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E. David Crawford: Hi, everyone. This is E. David Crawford. Just recently we've had the opportunity to talk with Dr. Jason Efstathiou, who is a professor of radiation oncology at Harvard, about a clinical trial called the PARTIQoL trial. It's a Phase III trial comparing proton beam therapy to IMRT for localized prostate cancer. He highlighted the potential benefits of proton therapy and challenges of conducting comparative studies. The trial focuses on patient-reported outcomes, particularly bowel function at 24 months. Innovative strategies such as electronic questionnaires, patient-centered initiatives, and minority recruitment efforts were employed to improve accrual.

The trial includes 450 patients from 29 centers. Jason emphasized the need for rigorous data to assess the benefits of proton therapy, which is still limited in availability across the United States. He has shared with us the outline of the study, the abstract, and now he is going to share with us the presentation that he is given at the ASTRO meeting in Washington, DC in the plenary session on the PARTIQoL trial.

Jason, thanks for spending time with us again. We're all excited to hear the details of this very important game-changing study.

Jason Efstathiou: Great to be with you again, Dave, and with my friends here at UroToday. I'm very pleased to present a study that has just been presented at the ASTRO annual meeting, plenary session, and it's the PARTIQoL trial. That's a play. The name is a play on particle therapy and stands for Prostate Advanced Radiation Technologies Investigating Quality of Life, a Phase III randomized clinical trial of proton therapy versus IMRT for localized prostate cancer. I'm proud to present this on behalf of all co-investigators and institutions represented on the trial.

Listed here are my disclosures.

As an introduction, we all know that patients with localized prostate cancer have a multitude of management options, including external beam radiation therapy with either photons or protons. Protons have certain dosimetric advantages with the potential to reduce morbidity and improve cancer outcomes, but it's also generally more resource-intensive than intensity-modulated radiation therapy, IMRT. To address the hypothesis that protons result in improved patient-reported outcomes, the PARTIQoL trial was conducted as a multi-center Phase III randomized clinical trial comparing the two modalities head-to-head.

The key eligibility was basically low or intermediate risk, localized prostate cancer, so no nodal involvement, no distant METs, no prior surgery, no prior pelvic radiation, no ADT. We also have the usual exclusions that are seen in most prospective radiation trials with the addition of bilateral hip prostheses.

After stratifying for institution, age, rectal spacers, and hypofractionation, participants were randomized to proton beam therapy or IMRT without hormonal therapy. Again, we wanted a clean head-to-head technology assessment here.

Participants were followed longitudinally to assess patient-reported outcomes for 60 months after completion of radiotherapy. The primary endpoint was bowel function at 24 months, and secondary objectives included comparison of urinary, sexual functions, toxicity, and efficacy in the economic endpoints. The sample size was 450 patients, providing 90% power accounting for 37% unavailable data at 24 months. Again, the primary outcome was mean change from baseline to 24 months in the EPIC bowel score, secondary outcomes for the urinary and sexual scores. And then there were a number of disease control endpoints including progression-free survival.

I think this is a helpful slide, and it shows a timeline of major milestones on this trial. The trial was activated in June of 2012. A month later, the first patient was accrued, and then we had a number of centers join the trial. In the end, we had 12 main proton centers and a total of 29 recruiting centers in a spoke-and-wheel model. The radiation community really came together. Our idea was to make it a pragmatic trial that allowed us to include changes in prostate cancer management that inevitably occur over the lifetime of a trial, such as the use of rectal spacers and hypofractionation. In 2019, we extended the accrual to 450 patients. Our last patient was accrued in November of 2021. Our primary endpoint was met this past April, and we're continuing for long-term follow-up for another decade.

I think this graph here and curves here are really telling as well. It shows the expected and actual accrual over time, demonstrating a typical randomized Phase as more centers joined the study. In the end, the rate of patient accrual was really accelerating at the end of that trial period with a slowing and plateauing off after the beginning of COVID-19. We know that COVID really affected clinical trials and especially localized prostate cancer trials. We also see that the accrual for low and intermediate-risk patients changed after the publication of the ProtecT trial in 2016 supporting active surveillance. Before publication of ProtecT, low-risk patients were enrolled at a slightly greater rate than intermediate-risk. But this pattern reversed soon after the publication of ProtecT with intermediate-risk patients representing the majority enrolled on the trial.

Here, we see that of the 450 randomized patients, 226 were assigned to protons, 224 to IMRT, of whom 221 and 216 started radiation on their respective arms. 167 and 162 participants respectively informed the primary endpoint, reflecting a 27% rate of missing data, which was better than what was anticipated or planned for in the design.

Here, we see baseline characteristics. Protons and IMRT were well-balanced. The median follow-up was about 60 months. Median age was 68 years. 80% were white, 20% were non-white with 13% Black African-American. Almost 60% had intermediate risk disease. 48% used a rectal spacer, 51% received hypofractionation, and 48% of proton beam patients were treated with pencil beam scanning technology.

Now let's turn to the primary endpoint. There was no difference between protons and IMRT in mean change of EPIC bowel score at 24 months with both arms showing only small, clinically non-meaningful decline from baseline. Similarly, there was no difference in bowel function at earlier time points or later time points. Scale, as you can see, goes from a range of zero to 100. Zooming in on the Y-axis, we see some small fluctuations, but at no time point did these reach statistical significance.

There were also no differences observed in other domains at any time point, including urinary incontinence, urinary irritation, or sexual function. Turning to disease control endpoints, looking at biochemical and clinical failure over time, for example, which events include biochemical failure, local or non-local recurrence, there were no differences throughout at two to five years. We followed the curves out to five years, which was again the median follow-up for these patients. Looking at other endpoints such as biochemical failure-free survival, which includes death from any cause, there was no difference. Looking at progression-free survival, there was no difference. This excludes biochemical failure. We examined cancer outcomes in three different ways and found no difference in cancer control out to five years.

There was no sustained difference in any quality of life domain or cancer control between the arms when analyzed by stratification factors or any key subgroups. For example, no difference by age, by disease risk, by rectal spacer use, or by fractionation schedule.

Here, we have to remember on this slide here that we're looking at an unadjusted post-hoc comparison, which really warrants further exploration in additional follow-up, and that's the proton delivery method. This curve does suggest some possible early potential advantages for pencil beam scanning over passive double scattering. However, there was no significant difference at 24 months. There was also no difference between pencil beam scanning and IMRT.

Our trial has some limitations in terms of disease scope, technology evolution, and practice evolution. Ultimately, we were limited to localized low- to intermediate-risk prostate cancer, receiving either conventionally or moderately hypofractionated therapy. We didn't look at higher risk disease or pelvic nodal therapy, concurrent use of ADT, or other systemic therapy, local recurrences or re-treatment scenarios. We all know that both protons and photons continue to evolve, and there's a lot of ongoing work to optimize delivery with improved advanced in-room imaging, arc therapy, adaptive therapy, and practices evolving even towards ultrahypofractionation with SBRT or intraprostatic boosts, or urethral-sparing techniques. But in conclusion, our Phase III randomized controlled trial shows that patients treated with contemporary radiotherapy for localized prostate cancer achieve excellent quality of life with highly effective tumor control without measurable differences between protons and IMRT. We, of course, continue to monitor patients for longer follow-up and secondary endpoints and ongoing subgroup analyses, as well as the results from our companion registry, which included patients who declined randomization or were insurance denied.

I would like to acknowledge all trial participants, their partners and families, the MGH Program for Coordination Oversight of Research Protocols, all investigators, clinical research, and nursing staff across all participating centers, and our funding sources. I also want to give a shout-out to the Red Journal, which we'll be discussing, the challenges and strategies employed in our trial to improve the feasibility of running such a randomized controlled trial, patient-centric initiatives we employ, as well as a full description of the baseline characteristics. That's being published in the Red Journal at this time today. In addition, there is an accompanying podcast.

For further updates on the PARTIQoL trial, please join me on Twitter, X. Thanks very much.

E. David Crawford: Jason, thank you very much. A great presentation. This is really a landmark study. I think it sets the pace for future studies on how you integrate a change and everything else into this. It's really great, and it's going to have a lasting imprint. I'm glad that you're going to be following patients because we know in prostate cancer, particularly localized disease, you're going to have to follow them for a long time.

I mean, this study is amazing because it addresses a very important issue, the quality of life and so forth, with IMRT and proton therapy. What do you think the biggest concern or criticism is going to be? No matter what study you do, there are always questions and it becomes a whack-a-mole game, so what do you think the biggest criticism is going to be?

Jason Efstathiou: Well, Dave, I think I went over some of the limitations. I think it's hard to argue against the design. It's a randomized control trial of Phase III design, but ultimately it's studying a certain population and that was low and intermediate risk localized prostate cancer. It wasn't addressing the other scenarios that I referred to.

At the end of the day, proton therapy has many use cases that are effective. To be clear, it is still a very effective option for localized prostate cancer as evidenced by our trial. One of the most advanced forms of conformal external beam radiation, it has some superior physical dosimetric properties and advantages like little or no exit dose leading to less scatter radiation to tissues beyond the beam path and less of a radiation bath when compared to IMRT. All of these technologies are evolving, and there's a lot of ongoing work to optimize proton delivery. Not only the pencil beam scanning that I was alluding to, but also the introduction of more advanced in-room imaging, arc therapy, adaptive delivery, et cetera. There may be subgroups that benefit from one technology over another, and we're actively continuing analyses of that.

Again, our trial was limited to low- to intermediate-risk prostate cancer receiving either conventionally or moderately hypofractionated therapy. There are other indications such as SBRT, higher risk disease, nodal treatment, boosts, treatment of recurrences, patients who have had prior radiation in the pelvic region and require re-treatment, and younger patients where we will want to look at rare risks, very rare risks of radiation-associated second cancers. There's lots more work to be done.

E. David Crawford: Right. Well, I think it's very interesting your follow-up. Your biochemical failure really is similar in both arms and is extremely low, and I think going forward, that's going to be a real concern: the higher risk disease and might there be an advantage.

Again, thanks for that outstanding presentation.

Jason Efstathiou: Yeah, Dave. No, I think you bring up a very important point. I mean, we're showing that each of both modalities achieved equally high rates of tumor control with no differences in patient-reported quality of life. This is a first-of-its-kind Phase III clinical trial comparing these two technologies for one of the most common cancers in the world.

Ultimately, I personally believe that our results represent a win for the field of radiation oncology overall. It was also a trial designed to put patients first. What I mean by that is it was an important undertaking to evaluate technologies we're using to treat patients with the same rigor that clinical trials for new drugs and therapies use.

E. David Crawford: I think people have to remember also this trial started in an era where the whole active surveillance was beginning to go forward, and they'll say, "Well, a lot of these patients should have been on active surveillance." That's not what happened back then. A lot of these patients, low-grade patients did get treated, and you do have intermediate.

I mean, to have those sorts of biochemical failure-free curves is very, very impressive with minimal toxicity. I mean, it's a great study. I think you're right. I think it's going to apply to other areas too, and obviously you didn't have ADT in here and a lot of other things that went on in the rectal spacers, which was good. You guys were adaptive. This was an adaptive study. You went along with the flow of things that changed, otherwise, there'd be significant criticisms about not using rectal spacers and other things.

Jason Efstathiou: No, you're definitely right. We look to be pragmatic and evolve with evolving practice. But you raised a really important point on the low-risk patients and active surveillance. There are a few important elements to consider there.

First, as you noted, our trial began in 2012, which was before the ProtecT trial was published in 2016. As the practice evolved, our trial evolved. As I showed you, our enrollment began with more of an even ratio between low and intermediate risk patients. But towards the end of the trial, we began to see really that trend shifting towards more intermediate risk patients enrolling, and that aligns with lower risk patients perhaps moving towards active surveillance appropriately.

It's also important to distinguish between low-risk patients and those who are low-risk but with a high volume of disease. You and I know there's plenty of patients who are younger, maybe in their 50s with decades of life ahead, who have a high volume of Gleason six disease. It's entirely appropriate to treat those patients.

Finally, at the end of the day, it's a patient's decision to receive treatment or to choose to actively watch with close guidance, to do active surveillance. I, and I'm sure you, do have plenty of patients who are considered low risk but want the peace of mind of moving forward with treatment, and that is also entirely appropriate.

E. David Crawford: Absolutely, absolutely. We always say a lot of times the train has left the station when someone's diagnosed, even with a low-grade prostate cancer. They worry about it for 10 years. There's a lot of crossovers and things like that.

Again, an outstanding presentation. Thank you.

Jason Efstathiou: Thanks so much, Dave. Great to be with all my friends here at UroToday. Thank you for having me.