Title: Extension of Follow-Up for High Risk Stage II Patients (additional 3 years) and Stage III Patients (up to year 3 follow-up) in the SCOT study
Funder: Chief Scientist Office, Scotland

Abstract: Background:SCOT ended recruitment on 29/11/13; 6087 patients with stage III/high risk stage II(HRII) CRC were randomized to 6months (standard) or 3months adjuvant treatment with fluoropryrimidine plus oxaliplatin. SCOT’s primary aim is to determine if treatment duration can be halved without reducing treatment efficacy so decreasing cost and toxicity. It’s a non-inferiority trial designed to exclude a 2.5% reduction in 3 year disease-free survival (dfs) from 78% to 75.5%. For 90% power, 9500 patients are required. The 6087 patients recruited, and current follow up schedule, gives 60% power to assess the primary question. We are the most important contributor to the IDEA stage III colon collaboration which is a planned analysis of data from 6 studies all asking this duration question. These studies will bring together over 10500 stage III colon patients; 4018 of these from SCOT (the next largest IDEA study will have 2500 at most) Problems: i. The HRII patients are a critical SCOT subgroup (n=1115), perhaps more important as better prognosis means avoidance of disabling neuropathy is paramount. However the lower event rate, sample size, and present follow up, limits our power to reliably answer the duration question in HRII. Extended follow up and pooled analysis are required ii. One of the key outcomes from SCOT will be the associated translational analyses. Sample collection started early in 2013 and to date more than 2860 blood samples and 2700 FFPE blocks have been obtained (ultimately we aim to collect 3000 samples of each type). Blood samples have largely been obtained from patients recruited late in the study ie from a subgroup with short follow up. To optimize power to define novel prognostic markers while maintaining reasonable study duration we need a minimum period of three years follow up for all stage III patients. Study Proposal i. Building on SCOT recruitment success, there is the opportunity to address the two problems above by extending follow up. We propose to increase the follow up of HRII patients from Nov 2014 to Nov 2017, increasing our projected number of HRII events from 110 to 230. In addition, 3 other IDEA studies also have HRII patients (target numbers 1323, 500 and 500 respectively) and we have secured agreement to pool their results with the SCOT team leading the analysis. This gives a projected total (across 4 trials) of 675 dfs events and 85% power (10% 1-sided) for an ITT analysis. The power considerations for this analysis assume the maximum clinically acceptable inferiority in DFS in HRII patients corresponds to a hazard ratio of 1.2 ie. a 3.1% drop in 5 year DFS rate from 82.3% to 79.2%, less than half the difference attributable to oxaliplatin in the MOSAIC HRII subgroup (ii).Extension also gives 80% power to carry out a key ‘per protocol analysis’ in the HRII subgroup, comparing patients on the 12 week arm that get 12 weeks and those on the 24 week arm that get >12 weeks. This latter analysis would only have 74% power without extension. ii.We propose to increase follow up for stage III patients who have not yet reached the 3 year point (max 24 month extension). As sites will be open and collecting data for HRII patients, the incremental cost is small, but the added benefit is huge in terms of the power of the translational analyses. It also increases the overall power of SCOT as a standalone study to answer the primary efficacy question in stage II/III CRC from 60% to 74%

Lay abstract: Bowel cancer is the 4th commonest cancer in the UK (affecting 41,500 people/year with 15,600 deaths per year). After potentially curative surgery the cancer returns in up to 40%. It has been shown that a 6 month course of chemotherapy following surgery reduces the chance of the cancer coming back (by killing any cancer cells that may have escaped from the primary bowel cancer) so increasing the cure rate. Combination chemotherapy is routinely considered in patients with lymph node (LN) involvement (stage III) and in patients without LN involvement, but other high risk factors; high risk stage II patients (HRII). Chemotherapy has side effects and many of these side effects are cumulative, being worse in the second 3 months of treatment. There is evidence from a single small study suggesting 3 months treatment may give the same benefit as 6 months, but a large study is needed to prove this. If 3 months of treatment is shown to be as effective as 6 months, in the future treatment will be shorter with fewer side effects and hence more cost effective. This will be of enormous benefit to individual patients, healthcare providers and society at large. We have recently completed recruitment to a study (called the SCOT study) to answer this question. In SCOT half the patients were allocated at random either to have the standard 6 months of treatment or to have 3 months of treatment. This study recruited 6087 patients from the UK, Denmark, Spain, Sweden, Australia and New Zealand. SCOT will provide guidance on treatment duration for the patients recruited to the study as whole, but by increasing the length of time that we follow up some patients will mean we can answer some specific questions more effectively: 1) We would like to focus more on a particular subgroup of patients, the so-called high risk stage II patients. These patients have a smaller chance of their cancer coming back than stage III patients and there are fewer of them in the study (only 1/5 of the total). To get a more accurate answer of recurrence in these patients we propose increasing the length of follow up by 3 years. In order make an accurate comparison between the two groups additionally we will pool our data with similar patients from 3 other trials that are being conducted worldwide. 2) We have been collecting blood samples plus tumour tissue samples from patients in the study. We will study these samples in the laboratory in order to determine features of the tumour or individual which may be associated with the likelihood of the tumour coming back. The chance of matching these features with whether the tumour comes back (relapsing) is increased if we have more observations when the tumour has relapsed. To do this we would like to ensure that all the stage III patients (those at greater risk of relapse) are followed up for a minimum of three years each. As the last patient was entered in Nov 2013, and the current funding for follow-up is just until Nov 2014, this would need to be extended to Nov 2016. This would run alongside the follow up of the stage II patients described above. We think that the small incremental cost of this part of the project is justified in terms of the large potential extra benefit with respect to the scientific outputs of the study.

Research activity codes: 6.1 PHARMACEUTICALS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CANCER AND NEOPLASMS