Study design:
This research study will perform multiple FIT testing in a prospective cohort of patients referred through the NHS Lothian CRC USoC/urgent pathway. This pathway is co-ordinated by the Colorectal Surgery team and the Interface Triage Office ('FIT office') situated at the Western General Hospital.
Current standard patient care:
A patient with 'red-flag' lower GI symptoms presenting to their GP is referred to the CRC USoC pathway. Urgent referrals for patients with similar symptoms outwith primary care are also included.
Referrals are sent to the NHS Lothian FIT office. Receipt of referral triggers the postage of 1 FIT collection kit (Minaris Medical Co. Ltd) and information leaflet to the patient. Within a few days, a second FIT collection kit and information leaflet is sent to the patient. The patient is instructed to provide a stool sample for FIT analysis, and to hand the samples into their GP practice. The patient is instructed to leave around 4 days between 1st and 2nd sample collection.
FIT samples are sent from the GP to the UKAS accredited NHS Tayside Blood Sciences laboratory based in Ninewells Hospital (Dundee) where samples are analysed to ISO15189 standards using the HM-JACKarc analyser (Minaris Medical Co. Ltd). Results are automatically transferred from NHS Tayside to the patient's electronic health record within NHS Lothian. The NHS Lothian FIT office monitor referrals and incoming FIT results day-to-day. A follow-up call is made to the patients if 10 days elapse from postage of the FIT kit without upload of a FIT result.
The highest result of the two FITs dictates patient management. Results range from \<10 to ≥400 µgHb/g. There are 3 main categories:
1. Highest FIT result \<10 µgHb/g: Patient referrals are sent to Consultant Colorectal Surgeons for review - the majority of these patients receive a clinical safety netting letter, however, \~30% undergo CT colonography or colonoscopy.
2. Highest FIT result 10-79 µgHb/g: A CT colonography is requested for the patient by the NHS Lothian FIT office. Results of this are sent to the Duty Consultant Colorectal Surgeon. If the patient is young or presents with rectal bleeding, a colonoscopy is requested instead.
3. Highest FIT result ≥80 µgHb/g: If clinically appropriate (deemed by GP within referral), a colonoscopy is requested for the patient by the NHS Lothian FIT office. Results are sent to the Duty Consultant Colorectal Surgeon.
If patients have two negative results they will receive a standardised letter from the Consultant providing safety netting. Otherwise, patients will subsequently receive correspondence from the relevant department with instructions of their planned investigation e.g. colonoscopy letter and pack from Endoscopy department, or similar information pack from Radiology department. Following investigation, patients are then appropriately managed based on investigative findings by the clinical team.
Implementation of intervention:
The clinical and research teams will monitor the FIT results from USoC and urgent referrals. Patients who have provided 2 FIT samples will be included. Patients with 2 negative results (\<10 µgHb/g) will be excluded.
Eligible patients will be contacted by a member of the research team after both FIT results have been returned and a clinical decision of investigation has been made by the clinical team (i.e. CT colonography or colonoscopy). If they are agreeable to take part in the study, they will be sent a research study information pack containing patient information sheets (PIS), additional FIT sample kits with instructions and a consent form with a prepaid envelope for return of consent form. The patient's GP will be sent a letter containing study details, what participation involves and any impact on clinical care.
The research study will deploy additional multiple FIT testing. Participants will be asked to provide a weekly FIT sample for 3 weeks - until they undergo colonic investigation. Patients will be advised to submit their collected stool sample to their GP for delivery to NHS Tayside, as what is carried out within the standard pathway. FIT results will be uploaded to the patient's EHR within NHS Lothian. In order to ensure adequate patient and sample recruitment, participants will be called one week into recruitment to discuss any concerns and encourage sample collection.
The additional 3 FIT results are unlikely to impact clinical care. Results will be monitored by the research team as they are received by the FIT office. Patients will continue with standard clinical care based on their 2 initial FIT results, as detailed above. Collection of samples should not be taken at the time of bowel prep for colonic investigations. There may be a small proportion of cases in which the additional FIT tests (tests 3-5) return a significantly higher FIT value than tests 1-2. This relates to a specific situation in which patients with initial FIT results of \<80 µgHb/g return an additional FIT result ≥80 µgHb/g. In the first instance they would have been scheduled a CT colonography as per our USoC/urgent pathway. Upon identifying a result of ≥80 µgHb/g, the research team will contact the relevant clinician to highlight this result, and as per our clinical pathway, recommend a colonoscopy to be performed. Conversely, there will be no de-escalation of pathway management should the additional tests are lower than the initial 2 FIT tests. Patients will not be routinely informed of their additional FIT results unless they are significantly higher than tests 1-2 or if the patient contacts the research team to enquire.
Patients will be included within our study for 10-year follow-up, to allow for data collection purposes (no further intervention will take place), in particular for cancer-related outcomes.
Additional sample collection:
The prospective intervention study represents a unique opportunity to collect samples for potential biomarkers that can aid early detection. Metabolomic analysis of patient faeces and blood serum has shown to improve CRC detection. The results of faecal and plasma short chain fatty acid (SCFA) analysis and plasma lipidomics can be used in combination with traditional FIT analysis to improve overall specificity for CRC. SCFAs are by-products from the gut microbiota digestion of starches and are altered in patients with CRC. These changes are detectable in both faeces and in blood serum. Furthermore, cf- and ct-DNA has been showed to have high sensitivity in the detection of early colorectal cancer.
Symptomatic patients scheduled for colonoscopy will only be included as attendance at endoscopy provides an opportunity for additional sample collection.
Additional faecal and blood samples will be stored at -80°C in a secure location in the Colon Cancer Genetic Group laboratories at the University of Edinburgh (UoE) Institute of Genetics and Cancer (IGC). Gas chromatography will be applied to analyse SCFA/lipid structure and concentration levels within samples, which will take place at the University of Glasgow. cf- and ct-DNA analysis will take place locally at the University of Edinburgh.
Recruitment:
Our study recruitment will take place for 1 year. Recruitment figures are based on pathway data. During 2024, 2,000 symptomatic patients were referred, and had at least one positive FIT result following submission of two FITs. CRC prevalence in this cohort is 0.077%.
There are no study comparators to estimate drop-out over five tests. The RFIT return rate was 64% and 57% for two and three FITs, respectively. Furthermore, in comparison to previous research within the unit (Gerrard et al, 2023), all patients within the proposed study will have a positive FIT and awaiting investigation. Thus, participants may have invested interest in providing more samples. Local data and experience signifies the importance of a patient follow-up call to encourage sample collection, which is incorporated into the research plan.
We anticipate around 25% of patients will not meet study eligibility, answer the phone or participate. A further estimated 25% will not submit additional FIT tests. Therefore, we predict a total of \~1,000 patients to submit five FIT tests over a 1-year period (50% of relevant cohort).
