Safety and Feasibility of Fasting-Mimicking Diet and Effects on Nutritional Status and Circulating Metabolic and Inflammatory Factors in Cancer Patients Undergoing Active Treatment

Francesca Valdemarin, Irene Caffa, Angelica Persia, Anna Laura Cremonini, Lorenzo Ferrando, Luca Tagliafico, Alberto Tagliafico, Ana Guijarro, Federico Carbone, Stefano Ministrini, Maria Bertolotto, Pamela Becherini, Tommaso Bonfiglio, Chiara Giannotti, Amr Khalifa, Moustafa Ghanem, Michele Cea, Marzia Sucameli, Roberto Murialdo, Valentina Barbero, Raffaella Gradaschi, Francesca Bruzzone, Consuelo Borgarelli, Matteo Lambertini, Claudio Vernieri, Gabriele Zoppoli, Valter D Longo, Fabrizio Montecucco, Samir G Sukkar, Alessio Nencioni, Francesca Valdemarin, Irene Caffa, Angelica Persia, Anna Laura Cremonini, Lorenzo Ferrando, Luca Tagliafico, Alberto Tagliafico, Ana Guijarro, Federico Carbone, Stefano Ministrini, Maria Bertolotto, Pamela Becherini, Tommaso Bonfiglio, Chiara Giannotti, Amr Khalifa, Moustafa Ghanem, Michele Cea, Marzia Sucameli, Roberto Murialdo, Valentina Barbero, Raffaella Gradaschi, Francesca Bruzzone, Consuelo Borgarelli, Matteo Lambertini, Claudio Vernieri, Gabriele Zoppoli, Valter D Longo, Fabrizio Montecucco, Samir G Sukkar, Alessio Nencioni

Abstract

In preclinical studies, fasting was found to potentiate the effects of several anticancer treatments, and early clinical studies indicated that patients may benefit from regimes of modified fasting. However, concerns remain over possible negative impact on the patients' nutritional status. We assessed the feasibility and safety of a 5-day "Fasting-Mimicking Diet" (FMD) as well as its effects on body composition and circulating growth factors, adipokines and cyto/chemokines in cancer patients. In this single-arm, phase I/II clinical trial, patients with solid or hematologic malignancy, low nutritional risk and undergoing active medical treatment received periodic FMD cycles. The body weight, handgrip strength and body composition were monitored throughout the study. Growth factors, adipokines and cyto/chemokines were assessed by ELISA. Ninety patients were enrolled, and FMD was administered every three weeks/once a month with an average of 6.3 FMD cycles/patient. FMD was largely safe with only mild side effects. The patients' weight and handgrip remained stable, the phase angle and fat-free mass increased, while the fat mass decreased. FMD reduced the serum c-peptide, IGF1, IGFBP3 and leptin levels, while increasing IGFBP1, and these modifications persisted for weeks beyond the FMD period. Thus, periodic FMD cycles are feasible and can be safely combined with standard antineoplastic treatments in cancer patients at low nutritional risk. The FMD resulted in reduced fat mass, insulin production and circulating IGF1 and leptin. This trial was registered on Clinicaltrials.gov in July 2018 with the identifier NCT03595540.

Keywords: body composition; cancer metabolism; circulating growth factors; feasibility; modified fasting; safety.

Conflict of interest statement

A. Nencioni and I. Caffa are inventors on patents of medical uses of fasting and FMD in oncology. V.D. Longo declares equity interest in L-Nutra Inc. M. Lambertini acted as a consultant for Roche, AstraZeneca, Lilly and Novartis, and received speaker honoraria from Sandoz, Roche, Takeda, Pfizer, Lilly and Novartis outside the submitted work.

Figures

Figure 1
Figure 1
Intervention (fasting-mimicking diet (FMD)), clinical and nutritional status evaluation and blood sampling schedule. * Patients underwent FMD cycles of shorter duration (3- or 4-day FMD) if phase angle decreased to values between 5.2° and 5.0°. If the phase angle was

Figure 2

Effects of cyclic FMD on…

Figure 2

Effects of cyclic FMD on the nutritional parameters of cancer patients undergoing active…

Figure 2
Effects of cyclic FMD on the nutritional parameters of cancer patients undergoing active anticancer treatments. (A) Pie chart representing the cancer diagnoses of the patients enrolled in the NCT03595540 clinical trial. (B) The adverse events of the FMD regime were graded according to CTCAE 5.0. (C–G) Body weight, phase angle, fat-free mass, fat mass and extracellular mass/body cell mass (ECM/BCM) ratio in patients with cancer receiving active medical treatment and cyclic FMD. To evaluate changes in these parameters, we fitted a linear mixed effects model taking into account absolute values as a function of time. (H) CT scan of Pt. #37 showing an increase in the total muscle area after one FMD cycle compared to the baseline. FMD: fasting-mimicking diet; BC: breast cancer; CRC: colorectal cancer; and PCa: prostate cancer.

Figure 3

Effects of cyclic FMD on…

Figure 3

Effects of cyclic FMD on circulating growth factors, adipokines, metalloproteinases and cyto/chemokines in…

Figure 3
Effects of cyclic FMD on circulating growth factors, adipokines, metalloproteinases and cyto/chemokines in cancer patients. Serum leptin, adiponectin, resistin, c-peptide, IGF1, IGFBP1, IGFBP3 ((A), n = 9), MMP8, MMP9, MPO, TIMP1, TIMP2, MMP9/TIMP1 complex (M/T c), OPN, ICAM1, VCAM1 and hs-CRP ((B), n = 7) before the start of a FMD cycle and immediately after it (on day 6, before re-feeding started); and before the start of the first FMD cycle (baseline) and a few days before the start of the second FMD (i.e., after 2 to 3 weeks of re-feeding; (C), n = 62; (D), n = 34) were measured by ELISA. The results are presented as fold changes vs. the pre-FMD values and were analyzed by paired two-tailed Wilcoxson rank-sum test, with the corresponding p-values shown on the top of each graph.
Figure 2
Figure 2
Effects of cyclic FMD on the nutritional parameters of cancer patients undergoing active anticancer treatments. (A) Pie chart representing the cancer diagnoses of the patients enrolled in the NCT03595540 clinical trial. (B) The adverse events of the FMD regime were graded according to CTCAE 5.0. (C–G) Body weight, phase angle, fat-free mass, fat mass and extracellular mass/body cell mass (ECM/BCM) ratio in patients with cancer receiving active medical treatment and cyclic FMD. To evaluate changes in these parameters, we fitted a linear mixed effects model taking into account absolute values as a function of time. (H) CT scan of Pt. #37 showing an increase in the total muscle area after one FMD cycle compared to the baseline. FMD: fasting-mimicking diet; BC: breast cancer; CRC: colorectal cancer; and PCa: prostate cancer.
Figure 3
Figure 3
Effects of cyclic FMD on circulating growth factors, adipokines, metalloproteinases and cyto/chemokines in cancer patients. Serum leptin, adiponectin, resistin, c-peptide, IGF1, IGFBP1, IGFBP3 ((A), n = 9), MMP8, MMP9, MPO, TIMP1, TIMP2, MMP9/TIMP1 complex (M/T c), OPN, ICAM1, VCAM1 and hs-CRP ((B), n = 7) before the start of a FMD cycle and immediately after it (on day 6, before re-feeding started); and before the start of the first FMD cycle (baseline) and a few days before the start of the second FMD (i.e., after 2 to 3 weeks of re-feeding; (C), n = 62; (D), n = 34) were measured by ELISA. The results are presented as fold changes vs. the pre-FMD values and were analyzed by paired two-tailed Wilcoxson rank-sum test, with the corresponding p-values shown on the top of each graph.

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