Optimal follow-up surveillance protocol
Systematic review evidence[edit source]
In patients who have had curative resection of colorectal cancer, what surveillance protocol achieves the best outcomes in terms of detected recurrent disease, 5-year survival, quality of life, and colorectal cancer-related mortality? (FUR1-2a)
A systematic review was performed to compare the outcomes of minimal and intensive follow-up modalities in patients who had undergone curative resection for colorectal cancer. Note: colonoscopy follow-up is covered in the Clinical Practice Guidelines for Surveillance Colonoscopy.)
- The UK CEA Second-Look (CEASL) trial performed carcinoembryonic antigen (CEA) testing in 1447 patients, and randomised those with significantly elevated CEA to aggressive follow-up (second-look surgery) or conventional follow-up.
- The UK Follow-up After Colorectal Surgery (FACS) trial compared minimal follow-up with three more intensive follow-up protocols that included additional imaging (approximately 300 patients per group): computed tomography (CT), CEA, or CEA plus CT.
- The Italian GILDA trial compared follow-up protocols based on minimal and intensive imaging.
- A Spanish study compared a simple surveillance protocol with an intensive protocol that involved abdominal CT or ultrasonography, chest radiograph, and colonoscopy.
- A French study randomised patients to conventional follow-up or positron emission tomography (PET) to detect tumour recurrence.
All studies reported on overall survival and rates of tumour recurrence. Other reported outcomes included time to recurrence and outcomes of curative surgery following the detection of recurrence.
The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.
Survival and mortality[edit source]
Survival and mortality data from all five RCTs showed consistent non-significant differences between different follow-up protocols for patients who had undergone curative resection for colorectal cancer.
The CEASL trial reported no significant differences in overall mortality between the conventional follow-up group and the aggressive follow-up group: risk ratio (RR) 1.16 (95% confidence interval [CI] 0.87 to 1.37).
The FACS trial reported no significant differences between groups for overall mortality (p = 0.45) and colorectal cancer-specific mortality (p = 0.66) on intention-to-treat (ITT) analysis. Furthermore, no significant differences in mortality rates were observed between protocols with and without CEA (p > 0.05), and between protocols with and without CT (p > 0.05).
The GILDA trial found no differences in outcomes between patients undergoing less intensive and more intensive follow-up protocols with 82.9% survival observed in the less intensive follow-up group and 81.6% survival observed in the more intensive follow-up group: hazard ratio (HR) 1.14 (95% CI 0.87 to 1.48, p = 0.34). Similar 5-year survival rates were also observed in this trial (84% versus 81%), but no statistical comparisons were provided.
The Spanish study also reported a non-significant difference in overall survival between simple and intensive protocols with a median follow-up time of 49 months (79.5%, versus 83.5%, p = 0.41).
The French PET study found no significant difference in rates of 2-year overall mortality between the conventional follow-up group and of the PET group (9.2% versus 5%, p = 0.33).
Tumour recurrence[edit source]
Overall, detection of tumour recurrence did not differ significantly according to follow-up modality. However there was a significant difference in the rates of detection of resectable recurrence between the conventional and intensive-imaging follow-up groups. CT scans were effective in detecting recurrences.
The CEASL trial reported higher recurrence rates in the conventional follow-up group (82.4%) compared with the second-look group (76.9%), but did not report statistical analysis of these data.
The FACS trial also reported non-significant differences in recurrence rates between the four follow-up groups: "minimum follow-up" 12.3%, CEA 19%, CT 19.1%, and CEA plus CT 15.9%, (p = 0.08). However, significant differences were observed for the rate of recurrence detected by each method: "minimum" 3%, CEA 11%, CT 16.1% and CEA plus CT 13.2% (p < 0.001). When follow-up groups were split into CEA versus no CEA, no significant differences were observed in overall recurrence rates (p=0.41) or the rate of recurrence detected during follow-up (p=0.14). By contrast, when patients receiving CT were compared with those who did not receive CT, a significantly higher rate of detected recurrences was observed in the CT groups than the no-CT group (14.6% versus 7%, p < 0.001). However this effect was not significantly different for rates of overall recurrence (p = 0.39).
Although the GILDA trial did not provide statistical comparisons between groups for recurrence rates, similar overall recurrence rates were observed between less intensive (18.8%) and more intensive (22%) follow-up groups. Comparable rates were also observed when recurrence was stratified by type, including local anastomotic, local extra-anastomotic, liver only, lung only, multiple, and other site recurrence.
The Spanish RCT comparing simple and intense protocols reported several tumour recurrence-related outcomes including overall recurrence, type of recurrence, and the rate of resectable tumour recurrence stratified across stage and location (rectal and colon). The overall recurrence rate was non-significantly higher in the intensive follow-up group compared with the simple follow-up group (27.6% versus 25.8%, p = 0.74), and the type of recurrence (metachronous versus loco-regional versus distant) did not differ significantly between groups (p = 0.81). Overall rates of resectable tumour recurrence were, however, significantly different between groups, with 51% recurrence observed in the intense group and 29% observed in the simple follow-up group: odds ratio (OR) 2.85 (95% CI 1.04 to 7.87, p = 0.04). However, when stratified by tumour stage (II versus III), only patients with stage II tumours showed a significant difference in recurrence, with patients in the intensive follow-up group having higher recurrence (73.3%) than the simple follow-up group (20%): OR 8.88 (95% CI 1.40 to 49.3, p = 0.01). When resectable tumour recurrence was stratified by location, patients with tumour of the colon did not show a significant difference between groups: OR 2.22 (95% CI 0.7 to 6.67, p = 0.89). By comparison, among patients with resectable rectal tumours, a higher proportion was detected by intensive follow-up than simple follow-up (80% versus 20%, p = 0.08). However, this effect was not significant after controlling for age, preoperative CEA levels, tumour stage, tumour location, and risk of metachronous lesions: OR 29.4 (95% CI 0.94 to 916.48, p = 0.054).
The French PET trial reported 2-year survival rates. It reported comparable rates of recurrence in for the conventional and PET groups both on ITT analysis (32.3% versus 38.5%) and per-protocol analysis (32.3% versus 38.3%). However no statistical comparison of these data was provided.
Time to recurrence[edit source]
In the FACS trial, Kaplan-Meier curves were used to compare time to recurrence between four different follow-up protocols (minimal, CEA, CT and CEA plus CT). No significant difference was observed between these protocols over 5 years of follow-up (p = 0.18).
Similarly, the Spanish study reported comparable mean time to recurrence for simple and intense follow-up protocols (39 months versus 39 months).
By contrast, the French RCT comparing conventional and PET protocols reported a significantly shorter mean time to detected recurrence in the PET follow-up group than the conventional follow-up group (12.1 versus 15.4 months) for patients included in the per-protocol analysis (p = 0.01), with similar rates observed on ITT analysis.
Curative follow-up surgery[edit source]
The French study reported higher rates of curative resection in the PET group compared with the conventional screening group on per-protocol analysis (65% versus 9.5%, p < 0.0001). Similarly, the rate of successful curative resection was higher for patients undergoing PET follow-up than conventional follow-up (43.5% versus 9.5%, p < 0.01).
Similarly to the Spanish study, the FACS trial also reported higher rates of attempted curative resection in the intensive follow-up group. On ITT analysis, the rate of surgical treatment with curative intent was significantly lower in the minimal follow-up group (2.3%), than the other three groups:
- CEA only (6.7%): OR 3.00 (95% CI 1.23 to 7.33, p = 0.004)
- CT only (8%): OR 3.10 (95% CI 1.27 to 7.57, p = 0.01)
- combination of CEA plus CT (6.6%): OR 6.71 (95% CI 1.96 to 22.9, p = 0.005).
The combination of CEA and CT did not add any benefit when compared with CEA alone or CT alone. The same significant effects were also observed on per-protocol analysis. No significant differences in overall recurrence were observed on ITT analysis when follow-up protocols that included CEA were compared with no CEA (p = 0.53), or when protocols that included CT were compared with no CT (p = 0.59).
Quality of life[edit source]
Quality of life was reported as an outcome in the GILDA trial. This study observed no significant difference between SF12 mental and physical health scores for patients undergoing less intensive versus more intensive follow-up protocols. Psychological General Well-Being Index questionnaire scores also showed no differences between patients undergoing different follow-up protocols. No statistics were provided for these comparisons.
Evidence summary and recommendations[edit source]
|Survival and mortality
No difference between intensive and less intensive follow-up groups was observed for both overall survival and mortality.
|II||, , , , |
Rates of tumour recurrence and detected tumour recurrence were inconsistent across studies, with the majority reporting no consistent or significant differences between different follow-up schedules.
There was a significant increase in the detection of resectable recurrence with intensive follow-up.
|II||, , , , |
|Time to recurrence
Time to recurrence was not consistently different between follow-up groups and may be dependent on the type, rather than the intensity, of the follow-up.
|II||, , |
|Curative follow-up surgery
More intensive follow-up schedules (including CEA, CT and PET/CT) may result in higher rates of curative follow-up resection and improved survival in those patients in whom resectable colorectal cancer was detected.
|Quality of life
Quality of life was only reported in one study, which showed negligible difference between follow-up groups.
These recommendations apply only to asymptomatic patients. All patients who develop symptoms should be investigated rigorously.
Colonoscopy should be performed at 12 months after surgery to exclude missed lesions. If the initial colonoscopy was incomplete then a colonoscopy should be performed at the latest 6 months after surgery. If the colonoscopy is normal, refer to the Clinical Practice Guidelines for Surveillance Colonoscopy for subsequent colonoscopies.
Intensive follow-up for colorectal cancer should be considered for patients who have had potentially curable disease, although optimal modality and frequency are yet to be firmly established.
Intensive follow-up can detect recurrences earlier, thus surgical resection for curative intent is possible. However, this is not associated with improved survival.
CEA and CT scans are readily accessible and relatively sensitive investigations.
Considerations in making these recommendations[edit source]
A Cochrane review of follow-up strategies for patients who had curative surgery for non-metastatic colorectal cancer was published after the literature cut-off date of this systematic review. The findings of the systematic review and Cochrane review were consistent. The Cochrane review concluded that there was no survival benefit for intensive follow up but did show a higher rate of resectable recurrent disease if patients were followed up in the intensive group. However, despite having surgery this did not improve their survival. The limitations of the Cochrane review included the heterogeneity of the follow up strategies and of the definitions for ‘intensive follow-up’.
The benefits from intensive follow-up include:
- the detection of potentially curable recurrent disease
- the ability to remove metachronous polyps and to detect early metachronous cancers
- the provision of audit and survival data
- patient support.
The most recent randomised controlled trials and meta-analyses support no survival advantage for patients who are followed up intensively after curative resection of colorectal cancer.
Health system implications[edit source]
Clinical practice[edit source]
Between 12 and 20 patients must undergo intensive investigation for one patient to have a resectable recurrence detected and receive surgery for curative intent.
CEA is relatively cost-effective when compared with CT scans. However, two-thirds of patients with recurrence were detected on CT scan first in the FACS study.9
Barriers to implementation[edit source]
No barriers to the implementation of these recommendations are envisaged.
Unresolved issues[edit source]
There are no significant unresolved issues.
Studies currently underway[edit source]
There are no significant ongoing studies.
Future research priorities[edit source]
Although the costs and complications of follow-up investigations can be considerable, the cost-benefit ratio needs to be assessed formally with further trials.
There is research on which to establish an algorithm based on the rate of change in CEA, to improve specificity for the detection of recurrent disease. This approach has been successful using cancer antigen 125 levels in the detection of ovarian cancer. The implementation of such an algorithm may lead to fewer CT scans and would reduce costs to the health system.
There is growing interest in systematic second-look surgery and HIPEC in patients who are high risk for CRC related peritoneal carcinomatosis (T4 lesions, perforation at primary operation and ovarian/low volume peritoneal metastases excised) due to the late onset of symptoms and low sensitivity of imaging techniques and tumour markers. A French multi-centre randomized trial is ongoing (Prophylochip). Patients at high risk after adjuvant treatment with FOLFOX 6 and with a negative follow-up are randomly assigned to surveillance or second-look laparotomy and HIPEC. The aim of the research is to evaluate rate of peritoneal recurrence at three years.).
- Primrose JN, Perera R, Gray A, Rose P, Fuller A, Corkhill A, et al. Effect of 3 to 5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: the FACS randomized clinical trial. JAMA 2014 Jan 15;311(3):263-70 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24430319.
- Rodriguez-Moranta F, Salo J, Arcusa A, Boadas J, Pinol V, Bessa X, et al. Postoperative surveillance in patients with colorectal cancer who have undergone curative resection: a prospective, multicenter, randomized, controlled trial. J Clin Oncol 2006 Jan 1;24(3):386-93.
- Rosati G, Ambrosini G, Barni S, Andreoni B, Corradini G, Luchena G, et al. A randomized trial of intensive versus minimal surveillance of patients with resected Dukes B2-C colorectal carcinoma. Ann Oncol 2016 Feb;27(2):274-80 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26578734.
- Sobhani I, Tiret E, Lebtahi R, Aparicio T, Itti E, Montravers F, et al. Early detection of recurrence by 18FDG-PET in the follow-up of patients with colorectal cancer. Br J Cancer 2008 Mar 11;98(5):875-80 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18301402.
- Treasure T, Monson K, Fiorentino F, Russell C. The CEA Second-Look Trial: a randomised controlled trial of carcinoembryonic antigen prompted reoperation for recurrent colorectal cancer. BMJ Open 2014 May 13;4(5):e004385 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24823671.
- Jeffery M, Hickey BE, Hider PN, See AM. Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev 2016 Nov 24;11:CD002200 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27884041.
- Jeffery GM, Hickey BE, Hider P. Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev 2002;(1):CD002200 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11869629.
- Renehan AG, Egger M, Saunders MP, O'Dwyer ST. Impact on survival of intensive follow up after curative resection for colorectal cancer: systematic review and meta-analysis of randomised trials. BMJ 2002 Apr 6;324(7341):813 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11934773.
- ClinicalTrials.gov. Trial Comparing Simple Follow-up to Exploratory Laparotomy Plus "in Principle" (Hyperthermic Intraperitoneal Chemotherapy) HIPEC in Colorectal Patients (ProphyloCHIP). [homepage on the internet]; Available from: https://clinicaltrials.gov/ct2/show/study/NCT01226394.