller volume because of the direct guidance that we have with the MRI compared to the standard of care margins that we use when we&rsquo;re treating with CT guidance.Do most physicians currently use CT-guided SBRT as opposed to MRI?Dr. Kishan: Basically, MRI-guided linear accelerators are newly available tools. Historically there have been a lot of physics-related challenges with combining an MRI with a radiation delivery platform, which is typically a linear accelerator, and that&rsquo;s because of interference. This is a newer technology. Essentially, we acquired this device here at UCLA in late 2019, and the trial began in 2020. Right now, there are not as many places that have an MRI-guided linear accelerator, and as with all technologies, it takes time to adopt. Hopefully with trials like the MIRAGE trial showing a true benefit to this approach, we&rsquo;ll see more widespread adoption.What will it take for physicians to adopt MRI SBRT in the future?Dr. Kishan: On the one hand, it&rsquo;s a very positive randomized trial, and so in medicine we say the highest-level evidence is a randomized trial, and we have that now. However, to be fair, we did look at short-term toxicity. We looked at toxicity that occurs within a 90-day period after the treatment. Arguably someone could say, &ldquo;There&rsquo;s less short-term toxicity with MRI guidance, what about long-term toxicity?&rdquo; Someone could say, &ldquo;I can get a patient through short-term toxicity.&rdquo; It&rsquo;ll take time to be able to show that; we plan on analyzing our data again at the two-year mark. The trial finished, all of its patients accruing in about October 2021. Later this year we will look at two-year patient reported outcomes, which is thought to be a kind of marker for long-term toxicity. We hope to see if there&rsquo;s a difference at that point.I think if we can show a difference in long-term side effects, then that pushes the needle even further in favor of MRI guidance. Obviously with prostate cancer, the cure rate is very, very high, thankfully. It takes a long time to be able to show if one treatment is actually superior to the other, and that&rsquo;s not what the trial was designed to do, but I think long-term outcomes showing that this enhanced precision at least has the same outcome, possibly even better if you&rsquo;re actually able to hit the target more would also be helpful.Are there any other future studies on the horizon that will further test the capabilities of MRI imaging?Dr. Kishan: Yes, we are also going to look at five-year outcomes on our trial. However, there are numerous other trials that are being run across the world. Our next trial that we hope to open in this fall will be looking at trying to leverage even some more sophisticated properties of the MRI-guided machine to maybe treat the area that has cancer in the prostate to an even higher dose and maybe able to drop the dose to the rest of the prostate, which may further reduce toxicity without compromising the effectiveness of the treatment. That&rsquo;s the next thing we plan on looking at.Were there any unexpected findings during the trial?Dr. Kishan: I would say that the unexpected finding was that we saw this robust benefit in all metrics. When you&rsquo;re designing a trial, you have to pick an outcome. For statistical reasons, you have to pick something that happens frequently enough that you can actually detect a difference. Urinary side effects from radiation are fairly common and we thought we could show that. We designed the trial to show that, but we actually didn&rsquo;t think that we would have enough patients to be able to show a difference in bowel toxicity or a difference in these patient-reported outcomes. It is hard to predict what that would&rsquo;ve been, and we did see them. It&rsquo;s unexpected. It goes in line with our theory that the better precision would allow, but the effect size was larger than we thought, which I guess in this case is a good thing.I would maybe add one other thing that we plan on looking at in the future, which is of a significant interest to many men with prostate cancer &ndash; the sexual side effects. It&rsquo;s too early to look at that because it&rsquo;s just three months after the treatment and many men are on hormone therapy, which can confound the picture, but we do plan maybe at the two-year outcome or longer term, seeing if there&rsquo;s a difference in erectile dysfunction, which in theory there may be again because they enhance precision. That will be another thing that might also tip the favors in the balance of treating with MRI guidance.

The MIRAGE Trial: MRI-Guided Versus CT-Guided SBRT for Prostate Cancer

Prostate Cancer

Amar Kishan, MD gives an overview of the MIRAGE trial that compared the safety and efficacy of MRI-guided and CT-guided SBRT for prostate cancer.