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Augmenting Cancer Therapy through Diet
Dr. Colin Champ presents the historical data on dietary manipulation and cancer care, how diet and nutrition play a role in cancer care, reviews existing data supporting nutritional intervention in cancer care, and explores future directions for diet in the management of cancer.
Upon completion of this activity, participants should be able to:
- Describe how nutrition and diet effect cancer formation and treatment
- Discuss metabolic states that may lead to poorer outcomes in cancer patients, such as those with high grade gliomas
- Describe the molecular pathways affected through diet
- Fine E et. al. Targeting insulin inhibition as a metabolic therapy in advanced cancer. Nutrition 2012.
- Saleh A, et al. Caloric restriction augments radiation efficacy in breast cancer. Cell Cycle 2013
- Champ CE, Baserga R, et al. Nutrient Deprivation and Radiation Therapy – When Less is More. The Oncologist, 1:2012
Dr. Champ has no relevant relationships with proprietary entities producing health care goods or services.
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Release Date: 6/19/2014 | Last Modified On: 6/19/2014 | Expires: 6/19/2015
And I’m going to talk about augmenting cancer therapy through diet. I have no conflicts of interest to disclose. And briefly my goals are to review the historical data on dietary manipulation and cancer care, to try to convince the listener that diet and nutrition play an integral role in cancer care, to briefly review existing data supporting nutritional intervention in cancer care and to explore future directions for diet in the management of cancer.
And in order to do this I’m going to discuss again the history of dietary manipulation in both the prevention of cancer and cancer treatment, the hypotheses and methods of action, current methods of dietary intervention during treatment, methods of implementing these dietary interventions and future directions.
So to start off the 3 most common questions that I get after discussing radiation therapy with patients beyond the obviously how am I going to do, how are the side effects occur, how will radiation affect me. The 3 most common questions that come next are first off can I have sex, secondly can I drink alcohol, and third what should I eat or more specifically will different foods interact with my treatment. I think the first question we can answer pretty easily, you know it depends on what we’re treating it depends on what we’re doing so on and so forth, I won’t go into too much detail there. The second question we always just kind of come up with you know in moderation, or if you’re being treated in an area that’s going to interact with the alcohol you probably shouldn’t drink etc. For number 3 we really don’t have a good answer and it’s usually oh there’s not good data, or we’ll send you off to the nutritionist or you know go on the internet which is probably even worse.
So I wanted to look into this and interestingly enough there is a study that answers both number 2 and number 3 and the study is the Radioprotective Effect of Moderate Wine Consumption in patients with breast carcinoma. This is in the Red journal this is radiation oncologies kind of flagship journal, and this study showed that a glass of red wine, a glass of Italian red wine per day decreased the toxicity of, the skin toxicity of radiation therapy for patients undergoing therapy for breast cancer. An interesting article, I’m a wine lover so any article that can promote healthy drinking of wine, I’m happy about. But nonetheless, it is pretty pathetic that within my field this is one of the few articles exists answering 2 of the 3 most common questions asked by my patients. There is a conflict of interest this study took place where that arrow is in the largest wine growing region in the country, so keep that in mind.
So as a result at my last institution in Philadelphia we wanted to look further into this so we did a survey. We asked all our patients where were they going for their dietary recommendations. If so many patients are asking what they should be eating and they’re not getting the answer from their oncologist, where are they going and of course most of them are going on the internet. So we looked to see where they were going. We went to the NCCN accredited institutions all 22 of them, we saw who made recommendations, we quantified these recommendations by food types, specific dietary recommendations i.e., a low fat diet, a high fat diet, a high calorie diet. We quantified macronutrients in regards to carbohydrates, proteins and fats and then we tallied them up. Only 4 of the 22 NCCN institutions even made recommendations and many of them cited other sites. So we went to these sites and looked to see what they were telling patients. And here’s the results, so there’s 8 total sites of all the NCCN institutions and all the places that they recommend and these were the American Cancer Society, etc., and here’s what you got. It’s quite a heterogeneous mix, a lot of different recommendations. I only put numbers down here this is straight from the paper, I initially had some of the institutions and I did make some inflammatory comments in the paper and as I was applying for a job at the time to many of those institutions, my chair told me I should probably remove the name if I wanted to get a job. But none the less, if you look on the left here number 10 and 11, so this was up at Harvard, MGH and Dana-Farber, and as you can see they recommend a very high carbohydrate diet, these are all carbohydrates on most what would resemble what’s considered a cardiac prudent diet even though nowadays that’s controversial, very little protein and even less fat. Then if you go all the way over here to the west coast to Stanford, you get the exact opposite recommendation and this is I think more what people think about when they think about a diet for cancer patients. It’s a very high calorie, a high fat diet, moderate amount of protein, and low carbohydrates and this is that typical don’t lose weight, potentially even gain weigh diet during cancer treatment. So as you can see there’s quite a big mix here, it’s understandable that patients don’t know where to turn and unfortunately the places they do turn is giving them drastically different recommendations. And these were not site specific these were just generally for cancer patients. So we though this was a very intriguing article, very intriguing finding, we submitted it to a very high power journal in the field of oncology and it got rejected in 2 weeks, further illustrating the lack of nutritional guidelines in the cancer world. These were the 2 responses I got, very brief first off. “We don’t have any data showing the effect of diet on cancer treatments or outcomes.” And I think the vast majority of the field that doesn’t think diet plays a role in cancer care would probably agree with this statement. And then the second statement, “Diet is unlikely to play any part in cancer care therefore this article is irrelevant for this journal”. That one I disagree with even more. That one hurt my feelings that was a little more, cut a little more deeply. So we submitted to another journal, the Journal of Nutrition in Cancer and it got accepted and it’s not a bad journal so overall I think it was a success though at the time it felt like a failure.
Then weeks later calls came in. The ASCO Post did an article on this article saying this was extremely important, we need more answers, we need to put more money towards dietary and nutrition studies. NCI/NIH also put out a flyer saying this as well. Medscape did an article on it as well and most importantly the most important peer review journal out in the literature The_____ Group, the __________ did an article on it as well. All 4 showing that you know perhaps as oncologists we uniformly don’t agree that nutrition and diet play a role in cancer care, but patients and the media do so since we’re taking care of patients I think it’s our responsibility to provide them with some answers. As for the first response, I think this one could be answered a little bit easier but this is the first study ever showing an interaction between diet and cancer and as you see down here, that’s 1909, this is a study from Germany, Dr. Moreschi and I’m not going to dwell on it too long but looking at this table, what he basically did was implant sarcomas in different groups of mice, he decreased the amount of food they ate on a daily basis this was the first calorie restriction study and he showed that in those mice that were calorie restricted that the sarcomas grew much slower. So this kind of got the field rolling. A crude study, he simply weighed tumors, the mice also lost weight so it was somewhat controversial but it got the field rolling. Over the next 100 years dozens if not hundreds of studies took place. The following year Rous, as in Rous sarcoma virus, who later got the Nobel prize, said let’s look at this from the way a physician would look at it. Let’s put the tumor in these mice first, and then start them on calorie restriction that way it would almost be a therapeutic intervention, and he saw the same thing, he saw slower growth in the calorie restricted mice. Over the next 50 years Tannenbaum really accelerated the field performing dozens of studies. In 1947 he reported on these and he saw both decreased occurrence of tumor and decreased tumor growth by 2-44 times in calorie restricted mice, and he restricted them by 30-50%, so not an insignificant decrease in dietary intake, something that would probably leave us a little worried with our cancer patients. And then over the next 50 years multiple studies advanced the field as well. One that sticks out to me the most is Berrigan, he looked back and said this 30-50% caloric restriction in cancer patients is not going to be doable, is there some other way to circumvent this, perhaps fasting one day per week. And he also said let’s start measuring this not just crudely measuring tumor size, he measured the IGF pathway and saw that when fasting these mice during 1 day per week it significantly down regulated the insulin in IGF pathway. So at this point the field was kind of in full swing, we had quantifiable methods of measuring dietary interaction with cancer.
Going back to Tannenbaum’s study he reported on, this is just a snippet of all the data that he did but crudely as you can see here this was drawn with pencil, he showed the decrease in tumor incidents and tumor growth in these mice when they were calorically restricted. As he discussed within his articles he saw the biggest reduction as you can see here where there’s a C above those lines that’s carbohydrates. So when he restricted carbohydrates he saw the biggest reduction in both tumor incidents and tumor growth. And when you take a closer look often times he wasn’t even calorically restricting these mice, he was simply decreasing their carbohydrates and often times replacing them with fat. So the caloric intake of these mice may have actually been increasing. But he found the greatest reduction in cancer when he reduced carbohydrates.
Others caught on. Dr. Crabtree looking at the date again, once again referring to that first reviewer, 1929, so some people think we don’t have data, yet 80 years ago he observed carbohydrate metabolism in tumors, he tried quantifying it and he discussed at length that tumors have a penchant for carbohydrate uptake and glycolysis. This was on the heals of this man, Dr. Warburg who later got a Nobel prize for his work with mitochondrial respiration and his theory depending on how you looked at it, basically what he observed was that cancer cells have a penchant for glycolysis and that’s anaerobic glycolysis. So whether oxygen was present or not, cancer cells would rely on the, pretty poor, inefficient process of glycolysis to derive energy from sugar. Even if oxygen was present, it wouldn’t switch to oxidative phosphorylation which gives you about 15 times more ATP it’s much more efficient. Depending on how you look at it some people say that he said that was the cause of cancer, some people said that he said that was the result of cancer, regardless, it was present.
And along the same time Dr. Crabtree and Cramer again 1933 they started to do some studies as well, this was an important one in my field, this is the first one that I know showing interaction between radiation and diet. This study is the action of radium on cancer cells, some factors determining the susceptibility of cancer cells to radium. So even as far back as 1933 these scientists knew that when cancer cells were able to engage in increased rates of glycolysis or carbohydrate uptake, that they could overcome death from radiation, or in this study radium.
As a result Crabtree and others tried to start blocking the uptake of carbohydrates of glucose. This is a study he did, Benzopyrene and Chloroacetone, these blocked the uptake of glucose in cancer cells and he watched decreased cancer growth in mice. His partner Dr. Cramer tried a medication called 2 Desoxy-D glucose, 2DG this is a glucose analog it gets bound and blocks glucose uptake and the same thing, he found that even in the face of high levels of glucose, when you block this uptake glycolysis decreased significantly in tumor cells. Weirdly enough this was Cramer’s last study, he had some great studies. I don’t know what happened to him he just disappeared off the face of the earth. I searched Google, I couldn’t find anything. I searched the social security death indices and he disappeared, so it must be some controversy, some conspiracy theory.
So none the less, we have about 100 years of data showing that diet and cancer therapies interact. Most of these studies placed mice on a restricted diet, whether that was calorie restriction or carbohydrate restriction is an area of controversy. They applied a carcinogen or implanted a tumor and after these dietary changes they revealed a decrease in tumor formation and slowed tumor growth. So naturally as a practicing oncologist the question that comes to mind is can we harness the effects of nutrient restriction to aid in the modern treatment of cancer?
So my previous group at Jefferson aimed to answer this very question. We did a, this is a very large study with several smaller studies so I’ll try to be as brief as possible. But we took mice, and we implanted triple negative breast cancer cells and we waited until these cells became palpable at 16mm cubed. At that point we randomized the mice to several treatment arms or dietary arms. They either got 8 gray radiation or no radiation and this is by no means a therapeutic dose of radiation, but it was what we considered radiobiologically an amount that would decrease the growth of these cells significantly. They were then placed on an ad libitum diet which is basically access to chow all day long they can eat as much as they want to eat. They were placed on an alternate daily feeding diet so this is every other day the mice were fasted for the entire day or they were placed on a calorically restricted diet and we reduced their calories by 30%. This was on the heels of Tannenbaum and others, this was kind of the magic number. So you get them down to 70% of their calories you may see some changes.
The first study that we did was just the alternate day feeding similar to Berrigan and we found as you can see here in the blue, these are the ad libitum mice, as soon as the tumors hit 2,000 mm cubed the mice were euthanized if they showed any struggling, any trouble breathing we assumed it was respiratory issues from lung metastases or other problems of the mice were also euthanized. And from this study as you can see the 8 gray single fraction of 8 gray which is the red here significantly reduced tumor velocity, tumor growth and overall tumor size, in theory increasing progression free survival. However when you fasted the mice, simply fasted them every other day you get the same effect as a quite large but single dose of radiation. So further pointing to an effect here from diet alone. When you added alternate day fasting with radiation you see a synergistic effect below here where you get significant decrease in tumor growth both velocity and overall size, once again would hint at increasing progression free survival. We did look at the weight of the mice, again Moreschi and these other groups simply weighed the tumors so the one thought is that perhaps if everything is just shrinking of course the tumor is going to shrink including the weight of the mice. We did weight the mice and initially they had a drop when we started fasting them but their weight quickly caught up and there was no significant difference in the weight between these 2 mice.
It is important to note that though these mice were fasted every other day, on the days when they were allowed to eat they quickly caught up and actually ate more than the 70% calorically restricted mice. So now these guys are looking at these 70%, excuse me 30% calorically restricted for overall 70% of their diet. And again, you see similar results however the curves start to separate a bit more. In the middle again is the blue line, these are the ad libitum fed mice, similar tumor growth, single fraction of 8 gray significantly reduces the growth of these tumor cells, next here in the red. And then as we move to the green 70% total diet, 30% caloric restriction actually revealed significant decreased tumor growth over radiation alone. And again when you put them together synergistically you see graphically you see quite a bit difference, obviously this study wasn’t made to compare fasting versus caloric restriction, just caloric restriction versus radiation. However as you see below here, the weights of these calorically restricted mice start to drop off and they don’t catch up. So as a practicing oncologist this creates a little more concern especially and often times in a patient group that we’re worried about weight loss and trying to get them to gain some weight back.
One question this study does not answer, the Tannenbaum question 50 years ago, is it calorie restriction or is it something else. This is a standard mouse diet, 70% of their calories come from carbohydrates so when you reduce their diet by 30% you’re basically reducing nearly all carbohydrates, so the next question that comes about, are we reducing carbohydrates in these mice resulting in these results or are we reducing overall calories.
The other issue is these are mice, they have quite a more, quite a higher metabolism rate than humans do so if I were a mouse I’d be 200 pound mouse and I would eat 40 pounds of chow per day. So in real life I eat what I don’t know 3 or 4 pounds of food per day so decreasing a pound versus decreasing 11 pounds does it have the same effect. And there’s been people very critical of this extrapolation from humans Dr. Seifried who I believe spoke here last year is one of these people claiming that to get 30% caloric restriction in mice, to get an equivalent result in humans you actually have to fast humans for multiple days, some say up to a week. So something that I don’t think many of us would be willing to do to our cancer patients.
So we wanted to quantify some markers in this study not just simply weigh the tumors like Dr. Moreschi or Dr. Tannenbaum did, but show quantifiably that these pathways that we targeted with chemotherapeutic interventions are monoclonal antibodies could actually be down regulated through diet alone. So we went back through 100 years of research and tried to figure out which pathways were most important, which pathways were affected by caloric or carbohydrate restriction and which pathways were affected by radiation and I did this paper with Dr. Beserga who actually worked with Dr. Tannenbaum and he found the IGF1 receptor igniting the field in terms of the insulin pathway. We found that these were the most important pathways, there’s quite a bunch overall, but the IGF1 pathway which combined with the insulin or IGF1 receptor in up regulating this pathway that we all know so well, the PI3 kinase and AKT pathway can be down regulated through caloric restriction and down regulation of this will sensitize these cells to radiation. So our hypothesis is down regulating this through diet will make these cells more radiosensitive and that will go for chemotherapy as well. The other pathway we thought was of vital importance is the new kid on the block this is the AMP kinase pathway, this blocks MTOR and this can be up regulated via Metformin which has sparked some interest in Metformin for breast cancer, endometrial cancer in some other patients and MTOR can be blocked by Rapamycin. And all these pathways if blocked will decrease cell survival, cell growth and inflammation. And briefly that’s exactly what we found in this study. So this was not simply decreasing tumor weight, or decreasing mouse weight, or both, there’s clear down regulation of these important cancer pathways. Radiation alone down regulates these pathways but as you can see calorie restriction in itself down regulates all these pathways. Our hypothesis was this is why you get to decreased tumor growth, again it’s not just starving these tumor cells, we wanted to look to see if these cancer cells were undergoing apoptosis or due to the decrease nutrients available to them if they started basically committing suicide and they did. We looked at BCL2 and as you go to the right here from an ad libitum diet, from radiation, from caloric restriction and from the combination of both you see BCL2 is significantly down regulated. So through diet alone these cells start committing programmed cell death.
So conclusions from this study is that caloric restriction augments radiation therapy efficacy via several mechanisms, by decreased IGF in the MTOR pathway, by increasing the AMP kinase pathway and by increasing apoptosis of these cancer cells. We found that intermittent fasting results in less weight loss and that calories restricted in the study were primarily carbohydrates so take that as you will.
Naturally the next question that comes about, do studies exist revealing the effect of diet on these pathways in humans? And frankly with cancer patients, they really don’t. We have non cancer patients, we have obese patients, diabetic patients, coronary patients at risk for coronary artery disease, where we actually do look at these pathways. But I think we can extrapolate data from these studies so I’ll briefly run through several.
This is from Luigi Fontana and the group in Italy and this is the group that’s been trying to figure out ways to increase longevity in humans. They’ve significantly increased longevity in multiple species by calorie restriction. They recently had a study in the last year you may have seen in Nature where they tried it with monkeys and unfortunately it didn’t pan out so well. This is a study in humans showing the same issue and this was the IGF1 pathway so that middle pathway in the last picture I showed you. They put people on calorie restriction over a long period of time and again there was no decrease in this pathway. They tried a caloric deficit exercise and again no change. And they did what they called healthy lifestyle which was a combination of both and they saw no difference in the IGF1 pathway. Many people think this is again because this extrapolation from mice, 30% caloric restriction in mice is not equal to 30% caloric restriction in humans. You may have to fast humans if you want to get that down regulation and there is a study hinting at this and this is Dr. Halberg and a group in I believe it was Germany. They put people on 20 day fasts, excuse me 20 hour fasts over a several week period and on the left here as you see in these men their blood glucose levels dropped significantly so as a result they had increased plasma beta hydroxybutyrate production. As blood glucose drops you have to feed your brain, you do so by creating ketones and that’s all that this shows. When you fast people ketone production goes up significantly. Ketones can cross the blood brain barrier in times of carbohydrate restriction they can feed the brain, they can feed the neurons, they can feed the mitochondrial within our brain that provide us with energy.
And looking at the plasma insulin pathway as you can see it bottoms out. If you have low levels of circulating blood glucose you don’t need very much insulin to pull that into the cells so the insulin level is blocked. A hypothesis is therefore then it would down regulate the IGF1 pathway for the insulin combined in that receptor. It’s an extrapolation but it’s one of the few studies that exists out there.
Again why is this happening? It’s very much likely because of this, because of down regulation of the insulin pathways. So if you get insulin dropping whether it’s via intermittent fasting in humans or caloric restriction in mice you’re going to down regulate this pathway directly. There’s basically less IGF and less insulin floating around to bind to this and up regulate it. If you increase insulin sensitivity or give Metformin you up regulate the AMP kinase pathway and you block MTOR. As a result you get decreased cell survival, decreased cell growth and decreased inflammation. And while ideally soon this will be implemented in the cancer world, this has been manipulated in the dietary world for years. Insulin is an adipose tissue regulator so when insulin is pregnant or pregnant excuse me-when insulin is present which is often when you’re pregnant insulin is raised, but it will cause fat cells and adipose tissue cells to increase in size. Therefore, if you can insulin sensitize people you can decrease the amount of adipose tissue circulating around and there are actually 26 randomized trials now in humans showing just this. These are in non cancer patients and this is an overall review. This is from a friend of mine of Al Hite, this was done in 2011, there are multiple studies that have shown similar data since. But when you put overweight diabetic patients, patients with coronary artery disease on a very low carbohydrate ketogenic diet which is controversial, this is a high fat diet, and compare them with a low fat diet and calorie restricted diet you see quite a difference in the decrease in several metabolic factors including body mass and fat mass, but most importantly for our concern here, circulating serum glucose decreases significantly by about 15% and insulin decreases by about 54%. That’s simply by telling patients to keep their amount of carbohydrates consumed below 50 grams and instead replacing them with fat which would you know scare some physicians but the results are as they are and this was in 26 total studies. And this is why placing patients on a ketogenic diet results in such quick fat loss and this may not be a surprise to many of you especially those that have read Anna Karenina. Leo Toystool _____ he’s not a physician he knew when discussing counts, Lonsky who was trying to lose weight, “He had no need to be in strict training as he had very quickly been brought down to the required weight of 160 pounds, but still had to avoid gaining weight and he avoided starchy foods and desserts.” Even Toystool knew that if you down regulated the insulin pathway and insulin sensitized people they would lose weight.
Just a side note, just I thought this was interesting, I won’t spend too much time on it but this same group in Italy has been looking at ways to extrapolate calorie restriction in humans. They have started doing some fasting studies. They did a fasting study in 10 cancer patients, again this provides a little trepidation to us practicing oncologists, but they showed in mice that even if you don’t give them cancer, but you do give them lethal doses of Etoposide, if you fast them first and there’s different methods of fasting here on the right, just straight nutrient restriction over a several day period, or if you do straight glucose with carbohydrate restriction, that these mice can actually withstand lethal doses of chemotherapy and live throughout it. So their theory is that differential stress resistance or basically fasting or caloric restriction may protect normal cells but not cancer cells from high dose chemotherapies. So this is way in the pre-clinical stages but interesting none the less. And I have the, you guys will get all the slides so check that out if you have a minute.
So as a result carbohydrate restriction and fasting better down regulate the insulin pathways, so the next question is what about MTOR what about the new kid on the block. MTOR is down regulated by AMP kinase which is basically an evolutionary metabolic regulator. AMP kinase is a pathway that’s up regulated basically to a degree in times of fight or flight so if you are if you don’t have food, if you’re fasting for several days, if you don’t have any carbohydrates around, if you have no glucose or if you’re running from prey, AMP kinase is activated and this is an evolutionary survival mechanism within us. If you think about you know you’re running from a bear that’s trying to eat you, you see the black here, you’re going to undergo glycolysis, you’re going to break down your sugar, you’re going to break down your glycogen to make some energy to run away from. That barrier cells are going to increase glucose uptake and you’re not going to produce anymore glucose because this a time of burning to get the heck out of there. As a result you will get decreased fat and cholesterol synthesis. Again, you’ll start burning fats as well, so you’re going to burn carbohydrates, you’re going to burn fat, you’re going to want to make energy. If you’re burning a lot of fat, you’re going to need more mitochondria to undergo the Krebs cycle to turn that fat into energy. So you’re going to get mitochondrial biogenesis and this is another controversial area that may show some therapeutic response to cancer cells as well. As a result you’re going to get increased insulin sensitivity so up regulation is going to down regulate the insulin pathway as well and you get direct down regulation of mTOR.
So we look through the data to see if any of these, if there are any current studies showing dietary manipulation resulting in deceased or increased regulation of the AMP kinase pathway. And Dr. Draznin and his group actually looked at this very question and they did it quite methodically. They went back and they looked at what Tannenbaum did and did a direct comparison in both overweight and normal weight individuals and they put them on a 5 day, eucaloric, standard American diet with 50% carbs, 30% fat and 20% protein and then they did 30% caloric restriction in both arms. So similar to Tannenbaum, similar to most of these studies over the past 100 years however they wanted to look to see which macronutrients may be affecting it to see if it’s something beyond caloric restriction. So they increased the carbohydrates on the bottom left here from 50% to 60% and then in the other group they decreased the carbohydrates from 50% to 30% right there but they increased the fat to 50%. And when they did biopsies of these patients muscles they found an increased up regulation of the AMP kinase pathway and that’s no surprise. Looking at the caloric restriction studies throughout history if you do 30% caloric restriction you will get up regulation of the AMP kinase pathway. They increased fat here doing what would be a Tannenbaum type approach. However in this other group they found that even in the face of 30% caloric restriction AMP kinase was down regulated when calories restricted were fat and carbohydrates were increased. They did the same study again in 21 lean individuals however this time around they did not decrease calories, they actually increased calories they let them go on a binge eating diet for 5 days and the up regulated, they increased their carbohydrates by 40%. Same thing, on the left here they increased the carbohydrates to 60%, the decreased them to 30% here and increased the fat to 50% and they followed the 2 groups for 5 days, at the end they did biopsies. AMP kinase was down regulated in this group which was expected. If you decrease calories but increase carbohydrates and AMP kinase is down regulated. If you increase carbohydrates and increase calories of course it’s going to be down regulated as well. Interesting finding from this study was even in the face of caloric over consumption if you decrease carbohydrates and increase the amount of fat, this AMP kinase is still up regulated potentially down regulated the mTOR pathway downstream. And for oncologists out there with patients who are risk of cachexia or severe weight loss and perhaps need to increase their calories this may give us a little insight into the ways to do it if we’re still trying to up regulate that AMP kinase pathway.
There’s a paper that recently came out I think about 3 weeks ago I wrote this with Raynor Klement who’s a physicist from Germany it’s called Calories, Carbohydrates and Cancer therapy with radiation exploring the 5 R’s through dietary manipulation. This is a long and interesting but very boring paper that goes through each macronutrient food and it’s effect on these pathways and the effect on radiation efficacy and a lot of these studies look at chemotherapy as well. But basically goes through each one trying to say as practicing oncologists if we’re going to create trials looking at these pathways where are we going to get the biggest bang for our buck. And protein restriction has been a potential target as well as has calorie restriction, as has carbohydrate restriction and a ketogenic diet. There’s also metabolic pathways that are up regulated or down regulated that might make chemotherapy and radiation therapy work better, it might be more therapeutic and it also might put patients in a better overall metabolic state after treatment as they go through their survivorship period.
Craig Thompson, he’s the head of Memorial Sloan Kettering recently commented on the therapeutic implications of different types of food and they said which foods can potentially decrease cancer growth and he said by limiting carbohydrates a lot, by limiting protein a little and fat not at all. So he may be onto something. Check out this paper if you get a minute. The reason that decreasing carbohydrates or calories or even lesser so, protein can increase the susceptibility of cancer cells to radiation is via these 5 mechanisms; its repair of cancer cells, repopulation of the cells, redistribution, intrinsic radiosensitivity and reoxygenation and all 5 of these pathways are affected via dietary intervention and this paper goes through them at length.
And this may be one of the reasons that data like this is starting to surface. This is from Johns Hopkins University it’s association between hyperglycemia and survival in patients with newly diagnosed Glioblastoma. And they took about 250 patients that underwent resection by Dr. Grossman at Johns Hopkins, they followed them out during treatment which was Temodar and radiation therapy, they followed their blood glucose levels statistically counting for steroids for Decadron usage, and put them in quartiles and find that this group down here on average their blood glucose was about 130. This group down here their blood glucose was less than 92 on average. There’s a significant increase in survival in this group. There’s another study out showing that patients under treatment for GBM with Temodar and Radiation, just 1-3 spikes in their blood glucose over 180 decreases their survival by 6 months. And this is a group of patients that lived for about a year to 15 months so that’s quite a significant detriment in survival.
One of the reasons why this may work and this is a more controversial topic, there’s mixed data at this point but there is a significant amount of data showing that blood normal cells when glycolysis is blocked, normal cells can undergo the Krebs cycle, they can up take fat, they can up take protein, they can up take ketones and they can make energy from this. They can drive ATP, cells in our brains are quite capable of using ketones for energy, whereas there is data showing that malignant cells are inflexible, metabolic inflexibility. They’re unable to adapt to blocking glycolysis. As a result, the cells undergo programmed death similar to what we found in our mouse study, BCL2 is down regulated, caspase 9 is up regulated, cells undergo apoptosis which is one of the reasons why when you give radioactive glucose to patients that go under a PET scan, it lights up where the cancer cells are because of their increase, increase in amount of glycolysis and glucose up take. Again this is a little more controversial.
So one method to cause the extreme lowering of blood glucose levels is a ketogenic diet. It’s been in the works for about a century, it’s been used for patients that have uncontrollable seizures. It’s the only disease modifying treatment for seizures. It’s less than 20-50 grams of carbohydrates per day and it’s about 70-80% fat within the diet so quite an extreme diet, it aggressively lowers insulin and IGF and up regulates AMP kinase. These are the Maasai tribesmen in Africa this was a minute after my-well not a minute, a couple minutes after my buddy gave them a goat to say thanks and they immediately opened the goat and he’s eating a kidney here, that’s the renal artery and they gave us back the meat that we traditionally eat here because it’s all protein. They inherently know that to sustain a ketogenic diet you have to eat mostly fat, so that’s something to keep in mind. This is a high fat diet, a very high fat diet, not a high protein diet.
Anecdotally, this was about 100 years from 1923, Dr. Fouche who was a district surgeon in this area in Africa around the turn of the century describes the population of 14,000 that he cared for and during that whole period of time he never saw a single case of cancer in any form, although these diseases were frequently seen amongst the white or European population. So I just thought that was, the whole article is quite interesting. You know it’s obviously unclear if diet was the result of this but Dr. Fouche thought it was and he thought it was interesting enough that he wrote to the British Medical Journal in 1923.
Jean Fine performed one of the first studies and one of the only studies at this point looking at a ketogenic diet in cancer patients. This was at Albert Einstein, he wanted to assess this pathway. He runs the nuclear medicine department there so he said let’s put 10 patients on a ketogenic diet and let’s decrease the amount of glucose that they can consume, let’s take their circulating levels of ketones and insulin and then let’s put them under a PET scan to see if their cancer can be down regulated via diet alone. And he saw just that, you know this is a pilot trial so it’s only 10 patients but he’s found that a higher level of circulating ketones in these cancer patients correlated with decreased levels of insulin less down regulation of the insulin pathways similar to that fasting study in health men. Then he really wanted to quantify it so he put these patients under a PET CT scan and found significant decrease in SUV avidity in these cancer cells.
This is also another reason why this study may have shown such significant results. This is at the Barrow Institute over in Arizona with Dr. Adrian Scheck’s group. The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant Glioma. So for those in the room that don’t know it, GBM is a very terrible cancer with a survival of about 1 year and we’re desperately looking at ways to increase this. A ketogenic diet has been one of these potential target treatments. In this study they took 40 mice and on the top left here they put half them on a ketogenic diet and then half them on a standard diet. They did reveal an increase in survival in these mice. So then down here they took it a step further and put these mice on a standard diet and gave them a therapeutic amount of radiation and then put them on a ketogenic diet and gave them a therapeutic amount of radiation and all the mice were euthanized at 250 days. Of the 11 mice on the ketogenic diet with radiation 9 of them were alive at those 250 days and when they did biopsies on their brain there was no sign of tumor whatsoever. One of those mice actually at 100 days went back on a standard diet and when they euthanized the mice and did a pathology there was no tumor as well. So this is a small study and it’s in mice but this could be quite substantial if we could see even a fraction of these results in humans.
One of the reasons why GBM and Gliomas have been such a big target in terms of the ketogenic diet is our ability to exploit the blood/brain barrier. There is data that shows that as the ketone levels start to increase and you get more than 1 millimole per deciliter in the serum that these 2 channels right here start to get, MCT gets up regulated, it pulls ketones above or across the blood/brain barrier creating the hyperketotic environment within the brain and GLUT1 transporters down regulates it so you get less glucose in the brain. At this point brain cells start to really rely on ketones so it’s really the one area where we potentially may be able to starve a tumor from glucose or potentially down regulate those pathways to let radiation, to allow radiation to work a little bit better.
I’ve given a similar talk a couple times throughout the country and as a result patients were contacting us at my past institution at Jefferson where we see quite a bunch, where we saw quite a bunch of GBMs with Dr. Dave Andrews group, so as a result several of our patients were undergoing ketogenic diet during treatment and we simply wanted to comment on it because we were trying to get a protocol through and there were some hold ups with concerns about the safety and feasibility of such a diet so we simply wanted to report that it was safe in 7 patients it was safe. It was very well tolerated and we measured serum glucose levels and serum ketone levels and did see quite a change. These are our patients before surgery, before radiation. As you can see their average blood glucose level was about 148 which puts them in the poorest quartile of the Johns Hopkins study with the detriment survival if you’re having that glucose level. When we put them on a ketogenic diet there blood glucose acutely lowered. On average it was 82 and that was throughout treatment. It’s important to know that half of these patients were on very high dose Dexamethasone which can really significantly raise blood glucose levels, yet their average blood glucose was. Many were 70’s. One patient had a maximum value of 91 which still puts him in the lowest quartile of that Johns Hopkins group and that was after, he was a chef and he had a feast of a meal and after that it went right back down. We compared this with our non ketogenic patients, the last 50 that were treated and their average blood glucose was about 124 putting them in the third or fourth quartile for overall outcome.
So it doesn’t say that diets going to be therapeutic, it does show that it significantly decreases glucose levels and more importantly that it’s safe. So I’m hopefully that at this point we can on the heels of this data we can move on and make some protocols implementing this diet and cancer care. Again important to note that this a patients average consumption that I tracked on FitDay, it is mostly a high fat diet 77%, 15% protein only. If patients eat high amounts of protein it can up regulate IGF and it can knock you of ketosis. This is a typical meal not tot shabby. For breakfast, coffee, cream, 3 eggs, bacon, broccoli cooked. For lunch a Greek salad, olive oil. For dinner coconut oil kale, salmon, and then a delicious snack of macadamia nuts for a total of 1800 calories so not too shabby. And then one thing we did not comment on that you can’t quantify first let me discuss this study, this was a study of patients that were treated with definitive chemo radiation for locally advanced lung cancer and they did psychological evaluations on these patients and cognitive evaluations on these patients both prior to treatment and throughout treatment and found that those patients that were not pessimistic lived significantly longer than those patients that were pessimistic. And they found no biologic reason why that happened and that’s something in this study you can’t quantify. These patients that come in these are GBM patients that come to see me that they’ve Googled they know that they have maybe a year left to live but they come in enthusiastic, they come in willing to take an active role in their care, their family members go on the diet with them. You take these patients that prior to this is was doom and gloom and a lot of these patients, these are educated for whatever reason a lot of them are men that just recently retired and it just, it really gives them a passion to live again, it really gives them a passion to make it through what can be a pretty tough treatment. It’s something we can’t really quantify but I think it does provide a benefit.
So in conclusion, there’s abundant data supporting the fact that diet on cancer induction and treatment, carbohydrates more than protein is likely the main target. Pre clinical, clinical and radiobiologic data support these effects and importantly patients are extremely interested in diet in cancer so we owe it to them to look further into these interactions. And again this empowers patients to be proactive with their role of care which as a treating physician it’s great to see. UPMC’s rich network of patients and physicians makes conducting these trials possible. At other sites it’s not possible. My last institution it was getting 7 patients through was nearly impossible but here we have some resources to make it happen.
Moving forward reducing glucose availability to cancer cells may be therapeutic and it may enhance cellular damage, but we need to do studies in humans to assess this. Is diet alone enough? Probably not. Can we creat synergy with pharmacologic intervention? Potentially. Two DG’s one area where we may explore, it’s again it’s a glucose analog of GLOX glucose up take in high doses it could be toxic to patients. In low doses though synergistically with a ketogenic diet, we don’t know. Can ketone production create a concentrated environment within the blood/brain barrier therefore make treatment more efficacious for Gliomas and GBM, potentially all this data would say yes. I think we need a future clinical trial to answer these questions in humans.
I’d like to acknowledge the following people. Jean Fine has been a great mentor to me. Dr. Bolek who’s run multiple randomized trials in humans looking at a ketogenic diet and he’s really helped make this diet possible for patients. Dr. Simone another mentor to me and my buddy Dr. Klement in Germany and at this point if anyone has any questions or comments.