Fasting, Cancer and Chemotherapy: the work of Valter Longo
Jacob Schor, ND,
Fellow of the American Board of Naturopathic Oncology
Feb 13, 2012
With the publication February 8 of Valter Longo’s most recent study on fasting and chemotherapy, we are close to the day when we tell our patients to fast during chemotherapy.  In earlier publications, Longo informed us that fasting reduced chemotherapy toxicity during treatment.  In this new paper published in Science Translational Medicine, Longo takes us a step further, presenting evidence that fasting enhances the benefit of chemotherapy by sensitizing cancer cells, making it more likely they will succumb to treatment.
Typically we like to only comment on human clinical trials and Longo’s study was conducted on mice not people.  Nevertheless the information Longo has reported, is so compelling that it’s worth talking about now. 
Over the past five years, Valter Longo has introduced fasting into cancer treatment. Fasting protects normal cells in mice and very possibly in people, from the side effects caused by chemotherapy drugs.  Up until this current study, the possibility still remained that fasting might also protect tumor cells from chemotherapy, decreasing the benefit of treatment.  In this new paper the authors show that fasting actually increases the efficacy of chemotherapy in the treatment of melanoma, glioma, breast cancer and neuroblastoma.
Fasting helps chemotherapy kill cancer cells.  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.
We were first introduced to Longo’s theory that fasting was helpful by an article about his work that appeared in 2008 in the journal Science.  Valter Longo, a professor at the University of Southern California (USC) had, until his recent foray into cancer research, studied the effect of caloric restriction on life span.  Animals who spend their lives hungry live longer than well-fed animals. Cutting calories slows the growth rate of cells and makes them more resistant to stress. Knowing this, Longo questioned whether this same reaction might be useful in cancer treatment.  Slowing the growth rate of cells might offer protection against chemotherapy, which preferentially injures faster growing cells.  Longo’s earlier research using yeast suggested that cancer cells might not be able to slow their growth rates when hungry the way healthy cells do. Thus fasting might have a two-fold effect during chemotherapy, protecting healthy cells while leaving cancer cells susceptible.
Healthy cells when hungry become stress resistant; they budget their energy to protective and maintenance functions rather than spending energy on reproduction and growth.
 Longo tested his ‘hunger protects theory’ on yeast and then on mice. Mice who had been without food for 48 to 60 hours showed no signs of toxicity when given high doses of chemotherapy. 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. [2]
Not unexpectedly, this 2008 paper created quite a stir.  Oncologists warned their patients not to try this at home.  Not surprisingly many patients did.  Anecdotal stories from patients suggesting similar reduction in chemo side effects appeared.        [3]
This 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.   [4]
Why would fasting have such an impact on cancer.  Monkeys on a 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 changes a range of biological parameters, decreasing IGF-1, blood glucose and inflammatory cytokines in particular.    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.  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
yeast cells.  If even a fraction of this DSR were seen in humans it would still be clinically relevant, significantly impacting long-term survival.        [4,5]
The current study found that fasting enhanced chemotherapy toxicity against various mouse cancer models including murine breast cancer, melanoma, glioma and neuroblastoma. 
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 chemo 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 immunocompetent mice .[check this. Perhaps it was incompetent?]  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 and to which organs to tumors settled compared to the normally fed mice. 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 who underwent two cycles of fasting and high dose doxorubicin compared to 100% mortality in the mice who ate freely while undergoing similar 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 findings scream for our attention.  Could it be this easy to increase cancer treatment effectiveness? 
Prudence tells me that we need to write: ‘While this is concept has advanced from in vitro experiments to early animal trials, increased efficacy of treatment has not been proven in humans.’ 
On the other hand, what do we have to lose?  Well weight is one thing that one loses during chemo and for a skinny and sick patient, fasting may not be a great idea.  Still, Longo’s earlier human study suggests that because patients don’t feel as ill from chemo, once they start eating they quickly regain the weight they lost while fasting.
There is a broader more philosophical question that this study raises.        The trend in medicine and especially oncology has been to customize treatment.        In oncology treatment is prescribed based on cancer type, staging and more and more it is chosen based on specific genetic characteristics of the tumor cells.        In the near future none of us will be surprised if treatments are custom tailored based on the patient’s individual genome.  Fasting a patient is the opposite of this trend.  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 between species and kingdoms of living things.  Rather than a specific treatment, it is a general treatment.  If testing for and treating Her-2 neu receptor status is on one extreme of a spectrum than fasting is on the opposite end of this spectrum.        It is probably not too great a generalization to suggest that modern medicine focuses on one end of this spectrum while traditional naturopathy and nature cure have focused on the opposite end.  Fasting is squarely on our side of the line and our profession and our patients should be paying attention to this research.
Primary Reference:
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.
Footnoted references:
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. Jennifer Couzin CANCER RESEARCH: Can Fasting Blunt Chemotherapy's Debilitating Side Effects? Science 29 August 2008 321: 1146-1147
4. 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.
5. 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.
6. 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.
7. 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):