Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study.

OBJECTIVES: AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. METHODS: We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. RESULTS: Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%. CONCLUSIONS: Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.

AGILE: a seamless phase I/IIa platform for the rapid evaluation of candidates for COVID-19 treatment: an update to the structured summary of a study protocol for a randomised platform trial letter.

BACKGROUND: There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions. METHODS/DESIGN: AGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol. DISCUSSION: Few approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tocilizumab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment. TRIAL REGISTRATION: EudraCT Number: 2020-001860-27 14 March 2020 ClinicalTrials.gov Identifier: NCT04746183  19 February 2021 ISRCTN reference: 27106947.

Monitoring advances including consent: learning from COVID-19 trials and other trials running in UKCRC registered clinical trials units during the pandemic.

The COVID-19 pandemic has affected how clinical trials are managed, both within existing portfolios and for the rapidly developed COVID-19 trials. Sponsors or delegated organisations responsible for monitoring trials have needed to consider and implement alternative ways of working due to the national infection risk necessitating restricted movement of staff and public, reduced clinical staff resource as research staff moved to clinical areas, and amended working arrangements for sponsor and sponsor delegates as staff moved to working from home.Organisations have often worked in isolation to fast track mitigations required for the conduct of clinical trials during the pandemic; this paper describes many of the learnings from a group of monitoring leads based in United Kingdom Clinical Research Collaboration (UKCRC) Clinical Trials Unit (CTUs) within the UK.The UKCRC Monitoring Task and Finish Group, comprising monitoring leads from 9 CTUs, met repeatedly to identify how COVID-19 had affected clinical trial monitoring. Informed consent is included as a specific issue within this paper, as review of completed consent documentation is often required within trial monitoring plans (TMPs). Monitoring is defined as involving on-site monitoring, central monitoring or/and remote monitoring.Monitoring, required to protect the safety of the patients and the integrity of the trial and ensure the protocol is followed, is often best done by a combination of central, remote and on-site monitoring. However, if on-site monitoring is not possible, workable solutions can be found using only central or central and remote monitoring. eConsent, consent by a third person, or via remote means is plausible. Minimising datasets to the critical data reduces workload for sites and CTU staff. Home working caused by COVID-19 has made electronic trial master files (TMFs) more inviting. Allowing sites to book and attend protocol training at a time convenient to them has been successful and worth pursuing for trials with many sites in the future.The arrival of COVID-19 in the UK has forced consideration of and changes to how clinical trials are conducted in relation to monitoring. Some developed practices will be useful in other pandemics and others should be incorporated into regular use.

AGILE-ACCORD: A Randomized, Multicentre, Seamless, Adaptive Phase I/II Platform Study to Determine the Optimal Dose, Safety and Efficacy of Multiple Candidate Agents for the Treatment of COVID-19: A structured summary of a study protocol for a randomised platform trial.

OBJECTIVES: Phase I - To determine the optimal dose of each candidate (or combination of candidates) entered into the platform. Phase II - To determine the efficacy and safety of each candidate entered into the platform, compared to the current Standard of Care (SoC), and recommend whether it should be evaluated further in a later phase II & III platforms. TRIAL DESIGN: AGILE-ACCORD is a Bayesian multicentre, multi-arm, multi-dose, multi-stage open-label, adaptive, seamless phase I/II randomised platform trial to determine the optimal dose, activity and safety of multiple candidate agents for the treatment of COVID-19. Designed as a master protocol with each candidate being evaluated within its own sub-protocol (Candidate Specific Trial (CST) protocol), randomising between candidate and SoC with 2:1 allocation in favour of the candidate (N.B the first candidate has gone through regulatory approval and is expected to open to recruitment early summer 2020). Each dose will be assessed for safety sequentially in cohorts of 6 patients. Once a phase II dose has been identified we will assess efficacy by seamlessly expanding into a larger cohort. PARTICIPANTS: Patient populations can vary between CSTs, but the main eligibility criteria include adult patients (≥18 years) who have laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We will include both severe and mild-moderate patients defined as follows: Group A (severe disease) - patients with WHO Working Group on the Clinical Characteristics of COVID-19 infection 9-point ordinal scale of Grades 4 (hospitalised, oxygen by mask or nasal prongs), 5 (hospitalised, non-invasive ventilation or high flow oxygen), 6 (hospitalised, intubation and mechanical ventilation) or 7 (hospitalised, ventilation and additional organ support); Group B (mild-moderate disease) - ambulant or hospitalised patients with peripheral capillary oxygen saturation (SpO2) >94% RA. If any CSTs are included in the community setting, the CST protocol will clarify whether patients with suspected SARS-CoV-2 infection are also eligible. Participants will be recruited from England, North Ireland, Wales and Scotland. INTERVENTION AND COMPARATOR: Comparator is the current standard of care (SoC), in some CSTs plus placebo. Candidates that prevent uncontrolled cytokine release, prevention of viral replication, and other anti-viral treatment strategies are at various stages of development for inclusion into AGILE-ACCORD. Other CSTs will be added over time. There is not a set limit on the number of CSTs we can include within the AGILE-ACCORD Master protocol and we will upload each CST into this publication as each opens to recruitment. MAIN OUTCOMES: Phase I: Dose limiting toxicities using Common Terminology Criteria for Adverse Events v5 Grade ≥3 adverse events. Phase II: Agreed on a CST basis depending on mechanism of action of the candidate and patient population. But may include; time to clinical improvement of at least 2 points on the WHO 9-point category ordinal scale [measured up to 29 days from randomisation], progression of disease (oxygen saturation (SaO2) <92%) or hospitalization or death, or change in time-weighted viral load [measured up to 29 days from randomisation]. RANDOMISATION: Varies with CST, but default is 2:1 allocation in favour of the candidate to maximise early safety data. BLINDING (MASKING): For the safety phase open-label although for some CSTs may include placebo or SoC for the efficacy phase. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Varies between CSTs. However simulations have shown that around 16 participants are necessary to determine futility or promise of a candidate at a given dose (in efficacy evaluation alone) and between 32 and 40 participants are required across the dose-finding and efficacy evaluation when capping the maximum number of participants contributing to the evaluation of a treatment at 40. TRIAL STATUS: Master protocol version number v5 07 May 2020, trial is in setup with full regulatory approval and utilises several digital technology solutions, including Medidata's Rave EDC [electronic data capture], RTSM for randomisation and patient eConsent on iPads via Rave Patient Cloud. The recruitment dates will vary between CSTs but at the time of writing no CSTs are yet open for recruitment. TRIAL REGISTRATION: EudraCT 2020-001860-27 14th March 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival. METHODS: New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0-2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m2 administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m2 administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m2 repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m2 administered intravenously over 2 h and oral capecitabine 1000 mg/m2 twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m2 followed by a weekly infusion of 250 mg/m2 with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367. FINDINGS: Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (IQR 58·0-77·5). Median progression-free survival was 22·2 months (95% CI 18·3-26·8) in the chemotherapy alone group and 15·5 months (13·8-19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 0·87-1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5-71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02-2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3-4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), oral mucositis (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]). INTERPRETATION: Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting. FUNDING: Cancer Research UK.

A randomised controlled trial to assess the cost-effectiveness of intensive versus no scheduled follow-up in patients who have undergone resection for colorectal cancer with curative intent.

BACKGROUND: Intensive follow-up after surgery for colorectal cancer is common practice but lacks a firm evidence base. OBJECTIVE: To assess whether or not augmenting symptomatic follow-up in primary care with two intensive methods of follow-up [monitoring of blood carcinoembryonic antigen (CEA) levels and scheduled imaging] is effective and cost-effective in detecting the recurrence of colorectal cancer treatable surgically with curative intent. DESIGN: Randomised controlled open-label trial. Participants were randomly assigned to one of four groups: (1) minimum follow-up (n = 301), (2) CEA testing only (n = 300), (3) computerised tomography (CT) only (n = 299) or (4) CEA testing and CT (n = 302). Blood CEA was measured every 3 months for 2 years and then every 6 months for 3 years; CT scans of the chest, abdomen and pelvis were performed every 6 months for 2 years and then annually for 3 years. Those in the minimum and CEA testing-only arms had a single CT scan at 12-18 months. The groups were minimised on adjuvant chemotherapy, gender and age group (three strata). SETTING: Thirty-nine NHS hospitals in England with access to high-volume services offering surgical treatment of metastatic recurrence. PARTICIPANTS: A total of 1202 participants who had undergone curative treatment for Dukes' stage A to C colorectal cancer with no residual disease. Adjuvant treatment was completed if indicated. There was no evidence of metastatic disease on axial imaging and the post-operative blood CEA level was ≤ 10 µg/l. MAIN OUTCOME MEASURES: Primary outcome Surgical treatment of recurrence with curative intent. Secondary outcomes Time to detection of recurrence, survival after treatment of recurrence, overall survival and quality-adjusted life-years (QALYs) gained. RESULTS: Detection of recurrence During 5 years of scheduled follow-up, cancer recurrence was detected in 203 (16.9%) participants. The proportion of participants with recurrence surgically treated with curative intent was 6.3% (76/1202), with little difference according to Dukes' staging (stage A, 5.1%; stage B, 7.4%; stage C, 5.6%; p = 0.56). The proportion was two to three times higher in each of the three more intensive arms (7.5% overall) than in the minimum follow-up arm (2.7%) (difference 4.8%; p = 0.003). Surgical treatment of recurrence with curative intent was 2.7% (8/301) in the minimum follow-up group, 6.3% (19/300) in the CEA testing group, 9.4% (28/299) in the CT group and 7.0% (21/302) in the CEA testing and CT group. Surgical treatment of recurrence with curative intent was two to three times higher in each of the three more intensive follow-up groups than in the minimum follow-up group; adjusted odds ratios (ORs) compared with minimum follow-up were as follows: CEA testing group, OR 2.40, 95% confidence interval (CI) 1.02 to 5.65; CT group, OR 3.69, 95% CI 1.63 to 8.38; and CEA testing and CT group, OR 2.78, 95% CI 1.19 to 6.49. Survival A Kaplan-Meier survival analysis confirmed no significant difference between arms (log-rank p = 0.45). The baseline-adjusted Cox proportional hazards ratio comparing the minimum and intensive arms was 0.87 (95% CI 0.67 to 1.15). These CIs suggest a maximum survival benefit from intensive follow-up of 3.8%. Cost-effectiveness The incremental cost per patient treated surgically with curative intent compared with minimum follow-up was £40,131 with CEA testing, £43,392 with CT and £85,151 with CEA testing and CT. The lack of differential impact on survival resulted in little difference in QALYs saved between arms. The additional cost per QALY gained of moving from minimum follow-up to CEA testing was £25,951 and for CT was £246,107. When compared with minimum follow-up, combined CEA testing and CT was more costly and generated fewer QALYs, resulting in a negative incremental cost-effectiveness ratio (-£208,347) and a dominated policy. LIMITATIONS: Although this is the largest trial undertaken at the time of writing, it has insufficient power to assess whether or not the improvement in detecting treatable recurrence achieved by intensive follow-up leads to a reduction in overall mortality. CONCLUSIONS: Rigorous staging to detect residual disease is important before embarking on follow-up. The benefit of intensive follow-up in detecting surgically treatable recurrence is independent of stage. The survival benefit from intensive follow-up is unlikely to exceed 4% in absolute terms and harm cannot be absolutely excluded. A longer time horizon is required to ascertain whether or not intensive follow-up is an efficient use of scarce health-care resources. Translational analyses are under way, utilising tumour tissue collected from Follow-up After Colorectal Surgery trial participants, with the aim of identifying potentially prognostic biomarkers that may guide follow-up in the future. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41458548. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 32. See the NIHR Journals Library website for further project information.

Comparative costs and activity from a sample of UK clinical trials units.

BACKGROUND: The costs of medical research are a concern. Clinical Trials Units (CTUs) need to better understand variations in the costs of their activities. METHODS: Representatives of ten CTUs and two grant-awarding bodies pooled their experiences in discussions over 1.5 years. Five of the CTUs provided estimates of, and written justification for, costs associated with CTU activities required to implement an identical protocol. The protocol described a 5.5-year, nonpharmacological randomized controlled trial (RCT) conducted at 20 centres. Direct and indirect costs, the number of full time equivalents (FTEs) and the FTEs attracting overheads were compared and qualitative methods (unstructured interviews and thematic analysis) were used to interpret the results. Four members of the group (funding-body representatives or award panel members) reviewed the justification statements for transparency and information content. Separately, 163 activities common to trials were assigned to roles used by nine CTUs; the consistency of role delineation was assessed by Cohen's κ. RESULTS: Median full economic cost of CTU activities was £769,637 (range: £661,112 to £1,383,323). Indirect costs varied considerably, accounting for between 15% and 59% (median 35%) of the full economic cost of the grant. Excluding one CTU, which used external statisticians, the total number of FTEs ranged from 2.0 to 3.0; total FTEs attracting overheads ranged from 0.3 to 2.0. Variation in directly incurred staff costs depended on whether CTUs: supported particular roles from core funding rather than grants; opted not to cost certain activities into the grant; assigned clerical or data management tasks to research or administrative staff; employed extensive on-site monitoring strategies (also the main source of variation in non-staff costs). Funders preferred written justifications of costs that described both FTEs and indicative tasks for funded roles, with itemised non-staff costs. Consistency in role delineation was fair (κ = 0.21-0.40) for statisticians/data managers and poor for other roles (κ < 0.20). CONCLUSIONS: Some variation in costs is due to factors outside the control of CTUs such as access to core funding and levels of indirect costs levied by host institutions. Research is needed on strategies to control costs appropriately, especially the implementation of risk-based monitoring strategies.

Patterns of progression, treatment of progressive disease and post-progression survival in the New EPOC study.

BACKGROUND: The addition of cetuximab (CTX) to perioperative chemotherapy (CT) for operable colorectal liver metastases resulted in a shorter progression-free survival. Details of disease progression are described to further inform the primary study outcome. METHODS: A total of 257 KRAS wild-type patients were randomised to CT alone or CT with CTX. Data regarding sites and treatment of progressive disease were obtained for the 109 (CT n=48, CT and CTX n=61) patients with progressive disease at the cut-off date for analysis of November 2012. RESULTS: The liver was the most frequent site of progression (CT 67% (32/48); CT and CTX 66% (40/61)). A higher proportion of patients in the CT and group had multiple sites of progressive disease (CT 8%, 4/48; CT and CTX 23%, 14/61 P=0.04). Further treatment for progressive disease is known for 84 patients of whom 69 received further CT, most frequently irinotecan based. Twenty-two patients, 11 in each arm, received CTX as a further line agent. CONCLUSIONS: Both the distribution of progressive disease and further treatment are as expected for such a cohort. The pattern of disease progression seen is consistent with failure of systemic micrometastatic disease control rather than failure of local disease control following liver surgery.

Effect of 3 to 5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: the FACS randomized clinical trial.

IMPORTANCE: Intensive follow-up after surgery for colorectal cancer is common practice but is based on limited evidence. OBJECTIVE: To assess the effect of scheduled blood measurement of carcinoembryonic antigen (CEA) and computed tomography (CT) as follow-up to detect recurrent colorectal cancer treatable with curative intent. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial in 39 National Health Service hospitals in the United Kingdom; 1202 eligible participants were recruited between January 2003 and August 2009 who had undergone curative surgery for primary colorectal cancer, including adjuvant treatment if indicated, with no evidence of residual disease on investigation. INTERVENTIONS: Participants were randomly assigned to 1 of 4 groups: CEA only (n = 300), CT only (n = 299), CEA+CT (n = 302), or minimum follow-up (n = 301). Blood CEA was measured every 3 months for 2 years, then every 6 months for 3 years; CT scans of the chest, abdomen, and pelvis were performed every 6 months for 2 years, then annually for 3 years; and the minimum follow-up group received follow-up if symptoms occurred. MAIN OUTCOMES AND MEASURES: The primary outcome was surgical treatment of recurrence with curative intent; secondary outcomes were mortality (total and colorectal cancer), time to detection of recurrence, and survival after treatment of recurrence with curative intent. RESULTS: After a mean 4.4 (SD, 0.8) years of observation, cancer recurrence was detected in 199 participants (16.6%; 95% CI, 14.5%-18.7%) overall; 71 of 1202 participants (5.9%; 95% CI, 4.6%-7.2%) were treated for recurrence with curative intent, with little difference according to Dukes staging (stage A, 5.1% [13/254]; stage B, 6.1% [34/553]; stage C, 6.2% [22/354]). Surgical treatment of recurrence with curative intent was 2.3% (7/301) in the minimum follow-up group, 6.7% (20/300) in the CEA group, 8% (24/299) in the CT group, and 6.6% (20/302) in the CEA+CT group. Compared with minimum follow-up, the absolute difference in the percentage of patients treated with curative intent in the CEA group was 4.4% (95% CI, 1.0%-7.9%; adjusted odds ratio [OR], 3.00; 95% CI, 1.23-7.33), in the CT group was 5.7% (95% CI, 2.2%-9.5%; adjusted OR, 3.63; 95% CI, 1.51-8.69), and in the CEA+CT group was 4.3% (95% CI, 1.0%-7.9%; adjusted OR, 3.10; 95% CI, 1.10-8.71). The number of deaths was not significantly different in the combined intensive monitoring groups (CEA, CT, and CEA+CT; 18.2% [164/901]) vs the minimum follow-up group (15.9% [48/301]; difference, 2.3%; 95% CI, -2.6% to 7.1%). CONCLUSIONS AND RELEVANCE: Among patients who had undergone curative surgery for primary colorectal cancer, intensive imaging or CEA screening each provided an increased rate of surgical treatment of recurrence with curative intent compared with minimal follow-up; there was no advantage in combining CEA and CT. If there is a survival advantage to any strategy, it is likely to be small. TRIAL REGISTRATION: isrctn.org Identifier: 41458548.