Low Carbohydrate Diets in Men with Recurrent Prostate Cancer: The CAPS2 Study - Stephen Freedland
April 18, 2020
Stephen J. Freedland, MD, Director, Center for Integrated Research in Cancer and Lifestyle, Co-Director, Cancer Genetics, and Prevention Program, Associate Director, Faculty Development Samuel Oschin Comprehensive Cancer Institute, Professor of Surgery, Cedars-Sinai, Los Angeles, Californi
Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Abstract: A Randomized Controlled Trial of a 6-month low carbohydrate intervention on disease progression in men with recurrent prostate cancer: Carbohydrate and Prostate Study 2 (CAPS2).
Read: (CAPS1) Full-Text Article: A Lifestyle Intervention of Weight Loss via a Low-Carbohydrate Diet Plus Walking to Reduce Metabolic Disturbances Caused by Androgen Deprivation Therapy Among Prostate Cancer Patients: Carbohydrate and Prostate Study 1
Read: (CAPS1) Editorial: Low-carbohydrate Diet Plus Walking to Reduce ADT-induced Metabolic Disturbances Among Prostate Cancer Patients
Watch: The Men’s Eating and Living (MEAL) Study, Diet Intervention in Men on Active Surveillance for Prostate Cancer - Interview with J. Kellogg Parsons
Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University. And I am so excited to have here with me today, a friend and colleague, Dr. Stephen Freedland, who is the Director of the Center for Integrated Research in Cancer and Lifestyle at Cedar Sinai, as well as multiple other things including Professor of Surgery, a wonderful urologist who works both at Cedar Sinai and at the VA in LA. Thank you so much for joining us here today.
Stephen Freedland: Thanks for having me.
Alicia Morgans: Wonderful. Dr. Freedland, I wanted to talk with you a little bit about the CAPS2 trial explaining what it is, why it's so important, and then thinking about what the implications might be. Can you get us started?
Stephen Freedland: Yeah, thanks for the interest. CAPS2 is Carbohydrate and Prostate Study 2, so certainly implies there's a CAPS1, which there was, we published, I don't know about a year or two ago now. And it's a series of studies. We're actually in our third study and planning our fourth now looking at the role of low carbohydrate diets in prostate cancer. They stemmed out of work we'd done in my laboratories as well as data from others showing that low carbohydrate diets can actually slow tumor growth in mice. It's kind of amazing. You feed them nothing but fat, so to speak, with a little bit of protein. It's kind of a sludge. You can't even get it into nice little mouse pellets and they actually slow tumor growth. It's kind of amazing. We think it's due to reduced inflammation, reduced insulin IGF signaling, some other mechanisms as well. We'd previously shown that as you expect with a low carb diet, you could actually prevent some of the side effects of hormonal therapy we see for prostate cancer patients. But really here, now we're asking the question can it actually slow tumor growth? That was the premise behind the study.
Alicia Morgans: Great. Well, it's very great, especially in mice and I think it's a really important question that humans want to know about too because they're the ones with the prostate cancers. But how did you bring the two together and get humans to eat a low carb diet if that's what you did in the trial?
Stephen Freedland: Yeah. I'll tell you a little bit about the trial and then, how do we get the people to actually eat this is another question. And so the trial, we actually took men with a rising PSA after failed surgery or radiation. In this biochemical recurrence for kind of old school D0, if you will, prostate cancer, biochemical recurrence, rising PSA. And we know based upon data from Hopkins and other places that the rate at which the PSA rises, what we can calculate as the PSA doubling time, will predict the development of metastasis and ultimately death from prostate cancer. There's a little bit of data that if you can actually suggestively slow down that doubling time, that that may portend lower risk of metastasis and ultimately death from prostate cancer. That's what we went and looked at in this Phase II modest-sized study.
We took men, again with rising PSA after failed surgery, radiation, randomized them to low carb, which is less than 20 grams of carbs a day. That's certainly what we told them to eat, versus make no diet change. And for six months I measured PSA at baseline, three and six months. Importantly, when you think about this is a) this is not a randomized trial of diet A versus diet B. These men were equally happy to be randomized to no change and not change their diet as make this extreme change. These were not guys coming and saying, "Look, I know I need to do something. Just tell me what that something is." These are guys just as happy to do nothing as something.
And then in terms of how we get them to eat the diet. That's an amazing dietician who helps with that. I think the fear of cancer recurrence, in that we say, "Look, we think this could help and slow this down. We don't know. But we think so," I think is motivating. But really it's working with them and they pretty quickly lose weight. Initially, it's a lot of water weight, but it's not uncommon to see five, 10 pounds weight loss in the first couple weeks. I think that becomes motivating for a lot of men. They start to feel, initially feel kind of bad from losing that much weight. You almost have like a flu, dehydration, hungover kind of feeling. That goes away and they actually anecdotally have told me they have more energy, they're more mentally aware. I think if you could get them through that first few weeks, the other benefits they start to see kind of ensure that the compliance is actually pretty good. It wasn't perfect, but it was pretty good.
Alicia Morgans: That's great. And it sounds like you had about 45 men in this trial and like you said, you were able to follow up with their PSA assessments at three and six months, but you also followed some other metabolic parameters. Can you tell us a little bit about what you measured and what you found?
Stephen Freedland: Yeah, absolutely. The primary outcome was looking at a PSA doubling time. Measured baseline at baseline, three and six months. But we looked a lot of metabolic effects as well. Certainly, weight would be one. But cholesterol, triglycerides, HDL, LDL, glucose, HbA1c levels, high sensitive C reactive proteins, waist circumference. A number of different things because it's all well and good if you can slow tumor growth but if it's causing negative metabolic effects because we know most of these men are actually more likely to die of heart disease than prostate cancer. We got to keep thinking heart conscious, heart-healthy, prostate healthy. We measured a lot of those outcomes as well. As well as diet, of course.
In terms of what we found was actually interesting. There are a few different ways of looking at the data. It was, as you say, 45 men actually completed this study. We had a few more start the study. Drop out was relatively low and actually was higher in the control group because a few of them went on to get treatment. Whether it be radiation or hormones. Actually a few more on the control group ended up getting treatment than the low carb. Not significantly more, but just a handful more. Those that complete the study when we looked at PSA doubling time, you see a very weak trend towards the low carb group having longer doubling times. A slower rate of PSA rise. That's certainly what we expected. The P-value is 0.4 so it's not even close to significant. The difference was six months, which if you had a large enough study and you could confirm six months indeed, that could be meaningful. But it's a small study.
Even though it's randomized, which is supposed to create equal groups in both, in small studies that doesn't always happen. When we actually start to adjust for some of the baseline characteristics that were subtly different between the arms such as baseline PSA, what their doubling time was before the study, as well as they received surgery, radiation. All of a sudden that six-month doubling time difference became a 12-month doubling time difference and was statistically significant, favoring the longer doubling times and low carbs. P of 0.04. We asked, more men had their PSA doubling time slowed, not significantly, but 70% of low carb men, the PSA doubling time slowed. Whereas about 44%, half in the control arm. If we start to think about adjustments as you lose weight, you're going to hemoconcentrate your PSA. If you adjust for that, you get an even bigger 15-month difference in doubling time between the groups.
To me, when we look at the metabolic effects, basically all those, many of those changed in favorable directions. You saw the low cholesterol, total cholesterol went up a little bit in low carb, not significantly, but a lot of that was driven by HDL cholesterol going up. Significant improvements in HDL. LDL again tended to go up a little bit, not significant, but you saw triglyceride significantly go down. Glucose didn't change, but these were non-diabetic men. But HbA1c levels went down significantly. When we looked at hs-CRP, at the high sensitive C reactive protein, no difference, weight loss on average was about 11 and a half kilos relative to control, so 23 some odd pounds, 23, 24 pounds of difference in weight between the groups. Very, very profound differences. We were very excited by these results. It's a small study but certainly says we may be onto something. And importantly, you're getting potential anti-cancer effects with what looks to be cardiovascular benefits. Unlike most of our treatments that are heart harmful, we might actually be heart beneficial and have anticancer activity.
Alicia Morgans: And I love that like you said, heart beneficial. It's kind of whole-body beneficial, but really of course for heart disease risk, if you're losing this much weight and you're actually feeling better, that's a phenomenal thing in addition to, of course, controlling your cancer. Did you have any other than anecdotal reports by the patients? Did you have any patient-reported outcomes integrated into this? Or is that something that if you haven't, is that something into which you might incorporate I guess into the Phase III that you're thinking about or not Phase III necessarily, but the larger study that you're planning next?
Stephen Freedland: Yeah, we did embed some PROs, patient-reported outcomes. We've not looked at them much. Part of the challenge is when we looked at them actually in our first study, they weren't completed thoroughly by the patients so it wasn't, we ended up with just a handful of patients. Even though that study was also about 40 patients give or take, there just weren't that many that had questionnaire data that we could really look at. We've not gone back and looked at that yet for this study. Thank you for the reminder. We have, we're in the process of now looking at the cardiovascular side effects and actually because we've done this CAPS1 now and CAPS2, of kind of doing a meta-analysis of our two studies, putting them together with now we'll have over 80 patients, half on low carb, half not, looking at some of the metabolic effects. Look for that to come out. We've got to finish writing it and submit it, but hopefully, it will come out later this year, early next year. That's been our focus. But yeah, we do need to circle back to those PROs.
Alicia Morgans: That's great because I think, I do think that when people lose that much weight and feel more energy, they probably are going to report that. And I could imagine that they actually feel quite a bit better, which is another reason to think about this as an intervention that might be not only doable but sustainable. Because at least when I think about dietary and lifestyle interventions, the most challenging piece of them is probably ensuring that they're sustainable by patients. And this one seems to be sustainable from what we understand, right?
Stephen Freedland: Yeah, absolutely. And so I think we saw continued metabolic benefits from three to six months, so continued weight loss. I think it was sustainable up through six months. That's certainly what our diet would say. And it's interesting, being at Cedar Sinai where we're both an academic hospital, but also a community hospital at some level, and there's a number of private practice urologists around and they started referring patients for the studies. They referred one patient who ended up, an N of one, but he lost 45 pounds on the study and he went back and told his doctor, his exact quote to me was, "This is life-changing." Whether his tumor slowed or not, the fact that he could lose 45 pounds, had more energy. This was life-changing. He goes back and tells his doctor, "This is amazing."
They started sending more and more patients to our studies. They actually enrolled a number on this study. And we have now in our third study, they're actually some of our key enrollers, so I think it is sustainable. The patients are starting to find this in that sense and so really for us trying to figure out, is this real, this effect on doubling time? What's the biology underlying this? How does it actually affect the tumor? And there are so many questions to ask but it's really an exciting area as you say that you can do an intervention that makes you feel better, improves your heart health, may actually slow down your cancer. That's a pretty rare find to find all of those in one intervention.
Alicia Morgans: I completely agree, especially if that intervention isn't a pill or an injection or an infusion, but it's something that you have the power to evoke yourself. I think that's something that many patients are really looking for and probably the most asked question, "Doc, what can I do on my own in terms of diet and lifestyle to do something both for me and against the cancer?" And honestly, even if it's only for you, even if you only find the cardiovascular benefits, the weight loss benefits, the quality of life benefits, I would say this is probably worth it. And for those individuals who do want to embark on something like this, off-study, again with no promises that it will control their cancer necessarily though that's a possibility for sure. And something that you've shown is something that we need to look at certainly more closely. What would you recommend? How do patients do this on their own if they are trying to do a low carbohydrate diet?
Stephen Freedland: Yeah, I think it's an important question and the way and honestly, in one second, the way I view this is, in the worst of scenarios we've shown it's safe. It doesn't accelerate the cancer. It may slow it down, as you say, that's certainly the hope, what the data suggests, but it is certainly not making it worse. There's no evidence this diet is making the cancer worse plus the metabolic benefits. I think it's safe and I think if patients want to adopt it, I think that's perfectly fine. Not necessarily recommending it, but if patients want to do it, I think it's great.
So something in terms of doing a research study... We had an amazing dietician who talked to the patients on the phone weekly for three months and every other week for the second three months. Really a lot of handholding. Really involvement and so not just someone says, "Hey, I need to go look up on it online and get a couple of recipes and all of a sudden make this, what I'm going to be doing it." It does require some energy, some effort in that place, particularly in getting started. I think people who are motivated can often see simple sources of carbohydrates, your breads, your cookies, your cakes, your sodas, your candies. I think that's pretty obvious for a lot of people. But when we were discussing with potential subjects, the idea that fruit is very high in carb, that would be off the table. I think that was surprising to a lot of people. I think even tomatoes and different things that there's debate whether it's a fruit or vegetable, but nonetheless has a fair amount of carbohydrates in it.
I think it's easy to forget about carbohydrates in things, different sauces, and things. I think for someone to really be conscientious, to really get into it, there's a lot now online available. I would recommend working with a dietician if possible and resources and if they're available. But again, there are so many recipes and books and forums and things online available. It's never been easier. And now, especially with the big keto craze, which is very similar to low carb, there are a lot more keto offerings even in stores and again, recipes and things. It's never been easier to be low carb than it is today.
Alicia Morgans: I agree. But for patients to really heed your caution that there are lots of hidden carbs in our diets, whether that's in fruit juices, fruits themselves, in sauces, in different condiments. These things are all carbs and sugars in fruits are still sugars and sugars are carbs. This is definitely not to say that anyone should do this outside of this study. It is something that if your diet and lifestyle interests go in this direction, you want to try it, I don't think there is any harm and that's what Dr. Freedland has shown. But using a dietician, the advice from a dietician and staying smart, staying safe and certainly talking to your doctor about it is always going to be the best way to go. But this is a really exciting study and as we wrap up here, Dr. Freedland, do you have any advice, overarching message to share with the listeners regarding this work?
Stephen Freedland: What I'd say is we're starting to see emerging data that lifestyle matters, diet and exercise matter. I don't think there is one single dietary approach that is the answer for everything and certainly our data I think support low carb as an option. But that's not to say a vegan diet is not also good or some other diet is not also good. It's just like treatments for prostate cancer. There's no one single treatment. It's what does it make sense to you? Is it surgery? Is radiation? Is it surveillance? Similarly here, there are multiple diets that are probably helpful. We happen to study one and there's a lot of bias out there against low carb diets but again, our data support that it's certainly not bad for the cancer and may have some other benefits and finding providers, find dieticians that will support you in the choices that you want to make regarding your diet, even though they may have slightly different opinions. There's a lot of providers, a lot of dietitians out there who are open to the concept that there is no single one perfect diet.
Alicia Morgans: Well that's a great message that the best diet is probably the diet that both makes you feel well, hopefully, make some good metabolic changes and is one that you can stick with. Having those conversations, being honest with yourself about those things, and then working with a dietician and your physician to do things that are both effective and safe is going to be the best way to go. And we really do look forward to hearing more about the meta-analysis that you're planning and certainly the larger studies that are to follow this exciting data. Thank you so much for your time here today, Dr. Freedland.
Stephen Freedland: Well, thank you so much for having me.