Fasting and Chemotherapy by Professor Robert Thomas

The role of fasting and chemotherapy has been evaluated in a number of small laboratory studies. Most reported that fasting for 24 hours pre and post chemotherapy reduced side-effects such as organ damage, toxic features, immunosuppression, reduced body weight and chemotherapy-induced death. fasting.  Moreover, it appeared to enhance the effectiveness of chemotherapy by suppressing tumour growth and spread thus improving survival. The reason for this benefit is that when normal cells are deprived of nutrients after short term fasting, it reduces circulating glucose, insulin and IGF-1 levels which down-regulate cell growth, diverting energy from growth to maintenance ultimately slowing their proliferation and protecting from chemotherapy. Conversely, dividing cancer cells continue to expend energy while starving and are then, in comparison, more susceptible to chemotherapy especially if chemotherapy dose intensity is maintained or even increased. Some researchers have termed this phenomenon as “Differential Stress Resistance (DSR)” and harnessing ways to induce it could help other treatments as well.

The effect of radiotherapy was improved in mice mammary tumours fed with an alternate day fasting regimen. The authors hypothesised this was due to enhanced oxidative stress and DNA damage during short-term fasting on cancer cells.
Acute fasting also may increase the efficacy of biological therapies such as targeted kinase inhibitors (TKIs), including erlotinib, gefitinib and lapatinib which slow cancer cell growth by inhibiting mitogen-activated protein kinase (MAPK). Laboratory studies, involving mice with implanted cancers, have shown that adding short term fasting with TKI’s significantly enhanced their effect. Studies in humans, involving fasting or fasting mimicking are planned [Caffa].





Human studies

Although these early laboratory studies are interesting, substantial clinical scientific evidence is lacking. In one uncontrolled case report of 10 patients being treated for a variety of cancers, those who fasted for a day before chemotherapy and up to 24 hours after reported greater tolerance to treatment and less fatigue, weakness, and nausea compared with previous non-fasting treatments. Authors commented that fasting did not appear to prevent chemotherapy-induced tumour shrinkage or affect tumour markers although it is not possible to make this conclusion with such small numbers is a group whose response to chemotherapy is likely to be highly variable. There were minor complaints during fasting of dizziness, hunger, headaches at a level that did not interfere with daily activities and weight loss which was rapidly recovered[Saftie].Another study evaluated the safety of fasting in twenty patients receiving platinum-based regimens fasted (<200 kcal calories/day) 48 hours pre and 24 hours post-chemotherapy. They were instructed to consume and to drink water and non-caloric beverages. There were no grade 3 toxicities attributed to fasting, and laboratory studies revealed no evidence of malnutrition. The researchers excluded patients with more than 10% recent weight loss, body mass index of less than 20.5, or diabetes mellitus [Dorff].

A small study from Holland randomised 13 women to fasting a day before and after chemotherapy (taxotere, adriamycin and cyclophosphamide) or standard nutrition. There was no difference in nausea, other symptoms, white blood cells levels or infection rates but platelets and red cells (haemoglobin) were statistically higher in the fasting group. They also measured levels of protein called γ-H2AX phosphorylation in blood lymphocytes which indicates the presence of DNA damage and is thought to serve as a marker for chemotherapy toxicity in healthy cells. By 7 days this was significantly lower in the fasting group suggesting that fasting may promote the recovery of chemotherapy-induced DNA damage in these cells [de Groot].

Effects of dexamethasone: Corticosteroids are frequently administered before and shortly after chemotherapy for anti-emesis and dampening of hypersensitivity reactions. Higher doses of steroids are usually given in highly emetic regimens or those more likely to elicit an allergic reaction particularly taxanes. The metabolic effects of steroids are likely to significantly affect the influence of fasting as it raises blood glucose and insulin levels.  Most of the studies summarised above do not mention steroids but most would have had them prescribed especially those containing taxanes. Perhaps clinical studies of fasting should initially use regimens which do not require steroids.

Fasting mimicking

Given the nutritional concerns of fasting and chemotherapy in most patients with cancer, interest has arising in manoeuvres which may trigger similar biochemical pathways, such as those which reduce blood sugar, tumour-associated inflammation or increase metabolic stress in the cancer cell. Several measures have been considered including exercise, weight reduction programmes, but the term fasting mimickers is usually reserved for drugs and those under investigation so far include which so far include everolimus, metformin, and hydroxycitrate and natural polyphenols:

Everolimus is a mTor inhibitor already licence for ER+advanced breast cancer but recent laboratory studies have revealed it can mimic the anticancer effects of fasting in mice, sensitising certain cells to chemotherapy and radiation therapy.  In humans, a number phase I and II clinical trials are ongoing to determine the effect of combining everolimus with chemotherapy for various of cancer types including breast, sarcoma, pancreas and myeloma.

Metformin is a biguanide commonly used to reduce glucose and insulin levels in type 2 diabetes by restoring insulin sensitivity inhibiting gluconeogenesis. Metformin, as a monotherapy, suppresses tumour development and growth in multiple experimental cell lines. In humans with diabetics with treated cancer who have been taking metformin, as opposed to other diabetic drugs, have lower relapse rates. Several phase II trials are currently underway to evaluate metformin as a potential combination with chemotherapy.

Hydroxycitrate is a citric acid derivative and over the counter weight loss drug that inhibits ATP citrate lyase, the enzyme that catalyzes the conversion of citrate into oxaloacetate and acetyl CoA. It’s effectiveness in weight loss has been questioned and hydroxycitrate alone does not affect systemic glucose or insulin levels. One small laboratory study showed enhanced anticancer effects combining hydroxycitrate with doxorubicin and cyclophosphamide although this was not confirmed in subsequent trials [Pietrocola]. Despite this weak laboratory data, clinical studies are underway.

Pomi-T-FoodPolyphenols are the largest group of natural phytochemical found many in plants. There have been some concerns that polyphenols may interfere with oncology treatments, especially considering their antioxidant properties but they also slow glucose absorption, reducing insulin resistance reduce excess inflammation, similar to short term calorie restriction which makes them the best choice as fasting mimickers. Thus, the antioxidant properties are only one of the many mechanisms of action exerted by polyphenols. Moreover, polyphenols mainly enhance the production and action of antioxidant enzymes, rather than having a direct effect on free radical absorption, unlike other nutrients such as vitamins A and E [Thomas]. What’s more, most chemotherapy agents exert their anticancer effects in ways that do not involve the free radicals. Laboratory studies have reported that polyphenols reduce damage to normal tissues by enhancing repair and reducing inflammation yet exert direct anticancer properties by inhibiting cell proliferation, de-differentiation, loss of cell adhesion, and metastasis, and supporting apoptosis [Thomas]. It is not surprising, then, that several studies have actually found that polyphenols enhance the cytotoxic effects of chemotherapy, rather than impede it. For example, a two-foldgreater anticancer efficacy of intravenous curcumin and docetaxol, a chemotherapy drug, compared with docetaxol alone, was reported in a transplanted xenograft mouse model of lung cancer, without an increase in damage to normal tissue [Yin]. This was confirmed in further laboratory study involving prostate cell lines which showed the combined treatment of curcumin and docetaxel inhibited the proliferation and induced apoptosis significantly higher than the docetaxel-treated group alone [Banerjee]. Curcumin has also been found to enhance the effectiveness of cisplatin, by helping to reduce cell proliferation in an in vitro laryngeal carcinoma cancer stem cell model [Zhang]. Another study showed it helped to overcome cisplatin resistance through STAT3 inhibition [Selvendiran]. Beetroot extract both promoted apoptosis of breast cancer cells after exposure of the cells to doxorubicin, and protected normal cardiomyocytes, or heart muscle cells, from the toxic effects of doxorubicin [Das]. Resveratrol, found in grapes, berries and, most famously, red wine, has also been under consideration as a CR mimetic. Several in vitro and in vivo studies have indicated that resveratrol can enhance anti-cancer treatments. Not all laboratory studies have shown the same positive effect on chemotherapy.

Not all laboratory studies showed polyphenols enhanced chemotherapy One study in cell lines suggested resveratol interference with paclitaxel [Fukui] and another cell line study suggested high levels of turmeric affected apoptosis [Somasundaram].

There is limited data in humans. One study involving women with metastatic breast cancer concluded adding turmeric to taxanes was well tolerated [Bayet-Robert]. Another small a non randomised study, presented at ASCO 2018 compared 35 women on chemotherapy who had also received vitamin C and curcuminoids with matched controls on chemotherapy. They found no significant difference in short-term efficacy between the two groups, and a trend towards prolong PFS and OS of patients with late stage triple-negative breast cancer[Ou].

A phase II trial, involving 30 men with hormone resistant metastatic prostate cancer gave 6g of curcuminoids with standard dose docetaxel. They concluded this combination was well tolerated and the response rate was better than expected (4 complete responses, 13 partial responses) justifying an ongoing randomised study [Mahammedi].

In conclusion

Many but not all laboratory studies all suggest that carbohydrate restriction, fasting and fasting mimickers may enhance chemotherapy benefits. Ongoing randomised trials will hopefully determine their impact in humans particularly:

Does fasting help humans at all?

• If there is a benefit – how much and is this clinically relevant?
• How long should fast last?
• How should fasting be timed in relation to chemotherapy?
• Is fasting mimicking as beneficial (or not) as dietary fasting?
• Could fasting be enhanced with higher polyphenol intake?

Intermittent fasting is gaining popularity as a way to improve health, lose weight, and even reverse type 2 diabetes. There is biochemical evidence that fasting reduces glucose, IGF-1 and markers of chronic inflammation. Laboratory studies have demonstrated improve effectiveness and reduced toxicities in animals. In humans, one study reported it reduced nausea but another did not show it reduced any symptoms despite a marker suggesting less genetic damage to normal cells. No study in humans showed better response rates but numerous studies are ongoing across the World both for intermittent fasting or drugs which may mimic fasting. Claims from websites or nationalist that fasting with chemotherapy in humans is beneficial is clearly unfounded. Hundreds of trials of interventions in animals have not gone on to have any benefit in humans or the benefit is so small it does not justify the inconvenience. Until robust data from RCT are available, oncologist should not be recommending fasting to the patients they serve as it may cause harm for those with sarcopenia or cachexia, patients who have eating disorders, diabetes, or low body mass index (<20.5).

That said, with the interesting laboratory data and the reassurance that no study has suggested inferior response after fasting, patients who disclosed this practice to their oncologists should not receive a dismissive, uninformed response. Fasting may help some patients avoid unwelcomed weight gain, common during cancer treatments. It may provide a sense of self control and studies have shown that those with a greater sense of empowerment have greater satisfaction and improved mood [Thomas].What’s more no data does not mean no effect and these trials may well eventually show some benefit in selected patients.

References

Banerjee S et al Combinatorial effect of curcumin with docetaxel modulates apoptotic and cell survival molecules in prostate cancer. 2017 Front Biosci, ;(9);235

Bayet-Robert M, Kwiatkowski F, Leheurteur M, et al: Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer. Cancer Biol Ther 9:8-14, 2010

Caffa I et al. fasting potentiates the anticancer activity of tyrosine kinase by strengthening MAPK inhibition. Oncotarget 2015; 6 (14).

deGroot S et al. The effects of short term fastig on tolerance to neoadjuvant chemotherapy: a randomized trial. Biomedical central (BMC) 2015; 15:652

Das S, Williams DS, Das A, Kukreja RC (2013) Beetroot juice pro- motes apoptosis in oncogenic MDA-MB-231 cells while protecting car- diomyocytes under doxorubicin treatment. JESS 2: 1-6.

Dorff TB, Groshen S, Garcia A, et al. Safety and feasibility of fasting in combination with platinum-based chemotherapy. BMC Cancer. 2016;16:360.

Fukui M et al Resveratrol Attenuates the Anticancer Efficacy of Paclitaxel in Human Breast Cancer Cells In Vitro and In Vivo. Eur J Can 2010, 46(10):1882

Mahammedi H et al. Docetaxel and curcuminoids (CCM) combination in patients with castration-resistant prostate cancer (CRPC): A phase II study. Oncology 2016;90(2):69-78

Ou J et al. A retrospective study of curcumin in combination with intravenous vitamin C (IVC) on triple negative breast cancer(TNBC). Clinical Oncology 2018 36, e13118J

O’Fanagan C et al When less may be more: calorie restriction and response to cancer therapy BMC 2107; 15 (106).

Selvendiran K, et al: HO-3867, a curcumin analog, sensitizes cisplatin-resistant ovarian carcinoma, leading to therapeutic synergy through STAT3 inhibition. Cancer Biol Ther 12:837-845, 2011

Somasundaram S , et al: Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res 62:3868-3875, 2002.

Sun L et al Effect of fasting during chemotherapy: a systemic review. Translational Cancer Research. 2017;6(2).

Safdie FM, Dorff T, Quinn D, et al. Fasting and cancer treatment in humans: a case series report. Aging (Albany NY). 2009;1(12).

Thomas R et al Phytochemicals in cancer prevention and management? BJMP 2015; 8 (2);78.

Thomas R et Exercise-induced biochemical changes and their potential influence on cancer: a scientific review. British Journal of Sports Medicine 2017;51:640-644.

Thomas R et al Phytochemicals in Cancer Management. Current Research in Compl and Alt therapy 2017; 105, 01.

Thomas R et al. Forewarned is forearmed – benefits of preparatory information for patients receiving chemotherapy and radiotherapy – a randomised controlled trial. European Journal Cancer (2000), 36 1536-1543.

Thomas R et al. Giving patients a choice improves quality of life: A multi-centre, investigator-blind, randomised, crossover study comparing two aromatase inhibitors. Clinical Oncology (2004) 16: 485-491.

Qiao Q et al: Curcumin improves the antitumor effect of X-ray irradiation by blocking the NF-kappaB pathway: An in-vitro study of lymphoma. Anticancer Drugs 23:597-605, 2012.

Yin H, et al. Synergistic anti-tumor efficiency of docetaxel and curcumin against lung cancer. Acta Biochimicaet Biophysica Sinica (2012) 44: 147-153.

Yu CX, Zhang PJ, Chen WW, Jiang AL, et al. (2007) Cur- cumin downregulates homeobox gene NKX3.1 in prostate cancer cell LNCaP. Acta Pharmacologica Sinica 28: 423-430.

Earthquakes and silver linings

 It’s mental health awareness week, and although I’m Chairman of a cancer charity, I thought I’d take the opportunity to write about the enormous mental challenges of receiving a diagnosis of cancer.

People who have had the dread diagnosis will tell you that there is ‘life before cancer’ and life after cancer’. That in a fundamental way, things are never the same again. Never again is there the same comforting feeling of a certain future underpinning life. This can be terrifying in much the same way as experiencing the normally trustworthy ground under our feet moving during an earthquake. It generates a level of fear that is existential and ongoing.

Coming to terms with this sort of fear can be one of the most attested to ‘silver linings’ of cancer, but that doesn’t make it something you’d wish on anyone. And even for those who do succeed in reaching silver lining territory, it can be a long and painful road, and one which requires a lot of support. The feelings of isolation that often accompany the fear tend to only compound the difficulties.

When in the midst of such turmoil, talk of silver linings is unlikely to provide much comfort and may even promote anger, but if this aspect of life-sized crises such as cancer were more widely appreciated, then it could hopefully lead to better support, which could in turn mean more silver linings, sooner.

Human beings are notorious for their inability to stomach too much reality at one sitting, and never more so than when it involves dismantling treasured futures. The one feature all our individual futures share is a complete absence of reality - they are products of a practically universal societal habit of living with a ‘security blanket’ that enables us to avoid lots of things in the present that we can’t or don’t want to deal with. This is so ingrained and widespread, so much the very ground on which we stand, that it goes entirely unnoticed… 

until that is, an earthquake 

like cancer comes along to wake us up to the fragile nature of our existence, to our mortality.

After a cancer diagnosis we find a new and unwelcome companion constantly by our side - uncertainty. Above all, humans like to ‘know’ in order to feel secure. But cancer has a way of stripping away our certainties and propelling us into a limbo of waiting - waiting for the next appointment, waiting for the next test result, waiting for the next scan, waiting, waiting, always craving some morsel of certainty. This limbo is purgatory to those who depend on knowing for their security.

But, of course, the truth is that life is fundamentally uncertain, the future completely unknown. Which means that to come to terms with the experience of cancer is in fact to come to terms with Life, with Reality, something few have the appetite for, unless severely pressed.

If, through providing the right kind of support, it was possible for people to move through the mental and spiritual crisis of a cancer diagnosis more quickly, the pay-off could be enormous, and on many levels. But what would appropriate support look like? Well clearly it couldn’t come from anyone still reliant on their own security blanket to feel safe enough to function in the world - this would be a clear case of the ‘blind leading the blind’. The only people qualified for the task are those who have come out the other side themselves. They are living proof of what’s possible and can authentically deliver their experience of the journey and of the benefits of making it.

Fortunately, social media has provided a platform for many - often lead by ‘extraordinary survivors’ - to contact one another, to inspire confidence, to provide support. This is an entirely unstructured process, and who knows, that may be the appropriate means to such an unusual end. But I like to think it could be more structured and thereby more visible as a resource, more accepted as a necessary part of dealing with cancer effectively. The concept of ‘expert patients’ has taken hold to some extent, so maybe it could be extended to a whole other level.

I mentioned that the pay-off for helping someone through the existential crisis of cancer could be on many levels. The reason for this is the now indisputable role of the mind in overcoming challenges to our physical health and regaining our wellbeing. On the macro level, someone drowning in hopelessness and terror - 

a ‘victim of cancer’ - is not even able to make decisions that will give them the best chances. They are likely to allow over-zealous professionals, family or friends to guide critical choices for them. By contrast, a person who finds a way to deal with the uncertainties of cancer will discover a growing autonomy and will place an increasing reliance on their intuition to navigate their best way forward.

On the micro level, science has now demonstrated clearly the effect our state of being has on the functioning of key body systems such as immunity. I often refer to what I find to be the most striking feature of the results of Dr Kelly Turner’s researches into the commonalities of what are described by doctors as ‘spontaneous remissions. In her book, Radical Remission, she dedicates a chapter to each of the nine factors that all extraordinary survivors attributed their recovery to (there were many more factors identified, but nine were listed by all those surveyed). The striking feature of these nine factors is that seven of them are in the realm of the mind and spirit, and only two in the physical. This gives some perspective on the importance of coming to terms with the reality of a diagnosis as quickly as possible.

The inseparability of our mental health from our physical wellbeing is deeply ingrained in our culture - notably in our language - but has only recently started to be accepted by science. With this growing recognition, I hope we can look forward to a time when people are supported at every level when dealing with cancer. The mental and spiritual health of someone with cancer is a major factor in the outcome of their treatment, one that has been discounted for far too long. Might it be possible to develop new streams of support that will enable more people who have had the misfortune to experience the earthquake of cancer to find those silver linings?

This week's blog is by Dr Mhairi ("Vari") Morris of Cancer Education .  Robin interviewed Vari last week for the Yes to Life Radio Show and we think the work she does needs a big 'shout out'. She has kindly shared her blog below. You can find out more about her work here:bit.ly/2V8xzFq.

If you want to hear Robin and Vari having a chat:  http://bit.ly/yestolifeshow

How “completing the past” can help with healing

Life After Cancer - Patient Engagement 

We have talked recently about getting “unstuck”, or “unfunking your funk”. Part of the reason we can sometimes find ourselves stuck is because we’re looping and re-looping the past in our heads.

As the Canadian philosopher Marshall McLuhan so eloquently put it:

“We drive into the future using only our rear view mirror.”

So. TRUE!

The trouble is, sometimes we’re too tied up in what’s happened in the past that we can’t fully consider the future.

Now, before I continue, I’m conscious that I run the risk of confusing my readers. Is this site for patients or is it for practitioners?

Well, yes, Essential Cancer Education primarily exists to serve the professionals who work directly with patients. However, this week - this month in fact - I want to shift the focus of my writing to help those living through the cancer experience. I’ve felt prompted to do something for patients for a while, and I’m not quite sure what that will look like in the longer term, so I guess in writing this month’s posts I’m experimenting a little with what that might look like. I’m a scientist - to my CORE - and I think I’ll always be playing around and experimenting with things!

And of course, as you know, ‘tis “Generous April”! So once again, I have another free download to help you complete the past.  

Completing the past

“Ok, Vari, what exactly do you mean by ‘completing the past’?” you may ask.

I first came across this idea in Michael Hyatt’s bestselling book*, “Your Best Year Ever” where he talks about the importance of doing so in order to design a better future. He tells us that we need to understand what happened in the past, and how that has affected our thinking, our feelings and our emotions, so that we can move on and not let it hold us back.

Psychologists Daniel Kahneman and Dale T. Miller call this “the power of backward thinking”. You see, an experience - whatever that may be - isn’t complete until it’s remembered.

BUT...and it’s a big BUT!...we human beings have evolved a canny knack for protecting ourselves against painful memories by repressing them. Have you ever found yourself waking up from a dream about something embarrassing or shameful that vaguely relates to something or someone from your past and then carried that guilt and shame around with you for the rest of the day? 

Yeah, me too….

THAT is the subconscious trying to help you process what happened, but it’s in conflict with its attempts to protect your ego by repressing your emotions.

But enough of the psychology. What YOU want to know is how to process it and move on, right?

Acknowledge what we’ve already experienced

It all starts with acknowledging what’s happened. As much as you might wish to never contemplate those darkest of days again, if you just ignore them and bury them, then I’m sorry to tell you, those repressed emotions are likely to haunt you for years to come. You might not be aware of them - it might happen in dreams, or be physically manifested in the body (e.g. ailments, illness, disease). But it WILL persist until you deal with it properly.

If we don’t address what’s happened in the past, the danger is we then go on to live inside unhelpful stories that we tell ourselves. And before too long, we begin to believe them.

...It must be something I did wrong…

...It’s all my fault…

...I deserved it…

...I’m just not meant to be here…

But you see NONE of that is TRUE!

If we entertain these thoughts, these negative, false beliefs about ourselves, our situations, our past and our future (which, by the way, we CANNOT tell!!), then we’re just going to end up dragging all our unfinished business and dirty laundry into the future. And it will get in the way - it’ll sabotage everything we’re trying to build!

Gleaning what you can from the experience

So, I’m guessing that you don’t want to be defined by what happened?

If you’ve lived through cancer, how can you use what’s happened to help you move on? How can you “complete the past”?

Step 1: State how you felt when you first received the news

However painful it might be to remember that time when you first heard the words, “You’ve got cancer”, it’s important to do this in order to complete the past.

Step 2: Acknowledge what happened

This may seem trite and pointless, but stick with me here. By first acknowledging what actually happened, and then stating what you’d have wished had happened instead, you are in fact helping your brain to process the trauma and allowing the emotions to flow freely, rather than repressing them.

Step 3: Learn from the experience

No one wants cancer, yet one in two people will experience it in their lifetime. I believe that we can learn something from every experience in our lives. Please don’t misunderstand me here. I’m not saying that these things happen in order for us to learn and grow, but rather that despite these things happening, we can learn and grow from the experience.

Step 4: Time to change

Maya Angelou famously wrote,

“If you don’t like something, change it. If you can’t change it, change your attitude.”

We have so much inherent power to change our situation simply by changing the way in which we view it and think about it. When you shift your perspective, what comes up for you? Write it down and reflect on it. Will you do anything differently as a result?

Download a free guide on 4 Steps to Completing the Past, designed to help you work through the four steps to completing the past. https://www.essentialcancereducation.com/4steps

Join the movement

Over the past week or two, I’ve been reflecting on my “mission” - why did I start Essential Cancer Education in the first place? What is my vision for its future? What impact do I want it to have in this world?

And the answer came to me in the form of a note written by my friend, Beth, in my little handy jotter that I took with me to a conference:

Now I know that sounds rather grandiose! And I’m not entirely sure I believe it’s possible. But you know what? I DO believe that through education and increasing public awareness of the impact of our dietary and lifestyle habits on cancer risk, we ALL have the power to reduce cancer incidence. Nearly half of all cancers can be prevented by making positive diet and lifestyle changes. Nearly half! That’s staggering!

And as the old adage goes, “there’s strength in numbers”. I can’t do this alone. I believe I’m part of something bigger. A movement of sorts. And I would LOVE to have you join me in this movement. If you sign up to the mailing list, I’ll keep you posted on news and events that I think might interest you. And I promise not to spam you either! Typically, you can expect to receive one email a week, with some additional surprises now and again when I have something special to share with you that I don’t want you to miss. Sign up here.

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