Cancer treatment can be brutal for patients. Many of the tools we have—chemotherapy, radiation—are big, blunt weapons that deal punishing blows to healthy tissues along with cancerous ones. So the hunt has been on for more and more finely targeted therapies that will attack malignant cells yet minimize damage to patients' bodies.

But a new study shows that we might be able to catch cancer cells off guard by using an ancient and body-wide tactic: fasting.

Fasting has long been practiced as part of various cultural traditions and has, more recently, gained favor in alternative and complementary medicine practices. But researchers are still figuring out whether nutritional deprivation can prevent or cure some diseases—and if so, how.

The new study found that in mice with cancer, fasting prior to chemotherapy often led to more tumor shrinkage than chemo alone. And in some cases, the combination apparently eliminated certain kinds of cancer. This fasting–chemo combo, the researchers suggest, "could extend the survival of advanced stage cancer patients by both retarding tumor progression and reducing side effects," they noted in their study, published online Wednesday in Science Translational Medicine. It might be able to help early-stage patients, too, they say.

One–two punch?

The new work builds on a 2008 mouse study that found fasting helped to protect healthy cells against chemotherapy's toxic effects. That finding raised flags in the cancer field. "The concern was we were also protecting the cancer cells," says Valter Longo, a professor of biology and gerontology at the University of Southern California Davis School of Gerontology and co-author of the new paper. So he and his colleagues embarked on five years of research to see whether that was the case, testing different fasting and chemotherapy regimens on a variety of cancers—glioma, melanoma, neuroblastoma, breast and ovarian—in mice. "We not only saw that the cancer was not protected but that it was sensitized" to the chemo, he says.

In the new work, fasting mice were allowed to drink water but were not given food for at least two days. When mice with breast cancer, glioma or melanoma were subjected to two rounds of 48-hour fasting before their chemo, their tumors shrunk more than those in mice that received chemotherapy alone.

Mice that had metastasized cancer and were put on the fasting-chemo plan showed a 40 percent greater reduction in their metastases than those that had been fed before receiving chemotherapy. They also seemed to live longer after getting this treatment. With two cycles of fasting and a high dose of chemo, 42 percent of mice with one of two types of metastatic neuroblastoma lived for more than 180 days, whereas all of their well-fed, chemo-treated mice had already died by then. Fasting and chemo together had an even more dramatic effect in a third type of metastatic neuroblastoma: about a quarter of mice lived for more than 300 days, at which point they still seemed to be cancer free.

Fasting appears to protect normal cells from chemotherapy's toxic effects by rerouting energy from growing and reproducing to internal maintenance. But cancer cells do not undergo this switch to self-repair and so continue to be susceptible to drug-induced damage—making for what the researchers call a differential stress resistance. Fasting, then, the authors wrote, should enhance the power of chemotherapies without having to resort to "the more typical strategy of increasing the toxicity of drugs."

The findings give a new boost to an old approach to medical research: generalized medicine. Personalized medicine will come around eventually, Longo says. But in the meantime, he is focused on finding treatments that can work across diseases. "Especially with cancer, we have an opportunity to look at what is common," he says. "What is it that, by definition, all cancer cells will have difficulty doing?" he asks. The fasting research suggests that the answer is adaptation.

As a cancer grows and its cells mutate, they become more specifically adapted to the environment—a tactic that often spell success for the malignancy. But, Longo says, "if you start changing the environment" by fasting, it has more trouble surviving chemo assaults than healthy tissue cells. Cancer cells, at least in breast cancer experiments, seemed to be fighting to stay alive in the starvation–chemo environment by eating up even more energy, which stresses the malignant cells and causes more damage in them.

Mary Helen Barcellos-Hoff, a professor at the New York University Langone Medical Center who was not involved in the new research, wonders if fasting is also having other effects in the body that is making it less hospitable to cancer, say by increasing immune system sensitivity to the cancer or helping to squelch vascularization of tumors. "I really think modifying the microenvironment to make it less permissive is really one of the untapped potentials for future cancer therapies, she says."

But as Longo notes, fasting—for two to three days in mice, which would be the equivalent of four to five days in humans—alters the body in myriad ways. "You look at their blood, everything changes," from the factors that control blood vessel growth to acids, he says. So now he and his team are going back to look for different signs of what is changing the fasting and chemo in hopes of further optimizing the timing and treatments.

From mice to people

The medical research field is strewn with promising cures-turned-casualties that had to be scrapped after showing promise in mice and failing to work in humans. The cancer battleground is one of the most littered. "Unfortunately we can cure cancer in mice, and we have a much harder time in humans," Barcellos-Hoff says.

The new study might help to quell some of the common reservations about promise in people. "One of the thing that's impressive about it is they used so many models of mouse cancer," Barcellos-Hoff says. The researchers tested more than a dozen different types of cancer lines in mice.

The other concern in translating this research to humans is that people with cancer—and especially those already undergoing treatment—have often already lost a substantial amount of weight. So prescribing days without food could be dangerous, especially for those who already have low blood pressure, diabetes or other metabolic conditions.

Most mice in the fasting groups were able to gain their weight back in five days or so. But humans, of course, are very different animals. Small fasting studies in cancer patients—some involving as long as 62 hours without food before treatment and 24 hours without food afterward—so far have produced only small side effects, Longo says, such as fatigue and headaches. And as Barcellos-Hoff notes, "I think humans would be much grouchier after two days without food." But so far the method seems to be relatively well tolerated in small, carefully controlled studies. And "chemotherapy does make you feel really bad," Barcellos-Hoff says. So fasting "is a lot less unpleasant than many of the things cancer patients are subjected to."

But the results from human trials are not conclusive yet, and Barcellos-Hoff emphasizes that even if it has looked promising in mouse studies, fasting alone (without chemotherapy) should not be something patients attempt on their own. Especially for a patient who already has decent odds of survival, undertaking an unproved approach can be quite risky.



And although many diets and alternative treatment regimens exist, Longo cautions, "if you do it without the science, you can end up doing more damage than good." For example, when a fast is too long the immune system starts to suffer, potentially leaving a patient even less protected.



"Everything has to be timed so that it maximizes the damage to the cancer," he says. Research into that is still ongoing. Even just finding out whether fasting with chemo will be as successful in humans as it is in mice might not come quickly. "You have so many cancers and so many chemos that it's almost like a never-ending process," Longo says.