El ejercicio como tratamiento del cáncer

Welcome to The Breastcancer.org Podcast, the podcast that brings you the latest information on breast cancer research, treatments, side effects, and survivorship issues through expert interviews, as well as personal stories from people affected by breast cancer. Here's your host, Breastcancer.org Senior Editor, Jamie DePolo

Jamie DePolo: Hello. As always, thanks for listening. The CHALLENGE trial found that a three-year, structured exercise program after chemotherapy for stage III colon cancer reduced the risk of the cancer coming back and also led to people living longer overall. This was the first trial on exercise and cancer to show these results, and it made quite a splash at the ASCO Annual Meeting this past June. I’m joined by the lead researcher, Dr. Kerry Courneya, professor of kinesiology, sport, and recreation at the University of Alberta, where he also serves as director of the Exercise Oncology Research Laboratory.

Although this study only included people who had been treated for colon cancer, Dr. Courneya thinks the results may have wider application, including for people with breast cancer. So, I’m very excited to talk to him about the research. Dr. Courneya, welcome to the podcast.

Dr. Kerry Courneya: Thank you for having me.

Jamie DePolo: So, I want to start by asking, why did you decide to include only people with stage III colon cancer in your study?

Dr. Kerry Courneya: So, we wanted to look at a cancer that we thought might be sensitive to exercise. And so, we’ve done a bunch of...as a field, a bunch of observational studies looking at exercise and cancer outcomes and some pre-clinical work, as well, in different animal models and in vitro models. And colon cancer cells seem to be particularly sensitive, and the observational studies were quite compelling, as well. So, colon cancer patients who reported higher levels of exercise had a lower risk of the cancer coming back, lower risk of dying.

So, colon cancer looked like a promising cancer. In terms of stage III, you know, we wanted to look at patients who had a reasonable risk of the cancer coming back. We know, just like breast cancer, colon cancer stage I lives forever. You know, it’s highly curable, and patients do quite well. Stage III colon cancer, I mean, kind of similar to the breast cancer. You know, that’s where you’ve got a concerning risk of the cancer coming back. So, in colon cancer, it’s about a 30% chance that the cancer may come back and spread. So we felt like it was a really good group to target from an exercise perspective.

Jamie DePolo: Okay, and they had already received chemotherapy. They completed that treatment, and were any of the folks, like, still...I apologize, I don't know that much about colon cancer treatment, but would they be taking anything long term, like a hormonal therapy or anything like that, or were they just done?

Dr. Kerry Courneya: Yeah, very different from breast cancer. So, the standard treatment for that stage III and high-risk stage II colon cancer is complete removal of the tumor by surgery and then three to six months of chemotherapy, and then that is it. There’s no further treatments offered at that time. So, they did this exercise program after they had completed their adjuvant therapy.

Jamie DePolo: Okay, and it was interesting to me, too, your study used a three-year exercise program, and a lot of the other studies I’ve read about or heard presented, it’s usually six to 12 weeks. It’s, like, very short, couple months, two to three months, and you’re done. So, I’m curious, why did you pick that time length, and was it hard to get people to stick to a three-year program?

Dr. Kerry Courneya: Yeah. So, we picked the timeline because, in this study, this was the first study to focus on survival as the primary endpoint. So, we’re trying to alter the course of a disease. A lot of those studies that are six weeks and 12 weeks, you’re right, we do a lot of those in the exercise science field. You know, we’re looking at changes in fitness, changes in muscular strength for symptoms and even quality of life, and we can get changes in fitness and quality of life in short times, four to six weeks, and certainly 12 weeks.

But we’re thinking now we’re trying to alter the course of a disease and keep this cancer from coming back, so we felt like we needed a much longer exercise intervention. The other reason we chose three years, in this case, is we know, at least in colon cancer, three-year disease-free survival is a very good predictor of overall survival, so living for a much longer time. So, we felt like, if we could keep these patients disease free for three years, they had a really good chance of being cured from the cancer.

Jamie DePolo: Okay. Now, the equipment you need for a lot of exercise, I mean, shoes can be kind of expensive. Gym membership, definitely expensive. I think...it’s just my opinion. I want to make that very clear. That if there was a new drug that showed the results in a study that you saw in your study about exercise, insurance would probably cover it. But it seems like it’s still really difficult to get insurance companies to help people pay for exercise. Is your study moving that needle at all?

Dr. Kerry Courneya: We’re very hopeful that this study will actually make the difference, because this is the first study to show that exercise is a treatment for cancer. This reduced the risk of recurrence, and it reduced the risk of dying as good as or better than many of the other drugs that’ve been approved to treat these patients. I think insurance companies have been reluctant in the past to fund exercise, because the benefits we show are things like improvements in fitness, improvements in strength. Helps with some of the side effects and so on.

So, these are viewed as kind of nice benefits, and you know, if you can do the exercise, that’s great, but they’re not viewed as an essential component of cancer care. I think this trial changes that, and I think the insurance companies, if they’re going to be honest and say we’re going to approve treatments that treat the cancer, this study met that bar. We ran this study just like you would run a study for a new drug, a new immunotherapy, and we showed very important clinical benefits to survival. So, this I think changes the ballgame, and it’s the first study to definitively show that exercise is a treatment, in this case, for stage III, high-risk stage II colon cancer. So, that’s why we think it’s the game-changer.

Jamie DePolo: I certainly hope it is, because, in my mind, if you think about the cost of an immunotherapy medicine versus the cost of a gym membership, it’s not even comparable.

Dr. Kerry Courneya: No, these new drugs that are being approved in various cancer patient groups, including breast cancer, as you say, are tens of thousands of dollars, sometimes exceeding $100,000 dollars, and sometimes for a small survival benefit, measured in terms of a few months or so on, and so, you compare that to exercise and the cost...we estimate that...we’re currently working on the cost effectiveness and the health economics from the CHALLENGE trial.

But we estimate that our intervention costs no more than about $3,000, and some of the oncologists joke that’s rounding error for what we spend on the drugs, right? So, $3,000 is a small amount for a very meaningful survival benefit. We had a 7% absolute difference in overall survival at eight years follow-up, and like I say, that compares to many of the chemotherapies, even many of the immunotherapies in terms of the actual benefit on survival. So, it’s going to be a very cost-effective intervention that’s, I think, going to be attractive to the health insurance companies.

Jamie DePolo: I certainly hope so. Now, when we spoke at ASCO, you mentioned that you thought the results could have implications for other types of cancer, including breast cancer. So, how do you see those results applying specifically to breast cancer?

Dr. Kerry Courneya: Yeah, that’s always the tricky question, because, of course, in the drug realm, they would not generalize across different patient groups. You know, if they showed something in colon cancer, nobody would say let’s roll it out in breast cancer without a clinical trial in breast cancer. So, I think there are some that are pushing that we...you know, hopefully, CHALLENGE will result in the launching of more of these clinical trials that are able to demonstrate that benefit, and there are a few ongoing right now. But in the absence of those trials right now, I think there’s a few reasons to believe that it may apply to breast cancer patients.

So, we look at the breast cancer data, and breast cancer is viewed very much like colon cancer, in that it’s one that’s sensitive to exercise. The observational studies show the same thing we see in colon cancer. You know, those breast cancer patients who report higher levels of exercise after their diagnosis have a lower risk of recurrence. So, it’s very similar data, and we have a lot of the pre-clinical data, as well, showing these breast cancer cell lines are very sensitive to exercise interventions. So, the data in breast cancer are just as promising as they were in colon cancer.

The other reason is many of the mechanisms that we propose for colon cancer likely apply to breast cancer, as well. So, you know, when we think about, well, how did exercise keep the colon cancer from coming back? Well, we think it’s improvements in immune system surveillance, things like natural killer cells, cytotoxic activity, cytotoxic T cells, macrophages, reductions in inflammation, things like C-reactive protein, interleukin 6, tumor necrosis factor-alpha, improvements in insulin, IGF, all these mechanisms, and we know these mechanisms work in breast cancer, as well.

And the final reason we think it might apply, you think about the clinical situation that we tested, right? So, these were patients who had the tumor completely removed surgically, so there’s no primary tumor left. They were treated with chemotherapy for three to six months, and so, what we showed is that exercise was able to treat those cancer cells that the chemotherapy left behind. So, for some of these patients, the chemotherapy didn't get rid of all those small numbers of cancer cells that might have left the primary tumor before the surgery.

Well, breast cancer has a very similar situation. Many patients have the tumor completely surgically removed, and then they go on to get some chemotherapy and radiation therapy, and so, any of those cancer cells that are left behind after the chemotherapy we think would also be sensitive to the exercise intervention. So, I think many people would say, you know, if there was one patient group we could generalize these findings to, they would all pick breast cancer.

Jamie DePolo: Oh, interesting. Okay.

Dr. Kerry Courneya: I have one more important point, Jamie. So, we followed these patients up for recurrence of their colon cancer, but also second cancers, so another new cancer being diagnosed. One of the interesting signals we saw is, the group that got the intervention had a much lower rate of a breast cancer happening. So, we showed, in the health education group, 12 of the women got breast cancer during follow-up. In our intervention group, only two of the women got breast cancer. So, one of the second cancers that we were preventing in this trial was breast cancer. So, again, more indication that breast cancer might’ve been sensitive to this exercise intervention.

Jamie DePolo: Oh, that’s really, really interesting. I was kind of thinking about your study, and we know that hormone receptor-positive breast cancer has a much longer window of recurrence than hormone receptor-negative breast cancer or triple-negative breast cancer. Those negative cancers tend to recur within three to five years, as opposed to hormone receptor-positive, which can take up to, I think, like, 10 to 20 years. It’s still a possibility. And I’m just wondering, would anybody ever do a study, say, in triple-negative or hormone receptor-negative breast cancer, a similar study to yours, because I guess the follow-up to see recurrence wouldn't have to be as long.

Dr. Kerry Courneya: You’re right. That’s one of the important issues. You know, how long can we keep these patients exercising for, to show that benefit? So, we do want patients, as I mentioned before, that had a reasonable likelihood of the cancer coming back, because that means you have room to actually make a difference and have a benefit, and so, we’d be looking for those patients that have a little bit higher risk of recurrence after their cancer. The downside of that is we’ve actually seen that hormone receptor-positive cancers are more sensitive to exercise. So, exercise also reduces estrogen levels in these patients.

So, a lot of the studies show that exercise lowers the risk of ER-positive breast cancer, compared to the ER-negative, and even in the post-diagnosis setting, when we look at those studies showing links to improved survival, we see a bit stronger associations in those patients who are ER-positive, because we know exercise has effects on the sex hormones and can lower the risk for the ER-positive cancers. Based on that kind of thinking, you know, there’s a big weight loss trial going on in breast cancer patients right now, and that trial is targeting the ER-positive breast cancers, but those were stage II and stage III, so a little bit higher risk, but I agree with you. The hormone-negative breast cancers would also be interesting to look at.

Jamie DePolo: Okay, that’s all very interesting, too.

You talked about this a little bit, about what is it about exercise? What’s going, actually, on in the body that makes it so beneficial for people who have been treated for cancer? There was a study that came out recently from Edith Cowan University that found that just one workout, just one, makes your muscles release a protein called myokines and that they have anti-cancer properties, and the hypothesis is that these myokines could slow cancer growth by about 20% to 30%, and I’m just wondering if you saw that study? What are your thoughts about it? Is that part of the whole mechanism that’s going on in the body, do you think?

Dr. Kerry Courneya: Yeah. The reason that study’s important is it’s helping us think through the question about how exercise might improve cancer outcomes, and oftentimes, we think that it’s the chronic effects of exercise. So, you do this exercise training, and then your body has a better immune system, or it has lower inflammation, kind of on a day-to-day basis. But what this study shows is another possibility, and that is the effects of exercise on these cancer outcomes are more these short bursts of acute effects.

So, once you go for an exercise session, a brisk walk, or a jog, all these changes happen in the system, these anti-inflammatory effects. The improved immune system gets distributed throughout the body, and so, maybe it’s these short-term, acute effects that are what are driving the reductions in cancer, rather than any sort of chronic or permanent changes to the system. If that turns out to be the case, then the recommendation becomes for more daily exercise for shorter bouts, because it’s really the stimulation.

So, you go for an exercise session, and then, for the next couple hours, your body has this wonderful biological response that’s fighting the cancer, and so, you go and do it the next day and the next day after that, as opposed to a training effect, where we say, okay, now that you’ve trained for 12 weeks, you know, these are sort of permanent biological changes. And so, we think the effects of exercise are probably a combination of the two. These short-term effects that were shown in that study, where exercise really stimulates the body with these anti-inflammatory and immune system responses, and then some more permanent, ongoing changes that happen over time.

Jamie DePolo: What was so fascinating to me about that study, and I realize it wasn’t your study, but it kind of opens the door for people who say I just don’t have time to work out for 45 minutes a day. Like, this kind of showed that 10 minutes, 15 minutes can really give your body some benefits.

Dr. Kerry Courneya: And it really gets you thinking about exercise like a drug, because we can think about the half-life. You know, when you go in and get your chemotherapy, it kills cancer cells for a couple of days. It doesn't kill them for three weeks or a month. The drugs work, and then the body sort of metabolizes and excretes them, and this is what that study suggested. You do this exercise session, and then there's a half-life of this effect, where everything’s stimulated, it’s killing the cancer cells, and it’s very effective, and then the exercise effect kind of dissipates from the body, and so, we want to keep doing it on a regular basis. And it suggests that, yeah, every single bout might be having these anti-cancer effects, and even these shorter durations of 15 minutes or 20 minutes can stimulate these biological effects and potentially, improve these cancer outcomes.

Jamie DePolo: Now, I know you’re head of the lab there at your university, and so, you must hear this, when people say they don’t know how to start exercising. They’re too tired from treatment. They’ve got fatigue. They don't have time to work out. Do you have any tips on how people can keep themselves motivated or how to motivate people to exercise?

Dr. Kerry Courneya: Yeah. So, we’re hoping our study will provide a big source of motivation. You know, it’s one thing thinking that exercise might help, thinking it might improve survival, and we know, at least in this context now, it does. So, patients can be as motivated to exercise now as they are to get their chemotherapy or to get the immunotherapy, with this survival benefit.

But I think the other thing we try and do for all patients, talking about the benefits and what it can do for them, but also letting them know, you know, starting out slow and progressing slowly is important. You don’t need to go out and run a marathon to get these benefits. Short bouts of walking for 5 or 10 minutes can be a great way to start. Small amounts of exercise that you accumulate during the day, and then slowly building up over time and being able to do, you know, 30 minutes of a walk three or four times per week. And incorporating it into our day and making it part of the day and part of the regular routine.

So, you know, our study didn't test an incredible amount of exercise. You know, it was a couple hours of walking a week that we showed had this profound benefit on recurrence and survival. So, we think this is feasible for many patients, and you do have to work around your symptoms and side effects, you know, what challenges you’re having, whether it’s fatigue, whether it’s peripheral neuropathy, and work around those side effects, but we think it’s realistic, for most patients, to do this amount of exercise.

Jamie DePolo: This is just so exciting to me, because it’s something that I feel like anybody can do.

Dr. Kerry Courneya: The other exciting thing about this area, Jamie, is the patients are genuinely interested in this, as well. You know, they want to know, what can I do for myself after getting these treatments? How can I help myself? And a lot of the oncologists we talk to say they get those patient questions all the time. You know, what exercise should I do? How much exercise? What’s the diet? So, you know, this is really an empowering type of intervention for patients, compared to, say, the drugs or the surgery, and we’re getting just a fantastic response from the patient advocacy groups saying, please, do more research on these lifestyle factors. We are keen to know what we can do to benefit ourselves.

Jamie DePolo: The other thing that occurs to me is, now, wouldn't it be fascinating if we found that exercise sort of negated any weight gain? You know, that weight became less of a factor, because I feel like there’s so much stigma around being overweight or you know, having excess weight, having obesity, and people, they’re kind of blamed. Like, oh, well, of course you had a recurrence, because you gained 35 pounds during treatment. So, it would be very interesting to see if it can negate that.

Dr. Kerry Courneya: Well, our study had a very important finding, and that is exercise improved the recurrence and survival without any weight loss. There was no difference between the groups in weight loss. So, that means patients who are overweight or obese don’t need to lose weight from exercise to benefit from exercise. It has the same biological and physiological changes for them, and so, they can get the same benefits, even if it doesn't produce weight loss.

We know that exercise can help a little bit with fat loss, but the even more important thing is the exercise builds muscle. We know a lot of the weight loss studies, including with the newer drugs, there’s some muscle loss going on there in addition to the fat loss. And so, the real critical thing, from an exercise perspective, is we can help patients maintain this muscle mass, and some of the studies are showing that it’s actually the amount of muscle that is more predictive of improved survival than the amount of fat. And so, this makes exercise, I think, potentially even more important.

Jamie DePolo: And one thing I thought was so interesting in your study, too, you let people pick what they wanted to do. You know, they could hike. They could swim. They could canoe. They could run. Whatever they wanted to, and I just feel like, if somebody can pick it and it’s something they want to do, they’re more likely to stick with it than if they’re told, like, you have to walk for 30 minutes a day.

Dr. Kerry Courneya: Yeah. I think that’s the beauty of exercise. You know, the exercise drug is energy expenditure. That’s what’s driving these physiological changes and these biological benefits. So, energy expenditure is the key component. How you get that energy expenditure, whether that’s through jogging, swimming, playing pickleball, playing tennis, we don’t think that matters very much. It’s really about getting the heart rate up, getting a little bit of sweating, getting breathing a little bit harder, and challenging the system physiologically, and that’s what the body responds to, is a good exercise stimulus. So, yeah, patients have all sorts of choices on the types of exercise and even the frequency and duration. You know, you can do shorter bouts more frequently, or you can do longer bouts. You can do a little higher-intensity exercise for a shorter duration, or you can do more moderate intensity for a longer duration. So, there’s lots of options for patients to get this energy expenditure drug, if you will.

Jamie DePolo: Excellent.

Finally, what are the next steps for your research? Where do you go from here? Do you have more studies planned, I hope? This is all so fascinating to me.

Dr. Kerry Courneya: So, with our CHALLENGE trial, we’re working on additional analysis of the data we’ve collected there. So, I mentioned we are doing a paper on the health economics to try and show the cost effectiveness of intervention. We’ve collected a lot of data on quality of life and fatigue and depression. So, we’ll be reporting on some of the psychological benefits and quality of life benefits from the intervention. We also looked at the motivational aspect. So, we’re going to be able to study there, who was able to make the exercise behavior change? Who was able to achieve the goal and benefit? And so we can then find out, you know, which patients might need a little more extra support, what patients might need less support because they were able to do it a lot on their own.

So, we’ll get a lot more information out of the CHALLENGE trial, and then the other papers will be on those mechanisms. So, we collected blood on these patients every six months, so we’re going to be able to look at did exercise affect those myokines? Did it affect the immune cells or the inflammatory markers? So, that’ll give us a good idea of what mechanisms might be at play.

The other interesting thing is there are some other studies going on looking at exercise and survival in other patient groups. There’s one in ovarian cancer patients who are on chemotherapy, and that study is going to be reporting their findings probably in the next few months. There is an exercise study in breast cancer patients on neoadjuvant chemotherapy.

This is a very interesting and exciting area, because some of the pre-clinical data shows that if you exercise while getting neoadjuvant therapy, you get better drug delivery to the tumor, because exercise improves tumor vasculature. So, some of these tumors are not well vascularized, and the drugs we give don’t get to the tumors. And in the neoadjuvant setting, that tumor still exists, and so, these studies have shown that exercise improves blood flow to the tumors and more drug delivery. So, there’s a big trial looking at whether or not exercise during neoadjuvant chemotherapy for breast cancer will improve the likelihood of a pathologic complete response, so the response of that treatment.

So, that’s going to be very important in the breast cancer realm. And then I mentioned one very large weight loss trial, as well. You know, many breast cancer patients are very interested in the role of weight loss. Lots of observational studies suggesting yes, the more overweight patients are, the higher risk of the cancer coming back. So, this is a very exciting study that randomized over 3,000 patients. So, it’s the largest study we have out there, and they are in the final follow-up, and they might be able to report the findings in another year or two.

So, I think you're going to see more of these studies trying to link lifestyle, especially exercise, to the survival outcomes, because we already have very good data for the quality-of-life benefits, the symptom management, fitness changes. So, many, many organizations already recommend exercise to breast cancer patients, to other patient groups during treatments, after treatments, really based on a quality-of-life benefit. But you’re seeing now more and more of these studies asking this question, can exercise also be a treatment for cancer? And that is altering the course of the disease and improving survival.

Jamie DePolo: Excellent. Dr. Courneya, thank you so much. This is so fascinating. I am following your research, and I hope to talk to you again, maybe in a few years when you have more things to report. Thank you.

Dr. Kerry Courneya: Thank you for having me.

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