Neha Vapiwala: Thank you so much for having me.

Alicia Morgans: Wonderful. So Neha, you are certainly a radiation oncologist, expert in radiation fields, and helped us think through how we use radiation for high-risk, locally advanced prostate cancer. Certainly, much of this is over the medical oncologist's head, but you really were wonderful at explaining it. Could you go through that again with us today?

Neha Vapiwala: Sure, I'd be very happy to. So I'll try to cover some of the highlights of the more exciting developments in radiotherapy for high-risk and locally advanced prostate cancer, and we'll try to cover a whole bunch of topics in the short time we have together. First, when we think about dose escalation in radiotherapy for high-risk prostate cancer, we know that in multiple clinical trials, there have been improvements in progression-free and distant metastasis-free survival, as well as freedom from additional therapies when we escalate dose. And typically that's 80 gray standard fractionation. And I have a little table here that gives you some context and terminology on the definitions. When we say standard fractionation, typically up to two gray, moderate hypofractionation and ultra hypofractionation is where we're going to focus some of our conversation today, and that's where you give the larger dose per treatment.

We recently learned from GETUG-AFU 18 at the ASCO GU meeting earlier this year, that modern dose-escalated external beam radiotherapy now also is associated with improved survival in combination with long-term androgen deprivation therapy for high-risk prostate cancer. So really driving home the point that dose escalation matters. So how do we do this, but in less time for patient convenience? Do so safely. This is where, and what you see here is the linear quadratic model that really describes the relationship between the dose of radiation per treatment and the cell-killing effect. Now, of course, that cell killing can impact normal tissues as well as tumor. So we have to be mindful of how do we get the most from cancer cell killing with minimal impact to tissues. And that's where this concept of the low, what's called alpha-beta ratio of prostate cancer is really central to our decision to hypofractionate. Because it would appear that being a less proliferative cancer, prostate cancer compared to other types of cancers is more sensitive to larger doses of radiation.

While at the same time, tissues like the GI mucosa, skin, and other tissues that can experience toxicity are less sensitive to larger radiotherapy doses because they are more high alpha-beta tissues. So this allows us to take advantage. And the prostate cancer study five in high-risk prostate cancer performed in Canada was a non-inferiority trial that demonstrated that we can accelerate the delivery of this dose-escalated radiotherapy, using moderate hypofractionation, that it's safe and it's viable. So how do we then push the envelope further to ultra hypofractionate? And many of you may think of SBRT when we say this. SBRT or stereotactic body radiotherapy is a way in which to achieve this concept of ultra hypofractionation. More dose, faster, and hopefully safely. This idea of the therapeutic index is what we're after. How do you escalate dose to the target while still sparing normal tissues? The thing that makes SBRT special is that there are very tight margins around what we want to treat. And a steep fall-off of dose when you get outside of the target. So this can be taken advantage of.

And in high-risk prostate cancer, we have a growing body of evidence. The SHARP consortium is among the bodies of literature out there. And it is while limited, a growing field of study as well as body of evidence supporting that this is safe and it's efficacious. The thing we have to be careful of though, remember I mentioned this alpha-beta for prostate cancer, it allows us to use these larger doses and take advantage of that feature of prostate cancer. Yes, there are tissues that are more sensitive to this as well. They're the late responding tissues. Meaning, late effects, chronic side effects. We always have to be mindful that although this is an exciting area of research, we must monitor for long-term side effects. And NCCN has demonstrated that we can use SBRT or ultra hypofraction or radiotherapy throughout the spectrum of prostate cancer, but we must be mindful that the appropriate technology and expertise is employed to ensure the minimal amount of long-term unintended side effects.

Briefly, micro-boost, switching topics, this idea of giving more dose, escalated dose, but now to a region within the prostate. So an intraprostatic lesion seen on MRI or on PET CT, how do we give extra dose there? Brachytherapy, as many of you may know, is the ultimate way of boosting the entire gland. But when it comes to partial boosting, we're really turning more towards external and beam techniques, and modern imaging is allowing us to do so. The FLAME trial is one example of this type of work that's being done, where we actually treat the entire gland in a moderate hypofractionated manner and then give even extra dose per day, per treatment to this area where the lesion resides. And this has been shown to be safe. And at 72 months median follow-up, it does appear to have a benefit in terms of disease-free survival.

We have to be cautious, however, about any impact on distant failure. Although the study suggested that there was a decrease in distant failure, the truth of the matter is that we are really seeing predominantly an impact on regional failures and the distant is too few an event, too uncommon an event at this stage of the study to comment. But again, reasons to be excited. And then how do we further hypofractionate to give these micro boosts? How do we use SBRT to do it? Here are several small trials that are in various stages of analysis, and you can see here that they do appear to be safe approaches and furthermore actually do seem to yield better outcomes in terms of at least biochemical failure thus far. So just keep your eyes out for these various studies: Five-star, HypoFLAME, SPARK, and also HypoFocal SBRT. Really trying to again, take advantage of modern imaging with PSMA PET and MRI and take these dominant lesions and give them an extra dose. And finally, how about radiotherapy for PET-detected node-positive disease? This idea of a nodal-only oligorecurrence, with oligo defined in the traditional fewer than five definition.

The PEACE V STORM trial, which is a randomized phase two trial, certainly did try to evaluate this in terms of ADT with metastasis-directed therapy of PET-detected nodal disease, with or without treatment of the rest of the lymph nodes that are not involved. And in this randomized study, not only did we see that it's well tolerated, but we await the outcomes in terms of the clinical efficacy. OLIGOPELVIS is a single-arm phase two trial that does suggest that this approach of stereotactically approaching the PET-positive areas can be done and that it yields pretty impressive progression-free survival at two and three years, and is generally well tolerated again. So lots to be excited about. And here's what I would say to all of you. I think there are a host of studies coming down the pipe, some of which are shown here: ASCENDE-SBRT, PACE-Nodes, the PRIME trial, where you're going to hear more and more about hypofractionation, about boosts either with brachytherapy or external beam, sometimes with SBRT. And then a biomarker-driven approach in general to what we do in radiotherapy.

And here are several examples of studies in the intact and post-operative setting, trying to incorporate imaging as a biomarker, as well as other genomic tests to try and again, determine who should get escalated radiotherapy and escalated systemic therapy or de-escalation of treatment. So a lot to be excited about in the future. Thanks so much for the time today.

Alicia Morgans: Thank you so much, Neha. That was such a wonderful presentation. I am glad that I got to see it for a second time because I really felt like I was understanding some of these concepts and radiation oncology for the first time at APCCC and you certainly have driven them home today. So, thank you for doing that. I wonder, there are so many different ways that our radiation oncology teams approach the treatment of prostate cancer and you've just beautifully walked us through a lot of that, including our historical routine fractionation and then all the way up. But at this point in time, I still am not sure always what different groups are going to do when I send the patient to see them. And of course, I know our team at my institution pretty well, but I never know when they go out into the community. From your perspective, what is the most commonly used fractionation version, and is there something we should aim for? Should we be going for this ultra-hypofractionation or even more? What's the right answer?

Neha Vapiwala: Yes. Well, great question, and you're right that the right answer can depend on the institution. It certainly depends on the context of the patient's wishes, and we always emphasize that patients need to participate in the process of shared decision-making. If we offer you convenience in this particular scenario and a shorter course of radiotherapy, some of the trade-offs may be, again, those late-responding normal tissues may manifest some side effects that could have been avoided if we'd gone in a slower, steadier approach. So what I would say is moderate hypofractionation, so that medium range I gave, is absolutely here to stay and essentially the standard of care for low, intermediate, and high-risk prostate cancer in the vast majority of cases. And of course, most of our low-risk prostate cancer patients are pursuing active surveillance. But in the event that they do get treated, there can be a role for ultra-hypofractionated or stereotactic body radiotherapy in those favorable risk patients.

And then this increasing possibility of using SBRT, either in concert with moderate hypofractionation to the rest of the gland and SBRT to really boost the areas of increased concern, or conversely, working with systemic therapy and determining perhaps some new clinical trials in which we could test intensification of the systemic therapy with possibly the shortest course of radiotherapy with SBRT. So I think a lot that we still have to understand and answer, but the short answer to your question is, moderate hypofractionation, for sure, I think is the current standard, and we're going to learn which patients are increasingly appropriate for the SBRT, for the hypo-fractionated approach, the ultra-hypofractionation.

Alicia Morgans: Yeah, wonderful. And to your point, patients love the convenience. They love the ultra-hypofractionated options, but I appreciate that we're continuing to do research in this area to understand, is this right for everybody? Is this going to be as effective in disease control? So I think that's all wonderful. One thing that's also evolved, and you spoke to this a little bit, is that when I was in training, granted this was a while ago, I remember learning that we could never re-irradiate the same area. And I feel like increasingly, and perhaps because we can be so targeted with the SBRT, when we have a patient with oligoprogressive local recurrence, even in the prostate, that has been radiated, we're sometimes thinking about radiating again, and we're often thinking about radiating nodal recurrences. Can you tell me about how we came to the conclusion that this was going to be okay and how we know how to do it?

Neha Vapiwala: Yeah, I'm so glad you asked that question because one of the points I want to make about why ultra-hypofractionated or SBRT approaches are not universally being used for high-risk prostate cancer is the management of the nodes. Even within our radiotherapy community, but really in the greater oncologic community, how to best manage clinically node-negative patients but with high suspicion of potential nodal involvement versus PET-positive nodal patients with negative conventional imaging, versus the truly clinically node-positive patients. It has evolved so much in different directions for each of those three types of patients. And I do believe those are three different categories of patients. Yet, we've sometimes had this one-size-fits-all approach, where we prophylactically treat all the lymph nodes in a slow and steady pace because the small bowel has always historically restricted us and we've been very, very cautious for good reason to go in that standard fractionated pace and maybe at most moderate hypofractionation.

But if we can get to a point where we feel comfortable not having to treat all of the nodes electively, only treating those that are PET-positive or feeling confident that if you're clinically node-negative that you are truly node-negative, maybe we can increasingly only use SBRT in the pelvic nodal purposes and just go after those regions. Which then, if there is a recurrence down the road, makes it more feasible and more possible to go back and "re-irradiate," because we haven't created this background of radiation exposure from the initial treatment that then limits future treatment. So one argument one could make in not treating elective nodes in a patient where you're pretty confident that imaging is clean is to say, "You know, if something pops up later, we could always... in theory, always go back and address the nodes at that time." So that is an approach that some folks are taking. Others, of course, feel that your best chance is to be comprehensive up front.

And so when you are seeing increasing referrals back for radiotherapy again and again and again, it's because those very tight margins and that steep dose gradient that I mentioned earlier are permitting us to go back and cherry-pick and add on to what was previously given because we don't feel like the rest of the surrounding bowel will necessarily be exposed. So it is super exciting that we're able to do that and to facilitate the systemic therapy, which of course is still the backbone of treatment for these node-positive patients. But we as radiotherapists love to be able to partner with our medical oncology colleagues to be able to offer what I think is true clinical benefit in a very tolerable fashion.

Alicia Morgans: Wonderful. Well, thank you so much for guiding us, for sharing your expertise, and taking the time today. I sincerely appreciate it.

Neha Vapiwala: I always appreciate our chats and always happy to help. So thank you for having me.