THE ROLE OF PROTON THERAPY IN THE MANAGEMENT OF SOLID TUMORS - IPCSG Sept 2024

THE ROLE OF PROTON THERAPY IN THE MANAGEMENT OF SOLID TUMORS - YouTube

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Dr. Ramesh Rengan is currently the Peter Wootton Chair and Professor in the Department of Radiation Oncology at the University of Washington School of Medicine and the Senior Vice President and Director in Radiation Oncology Division at the Fred Hutchinson Cancer Center. He also holds a joint appointment as faculty of the Integrated Immunotherapy Research Center, Fred Hutchinson Cancer Center.

Meeting of the IPCSG, 9/21/2024

Summary

Here's a summary of Dr. Rengan's talk on proton beam radiotherapy in solid tumors:

Dr. Ramesh Rengan's presentation explores the role of proton beam radiotherapy in managing solid tumors, with a particular focus on prostate cancer. The talk begins by emphasizing the importance of asking the right questions in problem-solving, setting the stage for a critical examination of radiation therapy's evolution and the potential benefits of proton therapy.

Historical Context and Evolution:

Dr. Rengan traces the development of radiation therapy from the 1960s to the present, highlighting how advancements have consistently aimed at improving local tumor control while reducing complications to surrounding healthy tissues. The progression from basic radiation techniques to more sophisticated methods like 3D conformal therapy and intensity-modulated radiation therapy (IMRT) is outlined. Proton therapy is presented as a logical next step in this evolution, offering more precise dose delivery and reduced exposure to healthy tissues due to its unique physical properties.

Early Evidence and Challenges:

The presentation discusses early evidence supporting the local control hypothesis in radiation therapy, citing studies in lung and prostate cancer that showed improved outcomes with dose escalation. The CHART trial in non-small cell lung cancer and dose escalation studies in prostate cancer are highlighted as key examples.

However, Dr. Rengan also presents data challenging this hypothesis, noting that improved local control doesn't always translate to better overall survival, particularly in prostate cancer. Long-term follow-up studies have shown limited survival benefits in some cases, and there are risks associated with treatment intensification. This balanced approach sets the stage for a nuanced discussion of proton therapy's potential benefits and limitations.

The Value of Toxicity Mitigation:

A key theme in the presentation is the importance of toxicity mitigation in cancer treatment. Dr. Rengan cites a study showing improved survival in lung cancer patients receiving early palliative care, underscoring the significance of quality of life considerations in cancer management. This perspective informs the subsequent discussion of proton therapy's potential advantages.

Applications of Proton Therapy:

The talk focuses on three main areas where proton therapy may offer particular advantages:

1. Pediatric cancers: Proton therapy's potential to reduce long-term side effects, especially neurocognitive impacts in medulloblastoma treatment, is discussed. Data from meta-analyses showing potential benefits in neurocognitive outcomes for pediatric patients treated with proton therapy compared to conventional photon therapy are presented.

2. Leptomeningeal carcinomatosis: Dr. Rengan explains how proton therapy may allow for effective treatment with reduced toxicity compared to conventional radiotherapy in this challenging condition. Data showing improved survival and reduced toxicity with proton craniospinal irradiation are presented.

3. Prostate cancer: The presentation delves into the potential benefits of proton therapy in prostate cancer treatment. Dr. Rengan discusses the ProtecT trial results, which compared active surveillance, surgery, and radiotherapy in prostate cancer, and explains how these findings inform the potential role of proton therapy. While proton therapy offers dosimetric advantages, the talk emphasizes that long-term clinical benefits are still being evaluated.

Clinical Evidence and Challenges:

Dr. Rengan addresses the challenges in generating clinical evidence for proton therapy, including the need for long follow-up periods to assess late effects and the difficulties in conducting randomized trials. He discusses the appropriate use of proton therapy in different patient populations, noting that younger patients with prostate cancer might benefit more due to the potential reduction in long-term side effects.

Future Directions - FLASH Radiotherapy:

The presentation introduces FLASH radiotherapy, an ultra-high dose rate technique that shows promise in maintaining tumor control while potentially reducing normal tissue toxicity. Dr. Rengan presents early preclinical studies showing encouraging results, including improved survival and reduced toxicity in animal models. He details the FLASH-RT setup at the University of Washington and the Fred Hutchinson Cancer Center, demonstrating ongoing research in this cutting-edge area.

Conclusions:

Dr. Rengan concludes by emphasizing that while proton therapy may provide clinical value for a subset of patients with narrow therapeutic spectrum tumors, ongoing prospective trials in various cancer types will be crucial in defining its role in cancer treatment. He highlights several ongoing trials in breast cancer, hepatocellular carcinoma, prostate cancer, and lung cancer that will provide important data on the efficacy and toxicity of proton therapy compared to conventional radiotherapy.

The presentation underscores the importance of continuous research, careful patient selection, and the need to balance the potential benefits of advanced radiation techniques with their costs and complexity. Dr. Rengan provides a balanced view of the current state of proton therapy, acknowledging its potential benefits while also recognizing the need for more robust clinical evidence to guide its optimal use in cancer treatment.

Overall, the talk offers a comprehensive overview of proton therapy's role in oncology, grounded in historical context and looking ahead to future innovations. It emphasizes the importance of evidence-based medicine and patient-centered care in advancing cancer treatment technologies.

Transcript [edited]

Introduction by Aaron Lamb

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Speaking of fantastic presenters and doctors, Dr. Rana McKay will be here next month. She is a medical oncologist and associate professor of medicine with the UCSD Department of Urology. She's an excellent speaker, very well attended. If you've not heard her before, she is going to be sharing the cutting-edge treatment options and research in PCA. I believe that she's imminently going to a very big conference that she'll be sharing info from, so that is not a meeting to miss or even to see online. Please do come in person so you can ask some questions.

For today, I'd like to thank Dr. Rengan for stepping up at the last minute to provide us a presentation. We unfortunately had a little bit of scheduling conflict occur at the last minute, and so we're excited still to have Dr. Rengan here. He'll be presenting on the role of proton therapy in the management of solid tumors. He's with the University of Washington, he's a professor at the University of Washington School of Medicine and I believe the senior VP of radiation oncology at Fred Hutchinson Cancer Center.

Now today we do have a hard cutoff at 11 a.m., so we're going to keep all the Q&A till the end. We'll give the doctor about until 10:50, and then we'll cut over to Q&A. So with that, let's go ahead and share your screen, doctor.

Dr. Rengan’s Presentation

I'll start off by extending a deep sense of gratitude to Bill and Aaron for inviting me here to speak today. It really is a privilege. I had the honor of having Bill attend a presentation I gave soon after taking on a larger role in the cancer center.

I wear a few hats. One is that I'm a prostate cancer doctor. I just wanted to be clear about that. I'm also a lung cancer physician. We have the good fortune here, just like you do in San Diego, of having access to multiple different ways to utilize radiation in the management of cancer. One of which is using a form of radiation known as proton beam radiation, and we happen to have access to that here in Seattle. So I have some expertise in that space. I'm also chair of the Department of Radiation Oncology here. It's a coalescence of all of these various roles that I wear that I think probably led to Bill initially extending an invitation to me to speak to your wonderful group.

We had the privilege of one of our more junior faculty members, Dr. Jonathan Chen, who was absolutely stellar, planning to be here today but unfortunately was called away because of a conflict, as Aaron said. So you are all stuck with me, and I will do my very best to earn the right to have presented to all of you.

I think it's also important for you to know some of my conflicts beyond the roles that I wear. To deliver proton therapy, it requires fairly expensive machinery that runs into the tens, in fact hundreds of millions of dollars. Every one of the proton facilities is customized and built by a team that is usually outsourced. There's a vendor that builds these facilities and they build something called a cyclotron that generates this proton beam. So you have to have dialogue with them to try to make sure that the machine continues to work. One of the roles that I wear is I'm on an advisory board. I do not get compensated for being on that advisory board except when we meet, they do provide food, drink, and coffee. So that is a benefit to me. I wanted to make sure that you were aware of that.

About two years ago, I was asked by Varian to play a role in providing some advice on a new technology which I will talk to you a little bit about called flash radiotherapy. For that, they did pay for my travel to meet with them and provide me some compensation for the time that I spent. I wanted to make sure you're aware of that. I also have some research funding for clinical trials that we have run that center around immunotherapy, none of which is going to be directly related to this talk, but I think it's important to be upfront about all of these things.

So with that being said, I thought it might be helpful to frame our discussion. I know I'm speaking to all of you as you have deep interest in the management of prostate cancer. Prostate cancer is one of the most significant cancer-related problems that we as oncologists and cancer professionals have been trying to address and solve for really the past century. This is true not only for prostate cancer but lung cancer, breast cancer, and all variety of different cancers. We have had a singular problem that we have been focused on.

I thought it may be helpful to crystallize our thinking around what it is that we are trying to do. Obviously, we're trying to cure the disease, but not all cures are created equal. The journey and how we cure the disease is really important. The person who ultimately should define which appropriate pathway to cure is the right one is the patient. You are our boss. You are the ones who have to define for us and provide us as physicians the marching orders for how we should chart our journey together. I think that's really important to convey. Aaron really said it well in his intro that you should use resources of information that are available to you, and the doctor is a part of that team, but ultimately you are the commander of the ship.

To crystallize our thinking, I thought it may be helpful to start with this quote: "If I had an hour to solve a problem and my life depended on the solution, I would spend the first 55 minutes determining the proper question to ask rather than focusing on the solution." I think that's important as you think about our history with how we have focused on the management of cancer over the years. This is a quote from Albert Einstein which I really like.

There was another quote that came out of the World War II era, actually from a researcher at Harvard who was the first to identify the potential use of proton beam radiation in the management of cancer. So it's not a new technology, believe it or not. The notion of using proton beam radiation to treat cancer has been around for almost as long as the notion of using x-rays. It's just the practical ability to deliver and to treat and use this technology has only come to the fore in the last 20-30 years. It was a gentleman by the name of Robert Wilson who really was the forefather who first articulated the notion that maybe we could use proton beam radiation as one of the weapons for the treatment of cancer.

I think it may be helpful to center our thinking on what problem we have been focusing on in the world of cancer care and the world of radiation oncology. For much of cancer management, there really were essentially two ways to permanently cure a cancer: one is to cut it out, to remove it, and the other is to radiate it. There is no such thing as absolute resistance to radiation. In other words, if I deliver a high enough dose of radiation, I can sterilize any tissue, I can sterilize any cancer. The catch is you have to be able to do that safely.

Similarly, a surgeon can cut anything out. The catch is to be able to do that safely. But these are the two essentially curative modalities that are available to us. Now we're adding some dimensions to that. Sometimes immunotherapeutics can cure, sometimes some forms of systemic therapies can cure, but by and large when it comes to a solid tumor, meaning not a leukemia or lymphoma, the two dominant curative approaches have been either using radiation to sterilize the tumor or using surgical resection to remove it.

Why do I think it's really important to coalesce around our understanding of the problem statement? Many of you in this room may know what this is, especially being in California and somewhat adjacent to where the tech sector is. This is an Osborne computer. This computer was launched in the late 1970s and early 1980s. There was a belief by the founder of Osborne Computer Systems, whose name was Osborne, that the reason why people were not adopting personal computers was because they were too big. So if we can make a portable computer - and portable in that era was defined as 24 pounds and could fit under the seat in an airplane - this actually fit those characteristics of airline travel in that era.

They said, look, if we can make a portable computer, then people will start adopting personal computers. Because prior to that time, everybody was usually using these larger mainframes and a terminal to attach to it, but not personal computers. For some reason, personal computer sales were not taking off. So this is a 24-pound laptop, as I said, that fit under the seat. It was not cheap - $1,800 in that era. The initial plan was they would sell maybe 10,000 units to business professionals.

What happened was it sold like gangbusters initially. So they believed that okay, we have caught lightning in a bottle here. We've solved the problem. The problem was that portability was not adequate, and now we've come up with a portable computer, and now we're going to start selling PCs left, right, and center. Although the initial results seemed very promising, very quickly the public kind of voted with its feet. They bought like 10,000 units in the first month, and very quickly there were 50,000 on back order. But the reason why we've never heard of this computer company is because we know what actually happened. The end of the story was this company went bankrupt.

The problem that they focused on, although it may have been a reasonable theory, was not the right one. The right theory was that computers of that era needed more computing power, and that was the challenge. The reason why people were willing to tolerate the pain of connecting to a mainframe and using COBOL and BASIC and all these archaic languages was because that was the only way to access the kind of computing power in that era that they needed to perform the calculations or whatever it is that they needed to do. The computing power that was available to them even in this 24-pound laptop was just not enough. So yes, it's nice to be portable, but it doesn't actually solve the real problem and the real reason why they were trying to access a computer. So yes, they came up with a solution, but I would argue it was the wrong problem that they solved.

We have run into this in medicine. In India and around the developing nations of the world, there was a problem with infant mortality. Diarrhea was observed as a big correlative cause of infant mortality. Kids in the first 10, 20, 30 days of life would develop diarrhea and they would succumb and die. So the question was, what is the problem? The community and the country doctors believed that the problem is the diarrhea and it's because the bowel is not functioning. What we need to do is find a way to stop the diarrhea, and one way to stop the diarrhea is to limit fluid. If you limit fluid, the stool started to harden, and they said aha, this is what we needed to do.

So they started to restrict fluid and the stool started to harden. We solved the diarrhea problem. Challenge was, mortality went up even further because the real problem was not the diarrhea but the loss of fluid. The treatment was exactly the opposite of what they were doing, which is you need to double down on giving more fluids to replace the fluid loss. That is how you reduce mortality. Oral rehydration therapy became absolutely transformative in terms of reducing mortality from cholera and these GI viruses worldwide. It became a critical vehicle of improving survival.

So again, the correct problem was to focus on fluid loss rather than the diarrhea. It kind of frames some of our thinking about what problem do we need to solve.

So with that context, what have we been focusing on in cancer care and radiation oncology? What we've been focusing on over the years is how do we kill as many cancer cells as we can. Straightforward, right? And in order to kill the cancer cells safely, we need to focus our beam on the tumor. We need to find a way to make the beam only hit the tumor and nothing else.

Now there are some challenges with that because x-rays, which is the standard form of radiation that is used worldwide not only for imaging but also to treat cancer, has a fundamental physical property whereby it goes in one side and out the other. All of you know that. All of you have had a chest x-ray ever. You stand and the beam is behind you and you have film in front of you, so the x-ray passes right through you.

That means if we're using it to treat a cancer, everything in front of the cancer and everything behind the cancer receives radiation dose as the beam passes through. Moreover, if you look at where we were with x-ray technology in the 1960s, we really didn't have any ability to really shape that beam other than delivering kind of a square beam.

In the 1970s, we started to develop technologies where we could find ways to block the beam and actually shape the beam in two dimensions, and that actually helped. Then in the 80s, we started to incorporate three-dimensional imaging. So rather than the era of two dimensions where we could just see like on an x-ray front to back, just a flat two-dimensional image of the insides, we actually started to get three-dimensional images like with a CAT scan. We started to incorporate that three-dimensional imaging into our targeting of how we deliver our beam.

We got fancier and fancier with x-rays, and frankly, we got pretty darn good with x-rays and ways to use x-rays and a multitude of x-ray beams to really center on the tumor. So that the tumor feels the impact of all of the beams, but the tissue only is exposed to a fraction of the total dose because any single beam is only carrying a small percentage of the dose. Therefore, we concentrate the impact where it needs to be, which is on the tumor.

As we evolved with x-ray, we're still stuck with that limitation though. No matter what, the beam passes in one side and out the other. That's a fundamental physical law that we can't get beyond.

So why are protons somewhat interesting? Well, the reason why protons are interesting is this is how protons interact with tissue. Because they are particles rather than an x-ray, they actually have mass and they also hold a charge. They're positively charged. When they penetrate into a patient, into tissue, they actually stop where we want them to stop. They don't keep going.

So if we calibrate the beam to stop within the tumor, then great, we've solved half of the problem right there. There's no dose being delivered beyond the tumor and the dose is stopping right at the tumor. There's another advantage, which is kind of depicted on this complicated slide here, but what I will say is x-rays, as they pass through you, if you think about x-rays sort of like being like heat from an oven - the closer you are to the heat source, the hotter it gets, right? The further you are from the heat source, the colder it is.

The way x-rays work, the closer my body is to the x-ray source, the more the dose. So in fact, the maximum dose that an x-ray beam delivers into my body is just beneath the skin surface because that's kind of the point that's closest to the source. Whereas protons function sort of like a microwave oven.

In a microwave oven, how close you are to the source of generating the microwave doesn't really determine how hot it gets. That's why you don't need an oven mitt when you put your hand into a microwave oven even after it's heated something up. You need the oven mitt when you touch what you heated, but just to put your hand in the box, you don't need that. Whereas in a conventional oven, everything is heated to 400° or whatever you're heating it to, and so you do need an oven mitt even if you're not touching what you heated.

The thing about microwaves, the way they heat in a microwave oven is they excite the water molecules within the food and that's how you specifically heat the water-containing food. That's how you get heat in a microwave. Protons function in a similar way - they deliver most of their impact close to where they stop rather than where they enter. The slower they are moving, the more damage they do.

So if we calibrate the beam to stop within the tumor, not only does the beam not continue forward beyond the tumor, it also has its maximal impact at the tumor. These two properties together led to the notion that hey, protons may be a tool for a subset of patients for whom we want to deliver a high dose of radiation but we need to really protect the surrounding normal tissues. So that's the idea and that's the practical potential advantage of proton beam radiation.

This is a logical next step if our job is to kill as many cancer cells as we can. This may be an additional weapon to do that with. So does this theory work? Was this the right problem statement? Is our job trying to maximize the intensity of our treatment to try to kill as many cancer cells as we can? Is that our job and does that work and does that translate into improved outcomes for our patients?

We had some early signals that it did. This is a trial from the world of lung cancer. I won't spend too much time on this, but it basically took almost 600 patients in the UK and they got one of two treatments: either standard daily radiation for 30 sessions, or an intensification of the radiation where they got admitted to a hospital and they got three treatments a day for 12 consecutive days. So they got the dose over 12 days rather than 30 days. That really intensifies the dose and they got three times a day so that tumor had no time to recover or anything - we just kept hitting it.

What they found - and there was no chemotherapy, there were no other treatments in the trial - was that these curves show you how well did the disease remain under control. The upper curve is the one where people got the more intensified regimen and the lower curve is where people got the standard regimen. So we had better control of the disease.

Well, did they live longer? And in fact, they did. People who were in the upper curve also lived longer, which is good. So it improved survival by controlling the disease. We were able to improve survival. So this was an early signal.

But I will note, yes we improved survival, but still for most patients we're not giving a permanent cure. Lung cancer is a very aggressive disease. It's a very different disease, and this is data from the 1980s and 1990s so we do much better now. But having said all that, although yes we can feel happy that we separated these two curves, we also should temper our enthusiasm by the fact that still 80% of the patients we treated, we failed to achieve a durable cure. So maybe we were focusing on the right problem a bit, but maybe not.

So what about the world of prostate cancer? Prostate cancer, as many of you may know, we were focusing on the exact same problem: how do we get enough radiation dose in safely to control the tumor? Because not everybody can undergo a prostatectomy. Many can, but not everybody, and not everybody's happy with the side effects of a prostatectomy.

So is there a way to provide an alternative? I would say for much of our history in the 80s and even in the early 90s, radiation was definitely not an equivalent option to surgery. It was a backup. It was only for patients for whom surgery was not an option, because we couldn't get enough radiation dose safely into the tumor to come up with an equal control rate to what you can get with surgery. That was the problem we had to solve.

So in the early 1990s, when the very first proton therapy unit hospital-based proton therapy units were launched - one at Harvard, one at Loma Linda just up the way from all of you - they ran a trial where they gave x-rays up to the maximum point that they could get x-ray dose in safely. So they used the x-ray beam to get as far as they could, and then when they hit water's edge with x-rays in terms of "boy, we give any more x-rays, there's going to be more side effects, rectal side effects, bladder side effects for these patients" - so what we're going to now do is pivot to using protons to get across the finish line, to get that last bit of dose, additional dose, 20 plus 30 plus units of radiation to get us to a higher dose threshold safely. And can we, by doing this, improve the control of the disease?

There were almost 400 patients who were randomized to what was the standard dose at 70 Gray. Like I said, we couldn't provide equivalent cure rates to surgery to prostatectomy. We could provide about 10% less in terms of cure rates, and that's not good enough. But when we got to close to 80 Gray, 79.2 Gray, we were providing about equivalent cure rates with surgery. That's what our modeling predicted.

But the problem was, when we tried to get to 79 Gray with x-ray technology of that era, we started to have about a quarter of the men having severe rectal side effects and other side effects which were just not acceptable. So how could we get there safely?

This is a trial that was launched in 1995, and what they found was - you can see this big separation now - that we got to that higher dose for patients with both low and intermediate risk prostate cancer. We started to see a significant improvement in control of disease and long-term control of their prostate cancer. These are in years, so we're talking about seven years out. The majority of men who got the high dose remained cancer-free, and this competes very equivalently with surgery.

So that meant we earned the right to say hey, we have, with this combination of treatments, an approach that is a reasonable alternative to surgery for men who want to choose to take that option. So that's where we were.

The one difference though, and you should note, I didn't show you survival curves because even though we did a better job of controlling the disease, most men, even after the disease comes back in prostate cancer, they still live a very long life because we have other options - hormone treatment, etc. to kind of keep things going. Maybe almost treat prostate cancer sort of like a chronic illness.

So even though we control the tumor - meaning if you're in this high dose group at this point, you're not getting any treatment whatsoever because your tumor is completely controlled - but even if the tumor does come back, it doesn't mean it immediately has an impact on your survival. So there were no survival differences, but the control of the tumor was significantly improved.

But we figured if we wait long enough, eventually we'll start to see those survival differences. We had a lot of data that showed that if we improve control of the cancer, eventually over time, on the scale of decades sometimes, we'll start to see an improvement in survival. And that kind of makes sense. This is just a paper that sort of confirmed that in the early days.

So we were feeling pretty good about this. We were feeling that hey, maybe this is where we need to be. We need to intensify treatment, give more dose, find a way to give more and more treatment to the tumor. If we're able to do this, we're going to be able to control and improve outcomes. And that's a reasonable theory of the case.

But the problem is we started to see some signals that maybe that wasn't true. As we waited and waited on this trial, we still maintained very good control of prostate cancer, maintained very good control of the PSA, which is great. But interestingly enough, we never see a separation in the survival curve. Even at nine years, we didn't see a difference in survival.

So men, for whatever reason, were dying of something. Maybe not necessarily prostate cancer, maybe of cardiac issues, maybe of other things. But some of these men were dying of prostate cancer because eventually you can see even with the higher dose, when you wait 10-11 years out, yes we're doing a better job of controlling the tumor, but about 30% of men did have relapse of their disease.

So we did improve outcomes. Yes, we're happy about that. But did we improve it permanently? Did we improve it in a way that in our ideal world, we deliver a treatment and you never have to think about this again?

So we earned the right to be an alternative to surgery, but the larger problem, whether it's surgery or radiation, still remains. Prostate cancer is still a deadly disease. So how do we help improve our patients' control but also be able to live well and move on with their lives so that they can do other things?

This is kind of a question that we've been wrestling with. This is just data from other diseases like lung cancer also, where we saw that even when we try to pound in more dose, one of the other things that we saw unfortunately - we've never seen this in prostate cancer - but when we treat diseases like breast cancer and lung cancer where there are vital organs sitting right around where the tumor is, there is a point where if you just keep pounding at the tumor, you do more harm than good.

This is what happened in the world of lung cancer where we tried to modestly increase the dose, not even to that 79-80 Gray dose level that we have been able to get to in prostate cancer. Just to get to 74 Gray for a tumor that's actually much bigger and much more resistant to treatment, when we tried to do that, we actually did more harm than good. The patients who got the higher dose are on the lower end of the curve. So that idea started to fall out of favor a little bit.

We can't just keep doing more of the same because for some patients, we're doing more harm than good. That's something that we've had to kind of - it was very sobering for us. What we saw in this trial was the higher dose we gave, the more harm we did. We also saw that organs like the heart, not surprisingly, did not like to receive any radiation. When we gave higher dose to a tumor in the lung, the heart gets exposed to radiation, and this was a problem.

So we learned a lot of things from this. One of the things that we started to ask is: okay, how should we make sure not just to focus on how many cancer cells we can kill, but how much of the healthy tissue we can protect? Maybe protection alone should be our priority.

There was a big trial in the world of lung cancer that actually looked at this, where they just took patients and they got very standard treatment, but the difference was one group of patients got that standard treatment with a toxicity control team, a palliative care team, who worked with those patients from day one to address any side effects that they had. That's all they did - they just addressed side effects. If patients were dehydrated, they gave them fluids. If they had pain, they gave them pain meds. They just helped manage side effects.

What they found was when they did that, patients were happy. These are curves - the higher curve shows that patients did much better in terms of side effects. They had much better quality of life, which was great, which makes sense, right? If you manage side effects better, quality of life improves. But what was surprising was they also lived longer.

So you're getting the same treatment, except one group is getting their side effects very actively managed, and they lived longer. This is the importance - and the reason a trial like this made it into the New England Journal of Medicine and it was kind of earth-shattering to all of Cancer Care - was that hey, you know, just doing more and more of the same, which is the journey that we had been on as cancer researchers for so long, is getting to a point where we are maybe crossing the threshold of not providing as much help to our patients and maybe actually creating harm.

So what we have to do is find a way to focus on safety and reduction of side effects. We need to do that. That's really, really, really important. And you might think that with focusing on all of these side effects, maybe the patients in the early palliative care group got more treatment, like maybe a little bit more chemo. No, they actually got less. They got less treatment, more focus on side effects, and they lived longer. So that's a win-win-win.

It goes against our grain of thinking because our grain of thinking up to that point was hey, let's get more treatment in there.

So where should we focus on proton beams and prostate cancer? What should we be doing and where do we go next? Well, I'm going to speak just very broadly for a second about how do we approach it in the world of Cancer Care when we have access to proton beam.

One of the things we do is we want to first focus on patients who do most poorly with x-rays. Believe it or not, the patients we really spend a lot of time worrying about are pediatric patients because their tissues are evolving and they're exquisitely sensitive to any radiation exposure.

The earliest uses of proton beam radiation, which is very unique in the world of cancer - usually the kids are the last group you ever try any new cancer treatment with - but in the world of proton beam radiation, the kids were the very first, dating back to the 1970s. We've been treating kids with proton beam radiation, and proton beam is actually a standard of care for the most common of a variety of different pediatric cancers.

Why? It's because of some of these pediatric cancers, you have to treat a very large area. You have to treat the entire CNS system because they have tumors - kids are very vulnerable to central nervous system tumors. They form these early in life and you have to treat the entire CNS system. To treat that entire CNS system with radiation, although it's very effective - 80 plus percent of these kids live well into adulthood - they suffer the ill effects of radiation: cardiac issues, thyroid issues, cognitive issues for their entire lives.

Whereas with protons, it significantly - you see there's no dose to the heart, there's no dose to the bowel, there's no dose to the abdomen, and even the impact on cognition is minimized because of all the other systemic reductions of dose.

So these are the very first groups of patients that got treated with proton beam radiation dating back to the 1970s. Interestingly enough, the longest body of data we have with proton beam radiation is with kids, showing safety and showing efficacy. Frankly, the one thing we don't have is randomized trials because no parent would allow their child to be randomized to this, and it would be challenging for us ethically to say to a parent, "Hey, you can either have this type of treatment or this type of treatment."

You have to have in the world of Cancer Care something called equipoise before you're willing to go to a patient. That means you have to go to them in good faith saying, "I don't know which of these two are better." But if we believe that one is better, then we can't run a randomized trial ethically asking a question, because then we may be putting patients in harm's way.

So that's kind of one of our founding principles when we run clinical trials. No governing body would approve a randomized trial between these two treatments because we've never found a beneficial impact on more radiation to tissues.

This just shows some data over the years of how across the board in a variety of different countries, proton beam radiation is just kind of a very major standard. One of the driving forces is for the treatment of kids.

So I have a few more examples, but I don't think this is really something that we have to spend a lot of time on right now. What I want to zero in on is prostate cancer. So in prostate cancer, where are we today?

I took you to where we were in 1995, right? Where have we gone since then? Well, from the lessons we learned in 1995, we learned that we can now deliver radiation in a way which we believed to be a reasonable alternative to surgery, but we still had to go out and prove it.

To the credit of the United Kingdom, they ran what has now come to be termed as the trial of the century in prostate cancer. This is a trial that all of you hopefully should be familiar with, but if not, I'm happy to kind of walk you through some of the fine details.

This was a trial of over 1,600 men, but 6,000 plus men were screened with prostate cancer in the UK. They had anything from low to intermediate to high-risk prostate cancer, but it had to be localized, meaning no evidence of spread to the bone or elsewhere. These patients - most of these patients had low and intermediate, very few had high risk. They were randomized to one of three potential options: one was active surveillance or active monitoring, the second was radiation using modern radiotherapy (so post-1995 modern radiotherapy), or radical prostatectomy.

What they found was that there was no difference whatsoever in survival between all three of these groups. Whether you were in active monitoring, whether you were in radiotherapy, whether you received modern radiotherapy or you got surgery, there was no difference in survival.

But one of the things that should be noted is patients had a higher rate of developing metastases if they were in the active monitoring arm. One of the things to remember when it comes to active monitoring - it doesn't mean that you never get treatment. It means you are delaying and being monitored, and then when there are signs of your disease progressing, then you have to undergo treatment.

That's what you can see on the right here. Men who are in the active monitoring arm, if you look at that, the majority of those men during that life cycle of the trial ended up having to get some form of treatment. So active surveillance, for the most part, doesn't mean you get to avoid treatment altogether. It means you are deferring it, and you're deferring it until later.

It's not a stress-free deferral. You're deferring it often at the cost of getting a more advanced disease at some point. That's why the distant metastases rates were higher in that arm. And you are deferring it, then you have to get treated at a later stage, which may or may not be what you want to do. You may prefer to get treated when you're 65 rather than when you're 75. For some men maybe not, but good news is if you choose to go under active monitoring with a really good group - I always tell my patients who we put on active monitoring, it's a full contact sport. You have to come in every year, we have to be able to do rebiopsy. So it's not just okay, I'll see you.

If you enter into a robust active surveillance program, a well-tuned program, then you're not going to be compromising your survival. So that's good news. Also learned that if you do radiation or surgery, hey, your survival numbers are very similar. So we now had hard data from a randomized trial to show that.

This was the difference in the metastasis rate. You can see the dashed line, the patients who ended up having a recurrence and a recurrence in terms of spread outside of the prostate organ on the active surveillance group.

What else did we learn? Well, remember I told you that it's not just about curing the disease, right? It's about quality of life and how do patients live with this disease and what are the kind of side effects. So they did collect patient-reported outcomes, and when they collected patient-reported outcomes, they looked at urinary function. What they found was, not surprisingly, patients who undergo surgery had a higher rate of incontinence. Why? Because when you remove the prostate and you reconnect the urethra, sometimes that - you've removed an obstruction, one, but in that reconnection sometimes you leave a risk of leakage afterwards. So patients have to use pads, etc.

You can see - I know it's a little bit hard to see here, but that higher curve there is surgery, and that's the pad utilization rate. I think I heard in the audience somebody was talking a little bit about pads even before, so I know you're all familiar with some of this. But that shows you some of the difference.

So is that all bad? Potentially it's not all bad. Why? Because if I have a gentleman who has a large prostate and a lot of outflow obstruction issues, and they come to me for radiation, I oftentimes will counsel them - surgery, you get two benefits in one. You get the cure of the prostate cancer, but you also get the removal of that obstruction, right? And for some gentlemen, that's an added benefit when they have bad BPH or really bad outflow obstruction.

How about sexual function? This is something that for some reason is not as well reported into the community or as well aware, but this is really hard data. They looked at sexual function and erectile function in patients and men, and what they found was that the men who lost erectile function with surgery, it never really came back. Whereas the men initially who lost erectile function with radiation, there was recovery, and so much recovery that after two years, men who underwent radiation were identical essentially to the active monitoring group in terms of their sexual function.

So that's an important lifestyle consideration. If sexual function is important to you, then hey, with radiation there is this chance of recovery. Two years after treatment, initially most men do have a decline in their sexual function whether they have surgery or radiation, but with surgery, there's a greater degree of permanence to that than there is with radiation. That's important to bear in mind if that side effect is an important one to you.

And then finally, bowel function - pretty much good across the board, but there were some small differences. I said with radiation, because the rectum sits right behind the prostate, there were slightly higher rates of some bowel decline in terms of having some bleeding or some incontinence after radiotherapy. That's an important difference too, and I counsel patients on that. That is a difference between surgery and active monitoring.

So where do we go from here? I want to round out quickly to kind of bring this talk to a conclusion. So this is the difference that we see now between using modern x-rays versus protons. With modern x-rays, this is how we get to the dose that we need, and with protons, this is how we get to the dose that we need.

The difference that may be apparent to you is that the red is the same on both sides, but with protons, the volume of tissue that's exposed to any radiation at all is smaller. It's smaller by about 80 to 90% compared to x-rays.

So is that something that's a meaningful difference? Well, not for everyone, right? Because the timeline in which this level of radiation exposure actually has an impact on the healthy tissue can be 5-10 years. In fact, if you look at data from radiation exposure, often times it takes decades before we start seeing an uptick in second cancers, etc. from tissues that have been exposed to radiation. So you have to wait a long time.

What does that mean for me? With younger men, when I have younger men in their 40s and 50s who for whatever reason don't want to undergo surgery but they want to have radiation, I strongly favor protons for them. But if I'm treating a 75-year-old or an 80-year-old, I counsel them that protons are a reasonable option, however, x-rays are an absolutely equivalent option as well. The likelihood of that difference in radiation exposure between x-rays and protons may not be meaningful to them because it plays out over decades, and if you're 75 or 85, you may not reap that benefit in your lifetime.

So what have we seen at our proton center? Pretty steadily over the years, we have seen that the prostate cancer population has ranged between 20 to 40% of the total patient volume that we treat at the proton center. The reason the circles are getting bigger is more and more patients have been coming to us for proton therapy, which makes sense. Over time we've learned more and there are more appropriate uses for this technology, and our volumes have grown. But in general, there's a subset of men with prostate cancer, not everybody, for whom proton beam radiation makes sense.

Are we ever going to run another randomized trial right now with protons versus x-rays? I'm not quite sure we will. I don't need to go into some of the details of how challenging it can be to create a clinical trial, but there is a trial that's ongoing. That was the reason I had those slides there, but in the interest of time, I'm not going to go into the finer details. There is an ongoing trial that is comparing the most modern form of x-rays with protons, and it's just looking at quality of life.

I'm hoping in the next 5-10 years we'll start to get some data from that trial. But do I think we're going to launch another trial anytime in the near future? I think that trial will give us information just in terms of hey, what are the quality of life differences. My expectation is we're not going to see any differences in cure, but who knows - until we see the trial, we won't know. But we may see a difference in quality of life, and that will give you all more information to select a treatment that's right for you.

I want to say a few words about Flash. So what is Flash radiation? One of the things I wanted to bring up is to provide some context. The world of prostate cancer is changing, and this trial kind of speaks to this. It is a trial known as the Stampede trial, and it looked at patients with metastatic prostate cancer. So these are not patients with localized prostate cancer, these are men with metastatic prostate cancer.

It asked the question: is there any value of adding radiation to the prostate in men in whom the disease is already spread? Why is this? Well, the logic is the largest concentration of cancer cells in that man's body is in the prostate organ. So maybe if we can reduce that burden of disease, that can translate into a benefit to the patient even though we're not getting all of it. If we just reduce the largest sanctuary of cancer cells in the body of a patient, is that going to be a benefit?

Lo and behold, it was. We didn't see a difference across everybody in overall survival, but we did see a difference in control. What did that mean? Why is that important? Well, men know that hormone treatment, as side effects go, it's hard. It's not easy when we put patients on hormones. But the alternative is standard chemotherapy when hormones no longer work. So the longer a man can stay on the hormone treatment, the better it is for them.

With this radiation, they were able to stay on hormone treatment for a much longer period of time, which meant they didn't have to get the other second-line treatments that we start to move to after hormone treatments, which have a greater impact on their quality of life, like Taxol and other things.

Moreover, when we looked at men with a low burden of metastatic disease - in other words, where we really believe the majority of the cancer cells are sitting within that prostate organ - they did have a benefit in terms of survival. So the disease remained controlled longer and they had a benefit of survival.

The reason I present this data is this is a situation where we know that we're not getting all of the disease underneath the beam. So we need to do it as safely and as side effect-free as possible. This is where I think the idea of Flash may make sense for men with prostate cancer.

Why Flash? Just for everybody's shared awareness, Flash is a way to deliver the dose of radiation that we usually deliver in modern clinics today over a period of 10-15 minutes in milliseconds. This is the dose rate - the rate at which we deliver 2,400 centiGray in a minute. That is a dose that - that's just units - 2,400 units in a minute with modern x-rays is what we are able to deliver today. With Flash, we're talking about 720,000 units in a minute. So it's several orders of magnitude higher.

Why is that important? It turns out if we deliver the radiation in an instant like that, for some reason it's invisible to our normal tissues. Moreover, right now we can only do this with protons because the generation of x-rays is very inefficient. So we can't get to this kind of dose rate with x-rays right now. Eventually, we may - an engineer may come up with a solution for it, but right now we can't. But with protons, our generation of proton beams is very efficient, so we can achieve these kind of dose rates with protons and deliver that treatment in a Flash.

At UW, we're very fortunate. We have not only an adult proton facility where we can use Flash, we also have a separate cyclotron facility where we can use Flash and create a Flash beam for use in animals, in small animals. Because you need to do very careful pre-clinical work before you ever take this to adults, to take this to humans, right? Often times the challenge is our proton facility needs to be used for patients first, and so we don't get a lot of time to do animal work on it. But we have a separate facility where we can do that.

I just want to show that this is what we saw when we started to treat the pelvis in mice with Flash at our facility. We delivered a dose, a fairly high dose of radiation, and what we found was that if you deliver no dose, the mice survive. That's fine. But if you deliver that same dose with Flash, not all the mice survive, but more of them survive than if you use the standard dose rates we use in the clinic. So it seems to be safer.

Is it as effective at controlling the tumor? It seems to be. These are just data that shows that when we use lung cancer models and other models, it's just as effective controlling the tumor, but for whatever reason, the normal tissue doesn't seem to feel the impact of the beam. So this is very exciting to us.

In conclusion, I think we're in a pretty exciting era when it comes to radiation for the treatment of prostate cancer. I think we have modernized what we are able to do to really provide a very good additional option for men with prostate cancer beyond surgery. That's great because surgery is a great option, but we also have other options because for some men, they need to have options in medical care, and this is another option - not just protons, but x-rays as well.

I think the future is very bright as we start to investigate technologies such as Flash, etc. We have a number of trials, like I said, that we're going to start to learn from in the coming years, but we're not quite there yet. We'll learn over the next few years, and I hope I've earned the right to come back to talk to you and update you as that data starts to emerge.

Closing

Aaron: All right, can I get a round of applause for the presenter today? Thank you very much, Professor.

Dr. Rengan: Thank you all. I appreciate the privilege of coming and speaking with you all today. Hopefully in the future, I get to come down to San Diego to meet you all. Aaron and Bill should have my contact information if there are any questions or anything else. I'd be happy to answer them. The one other disclosure I forgot to mention, I just wanted to be transparent: I have not been compensated in any way for this talk, which is exactly the way I wanted it to be. I wanted to just present because I think it's an important vehicle to be able to speak to all of you, but I also wanted to just clarify that so that people are aware.

Aaron: Thank you for that clarification. All right, thanks again for your time, Professor. Talk to you again in the future.

Dr. Rengan: Be well. Thanks, you all have a wonderful day.

Aaron: You too. Bye-bye. All right, thanks a lot everyone for attending. I would like to take a question in just a second. Please do join us for a light lunch after the meeting here, and of course, please do remember absolutely no food or drink brought back into the auditorium.

[Aaron addresses a few more questions and makes some announcements.]

Aaron: Dr. McKay is not to be missed.

[Final comments and wrap-up]

Aaron: For the newcomers, please return your cover sheet to me or to Bill before you leave. And please, newcomers, chat with people. The benefit of especially having the lunch and the time after the meeting is to share questions that you might have and share our experiences. So ask away. All right? Okay, thanks everyone.