Clinical trial NCT04534075: Dietary Fiber During Radiotherapy - a Placebo-controlled Randomized Trial
Official title: Dietary Fiber During Radiotherapy and Intestinal Inflammation - a Placebo-controlled Randomized Trial (FIDURA)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: 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
Keywords: 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
Bowel health
Urgency
Leakage
Mucus
Flatulence
Blood discharge
Lead sponsor: Sahlgrenska University Hospital
Sponsor class: OTHER
Collaborators: name: The Swedish Research Council
name: VGregion
name: Sjöbergstiftelsen
First posted: 2020-09-01
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Random allocation of patients and blinding of researchers, patients, healthcare professionals and outcome assessors.
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Sign of inflammation i blood
timeFrame: One month after the end of radiotherapy
measure: Intensity of the urgency syndrome
timeFrame: One year after the end of radiotherapy
Secondary outcomes:
measure: Tolerance to additional dietary fiber
timeFrame: During radiotherapy
measure: Signs of inflammation i blood
timeFrame: One month after the end of radiotherapy
measure: Intensity of the fecal-leakage syndrome, uncontrolled flatulence, excess mucus discharge and blood
timeFrame: One year after the end of radiotherapy
measure: Acute side-effects
timeFrame: During radiotherapy, primarily during week 3
Other outcomes:
measure: Composition of microbiota
timeFrame: During, one month and one year after radiotherapy
Locations:
city: Gothenburg
country: Sweden
facility: Jubileumskliniken, Sahlgrenska University Hospital
Study officials:
affiliation: Göteborg University
name: Gunnar N Steineck, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Göteborg University
name: Maria Hedelin, PhD
role: STUDY_CHAIR
affiliation: Göteborg University
name: Cecilia Bull, PhD
role: STUDY_CHAIR
References:
citation: Patel P, Malipatlolla DK, Devarakonda S, Bull C, Rascon A, Nyman M, Stringer A, Tremaroli V, Steineck G, Sjoberg F. Dietary Oat Bran Reduces Systemic Inflammation in Mice Subjected to Pelvic Irradiation. Nutrients. 2020 Jul 22;12(8):2172. doi: 10.3390/nu12082172.
citation: Malipatlolla DK, Patel P, Sjoberg F, Devarakonda S, Kalm M, Angenete E, Lindskog EB, Grander R, Persson L, Stringer A, Wilderang U, Swanpalmer J, Kuhn HG, Steineck G, Bull C. Long-term mucosal injury and repair in a murine model of pelvic radiotherapy. Sci Rep. 2019 Sep 24;9(1):13803. doi: 10.1038/s41598-019-50023-4.
citation: Hedelin M, Skokic V, Wilderang U, Ahlin R, Bull C, Sjoberg F, Dunberger G, Bergmark K, Stringer A, Steineck G. Intake of citrus fruits and vegetables and the intensity of defecation urgency syndrome among gynecological cancer survivors. PLoS One. 2019 Jan 2;14(1):e0208115. doi: 10.1371/journal.pone.0208115. eCollection 2019.
citation: Ahlin R, Sjoberg F, Bull C, Steineck G, Hedelin M. [Differing dietary advice are given to gynaecological and prostate cancer patients receiving radiotherapy in Sweden]. Lakartidningen. 2018 Oct 9;115:FALY. Swedish.
citation: Sjoberg F, Malipatlolla DK, Patel P, Wilderang U, Kalm M, Steineck G, Bull C. Elastase as a potential biomarker for radiation-induced gut wall injury of the distal bowel in an experimental mouse model. Acta Oncol. 2018 Aug;57(8):1025-1030. doi: 10.1080/0284186X.2018.1438652. Epub 2018 Feb 15.
citation: Bull C, Malipatlolla D, Kalm M, Sjoberg F, Alevronta E, Grander R, Sultanian P, Persson L, Bostrom M, Eriksson Y, Swanpalmer J, Wold AE, Blomgren K, Bjork-Eriksson T, Steineck G. A novel mouse model of radiation-induced cancer survivorship diseases of the gut. Am J Physiol Gastrointest Liver Physiol. 2017 Nov 1;313(5):G456-G466. doi: 10.1152/ajpgi.00113.2017. Epub 2017 Jul 20.
citation: Steineck G, Sjoberg F, Skokic V, Bull C, Wilderang U, Alevronta E, Dunberger G, Bergmark K, Jornsten R. Late radiation-induced bowel syndromes, tobacco smoking, age at treatment and time since treatment - gynecological cancer survivors. Acta Oncol. 2017 May;56(5):682-691. doi: 10.1080/0284186X.2017.1307519. Epub 2017 Apr 1.
citation: Steineck G, Skokic V, Sjoberg F, Bull C, Alevronta E, Dunberger G, Bergmark K, Wilderang U, Oh JH, Deasy JO, Jornsten R. Identifying radiation-induced survivorship syndromes affecting bowel health in a cohort of gynecological cancer survivors. PLoS One. 2017 Feb 3;12(2):e0171461. doi: 10.1371/journal.pone.0171461. eCollection 2017.
citation: Steineck G, Schmidt H, Alevronta E, Sjoberg F, Bull CM, Vordermark D. Toward Restored Bowel Health in Rectal Cancer Survivors. Semin Radiat Oncol. 2016 Jul;26(3):236-50. doi: 10.1016/j.semradonc.2016.03.002. Epub 2016 Mar 18.
citation: Lind H, Alevronta E, Steineck G, Waldenstrom AC, Nyberg T, Olsson C, Wilderang U, Dunberger G, Al-Abany M, Avall-Lundqvist E. Defecation into clothing without forewarning and mean radiation dose to bowel and anal-sphincter among gynecological cancer survivors. Acta Oncol. 2016 Nov;55(11):1285-1293. doi: 10.1080/0284186X.2016.1176247. Epub 2016 May 13.
citation: Thor M, Olsson CE, Oh JH, Petersen SE, Alsadius D, Bentzen L, Pettersson N, Muren LP, Waldenstrom AC, Hoyer M, Steineck G, Deasy JO. Relationships between dose to the gastro-intestinal tract and patient-reported symptom domains after radiotherapy for localized prostate cancer. Acta Oncol. 2015;54(9):1326-34. doi: 10.3109/0284186X.2015.1063779. Epub 2015 Sep 4.
citation: Alsadius D, Olsson C, Pettersson N, Tucker SL, Wilderang U, Steineck G. Patient-reported gastrointestinal symptoms among long-term survivors after radiation therapy for prostate cancer. Radiother Oncol. 2014 Aug;112(2):237-43. doi: 10.1016/j.radonc.2014.08.008. Epub 2014 Sep 4.
citation: Ahlin R, Bergmark K, Bull C, Devarakonda S, Landberg R, Sigvardsson I, Sjoberg F, Skokic V, Steineck G, Hedelin M. A Preparatory Study for a Randomized Controlled Trial of Dietary Fiber Intake During Adult Pelvic Radiotherapy. Front Nutr. 2021 Dec 7;8:756485. doi: 10.3389/fnut.2021.756485. eCollection 2021.