Chapter 7 Nutrition and Fasting-Mimicking Diets in Cancer Prevention and Treatment*

[For their review of this chapter, I thank Tanya Dorff, oncologist and associate professor of clinical medicine, USC Norris Comprehensive Cancer Center; Alessio Nencioni, associate professor and doctor of internal medicine and geriatrics, University of Genova San Martino Hospital; and Alessandro Laviano, professor of clinical medicine, Sapienza University, Rome.]

The Magic Shield

My graduate school training and research in pathology, immunology, and neurobiology was “translational”—meaning, I focused on turning basic scientific discoveries into medical therapies for humans. With this as my goal, fifteen years ago I decided to switch a large part of my lab to clinical research. As I mentioned in chapter 2, I was motivated by my experiences with children suffering from cancer at Children’s Hospital Los Angeles. The medical community, I realized, had a deep understanding of how DNA and cellular damage affect cancer cells, but almost no knowledge of how to protect normal cells, which was the focus of my lab.

Our first cancer-related mouse study, as mentioned in chapter 2, was very simple—basically a spin-off of our studies with microorganisms.

Paola Fabrizio, a postdoctoral fellow researcher in my group, and I coauthored a series of papers on studies using yeast as a model organism to identify what genes accelerate the aging process. Mario Mirisola, another researcher in my laboratory, helped me identify the links between genes that accelerate aging and make cells more vulnerable, and specific nutrients. Remarkably, the genes that made the cells weaker were the same genes central to cancer—the oncogenes.

Here’s how the process works: When certain genes in cancer cells are modified through a mutation (a change in the DNA sequence), they become oncogenes. This change lets cancer cells divide more than they should, regardless of the signals they receive to stop dividing. We discovered that oncogenes also make cells weaker and more vulnerable to the damage caused by toxins. This occurs because these same oncogenes give cells a key characteristic: the ability to disobey orders and continue growing.

When I began my cancer studies, every researcher was looking for a magic bullet that would seek out and destroy only cancer cells. I don’t remember when I first dreamed up the idea, but I remember calling one of my colleagues, a famous aging researcher, to float my theory: “I think I’ve figured out a way to distinguish all cancer cells from all normal cells,” I told her. “It’s not a magic bullet—it’s a magic shield.”

I don’t think she had any idea what I was talking about.

What I proposed, and eventually called “differential stress resistance,” was based on the idea that if you starve an organism, it will go into a highly protected, nongrowth mode—this is “the shield.” But a cancer cell will disobey this order and continue growing even when it is starved, because the oncogene is stuck in an “always on” mode.

Imagine a battlefield where ancient Romans and Carthaginians are mixed together wearing very similar uniforms. The common approach of cancer therapies is to seek a magic “arrow” (or “bullet”) that will kill only the Carthaginian soldiers, without harming the Romans. This is tricky, because the soldiers all look the same to archers standing fifty yards away.

But suppose before shooting their arrows, the archers ordered the soldiers, in Latin, to kneel and raise their shields. Because only the Romans would understand the command, they would take cover, while the Carthaginians would remain standing, exposed to the incoming arrows.

In this imaginary historical example, the Romans are the normal cells of the body, the Carthaginians the cancer cells, the archers the oncologists, and the arrows the chemotherapy. If you starve a cancer patient before injecting chemotherapy, normal cells will respond by putting up a defensive shield. But the cancer cells will ignore the command to kneel and thus remain vulnerable—providing a way to potentially eradicate cancer cells with minimal damage to normal cells.

When I first proposed starving cancer patients, oncologists thought it was a very bad idea. Because cancer patients often lose weight during chemotherapy, oncologists instruct them to eat more, not less. Clearly, we needed very convincing results in mice before we would get approval for a clinical trial with human subjects.

I asked Changhan Lee, one of my graduate students in the Los Angeles laboratory, and Lizzia Raffaghello, a researcher in Genoa, to perform a simple experiment: switch mice with cancer to a water-only diet for two or three days before giving them multiple cycles of chemotherapy.

The results were stunning: virtually all the fasting mice were alive and moving around normally after high-dose chemotherapy. Mice on a normal diet, however, were sick and moving very little after chemotherapy. In the following weeks, 65 percent of the mice that did not fast died, whereas nearly all the fasted mice survived. We reproduced this same effect using a wide variety of chemotherapy drugs. As hoped and predicted, starvation consistently caused “multi-stress resistance,” or protection against many different toxins in normal cells, but not cancer cells. We now knew this approach had great clinical potential, but it still would not be easy getting the medical community to give it a chance.

A Note to Animal Activists

This seems like a good place to say a word about animal testing. From time to time I receive emails from animal rights activists asking why mice must suffer and die for the sake of research.

Here is my answer:

First, we do as much of our work as possible with cells and microorganisms, not mice. However, before any human clinical trial can begin, we have no choice but to test interventions in mice.

Regarding the supposed cruelty of a forced fast, it’s worth noting that mice, like humans, are perfectly capable of going without food for a few days. Indeed, they benefit from fasting—with longer, healthier, less disease-prone lives. It’s true that when we give the mice chemotherapy, they suffer. I am troubled by this fact. It seems morally wrong. But I don’t see any alternative.

We confine our animal studies to the minimum required in the lead-up to human clinical trials. In almost every case, these studies target advanced-stage diseases either deadly or devastating to patients.

A few years ago, I responded to a letter from an animal activist with the following question: “If your child, sister, or father was dying, and the only treatment that might save his/her life needed to be tested first in mice, would you condone the mouse experiments? Or would you choose to see your loved one die?”

I know many activists will still object, but I ask that they be honest and consider the consequences. If they don’t condone animal experiments under any circumstances, even those necessary to develop treatments for deadly diseases, then they should never take any drug—even aspirin or antibiotics—and tell their family members to do the same.

I believe animal experiments should be undertaken only as a precursor to human clinical trials in the treatment of advanced-stage and major illnesses. In the absence of better options, these trials are, unfortunately, a necessary evil.

Curing Cancer (in Mice)

Here’s another military scenario with parallels to fighting cancer: In 1812, Napoleon invaded Russia with more than 450,000 men. As the French army moved toward Moscow, the Russian forces didn’t fight. They retreated, burning their own villages and towns before the enemy’s advance.

Napoleon was surprised and confused. The invasion had started in June, but the Russians refused to fight until December. The strategic retreat was meant to weaken the French army. By winter, Napoleon’s army was in tatters after enduring months of starvation, freezing conditions, and the final attack by the Russians. When the war ended, 400,000 French soldiers had perished.

Cancer cells behave like Napoleon’s army, advancing even when it would be wiser to stop. To stay alive, they require a lot of nourishment. The typical nutritional recommendation given by doctors to cancer patients is to “eat well,” and sometimes to “eat more than normal.” This makes intuitive sense, as it made intuitive sense for the Russian army to engage Napoleon’s invaders the moment they arrived, in the summer of 1812, when they were well fed. But because the Russians waited until the French soldiers were at their weakest, the combination of cold, starvation, and targeted attacks by the Russians defeated them permanently. In the same way, starved cancer cells are most vulnerable to the assault of chemotherapy after fasting.

7.1. Percentage of lung cancer remission in mice subjected to the FMD with and without chemotherapy¹

7.2. Cycles of FMD reduce and delay cancer in mice

Having conceived the idea of a starvation-induced magic shield, I remembered a basic lesson from evolutionary biology: the great majority of genetic mutations (changes in the DNA) are deleterious, but their negative consequences usually appear only under certain conditions. Abundant mutations in the DNA sequence of cancer cells may well increase their ability to grow, but those same mutations will greatly impede the cancer cell’s ability to survive in challenging environments, for example under the double onslaught of starvation and chemotherapy.

Could this theoretical scenario actually work? Our animal studies and those of other researchers show that fasting, in addition to protecting normal cells, makes chemotherapy much more toxic to melanoma, breast cancer, prostate cancer, lung cancer, colorectal cancer, neuroblastoma, and many other cancers. In many cases, cycles of fasting (or of a fasting-mimicking diet) are as effective as chemotherapy at fighting cancer. However, neither strategy alone is optimal. Permanent therapeutic effects are achieved only through the combination of fasting and chemotherapy. In mouse studies, we saw fasting combined with chemotherapy definitively cured cancer even in the disease’s end stages, after it had metastasized. Not all mice were cured, but we and others regularly obtained a 20 to 60 percent cure rate for a variety of cancers.

FMD and Immune-System-Dependent Killing of Cancer Cells

Among new therapies to treat and, in some cases, cure cancer, perhaps the most promising is immunotherapy, which relies on the immune system to kill cancer cells. In another very promising study at USC, we showed that FMD can trigger the same effects produced by immunotherapy.² The study, which looked at breast cancer and skin cancer cells, found that FMD performs two main functions: (1) it weakens cancer cells and removes the protective shield safeguarding them from immune cells; and (2) it renews and revs the immune system, making it more aggressive toward the cancer.³

FMD and Chemotherapy-Related Steroids

Corticosteroids such as prednisolone, methylprednisolone, and dexamethasone are frequently used in combination with chemotherapy in cancer treatment. In a recent publication, we showed that the corticosteroid dexamethasone increased the toxicity to mice of the chemotherapy drug doxorubicin by increasing the level of glucose in the blood.⁴ In earlier chapters, I described how glucose accelerates aging in cells but also makes them weaker when exposed to toxins. Thus, by increasing the levels of blood glucose, corticosteroids make normal cells in mice weaker while probably making cancer cells stronger. This effect was reversed by adding the fasting-mimicking diet to the dexamethasone and chemotherapy treatment. Thus, our results indicate that corticosteroids should never be combined with chemotherapy unless there is no viable alternative. In fact, high glucose levels in combination with chemotherapy in patients are associated with an increased risk of developing infections and with higher death rates when compared with patients with normal blood glucose.⁵ Thus, both our mouse data and preliminary clinical data indicate that steroid hormones that increase blood glucose levels can be detrimental in combination with chemotherapy.

Fasting and Fasting-Mimicking Diets in Human Cancer Treatment

After the 2008 publication of our first study on the powerful, protective effect of fasting on mice exposed to chemotherapy, the press was abuzz with stories on a fasting-dependent “magic shield” with the potential to protect cancer patients. One such article in the Los Angeles Times caught the eye of a local judge, Nora Quinn, who had recently been diagnosed with breast cancer and was about to undergo chemotherapy. Shortly after the story appeared, one of the judge’s friends called me at USC and informed me that Quinn had been fasting for eight days. I was horrified. “That’s crazy,” I said. “Please tell your friend to start eating immediately.”

As the news reached patients, many decided to improvise and came up with their own dangerous versions of the FMD. Luckily for Quinn, she ended up responding well to shorter periods of fasting in combination with chemotherapy, and didn’t suffer many of the treatment’s debilitating side effects. I’m happy to report that when I recently communicated with her, she remained cancer-free.

Another early adopter of FMD was Air France pilot Jean-Jacques Trochon. Diagnosed with metastatic kidney cancer and multiple masses in the lungs, he had read about our mouse studies in the news and contacted me seeking advice on fasting before chemotherapy. Working with his oncologist, Trochon followed all my instructions with disciplined rigor to combine an FMD with a plant-based therapy developed by another scientist. Two years later, he was cancer-free and had returned to flying.

These anecdotes aren’t proof that the combination of anticancer therapy and FMD cures some cancers. But together with the mouse and the clinical data, they point to a potentially effective strategy for improving conventional treatment options while reducing side effects.

After we published the 2008 fasting and chemotherapy mouse study, emails started pouring in from cancer patients interested in trying FMD. I put a young physician working in my laboratory in charge of following up and communicating with these patients’ oncologists.

In our initial interactions with clinical oncologists, we were not taken seriously. But we had compared the effects of fasting with the chemotherapy drug of choice in the treatment of various cancers. We knew that combining the two had produced a synergic boost in efficacy, at least in mice.

We called the oncologists of each patient who had contacted us. Some wouldn’t return our calls. In several cases, my researcher showed up at the clinic to personally request copies of the patients’ files. Eventually we collected data on ten patients: seven women and three men, between the ages of forty-four and seventy-eight, diagnosed with different types and stages of cancer:

Demographical and Clinical Information of Patients

	Gender	Age	Primary neoplasia	Stage at diagnosis
Case 1	Female	51	Breast	IIA
Case 2	Male	68	Esophagus	IVB
Case 3	Male	74	Prostate	II
Case 4	Female	61	Lung (NSCLC)	IV
Case 5	Female	74	Uterus	IV
Case 6	Female	44	Ovary	IA
Case 7	Male	66	Prostate	IV/DI
Case 8	Female	51	Breast	IIA
Case 9	Female	48	Breast	IIA
Case 10	Female	78	Breast	IIA

7.3. Personal and clinical data of ten patients involved in the study focused on fasting and chemotherapy combination

7.4. Self-reported side effects after chemotherapy with and without fasting

Each of these patients had voluntarily fasted for 48 to 140 hours prior to and 5 to 56 hours following chemotherapy. They had received an average of four cycles of various chemotherapy drugs in combination with fasting. None reported significant side effects caused by the fasting itself, other than hunger and lightheadedness. Six patients who underwent chemotherapy both with and without fasting reported a reduction in fatigue, weakness, and gastrointestinal side effects while fasting. In patients whose cancer progression could be assessed, fasting did not impede the chemotherapy-induced reduction of tumor volume or tumor markers.

Since then, several other clinical studies have followed.

Clinical Trials

In collaboration with oncologists at the USC Norris Comprehensive Cancer Center, we performed a clinical trial with eighteen patients on a water-only fast of 24, 48, and 72 hours’ duration before receiving platinum-based chemotherapy.⁶ Below are the results. In terms of side effects caused by chemotherapy, 72-hour fasting was generally associated with more protection than 24-hour fasting was. However, the water-only fasting was so difficult for patients that it took over 5 years to complete this small study. This limitation led to funding by the National Cancer Institute of the US National Institutes of Health to develop a FMD specific for cancer (see below).

Toxicity	24 hours # (%) N = 6	48 hours # (%) N = 7	72 hours # (%) N = 7
Constitutional / General
Fatigue Grade 1 or 2	6 (100%)	5 (71%)	6 (86%)
Alopecia Grade 1	6 (100%)	5 (71%)	7 (100%)
Gastrointestinal
Nausea Grade 1 or 2 Vomiting Grade 1 or 2	6 (100%) 5 (83%)	6 (86%) 3 (43%)	3 (43%) 0
Constipation Grade 1 or 2 Diarrhea Grade 1 or 2	3 (50%) 2 (33%)	2 (28%) 0	3 (43%) 4 (57%)
Hematologic
Neutropenia Grade 1 or 2 Neutropenia Grade 3 or 4	1 (17%) 4 (67%)	3 (43%) 1 (14%)	1 (14%) 2 (29%)
Thrombocytopenia Grade 1 or 2	4 (67%)	1 (14%)	1 (14%)
Laboratory / Metabolic
Hyponatremia (Low serum sodium) Grade 1 Hyponatremia Grade 3 Hypokalemia (Low serum potassium) Grade 1 Hyperglycemia (Low serum glucose) Grade 1 or 2	1 (17%) 1 (17%) 1 (17%) 4 (67%)	1 (14%) 0 2 (28%) 1 (14%)	1 (14%) 0 0 0
Elevated AST/ALT Grade 1	4 (67%)	0	3 (43%)
Neurologic
Peripheral Neuropathy Grade 1	3 (50%)	1 (14%)	1 (14%)
Dizziness Grade 1 or 2	1 (17%)	5 (71%)	2 (29%)

7.5. Different protective effects of fasting for 24, 48, and 72 hours against side effects of platinum-based chemotherapy in breast, ovarian, uterine, and pulmonary cancer patients

Leiden University in Holland also published a small, randomized clinical trial of thirteen patients undergoing two days of water-only fasting compared with a control group.⁷ The study is also consistent with the protective benefits of fasting with respect to chemotherapy side effects.

Finally, a study at Charité–University Medicine Berlin tested the impact of a very low-calorie FMD in thirty-four women with breast and ovarian cancer. Each woman received multiple cycles of chemotherapy either with or without fasting. Those on the FMD experienced a clear reduction in the side effects caused by chemotherapy. That study has not yet been published.

Ongoing clinical trials involving more than three hundred patients are currently testing the efficacy of a four-day FMD in combination with standard cancer therapy. Centers involved in these trials include the Mayo Clinic, the USC Norris Comprehensive Cancer Center, Leiden University Medical Center, and the University of Genova San Martino Hospital. An additional ten European and US hospitals are committed to begin similar trials once funds become available.

FMD AND CANCER THERAPY: CLINICAL EVIDENCE AND GUIDELINES FOR ONCOLOGISTS AND CANCER PATIENTS

Extensive animal testing from at least six independent laboratories shows the efficacy of fasting or FMD in protecting against the side effects caused by a wide range of chemotherapy drugs.
Extensive animal testing from at least six independent laboratories shows the efficacy of fasting or FMD in increasing the effect of standard therapy on breast cancer, prostate cancer, colorectal cancer, pancreatic cancer, neuroblastoma, glioma, lung cancer, mesothelioma, melanoma, and others.
Three completed small clinical trials and one case series report involving seventy-five patients provide initial evidence that fasting and FMD are safe and potentially effective in protecting patients from multiple side effects of chemotherapy.
Ongoing clinical trials on Chemolieve at leading cancer centers, which have now tested over two hundred patients, provide additional evidence for the safety and potentially protective effect of the FMD against chemotherapy side effects.

The FMD product for cancer patients, Chemolieve, can be recommended to patients by their oncologists once additional tests are done and if the results are positive. Until this product is shown to be effective and comes to market, the FMD remains an unproven method of cancer treatment and should be considered preferably as part of clinical trials and only in combination with standard-of-care therapies under medical supervision. The patient should be informed of the risks of undergoing a support therapy that is not yet fully tested. Following are my FMD recommendations to oncologists and cancer patients:

If the oncologist agrees, the patient may fast or adopt an FMD for three days before and one day after receiving chemotherapy or other standard-of-care drugs. Depending on the type of chemotherapy being administered and the interval between cycles, this regimen could change. Patients should hold off on resuming their regular diet until the chemotherapy is below toxic blood levels (usually 24 to 48 hours after administration). For treatment lasting up to three days, patients can adopt an FMD one day prior to, three days during, and one day after chemotherapy for a total of five days. Longer treatment periods, while difficult to integrate with fasting, may still be combined with a higher-calorie FMD with the oncologist’s approval.
We have rarely seen major side effects caused by FMDs, and all occurred when people made their own fasting or FMD; one patient showed an increase in liver toxicity markers while doing her own fast while receiving a chemo cocktail. Several patients fainted while taking hot showers after multiple days of fasting—probably because of the reduction in blood pressure and glucose levels. Another FMD-related risk: resuming regular eating habits immediately following chemotherapy could cause liver damage due to the combination of hepatotoxic drugs and the proliferation of liver cells. For this reason, it is important to wait a minimum of 24 hours after the chemotherapy is administered before resuming a normal diet.
While most people can safely drive or operate machinery while fasting, a few will be impaired. When in doubt, avoid both activities during the fasting period.
Starting 24 hours after chemotherapy, the patient should eat only rice, pasta, bread or a similar source of carbohydrates, vegetables, and vegetable soups, and some fruit for a full 24 hours. Then a normal diet can be resumed, paying particular attention to nourishment (vitamins, minerals, protein, and essential fats).
The patient should try to return to regular body weight before undertaking another fasting cycle.
With regard to weight loss caused by fasting, obese patients should consult their personal physician on the advisability of maintaining their new weight or regaining what they lost.
Diabetic patients should not undergo fasting unless it is approved by their diabetologist or endocrinologist.
Patients should not fast while taking metformin, insulin, or similar drugs.
Patients on hypertension medication should speak to their doctor about blood-pressure drops caused by fasting and the risk of combining fasting with medications.
Until clinical trials are completed, fasting will remain an experimental procedure and should be considered only with the approval of a patient’s oncologist in combination with standard-of-care therapies, preferably as part of a clinical trial and when other options are not available or are known to be ineffective.
Between fasting cycles, we recommend that cancer patients maintain a low-sugar, mostly plant-based, low-protein but otherwise high-nourishment diet which allow them to maintain a healthy weight and normal BMI. A registered dietitian should be consulted to avoid malnourishment and unwanted weight loss (see the Longevity Diet in chapter 4).

Nutrition and FMD for Cancer Prevention

Although the Longevity Diet (see chapter 4) can be generally applied for cancer prevention, it has the potential to be especially beneficial for people with certain genetic mutations—such as the BRCA genes—which put them at a greatly increased risk of cancer. Prophylactic mastectomies and other surgical procedures can reduce the incidence of genetically induced cancers, but nutrition and FMD may also help. Dietary interventions additionally have the potential to reduce the chance of recurrence in previously diagnosed patients whose cancer is in remission. It is important to stress that patients should not attempt to replace prophylactic mastectomies with nutritional interventions whose efficacy remains to be established.

7.6. Insulin-like growth factor-1, associated with cancer and aging, is reduced more effectively, after three cycles of FMD in individuals at risk for cancer (>225, or with IGF-1 levels above 225 ng/mL at the beginning of the trial)

BELOW ARE DIETARY RECOMMENDATIONS FOR PEOPLE AT HIGH RISK FOR CANCER:

Follow the Longevity Diet, described in chapter 4, with protein intake reduced to the lower range of about 0.31 grams per pound of body weight per day.
Limit fish intake to one or two times a week; otherwise stick to plant-based foods.
Reduce sugars to very low levels. Also minimize the consumption of pasta and breads. It is important to keep blood-sugar levels as low as possible within the safe range.
Maintain a healthy weight and BMI (see chapter 4).
Exercise regularly (see chapter 5).
Undergo a five-day FMD every one to three months, depending on your weight and health status (once every three to six months if you are very healthy with ideal weight and abdominal fat; once every month if you are overweight or obese and at high risk for cancer). Remember that in mouse studies, FMD was as effective as chemotherapy against cancer. Instead of damaging normal tissues and organs, it protected them.
Nourish yourself with essential fatty acids (omega-3 and omega-6), vitamins, and minerals from a variety of vegetables (broccoli, carrots, green peppers, tomatoes, garbanzo beans, lentils, peas, black beans, etc.) and fish (salmon, anchovies). Your immune system is one of the major defenses against cancer. The diet must be balanced to kill cancerous or precancerous cells without causing deficiencies in your immune system or hormonal changes that can make you frail. See the high-nourishment diet examples at the end of this book.
Discuss with your oncologist the option of taking 6 grams of vitamin C or Ester-C® daily for a few weeks every 6 months. Multiple studies have demonstrated vitamin C to possess cancer-fighting properties, although its effectiveness in preventing cancer is controversial. Either way, vitamin C taken for a few weeks every 6 months at this level is not known to have major side effects, and the patient and doctor could consider continuing high-level vitamin C consumption for longer periods.
Consume plenty of good fats from olive oil, nuts, and fish, but minimize saturated fats, even those that are vegetable-derived.
Consume as little alcohol as possible.

Our clinical trials looking into FMD and cancer prevention and treatment are ongoing, but if early results are any indication, it could be a powerful new weapon in the arsenal we have to fight, and one day defeat, cancer. Next up, a look at our studies into FMD and diabetes.