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
References
- Caffa I., D’Agostino V., Damonte P., Soncini D., Cea M., Monacelli F., Odetti P., Ballestrero A., Provenzani A., Longo V.D., et al. Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition. Oncotarget. 2015;6:11820–11832. doi: 10.18632/oncotarget.3689.
- Caffa I., Spagnolo V., Vernieri C., Valdemarin F., Becherini P., Wei M., Brandhorst S., Zucal C., Driehuis E., Ferrando L., et al. Fasting-mimicking diet and hormone therapy induce breast cancer regression. Nature. 2020;583:620–624. doi: 10.1038/s41586-020-2502-7.
- Levesque S., Le Naour J., Pietrocola F., Paillet J., Kremer M., Castoldi F., Baracco E.E., Wang Y., Vacchelli E., Stoll G., et al. A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice. Oncoimmunology. 2019;8:e1657375. doi: 10.1080/2162402X.2019.1657375.
- Nencioni A., Caffa I., Cortellino S., Longo V.D. Fasting and cancer: Molecular mechanisms and clinical application. Nat. Rev. Cancer. 2018;18:707–719. doi: 10.1038/s41568-018-0061-0.
- Bianchi G., Martella R., Ravera S., Marini C., Capitanio S., Orengo A., Emionite L., Lavarello C., Amaro A., Petretto A., et al. Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models. Oncotarget. 2015;6:11806–11819. doi: 10.18632/oncotarget.3688.
- Di Biase S., Lee C., Brandhorst S., Manes B., Buono R., Cheng C.W., Cacciottolo M., Martin-Montalvo A., de Cabo R., Wei M., et al. Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity. Cancer Cell. 2016;30:136–146. doi: 10.1016/j.ccell.2016.06.005.
- Lee C., Raffaghello L., Brandhorst S., Safdie F.M., Bianchi G., Martin-Montalvo A., Pistoia V., Wei M., Hwang S., Merlino A., et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci. Transl. Med. 2012;4:124ra27. doi: 10.1126/scitranslmed.3003293.
- Pietrocola F., Pol J., Vacchelli E., Rao S., Enot D.P., Baracco E.E., Levesque S., Castoldi F., Jacquelot N., Yamazaki T., et al. Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance. Cancer Cell. 2016;30:147–160. doi: 10.1016/j.ccell.2016.05.016.
- Di Biase S., Shim H.S., Kim K.H., Vinciguerra M., Rappa F., Wei M., Brandhorst S., Cappello F., Mirzaei H., Lee C., et al. Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy. PLoS Biol. 2017;15:e2001951. doi: 10.1371/journal.pbio.2001951.
- Raffaghello L., Lee C., Safdie F.M., Wei M., Madia F., Bianchi G., Longo V.D. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc. Natl. Acad. Sci. USA. 2008;105:8215–8220. doi: 10.1073/pnas.0708100105.
- Lee C., Safdie F.M., Raffaghello L., Wei M., Madia F., Parrella E., Hwang D., Cohen P., Bianchi G., Longo V.D. Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Cancer Res. 2010;70:1564–1572. doi: 10.1158/0008-5472.CAN-09-3228.
- Bauersfeld S.P., Kessler C.S., Wischnewsky M., Jaensch A., Steckhan N., Stange R., Kunz B., Bruckner B., Sehouli J., Michalsen A. The effects of short-term fasting on quality of life and tolerance to chemotherapy in patients with breast and ovarian cancer: A randomized cross-over pilot study. BMC Cancer. 2018;18:476. doi: 10.1186/s12885-018-4353-2.
- de Groot S., Lugtenberg R.T., Cohen D., Welters M.J.P., Ehsan I., Vreeswijk M.P.G., Smit V., de Graaf H., Heijns J.B., Portielje J.E.A., et al. Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial. Nat. Commun. 2020;11:3083. doi: 10.1038/s41467-020-16138-3.
- de Groot S., Vreeswijk M.P., Welters M.J., Gravesteijn G., Boei J.J., Jochems A., Houtsma D., Putter H., van der Hoeven J.J., Nortier J.W., et al. The effects of short-term fasting on tolerance to (neo) adjuvant chemotherapy in HER2-negative breast cancer patients: A randomized pilot study. BMC Cancer. 2015;15:652. doi: 10.1186/s12885-015-1663-5.
- Dorff T.B., Groshen S., Garcia A., Shah M., Tsao-Wei D., Pham H., Cheng C.W., Brandhorst S., Cohen P., Wei M., et al. Safety and feasibility of fasting in combination with platinum-based chemotherapy. BMC Cancer. 2016;16:360. doi: 10.1186/s12885-016-2370-6.
- Safdie F.M., Dorff T., Quinn D., Fontana L., Wei M., Lee C., Cohen P., Longo V.D. Fasting and cancer treatment in humans: A case series report. Aging (Albany NY) 2009;1:988–1007. doi: 10.18632/aging.100114.
- Zorn S., Ehret J., Schauble R., Rautenberg B., Ihorst G., Bertz H., Urbain P., Raynor A. Impact of modified short-term fasting and its combination with a fasting supportive diet during chemotherapy on the incidence and severity of chemotherapy-induced toxicities in cancer patients—A controlled cross-over pilot study. BMC Cancer. 2020;20:578. doi: 10.1186/s12885-020-07041-7.
- Brandhorst S., Choi I.Y., Wei M., Cheng C.W., Sedrakyan S., Navarrete G., Dubeau L., Yap L.P., Park R., Vinciguerra M., et al. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015;22:86–99. doi: 10.1016/j.cmet.2015.05.012.
- Wei M., Brandhorst S., Shelehchi M., Mirzaei H., Cheng C.W., Budniak J., Groshen S., Mack W.J., Guen E., Di Biase S., et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci. Transl. Med. 2017;9 doi: 10.1126/scitranslmed.aai8700.
- Lugtenberg R.T., de Groot S., Kaptein A.A., Fischer M.J., Kranenbarg E.M., Carpentier M.D., Cohen D., de Graaf H., Heijns J.B., Portielje JE A., et al. Quality of life and illness perceptions in patients with breast cancer using a fasting mimicking diet as an adjunct to neoadjuvant chemotherapy in the phase 2 DIRECT (BOOG 2013-14) trial. Breast Cancer Res. Treat. 2021;185:741–758. doi: 10.1007/s10549-020-05991-x.
- Arends J., Bachmann P., Baracos V., Barthelemy N., Bertz H., Bozzetti F., Fearon K., Hutterer E., Isenring E., Kaasa S., et al. ESPEN guidelines on nutrition in cancer patients. Clin. Nutr. 2017;36:11–48. doi: 10.1016/j.clnu.2016.07.015.
- Caccialanza R., Aprile G., Cereda E., Pedrazzoli P. Fasting in oncology: A word of caution. Nat. Rev. Cancer. 2019;19:177. doi: 10.1038/s41568-018-0098-0.
- Rossi F., Valdora F., Barabino E., Calabrese M., Tagliafico A.S. Muscle mass estimation on breast magnetic resonance imaging in breast cancer patients: Comparison between psoas muscle area on computer tomography and pectoralis muscle area on MRI. Eur. Radiol. 2019;29:494–500. doi: 10.1007/s00330-018-5663-0.
- Safdie F., Brandhorst S., Wei M., Wang W., Lee C., Hwang S., Conti P.S., Chen T.C., Longo V.D. Fasting enhances the response of glioma to chemo- and radiotherapy. PLoS ONE. 2012;7:e44603. doi: 10.1371/journal.pone.0044603.
- Pelzer U., Arnold D., Govercin M., Stieler J., Doerken B., Riess H., Oettle H. Parenteral nutrition support for patients with pancreatic cancer. Results of a phase II study. BMC Cancer. 2010;10:86. doi: 10.1186/1471-2407-10-86.
- Malecka-Massalska T., Smolen A., Morshed K. Extracellular-to-body cell mass ratio and subjective global assessment in head-and-neck cancers. Curr. Oncol. 2014;21:62–66. doi: 10.3747/co.21.1671.
- Norman K., Stobaus N., Pirlich M., Bosy-Westphal A. Bioelectrical phase angle and impedance vector analysis—clinical relevance and applicability of impedance parameters. Clin. Nutr. 2012;31:854–861. doi: 10.1016/j.clnu.2012.05.008.
- Małecka-Massalska T., Powrózek T., Mlak R. Bioelectrical Impedance Analysis and Malnutrition in Cancer. In: Preedy V.R., Patel V.B., editors. Handbook of Famine, Starvation, and Nutrient Deprivation. Springer International Publishing; New York, NY, USA: 2019. pp. 809–829.
- Desmedt C., Fornili M., Clatot F., Demicheli R., De Bortoli D., Di Leo A., Viale G., de Azambuja E., Crown J., Francis P.A., et al. Differential Benefit of Adjuvant Docetaxel-Based Chemotherapy in Patients with Early Breast Cancer According to Baseline Body Mass Index. J. Clin. Oncol. 2020;38:2883–2891. doi: 10.1200/JCO.19.01771.
- Di Cosimo S., Porcu L., Agbor-Tarh D., Cinieri S., Franzoi M.A., De Santis M.C., Saura C., Huober J., Fumagalli D., Izquierdo M., et al. Effect of body mass index on response to neo-adjuvant therapy in HER2-positive breast cancer: An exploratory analysis of the NeoALTTO trial. Breast Cancer Res. 2020;22:115. doi: 10.1186/s13058-020-01356-w.
- Renehan A.G., Zwahlen M., Egger M. Adiposity and cancer risk: New mechanistic insights from epidemiology. Nat. Rev. Cancer. 2015;15:484–498. doi: 10.1038/nrc3967.
- Jones J.I., Clemmons D.R. Insulin-like growth factors and their binding proteins: Biological actions. Endocr. Rev. 1995;16:3–34. doi: 10.1210/edrv-16-1-3.
- Hopkins B.D., Pauli C., Du X., Wang D.G., Li X., Wu D., Amadiume S.C., Goncalves M.D., Hodakoski C., Lundquist M.R., et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature. 2018;560:499–503. doi: 10.1038/s41586-018-0343-4.
- DeVita VT J., Lawrence T.S., Rosenberg S.A. DeVita, Hellmann and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; Philadelphia, PA, USA: 2018.
Source: PubMed