Dietary Fiber During Radiotherapy - a Placebo-controlled Randomized Trial

Study Overview
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Brief Summary
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The investigators hypothesize that an increase in dietary fiber intake during radiation therapy may provide better long-term intestinal health for the cancer survivor. If the hypothesis is not correct, the increased intake may only mean an increase in acute side effects. All participants are advised to consume at least 16 g of dietary fiber/day via food. In addition, participants are invited to take capsules that together contain either 5.5 g of dietary fiber from psyllium husk or placebo.

Detailed Description
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The overall working hypothesis is that intake of dietary fiber during radiotherapy can mitigate or hinder end states or the triggering of long-lasting pathophysiological processes that decreases intestinal health in the cancer survivor. If correct, there is a dose-effect relationship to be documented. Moreover, if correct, different kinds of dietary fibers may have different effects. Mechanisms for the mitigatory effects may be that dietary fiber helps to preserve the two protective mucus layers and hinder gut-wall starvation. Lack of protection, as well as gut-wall starvation, may decrease the gut walls' integrity. That, in turn, may enhance bacterial migration from the lumen into the gut wall, causing unnecessary inflammation. This inflammation may, in turn, lead to a number of different pathophysiological processes, including a chronic self-propagating low-grade inflammation. Clinical experience suggests the intake of dietary fiber during radiotherapy may increase acute intestinal side effects. Our own data suggest a modest, if any, increase by dietary fiber. Through recipes of tasty meals by price-winning chefs and general advice, the investigators guide the participant to try to consume at least 16 g of dietary fiber per day via food. The guidance takes place through telephone calls, calls via video link, and text on a website or paper material. The participant gets access to a mobile application that measures the daily intake of dietary fiber. Dietary fiber is ingested in 15 capsules with psyllium husk which contains a total of 5.5 g of dietary fiber. The investigators ask the participant to take the capsules two weeks before radiotherapy, during radiotherapy, and to stop four weeks after the end of radiotherapy. Placebo capsules (maltodextrin) are taken in the same way. To document the frequency of acute side effects, and what symptoms they cause, the participant is asked to report patient-reported outcomes once a week via a mobile application. They are also welcome to report side effects to the study office. One month after the end of radiotherapy, the degree of inflammation is measured via markers in the blood and feces. One year after the end of radiotherapy, intestinal health is measured via patient-reported outcomes. Blood and feces are collected and patient-reported outcomes are reported in questionnaires and a mobile application before, during, and at least one year after the end of radiotherapy. This data will be a source of in-depth analysis. Radiotherapy gives rise to increased intensity of five different syndromes, fecal-leakage syndrome, urgency syndrome, uncontrolled flatulence, excess mucus discharge, and anal blood discharge. Damage of nerves and small vessels, weakening the anal-sphincter function by muscle fibers turning into the connective tissue (fibrosis), may explain some of the intensity of the fecal-leakage syndrome. An ongoing self-propagating low-grade inflammation, small-vessel and nerve damage in the gut wall may be related to urgency. Reasonably the microbiome, and the communication between the microbiome and the gut wall, is related to uncontrolled flatulence and excess mucus discharge. It is not known to what extent telangiectasias on a fibrotic inner gut wall explains anal blood discharge. Ad hoc studies in FIDURA will explore suggested mechanisms. An interim analysis will be performed for the primary outcome to identify if there is any effect of the intervention, to decide whether to continue or terminate the inclusion of patients in the study. The concentration of c-reactive protein will be analyzed for all included patients who have donated blood to date (May 2023). To ensure that the blinding is not revealed, all analyses (biochemical and statistical) will be made by external personnel not included in the research group. The capsules are marked with X and Y, and the code for which is intervention or placebo will not be revealed even for the external personnel performing the interim analysis.

Official Title
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Dietary Fiber During Radiotherapy and Intestinal Inflammation - a Placebo-controlled Randomized Trial (FIDURA)

Conditions
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Malignant Neoplasm, Malignant Neoplasm of Rectum, Malignant Neoplasm of Anus, Malignant Neoplasm of Urinary Bladder, Malignant Neoplasm of Cervix, Malignant Neoplasm of Ovary, Malignant Neoplasm of Prostate, Malignant Neoplasm of Large Intestine, Malignant Neoplasm of Colon, Gynecologic Cancer

Intervention / Treatment
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* Biological: Capsules containing either dietary fiber or placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Planned preoperative (neoadjuvant) or curative radiation therapy for a tumor in the pelvic cavity (including all forms of gynecological cancer, colorectal cancer, anal cancer, prostate cancer, and urinary bladder cancer). Exclusion Criteria: Preoperative stoma which, according to the attending physician, prevents participation Difficulty swallowing or ileus conditions which, according to the treating physician, prevent participation Cognitive dysfunction which, according to the treating physician, prevents participation Need for an interpreter to communicate in Swedish

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Random allocation of patients and blinding of researchers, patients, healthcare professionals and outcome assessors.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Additional dietary fiber through Psyllium husk<br>The participants are allocated to intake the fifteen capsules per day, for example, five capsules three times per day. Altogether the fifteen capsules contains 5.5 g dietary fiber in psyllium husk. | Biological: Capsules containing either dietary fiber or placebo<br>* The participants are invited to eat 15 capsules per day. The capsules either contain dietary fiber from psyllium husk or placebo.<br>|
| Placebo Comparator: Placebo (no additional dietary fiber)<br>The participants are allocated to intake the fifteen capsules per day, for example, five capsules three times per day. The capsules contain placebo (maltodextrin) and have a similar look as in the experimental arm. | Biological: Capsules containing either dietary fiber or placebo<br>* The participants are invited to eat 15 capsules per day. The capsules either contain dietary fiber from psyllium husk or placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sign of inflammation i blood | Concentration of c-reactive protein in plasma or serum | One month after the end of radiotherapy | 
| Intensity of the urgency syndrome | Patient-reported outcomes through a validated questionnaire. The metric for the intensity of the urgency syndrome weighs the frequency of several symptoms by factor loadings, as described in PubMed ID 28158314. Examples of the previous usage can be seen in PubMed ID 28366105 and PubMed ID 30601820. | One year after the end of radiotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerance to additional dietary fiber | Deviation from the recommended intake of 15 capsules per day | During radiotherapy | 
| Signs of inflammation i blood | Concentration of selected markers in blood and feces. The selection of cytokines and chemokines for this outcome is work in progress 26 august 2020 and will be be given as updated information later on. In feces we will primarily use elastase and calprotectin. | One month after the end of radiotherapy | 
| Intensity of the fecal-leakage syndrome, uncontrolled flatulence, excess mucus discharge and blood | Patient-reported outcomes through a validated questionnaire. The metric for the intensity of the syndromes weighs the frequency of several symptoms by factor loadings, as described in PubMed ID 28158314. Examples of the previous usage can be seen in PubMed ID 28366105 and PubMed ID 30601820. | One year after the end of radiotherapy | 
| Acute side-effects | Distress from gastrointestinal symptoms as reported through a mobile phone application (ePROMS). Primarily we ask for defecation frequency, stool consistency (Bristol Scale), and frequency of abdominal pain. The participants may also report other side-effects, either by the mobile phone application, video link, or telephone with the study secretariat. | During radiotherapy, primarily during week 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bowel health, Radiotherapy, Irradiation, Radiation therapy, Dietary fiber, Psyllium husk, Placebo-controlled, Double-blind, Randomized, Patient-reported outcomes, ePROMS, Gut-wall inflammation, Late adverse effects, Late effects, Treatment-induced cancer survivorship diseases, Treatment-induced cancer survivorship syndromes, Intestinal health, Urgency, Leakage, Mucus, Flatulence, Blood discharge