Clinical Insights on Optimal Perirectal Spacing

Opinion
Article

In the third article of this series, Amar U. Kishan, MD, provides clinical insights on the use of perirectal spacers for patients who receive hypofractionated radiation or SBRT.

In the prostate cancer treatment space, perirectal spacers have been used to reduce the amount of radiation toxicity that patients experience. In this Urology Medical Perspectives series titled “The Role of Perirectal Spacers in the Treatment of Prostate Cancer,” Amar U. Kishan, MD, a radiation oncologist at the University of California, Los Angeles, provides expert perspectives on clinical factors to consider when using perirectal spacing for patients receiving hypofractionated radiation or stereotactic body radiotherapy and gives comprehensive insight on unmet needs in this treatment space.

Urology Times®: What factors do you consider when conducting perirectal spacing for patients with prostate cancer who are receiving hypofractionated radiation?

Amar U. Kishan, MD: One thing to always consider is the patient’s absolute risk of a significant bowel or rectal toxicity. We have some evidence for spacers reducing the risk of toxicity, specifically grade 2 toxicity, which in [simple] terms would be an adverse effect that requires the use of medication to treat. We have data showing that risk is reduced. However, it’s also important to understand the risk going in. It’s very different to reduce a 2% risk of an adverse effect to a 1% risk versus reducing a 10% risk to a 5% risk. You get a lot more bang for your buck if the actual level of risk reduction is higher.

Things that I’m thinking about include, does this patient have a history of bowel or rectal problems? Do they have a history of hemorrhoids? Do they have a history of diabetes, which may potentially play a role in increased likelihood of bleeding or increased complications related to injury in the rectum? Does the patient have a history of taking blood-thinning medications or blood thinners of any kind that might predispose them to bleeding? Do they have any history of an inflammatory bowel disease, where we might not even be thinking about radiation, but say we have to, for instance? Or a history of prior radiation in the pelvis? Anything that would increase a patient’s preexisting risk for a rectal toxicity would factor into my decision of whether to offer a perirectal spacing technology.

Urology Times: Can you talk about any data available on how a hyaluronic acid–based rectal spacer might impact tumor control and GI [gastrointestinal] toxicity reduction in patients receiving hypofractionation?

Amar U. Kishan, MD: There are data to support the use of a hyaluronic acid–based perirectal spacer in the context of moderate hypofractionation. As of 2023, there has been the publication of a randomized clinical trial that investigated the use of a hyaluronic acid spacer in this context. The trial was designed specifically to look at reduction in dose to the rectum. That was the primary end point. But they also looked at other factors, including patient-reported outcomes and physician-scored toxicity, specifically grade 2 or greater physician-scored toxicity, which, as I mentioned, typically means the use of a medication. That’s one way to think about it. That trial did show a significant reduction in the incidence of grade 2 or greater bowel adverse effects within the first 90 days of treatment in patients who had the hyaluronic acid–based perirectal spacer replaced.

Urology Times: Are there any data on any other kinds of perirectal spacers yet?

Amar U. Kishan, MD: The other major spacer that is available is a PEG-based spacer that has been studied in a randomized trial that looked at what we call conventional fractionation. That’s the form of radiation where patients get daily doses of radiation over the span of multiple weeks, 7 to 8 or even 9 weeks. In that context, there was also a randomized trial looking at this other type of spacing material, which ultimately showed a reduction in the dose delivered to the rectum, and in longer-term follow-up, also indicated a reduction in grade 2 or greater rectal adverse effects. There are a number of ongoing trials looking at the role of either type of spacer in the context of even more abbreviated courses of radiation, such as ultrahypofractionated radiotherapy or SBRT, stereotactic body radiotherapy. There’s an ongoing randomized trial in that space. There are also other kinds of nonrandomized trials, single-arm studies that are looking at potentially how toxicity might be reduced by using one or the other type of spacing material.

Urology Times: Are there any additional considerations when you’re thinking about using SBRT in patients with prostate cancer?

Amar U. Kishan, MD: [At the University of California, Los Angeles,] we have one of the oldest prostate SBRT programs in the country. We use SBRT very routinely. There are a couple of things that I take into account. We take into account the size of the prostate, the preexisting urinary symptoms the patient has, and any other comorbidities or illnesses they may have that might play a role in increasing the adverse effects of radiation. Personally, I think those are things to take into account with whatever type of radiation is being delivered, whether it’s SBRT or a longer course of radiotherapy. At our institution, we also test whether patients are genetically sensitive to a higher dose of radiation. That is something that is being validated. But on paper, can a patient be a candidate for SBRT? Technically, any patient with low- through high-risk prostate cancer is a candidate for SBRT, per the National Comprehensive Cancer Network guidelines. It is a standard-of-care option.

Urology Times: What unmet needs exist for the use of perirectal spacing and the safety and efficacy for patients with prostate cancer?

Amar U. Kishan, MD: One could ask if there are unmet needs in this area with perirectal spacing, and I think so. There are a couple of areas where we could use more data. One would be in the reirradiation setting. We are using radiation more and more frequently for men with prostate cancer. And, thankfully, people are living longer due to improved treatments for prostate cancer and due to improved treatments in general. There are men who are experiencing recurrences within the prostate itself after a definitive treatment, and we have learned that these men can be treated successfully potentially with repeat radiation and other types of treatments. But repeat radiation in particular has a large amount of data supporting its use, and that would be an interesting situation. It would be helpful to know if the spacer can be useful. Because in that case, I think the patient is at higher risk for a radiation-based adverse effect to the rectum. And as I mentioned in the beginning, that’s the main thing I take into account with regard to whether someone is a good candidate for any type of perirectal spacer. So I think one would be the reirradiation setting.

The other [thing] we have learned [is] that when you’re seeing a patient with prostate cancer, oftentimes we get an MRI or another type of a scan called a PET scan. That might tell us where the dominant nodule within the prostate is. When we’re treating with radiation, we treat the whole prostate, but there are data to suggest that treating the dominant nodule to an even higher dose may improve outcomes substantially. That was shown in a phase 3 randomized trial called the FLAME trial [NCT01168479] and is being extensively studied in other trials. Many lesions are actually located in the posterior portion of the prostate, which will be closer to the rectum. So I think an interesting application would be to study how we can safely escalate the dose to these bulkier posterior lesions, maybe leveraging advantages we could get from the spacer technologies, to keep the adverse effects low but increase that dose to the dominant nodule, which we know would be helpful oncologically. That’s another exciting aspect.

The third aspect, which is being studied in a couple of trials—one being the POTEN-C trial [NCT0352526] out of UT Southwestern—is whether by creative use of perirectal spacing we may be able to better spare the neurovascular bundles from radiation. The neurovascular bundles are running posterolaterally along the sides of the prostate. They contain blood vessels and nerves that are important for erectile function. And, of course, because prostate cancer is so easily treatable and so curable in many patients, post-treatment quality of life is really important to many men, and erectile function is of high importance. So if there are ways to potentially spare more of the neurovascular bundles and other important structures using a perirectal spacer, that would be important to know as well. That is an ongoing trial. There are several trials—one being the [phase 2] POTEN-C trial in particular—that are investigating that. To summarize, some novel applications would be in the radiorecurrent setting to allow us to more safely and aggressively dose intraprostatic lesions, and for preservation of erectile function.

Urology Times: Are there any products or technologies in development that might help address these unmet needs?

Amar U. Kishan, MD: As a stickler for clinical research, the products that I would be looking forward to are clinical trials themselves that show that these are of value. And to their credits, the commercial entities that make these spacer technologies are interested in supporting these trials. To truly have data to guide us, we will need in-human clinical trials, and those are underway or being developed.

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