Short-term Fasting as an Enhancer of Chemotherapy: Pilot Clinical Study on Colorectal Carcinoma Patients

Fasting Clinical Trial

— CHEMOFAST  

Official title:

Evaluation of Short-term Fasting Effects on Chemotherapy Toxicity and Efficacy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04247464
• Other study ID #: HULP PI-3536
• Status: Completed
• Phase: N/A
• Start date: September 23, 2020
• Est. completion date: February 1, 2023

Study information

• Verified date: September 2023
• Source: IMDEA Food
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will evaluate the ability of short-term fasting to reduce chemotherapy toxicity and enhance anti-tumour response in patients with colorectal carcinoma subjected to chemotherapy.

Description:

Fasting for 24-48 hours during chemotherapy improves the response of the immune system against tumors and reduces chemotherapy toxicity through yet unknown mechanisms. The investigators have found that fasting induces the activation of p21, a protein that stops cell proliferation and plays important immune roles. The investigators hypothesize that p21 induction with short-term fasting enhances the immune anti-tumour response and reduces chemotherapy toxicity. To test this, half of the colorectal carcinoma (CRC) participants will follow 48 hours of fasting, 24 before and 24 after chemotherapy, under constant and specialized nutritional supervision. While the other half will follow a standard diet. A complete blood immunological profile at each chemotherapy cycle will be generated in collaboration with expert cytometrists, and gene expression, biochemical parameters, tumor evolution and toxicity markers will be measured. The investigators will (1) perform a complete analysis of immune cells to characterize the immune effects of fasting during chemotherapy; (2) analyze the effects of fasting on genes, metabolites and other molecules, to identify the responsible biological mechanisms, focusing on p21; (3) assess the reduction of chemotherapy toxicity in patients of colorectal carcinoma subjected to short-term fasting during chemotherapy. Our project will further explore a safe, inexpensive, relatively unexplored and powerful nutritional intervention that can improve the quality of life and survival rates of millions of cancer patients: short-term fasting. Also, our project will have an important scientific impact, since previous reports have not yet described a clear mechanism explaining the beneficial effects of short-term fasting with chemotherapy

Recruitment information / eligibility

• Status: Completed
• Enrollment: 11
• Est. completion date: February 1, 2023
• Est. primary completion date: February 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Participants with malignant colorectal neoplasia
• Good metabolic state (BMI>22)
• Good nutritional tests
• Normal Haematological and biochemical parameters
• Normal renal and hepatic function
• No loss of weight during the chemotherapy treatment

Exclusion Criteria:

• BMI<22
• Pregnancy or lactating women
• Bad nutritional state
• 3% weigh loss during the last month or more than 5% in the last three months
• Diagnosis of type 2 diabetes mellitus or hypertension
• Diagnosed hepatic, renal or cardiovascular disease
• Respiratory of psychiatric disease
• Nausea or vomiting, gastrointestinal disease

Related Conditions & MeSH terms

• Fasting

Intervention

Procedure:
• Fasting
Food intake restriction

Locations

Country	Name	City	State
Spain	IMDEA Food	Madrid

Sponsors (3)

Lead Sponsor	Collaborator
IMDEA Food	Hospital Infanta Sofia, Hospital Universitario La Paz

Country where clinical trial is conducted

Spain, 

References & Publications (12)

Arnason TG, Bowen MW, Mansell KD. Effects of intermittent fasting on health markers in those with type 2 diabetes: A pilot study. World J Diabetes. 2017 Apr 15;8(4):154-164. doi: 10.4239/wjd.v8.i4.154. — View Citation

Arumugam TV, Phillips TM, Cheng A, Morrell CH, Mattson MP, Wan R. Age and energy intake interact to modify cell stress pathways and stroke outcome. Ann Neurol. 2010 Jan;67(1):41-52. doi: 10.1002/ana.21798. — View Citation

Bouwens M, Afman LA, Muller M. Fasting induces changes in peripheral blood mononuclear cell gene expression profiles related to increases in fatty acid beta-oxidation: functional role of peroxisome proliferator activated receptor alpha in human peripheral blood mononuclear cells. Am J Clin Nutr. 2007 Nov;86(5):1515-23. doi: 10.1093/ajcn/86.5.1515. — View Citation

Caffa I, D'Agostino V, Damonte P, Soncini D, Cea M, Monacelli F, Odetti P, Ballestrero A, Provenzani A, Longo VD, Nencioni A. Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition. Oncotarget. 2015 May 20;6(14):11820-32. doi: 10.18632/oncotarget.3689. — View Citation

Di Biase S, Lee C, Brandhorst S, Manes B, Buono R, Cheng CW, Cacciottolo M, Martin-Montalvo A, de Cabo R, Wei M, Morgan TE, Longo VD. Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity. Cancer Cell. 2016 Jul 11;30(1):136-146. doi: 10.1016/j.ccell.2016.06.005. — View Citation

Duan W, Guo Z, Jiang H, Ware M, Mattson MP. Reversal of behavioral and metabolic abnormalities, and insulin resistance syndrome, by dietary restriction in mice deficient in brain-derived neurotrophic factor. Endocrinology. 2003 Jun;144(6):2446-53. doi: 10.1210/en.2002-0113. — View Citation

Lopez-Guadamillas E, Fernandez-Marcos PJ, Pantoja C, Munoz-Martin M, Martinez D, Gomez-Lopez G, Campos-Olivas R, Valverde AM, Serrano M. p21Cip1 plays a critical role in the physiological adaptation to fasting through activation of PPARalpha. Sci Rep. 2016 Oct 10;6:34542. doi: 10.1038/srep34542. — View Citation

Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017 Oct;39:46-58. doi: 10.1016/j.arr.2016.10.005. Epub 2016 Oct 31. — View Citation

Pietrocola F, Pol J, Vacchelli E, Rao S, Enot DP, Baracco EE, Levesque S, Castoldi F, Jacquelot N, Yamazaki T, Senovilla L, Marino G, Aranda F, Durand S, Sica V, Chery A, Lachkar S, Sigl V, Bloy N, Buque A, Falzoni S, Ryffel B, Apetoh L, Di Virgilio F, Madeo F, Maiuri MC, Zitvogel L, Levine B, Penninger JM, Kroemer G. Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance. Cancer Cell. 2016 Jul 11;30(1):147-160. doi: 10.1016/j.ccell.2016.05.016. — View Citation

Raffaghello L, Lee C, Safdie FM, Wei M, Madia F, Bianchi G, Longo VD. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8215-20. doi: 10.1073/pnas.0708100105. Epub 2008 Mar 31. — View Citation

Safdie FM, Dorff T, Quinn D, Fontana L, Wei M, Lee C, Cohen P, Longo VD. Fasting and cancer treatment in humans: A case series report. Aging (Albany NY). 2009 Dec 31;1(12):988-1007. doi: 10.18632/aging.100114. — View Citation

Tinkum KL, Stemler KM, White LS, Loza AJ, Jeter-Jones S, Michalski BM, Kuzmicki C, Pless R, Stappenbeck TS, Piwnica-Worms D, Piwnica-Worms H. Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival. Proc Natl Acad Sci U S A. 2015 Dec 22;112(51):E7148-54. doi: 10.1073/pnas.1509249112. Epub 2015 Dec 7. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in the Common Terminology Criteria for Adverse Events CTCAE 5.0 toxicity table score.	To evaluate changes in chemotherapy toxicity, the Common Terminology Criteria for Adverse Events (CTCAE) 5.0 toxicity table score will be calculated, taking into account different analysis and questionnaires on toxicity symptoms.; Analysis will include: Hematological analysis (erythrocytes, thrombocytes, white blood cells, Neutrophil/lymphocyte ratio and Platelet/lymphocyte ratio).; Biochemical analysis (sodium, potassium, calcium, phosphate, urea, creatinine, total protein, albumin, bilirubin, alkaline phosphatase, lactate dehydrogenase, alanine transaminase, aspartate transaminases, creatine kinase, troponin T, C Reactive Protein (CRP), cortisol and prealbumin); Subjective symptoms obtained from health questionnaires (hunger, nausea, dizzying, weakness, diarrhea, constipation, gastroesophageal reflux disease)	Baseline and after three weeks
Primary	Changes in the immune response	To evaluate the effect of short-term fasting on the immune response a complete immune phenotyping by flow cytometry will be done: cluster of differentiation 3 (CD3), cluster of differentiation 4 (CD4), cluster of differentiation 8 (CD8) (for T cells); cluster of differentiation 19 (CD19) (for B-cells), the high affinity Interleukin-2 receptor alpha subunit (CD45RA), CD62L (for T cell subsets: Memory, Effector); cluster of differentiation 25 (CD25) and cluster of differentiation 127 (CD127) (both for Treg cells); cluster of differentiation 11b C(D11b) (for granulocytes and macrophages); cluster of differentiation 14 (CD14) (for monocytes); cluster of differentiation antigen 16 (CD16), cluster of differentiation 56 (CD56) (NK cells); cluster of differentiation 15 (CD15) (for granulocytes and monocytes) markers will be analyzed	Baseline and after three weeks
Primary	Changes in the correlation between chemotherapy response and p21 and/or other fasting genes expression in peripheral blood mononuclear cells (PBMCs)	The expression levels of p21 and/or fasting genes in peripheral blood mononuclear cells (PBMCs) will be correlated with toxicity parameters previously described in the primary outcome measure 1	Baseline and after three weeks
Secondary	Subjective evaluation of tolerance to fasting	To evaluate the tolerance to fasting, participants will fill in a fasting tolerance test based on the symptoms they feel, this will result in a final score of tolerance to fasting.	48 hours of fasting, including 24 hours prior and 24 hours after chemotherapy administration.
Secondary	Changes in glycemia in response to fasting	Glucose levels (milligrams per milliliter) will be measured with a kit from Abbott Laboratories, by enzymatic spectrophotometric assays using an Architect instrument from Abbot Laboratories.	Baseline and after three weeks
Secondary	Changes in Free Fatty Acids levels in response to fasting	Free fatty acids levels (moles per milliliter) will be evaluated with a kit from Abbott Laboratories, by enzymatic spectrophotometric assays using an Architect instrument from Abbott Laboratories.	Baseline and after three weeks
Secondary	Changes in Insulin levels in response to fasting	Insulin levels (International Units per milliliter) will be measured with a kit from Abbott Laboratories, by luminescent immunoassay using the Architect instrument from Abbott Laboratories.	Baseline and after three weeks
Secondary	Changes ketone bodies in response to fasting	Ketone bodies concentration (moles per milliliter) will be measured with a kit from Sigma-Aldrich, by an enzymatic spectrophotometric assay using an microplate reader from Thermo Fisher.	Baseline and after three weeks
Secondary	Changes in gene expression in PBMCs after fasting	To evaluate changes in gene expression in PBMCs the following fasting genes will be analyzed by qRTPCR: p21; Pyruvate Dehydrogenase Kinase 4 (PDK4); Carnitine palmitoyltransferase 1 (CPT1); Adipophilin (ADFP); Solute carrier family 25, member 50 (SLC25A50)	Baseline and after three weeks
Secondary	Antitumoral response associated to fasting after chemotherapy treatment	To evaluate the clinical antitumoral response, different tumoral markers such as carcinoembryonic antigen (CEA) and Carbohydrate antigen (Ca 19.9) will be analyzed in serum samples	Baseline and after three weeks