A severely calorie-restricted, low-carbohydrate, low-protein, 5-day dietary regimen that mimics fasting was shown to be safe and feasible, and it resulted in a decrease of blood glucose and growth factor concentration, a reduction in peripheral blood immunosuppressive cells, and enhanced intratumor T-cell infiltration in patients with cancer receiving standard-of-care therapy, according to a small prospective clinical trial by Vernieri et al published in Cancer Discovery. Phase II/III trials are needed to investigate fasting-mimicking diet antitumor activity and efficacy in combination with standard antineoplastic treatments in these patients, according to researchers.

Preclinical research has found that cyclic fasting or fasting-mimicking diets enhance the activity of antineoplastic treatments by modulating systemic metabolism and boosting antitumor immunity. In this clinical trial, the researchers investigated the safety and biologic effects of cyclic, 5-day fasting-mimicking diets in combination with standard antitumor therapies in patients with various tumor types treated with different standard anticancer therapies.

Study Methodology

The researchers enrolled 101 patients with a variety of solid tumors, including lung, prostate, ovarian, pancreatic, and breast cancers, and hematologic cancers, including multiple myeloma, chronic lymphocytic leukemia, and non-Hodgkin lymphoma, into the study. All of the trial participants received an experimental fasting-mimicking diet consisting of a plant-based, calorie-restricted diet of up to 600 Kcal on day 1 and up to 300 Kcal on days 2, 3, 4 and 5, for a total of 1,600 Kcal in 5 days, in combination with their standard-of-care treatments. 

The cycle was repeated every 3 or 4 weeks for up to a maximum of eight consecutive cycles. Calorie restriction was followed by a refeeding period of 16 to 23 days, during which time patients were not subjected to specific dietary restrictions, but were recommended to adhere to international guidelines for a healthy diet and lifestyle. The investigators also evaluated the effects of fasting-mimicking diet on patient metabolism and immune responses in their peripheral blood.

To investigate the effects of the fasting-mimicking diet on intratumor immunity, the researchers performed an interim analysis of another ongoing trial, DigesT, which is testing a 5-day fasting-mimicking diet cycle 7 to 10 days before surgery in patients with early-stage breast cancer and melanoma. Specifically, they evaluated the tumor-infiltrating immune cells and trasnscriptomic immune profiles in 22 patients with breast cancer for whom enough tumor tissue had been collected before and after a fasting-mimicking diet.

Results

The researchers found that cyclic fasting-mimicking diet is safe in combination with standard anticancer treatments. The trial had a global compliance rate of 91.8% when considering all fasting-mimicking diet cycles, and met its primary safety endpoint, with an incidence of severe fasting-mimicking diet–related adverse events of 12.9% (significantly lower than the prespecified 20% threshold). The most common adverse event was fatigue, which was rarely severe. These results demonstrated that short-term severe calorie restriction was safe, feasible, and well tolerated by the majority of patients, regardless of the tumor type and the concomitant antitumor therapies. The loss of body weight that occurred during the 5 days of severe calorie restriction was reversible in most of the patients during the refeeding period.

In 99 evaluable patients, the fasting-mimicking diet regimen reduced the median plasma glucose concentration by 18.6%, serum insulin by 50.7%, and serum IGF-1 by 30.3%, with these modifications remaining stable over the course of eight consecutive cycles.

In an analysis conducted on 38 patients at the end of a 5-day fasting-mimicking diet cycle, the researchers found a significant decrease of circulating immunosuppressive myeloid subpopulations and an increase of activated CD8-positive T cells. Both of these effects occurred independently of concomitant antitumor therapies and were also observed in a small group of healthy volunteers.

The interim analysis of the DigesT trial revealed a significant increase in tumor-infiltrating CD8-positive T cells and other changes, indicating a functional switch toward an antitumor immune microenvironment following a fasting-mimicking diet.

“Our findings lay the foundations for phase II/III clinical trials aimed at investigating fasting-mimicking diet antitumor efficacy in combination with standard antineoplastic treatments,” concluded the study authors.

Clinical Significance

“Our results from a first-in-human clinical trial showed that a scheme of severe short-term calorie restriction was safe and biologically active in patients, and that its activity likely involved the activation of immune responses,” said lead study author Claudio Vernieri, MD, PhD, a medical oncologist in the Breast Unit of Fondazione IRCCS Istituto Nazionale dei Tumori and Director of the Metabolic Reprogramming in Solid Tumors program at IFOM (the FIRC Institute of Molecular Oncology), in a statement. “Since calorie restriction is a safe, inexpensive, and potentially effective approach that could be easily combined with standard antineoplastic therapies, we think these findings might have relevant implications for cancer therapy.”

Dr. Vernieri is the corresponding author for the Cancer Discovery article.

Disclosure: Funding for this study was provided by Fondazione IRCCS Istituto Nazionale dei Tumori, Associazione Italiana per la Ricerca sul Cancro (AIRC), and the European Union Framework Program Horizon 2020 funded by the Italian Ministry of Health. For full disclosures of the study authors, visit cancerdiscovery.aacrjournals.org.