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E. David Crawford: Hi, everyone. My name is E. David Crawford. I'm a professor of urology at the University of California in San Diego. For nearly three decades, I had the honor of being the chairman of the GU Committee of the Southwest Oncology Group. During that time, we performed a number of studies. We had something like 15 in New England Journal of Medicine and some really important trials that were done in prostate cancer. But one of the challenges that we faced was every trial that we tried comparing surgery to radiation, radiation to other things, seed implants to surgery, biochemical failure, neoadjuvant hormone therapy, and adjuvant and prostate cancer, we didn't accrue to.

Joining me is Dr. Jason Efstathiou. He is a professor of radiation oncology at Harvard Medical School and director of the genitourinary division of the Department of Radiation Oncology, and co-director of the GU Cancer at Mass General. He really is a recognized expert in the area of GU malignancies and radiation oncology. Jason got his undergraduate degree at Yale Medical School and Harvard and a PhD at the University of Oxford. Jason is going to be reporting on an important trial involving proton therapy versus IMRT for men with localized prostate cancer. He's going to spend a few minutes with us talking about the design of that study and some of the challenges that it certainly takes to do a study like that. Jason, welcome and thanks for taking your time to be with us today.

Jason Efstathiou: Dr. Crawford, great to be with you as always and to be with all our friends here at UroToday. So yes, I'll be talking about protons for prostate cancer. I think we all know there's many cogwheels in prostate cancer practice influencing management, and sometimes it feels like data is a wheel there spinning on its own. I think we can apply a lot of new technologies to Gartner's Hype Cycle with the peaks and troughs of technology adoption, and really providing the best evidence-based care calls for rigorously testing the tools we use for that care. And we commonly use RCTs to evaluate new drugs, for example, but not necessarily for new technologies, and we really need to provide rigorous evidence to inform the smooth adoption of new technologies.

Turning to proton therapy, it's not a new technology. The cyclotron was invented in 1929. In the 1940s, it was proposed as a possible treatment for cancer, and in 1954 at Berkeley, the first pituitary tumor was treated in a patient. In 1961, we treated our first patient at the Harvard Cyclotron, which MGH oversaw. And in the 1970s, we were treating even our first patient with prostate cancer. In 1988, the FDA approved protons for selected cancers, and then we saw a lot of other centers kind of opening facilities. And nowadays, there's well over almost 120 operating centers worldwide with close to 200 that are planned. So if we look at the United States, there are 45 centers operational in the country.

So you might ask, how are clinical proton beams generated? Well, it's a cyclotron which uses magnetic fields. The cyclotron accelerates hydrogen protons to two-thirds the speed of light, and then there are these electromagnets that focus the proton beams towards the gantry. The gantry—many of them can rotate 360 degrees around the patient to position the nozzle—and there's magnets that guide the beam to the patient through the nozzle.

So here's just a quick schematic of our multi-gantry proton facility here at Mass General. We also have a separate single-room facility as well. And that's interesting. There's been a real move towards maximizing efficiency of proton delivery, and single-room facilities become more and more popular. So most types of radiation therapy use photon beams, and that's the same that's used in lower doses in X-rays. And photon beams can reach tumors deep inside the body but can scatter bits of radiation along the way, which can lead to side effects in the area treated. So IMRT, for example, is a very advanced form of photon-based radiation that allows us to shape and modulate the radiation beams to conform to the three-dimensional shape of a tumor.

And we know that the principles underlying radiation is that radiation complications can't happen in unirradiated tissues, and normal tissue radiation never benefits the patient, so that's where we turn to proton beam, which is another external beam option. And that uses protons rather than photon beams, and these positively charged particles which have mass kill cancer by producing a sudden burst of energy once they stop inside a tumor. So there are these pristine Bragg peaks where it goes to a certain depth based on the energy and deposits that maximal energy inside the target. And because this release happens directly at the tumor site, protons can deliver less radiation along their path and are potentially less likely to harm surrounding healthy tissue. And that might lead to decreased toxicity, improved treatment tolerance, less interrupted radiation courses, better integration with systemic therapy, maybe ability to deliver higher doses, or to retreat neighboring regions that receive prior radiation. And this may all lead to reduced late effects, especially in children.

And if we look at pediatric medulloblastoma, for example, using photons up here versus protons down there, you can see protons avoid all the anterior organs when treating the craniospinal axis, including the heart. If you look at something like orbital rhabdomyosarcoma, you can treat the tumor and avoid exit through the other side of the brain. And in a young child, that's going to lead to higher IQ later in life. And there are many other accepted adult indications for protons, for example, skull base tumors, eye tumors, spine and sacral tumors, and there's many other opportunities, some of which are listed here including prostate cancer.

But with the increased precision of proton therapy also comes potentially significantly higher costs. So the specialized equipment and facilities that we need for proton therapy are less widely available than those, for example, for IMRT. And the treatment can be substantially more resource-intensive. And so, really, protons got into the crosshairs even in national news media, lay media such as The New York Times. Here's an editorial from 2012, and that's when our prostate trial was actually starting, so this is the environment in which the trial began. If we look nationally, both the number of proton beam facilities and proton beam use has increased over the years very dramatically, but still a real minority—less than 2% of patients eligible for protons actually receive protons nationally. And if we look at other types of barriers, certainly, insurance can be a big barrier for receipt of proton therapy in terms of it not being covered.

So let's turn now to prostate cancer. What is the potential of proton therapy and what's the state of evidence? So if we look at these plans here with protons on the left and photons on the right, you see the targets are treated, whether it be the prostate, the pelvic nodes, but there's less of a radiation dose bath in the pelvis. And if you minus one out from the other, this is what you get. The target of the prostate is treated with the same dose. But again, there's this less of a low to moderate dose bath in the pelvis, so less excess volume of tissue being treated, but again, in the lower dose range. There's less scatter dose the further away you get from the prostate with proton therapy as well, and that might lead to reduced risk of radiation-associated second cancers. There's the suggestion that protons may reduce that risk by more than a third. That could be especially relevant in younger patients.

But the question is, does all of that translate into meaningful differences in terms of toxicity, quality of life, disease outcomes? And so, what does the available data tell us? Well, unfortunately, we're not really informed by a lot of high-level data. There were SEER-Medicare studies that informed Men's Health news articles back in 2011 and 2012. There are certainly some excellent large single-institutional cohorts such as from MD Anderson that have shown good results with proton therapy. There were some early patient-reported outcomes that we generated looking, for example, at bowel quality of life, suggesting less of a decrement early on with proton therapy compared to IMRT. There are some other large multi-institutional studies that have also looked at this and have suggested that both treatments are safe and well-tolerated and that there isn't really a difference in late GI/GU toxicity between the modalities.

And then, there's lots of SEER-Medicare type studies suggesting perhaps less GU toxicity with protons. Some other ones suggesting less GU, less sexual toxicity. But if you step back and look at this, all of this retrospective, non-randomized observational datasets really have conflicting results. Some arrows go up, some arrows go down. And so, really, there is equipoise to the question. And the most recent SEER-Medicare study in JCO this year suggested actually no real differences between GU and GI toxicity when looking at procedure codes and things like that. The VA did a great synthesis program looking at the evidence and said the comparative evidence between protons and photons is low strength, and they really called out underway RCTs, our trial in particular, that could provide important additions to that evidence base.

So let's pivot to the randomized phase three trials looking at protons versus photons. There are some other studies in big common cancers such as breast cancer, lung cancer, and those trials comparing protons versus photons, some of them have had to really amend their accrual goals in part based on the challenges of pulling these kinds of trials off. So we're going to focus on the trial in prostate cancer. So that's the trial that I'm presenting at the ASTRO Plenary Session. It's called the PARTIQoL trial. It stands for Prostate Advanced Radiation Technologies Investigating Quality of Life. And we all know patients now have many options for how they might manage their prostate cancer, but trying to sift through all of the information to understand the consequences to their own patient quality of life, especially if they have many years to live, that can be very confusing to patients.

And so, the PARTIQoL trial was really designed to put the patient first and focus on patient-reported outcomes, and to aid the patients in making these types of decisions, we compared two of the most advanced forms of external beam radiation, IMRT and proton beam therapy, head to head in a large multi-center trial. In fact, the PARTIQoL trial was the first contemporary phase three randomized clinical trial initiated to compare protons versus photons for any disease site, and it's the largest fully accrued, completed randomized clinical trial comparing these modalities to date. So here, you see the study schema where we randomly assigned 450 patients with low or intermediate-risk localized prostate cancer, enrolled from 29 recruiting centers to receive either protons versus photons without hormone therapy. We wanted this to be a very clean technology assessment trial. And then, patients were asked to self-report bowel, urinary, sexual functions via questionnaires at baseline and at multiple time points thereafter.

Primary endpoint was a two-year one, but patients were followed for a minimum of five years, and we have longer follow-up ongoing. Again, the primary endpoint is patient-centric, by looking at patient-reported outcomes, which we all know can be more reflective of the patient experience. Specifically, the primary endpoint is patient-reported bowel function and change from baseline bowel quality of life using the EPIC score at 24 months. This was selected because it's a sensitive endpoint, and bowel symptoms are frequently associated with radiotherapy, and prior work suggested that the study timeframe would be sufficient to assess any potentially important clinically relevant differences between the modalities in terms of quality of life. So there are many barriers and challenges to pulling this off, any trial comparing protons to photons due to a number of factors. So patients often have a myriad of treatment options, especially for localized disease such as low and intermediate-risk prostate cancer.

Recruitment can be challenging due to patient or provider preference, especially when some patients may be reluctant to be randomized after hearing about potential benefits of proton therapy. Furthermore, proton therapy is available, as we know, as we already heard, at only specialized treatment centers, and that limits the geographical accessibility for patients and limits the number of patients who are able to be recruited to such a trial. In fact, as I showed you, less than 2% of patients eligible for proton therapy actually receive it. So this necessitates that multiple centers collaborate to complete accrual for such a large randomized trial.

E. David Crawford: Jason, it's difficult to do studies like this. We all know it. You've gone through it. Give us an overview of that and some of the things that you might've done to help the accrual and keep patients on the trial and get investigators. I mean, when you think about it, these are all proton centers, and they've got a vested interest in wanting to see this be a very positive study because that's what people are reading out there. So what did you do?

Jason Efstathiou: Yeah, absolutely. So as I was alluding to, we needed the critical mass centers to come together. And so, getting them all together was a big part of it. The other big challenges I alluded to is the high frequency of insurance denial, state-specific differences in coverage plans, which really have the potential to introduce, for example, racial bias, other disparities, age, socioeconomic disparities, which can skew study populations, can contaminate randomized trials and really hinder patient accrual. But despite all these kinds of challenges, we hypothesized that through patient-centric, thoughtful recruitment and retention approaches, thoughtful study design that adapts to incorporate modern radiation techniques—so you may have noticed on the study schema slide, we introduced rectal spacer usage, we introduced moderate hypofractionation—we really wanted this to be pragmatic and evolve with evolving practice. Through multi-center collaboration, through payer engagement, we could successfully enroll a diverse representative cohort in a contemporary study comparing photons and protons.

So you'll see that actually, before launching the PARTIQoL trial, we informed the design through a prospective assessment of patient willingness to participate in such a study. And we also introduced a companion registry, which concurrently enrolled patients who declined randomization or who had insurance denial as a comparative group. That's almost another 400 patients. Patient recruitment, satisfaction, retention was really a major focus and supported through patient-centric initiatives, some of which I list here. So we included patient modest compensation dispersed over three time points—baseline, one year, two years—really aimed at encouraging retention over the study. Ongoing outreach efforts were carried out throughout the study using social media, web resources, newsletters, and these newsletters were designed to foster a sense of community amongst patients, share study updates, provide educational materials and patient testimonials. And I'll just show you here a few of the newsletters with some investigators we may know.

Here is a patient testimonial talking about what it's like to be randomized. Here's a story of camaraderie amongst three patients on this study. We address the era of doing trials during COVID-19. We have patient education material on what's Flomax, what's Metamucil and even patient radiation-friendly recipes as they go through. So it was stuff like that. Another really important thing was to enhance participant retention satisfaction with the study experience. We prioritized simplifying the completion of these battery of quality of life questionnaires by implementing an electronic platform that allowed direct entry from a phone or a tablet. And all of these efforts were critical to maintain engagement over long-term follow-up. In addition, to prevent the imbalances and contamination between the proton and photon arms because of insurance denial, insurance approval for protons and IMRT had to be secured for each patient prior to randomization.

And very importantly—and Dave, this is a real important one—to address those barriers with payers, we partnered in Massachusetts with Blue Cross Blue Shield, which resulted in their approval of proton therapy for patients enrolled in a prospective trial or registry as part of evidence development. And this policy shift by Blue Cross Blue Shield Massachusetts made them the second-largest insurer represented in the trial after Medicare, and this significantly enhanced patient accrual, especially in Massachusetts. There were similar efforts employed in Pennsylvania and elsewhere. When it came to minority populations who are at risk for worse prostate cancer outcomes, as we know, and are historically underrepresented in clinical trials—and not only that, patients who receive proton beam therapy are far more likely to be white and reside in high-income areas—to this end, the PARTIQoL trial utilized targeted recruitment of minority populations. So I think this gives you a flavor of some of the initiatives we had to enhance accrual to the trial.

And I think this slide here really highlights that full accrual would not have been possible without the collaboration commitment of multiple proton centers and their affiliated networks, which worked together to recruit and enroll patients. And it wouldn't have been possible without that critical mass of operational proton facilities and invested investigators. So we have 12 main proton centers represented in the trial and overall, 29 academic and community-based sites with a spoke-and-wheel model consisting of major proton centers and additional recruiting centers for each site. So I think that gives you a flavor.

E. David Crawford: I know our listeners realize what an undertaking this was. I think you've established a new template about getting patients on trials and keeping them on trials. I like the thing you did with the insurance companies too, I mean, because they have something to gain from this also. And we're going to interview you in a couple of days. We all can't wait for the results of this trial, and I would bet that it's going to be on the front page of a lot of newspapers, including The Wall Street Journal, and we'll see. We'll talk to you after you present it and get right on it. And also, we want to be on the list for when you guys are invited to Stockholm for your Nobel Prize for this work. And I'm serious about it. This is an outstanding contribution to our understanding of prostate cancer. Do you have a couple of closing thoughts there you want to say before we hang up here?

Jason Efstathiou: Sure. I think you did actually a beautiful job, Dave. We certainly don't expect to go to Stockholm, but yeah, I mean, I can just, for the audience, quickly summarize and say, look, proton therapy is a safe, effective treatment. It does have some physical dosimetric advantages over IMRT. It can spare normal tissues and avoid that lower dose radiation bath, so it decreases the integral dose, which could lead to fewer side effects and lower rates of second cancers, especially in younger patients. It's the treatment of choice for pediatric solid tumors and selected adult tumors, but the relative benefit in other disease sites such as prostate cancer requires further rigorous data generation. I think you saw that proton availability and use has increased in the US, but the receipt is still only for a small minority of proton-eligible patients under 2%. And the available data in prostate cancer suggests that it's as effective as alternative radiation modalities such as IMRT per those non-randomized observational studies.

But the rigorous randomized trial data that you're alluding to is coming very, very soon and will be the subject of our next chat. And we've got to support clinical trials like that. It's not easy to run these trials or to fund these trials. At the end of the day, we need proton therapy nationally. Ideally, it's going to be geographically well distributed for access with an emphasis on pediatrics, an emphasis on evidence development, and an emphasis on decreasing access disparities. We've got to encourage those patient-centric approaches I was alluding to, develop collaborative models of payer involvement, and we ultimately need to invest in and promote scientific innovation and creativity while developing the requisite evidence. That includes all fields of medicine and certainly in urologic oncology. And so, it's been a real pleasure to be with you, Dave, and I look forward to our next chat.

E. David Crawford: Thank you. Well, the suspense is here. Thank you.