Fasting and Cancer (Part I)

We have a lot of choices to make about our diet. Add to that – doing the right thing when it comes to treating a chronic illness, fighting a virus, or losing weight, and suddenly, our nutrition choices can seem almost overwhelming.  

Well, I’m here to help. Welcome to the Nutrition Facts podcast. I’m your host – Dr. Michael Greger.

Today, we begin a two-part series on the effects of fasting on cancer. Do we feed cancer? Do we starve it? What do randomized trials tell us? Here’s our first story.

In 1974, an influential paper was published decrying “physician-induced malnutrition” as the skeleton in the hospital closet––the fact that many patients in hospitals were malnourished, which the editorial board of the journal of the AMA described as shocking. Even a single case is one too many, yet still, to this day the issue persists. If anything, people with serious illness would seem to need even more nutrition, not less.

Yet underfeeding persists, involving as many as 50 percent of hospitalized patients. The ethical principle of justice requires that every patient be fed enough, given that hospital malnutrition has been associated with increased risk of disease and death—but is it cause and effect? Does eating less make you sicker, or does being sicker just make you eat less? You don’t know, until you put it to the test. But would it be ethical to randomize patients to remain starved? I mean, wouldn’t nutritional support obviously help? It turns out, no. Not one but 22 randomized controlled trials involving thousands of malnourished patients found that sure, you can plump them up; however, there seems to be little effect on clinical outcomes. In fact, sometimes it can actually make things worse. Maybe, your body is losing your appetite on purpose.

Ever since Hippocrates, fasting has been offered as treatment for acute and chronic diseases, based on the observation that when people get sick they frequently lose their appetite. So, maybe that’s part of our body’s wisdom, and we shouldn’t force it? Okay, but that was 2,400 years ago. What have we learned since?

Along with fever, decreased food consumption is indeed one of the most common signs of infection––often regarded as an undesirable manifestation of sickness, but it’s actually an active, beneficial defense mechanism. Now obviously, chronic under-nutrition can impair our defenses, but data suggest that in the short-term, immune function can be enhanced by lowering food intake. Some of the data are crazy, like 95 percent alive versus 95 percent dead after the same infection, but that was in mice (starved for 48 hours). Obviously, we can’t randomize people to a fatal infection, but what they showed is that the blood from starved mice was nearly eight times better at killing off the invading bacteria in a petri dish. It dramatically boosted the capacity of their white blood cells to kill off the pathogens. Why can’t we just test people like that?

Indeed, we can. Researchers fasted people for two weeks on an 80-calorie-a-day diet, and their white blood cells showed the same kind of boost in bacteria-killing activity, a boost in antibody production, and natural killer cell activity increased by an average of 24 percent. Now, that’s especially interesting because our natural killer cells don’t just help clear infections, but also kill cancer cells. In fact, that’s how they measured natural killer cell activity, by pitting them against K562 cells––those are tumor cells, human leukemia cells. So, two weeks of fasting boosted their bloodstream’s ability to kill off cancer cells by 24 percent.

So, fasting is said to improve anticancer immunosurveillance, or, more poetically, “stimulate the appetite of the immune system for cancer.” So, why isn’t fasting used more to treat cancer?

Until recently, fasting therapy was not considered to be a treatment option in cancer, related to the fact that a common therapeutic goal in palliative cancer treatment is to avoid weight loss, and to counteract the wasting syndrome known as cachexia, which is the ultimate cause of death in many cancer cases.

Tumors are voracious, rapidly expanding, needing lots of energy and protein, and so cancer metabolically reprograms the body to start breaking down to feed it. It does this by triggering inflammation throughout the body. It’s not just that people lose their appetite. The fundamental difference between the weight loss observed in cancer cachexia and that seen in simple starvation is the lack of reversibility with feeding alone.

For example, here’s the weight of a cancer patient that started to drop. No wonder, they were only taking in a few hundred calories a day. So, in addition to giving them about 100 grams of protein a day, they stuck a tube into a vein and infused up to 4,000 calories a day. But it didn’t matter. They continued to lose weight. Therapeutic nutritional interventions to correct or reverse cachexia have met with little success. The best treatment for cancer cachexia, therefore, is to treat the cause and cure the cancer. In fact, maybe forcing extra nutrition on cancer patients could be playing right into the tumor’s hands. Like in pregnancy when the fetus gets first dibs on nutrients even at the mother’s expense, the tumor may be first in the feeding line. Maybe our loss of appetite when we get cancer is even a protective response.

But in the 1960s, TPN was born––total parenteral nutrition––where people no longer had to eat—you could infuse all the nutrition people needed straight into their veins, and the modern era of nutrition support was born. It became widely accepted and implemented, growing into a multibillion-dollar industry. So, should it be routinely given to malnourished cancer patients? The answer is not as obvious as one might think. When it was put to the test in dozens of randomized trials, the results were both disappointing and surprising. Parenteral nutrition didn’t just fail to provide any benefit to these patients; it caused harm. Not only did it appear to provide zero survival benefit; there was an increase in complications and infections, and a decrease in tumor response to chemotherapy––presumed to be due to all those extra nutrients stimulating tumor growth.

Similarly, oral nutritional interventions in malnourished patients with cancer, like giving them bottles of Ensure, found no survival advantage. Despite the lack of demonstrated benefit, the knee-jerk reaction of many oncologists to the idea of cancer patients fasting is the concern they’re not eating enough already. But you don’t know until you put it to the test, which we’ll explore, next.

For the past 50 years, chemotherapy has been a major medical treatment for a wide range of cancers. Its main strategy has been largely based on targeting cancer cells, by means of DNA damage caused in part by the production of free radicals. Although these drugs were first believed to be quite selective for tumor cells, we now know that normal cells also experience severe chemotherapy-dependent damage, leading to dose-limiting side effects, including bone marrow and immune system suppression, fatigue, vomiting, diarrhea, and in some cases, even death. And if you do survive, the DNA damage to normal cells can even lead to new cancers down the road. There are cell-protecting drugs that have been tried to reduce the side effects so you can pump in higher chemo doses, but these drugs have not been shown to increase survival––in part because they may also be protecting the cancer cells. What about instead using fasting for cellular protection during cancer treatment?

Fasting may have an unrecognized role in cancer prevention and treatment. Short-term fasting before and immediately after chemotherapy may minimize side effects, while at the same time may actually make cancer cells more sensitive to treatment. That’s exciting. During nutrient deprivation, healthy cells switch from growth to maintenance and repair, but tumor cells are unable to slow down their unbridled growth due to growth-promoting mutations that led them to become cancer cells in the first place. This inability to adapt to starvation may represent an important Achilles’ heel for many types of cancer cells.

As a consequence of these differential responses of healthy versus cancer cells to short-term fasting, chemotherapy causes more DNA damage and cell suicide in tumor cells, while potentially leaving healthy cells unharmed. Thus, short-term fasting may protect healthy cells against the toxic properties of chemotherapy and render tumor cells more sensitive––or at least that’s the theory. Let’s test it out.

Tyrosine kinase inhibitors are a group of chemo drugs that are now the mainstay of treatment in many types of cancer. The researchers conclude that these TKI drugs that are commonly administered for treating solid tumors become potentiated in their activity by 24 hours of starvation––but that’s in a petri dish.

Similar results were found for breast cancer and a chemo drug called doxorubicin. Starve those cells for 48 hours first, and the chemo can completely keep them in check. Even the short-term starvation alone can restrain growth. Short-term fasting raises the possibility that you could get twice the effect, for half the dose, which may be particularly important for a drug as toxic as doxorubicin, which causes heart failure in as many as one in three at higher doses. Again, though, these are just in vitro studies in a petri dish.

Then, researchers moved to mice and found the same dual benefit: less toxic chemo, yet at the same time more effective, and not just by a little. A high enough chemo dose to kill 100 percent in less than a week. But after being starved for 60 hours, after the same dose, 100 percent survived. Okay, that’s the toxicity. What about efficacy? And, this translated into improved survival.

Interestingly, fasting alone appeared to work as well as the chemo, and the same thing with radiation. Unbridled tumor growth knocked down by radiation therapy, and even more so after the combination of radiation and alternate-day fasting. But alternate-day fasting alone seemed to do as well as the radiation.

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