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

Study Overview
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Brief Summary
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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.

Detailed Description
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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

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

Conditions
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Fasting

Intervention / Treatment
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* Procedure: Fasting


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard diet<br>The participants will follow an standard diet during the chemotherapy treatment | |
| Experimental: Fasting<br>The participants will follow a short-term fasting period for 44-48 hours, starting 24 hours before chemotherapy treatment | Procedure: Fasting<br>* Food intake restriction<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Short-term Fasting, Colorectal Cancer, Chemotherapy, Toxicity, Immune response