Putting cancer patients on a ketogenic diet that forces the body to burn fats preferentially rather than carbohydrates may sensitize cancer cells to radiation therapy and chemotherapy, according to new research.
While normal cells produce energy by using oxidative metabolism to break down glucose, fatty acids and amino acids, cancer cells are believed to have mitochondrial electron transport chain defects creating increased levels of reactive oxygen species (such as hydroperoxides) and oxidative stress, relative to normal cells. To compensate for the increased oxidative stress, cancer cells appear to depend upon glucose metabolism to remove hydroperoxides.
The high-fat ketogenic diet restricts the amount of glucose in the blood, forcing cancer cells to rely more heavily on oxidative metabolism, according to Bryan Allen, M.D., Ph.D., of the Radiation Oncology Department at the University of Iowa (UI), whose project was funded through a 2010-2011 RSNA Research Resident Grant.
“The ketogenic diet reduces glucose metabolism decreasing the production of the antioxidant co-factor, NADPH, necessary for hydroperoxide metabolism while increasing the cancer cell dependence on mitochondrial oxidative metabolism,” Dr. Allen said. “This results in increased oxidative stress in cancer cells, theoretically making them more sensitive to traditional chemotherapy and radiation.”
A ketogenic diet, which is 90 percent fat, 8 percent protein and 2 percent carbohydrates, has been used for at least two decades in the treatment of epilepsy and grand mal seizures in juvenile patients. Dr. Allen’s research focused on two cancers with poor outcomes: pancreatic and lung.
Researchers conducted animal trials before moving to patients in Phase I clinical trials. In that phase, two patients were placed on the ketogenic diet for five to seven weeks and entered ketosis before undergoing traditional radiation or chemotherapy. A standard of care at UI for pancreatic cancer patients eligible for this trial is radiation and gemcitabine; for lung cancer patients eligible for the trial, a standard care is radiation and carboplatin-taxol, according to Douglas R. Spitz, Ph.D., a professor and director of the Biosciences Program and Free Radical and Radiation Biology Program in the UI Holden Center’s Department of Radiation Oncology.
“In this trial, we have two patients who stayed in ketosis for six weeks and they were able to complete a course of radiation and chemotherapy,” said Dr. Spitz, who is Dr. Allen’s mentor. “They didn’t appear to have any adverse events during the therapy that could be related to the diet.”
Because the diet is so high in fat, physicians must keep a close eye on patients for possible adverse events. If a patient gets sick, physicians need to examine the patient’s lipid levels and blood counts to determine if the diet is the source of the illness. “If there’s any evidence that there is problem with the lab tests or is having significant side effects associated with chemo-radiation therapy, we reduce the amount of fat in the person’s diet or take them off the protocol,” Dr. Allen said.
Still, the idea of putting a sick patient on what would normally be considered an unhealthy diet could be a source of some concern, according to John Michael Buatti, M.D., chair of the radiation oncology department and a clinical investigator who also served as a mentor to Dr. Allen.
“The concept is a little bit counterintuitive to the way most people think about cancer,” Dr. Buatti said. “We have always worried about maintaining nutrition and if anything, trying to make sure patients didn’t potentially lose weight during their cancer therapy.” But for patients battling cancer, the ketogenic diet may offer benefits that researchers say can potentially outweigh its high-fat protocol. “The ketogenic diet, which doesn’t necessarily cause weight loss but does manipulate metabolism, had a very profound impact in terms of overall responsiveness of tumors relative to normal tissues in animal models,” Dr. Allen said. “It’s a very innovative way to approach sensitizing cancers to other therapies and the patients only need to eat the diet for six weeks.
“Traditional cancer therapies are based on exploiting the cellular differences between cancer cells and normal cells,” Dr. Allen continued. “A ketogenic diet may further enhance these differences in lung and pancreas cancer cells making them more sensitive to traditional chemotherapy and radiation.”
Another benefit of this approach is that it empowers patients to be actively involved in their treatment. “As opposed to just coming in and receiving chemotherapy or radiation therapy, patients are doing something with their diet that can also potentially help their treatment,” Dr. Buatti said.
Researchers plan to complete Phase I of the study this year and have submitted their findings in animals to the Clinical Cancer Research Journal for review. They are also applying for a renewal of a National Institutes of Health grant to fund Phase II of the study.
Dr. Allen credits the RSNA Research Resident Grant for laying the foundation for this and future research. “The RSNA grant provided the funds to perform many of the preclinical studies (animal studies and metabolic studies) necessary to move the ketogenic diet from the bench to the clinic,” he said. “From this initial funding, we determined that a ketogenic diet is tolerable, safe and effective in animals and felt comfortable moving on to a Phase I clinical study.”
Bryan Allen, M.D., Ph.D.
RSNA Research Resident Grant
“Sensitization of Lung Cancer to Chemo-Radiation Therapy Using Ketogenic Diets”
“The RSNA Research Resident Grant allowed me to obtain preliminary data that will aid in applying for future grants, specifically a National Institutes of Health grant that will greatly assist in my goal of becoming a physician scientist,” Dr. Allen said.
“Since ketogenic diets are relatively non-toxic and are well tolerated in human therapy protocols (such as epilepsy), these studies have the potential to allow for both improved cancer control as well as reduced normal tissue toxicity through de-escalation of radiation and/or chemotherapy doses without sacrificing efficacy,” Dr. Allen said.
For more information on all R&E Foundation grant programs, go to RSNA.org/Foundation or contact Scott Walter, M.S., Assistant Director, Grant Administration at 1-630-571-7816 or firstname.lastname@example.org.
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