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].
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.
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.
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].
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.