Aug 22, 2018

Fasting and chemotherapy

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. fastingMoreover, 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

patient-chemotherapyAlthough 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.

Comments

Leave a Reply

Your email address will not be published. Required fields are marked *