Effect of an Anti-inflammatory Diet on Patients With Cervical Cancer

Study Overview
=================
Brief Summary
-----------------
During radiation therapy (RT) to pelvic tumors, the small intestine, colon and rectum are inevitably included in the radiation field and are healthy tissues that suffer damage as an adverse effect. Pelvic radiation disease (PRD) is the group of gastrointestinal symptoms experienced by patients that receive pelvic radiation. Intestinal inflammation, tissue damage, oxidative stress and tumor metabolism lead the patient to a catabolic state associated with an increase in energy demands. Also, the painful abdominal symptoms restrict the patients' food intake, leading the patients that develop PRD to an increased risk to develop protein-energy malnutrition and micronutrient deficiencies, all of which affect the patients' quality of life. Studies developed in patients with inflammatory bowel disease have suggested that probiotics may have an anti-inflammatory effect in the intestine. In addition, micronutrients and trace elements provide antioxidant capacity and exert immune-modulating effects during periods of intestinal inflammation. Thus, probiotics and immune-modulating nutrients may provide a means to diminish intestinal inflammation and symptoms associated with PRD. In this project the investigators propose that the nutritional management of cervical cancer patients be based on an anti-inflammatory diet, taking into account the nutritional status, age, comorbidities that the patient may present and symptoms developed during treatment. The nutritional intervention will include food rich in immune-modulating nutrients: omega-3 fatty acids, soluble fiber, antioxidants and polyphenols, and probiotics.

Detailed Description
-----------------
Cervical cancer is the second most frequent cancer in Mexican women, representing 16.9% of the total female population. At the National Cancer Institute of Mexico (Instituto Nacional de Cancerología), 80% cervical cancer patients arrive at locally advanced stages (IB2-IVA). Standard treatment for these stages is based on concomitant chemo-radiotherapy. During radiation therapy (RT) to pelvic tumors, the small intestine, colon and rectum are inevitably included in the radiation field and are healthy tissues that suffer damage as an adverse effect. Pelvic radiation disease (PRD) is the group of gastrointestinal symptoms experienced by patients that receive pelvic radiation. Acute PRD occurs during the time of treatment in 60 to 80% patients, symptoms include nausea, diarrhea, tenesmus, abdominal pain, urgency, mucositis, anorexia, bleeding and fatigue; these symptoms limit cancer treatment and affect the patients' quality of life. Chronic PRD is a progressive condition and a problem for cervical cancer survivors, symptoms include altered intestinal traffic, altered intestinal motility and nutrient malabsorption. The intestinal immune system plays an important role in the development of PRD and the secondary effects of RT. Intestinal inflammation, tissue damage, oxidative stress and tumor metabolism lead the patient to a catabolic state associated with an increase in energy demands. Also, the painful abdominal symptoms restrict the patients' food intake, leading the patients that develop PRD to an increased risk to develop protein-energy malnutrition and micronutrient deficiencies, all of which affect the patients' quality of life. Among some of the nutritional intervention assays for patients with PRD, some have described that a low residue diet, restricted in fat (20-25%), lactose (5g) and fiber (20g), reduces the frequency and severity of diarrhea; however, this dietary intervention does not prevent weight loss or malnutrition in patients. Furthermore, low residue diets limit the beneficial effect of dietary fiber and fatty acids that may aid in the inflammatory response. Likewise, patients with inflammatory bowel disease (IBD) develop similar symptoms to PRD. Studies developed in these patients have suggested that probiotics may have an anti-inflammatory effect in the intestine. In addition, micronutrients and trace elements provide antioxidant capacity and exert immune-modulating effects during periods of intestinal inflammation. Thus, probiotics and immune-modulating nutrients may provide a means to diminish intestinal inflammation and symptoms associated with PRD. In this project the investigators propose that the nutritional management of cervical cancer patients be based on an anti-inflammatory diet, taking into account the nutritional status, age, comorbidities that the patient may present and symptoms developed during treatment. The individualized energy requirements and nutrient proportions for patients without comorbidities, and for patients with comorbidities such as obesity, type 2 diabetes, hypertension and renal dysfunction, will be calculated according to the recommendations derived from the Consensus of Nutrition in patients with cancer treated with chemo-radiotherapy to the abdominopelvic area. Furthermore, the nutritional intervention will include food rich in immune-modulating nutrients: omega-3 fatty acids, soluble fiber, antioxidants and polyphenols, and probiotics. Because the low residue diet is routinely used for patients that receive pelvic radiation in other institutions, the anti-inflammatory nutritional intervention will be compared with the low residue diet. An open controlled randomized clinical trial will be performed on women with locally advanced cervical cancer. Candidates will be randomly assigned to one of the two dietary interventions. Experimental group will receive an anti-inflammatory diet with an energy intake of 28-31 kcal/kg/day, based on 30-40% fat, 20% protein, and 40-50% carbohydrates, the diet will include foods rich in omega-3 fatty acids, soluble fiber, antioxidants and polyphenols, and probiotics. The control group will receive a low residue diet with 28-91 kcal/kg/day, based on 20% fat, 20% protein, and 60% carbohydrates, with no more than 20g fiber and 5g of lactose. In both groups, before, during and after cancer treatment, a thorough nutritional evaluation will be performed, gastrointestinal toxicity will be assessed, and serum cytokine levels and fecal calprotectin and lactoferrin levels will be determined to establish the local and systemic inflammatory response. The quality of life of patients will also be assessed before and after treatment.

Official Title
-----------------
Effect of an Anti-inflammatory Diet on the Nutritional Status and Cytokine Expression of Patients With Locally Advanced Cervical Cancer: A Randomized Clinical Trial

Conditions
-----------------
Cervical Cancer, Uterine Cervical Neoplasm, Pelvic Inflammatory Disease, Radiation Toxicity, Diet Modification

Intervention / Treatment
-----------------
* Other: Omega-3 fatty acids
* Other: Antioxidants
* Other: Soluble fiber
* Other: Probiotics
* Other: Lactose restriction
* Other: Fiber restriction
* Other: Fat restriction


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Ability to understand the study and provide informed consent. ECOG: 0-2. Willingness to assist to every programed visit, to keep to the dietary intervention and lab tests. Diagnosed with cervical cancer. Clinical stages IB-2-IVA. Candidate to receive concomitant chemo-radiotherapy followed by brachytherapy. Disease measured by CT scan. No previous treatment based on chemo-radiotherapy. Hemoglobina levels >10g/dL. Leucocytes >4000/mm3. Platelets > 100000/mm3. Adequate hepatic function. Exclusion Criteria: Patients under nutritional treatment or supplement. Patients with active uncontrolled infections. Patients under treatment with an experimental drug. Patients with fistula at the moment of diagnosis. Patients with previous malignancy.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anti-inflammatory Diet<br>Dietary intervention providing: Energy: 28-31 kcal/kg/day. Protein: 20-30%. Fat: 30-40%. Carbohydrates: 40-50%. The diet will be individualized according to the patients' comorbidities (obesity, type 2 diabetes, hypertension, renal insufficiency). This group will include the consumption of foods that contain immune modulating nutrients: Omega-3 fatty acids, antioxidants, soluble fiber, probiotics. The recommendation to include these foods will be made according to the patients' access to food in their home area. | Other: Omega-3 fatty acids<br>* Diet will include foods rich in omega-3 fatty acids.<br>Other: Antioxidants<br>* Diet will include foods rich in antioxidant vitamins, trace elements, and polyphenols.<br>Other: Soluble fiber<br>* Diet will include foods rich in soluble fiber.<br>Other: Probiotics<br>* Diet will include foods rich in probiotics.<br>|
| Active Comparator: Low residue Diet<br>Dietary intervention providing: Energy: 28-31 kcal/kg/day. Protein: 20%. Fat: 20%. Carbohydrates: 60%. Diet will have lactose restriction, fiber restriction and fat restriction. | Other: Lactose restriction<br>* Diet will be restricted to 5g lactose/day<br>Other: Fiber restriction<br>* Diet will be restricted to 20g fiber/day<br>Other: Fat restriction<br>* Diet will be restricted to 20% total energy intake<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in body mass index | weight/height squared | Baseline, 3 weeks after treatment initiation, 12 weeks after treatment initiation, 6 months after treatment initiation | 
| Change in levels of IFN-g [pg/ml] | Determination of serum IFN-g using immune assay ELISA | Baseline, 3 weeks after treatment initiation, 6 months after treatment initiation | 
| Change in levels of calprotectin [pg/ml] | Measurement of fecal calprotectin using immune assay ELISA | Baseline, 3 weeks after treatment initiation, 6 months after treatment initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Gastrointestinal toxicity symptoms grading (severity) scale using the Common Toxicity Criteria for Adverse Events (CTCAE v4) | Evaluation of the severity of gastrointestinal symptoms according to the Common Toxicity Criteria for Adverse Events (CTCAE v4). A grading (severity) scale is provided for each adverse event (AE) term. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. | Baseline, 3 weeks, 12 weeks, 6 months | 
| Change in quality of life summary score using the the quality of life questionnaire specifically developed for cancer patients (EORTC QLQ-C30 v3) | Quality of life questionnaire developed and validated for cancer patients (EORTC QLQ-C30 v3, in spanish) will be applied, and the change in summary score will be evaluated. | Baseline, 3 weeks after treatment initiation, 12 weeks after treatment initiation, and 6 months after treatment initiation | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cancer, Intestinal inflammation, Diet