Title: Improving the prediction of metastatic disease in primary colorectal cancer: Prospective multicentre evaluation of a prognostic model of conventional predictive variables and novel variables derived from perfusion computed tomography (Perfusion CT)
Funder: Department of Health and Social Care

Abstract: Cancer of the large bowel is common, newly diagnosed in 37500 patients a year in the UK. Current diagnostic imaging tests (e.g.CT) before surgery separates patients into those with and without metastases. Up to 80% of patients are operated on with curative intent, yet approximately half of the patients will die of their disease ultimately. Once disease has metastasized, outcome is poor. The challenge is to identify ‘high-risk’ patients ahead of time, and to start further treatment at an earlier stage, e.g. neoadjuvant chemotherapy, which may prevent metastases & enhance survival. Perfusion CT is an emerging test in this clinical scenario. This study aims to improve the prediction of metastatic disease in patients with colorectal cancer by the prospective development using leading edge statistical modelling of a prognostic model incorporating both standard clinicopathological & novel predictors derived from Perfusion CT. This prospective multicentre study will aim to recruit 370 patients with primary colorectal cancer from 10-15 UK sites over 15 months. Eligible patients will undergo an additional perfusion CT sequence during the staging CT, and followed up for 3 years, including clinical examination, serum CEA, endoscopy, & whole body CT. Disease relapse, where present, will be confirmed via histology or clinical outcome. Disease free and overall survival at 3 years will be determined. The prognostic model including Perfusion CT measurements will be used to develop a prognostic scoring rule. The final rule will be given in the form: Prognostic score = a.Tstage + b.Nstage + c. Perfusion_ CT_measurements + d.other_variable, where a, b, c and d are coefficients from the Cox model. This prognostic score will be used to predict patients at high risk, who are predicted to develop metastasis. The value of including Perfusion CT measurements in the prognostic score will be assessed based on the change in patients with a correct and incorrect diagnosis compared to predictions made using current clinical practice rules to predict metastasis. The primary outcome will be expressed as two metrics, 1) the change in sensitivity (due to use of the primary outcome model using Perfusion Ct parameters and 2) the change in specificity both adjusted for prevalence of metastasis. Sensitivity analyses for patient and clinician weightings of measures will facilitate an overall assessment of model performance.

Lay abstract: ADDRESSING THE BRIEF: Cancer of the large bowel is a common cancer, newly diagnosed in 37500 patients a year in the UK. Approximately half of the patients will die of their disease ultimately. Once disease has spread (metastasized), outcome is poor with only 3% surviving at 5-years. The challenge is to predict this ahead of time. Current diagnostic imaging tests that perform this are blunt. CT imaging before surgery separates patients with and without metastases. In the UK up to 80% of patients are operated on with curative intent, yet 50% will relapse ultimately. Earlier / better identification of ‘high-risk’ patients is needed to start further treatment at an earlier stage, e.g. additional chemotherapy before surgery, which may prevent metastases & enhance survival, with potential cost savings for the NHS. This is the challenge for current imaging methods. Perfusion CT is an emerging test in this clinical scenario. Coupled to the staging CT, this validated & reproducible imaging test provides information of the tumour’s blood supply in addition to anatomy. Recently published data suggest that patients with low blood flow tumours are especially at high risk (Goh, Eur Radiol 2009;19:79-89) & further statistical analysis of this data suggests Perfusion CT has strong potential as a predictor. This study aims to improve the prediction of metastatic disease in patients with colorectal cancer by the prospective development & validation of a prognostic model, by leading-edge statistical modeling (Altman, BMJ 2009;338/9) using both standard predictors e.g. tumour stage & novel predictors derived from Perfusion CT in a multicentre setting. The secondary objectives are: 1) To assess the added value of using novel Perfusion CT parameters to predict metastasis by: (a) comparing the best prognostic model with & without CT parameters included; (b) comparing prediction of 3-yr overall survival using the best prognostic model with & without CT parameters; 2) To examine the impact on the model of different weightings of clinical and patient assigned values for (a) correct prediction of an additional patient with metastasis & (b) one less patient given a false prediction of metastasis. i.e. what weighting clinicians and patients place on these results; 3) To determine the generalisability of Perfusion CT in a multicentre setting: to assess the variability of measures & estimate whether their limits of agreement are clinically acceptable. Sources of variation including observer & CT data acquisition will be examined. Effect on the model will be assessed. HOW & WHERE THIS WILL BE CARRIED OUT: This multicentre study will be supported by the British Society of Gastrointestinal Radiology (BSGAR) & national cancer (NCRN) research networks & co-ordinated by Cancer Clinical Trials Unit Scotland (CaCTUS). 10 centres (teaching & district generals) reflecting standard UK NHS practice will aim to recruit 370 patients with suspected/proven colorectal cancer over 12-15 months. Following informed consent eligible patients will undergo an additional perfusion CT sequence during pre-operative staging CT. Patients will undergo standard follow up for 3 years, including clinical examination, serum CEA, endoscopy, & yearly whole body CT, to detect disease relapse. Where present, confirmation of relapse will be via histology or clinical outcome. Central data review will be undertaken at Mount Vernon Hospital. OUTCOME: The primary outcome is the ability of the model to correctly categorise patients who will or will not develop metastasis subsequently, using both standard predictive variables & novel variables from Perfusion CT. Secondary outcomes include 1) Clinician & patient-derived weightings & their effect on the model: for a given improvement in sensitivity (i.e. 1 additional patient with metastasis correctly identified by the model), the relative weightings for an acceptable decrease in specificity will be determined (i.e. how many false positive diagnoses clinicians/patients are willing to tolerate); 2) Level of measurement agreement between observers, machines and software & effect on the model. ETHICAL ISSUES: The main ethical issue is the additional radiation dose from the perfusion CT study (equivalent to 1 additional whole body CT). Multicentre ethical approval will be obtained from National Research Ethics Service (NRES). Eligible patients will be given a patient information sheet & recruited after they have given fully informed consent. The patient will keep a copy of the consent form, another copy will be entered into the patient's notes, & another copy will kept as part of the trial documentation. WHY THE TEAM IS WELL PLACED FOR THIS: Our team consisting of clinicians, academics & world-class statisticians is well placed for this study. All applicant are internationally-renowned experts in their field: Perfusion CT (VG, KM,AG), oncology (RGJ), imaging (SH, ST) with vast combined experience of multicentre trials. Statisticians (DG,SM) are world leading experts in prognostic model research. SH & DG are NIHR senior investigators & 5 of the co-applicants work in NIHR biomedical research centres all ensuring this study will be appropriately designed, conducted & analysed. CaCTUS has an exellent track record in co-ordinating Phase II/III clinical trials. JUSTIFICATIONS OF COSTS: Research costs: Costs have increased from the outline stage due to: 1) additional patients to account for patients who will not proceed to surgery; 2) an additional £200 per patient payment to ensure successful recruitment/follow up; 3) appointment of CaCTUS to co-ordinate the study; 4) the difference in salary costs in line with the time between the outline & full application. Posts & salaries: A study co-ordinator (up to 0.5FTE for 5 years) is required to co-ordinate regulatory approval, ensure trial data recorded accurately & monitored, as specified by study protocol, & organize steering committee meetings. A research fellow (1.0FTE for 2.5years), radiographer (1.0FTE for 1 year), & physicist (0.5FTE for 2 years) are required for set up, training, QA, successful Perfusion CT analysis, & completion of substudies. Funding for co-applicants is requested to ensure successful management & completion of study. Funding for statisticians is requested for study design, model development & all analyses (0.5FTE for 3 years). Running costs: for administration, paperwork, case report forms, database, communication & associated committee meetings & travel to ensure successful trial completion. Equipment: Funding requested for a CT workstation, calibration phantom, computers & software. Other direct costs: Payment per patient (£200 for 370 patients) is requested to additionally support patient recruitment, consent, arranging CT scans, & CRF completion. NHS support costs: Support is requested on a per patient basis for the additional time that will be required for the staging CT, data transfer, NIHR nurse time, and extra administration. NHS treatment costs: No additional costs are requested.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS