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Dr. Alicia Morgans: Hi, and welcome to continued AUA 2018 coverage. I'm so delighted to have with us Kelly Parsons, Professor of Urology at UC San Diego. Thanks so much for taking the time, Kelly.

Dr. Kelly Parsons: Well, thank you so much for having me here.

Dr. Alicia Morgans: Well, great. Big news, you've been working on the MEAL Study for a number of years. Can you tell us about the study, why it's so important, and give us some information that you might be talking about at AUA this year?

Dr. Kelly Parsons: Sure. MEAL stands for the Men's Eating and Living Study. It was originally classified as CALGB70807, Cancer Leukemia Group B, which is now known as the Alliance for Clinical Trials in Oncology, and what we did, this was back beginning of 2006, 2007, and there were all these data coming out about lifestyle and diet in particular and effecting the incidence of prostate cancer. There were some interesting and preclinical models, and there was some interesting early clinical studies focused on whether or not some kind of diet or physical activity or any kind of a behavior change could alter the natural history of prostate cancer, and more specifically, alter outcomes in the disease.

I was fresh out of fellowship, and developing my career, and I'd had some experience looking at diet in particular in prostate cancer and some preclinical models, and was interested in applying it in a larger clinical setting. One of the things that we set out to do early on was to distinguish this particular study, this particular randomized clinical trial, because it is essentially a phase three randomized clinical trial, was to distinguish it from complementary medicine or wellness, though those are very valid pursuits.

What we developed is behavior change. Think cognitive psychologies, think behavioral economics, think of the sorts of things that come up if you ever read Freakonomics or you listen to the podcast, as I like to. We were looking at doing something on a large scale where you could potentially intervene to alter somebody's behavior in a beneficial way to guide them toward eating a healthier diet.

Dr. Alicia Morgans: That's one of the hardest things to do, isn't it? To really change someone's behavior rather than just giving them a pill. How did you go about doing that in this study, and who were the patients who ended up enrolling?

Dr. Kelly Parsons: I linked up with a fantastic group. My mentor is John Pierce who had done similar interventions in breast cancer for many years, and we developed an approach for prostate cancer patients, and we ran a pilot, because the first thing you have to ask is, okay, we've got an intervention. In this case the intervention that we developed is actually a call center. It's modeled, uses behavioral psychology, and coaching essentially, and it's a call center of nutrition counselors. We developed that at UC San Diego and the first thing we wanted to do was to pilot test it because of course if you're developing this intervention the first question you have to ask is well, will you really change things?

We developed it as a pilot, it worked out well. We were able to show that specifically with active surveillance a cohort of men, we were able to significantly alter diet at six month follow up. What we were looking for in particular were total fruit and vegetable intake, because if you look at the epidemiological and the preclinical data it suggests that that is a healthy lifestyle to focus on. 

One of the things that often comes up that folks as about is well, what about fat and meat and that sort of thing? We focus on vegetable intake, and what we generally find is that because the men are so fixated on eating vegetables, they end up eating a lot less fat and a lot less meat and those sorts of things, refined carbohydrates, all the things that we're not supposed to eat but we love to eat.

We pilot tested it, we published it, we went forward, we got grant funding. We ended up percolating through the cooperative group system, which any of your viewers probably know if they've ever attempted to do that, it's a long process.

Dr. Alicia Morgans: It's a long road.

Dr. Kelly Parsons: We eventually were able to open the trial end of 2010, 2011, and we developed it for active surveillance. We looked at men with localized prostate cancer on active surveillance, which these days, if you had to categorized them, they would be categorized as either NCCN very low risk, and I know I’m painting with a very broad brush, because a lot of folks they'll want us to say more specifically what does that mean in terms of their risk for progression that sort of thing?

I think NCCN very low risk is something that I think your viewers will understand that that is low volume Gleason six disease.

Dr. Alicia Morgans: Yes.

Dr. Kelly Parsons: Then, also we allowed in older patients over the age of 70 to have low volume Gleason 3 + 4, so grade group 2 disease. We focused it on that particular group of men, and we looked for a two year follow up from the time of their entry to the trial until the time they finished.

Dr. Alicia Morgans: That's great. I have to say one of the key things that men say that they're interested in engaging in when they see me in clinic, and I don't see a big active surveillance population, but in general, for men with prostate cancer, is they just want the tools they need to change their diet, to change their lifestyle, and I think these are really hard things to come by in normal clinical practice.

What were some of the changes that you had in the study or the ways that you supported men to eat more vegetables or think more clearly about that, and was there a control arm, and what did that look like, too, in the study?

Dr. Kelly Parsons: Absolutely. This was a randomized clinical trial, so there was an intervention and there was a control. The intervention was after men were enrolled in the study, they were consented and enrolled, and you had to meet certain eligibility criteria, not just for the prostate cancer, but in addition you couldn't be eating too many vegetables at base line, because if you're already eating a lot of vegetables, then there's no point in having an intervention that makes you eat more.

The intervention itself is focused on a series of calls in which patients are coached. They're taught to keep diet diaries and that sort of thing. I think the best way to say it is they're basically enabled through counseling and principles of social psychology to eat more vegetables, and arguably this is a group of motivated patients to begin with, because they have been given a diagnosis of prostate cancer.

The control group were given the Prostate Cancer Foundation Wellness booklet, and said, here change your diet, which previous studies have suggested, sure you'll have a couple of men on average that will change their diets, but they're not going to have as big risk of change as if you counsel them.

Dr. Alicia Morgans: And support them.

Dr. Kelly Parsons: And support them. Right, so it's a series of phone calls that go on really for the two years of the intervention. They're more intense, more phone calls up front, and then they're spaced out gradually later on as men develop this sense of self efficacy at controlling their diet. 

What I think is unique about our particular approach is that it is centralized, so it's easy to leverage to large populations. It's cheap. It has economies of scale, and really it takes the burden off of patients, because you think about it, a lot of the interventions that I've seen in literature, are well meaning, but they're these very intense face-to-face, person-to-person counseling sessions. That's a lot of time and money and resources for a patient to come in and make an appointment, park the car, that sort of thing. We're able to do that from a centralized location, and so when we did the study, we had 91 sites across the entire United States participate. Almost 500 men were randomized, and that's from one center, we were able to apply that intervention.

Dr. Alicia Morgans: That's phenomenal, because for something to really be scalable, for something to be integrated into clinical practice, it can't be its own little center at every single site. There are community urologists, community oncology practices that may want to engage in something like this but can't design their own MEAL support system, essentially, at every individual practice, so what a thoughtful and forward thinking method to really allow something to be scalable from the get go and then you showed that it was feasible because you ran it through a cooperative group system, which inherently has, as you said, 91 sites, inherently is a scaled operation.

What were the outcomes that you were looking for in this study? I don't know if you're able to give us any of the data, but if you're able to share, we'd love to hear some of the results. 

Dr. Kelly Parsons: Sure, sure, sure. Because we are taping, prior, of course, to the presentation in a couple of days, but then this is going to be released after the presentation. The outcomes that we were looking for, the primary outcome, was progression. It's interesting, over the course of my career, over the last seven or eight years, to see how we've adopted to active surveillance, because at the time we were developing the study, people were still very anxious about the idea of active surveillance in general.

It's interesting to see how comfortable I think both physicians and patients have come to approach active surveillance and under some data in fact being presented recently and at this meeting about the fact that active surveillance as a modality is enhancing its uptake, it's diffusing. 

Our primary outcomes were two general types. All the patients underwent repeat biopsy at 12 and 24 months after their enrollment. Then in addition, they went discretionary biopsies depending on the urologist and whether or not there was a fore caused reason to have a biopsy. 

That was one endpoint, and then the other endpoint was related to PSA. The PSA greater than 10 was considered to be a progression event. A PSA doubling time less than three years was considered to be a progression event, and then going back to the biopsy piece of it, for men under the age of 70, it sounds all very complicated to say, but for men under the age of 70, you could only have Gleason 6 disease, and so if you were upgraded to Gleason 7, that's a progression event. If you had an increase in the volume of your cancer, the percentage of cores that were involved, that was a progression event.

For men over the age of 70, we allowed for Gleason 3 + 4 to be entered into the study, so a progression event was considered a 4 + 3 or an increase in the volume of the cancer on the repeat cores. That was our primary outcome.

Our secondary outcome was the incidence of treatment, comparing between the arms, the men who went on to receive surgery or radiation, and then we had a whole number of secondary outcomes related to quality of life, correlated sciences related to prediction of progression, biomarkers, those sorts of things.

For the primary outcome, which was a composite, so you would meet the primary outcome if you met the biopsy criteria, or the PSA doubling time criteria, or the PSA greater than 10 criteria. At two years, there was no overall significant difference between groups.

That's the preliminary message. Because we are continuously having data come in right now, with the suggestion that at two years there is the possibility that the groups are beginning to diverge, and that longer follow up will perhaps tell a different story, which in this particular patient population, I think a lot of folks would know is not particularly surprising. It's a low-risk prostate cancer group, and you're probably going to need a couple more years to be able to see more of the natural history of the disease with respect to progression.

Importantly, though, one of the most positive aspects of the trial was the inherence data. Because arguably, you can say okay, sure, Kelly, you folks did a pilot trial in a fairly small number of patients for six months. What about 480 plus patients at 91 sites, what happened there? The inherence data are very, very promising, and very, very significant. 

It turns out if you look at 12 and 24 month total vegetable intake, total fruit and vegetable intake, those increased significantly in the intervention arm, but did not change significantly at all in the control arm. Substantially, that change in the intervention arm, that lasted to 24 months, so for two years, we were able to maintain a significantly increased intake of vegetables in that particular group of patients. That's never been shown before in prostate cancer, really in any urologic cancer at all, and so we are very interested in developing this further. Our group is interested in developing other ancillary types of interventions such as physical therapy exercise that you can conjoin with this.

Most notably, though, we're very interested in seeing, if we follow these patients out longer, splitting some of the outcomes, we're also adjusting for baseline diet. We're looking to see what exactly will happen over the longer term with these patients. I would say at this point our primary conclusion is that with this diet based intervention, we significantly changed men's behavior for the better. We got them to eat more vegetables, that that change was sustained over the course of two years, that that change thus far in the shorter term has not let to a clinically significant difference between groups, between the intervention and the control arm, at two years, but the possibility still remains that the longer we follow them out, that we may yet see a difference.

Then, notably, we haven't done any of the quality of life analyses yet. We have, gosh, Alicia, we have so many different quality of life metrics that we need to look at. We have the Max PC which measures prostate cancer-related anxiety. We have the Fact P, we have the Epic, we have the IPSS, so we haven't begun to drill down or unpack these data really in any substantive way yet, so I'm really looking forward to being able to do that.

Dr. Alicia Morgans: That's fascinating. What I would think as a clinician and internist at heart, too, you haven't shown a difference necessarily, but the data still is maturing and I agree with you, you're going to need time for this, that there are prostate cancer-specific outcomes, but you changed behavior. In the scheme of the life of a man who is on active surveillance, it may be more plausible or likely that he could die of cardiovascular disease, or that he could develop colon cancer. We do know that intake of fiber and decrease in saturated fats, which is happening kind of automatically as you're increasing your vegetable intake, might reduce his risk of colon cancer, certainly should change his risk of cardiovascular disease, and so ultimately, you're changing potentially the trajectory of these men's lives. Not necessarily in a prostate cancer-specific way, but it's a whole patient that you're seeing and you're caring for, and you may be dramatically changing these patients' lives forever.

What is fascinating to me is that you, in this prostate cancer population, have truly been able to change behavior and to make that behavior change last for two years. Populations in diabetes care or in cardiovascular disease have not necessarily been able to make the same change, and so I truly commend you for making the lives of these patients potentially better across the board, not just in terms of their prostate cancer risk. This is really an incredible accomplishment and I think you may be kind of shifting the paradigm in prostate cancer care, and kudos to you.

Dr. Kelly Parsons: Oh, well, thank you very much, and it's interesting that you bring up the general global health issue, because one of the things I failed to mention earlier was that when we looked at total fat intake measured in kilocalories, it went down significantly in the intervention arm, and that was sustained through two years and didn't move at all in the control group, and so absolutely, we're really looking forward to being able to see those quality of life data and we have any number of analyses we want to look at, looking at different ways.

We have a lot of blood and plasma that we've collected, and one analysis that we've already done is that there's a biomarker of carotenoids that you can look at which is a strong, a robust biomarker for vegetable intake. Because vegetable intake, technically you could cheat, if you're talking to somebody on the phone, how many vegetables did you eat yesterday, sir? Oh, I had ten servings, and they might have really just had cheeseburgers all day. 

The carotenoids are very robust because the carotenoids you can't cheat on, and we got plasma carotenoids at zero, 12, and 24 months. Those also were significant changes, so the carotenoid levels went up significantly and were sustained in the intervention arm but not in the control arm, and so we have any number of analyses that we now want to do related to the carotenoids, related to prediction. Can you predict someone who is going to respond in the short term to diet, based on genetic patterns? There's so many different questions that you can ask.

Then, related not just to prostate cancer, we did the same thing in bladder cancer a couple of years ago. We did a pilot trial, using diet intervention focused actually on cruciferous vegetables in particular for bladder, for noninvasive bladder cancer. We had a very positive pilot study that we published in cancer prevention research. We just got so busy with MEAL and things related to it that we kind of put that project aside, but now we're ready to dust it off and pull it out and move forward potentially with doing some bladder cancer, additional bladder cancer studies as well.

I don't think we should even, since we are talking about a urological GU/MedOnc audience here, and GU/RadOnc, of course, I think since we are talking about GU cancers, in this setting we really should be developing ways to enhance all kinds of different paradigms as you mentioned, in the diseases that we treat. Survivorship paradigms, absolutely, if we're able to enhance our patients' approaches to things.

I had been talking with some of my colleagues about patients who are going to get cystectomies. There's a lot of very robust data coming out to suggest that if you are able to enhance a patient's nutritional status prior to cystectomy, they're going to have better postoperative outcomes. They're going to get better faster, they're going to have lower perioperative morbidity and mortality, that sort of thing. 

There's lots of things I think we don't understand about this topic, but that we can approach in a very scientifically valid, robust way.

Dr. Alicia Morgans: I completely agree, and I'm really excited to hear how all of this data matures. You have a huge wealth of information to share with us I think over the coming decade probably. Not the least of which will be the longer term outcomes in this study, plus all of the quality of life, plus all of your correlatives, and we are very excited to hear and continue these conversations. 

Do you have a closing thought or an overarching theme that you'd like to share with the listeners as we wrap up?

Dr. Kelly Parsons: I think that my closing thought would be this is one of the topics that it kind of gets pushed to the side a little bit. I think it speaks a little bit more to the physician-patient relationship in considering the whole patient. Because, certainly, as a surgeon it's very easy to get focused on the surgery, on the treatment, and I think this is the kind of topic that can be studied in a very scientifically valid, very robust way, that can enhance the health of our patients in ways that we really don't understand yet.

Really, I think also, though, speaks to us developing, going back to the model of developing more global relationships with our patients. I had plenty of patients who came back in the MEAL study who were on the intervention, it was not blinded, so of course they knew if they were on the intervention. They came back and they would say things like, "Boy, this is the best I've felt in years."

I think that that aspect of that, that component of it, not just the actual natural history of the disease that we may be altering and the actual outcomes, but just the more global, sometimes less tangible kinds of things. I think it really speaks to that, and I would encourage anyone who has an opportunity to listen to this interview, that if you want to reach out, contact me, our group is very interested in discussing potential projects. As I said, we're very centralized. We're interested in developing projects that could relate to other disease states within general urinary cancers.

Dr. Alicia Morgans: That's fantastic, and I love and want to emphasize again that your group in this whole process is listening to and caring for the whole patient, but also empowering the patient to help do something positive for himself, and when we get to bladder cancer, eventually for himself or herself, but really, empowering the patient to participate and buy in that much more to health, I think is a powerful message as well.

Thank you for talking today and for sharing all of the work that you do.

Dr. Kelly Parsons: Well, thank you very much. This has just been a pleasure.