Fasting Cancer Patients Works: the research of Valter Longo PhD.
Jacob Schor, ND, FABNO
June 6, 2013
I believe that the current research on the natural treatment of cancer conducted by Valter Longo PhD may be one of the most exciting, interesting and clinically useful new developments in the field of oncology. Not just naturopathic oncology, but in the entire field of oncology.
Longo’s early research looked at the impact fasting has on longevity, but in recent years he has shifted his focus to fasting and its impact on cancer chemotherapy. Longo now claims that fasting increases the effectiveness of many chemotherapy drugs at slowing cancer growth, while simultaneously reducing the deleterious side effects of treatment.
Even though fasting is such a fundamental part of naturopathic therapy I am still surprised at the extent of the benefits it may bring to cancer treatment. On a more fundamental level, Longo’s work brings insight into how naturopathic therapies work.
I was first introduced to Longo’s ideas by an article in an August 2008 issue of the journal Science. Longo is a professor at the University of Southern California (USC) and until his recent foray into cancer research had studied the effect of caloric restriction on life span. Animals that spend most of their lives hungry live longer than well-fed animals. Cutting calories slows the growth rate of cells and makes them more resistant to stress. Healthy cells when hungry become stress resistant; they budget their energy and spend it on protective and maintenance functions rather than on reproduction and growth.
Longo questioned whether this same phenomenon might be utilized in cancer treatment. Slowing the growth rate of healthy cells might protect them from chemotherapy, which preferentially injures faster growing cells. Longo’s earlier research using yeast suggested that cancer cells could not slow their growth rates when hungry, the way healthy cells do. Thus fasting might have a two-fold benefit during chemotherapy, selectively protecting healthy cells while leaving cancer cells susceptible. 
The first experimental results were published in 2008. Longo tested his ‘hunger protects theory’ on yeast and then on mice. Mice who had been without food for 48 to 60 hours exhibited no signs of toxicity when given high doses of chemotherapy (LD-50 doses). Half of the control animals used in this experiment that were allowed to eat up to and during the chemo treatment died. While fasting lessened chemo side effects in this first report, tumor cells, at least neuroblastoma cells, remained sensitive to chemotherapy. 
When Longo’s 2008 paper was first published, it was met with concern from oncologists. They warned curious patients against fasting. After all, “The dietary recommendation for cancer patients receiving chemotherapy, as described by the American Cancer Society, is to increase calorie and protein intake.”
It is reasonable to worry that patients will lose weight. Weight loss is a red flag for all of us. With advanced cancer, the body’s metabolism gets tangled up. The chemical cycles that generate energy from food become less efficient. With advanced cancer, it’s as if people get lousy gas mileage from their food. Even if they eat plenty of calories, they still lose weight. Since they can’t eat as much food as they did when well, they lose weight even faster. This ‘cachexia’ often marks the beginning of the end. As a result, people who work with cancer patients are frightened to see them lose weight. The idea of patients fasting is scary.
Even so, desperate times call for desperate measures and people started fasting on their own shortly after Longo’s very first paper was published. Anecdotal reports of good results encouraged others to try doing it.
Science described one of these experimenters:
“One enthusiast is Thomas Cravy, a 66-year-old retired ophthalmologist in Santa Maria, California, who is battling metastatic prostate cancer. Cravy just finished his third round of chemotherapy in 2 months, each combined with fasting. After the first round left him suffering some side effects, Cravy extended the time he fasts after treatment from about 8 hours to 24 hours, to go beyond the half-life of the most toxic drug; he also fasts for about 64 hours before treatment. Cravy now reports virtually no ill effects from chemotherapy. ‘On day five [after treatment] was the first time I played golf and walked the whole golf course,’ he says. He admits that his mental sharpness fades during the 3½ days he fasts. But the approach has made him much more willing to try chemotherapy, which he had long resisted because he so feared its side effects.”
These stories led to a report published in the December 2009 issue of Aging. Safdie et al describe the results of human experiments they conducted with Longo. They described 10 cases in which patients diagnosed, “… with a variety of malignancies had voluntarily fasted prior to … and/or following … chemotherapy. None of these patients, who received an average of 4 cycles of various chemotherapy drugs in combination with fasting, reported significant side effects caused by the fasting itself other than hunger and lightheadedness. …. The six patients…. reported a reduction in fatigue, weakness, and gastrointestinal side effects while fasting. …. fasting did not prevent the chemotherapy-induced reduction of tumor volume or tumor markers. …the 10 cases presented here suggest that fasting in combination with chemotherapy is feasible, safe, and has the potential to ameliorate side effects caused by chemotherapies…”
While Longo and colleagues were not ready to, “… establish practice guidelines for patients undergoing chemotherapy,” they had set an example that spurred our interest and that of our patients. 
Why would not eating have such an impact on cancer? Monkeys on long-term caloric restricted diets experience half the cancer rate as monkeys on a standard diet. But what about these short term diets? Short-term starvation (STS) is the term Longo now favors in his writing. STS causes healthy cells to rapidly switch to a ‘protected mode,’ which triggers significant changes in IGF-I and many other proteins and molecules and is capable of protecting mammalian cells and mice from various toxins, including chemotherapy. A range of biological parameters decrease including IGF-1, blood glucose and inflammatory cytokines in particular. 
Longo coined the term “Differential Stress Resistance (DSR) to describe the ability of STS to trigger protective reactions in healthy cells but not in cancer cells. In the early yeast experiments, the effect was dramatic, a 1,000-fold difference in protection against chemotherapy induced oxidative stress between normal cells and cancer-like yeast cells. If even a fraction of this DSR were seen in humans it would still be clinically relevant, significantly impacting long-term survival. [5,6]
A milestone study was published February 8, 2012 that brought us closer to the day when telling patients to fast during chemotherapy becomes the standard of care. While the earlier publications informed us that fasting reduced chemotherapy toxicity, in this paper published in Science Translational Medicine, Longo presented evidence that fasting enhanced the benefit of chemotherapy by sensitizing cancer cells.
Granted that we prefer to base our decisions on human clinical trials and this study was conducted on mice not people, even so, the information is so compelling that it’s worth taking note of.
Remember that up until this point, the possibility remained that fasting might also protect tumor cells from chemotherapy’s action. In this paper the authors show that fasting actually increases the efficacy of chemotherapy in the treatment of melanoma, glioma, breast cancer and neuroblastoma. In some instances, fasting was as effective as chemotherapy at inhibiting tumor growth. Fasting sensitized 15 of the 17 cancer lines tested to chemotherapy in vitro. Combining fasting with chemotherapy resulted in a synergistic 20-fold increase in cancer cell DNA damage while healthy cells were unaffected. This work suggests that fasting has the potential to sensitize a range of tumor types to chemotherapy treatment while at the same time increasing tolerance.
The greatest therapeutic effect was seen when fasting was combined with either doxorubicin (10 mg/kg) or cyclophosphamide (150 mg/kg). In the breast cancer mice, two fasting cycles along with chemotherapy resulted in tumors less than half the size of those in mice treated with cyclophosphamide alone. Similar benefits were seen in the treatment of melanoma and glioma.
In neuroblastoma injected mice, 5 two-day periods of fasting spread over 34 days limited tumor size to half of that reached in normally fed mice.
A combination of multiple fasting cycles and high dose chemotherapy resulted in cancer free survival in aggressive metastatic models in which murine breast cancer cells, melanoma cells, or neuroblastoma cells were injected into mice. Fasting potentiated chemotherapy and extended the survival of all the mice models of metastatic cancer. Fasting the mice in combination with doxorubicin reduced the metastases of melanoma cells. Fasting the mice reduced lung metastases by 35% and no metastases were detected in the liver or spleen of fasted mice.
Long-term survival (>180 days) occurred in 42% of murine neuroblastoma mice that underwent two cycles of fasting and high dose doxorubicin compared to 100% mortality in the mice that ate freely while undergoing the same chemotherapy treatment. In a model of pediatric malignancy that combined fasting with a chemotherapy cocktail of cisplatin and doxorubicin, 25% of the mice achieved long-term survival (>300 days) while all of the mice that ate freely died by day 75. 
These experiments, while certainly of interest to a cancer patient, have greater implications. Our usual mindset when dealing with illness is to think in terms of deficiency. We assume illness is caused by a lack of something necessary and that cure will be achieved by giving that missing ingredient. We take daily multivitamin supplements in fear that missing our full complement of required nutrients for a single day will precipitate illness. Patients will look at me openmouthed if I suggest they take a break from swallowing the countless pills they’ve been told are necessary for health. People do surprisingly well with out supplementation. It may be that they do just as well with periods of deprivation.
Being a couch potato is, in a way, the natural state of any organism. By this I mean that an organism, be it yeast or person, is unlikely to expend any more energy than is required. It will make the fewest enzymes needed. It will not mount defenses unless necessary. It will not protect itself from famine if well fed. Living things only move in response to need, be it pain, hunger or pleasure. Organisms will get up off the couch only when they have to. Sometimes they need to be prodded. Fasting wakes them up and prepares them to confront stress. Using stressors to stimulate the natural protective mechanisms in the human body are at the basis of many if not all nature cure therapies and fundamental to the practice of naturopathic medicine.
Little about fasting sounds like a piece of cake to patients. Other, easier, approaches have been suggested. Studies using mice by Krista Varady et al from the University of California at Berkeley suggest that alternate day fasting may also trigger a protective response. Their results, albeit in mice, suggest that modified alternate day fasting in which even on the fasting days one still eats a little, about 15% of normal total calories, can cause some impact.  Varady has applied this alternate day fasting to weight loss and treating cardiovascular disease, but has not published data on reducing chemotherapy side effects or hindering cancer.
Longo’s work though suggests that this alternate day caloric restriction suggested by Varady may not be as effective as the short term starvation that he has been testing. He points out, “…the protective effect of fasting is mediated, in part, by an over 50% reduction in glucose and insulin-like growth factor 1 (IGF-I) levels.” Caloric restriction causes relatively moderate changes.  Though, again in mice, it has been shown that alternate day fasting with 100% caloric reduction (that means zero calories every other day) has been reported to reduce IGF-1 by 40%. 
Several authors, in particular Thomas Seyfried, have suggested that a ketogenic diet might be useful in treating glioblastomas and other cancers. [11,12] Experiments using mice that compared ketogenic diets against Longo’s short-term starvation diet were published in February 2013. Short-term caloric restriction in which mice received only half their normal calories did improve resistance to chemotoxicity if the diets completely lacked protein, but a high protein diet did not provide protection. Even a 20 day low protein diet did not delay tumor progression and short 3-day cycles of caloric restriction did not augment the chemotherapy action of cisplatin. Thus while these other caloric restricted diets may reduce side effects, it takes full out short term starvation to increase the action of treatment or slow tumor growth. 
In a 2012 paper, Safdie et al reported that in rodent models of glioma, fasting enhanced the response of glioma to both chemo- and radiotherapy.
“Starvation-mimicking conditions sensitized murine, rat and human glioma cells, … to chemotherapy. In vivo, starvation for 48 hours, which causes a significant reduction in blood glucose and circulating insulin-like growth factor 1 (IGF-1) levels, sensitized both subcutaneous and intracranial glioma models to radio-and chemotherapy……Starvation-induced cancer sensitization to radio- or chemotherapy leads to extended survival in the in vivo glioma models tested. These results indicate that fasting and fasting-mimicking interventions could enhance the efficacy of existing cancer treatments against aggressive glioma in patients.” 
Getting your average patient to fast is no easy chore. In the last few years Longo has developed a program for patients to use that makes the process easier. He provides boxed kits to his patients that contain daily rations of teas, nut bars, vegetable broth and selected nutrients that all together provide minimum calories but create a sense of satiety, which makes this short-term starvation process easier. Trademarked as Chemolieve ™, Longo’s program covers a period of 4 continuous days and is administered under physician supervision during every cycle of chemotherapy. No other food except water is consumed during those 4 days. It is started three days prior to chemotherapy (day 4). On day 5 the patient transitions back to a normal diet. On day 6 the patient kit provides some additional nutrients. It seems that much thought, testing and calculation have gone into designing these ‘foods’. These design factors remain confidential or proprietary. On day 1 the diet is reduced calories but high fat. For the next three days it is very low calorie (<300 kcal). The products are manufactured by L-nutra, a company spun-off from the University of Southern California for the purpose of making use of Longo’s research
We have recently watched a patient as she has gone through this process using Longo’s product. She found the three-day fasting period prior to chemo far easier than she expected and reported no major discomfort during the entire week after chemo. In her prior treatment she had eaten her normal diet right up until her chemotherapy infusion and found the post treatment week to be very uncomfortable (though she used stronger words to describe the experience). This was a profound difference to see.
At this time Longo’s ‘Chemolieve™ product is not yet available for sale awaiting the outcome of clinical trials still in process.
Fasting profoundly changes physiology on a cellular level. It is as if every cell in the body suddenly realizes that if things continue the way they’re heading, everyone is going to die. A sense of alarm pervades the entire organism. Protective mechanisms are turned on. Cells become more resistant to toxic damage. They grow slower.
Fasting triggers compensatory reactions that protect the body from additional stress. In naturopathic medicine we speak of stimulating the healing force of nature, often using the old Latin term, Vis Medicatrix Naturae. Perhaps we can think of this Vis as that protective reaction that is mobilized in response to some sensed attack, part of the deep desire at the core of any living thing to stay alive. Fasting has been part of nature cure for centuries. It is reasonable to assume that other techniques of nature cure provide similar and useful recruitment of the body’s defensive mechanisms.
Longo’s ideas beg for our attention. Could it be this easy to reduce treatment discomfort? Could it be this easy to increase treatment effectiveness? Patients will be motivated by the first possibility and, though as their physicians we are interested in the later, it will have little to do with their decision making. If fasting works well enough that they feel the difference, they will choose to fast.
There is a broader more philosophical question that these studies raise. The recent trend in medicine, especially in oncology, is to customize treatment. In oncology, treatment is prescribed based on cancer type, staging and more upon specific genetic characteristics of the tumor cells. In the near future treatments will be custom tailored based on the tumor’s genome. Fasting as cancer treatment goes in the opposite direction of this trend of customization. Rather than employing individual genetic characteristics to fine tune treatment, fasting employs basic universal compensatory reactions that are shared not just by certain individuals but by all people and between species and kingdoms of living things. Fasting returns us to a ‘one size fits all’ approach to treatment, a general treatment rather than a specific. If testing for and treating specific oncogenes is on one side of the spectrum then fasting is certainly on the far opposite end. Naturopathic medicine and nature cure focus on the end of the treatment spectrum that engages these universal reactions that trigger the Vis.
Fasting is squarely on our side of the line and our profession should be paying attention to, promoting and making use of this research.
1. Jennifer Couzin. Can Fasting Blunt Chemotherapy's Debilitating Side Effects? Science 29 August 2008:
2. Raffaghello L, Lee C, Safdie FM, Wei M, Madia F, Bianchi G, Longo VD. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8215-20. Epub 2008 Mar 31.
3. Safdie FM, Dorff T, Quinn D, Fontana L, Wei M, Lee C, Cohen P, Longo VD. Fasting and cancer treatment in humans: A case series report. Aging (Albany NY). 2009 Dec 31;1(12):988-1007.
Free PMC Article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815756/?tool=pubmed
4. Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms.Trends Pharmacol Sci. 2010 Feb;31(2):89-98. Epub 2010 Jan 25.
Free PMC Article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829867/?tool=pubmed
5. Raffaghello L, Safdie F, Bianchi G, Dorff T, Fontana L, Longo VD. Fasting and differential chemotherapy protection in patients. Cell Cycle. 2010 Nov 15;9(22):4474-6. Epub 2010 Nov 15.
Free PMC Article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048045/?tool=pubmed
6. Lee C, Longo VD. Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients. Oncogene. 2011 Jul 28;30(30):3305-16. doi: 10.1038/onc.2011.91. Epub 2011 Apr 25.
7. Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, Pistoia V, Wei M, Hwang S, Merlino A, Emionite L, de Cabo R, Longo VD. Fasting Cycles Retard Growth of Tumors and Sensitize a Range of Cancer Cell Types to Chemotherapy. Sci Transl Med. 2012 Feb 8. [Epub ahead of print]
8. Varady KA, Roohk DJ, McEvoy-Hein BK, Gaylinn BD, Thorner MO, Hellerstein MK. Modified alternate-day fasting regimens reduce cell proliferation rates to a similar extent as daily calorie restriction in mice. FASEB J. 2008 Jun;22(6):2090-6.
9. Lee C, Longo VD. Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients. Oncogene. 2011 Jul 28;30(30):3305-16.
10. Varady KA, Roohk DJ, Hellerstein MK. Dose effects of modified alternate-day fasting regimens on in vivo cell proliferation and plasma insulin-like growth factor-1 in mice. J Appl Physiol. 2007 Aug;103(2):547-51. Epub 2007 May 10.
11. Zuccoli G, Marcello N, Pisanello A, Servadei F, Vaccaro S, Mukherjee P, Seyfried TN. Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report. Nutr Metab (Lond). 2010 Apr 22;7:33. doi: 10.1186/1743-7075-7-33.
Free PMC Article http://www.ncbi.nlm.nih.gov/pubmed/20412570
12. Seyfried TN, Marsh J, Shelton LM, Huysentruyt LC, Mukherjee P. Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer? Epilepsy Res. 2012 Jul;100(3):310-26.
13. Brandhorst S, Wei M, Hwang S, Morgan TE, Longo VD. Short-term calorie and protein restriction provide partial protection from chemotoxicity but do not delay glioma progression. Exp Gerontol. 2013 Feb 21. pii: S0531-5565(13)00047-8.
14. Safdie F, Brandhorst S, Wei M, Wang W, Lee C, Hwang S, Conti PS, Chen TC, Longo VD. Fasting enhances the response of glioma to chemo- and radiotherapy. PLoS One. 2012;7(9):e44603. doi: 10.1371/journal.pone.0044603. Epub 2012 Sep 11.
Free PMC Article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439413/