Leslie Ballas: Hi, I'm Leslie Ballas. I'm a radiation oncologist at Cedars-Sinai in Los Angeles, and I am joined today by Dr. Daniel Song, a professor of radiation oncology with joint appointments in urology and oncology. He serves as the co-director of the Prostate Cancer Multidisciplinary Clinic at the Johns Hopkins Hospital. We are very excited to have him join us today.

Dr. Song, thank you so much.

Daniel Song: No, thank you, Dr. Ballas, for inviting me. Title of my presentation is Long-term Toxicity and Patient Reported Quality of Life After Prostate IMRT With or Without Biodegradable Balloon Rectal Spacer: Analysis of a Pivotal Randomized Trial.

Some disclosures.

The overview of our study is that this was a pivotal study to test the safety and efficacy of a biodegradable balloon spacer in prostate cancer IMRT. This was, again, multicenter randomized subject-blinded phase three study. There were 222 subjects enrolled with a two-to-one distribution between balloon and control. At 16 different sites, and these were both academic and private. IMRT was either given as moderately hypofractionated or conventional, and it was done at physician discretion per center.

And the initial co-primary endpoints were safety and efficacy. The efficacy was looking for a greater than 25% reduction in the rectal V70 in more than 75% of the balloon receiving subjects. And then the safety endpoint was to demonstrate non-inferiority in rectal and procedure-related adverse events, so basically confirming that these patients did not have any more adverse events than their counterparts who did not get the balloon.

These were previously presented. But just to recap, that showed that the reduction of 25% of the volume receiving the rectum was met in 97% of the subjects. The mean pre-rectal V70 was 7%, but after the balloon, it went down to 1.1%.

With regard to the safety, there were a rate of 18% grade one greater or greater rectal or procedure-related adverse events through six months in the balloon group. Again, 18% in the balloon group, and the control group actually had a slightly higher rate of 23.1%. The safety endpoint of the study was also met.

There were secondary endpoints, which are the highlight of the data being presented today. These were to look at physician-reported toxicity using the CTCAE version 4, as well as patient-reported quality of life using the EPIC-26 short form. Patients were followed long-term defined as six to 48 months of follow-up.

This just shows the enrollment numbers. Again, 222 enrolled, and then the number of patients reaching the different time points in follow-up. There was some drop-off as is normally expected, and this was also concurrent with the pandemic to some degree. But we did have patients getting out to that four-year follow-up mark.

Here are the physician-reported rectal toxicities, and these are grade two or greater. You can see the control group is shown in red, and the balloon receiving group is shown in blue. And so those differences after day 90 were 21% in the control group versus 5.9% in the balloon group. The P-value on this was 0.023, so it was statistically significant.

If you look at the distribution over time of these rectal toxicities, these are showing both grade one and grade two. In the zero to three-month period, there is a trend toward lower rates of grade one toxicity and grade two toxicity in the balloon group. And then in the three to 18-month period, those differences are statistically significant, as well as in the 18 to 48-month period as well.

These are the urinary toxicities. Again, grade two or greater. The cumulative incidence of grade two events after day 90 was 18.9% in the control group versus 9.1% in the balloon group at 48 months. This was just almost reaching statistically significant P-value with a value of 0.07.

Again, similarly, showing the distributions and differences over time. Relatively similar at the zero to three month, but at three to 18 months follow-up, you do get significant differences in both the grade one and the grade two. Urinary toxicities, a trend towards improvement in the 18 to 48 months time point as well.

Now we're getting into the EPIC-26 quality of life outcomes, and these are, of course, patient reported. This is the bowel quality of life. Overall difference between groups using the analysis of variance measure was statistically significant, but as you can see, really, that is reflective of the differences going out long-term. Past 24 months is when you really see the curve start to separate, and almost like a recovery within the patients who are getting the balloon versus a slight decline in the control group. And then if we look at the patients, those percentages of patients who have a minimal clinically important difference, or MCID, which is generally five or six points on that scale, then there were 30% within the control group versus 9.8% in the balloon group.

Again, these are urinary incontinence and irritative scores now for the EPIC-26. Looking at the incontinence scores, these were overall using the analysis of variants P-value .253, so not quite statistically significant overall. But at specific time points, if you use a T-test, then there were differences at the 24-month, 30-month, and the 42-month time points. And then for urinary irritative, as you can see, the patients at the end of the radiation, both groups dip. But then the balloon group patients gradually have improvement basically back to baseline, whereas some of the control group patients have continued issues with urinary irritative quality of life.

And then sexual, so this was a very nice surprise for us showing that actually the sexual quality of life outcomes were statistically significantly different between the groups. Again, if we look at those with the MCID decline, then there were 66% in the control group versus 27% in the balloon group, which was, again, statistically significant. That's in the patients who started out with an EPIC score over 60. As you know, the higher the EPIC score, the better. But if we also look at patients with somewhat impaired erectile function going into this study, those with scores of 60 or below, there were also differences there. The balloon groups seemed to also benefit even if they had some impairment of their erectile function at the baseline.

And so what explains these differences, especially in the urinary and sexual domains? Well, we know that obviously rectal spacer is going to reduce the dose to the rectum, but we also found that the mean doses to bladder as well as penile bulb were improved with the use of the balloon spacer.

In conclusion, the rectal spacer improved long-term physician and patient-reported bowel outcomes after IMRT, but it also improved long-term urinary and sexual outcomes. To our knowledge, these are the first data which are randomized to demonstrate statistically significant improvements in sexual quality of life outcomes with the rectal spacer.

And so with these improved quality of life outcomes with balloon spacing, we feel that there may be a new basis for comparison when evaluating IMRT against other competing treatment modalities such as surgery.

That's the conclusion of our talk.

Leslie Ballas: Thank you, Dr. Song. Those are exciting results, and we really appreciate you sharing them with us.

Can you tell me a little bit about your results and put that into light in comparison with non-balloon rectal spacers? We've read or heard about under-reported complications or toxicities from non-balloon-based spacers, which obviously you don't have anywhere near that in this randomized trial. Do you feel like there is a difference between these spacers?

Daniel Song: Yes, I do. The balloon obviously is going to be cohesive, whereas the gels or both polyethylene glycol and hyaluronic acid do have more liquid properties to them. And so what we think is less of a risk with the balloon is for it to actually extravasate into the rectal wall.

One of the benefits in terms of placing the balloon is that you can actually adjust the positioning. Some studies have shown that the apical spacing is really what's critical to improve the rectal toxicity, and you can do that in real time with the balloon. You can also adjust left to right to get that precise symmetry that you want. You're also not going to get that extravasation into the rectal wall.

There's some data which one of our urology fellows had looked at and published in urology, and what the trend... It wasn't statistically significant, but there was a trend towards more risk of slight extravasation into the rectum in patients who had transperineal biopsies. There's some thought that there may be some microchannels there which do not close up permanently. When you're putting a gel in, there may be more risk, particularly in those patients.

Leslie Ballas: That's interesting.

As you know at ASTRO, another trial that presented a toxicity outcome in terms of health related quality of life in the prostate cancer space was NRG-GU005. That was a trial randomizing to stereotactic body radiotherapy versus hypofractionated IMRT. And so their main question was different, but their health-related quality of life in the IMRT arm was a bit higher than what you guys reported in your study.

How would you reconcile that?

Daniel Song: Yeah, I think it's hard to know exactly what those differences might be due to, but there was a little bit more leeway towards margins, potentially slightly more generous margins. One centimeter margins were even allowed in this trial. I know some centers did use that, whereas the NRG trial I think was a little bit more controlled in terms of the exact margins that were utilized.

I'd have to go back and look at that, but that may be one difference there.

Leslie Ballas: Based on your results, are you using a balloon rectal spacer in all of your intact prostate cancer patients?

Daniel Song: Yeah, that's an interesting comparison. I would say that although it's certainly tempting to compare toxicities across trials, there are certainly differences which could limit the accuracy of doing so, including different populations, different eligibility criteria. In the balloon trial, we did have patients who had T3 disease. That was allowed as long as there was no posterior extra prostatic extension. And so that could lead to target volume differences compared to NRG-GU006.

There's definitely some subjectivity involved in physician-reported toxicity grading. Our trial had an independent clinical events committee, who were actually blinded to subject randomization. They adjudicated all the toxicity grading. I'm not 100% sure how NRG works their toxicity grading, but I believe it's done by the site PI as well as the overall PI. It's just a different process, but that could contribute to differences in how they are graded.

And then I think this just emphasizes the fact that the patient-reported outcomes are also very important to confirm the results of the physician-toxicity grading.

And then finally, I would just add that the NRG-GU006 results did confirm the value of rectal spacing because their results showed that patients who got rectal spacing actually did have lower rates of GI toxicity. I think they're actually in line with our own results.

Leslie Ballas: Great.

Well, we really appreciate you taking the time to speak with us today and share your insights. This was very helpful, thank you.

Daniel Song: Okay, my pleasure. Thank you for inviting me.