What if one of the most powerful tools to improve survival after a colon cancer diagnosis wasn't a new drug, but actually was exercise? Sounds too good to be true? Today, we're talking all about a new article that was just published looking at that exact question. Let's dive in. And welcome back, team, to the Building Lifel Ath podcast. Thanks so much for stopping by, really appreciate it. We haven't had the to meet yet. My is Jordan Rennke I a dual-board certified physician in family and sports medicine. And the goal of this podcast is to help keep you active and healthy for life through actionable evidence form education. And today we're diving deep into the landmark study called the Challenge Trial. Which is poised to change how we think about exercising cancer potentially. So let's dive in. So, for a long time, the oncology world has been sitting on a bunch of observational studies, and the data is all kind of pointing in the same direction. We've had meta-analyses that have looked at it and they've said, hey, typically on average, those who are more physically active, those people who had cancer who were survivors, if they were more physically active, they had a 30 to 40 percent lower risk of dying. You know, that's generally what they've seen. But here's the problem with this kind of evidence: it's not definitive proof, right? You can say for sure that exercise caused these better outcomes. There's two big confounders. The first is, you know, kind healthy user bias, meaning People who exercise more just tend to be healthier in other ways as well. And so, is it actually exercise that does it or is something else going on? And second is reverse causality, where patients with undiagnosed recurring cancer feel too sick to exercise, right? So, they can't exercise. Making it look like the inactivity caused this recurrence when in reality, it's kind of just a consequence of it. And so, because of these limitations, expert panels like the Global Cancer Update Program had Kind labeled the evidence so far as limited and sub. So, meaning, hey, yeah, we not quite sure. And so, everyone knew that there's a potential trend, but we couldn't say definitively. And so, they said we need to get more randomized controlled trials. And that's kind of where we take off here. And this is where the challenge trial comes in. So, its full name is the Colon Health and Lifelong Exercise Change Trial. So, that's awesome. Great job. Naming trials, it's always so fun to see the names of trials. I love it. So, and this was specifically designed to kind of fill this evidence gap, right? So, This was the first ever multi-center phase three randomized control trial to look at a structured exercise program and its effects on hard clinical endpoints, right? So, disease-free survival or DFS, that we're kind of looking at: hey. Do you live longer? Does cancer come back? Stuff like that. The study enrolled patients with high-risk stage two or three colon cancer after they had already finished their adjunt. So typically, You get the diagnosis, you either get some sort of resection typically for colon cancer, and then you have chemotherapy after that. And then, here is we're getting these patients after they've had that chemotherapy. And it's a randomized design. And that's really key, right? So, by randomly assigning patients to either the exercise group or the control group, we are hopefully washing out those confounding factors we've talked about previously. And this trial kind of moves the conversation from exercise is associated with better outcomes to does a structured exercise program actually cause better outcomes? That's the whole idea behind this RCT. And it elevates it from a simple wellness tip to providing potential evidence-based Practice and evidence-informed education about cancer therapy, which is really cool. And let's now get into the kind of nitty-gritty of the study design. So, specifically, a PIC framework. So, if you are familiar with Looking at papers from a medical perspective, a lot of times we have a PICO, right? So that's the population intervention comparator and outcome. That's how we analyze papers a lot of times. And so we're going go through that framework here. The population included 889 patients after they had the resection of their high-risk stage 2 or stage 3 colon cancer. And they were enrolled two to six months after finishing chemo, and they had a good performance status, meaning they were mostly active and could do the minimum exercise. So it not like these people. Are robust, we talk about it in a second, but they could actually do exercise. So it did limit out some people. We'll talk more about that. But they were exercising less than 150 minutes per week to start. So not. Very physically active, but could be active potentially. The inter was a three-year structured exercise program guided by physical activity consultants. So essentially, they said that physical activity consultants. So, like, okay, a trainer, like, that what it is. But over this three years, and the goal was to hit at least 10 Met hours of activity per week. We've talked ad nauseum about Met met equivalents. One met is just existing in life, and then you get certain mets for doing certain activities. You know, if you're brisk walking, it's this many met versus this many mets, and you're like four or five versus you know, 10 met is like running hard. And so, they're saying 10 met hours per week is what they're looking for. And the comparator group or the control group wasn't inactive, though, right? So it wasn like they did nothing. They received health education materials, and they also were encouraged to have physical activity and eat a health-promoting diet. And the primary outcomes that they measured were disease-free survival or DFS with overall survival or OS, you might see here as well as the key secondary import. So, once again, disease-free survival and overall survival. And moving on here, we know that no study is perfect, right? So there definitely are some things we have to consider here. It's important to look at limitations. The first one we see right away is who they studied. As I mentioned before, by design, the trial enrolled a healthier survivor. So, this cohort, these are patients, they had to be functionally well, able to do a treadmill test. And who's enrolled, who are a couple months after chemo, which screens out those who had very early recurrence or like weren't well enough to do any physical activity, right? So it's a relatively healthy group. And the authors were upfront about this, they said that, but it does create a potential selection bias, just to mention there. But the big implication here is that the results might not be fully generalizable to all stage two and three colon cancer survivors. Especially those who are older, frailer, or just less motivated or can't go out. So it's possible that the effect we see in this paper is an overestimation of what would actually happen in a broader real-world population. You just have to think about that right away. And another interesting nuance is the control group, right? They didn't just get quote usual care. They received health education materials that actively encouraged them to be more active. It's kind of interesting. They weren just saying, like, okay, just live your life, which I appreciate. I think it would be hard to have academic integrity to tell patients, like, hey, just don't do anything when you know, like, hey, exercise is probably good. For you, just for so many other reasons, whether it's the cancer or whatnot. But so I do respect that. But it was interesting there. It definitely creates some nuance. And the data showed, though, that it did work. The control group actually improved their fitness as well. And their activity levels from bas, just not quite as much as the inter group. But it does mean that it wasn't comparing exercise to being sedentary. It was comparing a High, you know, higher exercise group to a smaller exercise group. That's kind of what it is. And I think it's really important, right? So there, we talk, we'll talk in the future about hazard ratios. But it could be true that that underestimates the true benefit of this exercise program compared to a truly inactive lifestyle, right? So we comparing one group to another. So one group did this much exercise, and another one just a little bit less. So the change between an actual sedentary person and what we saw in the study might be even greater. So that's kind of something we talked about. And then also, the intervention wasn't just exercise, though. I do want to mention that. It was supported and structured exercise. So the exercise group had a regular long-term contact with a physical activity consultant. Which is a form of social support the control group didn't necessarily get. And so, while the authors argue this is unlikely to explain the survival benefit, it's plausible and it's an unmeasured con. So,'s just something I have to mention that. Hey, if you are consistently seeing people for three years, either virtually or having someone have accountability there, that's definitely something you can't control for. And let's get into the headline results, though, because they're really kind of the buzz why everyone's talking about these on social media. The trial successfully met its primary end point. And they found a 28% relative reduction in the risk of disease-free survival events. That means recurrence or death is kind of what they're talking about there. And the hazard ratio is 0. In absolute terms, that's a 6.4%. Improvement in five-year disease-free survival. And that's absolutely clinically meaningful, right? So the over re for survival were also kind of striking. So we did disease -free, and then overall survival, we saw a 37% relative reduction in the risk of death. With an eight-year absolute survival benefit of 7. 1%. And this is kind of on par with different therapies as well in terms of many standard drug therapies. This is why it got a lot of attention. They're saying, hey, You're having a 28% reduction in disease-free survival. You have a 37% decrease in relative reduction in all causes of death. Like, that's pretty big news. And they say that's similar to a medication, like the standard drug therapies, and this could be a paradigm-changing thing. That's why a lot of people had a really, really big made a big fuss about this on social media because these were enormous results. And anytime you get enormous results, you have to wonder, like. Okay, is this true? Like, what's going on? But that's what they showed him, which is kind of interesting. And now, here's one of the most fascinating things and details about this study: when you look at the objective. Fitness improvements between the groups, the numbers aren't actually that much different. So they're quite modest. So the between group improvements in predicted VO2 max. So what We saw, and VO2 max is kind of an indicator of your cardiovascular fitness. We saw an increase that ranged anywhere from 1. 3 to 2. 7 milliliters per kilogram per minute, which is how they measure that over the course of the study. I mean, to me, when we start getting like a 1. 3, like, do I know if that's statistically important or meaningful, or is that just, you know, variation of the material? I don know. It's not robust, that's for sure. I, it not a huge, huge difference in V max. So that 's one thing. And then, similarly, looking at the difference between the groups in the six-minute walk test, it was just about 13 to 30 meters for the exercise group. So they're saying, Hey, the exercise we did, and I think it's kind of where a lot of people were not super happy with this. They said, Hey. Look, these people got more fit on this program, and because they're more fit, they're striving. It's like, okay, they walked 13 more meters, like 13 more meters. Really think that is a significant improvement? That could just be you doing the test for a second time, right? You think about specificity when you test something. Let's say you've never squatted in your life, right? They get you and they say, Hey, we're going do a barbell squat, and you squat down, you can only do 45 pounds. Oh gosh, that was it. And then you like go exercise for three years and come back into a squat, and then you're probably going to be able to do a lot more. Or let's just say you don't even exercise at all. You do a squat test and then come back later, you did it once before, you'll probably be able to do more. Maybe put fives on the side, and is that better? Did you get more fit? I don't know that, and so I just want to be put a caution out there: like, I'm not sure how much more fit these people got. Regardless, it doesn't necessarily take away the findings, and we'll talk more about that. But I think that we have to be careful of like, hey, were these actually clinically meaningful? And so they're not massive, earth-shatter changes in ro fitness. We did see some improvements, and then we saw these other things. And so, the question for that is: okay, was it actually causing that? And what is the mechanism behind it if it wasn't necessarily getting more fit? And we'll talk more about that. And of course, when we prescribe any intervention, we have to talk about safety, right? So it's not surprising that the exercise group had more side effects. Effects, right? Musculoskeletal injuries were more common in the exercise group at 18. 5% compared to 11. 5% in the control group, but not a whole lot more, right? 7% more. Similarly, though, more serious grade three or higher adverse events were also higher in the exercise arm at 15. 5 versus 9. 1. However, the authors note that most of these events were manageable, right? Nothing was really big. What this really tells us is that you can't just tell a cancer survivor to go hit the gym hard with no supervision or a plan at all, and you can have injuries. But if you look like the general population, you'll also get injuries as well. So the Control group was, you know, an 11, the other one was 18. And so when you exercise, you're going to have aches and pains. And most of these things were very minor. Right. And so. Not big things that set anyone back for a long time or massive injuries. And so I read this more as: hey, exercise is safe, and it's also safe for people who had. Cancer and chemo. So that's a very, very wonderful thing. But yeah, just another encouragement that hey, exercise is safe, it's good, but we should probably have a plan going into it. That's kind of my idea. And so now we want to dive a little bit deeper here onto the mechanisms for why this might be happening, right? So when we dig into the event breakdown, we find a crucial clue. About how this program might have been working. So it might have, we don't necessarily know. The survival benefit wasn't driven by things like preventing heart attacks, right? It seemed like the number of non-cancer deaths was very low and almost identical between groups. That means they weren't necessarily dying from things other than cancer. Instead, it seemed like the benefit came from a reduction in cancer rec and incredibly nearly a 50% reduction in new primary cancers in the exercise group. And so this pattern does suggest that the exercise intervention had a direct Biologic impact on cancer, almost an anti-cancer effect. It seemed to be going and doing more than just improving general health. It may be actively. I know whether it's suppressing cancer or boosting the immune system or decreased inflammation, we're not entirely sure. But it seems like exercise may be doing something more. Even if it's not producing enormous fitness improvements, it might be doing something else that's very beneficial. And what also makes these findings so potentially powerful is how well they line up with previous observational data, right? So we saw these results of 28, 30%, and that's enormous. That's huge. When you look back, that's kind of consistent with what we saw previously. And as we mentioned, we couldn't tease out: is it exercise versus other healthy lifestyle factors? And that's kind of why they did this study. And previous meta-analyses reported overall survival hazard ratios of 0. 64 and 0. 67, which is remarkably close to the 0. 63 found in this challenge trial. So the strong consistency here just makes it More likely that the result isn't just a fluke. Obviously, it's just one study, and one study is never perfect, but it's cool when we see things starting to line up there. Interestingly, while observational studies were mixed on whether activity prevented recurrence, this trial found a clear benefit. And so that's kind of where we did have some discordance here. This trial, they suggest that while general activity is good, a structured specific exercise prescription might be actually needed to improve recurrence risk. That's a big leap to take. I'm not willing to say that by any means, but that's a potential way you could read into it. But the bottom line of the trial is that it provides level one evidence, which is a randomiz controlled trial, which is desperately needed, right? I think it's wonderful to do that. And it definitely gives a potential to have stronger clinical recommendations for exercise with patients who have colorectal cancer in that specific, you, grade two and three. And so we have to always remember that we're kind of targeting them there. With this level of evidence, though, now here's the question, right? And people are going to talk about it all the time: does the conversation need to shift, right? Should we now be talking about integrating structured exercise as a component of a standard adjuvant care for these patients? And the cool thing is, this, we have now data. You can, hey, it's no longer an alternative therapy to prescribe exercise. It can be an evidence-based treatment. Will, am I willing to say, hey, this is like definitely definitively there? It's though, but back in the day, I step back, right? When I talk about suggesting an intervention. What am I going to suggest? Like, I will suggest exercise to pretty much everybody for any condition because it's so good for so many things. And so, before I would say, hey, like. You should be exercising. And so this doesn't change that for me. But, but in America here, the big thing is that if we have a trial showing that this works and it's beneficial, now potentially could we get insurance to cover it. And that's a really, really big thing that I'm excited about and why I'm so So, appreciative of this study because they're cool. If we have exercise showing that may be beneficial for these people and it can get covered then by insurance as a treatment plan, then that'd be wonderful. I would love that. And so. Yeah, the biggest barrier for them is usually if insurance is going to cover a night. So, yeah, it we're scheduled right now, we're set up to deliver drugs, procedures, whatnot, and not Interventional things. And if we could do that, that'd be amazing. And I think typically most on aren't formally prescribing exercise. I'm not saying that's their role, that they need to, but. Can we incorporate a multid team to do that? That would be wonderful, right? And get it reimbursed. And so, simply publishing these results is really important because it could potentially lead to new opportunities and new treatments for people that they couldn't previously have before. Because we definitely didn't have the data, and so I think that's really cool. That's why I'm really, really excited to see this and talk about it. I do want to talk about different unanswered questions, though, right? So, the success of the challenge trial opens the door to a whole new wave of important research questions, right? So What about timing? The trial started after chemo. Would it be even better if we started before having a surgery at all or during chemo or something like that? Um, who knows? We're not necessarily sure. You know, what is the dose response? Is it always a more better thing, or is there one size fit all? Could we obviously never, nothing's ever one size fits all? Like, that's just an obvious answer. Would more be better, or is there a certain kind of sweet spot there? Also, about the different mod and generalizability. Would you know, high-intensity interval training work better, or resistance-only training? And this is pretty much just aerobic training, is all they did. And so. Would that work better? Who knows? And yeah, would we see the same amazing results doing other things? And the real, real question we have is implementation, right? So How do we implement this? This is intense. Three years of like people were following them like every week for touch points and follow-ups. And that's a huge thing that. Honestly, nobody really gets. And so that's the big thing. How do we implement this? And, you know, everyone says we need more research on implementation, but we just need more resources, really it comes down to. Can things like telehealth, group-based programs deliver similar benefits? That's going to be a big, big one. And so. My takeaway from this, I'm excited to see it. A couple concerns I also had: their recruitment period lasted like a decade. It was like super long. I forgot the actual one off the top of my head, but it was like a very, very long time. I'm like, Colon cancer is not that rare. Why did it take that long? For me, that's almost like: did they wait for like the absolute perfect person who had this 2-3 and was Bit, but I don know. It was that wasn interesting enough for me to think about. And these numbers are really big, and there's no real mechanistic explanation, right? So we talk about: hey. Maybe exercise decreases inflammation. Maybe it has anti-cancer properties. Maybe it does whatever exercise says it does. We still have no real clue as to why it is because I don't think it was the fitness changes. Yeah, we had some mild fitness changes, but not a huge thing. And so that's just a question mark there. Once again, do I need to know every mechanism? No, we use like met all the time or the medication. We're kind of like, oh, we think it works like this. So we do things all the time, medicine, without a complete understanding. It's just always helpful and nice to have that. But regardless, Does this drastically change everything for me? Like, no, exercise I've done previously before, exercise and cancer, right? It's very helpful for almost all medical conditions, and I'd expect it to be here. What's kind of shocking is the number. I don't know what to make about how big that was. If that's true, that's awesome. I love that and I'm all for it. But usually when I see numbers that big, I kind of. Temper my expectations a little bit and figure out in future studies, we'll probably see a smaller increase. But an increase is good, right? We're talking about the disease recurrence, we're talking about life and death. And so that's wonderful in any direction. If we're heading in a positive direction, Pretty much, it's always even worth it for me, right? So, if you're 2% reduced, I still think it's worth it because exercise does so many other things in terms of quality of life and many, many other things. And so Overall, it was a cool, cool study. I think I learned a lot here reading it. Hopefully, you did as well. But that's going to be it for today. Thanks so much for stopping by. If you did enjoy this podcast, though, it would mean the world to me if you either share this with a friend. Left a five-star rating on your podcast platform of choice or subscribed on YouTube. But now, get off your phone, get outside, have a great rest of your day, and we'll see you next time. Disclaimer, this podcast is for entertainment, education, and informational purposes only. The topics discussed should not solely be used to diagnose, treat, or prevent any condition. The information presented here was created with an evidence-based approach, but please keep in mind that science is always changing and at the time of listening to this, there may be some new data that makes this information incomplete or inaccurate. Always seek the advice of your personal physician or qualified healthcare provider for questions regarding any medical condition.
