We must start by acknowledging that results of only two individual studies [40
] showed a statistically significant benefit in survival for organized programs of follow-up of patients with curatively resected colorectal cancer. However, some of these studies [36
] lacked the power to detect statistically significant differences in survival associated with two follow-up programs of different intensities. Meta-analysis, by pooling the results of under-powered studies, may detect small but clinically significant differences. Indeed, meta-analyses by Renehan et al [44
] and Jeffery et al [45
] have shown significant improvements in survival for patients on more intense follow-up. The results obtained in our pooled analysis of the six randomized trials comparing two intensities of follow-up also demonstrated that patients on more intensive programs of follow-up have improved survival compared with patients on minimal or no follow-up (Relative Risk Ratio 0.80 (95% CI; 0.70 to 0.91; p = 0.0008).
The finding of decreased mortality with more intensive follow-up does not permit us to recommend a specific program of follow-up. To be more specific, we investigated the role of CEA monitoring and use of liver imaging. Our results demonstrate that only trials including CEA testing and/or liver imaging give significant improvements in survival (Figure and ). It must be stressed that all studies including liver imaging also used blood CEA monitoring. CEA testing alone was investigated in a randomized trial by Lennon et al [42
] but unfortunately other screening tests were not controlled. Patients were randomized only after a period of follow-up and when the CEA level was significantly elevated over several weeks and then to either an aggressive surgical approach to search and resect recurrence or a more conventional approach. Preliminary results indicate no difference in post-randomization survival. The lack of survival benefit of an aggressive surgical approach to CEA elevation may be due to several causes: 1) More than 60% of patients with elevated CEA had symptoms suggestive of disease. 2) There was no control for other tests which may render the CEA screening ineffective. 3) The criteria for CEA elevation required two values over 20 ng/ml or two values over 10 ng/ml but with a rise of greater than seven units. This conservative estimate of elevated CEA will decrease the diagnostic sensitivity of the test and may delay the diagnosis by two or three months, which may have an impact on patient survival. 4) This trial required an "aggressive" pursuit of the diagnosis of recurrent disease that might include a second-look laparotomy. This "aggressive" approach may cause some harm, reducing the benefit of CEA monitoring. Therefore, the negative results of this trial do not negate a potential benefit for CEA testing. Our finding of a CEA effect may simply represent confounding factors. CEA testing has been combined with chest and abdominal imaging and endoscopic examination. These factors as well as CEA testing may have an impact on survival results.
In regard to liver imaging, three studies used computerized tomography (CT) [36
] while one study used ultrasonography (US) [41
]. Computerized tomography has been shown to be more sensitive than US in detecting liver metastases [47
]. In a cohort study of 100 patients with resected colorectal cancer (mostly Dukes' stage C) who had normal livers as determined by CT, US, and intra-operative palpation of the liver [49
], several imaging tests and CEA were performed after a median follow-up of 41 months (range 36 to 48). Sensitivity for the detection of liver metastases was: for CT 0.67 (95% CI; 0.43 to 0.91), for US 0.43 (95% CI; 0.17 to 0.69), and for CEA 0.33 (95% CI; 0.09 to 0.57). The addition of CEA to CT and US increased the sensitivity up to 0.53 and 0.73, respectively. This study did not address the question of whether detection of resectable liver lesions was better by any of the screening methods.
Imaging of the chest by plain radiographs has been included in all intensive follow-up programs. Lung metastases occur in 25% of patients with resected colorectal cancer (Table ); localized lesions are less common but resection led to 30% long-term survival [50
]. In a large cohort study of 1247 patients with resected colon cancer [51
], recurrences occurred in 548 after a median follow-up of 7 years. There were 22 patients with resectable lung metastases, all detected by plain chest radiographs, and 6 were long-term survivors. In the same study, only 49 patients had hepatic resections and 32% survived more than 5 years. Thus, although plain radiographs detect very few patients with localized lung metastases, the situation is very similar to that of liver metastases. Computerized tomography of the chest has not been used as a screening test in colorectal cancer.
In regard to the incidence of second bowel cancer, no definite comments can be made based on the evidence reviewed. Only three randomized trials reported on the incidence of such tumors and the rates were similar for both follow-ups. Most studies had median observation periods around five years. Therefore, the expected number of metachronous cancers in these patients is <3% [6
Patient compliance with the follow-up plans is described in three trials [37
]. Overall, it appears that patients are quite willing to undergo frequent visits and tests.
The improvement in patient survival receiving intensive follow-up programs is achieved at the cost of frequent visits, extensive testing, earlier knowledge of disease recurrence, and increased number of further testing and surgical interventions. Harmful consequences of such extra testing and intervention have rarely been measured in randomized trials. One trial noted two perforations and two episodes of bleeding after polypectomy in 731 colonoscopies, a complication rate of 0.55% [39
]. This complication rate is comparable to that of other colonoscopy series [52
]. The quality of life and attitudes of patients participating in follow-up programs were initially investigated in a pilot study by Stiggelbout et al [53
]. Results indicated that regular contact with a physician reassured patients and that visits and tests caused only slight anticipatory anxiety and other minor inconveniences. Kjeldsen et al [46
] confirmed these findings in a subgroup of patients participating in a randomized trial comparing minimal to regular follow-up and which demonstrated similar survival for both follow-ups [38
]. Quality of life (Nottingham Health Profiles) and patient attitudes toward follow-up were investigated on 350 of 597 patients who were alive after closure of the randomized trial. Patients were mailed the questionnaires to complete at home. Ninety-one percent of patients returned completed questionnaires. Quality of life measures and attitudes were almost the same for patients on the minimal and intensive follow-up indicating the extra tests or inconveniences were balanced by the more frequent reassurance of health. These results are also consistent with those of one of the randomized trials in resected breast cancer follow-up where there was no impact of follow-up on the patients' quality of life, even after knowing that the follow-up program had not improved their survival [54
In summary, follow-up programs for patients with curatively resected colorectal cancer do improve survival. These follow-up programs include frequent visits and performance of blood CEA, chest x-rays, liver imaging and colonoscopy. It is not clear which tests or frequency of visits is optimal. There is a suggestion that improved survival is due to diagnosis of recurrence at an early and asymptomatic stage which allows for more curative resection of recurrence. There is almost no data on complications from testing and therapies. Patients' quality of life does not appear to be affected.
Development Of The Clinical Practice Guideline
Gastrointestinal Cancer Disease Site Group Consensus
Intense debate occurred during several sessions around the interpretation of the presented evidence as well as the consideration of common practices and our role in guiding other physicians as to what is an acceptable follow-up program. Further, there are other goals for follow-up than to increase survival, including psychosocial support, documentation of disease course and close contact with patients to test new therapies. The evidence presented clearly demonstrates a survival benefit for patients receiving programs of more intense follow-up. The evidence for the schedule of visits and screening tests to detect disease recurrence is soft or non-existent. The evidence for the use of colonoscopy to detect second colorectal cancer and its precursors must derive from other investigations such as the Polyp Surveillance Study in the United States [55
]. Common practice has been to follow patients at high risk of recurrence (stages IIb and III) with clinical assessment and blood tests including CEA every three to four months for the first two or three years, and every six to 12 months to complete five years following resection. Blood CEA monitoring seems to uncover resectable liver metastases, is relatively inexpensive and causes minimal inconvenience. Patients also have colonoscopy in the perioperative period, and if adenomatous polyps are present, colonoscopy is repeated yearly or, if no polyps are detected, every three to five years. This practice was recommended in a document prepared by the Gastrointestinal Cancer DSG in January 1997 (see Appendix 2 - see Additional file: 2
) and a group of experts of the American Society of Clinical Oncology recently supported similar views [56
]. These recommendations encompass the available evidence from clinical trials and what is known about the clinical biology of colorectal cancer recurrences and second tumours, and should serve as a guide to other physicians. These recommendations and the reviewed evidence were distributed to Ontario physicians caring for patients with colorectal cancer. The Gastrointestinal Cancer DSG also emphasized that further trials are needed to determine which tests lead to the detection of resectable recurrent disease and whether patients' quality of life is also improved.
Practitioner feedback was obtained through a mailed survey. The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations should be approved as a practice guideline. Written comments were invited. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The Gastrointestinal Cancer DSG reviewed the results of the survey.
1. Number surveyed: 153 practitioners in Ontario involved in the care of patients with cancer (9 medical oncologists, 20 radiation oncologists, and 104 surgeons).
2. Return rate: 62%
3. Written comments attached: 44%
4. Agreement with the summary of evidence: 88%
5. Agreement with the recommendation: 76%
6. Approval of the recommendation as a practice guideline: 73%
Summary of Main Findings
Written comments provided by practitioners varied. One practitioner believed that liver and lung imaging should be included in the recommendations, since the only positive study included liver ultrasound. Another practitioner thought that the lack of specificity of CEA testing, its cost, and the poor results with resection of intraperitoneal recurrences argued against its routine use. Based on the studies that were reviewed, it is not clear how CEA testing every four months was recommended, and this practitioner suggested adding the following recommendation: "If a patient would not be considered fit for resection of liver, lung, or intraperitoneal metastases, there is no value to CEA monitoring." Another practitioner thought that clinical exam every four months would not be effective as no resectable disease can be diagnosed on exam. Another practitioner thought that if several randomized controlled studies showed survival benefits for yearly colonoscopy on an intensive follow-up program, then routine annual colonoscopy should be recommended as suggested by the literature review, but that the lack of evidence for the schedule of visits should be emphasized.
Gastrointestinal Cancer Disease Site Group Modifications and Actions
Although 80% of the respondents were favourable to the draft recommendations, 20% were not in full agreement and wrote specific comments. Major concerns were low sensitivity of clinical assessment and blood CEA, and the more specific value in detecting resectable solitary metastases by liver and chest imaging. These concerns are reflected in a recent survey of Canadian oncologists regarding frequency of visits and tests performed in the follow-up of curatively resected colorectal cancer: Of oncologists surveyed, 35% recommend liver ultrasound and 50% recommend chest x-rays (Grunfeld et al, unpublished results). In the randomized trials reviewed, the more intensive follow-up programs which showed an increase in survival did indeed use liver and chest imaging. Therefore, we suggested the use of chest radiographs and liver imaging with CT or US. Although CT is more sensitive than US, availability and cost of CT are significant problems. Similarly, modifications were made to address the importance of an optimal decision regarding treatment of disease recurrence. In regard to colonoscopy, we advise the recent American Gastroenterology Association Guidelines recommendations [57
]. Other comments were also considered, including colonoscopy for patients with stage I disease and more intense follow-up of patients who are fit and willing to undergo investigations and potential intervention for recurrence, regardless of age. An Information Sheet to be given to the patient at the start of the follow-up (Appendix 1 - see Additional file: 1
) was added.
Several recent practice guidelines for surveillance after colorectal cancer resection were reviewed [58
]. Two of these practice guidelines discussed levels of evidence for the recommendations [58
] but only one or two of the RCTs analyzed in this paper were considered. The recommendations are not consistent between practice guidelines, partly because of the use of biased data from cohort and non-randomized studies. Clearly, even after considering only randomized studies neither of the overviews provided definite answers to the tests required, and further research with support from sources other than those dedicated to patient care is required [12
Patients should be made aware of the importance of these research trials, and should be encouraged to participate in them. These clinical studies should be randomized to prevent biases and should be directed to homogeneous groups of patients stratified according to risks. Patients should be randomized to specific screening procedures (i.e., abdominal ultrasound or CT, PET scanning), and should measure quality of life and survival. Sufficiently long observation periods will be important to achieve reliable differential rates of risk, and sufficiently large sample sizes are necessary to obtain conclusive results. In planning such trials, a cost-benefit analysis must be performed to assess the economic costs of potential improvements in survival and quality of life [13
]. Several such trials are under way [44