Dietary Intervention for Patients Receiving Chemoradiotherapy for Lung Cancer
Name of the Trial
Phase I Trial of a Ketogenic Diet with Concurrent Chemoradiation for Non-Small Cell Lung Cancer (KETOLUNG; NCT01419587). See the protocol summary.
Drs. Sudershan K. Bhatia, Daniel James Berg, John Michael Buatti, and Douglas R. Spitz, University of Iowa Holden Comprehensive Cancer Center
Why This Trial Is Important
One of the fundamental differences between cancer cells and normal cells is in how they break down (metabolize) nutrients to obtain the energy they need to grow and survive. Normal cells typically rely on oxidative metabolism of glucose, fatty acids, or amino acids to produce energy. In this process, which takes place inside cellular structures called mitochondria, chemical reactions that require oxygen are used to maximize the amount of energy produced from each molecule being metabolized.
Cancer cells, on the other hand, have defects in mitochondrial oxidative metabolism, leading to excess production of potentially harmful molecules known as reactive oxygen species. This can create a condition called metabolic oxidative stress. To compensate for this defect in mitochondrial metabolism, cancer cells use mitochondrial oxidative metabolism, as well as another metabolic process called glycolysis, to break down glucose.
Cancer cells are believed to use much more glucose than normal cells because, in addition to using it for energy production, cancer cells can use the products of glucose metabolism to detoxify reactive oxygen species. Researchers are exploring ways that this difference in cellular metabolism between cancer cells and normal cells might be exploited to selectively kill cancer cells.
Carbohydrates in the diet provide a readily available supply of glucose that can be used to fuel cancer cell growth. Therefore, one method being investigated is the use of a specialized diet that dramatically reduces the amount of glucose in the blood, called a ketogenic diet. This type of diet has been used for decades to help children and young adults with treatment-resistant epilepsy that causes grand mal seizures.
Ketogenic diets are so named because they force the body into a starvation-like state called ketosis, in which the liver converts fats into molecules called ketones that circulate in the blood and can serve as mitochondrial energy sources for certain tissues. Ketogenic diets, therefore, restrict the amount of glucose available to cancer cells and force them to rely more heavily on oxidative metabolic pathways that might selectively induce oxidative stress in cancer cells.
"We're interested in a ketogenic diet for cancer therapy because it limits glucose metabolism and emphasizes oxidative metabolism of fatty acids, ketone bodies, and amino acids in mitochondria. We think that mitochondria from tumor cells produce more superoxide and hydrogen peroxide [two types of reactive oxygen species] than mitochondria from normal cells," said Dr. Spitz. "Consuming a ketogenic diet should therefore selectively enhance the sensitivity of tumor cells to treatments that increase oxidative stress, such as radiation and chemotherapy."
Radiation therapy is thought to kill cancer cells by generating free radicals that cause oxidative stress, and this can be enhanced by the simultaneous use of chemotherapy (chemoradiation). "If oxidative stress is selectively enhanced in cancer cells by the ketogenic diet, the reactive oxygen species produced by the radiation and chemotherapy can more effectively damage DNA, proteins, and other critical biomolecules in the cancer cell and improve cancer cell killing, as well as improving therapeutic outcome," he explained.
In this phase I clinical trial, patients with stage III or IV (with limited metastasis) non-small cell lung cancer who are about to undergo chemoradiation therapy will consume a ketogenic diet for the duration of their treatment. Doctors will assess the safety and tolerability of the diet in conjunction with chemoradiation treatment, as well as measure the levels of glucose and ketones in the blood and oxidative stress markers in plasma and urine.
About 90 percent of calories in the ketogenic diet used in this study come from fat, whereas less than 2 percent of calories come from carbohydrates, with protein supplying the remaining calories. Participants will consume specially formulated shakes in the morning and work with a dietician to maintain a similar calorie balance throughout the day. They will begin the ketogenic diet 48 hours before the initiation of chemoradiation therapy and continue through the end of the 6- to 7-week treatment period.
"An excellent example of the role of increased glucose metabolism in cancer is the FDG-PET scan," said Dr. Bhatia. "We use PET scans with all of our lung cancer patients as part of our diagnostic and staging tests. At a fundamental level, the PET scan is done using glucose with a radioactive tag (18F-FDG) injected into the patient, and that glucose lights up the area of tumor cells because of their metabolic pathway. That's how we determine where the tumor is and, in metastatic disease, where the cancer has spread. With this diet, we hope to deprive the tumor of the glucose it depends on for energy as well as enhance oxidative stress."
This study, as well as a similar study for pancreatic cancer patients, is being conducted at the University of Iowa's Holden Comprehensive Cancer Center.