Daniel Spratt: So it's a pleasure to be here. This talk, I hope every single person is going to take a lot away from. This is not to tell you, bore you about radiation physics and biology is really practical aspects of the technological evolution in radiation therapy. So, I've heard a lot of you actually have joint ventures or business relations with radiation oncology, but a lot of people don't understand exactly what we do all day.

In terms of technological advances. I sort of bend them in three groups that we'll touch on. One is sort of a hybrid of software and hardware, which is the technology of our ability to plan radiation therapy going from a 2D to 3D to IMRT era, and I'm going to visually let you see this so you understand what that means.

The next is really how well can we image tumors when you put a patient on a machine, can we actually see what we're treating? And that's gone from basically an X-ray to three-dimensional imaging, CT, MRI, and then the particle type of therapy, electrons, photons, protons, we'll touch on at the end.

So the goal of technological advances in radiation is to increase the amount of dose we can be delivered to the tumor while sparing maximally all the healthy tissue. In a perfect world, you give all the dose to the tumor, none to the normal tissue, we can't do that. And that's why there still are side effects.

So to give you kind of an evolution of radiation therapy and depending on your age, when you started treating patients, that'll be probably has biased your view of radiation greatly. So in the 19 up to even like the 1990s if you look at publications from the 1980s trials done at like Mass General, they would show those survival curves but they weren't survival curves, they were rectal bleeding rates. And it was like 30% of guys would have rectal bleeding. I mean like real rectal bleeding, something I've never seen in my life, the rates that they reported. And you could give a very low dose of radiation, that's just what you could do. And they use an X-ray. And so you can see here basically the prostate, they estimated where it was. And so they gave huge fields and obviously the bladder and rectum are in that field.

That evolved to three-dimensional radiation therapy where now you've got 3D imaging, you have a CT scan, you actually can see a prostate. So, you can give a crude square here, a box around the prostate. But the rectum, which is right behind the prostate is getting almost all of the full dose in red there. So you could jack the radiation up now to 70 gray so you can give more radiation. And the toxicity was actually quite a bit lower by just shrinking the volume.

So what people often don't realize that the landmark study is many of you and people teach is the ProtecT trial, the PROSTQA registry, and many others. That's 3D radiation therapy. And amazingly you can see here's the ProtecT trial with you have surgery, radiation, the active monitoring group. You can see the EPIC or the patient reported urination scores. You get some irritation around the time of treatment, largely resolves there in orange. And the bowel function you can see is worse than all the groups and it doesn't fully recover. But even just going from 2D to 3D, that's quite a bit of improvement.

And then the joys of IMRT came around, which no one really understands what IMRT is. But what it is is that we spend hours a day basically drawing, okay. So we draw what we want to treat, what we don't want to treat, and we use a linear accelerator with hundreds of what are called multi-leaf collimators. You can think of them as now we can shape our radiation therapies. You don't just have a square, you can have intricate shapes, concave and convex shapes.

And so here's an example of a patient getting IMRT. So you still use a CT scan, but now you could think of it almost as you're bending or shaping the radiation therapy. I'm showing you kind of the middle or lower dose on your left. That's the 50% dose. So the high dose is in red, and you can see that even the middle range dose is just skimming the top of the rectum now. And if you look at the right, this is the high dose that we're trying to give the tumor, it just barely touches the anterior wall of the rectum. So this is dramatically decreased rectal side effects. Most of the published trials show somewhere between two to 5% will have long-term rectal bleeding and the dose of radiation. We can now give up to 80 gray of radiation therapy with much better tumor control rates.

But this is sort of an artificial view is, right? We took a planning scan of a patient. We created this beautiful plan, but if they're coming in for 40 treatments, how do I know they look like that every one of the 40 treatments? And the reality is they don't. And so the next advancement with what's called IGRT; image-guided radiation therapy. When they actually lay down on the, we call it the treatment table, we can now get imaging right before we treat them to make sure that the prostate's in the right location, the bladder is approximately the right size, the rectum is not overly distended.

And so here's an example. CBCT stands for a cone-beam CT. This is now incorporated on any modern linear accelerator. You can see the simulation scan, that planning scan on the left and the actual treatment scan right before we treat them on the right and you can make sure that what you thought you're delivering, you're actually delivering. And this is decreased toxicity. You could also put Gold Fiducial markers because on a CT scan you can't really see the prostate anatomy that well so you can triangulate to three little gold beacons, our urologists place them. Some people prefer things like Calypso beacons. These are electromagnetic transponders. You can think of them as GPS beacons in the prostate. And if the patient's prostate moves by more than about two millimeters, the beam stops treating. So if a guy passes gas, coughs, sneezes, takes a big deep breath and it moves, you can make sure the radiation is only on when it needs to be on.

The next advancement, and again, thanks to our urology group, we do a huge chunk of these throughout the state of Michigan. We do about, our urologist does about 20 of these a week. It's basically, it got FDA approved a couple of years ago. It's a hydrogel spacer that gets placed transparent needle between the prostate and the rectum. It solidifies into a gel that auto dissolves over about three months' time and then disappears. And so this is an example of my patient. Now, this is pretty much my standard practice to use. You can see here that even that lower 50% of the dose I give doesn't even touch the rectum and that pink structure, which is kind of hard to see, that's the rectal spacer. And if you look on the right, which is the high dose, it's now nowhere near the rectum. Okay. And so this has led to, and I'll show you the data, 0% in the randomized trial is a sham-controlled randomized trial of rectal bleeding rates.

And additionally is, I'm going to get to in a moment, a lot of people are now doing about 20% of people who give external beam have transitioned towards SBRT, which is a hypofractionated form of radiation. You can give closer to a hundred gray equivalents with SBRT.

So this is that randomized trial that was done and you can see here, this is grade two rectal toxicity. So this is like popping an IMODIUM® pill for diarrhea or rectal bleeding. There was not a single guy out to 40 months that had rectal bleeding with a rectal spacer. So this has been a huge game-changer for us. We've dramatically incorporated our urologist to place the gold markers, as well as the rectal spacer and this, has really increased the utilization of radiation in our group and sort of the collegiality between radiation and surgery. So where we're at and where we need to keep improving.

So obviously one of the differences is that urinary incontinence should be close to 0% if you're using, and you are good at placing rectal spacers, it's close to 0%. We still have in modern number, somewhere between 30 to 40% five-year erectile dysfunction. And probably the biggest reason when I'm in clinic, let's say four years ago, that patients want to have the surgery and it's a very valid reason. It is a pain in the butt to get 40 treatments of radiation therapy. And so many patients want to have surgery go home the next day.

So what's evolved is because of all these technological advancements, there's been about 10 randomized trials to go from these 40 treatments of radiation to about 20 to 28 treatments. We call that 20 to 28 moderate hypofractionation in the middle. It's just reducing the number of treatments by cranking up the dose a little bit because we're a little more precise. It's now in AUA/ASTRO guidelines, NCCN guidelines. That's probably the preferred standard of care for most men with prostate cancer, with a prostate. What's come newer and it's also an NCCN guidelines and it's going to be updated to be even more inclusive this year is what's called extreme hypofractionation. That's doing it in just five treatments. This is not unique to prostate and lung cancer. They've gone all the way down to one of three treatments in breast cancer. They've gone from six weeks down to two weeks. It's again simply because we can now see what we're treating and shape it to what we need to treat. In prostate, the reason it kind of started earlier, and I'll show you all the data that supports it, is that there's probably biologically a widening of the therapeutic ratio to give more hypofractionated treatments such as more dose per treatment and fewer fractions.

And so there's lots of names. I would say the names that probably are most used is SBRT or SABR. People thought they could come up with some cool term. What is largely disseminated though is the term CyberKnife®. CyberKnife® is a brand, it's not an actual treatment, but they're usually referring to SBRT and some more kind of traditional names like extreme or ultra hypofractionation.

So I'm going to show you the first. This is a large 1200 person non-inferiority randomized trial. It's comparing the traditional about eight weeks of radiation. In this case to seven fractions of, it's almost slightly low dose SBRT, but it sort of falls into that. No rectal spacers were used. And you can see here that the tumor control was identical. This is showing you grade two bowel toxicity. And again, fairly low rates, about 10 plus percent long-term and identical between the groups. So this now after this was published, NCCN is going to be expanding it and Canada's already made it a standard of care treatment.

Another trial that was just published in Lancet Oncology is the PACE-B trial. It's about 800 patients, again, about eight weeks of radiation versus the more traditional five treatments of radiation. Again, no rectal spacers were used from when this trial was started. They've reported sort of their early toxicity results. The top curves are grade one. The kind of middle curves are grade two, the curves that barely look different than the X-axis are grade three so less than 1% of patients have had grade three toxicity. About 5% so far I've had grade two toxicity, so very favorable even without rectal spacers.

We published this study that we took almost 40 prospective clinical trials, about 6,000 patients that have various lengths out to 10 years of follow-up. Showing that at about five years, about 1% of men have a grade three plus GI toxicity, and this is why I think rectal spacers can help to reduce that and less than 1% have a grade three GU toxicity. Okay and this is the patient-reported EPIC urinary and bowel scores. You're going to have inflammation and irritation around the time of treatment that's unavoidable. You are radiating the urethra and low doses will get near to the other structures, but largely it recovers by six months to one year.

So we've now been able to just simply with becoming more hypofractionated, a little more accurate, grade three cystitis, which is again something that people who treated patients 10 years ago, 20 years ago, this was rampant, even hemorrhagic cystitis. It's now much more convenient. I would say about 75% of our patients now get just five treatments of radiation. And so something to look forward to that we're running a randomized trial is what do we do about this erectile dysfunction rate?

We have not made progress in radiation oncology and so there's now a lot of trials ongoing. This paper in Lancet Oncology from three years ago was talking about that's very relevant to urologist and radiation oncologists is sort of favorable and unfavorable anatomic variants. That could be the sphincter length. It could be the location of the neurovascular bundles. Something that's come out in the literature. Important for us at least is the internal pudendal artery is something that we may injure with our radiation therapy contributing to erectile dysfunction.

And so this provocative but by no means definitive paper published in European Urology a few years back. It was a single-arm study at University of Michigan that did vessel sparing and basically spared the nerves, those internal penile arteries, the penile bulbs, some cavernosal nerves and vessels and compared it to this PROSTQA model and simply, and it's flawed beyond belief because I think that the rates for both surgery and radiation are a little bit better than what was in the PROSTQA paper. But the point is that almost 90% of patients with vessel sparing radiation therapy had five-year preservation of erectile function, which even for radiation therapy is unprecedented. So the way you have to prove this is a randomized trial. And so this is called the POTEN-C randomized trial and it's using all the things I've just discussed. It's SBRT, so five treatments. They all have a rectal spacer, which is image-guided radiation therapy and it's randomized to our normal treatment. We're sparing all these structures. And it's a multicenter study about 25% enrolled. So to be determined.

So we really need that data to see if we can move the needle there. I don't know if any people here work at places that have an MRI-LINAC they call it. There's a view ray, you now rather than doing a cone-beam CT, you can do an MRI scan and obviously on a CT scan, it's very hard to be very accurate with the prostate anatomy. With the MRI it's much easier. We'll see if this actually helps patients. As you can see the side effect rates are becoming very low. It's harder and harder to prove benefit. One of the challenges, these are very pretty pictures, is that our traditional linear accelerators treat 30 to 40 patients a day and MRI-LINAC treats about 10 patients a day, so that's a logistical challenge.

Protons, anyone that knows me will know what I'm going to say next. These are, and this is, you know, almost every organizational body will agree with this. Experiment, they are experimental for prostate cancer and I'm not going to talk anything about other cancers. These should be on a randomized trial. Harvard MGH system has one that's almost accrued and I think they need to accrue it. It's taken so many years to accrue because most patients are not treated on trial and we shall see. It's going to be very hard for me to believe that proton beam is going to reduce rectal or urinary side effects when we're talking about low single-digit percentage points right now.

Working at a proton facility is a conflict of interest. So, of course, I've had many debates with people who work there. So this is, you know, stay informed and I give this lecture and we update this every year for our urology program is, yeah, radiation therapy absolutely caused a ton, a ton of side effects and if given poorly today it can cause a ton of side effects. But if done well it can be very convenient with very favorable side effect profile.

We have at the University of Michigan, we've quadrupled our radiation volume for prostate cancer in the past four years and doubled it in the past two years. And now we get patients, even from Chicago driving up for this treatment. It's going further. So radiation oncologists keep running trials. They've done a randomized trial of five versus two fractions and there's now Phase I trials with single fraction. Theoretically, there's no reason it can't be one fraction. Brachytherapy is one fraction. So time will tell if this is safe. Thank you.

Deepak Kapoor: Thank you. Okay, that was really kind of a whirlwind and really comprehensive overview of this. We had a little dialogue between us yesterday and there was a question from the audience that was kind of germane. I'd like maybe Connie you could take it. The question from the audience was the data that you're presenting, a lot of it is five years in that time really matters in prostate cancer.

There was a recent report from Zaleski et al that showed a PSA failure rate of only 2% in the short-term, but they had a positive biopsy rate of over 12%. Connie, maybe you can give your thoughts on it and see are we just setting ourselves up by changing the therapy for more problems down the line?

Constantine Mantz: Right. I mean, to me the real question is how much confidence are we going to grant to these data, which are of a shorter term than what we have with other more conventional longstanding therapies. And so as it has to do with stereotactic therapy and treatment localized prostate cancer, we have very good data. The limiting factor of it is that it doesn't really extend out past 10 years. So Dan, what prediction do you make?

Daniel Spratt: Yeah, I think a lot of people and radiation oncologists included in that conversation like to say we need longer data. The challenge is you go look at every one of the studies, you go pull up the ProtecT trial PROSTQA. Those curves are about as boring as they can be after three years. And if you look pretty much at the curves, you can still have toxicities later, don't get me wrong, but it is a slow trickling increase. And so the vast majority of toxicities occur early and the biggest predictor of late toxicity is early toxicity.

So, I mean, usually, they adopted all the... They changed all the guidelines for moderate hypofractionation after five years of data. I think once we have solid five-year evidence, rigorous, we're talking large studies closely followed. I think it becomes an option. I think it doesn't mean you can't do longer course radiation therapy. I just think that it becomes increasingly harder to justify.

Constantine Mantz: And at present for the interested patient who comes to you, what selection criteria do you consider before recommending stereotactic?

Daniel Spratt: Yeah, so I mean the gland size, I don't like it to be too big. Usually, I want to under 80 ccs I want them to have an AUA or IPS score are usually under 15. I mean, I'm someone, I work very closely with our urologist guys who have obstructive symptoms. I have a very low threshold for having them either do a procedure like a hole up or have a surgery.

I think one of the reasons of how both specialties actually can get better toxicity rates is simply selection of patients. And I think sometimes radiation oncologists and urologists, we overcompensate by thinking we can manage everything. And so I have, I think that very few patients I've had bad outcomes on have been patients who are ineligible for surgery that really should have had surgery if they were healthier.

Deepak Kapoor: One other point is, and this is sort of my hat, which is socioeconomic, is there's a clear cost advantage to hyperfractionation and ultra-high production SBRT over conventional IMRT. And we see that in the proposed radiation therapy oncology rule. One concern that I have is that the drivers of the fraction numbers in some cases was way ahead of the data. And are we going to have socioeconomics or, or cost implications drive us toward therapy that we may not have complete data on? And I'll just get your response to that. And I think that's probably all the time that we have. We see a lot of advertising, which I think I know your feelings on. My concern is that the tail is wagging the dog, that the economics is driving the treatment as opposed to the data driving the treatment.

Daniel Spratt: I'm hugely against advertising for CyberKnife® ads, proton ads, anything. I'm equally against when my own specialty does these things. I think it's a disgrace and I think the claims they make are not supported by data. I think there are many treatments that are very good for prostate cancer. These advertisements started way before all this data I showed. I mean, they'd been going on for probably about a decade and so it's a huge problem. As many of you may know, the bundle for radiation oncology is coming in 2020 so pretty much everything, whether it's five treatments or a hundred treatments, it's going to be about something like $20,000 that Medicare will cover.

So this will be a push for practices to probably start doing five treatments. Like anything, if you're not trained in it, you could harm patients and so it's going to be very important that if your groups are closely linked with radiation oncology centers that you get the right image guidance and you get your system set up.

But this is going to be coming here very rapidly I think in a few years. Once one of those trials I showed you gets five-year data, the guidelines in the US and in the United Kingdom are going to make it... It'll probably, my guess is it will be the preferred radiation therapy modality in the next few years.