Radiation-induced Diarrhoea During Curative EBRT of Prostate and Rectal Cancer

1. Background Prostate and rectal cancer are among the most common cancer types in Denmark and make up the majority of patients who receive curative radiation therapy of the small pelvis. A well-known side effect of external beam radiation therapy (EBRT) to the pelvis is radiation-induced diarrhoea (RID). When ionising radiation is given to the patient, both tumour and the surrounding cells are damaged. Thus, irradiating prostate and rectal cancer will inevitably lead to the damage of the nearby gut mucosa cellular components. This cellular damage is causing the RID. RID is reported as the problem with the greatest impact on health-related quality of life (QoL) and social behaviour.

   Up to approx. 70% of patients who receive pelvic radiation experience acute RID. It usually occurs two weeks after start of EBRT and peaks during 4-5 weeks. Acute RID may cease a few weeks after the end of EBRT but increases the risk of developing chronic RID.

   Recently, a systematic Cochrane review reveals low evidence for dietary interventions in RID due to few studies and low scientific quality. A serious drawback of the Cochrane review was that it included studies prior of 2005, with radiotherapy given both pre- and post-surgery, as well as with radiotherapy techniques resulting in higher doses to the normal tissue. It is well known that the volume of the radiation field greatly impacts the severity of RID and newer radiation techniques allow smaller volume fields.

   There is a lack of consensus about how acute RID is reported, such as definition of RID (frequency), classification and the changes during EBRT. There is also a lack of knowledge of changes in microbiomes which can contribute to RID. The role of dietary intervention during EBRT could also influence RID.

2. Aim The aim of this prospective observation study is to investigate the frequency, severity and changes of acute RID in patients with prostate and rectal cancer as well as the role of nutrition and changes in microbiome during curative EBRT.
3. Method This is an observational multicenter study of acute RID in patients with prostate and rectal cancer during curative EBRT. The study will take place in parallel with the patients' EBRT, which is ongoing on weekdays over 39 days for patients with prostate cancer and 28 days for patients with rectal cancer.

Study procedure Candidates will be identified according to the inclusion and exclusion criteria. The patients will be informed orally and in written form by a doctor or project nurse at the first oncology appointment.

The observations will start at baseline and concomitant with EBRT. All examinations and observations will be carried out in parallel with the patient's EBRT.

Data collection

1. Patient data: Civil status, age, sex, comorbidities, smoking, histopathology data: Primary diagnosis, date, stage, Electronic patient's record (EPR) 2. Treatment data: Treatment start and end date, fractionation and total dose (Gy), field size and anatomical location, EPR 3. Clinical examinations: ECOG performance status, body weight, height, rectal exploration, rectal haemorrhage or mucus, bloating, flatulence, obstipation, abdominal pain or tenesmus, faecal or urine incontinence, EPR, Common Terminology Criteria for Adverse Events (CTCAE) 4. Medication: Anti-diarrhoeal medication, laxatives, antibiotics, opioids, EPR 5. Frequency and classification of RID, body weight, Bristol Stool Scale and patient reported stool diary 6. Nutrition screening: Nutrition-related symptoms, dietary intake development, PG-SGA-short form 7. Dietary assessment: 3-day food records, online food database (Vitakost, 2006-2018, Denmark 8. Patient's physical activity, International Physical Activity Questionnaire (IPAQ-short form) 9. Quality of life (QoL), EORTC QLQ-C30, EORTC QLQ-PRT20 questionnaires 10. Biochemistry: Routinely blood samples collected at baseline will be obtained, EPR (biochemical record) 11. Faecel samples only for patients treated in Aalborg: F-calprotectin, short chain fatty acids. Samples will be frozen for subsequent microbial analysis, EPR (microbiological record)

4. Statistical considerations It is expected to include at least 100 patients during the inclusion period from 1 June 2022 to 31 December 2023. We expect to find above 30% of the patients with acute RID, why the required number of patients is estimated as above. The data are processed descriptive, as current numbers and percentages.

Uni- and multivariate analyses will be conducted using the Stata software, version 16 (StataCorp, LLC, TX, USA).

5. Subjects Patients with prostate and rectal cancer patients commenced to start curative EBRT, referred to the oncology department at Danish hospitals participating in the study will be consecutively screened for study eligibility according to the inclusion and exclusion criteria.

1. Inclusion criteria

   1. Histopathologically verified prostate or rectal adenocarcinoma 2. Commenced to start curative EBRT to the pelvis, with or without chemotherapy or with or without androgen deprivation therapy (ADT) 3. Performance status 0-1 4. ≥ 18 years of age 5. Understanding and acceptance of written and orally informed consent in Danish

2. Exclusion criteria

   1. Earlier treated with EBRT or other type of radiation to the pelvis
   2. History of diagnosed inflammatory bowel disease
   3. Colostomy
   4. Pregnancy
   6. Risks, side effects and disadvantages in short and long term This observational study does not include any risks for the included patients. Their treatment will be carried out as standard of care. Disadvantages are only related to answering the questionnaires and extra blood-samples and for Aalborg-patients also the collection of stool-samples.
   7. Information from patient records

   The following data will be registered:

   Civil status, age, sex, smoking, comorbidities, histopathologal data: primary diagnosis, date, stage.

   Treatment start and end date, fractionation and total dose (Gy), field size and anatomical location.

   Clinical examinations: ECOG performance status, rectal exploration, rectal haemorrhage or mucus, bloating, flatulence, obstipation, abdominal pain or tenesmus, faecal or urine incontinence.

   8. Data collection The tools (PG-SGAshort form, IPAQ short form, EORTC QLQ-C30 and EORTC QLQ-PRT20) will be sent to the patient's email address or security electronic mailbox (e-Boks) via RedCAP. Patient's responses will be registered directly in RedCAP.

   Patient reported stool diary and 3-day food records will be handed out in paper versions at the 1st visit at the radiation center. These paper versions will be returned to the primary investigator via franked envelopes and the data recorded will be registered in RedCAP. Data collected will be handled according to the Danish law of data protection and Personal Data Act. It is the responsibility of the principal investigator to ensure that the rules and regulations of data collection and storage comply with the Personal Data Act.

   9. Data storage The patient's personal identification/CPR number will be removed and replaced by a code number.

   All data will be stored in the MM-ICI-ABX research database in the system of the Research Electronic Data Capture (REDCap) at the clinical research unit, Dept. of Oncology, Aalborg University Hospital, the North Region of Denmark.

   10. Data protection All data stored in the REDCap research data MM-ICI-ABX will be handled according to the rules of Good Clinical Research Practice (27). The research database will be stored at the Clinical Research Unit, Dept. of Oncology, Aalborg University Hospital and owned by the Northern Region of Denmark. The password will be established for the principal investigator only (Mette Overgaard Holm). The members of the project group will handle the data according to the Danish laws of personal data protection. The patient's personal identification number will be removed and replaced of a code number (anonymisation). The key document with information on both personal ID and code number will be deposited at the clinical research unit project secretary according to GDPR and the Danish laws of personal data protection.
   11. Data deletion All data in this study will be deleted 5 years after publication of all results.
   12. Collaboration agreement Collaboration agreement will be made between the principal investigator in the North Denmark Region and the participating local investigators of the actual regions of Denmark (The Capital Region of Denmark, Region Zealand and South Denmark Region).

   The study will be performed between the North Denmark Region, the Capital Region of Denmark, region Zealand and South Denmark Region. The study will be designed by all responsible parts.

   13. Economy The initiative for this project was taken by the project group, employed at Aalborg University Hospital and Clinical Institute, Aalborg University. Participants in the project group are financed (partial or completely) through their employment at Aalborg University Hospital and Clinical Institute, Aalborg University.

   Funding of 320,000 DKK has been obtained from the Clinical Institute, Aalborg University (research fund, U. Falkmer) and from the Region North Denmark of 86,000 DKK (research fund, M.O. Holm), as well as 191,850 DKK from the Danish Comprehensive Cancer Center (DCCC) and will be used for salary for the PhD student (Mette Overgaard Holm), statistician, as well as a coordinative staff from each participating radiation therapy center. There is no economic benefit for neither the participating departments nor the hospital employees.

   The funders have no role in study design, data collection and analysis, and decisions to publish, or preparation of the manuscript.

   14. Compensation and/or other benefits to the subjects The patients will not be offered any financial compensation or other benefits due to study participation, nor travel expenses.

   Patients participating in the study are covered by national regulation.

   15. Publication The results regardless of positive, negative, and inconclusive character will be published in international peer reviewed scientific journals and in the PhD thesis of Mette Overgaard Holm.
   16. Science ethics section All patients included in the study have signed their information used for this clinical research project. The study is initiated as an academic protocol of the project group. The members have no conflict of interest. The approval will be applied for at the Scientific Ethics Committee Northern Region of Denmark. The study protocol will be registered in ClinicalTrial.gov and in the Region North Denmark.
   17. Compensation scheme information Not relevant for this project.