The study was closed prematurely because the interim analysis found that subjects in the experimental group had less gastrointestinal toxicity.

In Mexico, cervical cancer (CC) ranks second in incidence and mortality among women. The National Institute of Cancer in Mexico (lNCan) receives annually about 500 patients with CC, 80% of which are diagnosed with locally advanced disease. The standard treatment for locally advanced disease consists in concomitant chemo-radiotherapy based on cisplatin (QT-RT), followed by brachytherapy, with an absolute benefit of 10%. Adverse effects include gastrointestinal toxicity, which is the most important factor limiting the dosage of pelvic radiation. Cancer treatment, in any modality, induces malnutrition, more so when combined treatments are administered. Radiation induced gastrointestinal toxicity is caused by different factors, among which are malabsorption of bile, fat and carbohydrates, decrease in brush border enzymes, diverticular disease, proctitis, and psychological factors. International guidelines for cancer patients recommend nutritional assessment in these patients before they start treatment, so nutritional risk can be detected and the patient may get started on dietary intervention to prevent malnutrition. Several authors have studied the dietary management that may help reduce the gastrointestinal effects in cancer patients receiving pelvic radiotherapy. To reduce diarrhea and prevent malnutrition the recommended dietary approach is a low residue diet consisting on 20-25% kcal from fat, 5g of lactose and 20g of fiber. Currently the INCan does not follow the nutrition care process for cervical cancer patients; written recommendations are given to the patients with a list of foods allowed or not allowed, with no further nutritional assessment or intervention. From previous studies, the investigators have demonstrated that the current recommendations do not help the patients maintain their nutritional status, during their treatment most patients become malnourished (81%, p<0.01). Therefore, the aim of this clinical trial is to evaluate a diet low in residue in CC patients, considering the necessary modifications for each patient if morbidities are present, in comparison with the current dietary recommendations used in the INCan.

In Mexico, cervical cancer (CC) is the second most frequent cause of death among women, with a mortality rate of 4000 women/year. Among the patients attended by the INCan, 80% are diagnosed with locally advanced CC and 30% of these present comorbidities. Hypertension may be present in 20% of patients, obesity in 18% and diabetes in 6.8%. These comorbidities affect the efficacy of treatment, increase the risk of malnutrition, of adverse events, hospitalization, increase hospital stay and worsen the quality of life, and even increase the risk of death. Furthermore, 10 to 20% of patients present kidney deterioration. The main reason for kidney disease is ureteral obstruction. The glomerular filtration rate deteriorates with age and many patients have comorbid medical illnesses that further compromise the kidneys. The standard treatment for CC is concomitant chemo-radiotherapy using cisplatin as a radiosensitizer, and brachytherapy at the end of treatment. Studies developed in the INCan described the acute toxicity symptoms in CC patients using this treatment: nausea, vomiting, diarrhea, cystitis, radioepithelitis, leucopenia, neutropenia, thrombocytopenia. Pelvic radiotherapy causes gastrointestinal toxicity, which is the most important limiting factor for the patients to complete their treatment. Cancer treatment, along with the tumor itself and other factors, causes malnutrition, and this confers a bad prognosis for the patient's response to treatment and survival. There is a nutritional risk in these patients at the moment of diagnosis, because of the metabolic alterations caused by the tumor, and the treatment-induced side effects. International guidelines for cancer patients recommend nutritional assessment in these patients before they start treatment, so nutritional risk can be detected and the patient may get started on dietary intervention to prevent malnutrition. Several authors have studied the dietary management that may help reduce the gastrointestinal effects in cancer patients receiving pelvic radiotherapy. To reduce diarrhea and prevent malnutrition the recommended dietary approach is a low residue diet consisting on 20-25% fat, 5g of lactose and 20g of fiber. Currently the INCan does not follow the nutrition care process for cervical cancer patients; written recommendations are given to the patients with a list of foods allowed or not allowed, with no further nutritional assessment or intervention. The investigators described the nutritional status of CC patients undergoing concomitant chemo-radiotherapy. It was observed that by the end of cancer treatment, a period of 9 weeks, 81.8% of patients became malnourished; 96% of patients lost weight, 78% of which had severe weight loss.

The aim of this clinical trial is to evaluate a diet low in residue in CC patients, considering the necessary modifications for each patient if morbidities are present, in comparison with the current dietary recommendations used in the INCan. A thorough nutritional evaluation including anthropometric data, dietary data, gastrointestinal toxicity and quality of life evaluations, will be performed.

Particular objectives are the following:

1. Identify the nutritional status of CC patients before, during and after treatment with chemo-radiotherapy, in intervention and control groups.
2. Determine the association of malnutrition and gastrointestinal toxicity during and after treatment, in intervention and control groups.
3. Evaluate the quality of life of patients before, during and after treatment, in both groups.
4. Establish the association of nutritional status and response to treatment, in both groups.

The aim is based on the following hypothesis: Patients receiving the personalized nutritional intervention with the low residue diet will maintain a better nutritional status during treatment, reflected in fewer malnourished patients, compared to the control group.

Methods.

Study design. Randomized clinical trial, open, factorial 3X2. To evaluate the efficacy of a low residue diet on the nutritional status, gastrointestinal toxicity and quality of life of CC patients referring to the National Institute of Cancer in Mexico (INCan). 320 patients will be included, with cervical malignant tumors of epithelial origin in the neck of the uterus, candidates for chemo-radiotherapy.

Dietary intervention will consist on a low residue diet: 20% kcal from fat, 5g lactose/day, 20g fiber/day (5g from insoluble fiber).

Dietary intervention will be adapted to the patient's individual requirements, according to the presence of comorbidities or renal deterioration.

1. No comorbidities. Energy: 20-30 kcal/kg of body weight/day. Protein: 1.3 g/kg of body weight/day.
2. Comorbidities (diabetes, hypertension), or geriatric patient. Energy: 25-30 kcal/kg of body weight/day. Protein: 1.5 g/kg of body weight/day.
3. Renal deterioration.

Energy: 30-35 kcal/kg of body weight/day.

Protein: 1 g/kg of body weight/day.

Sodium: 2000-2300 mg/day

Potassium: 1900-2730 mg/day

Phosphorus: 800-1000 mg/day

Control group will receive the standard written recommendations from the INCan, which enlist allowed foods and not allowed foods.

Sample size.

A sample space of 320 patients will be included if prior consent is acquired and if they meet the inclusion criteria. This clinical trial contemplates 3 strata with 2 levels.

Statistical analysis.

A univariate analysis will be performed to describe the study population. Descriptive statistics will be used to obtain measures of central tendency and dispersion, as well as frequency of distribution for qualitative variables. Percentage change of nutritional status will be calculated using the Friedman test. Chi square test will be used to compare basal vs final assessment, and chi square test will be used to compare among study groups. All confidence intervals will be constructed with a confidence of 95% (α=0.05). The interpretation of the study results will be responsibility of researchers. Data processing and analysis will be performed with the SPSS package (version 19.0®) for Microsoft.

Efficacy analysis.

Efficacy will be evaluated in patients that qualify to be included in the protocol analysis. To evaluate efficacy, nutritional diagnosis through the clinical course will be analyzed in both, intervention and control, groups. Also, toxicity and quality of life responses will be obtained.

Procedures.

Treatment. Anticancer treatment will consist of Cisplatin as a radiosensitizer, at a dosage of 40 mg/m2/week for 6 weeks. For patients with renal deterioration Gemcitabine will be used instead of Cisplatin, at a dosage of 300 mg/m2/week for 6 weeks. Concomitantly, external pelvic radiotherapy will be applied at a total dosage of 50.4 Gy divided by 28 fractions, 1.8 Gy/day/5 days a week, for 6 weeks. After completing concomitant chemo-radiotherapy, intracavitary brachytherapy will be administered at low dosage (30 Gy of Cesium 137) or high dosage (Iridium). Before initiating chemo-radiotherapy, a complete evaluation will be applied as mentioned.

Once eligibility criteria are verified, patients will be randomly assigned to intervention group or control group.

Visits during the study. After signing the informed consent, the patient will be informed when she will begin participating in the study (screening visit). If the patient complies with the inclusion criteria, a total of 5 visits will be scheduled: (1) at week -2, 2 weeks before treatment; (2) at week 0, on initiation of treatment; (3) at week 3, on the 3rd cycle of chemotherapy; (4) at week 9, by the end of brachytherapy; and (5) at week 21, 3 months after treatment completion.

Monitoring.

A thorough evaluation on each visit will be performed using the following tools:

• Patient generated subjective global assessment.
• Anthropometric data: weight, height, waist circumference, hip circumference, arm circumference.
• Body mass index.
• Waist to hip ratio.
• Body composition (bioelectrical impedance).
• % weight loss.
• Hand dynamometry.
• Dietary data: 24 hour recall and frequency of food intake questionnaires.
• % recommended energy intake.
• Biochemical markers: serum albumin, number of lymphocytes.
• Gastrointestinal toxicity using the CTCAE v4.03.
• Quality of life using the QLQ-C30 and CxC24.

Sample collection. No tissue or additional blood samples will be obtained, other than the blood samples used as part of the routine clinical laboratory tests.

Informed consent acquisition. On the screening visit, the written consent will be read and explained to the patient, clarifying the risks and benefits involved in the study. Two witnesses, independent from the study, will be present. The patient will have the choice to not participate or withdraw from the study at any time, her decision will not affect the quality of care and treatment that the attending physician will provide. The researcher will be governed by the ethical principles established in the Helsinki Accord. The physician will adequately respond all the matters of interest to the patient.

Ethical considerations.

The Research Committee and the Ethics Committee of the National Institute of Cancer in Mexico has approved the protocol and the informed consent document.

Patients participating in this study will be informed, through the informed consent, of all the details concerning this trial. The patients who agree to participate in the trial will express their willingness by signing the informed consent document, being clarified that they can leave the trial at any time, if they wish to do so.

Regulatory considerations.

This study abides by the ethical principles established by the international community, in accordance to the Good Clinical Practices, the Nüremberg Code, the Helsinki Accord, the Statement of Compliance with International Conference on Harmonization Guidelines for Good Clinical Practice, and the Regulations of the General Law of Health in the matter of research for health.

Inclusion Criteria:

• Women 18 years of age and older.
• Ability to understand the study and be able to sign the informed consent.
• Functional stage ECOG 0 - 2.
• Negative pregnancy test, null reproductive potential, or currently using an contraceptive method.
• Willing and able to attend the programmed visits.
• Diagnosed with cervical malignant tumors of epithelial origin in the neck of the uterus, clinical stages IB2-IVA.
• Candidates to receive concomitant Chemo-Radiotherapy, followed by Brachytherapy.
• In case of presence of diabetes mellitus and/or hypertension, without retinopathy or albuminuria <300 mg/dl.
• In case of renal deterioration, a creatinine clearance >20 ml/min.
• Hemoglobin >10 g/l.
• Leucocytes > 4000/mm3.
• Platelets >100000/mm3.

Exclusion Criteria:

• Under a different nutritional treatment using a nutritional supplement.
• Carrying other uncontrolled diseases, including cardiovascular insufficiency, arrhythmia, psychiatric illnesses.
• Concomitant treatment with another experimental drug.
• Active TB.
• Infected with HIV.
• History of LES and other rheumatologic diseases that involve renal deterioration.
• Presence of vesicular-vaginal fistulae at moment of diagnosis.
• Previous malignancy.

Study Discontinuation Criteria:

• Loss of follow up for 21 days.
• Evidence of disease progression.
• At the request of patient.
• By unacceptable toxicity.
• Pregnancy.

Criteria must be followed punctually. If a patient were inappropriately included, she must be discontinued from the study.