A randomized trial of intensive versus minimal surveillance of patients with resected Dukes B2-C colorectal carcinoma

Rosati, Gerardo; Ambrosini, G.; Barni, Sandro; Andreoni, Bruno; Corradini, G; Luchena, Giovanna; Daniele, Bruno; Gaion, Fernando; Oliverio, Giovanni William; Duro, Mary; Martignoni, G.; Pinna, N.; Sozzi, Pietro; Pancera, Gianfranco; Solina, G.; Pavia, Gianfranco; Pignata, Sandro; Johnson, F. Bing; Labianca, Roberto; Apolone, Giovanni; Zaniboni, Alberto; Monteforte, Marta; Negri, Eva; Torri, Valter; Mosconi, Paola; Fossati, Roldano

doi:10.1093/annonc/mdv541

Cited by 112 publications

(86 citation statements)

References 11 publications

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“…Similar conclusions were reached in the GILDA (Gruppo Italiano di Lavoro per la Diagnosi Anticipata) trial, an RCT comparing imaging follow‐up strategies for colorectal cancer, in which 1228 patients were randomized to either minimal or intensive surveillance. Liver ultrasonography was performed twice over the 5‐year study period in the minimal surveillance group, compared with every 4 months in the first year and often combined with chest X‐rays in the intensive surveillance group.…”

Section: Discussionsupporting

confidence: 66%

Survival analysis of the CEAwatch multicentre clustered randomized trial

Verberne

Zhan

Heuvel

et al. 2017

British Journal of Surgery

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There was no direct survival benefit in favour of the intensive programme, but the CEAwatch protocol led to a higher proportion of recurrences being detected by CEA-based blood test and reduced the number detected by patient self-report. This is important because detection of recurrence by blood test was associated with significantly better survival than patient self-report, indirectly supporting use of the CEAwatch protocol.

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Section: Discussionsupporting

confidence: 66%

Survival analysis of the CEAwatch multicentre clustered randomized trial

Verberne

Zhan

Heuvel

et al. 2017

British Journal of Surgery

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“…The Italian GILDA study 85 examined the addition of ultrasound to CEA-based follow-up of colorectal cancer patients, although, confusingly, rectal cancer patients were also permitted a CT scan. As ultrasound is an insensitive method of examining for recurrence, and as all patients had regular CEA measurement, it is unsurprising that the experimental arm in this study did not demonstrate benefit.…”

Section: Discussionmentioning

confidence: 99%

“…As ultrasound is an insensitive method of examining for recurrence, and as all patients had regular CEA measurement, it is unsurprising that the experimental arm in this study did not demonstrate benefit. 85 A French study registered on ClinicalTrials.gov (NCT00199654) examines the use of PET compared with conventional imaging and CEA testing. The end point is time to diagnosis of recurrence, and the study authors planned to recruit 376 patients.…”

Section: Discussionmentioning

confidence: 99%

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

Mant

Gray

Pugh

et al. 2017

Health Technol Assess

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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.

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“…However, the authors found that methods were poorly reported and concluded that ‘large trials are required to identify which components of intensive follow up are most beneficial’. Since then, three large trials of intensified monitoring have reported. An updated search, systematic review and meta‐analysis have been undertaken to examine the effect of these programmes on overall survival including all randomized studies identified.…”

Section: Introductionmentioning

confidence: 99%

Meta-analysis of colorectal cancer follow-up after potentially curative resection

Mokhles

Macbeth

Farewell

et al. 2016

British Journal of Surgery

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BackgroundAfter potentially curative resection of primary colorectal cancer, patients may be monitored by measurement of carcinoembryonic antigen and/or CT to detect asymptomatic metastatic disease earlier.MethodsA systematic review and meta‐analysis was conducted to find evidence for the clinical effectiveness of monitoring in advancing the diagnosis of recurrence and its effect on survival. MEDLINE (Ovid), Embase, the Cochrane Library, Web of Science and other databases were searched for randomized comparisons of increased intensity monitoring compared with a contemporary standard policy after resection of primary colorectal cancer.ResultsThere were 16 randomized comparisons, 11 with published survival data. More intensive monitoring advanced the diagnosis of recurrence by a median of 10 (i.q.r. 5–24) months. In ten of 11 studies the authors reported no demonstrable difference in overall survival. Seven RCTs, published from 1995 to 2016, randomly assigned 3325 patients to a monitoring protocol made more intensive by introducing new methods or increasing the frequency of existing follow‐up protocols versus less invasive monitoring. No detectable difference in overall survival was associated with more intensive monitoring protocols (hazard ratio 0·98, 95 per cent c.i. 0·87 to 1·11).ConclusionBased on pooled data from randomized trials published from 1995 to 2016, the anticipated survival benefit from surgical treatment resulting from earlier detection of metastases has not been achieved.

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A randomized trial of intensive versus minimal surveillance of patients with resected Dukes B2-C colorectal carcinoma

Abstract: NCT02409472.

Cited by 112 publications

References 11 publications

Survival analysis of the CEAwatch multicentre clustered randomized trial

Survival analysis of the CEAwatch multicentre clustered randomized trial

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

Meta-analysis of colorectal cancer follow-up after potentially curative resection

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