Safe, feasible and well tolerated short-term severe calorie restriction in cancer patients

Conclusion: A diet involving severe short-term calorie restriction was safe, feasible, and resulted in decreased blood sugar and growth factor concentration, reduction in peripheral blood immunosuppressive cells, and increased intratumoral T cell infiltration in patients. cancer patients receiving standard of – care therapy, according to clinical trial results.

Journal in which the study was published: Discovery of cancer, a journal of the American Association for Cancer Research.

Authors: The corresponding co-authors of the study are Claudio Vernieri, MD, PhD, medical oncologist at Fondazione IRCCS Istituto Nazionale dei Tumori and director of the metabolic reprogramming program in solid tumors at IFOM (FIRC Institute of Molecular Oncology); Filippo de Braud, MD, Director of the Oncology and Hematology Department of the Fondazione IRCCS Istituto Nazionale dei Tumori and Professor of Medical Oncology at the University of Milan; and Licia Rivoltini, MD, head of the Human Tumor Immunotherapy Unit at the Fondazione IRCCS Istituto Nazionale dei Tumori.

Background: Preclinical research has shown that severe calorie restriction in the form of cyclical fasting or a fast mimic diet (FMD) has potent anticancer effects when combined with standard pharmacological treatments. However, the safety and biological effects of calorie restriction in cancer patients have been little studied so far.

How the study was conducted: Vernieri and his colleagues enrolled 101 patients in the study with various types of tumors treated with different standard cancer therapies.

Researchers gave study participants a foot-and-mouth disease diet that consisted of a plant-based diet low in carbohydrates and protein, providing up to 600 Kcal on day 1 and up to 300 Kcal on day 1. days 2, 3, 4 and 5, for a total amount of up to 1,800 Kcal in five days. The cycle was repeated every three or four weeks up to a maximum of eight consecutive cycles. Calorie restriction was followed by a 16-23 day refeeding period, during which patients were not subjected to specific dietary restrictions but were instructed to adhere to international guidelines for proper nutrition and healthy lifestyle.

The researchers also evaluated the effects of foot-and-mouth disease on patients’ metabolism and immune responses in their peripheral blood.

To study the effects of the foot-and-mouth disease diet on intratumoral immunity, Vernieri and colleagues performed an interim review of another ongoing trial (DigesT) testing a five-day cycle against foot-and-mouth disease seven to 10 days before. surgery in patients with early breast cancer and early melanoma. Specifically, they assessed tumor-infiltrating immune cells and transcriptomic immune profiles in 22 breast cancer patients for whom sufficient tumor tissue had been collected before and after FMD.

Results: The trial achieved an overall compliance rate of 91.8% considering all FMD cycles and met its primary safety endpoint, with an incidence of FMD-related serious adverse events of 12 , 9%, the most common being fatigue, which was rarely severe. These results demonstrated that severe short-term calorie restriction was safe, feasible and well tolerated by the majority of patients, regardless of tumor type and concomitant anti-tumor therapy. Body weight loss that occurred during the five days of severe calorie restriction was reversible in most patients during the refeeding period.

In 99 evaluable patients, the FMD regimen reduced the median plasma glucose concentration by 18.6 percent, serum insulin by 50.7 percent, and serum IGF-1 by 30.3 percent, these changes remaining stable over eight consecutive cycles.

In an analysis of 38 patients at the end of a five-day cycle of foot-and-mouth disease, researchers found a significant decrease in circulating immunosuppressive myeloid subpopulations and an increase in activated CD8 + T cells. These two effects occurred independently of concomitant anti-tumor therapies and were also seen in a small group of healthy volunteers.

Interim analysis of the DigesT assay revealed a significant increase in tumor infiltrating CD8 + T cells and other changes, indicating a functional shift to an anti-tumor immune microenvironment after foot-and-mouth disease.

Author’s comments: “Our results from a first clinical trial in humans showed that a severe short-term calorie restriction regimen was safe and biologically active in patients, and that its activity likely involved the activation of immune responses,” said declared Vernieri. “Since calorie restriction is a safe, inexpensive and potentially effective approach that could be easily combined with standard antineoplastic therapies, we believe these findings could have relevant implications for cancer treatment. “

Commenting on the reversibility of body weight loss that occurred during the five days of severe calorie restriction, De Braud said, “This is a particularly important finding because it rules out the risk that patients will experience weight loss. progressive and / or malnutrition, which is associated with reduced effectiveness of cancer therapies and reduced survival. “

According to Rivoltini, “Severe calorie restriction generated a metabolic ‘shock’ that activated several populations of immune cells that could stimulate the antitumor activity of standard antineoplastic treatments. “

According to the authors, the desirable immunomodulatory effects induced by the experimental diet were observed at both the systemic and tumor level, indicating a consistent immune response that originates in the blood and then spreads to the tumor.

The authors recently launched new clinical trials, including the BREAKFAST trial, to investigate the anti-tumor effects of the dietary approach to foot-and-mouth disease in cancer patients. These studies represent the next step in understanding whether the metabolic and immunological effects induced by calorie restriction have clinically relevant consequences improving the effectiveness of antineoplastic therapies and prolonging the life expectancy of cancer patients.

Limitations of the study: The main limitation of this study is that it does not allow researchers to draw conclusions about the antitumor efficacy of calorie restriction, due to the recruitment of a heterogeneous group of patients with different types of tumors and different concomitant cancer therapies. , which prevents proper assessment. the therapeutic impact of calorie restriction in patients.

Funding and Disclosures: This study was funded by the Fondazione IRCCS Istituto Nazionale dei Tumori (Milan, Italy), the Associazione Italiana per la Ricerca sul Cancro (AIRC) and the European Union framework program Horizon 2020 funded by the Italian Ministry of Health. Vernieri, Rivoltini and de Braud were the inventors of the foot-and-mouth disease diet that was investigated in this study (patent pending).