Fasting and Chemotherapy

Jacob Schor

October 8, 2008

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’ve been heading, everyone is going to die.  An alarm pervades the entire organism. Protective mechanisms are turned on. Cells become more resistant to toxic damage. They grow slower. One might wish that we were seeing as unified a response to our nation’s current economic situation, but let me not editorialize about such matters here.

Even knowing the magnitude of the response to fasting on a cellular level, I was surprised by the magnitude of benefit seen in an experiment in which mice were fasted prior to chemotherapy that was published last June.  So exciting are the results, a human trial is already underway.

The fellow behind this research, Valter Longo, specializes in aging and studies how caloric restriction extends life span in many species. Although still poorly understood, it is well known that animals that spend most of their lives hungry, live longer than the well fed. Cutting calories slows the growth rate of cells and makes them more resistant to stress.  The cells live longer.  So do the animals they are part of.

“Longo wondered whether this effect might help protect healthy cells from chemotherapy, which kills rapidly dividing cells, whether normal or cancerous. In yeast, he found, most cells, as expected, became more stress-resistant when nutrients were dialed down. But yeast cells expressing genes similar to the oncogenes that help drive cancer did not react to calorie restriction; they kept on growing and dividing. Longo reasoned that in cancer cells "it's the oncogenes that regulate the stress resistance," and "those are always on," causing the cells to produce growth factors unaffected by calorie restriction.” (Science 2008)

Let me try rewording that.  Hungry yeast cells become stress resistant but special yeast that are used as models for cancer cell behavior didn’t.  Anyway, Longo tried this out on mice.  Working with Lizzia Raffaghello in Genoa Italy and other colleagues at USC they subjected mice to the extreme version of caloric restriction, total fasting.  Mice who were starved for 48 to 60 hours and then given high doses of chemotherapy showed no signs of toxicity.  Many of the control animals that ate normally up to the chemo treatment died.  Dying is a rather clear sign of toxicity. 

In the next round of the experiments, the mice were injected with a nasty neuroblastoma cell line that mimics pediatric cancer. Fasting before chemotherapy did not lessen the effect of the drugs at killing these cancer cells.  Healthy cells were protected but not the cancer cells.

When this paper was published last June, it was met with a great deal of concern and cautionary quotes from oncologists.  Their warning was basically, “Don’t try this at home.”  Though the mouse response is impressive there is no certainty that people will respond as well.  Plus think about it, a 60 hour fast in a mouse may not equal to 60 hours in a person.  Three days of not eating to a mouse whose total life span is 3 years may have a larger effect in a mouse than in a person. How long should a person fast to trigger the same reaction, assuming a life span of 80 years?

The real worry about fasting cancer patients is weight loss.  Seeing a cancer patient lose weight is a red flag, a herald of bad news, for oncologists.  With advanced cancer, the body shifts how it utilizes food and derives energy from it.  The internal chemical cycles that generate energy from food become less efficient. It’s as if with advanced cancer people get terrible gas mileage from their food.  Even if they eat the same calories per day they still lose weight rapidly.  Often they aren’t able to eat as much food as they did when well.  They lose weight even faster.  This condition is called ‘cachexia.’  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 a 3 day fast sounds risky.

Even so, desperate times call for desperate measures and people have tried this at home.  Some are reporting good results encouraging even more people to try fasting prior to chemo. 

The magazine, Science, reports on one such self experimenter;

“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.”

Human trials are set to start testing this ‘treatment’ on bladder and lung cancer patients shortly.  Longo plans to recruit a dozen and a half patients who will fast for 1, 2 or 3 days before and just after chemotherapy.  They will begin gradually, starting with a single day fast and then working up to longer fasts.

Data from Longo’s mice suggest fasting would not only decrease chemo toxicity but it might also make the cancer cells more sensitive to chemo.  The study was too small to prove this but the results were suggestive it would.

This avenue of thought while certainly of interest to cancer patients, has greater implications.  Our mindset when dealing with illness often 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 adding back in those missing ingredients.  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.  Life responds to stress.  Organisms adapt to confront stress.  Using stressors to stimulate the natural protective mechanisms in the human body are at the basis of all nature cure therapies and fundamental to the practice of naturopathic medicine.

The Journal of the American Geriatric Society published an article this past March looking at Nazi concentration camp survivors and asking whether the deprivation they suffered early in life led to worse health in their later years.  It turned out that they were often in worse shape mentally, judged by the data that they were taking a greater number of psychiatric medications than the control group. Yet physically, the camp survivors were in no worse shape.  There was no difference in 7 year mortality “Fifty years after their Holocaust trauma, survivors still displayed….. no evidence …. to support the hypothesis that the delayed effects of the trauma of the Holocaust negatively influence physical health, health trajectories, or mortality.”

If enduring the Holocaust doesn’t appear to change one’s life expectancy, surely one can skip a daily vitamin now and then without adverse repercussions.  Perhaps purposefully absenting specific nutrients from the diet will trigger better absorption and utilization when the nutrients are added back in.

Longo in his next study is going to test full fasting to prepare patients for chemotherapy.   This might not be the best way to go about this. Last June, Varady et al have published results comparing caloric restriction, alternate day fasting and a modified less intense alternate day fast.  Their results, albeit in mice, suggest that modified alternate day fasting in which on the fasting days one still eats a little, about 15% of normal total calories, is just as effective at slowing cancer cell growth as the stricter diets.   Although they weren’t testing this as a preparation for chemotherapy, it does suggest that less difficult regimes than those Longo will test may still be useful

Fasting brings stress to the entire physiology.  This stress triggers compensatory reactions that protect the body from additional stressors.  In naturopathic medicine we speak of stimulating the healing force of nature, what we call in Latin, the vis medicatrix naturae. Perhaps we can think of this vis as that protective reaction that is mobilized in response to some sensed attack. 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. 

References:

Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8215-20. Epub 2008 Mar 31.Click here to read Links

    Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy.

    Raffaghello L, Lee C, Safdie FM, Wei M, Madia F, Bianchi G, Longo VD.

    Andrus Gerontology Center, Department of Biological Sciences and Norris Cancer Center, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA.

    Strategies to treat cancer have focused primarily on the killing of tumor cells. Here, we describe a differential stress resistance (DSR) method that focuses instead on protecting the organism but not cancer cells against chemotherapy. Short-term starved S. cerevisiae or cells lacking proto-oncogene homologs were up to 1,000 times better protected against oxidative stress or chemotherapy drugs than cells expressing the oncogene homolog Ras2(val19). Low-glucose or low-serum media also protected primary glial cells but not six different rat and human glioma and neuroblastoma cancer cell lines against hydrogen peroxide or the chemotherapy drug/pro-oxidant cyclophosphamide. Finally, short-term starvation provided complete protection to mice but not to injected neuroblastoma cells against a high dose of the chemotherapy drug/pro-oxidant etoposide. These studies describe a starvation-based DSR strategy to enhance the efficacy of chemotherapy and suggest that specific agents among those that promote oxidative stress and DNA damage have the potential to maximize the differential toxicity to normal and cancer cells.

CANCER RESEARCH: Can Fasting Blunt Chemotherapy's Debilitating Side Effects?

    Jennifer Couzin

    Science 29 August 2008 321: 1146-1147

J Am Geriatr Soc. 2008 Mar;56(3):470-7. Epub 2008 Jan 5.Click here to read Links

    Holocaust survivors in old age: the Jerusalem Longitudinal Study.

    Stesssman J, Cohen A, Hammerman-Rozenberg R, Bursztyn M, Azoulay D, Maaravi Y, Jacobs JM.

    Department of Geriatrics and Rehabilitation, Mount Scopus, Jerusalem, Israel.

    OBJECTIVES: To examine the hypothesis that Holocaust exposure during young adulthood negatively affects physical aging, causing greater morbidity, faster deterioration in health parameters, and shorter survival. DESIGN: A longitudinal cohort study of the natural history of an age-homogenous representative sample born in 1920/21 and living in Jerusalem. SETTING: Community-based home assessments. PARTICIPANTS: Four hundred fifty-eight subjects of European origin aged 70 at baseline and 77 at follow-up. MEASUREMENTS: Comprehensive assessment of physical, functional, and psychosocial domains; biographical history of concentration camp internment (Camp), exposure to Nazi occupation during World War II (Exposure), or lack thereof (Controls); and 7-year mortality data from the National Death Registry. RESULTS: Holocaust survivors of the Camp (n=93) and Exposure (n=129) groups were more likely than Controls (n=236) to be male and less educated and have less social support (P=.01), less physical activity (P=.03), greater difficulty in basic activities of daily living (P=.009), poorer self-rated health (P=.04), and greater usage of psychiatric medication (P=.008). No other differences in health parameters or physical illnesses were found. Holocaust survivors had similar rates of deterioration in health and illness parameters over the follow-up period, and 7-year mortality rates were identical. Proportional hazard models showed that being an elderly Holocaust survivor was not predictive of greater 7-year mortality. CONCLUSION: Fifty years after their Holocaust trauma, survivors still displayed significant psychosocial and functional impairment, although no evidence was found to support the hypothesis that the delayed effects of the trauma of the Holocaust negatively influence physical health, health trajectories, or mortality.

FASEB J. 2008 Jun;22(6):2090-6. Epub 2008 Jan 9.Click here to read

Modified alternate-day fasting regimens reduce cell proliferation rates to a similar extent as daily calorie restriction in mice.

Varady KA, Roohk DJ, McEvoy-Hein BK, Gaylinn BD, Thorner MO, Hellerstein MK.

Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Morgan Hall, Rm. 308, Berkeley, California, 94720-3104, USA. kvarady@nature.berkeley.edu

Calorie restriction (CR) and alternate-day fasting (ADF) reduce cancer risk and reduce cell proliferation rates. Whether modified ADF regimens (i.e., allowing a portion of energy needs to be consumed on the fast day) work, as well as true ADF or CR to reduce global cell proliferation rates, remains unresolved. Here, we measured the effects of true ADF, modified ADF, and daily CR on cell proliferation rates in mice. Thirty female C57BL/6J mice were randomized to one of five interventions for 4 wk: 1) CR-25% (25% reduction in daily energy intake), 2) ADF-75% (75% reduction on fast day), 3) ADF-85% (85% reduction on fast day), 4) ADF-100% (100% reduction on fast day), and 5) control (ad libitum intake). Body weights of the ADF groups did not differ from controls, whereas the CR-25% group weighed less than all other groups posttreatment. Epidermal cell proliferation decreased (P<0.01) by 29, 20, and 31% in the CR-25%, ADF-85% and ADF-100% groups, respectively, relative to controls. Proliferation rates of splenic T cells were reduced (P<0.01) by 37, 32, and 31% in the CR-25%, ADF-85%, and ADF-100% groups, respectively, and mammary epithelial cell proliferation was 70, 65, and 62% lower (P<0.01), compared with controls. Insulin-like growth factor-1 levels were reduced (P<0.05) in the CR-25% and ADF-100% groups only. In summary, modified ADF, allowing the consumption of 15% of energy needs on the restricted intake day, decreases global cell proliferation similarly as true ADF and daily CR without reducing body weight.