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Neha Vapiwala: Good morning. Thank you. And yes, I had a little fun with the title, because while I have no relevant disclosures, my disclaimer is this is an attempt at a crash course on many different topics within radiation, so I'm going to do my best, and I wish us all luck. Okay, so let's start with some terminology. When we talk in radiation oncology about standard moderate hypofractionation and ultra-hypofractionation, these are the typical Gray per fraction that we are referring to. It's been established that dose-escalated external beam radiation therapy, typically in older studies given in standard fractionation, up to about 80 Gray, has improved outcomes—specifically biochemical progression-free survival, distant metastasis-free survival, but not overall survival until more recently. In our presentation earlier this year at ASCO-GU from Dr. Hennequin and colleagues on GETUG-AFU 18, we showed that modern dose-escalated external beam standard fractionation improved progression-free survival as well as overall survival when given in combination with long-term ADT.

Very exciting. But nonetheless, we are always asking ourselves how can we improve on this? And again, quick crash course, on the right here you see the linear quadratic model. It's a very simple way of describing the relationship between cell killing and dose delivered, and it is tissue-specific, so that includes cell death for tumors as well as normal tissues. In general, for more slowly proliferating cancers such as prostate cancer, the feeling is that there's a greater sensitivity to the size of the fractionation and so, therefore, we can take advantage of that—you can see the shoulder of that curve—by giving a larger dose. Whereas there's less sensitivity, if any, to the duration of the treatment. So why not capitalize on that feature of prostate cancer cells and give that dose escalation, but in less time?

That's where our Canadian colleagues from Quebec Prostate Cancer Study 5 did establish in high-risk prostate cancer through this non-inferiority phase three trial that compared to standard fractionation of EBRT, that moderate hypofractionation, given as what's called a concomitant boost, can in fact be a safe and viable alternative. So this, in many centers including our own, is very much accepted practice: at a minimum, give more radiation in less time.

To take this further, ultra-hypofractionation—and oftentimes we talk about stereotactic body radiation therapy or SBRT—that is a type of ultra-hypofractionation that requires significant expertise as well as experience. But at the end of the day, it's really taking that therapeutic index and trying to improve further, giving more dose to the target and taking advantage of the highly conformal nature of SBRT, the tight margins, the steep dose gradients. We have relatively limited data in high-risk prostate cancer, but it is absolutely growing. One of the earlier reports is the SHARP consortium, which is comprised of seven different institutions and two registries, and they reported on 344 patients with high-risk prostate cancer, follow-up to 49.5 months, a favorable toxicity and efficacy profile. So again, setting the stage for continued research in this area. And already in the NCCN, it is very much accepted that SBRT can be used for prostate cancer across all risk groups.

And note in practices with appropriate technology and expertise, and I bring back that linear quadratic model, because although I pointed out that prostate cancer is sensitive to higher doses, we must always remember that late-responding normal tissues are also sensitive to those higher doses. And so we want to continue to collect these data and make sure that centers are providing us with the information we need to do this safely.

In terms of moving forward to boosts, I was asked to address. So the original version of boosting, if you will—whole gland boosting—is brachytherapy, the idea of more radiation therapy in less time. Many of you might be familiar with the ASCENDE-RT trial, in which low-dose-rate brachytherapy interstitial implantation was evaluated as a means of boosting compared to pure escalation through external beam. Although it did improve biochemical control to use the brachytherapy, there was also an association with worse late GU toxicity and no difference in overall survival, even at 10-year median follow-up, despite continued improvement in biochemical control. So it did put a little bit of a damper in the enthusiasm for this approach.

In the US, at least, in most places when brachytherapy is used for whole gland dose escalation, it's generally high-dose-rate. Here's an example of a small phase III study with long-term follow-up at 131 months of median follow-up using high-dose-rate brachytherapy boost, an improvement in 12-year relapse-free survival of 21%, and an "equitoxic" outcome in terms of late effects. So again, no overall survival difference, but in general, high-dose-rate brachytherapy when used for dose escalation is usually the preferred method where available.

Now, in terms of microboosts—and this is a different kind of boosting—this has been enabled by, as you've heard a lot about already, multiparametric MRI as well as PSMA PET and PET MRI. This idea of finding dominant intraprostatic lesions and how do we deliver greater dose to those regions within the prostate. The FLAME trial, as was referenced a little bit earlier, 571 patients including high-risk patients, no elective nodal RT, and about two-thirds of patients receiving neoadjuvant ADT, looked at the delivery of focal simultaneous integrated boost. So again, as the rest of the gland is being treated, you are treating this dominant intraprostatic lesion to a higher dose up to—and it's important to say this was a variable amount of dose delivered depending on what was safe and feasible for each patient—but up to 95 Gray in 2.7 Gray fractions. And there was this disease-free survival benefit as you see here at 72 months median follow-up.

Also, patterns of failure reported decreased local, and what's called regional and distant failure. I have an asterisk there because it's important to note regional and distant failure was lumped together, implying that there might have been a distant failure benefit, but in reality this was really driven by regional failures. The distant failures were not particularly different between the group that did or did not get the boost. I don't think we want to overstate the benefit of this in terms of improvement of metastatic or long-term outcomes, but again, important to see the feasibility of this and the benefit thus far.

What about the use of SBRT for microboosts? This is where we have emerging data, and here's just some examples of small but important studies that are evaluating the use of SBRT to, again, boost those dominant intraprostatic lesions at various fractionations that are provided here. Again, the thought is that these appear to be safe, and perhaps a more novel—most novel of all—hypofocal SBRT really incorporating PSMA PET MRI-defined focal boosts. It's important to note here, there are a lot of questions still. We think about SBRT, we often talk about fiducial markers for safety. We talk about rectal spacer gels. We don't know the impact of the spacer gels in terms of deforming these lesions and how that might impact the day-to-day treatments. So there's still a lot that needs to be worked out in terms of technique and safety, but exciting work nonetheless.

Talking about new questions but also an age-old question, I've also been asked to talk about pelvic lymph node radiation. The benefit of whole pelvis is something in high-risk clinically node-negative patients that we have been asking ourselves in our field for quite some time. RTOG 9413 was one of the original trials that looked at this in patients with greater than 15% lymph node risk per the Roach formula. Unfortunately, at further follow-up, there was no significant progression-free survival difference.

You heard about POP-RT earlier from Dr. Spratt, this was a very highly imaged group. So 80% of patients had PSMA PET and a high-risk group compared to the 9413 with modern radiation therapy image guidance, and we did in fact see a benefit to whole pelvis radiation. There are still many centers where this remains a controversial area. Some people will treat the pelvic lymph nodes routinely in node-negative patients, some will not. We are awaiting additional phase III trials, as you can see here, as well as ongoing SBRT whole pelvis studies, which are going to be challenged by the inherent sensitivity of small bowel and the challenges of positioning. So more on that to be seen.

As far as clinically node-positive patients, we have various database studies that demonstrate the benefits to overall survival of adding radiation in this population that previously did not use to receive radiation. You heard earlier about the STAMPEDE group, which is a higher risk population. Exploratory multivariate analysis of the node-positive patients in this group did in fact find failure-free survival benefit for patients who had planned as well as received radiation therapy. So an argument to be made there.

And finally, radiation for PET-detected node-positive disease, the idea of nodal-only oligorecurrence, as you'll hear from my colleague on the stage, Dr. Roach, more about this. But the PEACE-V STORM is a randomized phase II superiority trial that looks at metastasis-directed therapy of PET-directed nodes as well as six months of ADT. In a group of about 196 patients, randomized to plus/minus pelvic nodes, you can see here no significant differences in toxicity. Very promising, as is the OLIGOPELVIS trial, a single-arm phase II trial, providing the same with simultaneous in-field boost to PET-positive nodes, appears to have excellent progression-free survival benefit and very well tolerated.

So in my final slide, putting it all together, a lot of studies coming our way incorporating all of this—incorporating SBRT, incorporating the treatment of nodes, evaluating hypofractionation as well as biomarker-driven trials, which you'll hear more about from my colleagues. There's a lot to be excited about. With that, I will say thank you and pass it on.