Sep 12, 2022
Dr. Westin and Dr. Justin C. Brown discuss how physical activity can improve disease-free and overall survival in colorectal cancer and its potential application across all cancer types.
The guest on this podcast episode has no disclosures to declare.
Dr. Westin: Hello, everybody, and welcome to another episode of JCO After Hours, the podcast where we get in depth on recent manuscripts published in the Journal of Clinical Oncology. And it is my great pleasure today to tell you we're going to be talking about a really important manuscript: “Physical Activity in Stage III Colon Cancer: CALGB/SWOG 80702 Alliance Study.” And this was published in the JCO on August 9th, 2022.
All participants in the podcast have no conflicts of interest.
And I am very excited to welcome the first author on this important paper, Dr. Justin C. Brown.
He is the Director of the Cancer Metabolism Program and Assistant Professor in Cancer Energetics at the Pennington Biomedical Research Center at Louisiana State University.
Welcome, Dr. Brown. Thank you for being here.
Dr. Justin C. Brown: Thanks so much for having me.
Dr. Westin: So, this is some really important work, and I think we're starting to see more and more really objective data around the importance of physical activities. But before we get too far down the road, I do want to level set because this was a study in colon cancer. So, just because we have a really mixed audience, give us a quick bit of information about the standard treatment for colon cancer and where we are with survival outcomes.
Dr. Justin C. Brown: Yeah. So, for most patients with early colon cancer, they'll get upfront surgery. And then a subset of patients who have high-risk features for recurrence, or have positive lymph nodes or tumor deposits, will get three or six months of chemotherapy. And outcomes have improved over time for this population, but there is still a lot of heterogeneity, in that, some patients do better than others. And you know, a lot of patients ask as they finish therapy or as they're starting therapy, "Are there things I can do that potentially could improve my outcomes?" And so, we think that this data will provide physicians with a lot of really important information regarding the benefits of physical activity during chemotherapy, as well as after therapy, for patients with stage three colon cancer.
Dr. Westin: Okay, that's great. And so, again, continuing on that level-setting piece, before this study, what did we know about the impact of physical activity on outcomes in colon cancer?
Dr. Justin C. Brown: So, we knew that there was some association between physical activity during chemotherapy and after chemotherapy with disease-free survival and overall survival. There have been studies that have linked those two things. There was some uncertainty about, what is the best exercise or physical activity prescription? And so, a lot of the current recommendations before this study basically said encourage patients to avoid sedentary behavior, encourage them to be as active as they can be, because some activity provides benefits over no activity. But for the patient who really wanted the specifics of how much should I be doing, when should I be doing it, what types of activities should I be doing, should I avoid certain things, the evidence was really absent. And so, what this study provides is a lot of important clarity for both physicians and patients about the types of activities that can maximize their disease-free survival and overall survival.
Dr. Westin: I think that's so important because you're exactly right. We all have those patients that you give them a vague, and they're like, "No, I need instructions. I need to know how much time. I need to know what I'm doing." And it can be really frustrating because—I know personally, I'm like, "Well, this is what I do.” And I'm like, is that enough? I have no idea. So, this is really important work.
And before we get into the specifics of the work, can you just give our listeners a little information? Do we know anything else about physical activity in other cancer types? Like, beyond colon cancer, is this something that's broad-based across everybody?
Dr. Justin C. Brown: Yeah. So, there is emerging observational evidence that physical activity after diagnosis of early breast cancer, of early prostate cancer, is associated with improved disease outcomes, so disease-free survival, overall survival; that's observational data. We do have randomized clinical trial data on other quality of life endpoints and biologic endpoints in a variety of tumor types. And we know that patients who engage in physical activity or exercise during and after treatment tend to have better quality of life, they have less fatigue, they have improved physical functioning, they have reduced inflammation, improved insulin sensitivity. So, there's a variety of short, medium and potential long-term benefits to being physically active after your diagnosis of cancer.
Dr. Westin: Perfect. And how did you end up here? What made you interested in this work?
Dr. Justin C. Brown: So, my story dates back all the way to 2002. So, my father died from metastatic colorectal cancer.
Dr. Westin: I'm sorry.
Dr. Justin C. Brown: No, no, it's okay. I mean, if that didn't happen, I wouldn't be here today. And so, he is with me every day. And, when he asked his physician, "Is there anything I can do to improve my long-term outcome?" This was 2002 before we knew how patient lifestyle factors really improved or impacted disease outcomes. And so, my whole life's mission has been focused on trying to empower cancer survivors, so people from the point of diagnosis on, with information about how the choices they make outside of the oncology clinic have a profound impact on how they feel, function, and survive.
And so this has come full circle for me because now I'm able to generate evidence that hopefully will inform clinical practice about how patients who are exactly like my dad and wanted to know what they could do to improve their outcomes, we now have the data that we can provide more precise recommendations about what patients might consider doing to improve their long-term disease outcomes.
Dr. Westin: Great. Wow. It's so inspiring, and again, I am sorry for your loss. But I'm glad that you're really transitioning it into positive things.
So, let's help everybody understand first just the overall design of the trial that you utilized, the CALGB/SWOG 80702 clinical trial.
Dr. Justin C. Brown: Yeah. So this trial was a two-by-two factorial trial, and it randomized patients to three years of Celecoxib; the anti-inflammatory drug, or three years of placebo. And that was the primary analysis. The primary hypothesis was that Celecoxib would improve disease-free survival versus placebo. And that paper was published by my mentor, Jeff Meyerhardt, in JAMA last year. And that analysis showed that Celecoxib did not improve disease-free survival over placebo.
The other factor of the two-by-two design was a randomization to three months of FOLFOX therapy, 5- fluorouracil and oxaliplatin, or three months of FOLFOX. And that analysis contributed to an international pooled consortium called the IDEA Consortium. And that analysis was published in 2018 in New England Journal of Medicine, and the follow-up overall survival analysis was published in Lancet Oncology in 2020. And that showed that while overall, three months of FOLFOX was not inferior to six months, there were some lower-risk patients that achieved good disease control with a shorter regimen of chemotherapy. And so, that has changed practice, and now there are certain lower-risk patients that are getting treated with three months of FOLFOX chemotherapy instead of six months.
But patients with high-risk features still continue to get six months of therapy. That was the primary questions that that study was designed to answer: the Celecoxib versus placebo and then the contribution to the international pooling project to answer the question of three versus six months of postoperative therapy.
Dr. Westin: Well, that's a really clever design. And then I love how you have an additional question built in here. So, why don't you explain how you incorporated your exercise objectives and also what this nested cohort design is?
Dr. Justin C. Brown: Yeah. So, this is a unique opportunity to leverage an ongoing clinical trial to conduct an observational study. So, what we did is, about midway through chemotherapy, we asked patients if they wanted to participate in a lifestyle substudy. And if they chose to participate in the lifestyle substudy, they were asked questions about their physical activity and their dietary patterns and how much they weighed. And we measured those things midway through chemotherapy, and then we also measured them again about six months after patients finished their chemotherapy.
And so, what this allowed us to do is to leverage all of the amazing resources that were put into place in the randomized clinical trial—that is, a homogenous patient sample, uniform treatments—and systematically ascertain disease outcomes to answer a question in an observational setting—that is, "Does physical activity relate to disease-free survival and overall survival?" So that is the nested cohort within the larger randomized clinical trial.
Dr. Westin: Okay, perfect. And then just tell us how you measured the physical activity and the questionnaire that you utilized.
Dr. Justin C. Brown: Yeah. So physical activity was measured by a self-reported questionnaire, and the questionnaire is included as a supplement to the JCO paper.
So, if people are interested in using this questionnaire, it is available. And it asks 10 different types of physical activities, and it asks the frequency with which those activities are done in the past two months. And using the answers that the patients provided, we were able to calculate which patients were more physically active versus those that were less physically active.
And we were also able to understand were the activities that they participated in more vigorous or less vigorous. So, it provided us with a lot of important details regarding the types of physical activities that patients reported during and after chemotherapy.
Dr. Westin: Great. That's so interesting. And then, of course, we know diet is important, right? So, you did assess diet as well in this group. You want to give us a little bit of detail on that?
Dr. Justin C. Brown: Yeah. So, we measured diet with what's called a Food Frequency Questionnaire, and it asks a series of questions regarding habitual dietary intake. And we know that people who are more physically active tend to be more mindful about what they eat. And so, that's an important confounding variable in trying to understand the relationship between physical activity and disease-free survival. So, we measured diet using that questionnaire. At the same time, we measured physical activity during and after chemotherapy. And that was included in our analysis so that we can attribute the association that we observed to the physical activity per se.
Dr. Westin: Okay. And how often did you assess these time points? I'm sorry if I missed it.
Dr. Justin C. Brown: So, we measured physical activity and diet two times. We measured it midway through chemotherapy, and then about six months after patients finished their chemotherapy. Because we know that activity, as well as diet, changes from when patients are being actively treated to after they finish their systemic therapy.
Dr. Westin: Okay. Perfect. Great. All right, so let's hear it. What were your primary findings?
Dr. Justin C. Brown: So, the benefit for the simple messaging is that any activity is better than no activity. That is, if patients need to know the bottom line, my advice is that they find an activity that they like to do and they do it for the rest of their life.
For patients who want a little bit more precision, we can think about physical activity on a spectrum of intensity. So the examples I would give a patient is we can do walking, we can do jogging, and we can do running. And jogging is more intense than walking, and running is more intense than jogging. And so, if you decide to do more intense activities, you don't have to do them as much in a week. If you choose to do walking, you need to do more walking than if you choose to do running. And so, this will help to clarify what types of activities are beneficial. So, some people might choose to play tennis, which is a vigorous activity, one day a week. And that would provide them—from our analysis, that provides them with a disease-free survival and overall survival benefit.
If a patient says, "My joints are too old and too achy that I can't play tennis, but I can walk around my neighborhood," then we know that those patients may need to do a little bit more activity, maybe a 20 to 30 minutes a day, three to five days a week, in order to achieve a meaningful disease-free survival benefit.
So, this helps us to understand with a little bit more precision what we should be advising patients. And if patients say, "I can't do this” or “I prefer to do that," that helps us to have evidence-based recommendations about what is likely to be beneficial and worthwhile to improve their long-term disease outcomes.
Dr. Westin: It's so awesome. And I think it's so great to have just very clear guidelines that we can give our patients. I know I've said it already during this podcast, but every time I—because I think we all get so frustrated with these vague recommendations, like, "Okay, drink water, eat healthy." You know, really, I want bullet points of what I can do.
Now, we talked a little bit about some of the findings in other cancer types that were already existing. So, can we extrapolate your findings to other cancer types?
Dr. Justin C. Brown: I think there is a reasonable expectation that our findings can probably generalize to early-stage breast cancer and maybe to prostate cancer.
And the reason I say this is because these are tumor sites where there is existing evidence that being more physically active is associated with improved long-term disease outcomes. Now, the specific magnitude of benefit, I'm not sure if that will generalize. But I do think that this study provides a framework to start thinking about how we can understand the specific characteristics of physical activity that might be more or less important in terms of maximizing long-term disease outcomes.
Dr. Westin: That is perfect. So, tell me, what are your next steps with this work?
Dr. Justin C. Brown: So, one of the findings that this study reported was that patients who were more physically active during their chemotherapy were more likely to receive more of their planned chemotherapy. They had a higher chemotherapy RDI. So, some of us on this paper have been very fortunate that we received funding from the National Cancer Institute to launch a Bayesian Adaptive Trial of exercise, aerobic exercise, during chemotherapy, and the primary study endpoint is chemotherapy relative dose intensity.
So, what we're going to be able to do is to understand, in a randomized clinical trial setting, does different doses of aerobic exercise have a causal effect on improving chemotherapy RDI? Because one of the hypothesized mechanisms through which we think physical activity may improve disease-free survival and overall survival is it enhances a patient's ability to tolerate systemic therapy. And so, we have the funding. We are in the process of planning that study. It should begin later this year, and that will provide us with concrete randomized evidence to understand if exercise during chemotherapy for colon cancer has a causal effect and can improve adherence to systemic therapy.
Dr. Westin: That's outstanding. And can our listeners potentially participate in that? Are you looking for sites?
Dr. Justin C. Brown: So this study will be launched at Pennington Biomedical Research Center, where I am, in Baton Rouge. This study will also take place at Kaiser Permanente, Northern California, so if there are people on the West Coast listening, as well as at Dana-Farber Cancer Institute in Boston.
And so, we are part of a larger consortium of four studies that are trying to understand the benefits of both exercise as well as nutrition and their role in impacting how patients feel, function, and tolerate anti-cancer therapy in a variety of cancer sites. And we are focused on colon cancer, specifically.
Dr. Westin: Well, that's great. I hope our listeners will get involved. And those of our listeners that are survivors, you heard some very clear data on what you can do to help impact your overall survival, as well as quality of life. So, I hope you’ll implement that.
Thank you again so much for being here, Dr. Brown. The time just flew by.
And again, for the listeners, this was the JCO manuscript published August 9th, 2022, “Physical Activity in Stage III Colon Cancer: The CALGB/SWOG 80702 Trial.” And until next time, we'll see you at JCO After Hours. Take care.
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