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Clinical Review ABC of colorectal cancer

Effectiveness of follow up

BMJ 2000; 321 doi: https://doi.org/10.1136/bmj.321.7272.1332 (Published 25 November 2000) Cite this as: BMJ 2000;321:1332
  1. Colin McArdle

    Population based studies show that for rectal cancer the incidence of local recurrence after apparently curative resection is about 20%. Local recurrence after surgery for colon cancer is less common. The liver is the commonest site of distant spread, followed by the lungs; brain and bone metastases are relatively rare. Most recurrences are within 24 months of surgery.

    Symptomatic recurrence of colorectal cancer is seldom amenable to curative surgery

    Aim of follow up

    Traditionally surgeons have reviewed their patients at regular intervals after apparently curative resection. Recent surveys, however, have highlighted the lack of consensus among surgeons about the optimal modality and intensity of follow up; surveillance strategies range from a single postoperative visit to lifelong surveillance. Enthusiasts believe that intensive follow up and early intervention will lead to a reduction in the number of deaths from colorectal cancer; others point to the fact that the value of follow up is unproved. With so many tests available and no consensus on their value, it is not surprising that individual clinicians have tended to devise their own protocols.

    Aims of follow up

    • Early detection and treatment of recurrent disease

    • Detection of a second, or metachronous, tumour in the large bowel

    • Provision of psychological support and advice

    • Facilitation of audit

    Results of meta-analysis

    A meta-analysis in the mid-1990s did little to clarify the situation. The researchers evaluated the results of seven non-randomised studies (covering over 3000 subjects in total) that compared intensive follow up with minimal or no follow up. Clearly several potential biases could and did exist. In the intensive group, investigations included clinical examination, faecal occult blood testing, liver function tests, measurement of the carcinoembyronic antigen, sigmoidoscopy, and either colonoscopy or barium enema examination. Liver ultrasonography was performed in only three studies and even then infrequently. In the intensive group more asymptomatic recurrences were detected, more patients underwent “second look” laparotomy, and more patients had a second potentially curative resection; more metachronous tumours were also detected and resected. However, although there were fewer deaths in the group receiving intensive follow up, this difference did not reach significance.

    Figure1

    Results of meta-analysis of seven non-randomised trials that compared intensive with minimal or no follow up (Bruinvels et al, 1994)

    Results of randomised clinical trials

    Since the meta-analysis, four randomised trials of intensive follow up have been reported. Ohlsson and his colleagues randomised 107 patients to no follow up or to intensive follow up, similar to that described above. No liver imaging was performed routinely. No differences were found in recurrence rates or in overall or cancer specific mortality.

    The results of the four randomised controlled trials of intensive follow up should be interpreted with caution. Despite consistently fewer deaths in the intensive group in each study, the numbers in each were small, and no study had sufficient power to detect a survival advantage

    Mákelá and his associates compared conventional with intensive follow up in 106 patients. In the intensive group flexible sigmoidoscopy was performed every three months, ultrasonography every six months, and colonoscopy and abdominal computed tomography at yearly intervals. Recurrences were detected at an earlier stage (median 10 months v 15 months) in the intensive group. Despite this, no difference in survival was found between the two groups.

    Kjeldsen and his colleagues randomised almost 600 patients to either six monthly follow up or to follow up visits at five and 10 years only. Investigations included chest x ray and colonoscopy; no routine liver imaging was performed. Recurrence rates were similar (26%) in both groups, but the recurrences in the intensive group were detected on average nine months earlier, often at an asymptomatic stage. More patients with local recurrence underwent repeat surgery with curative intent. No difference existed, however, in overall survival (68% v 70%) or cancer related survival.

    Figure2

    Combined results of three randomised trials of intensive follow up

    Results of intensive follow up*

    Results of intensive follow up*

    View this table:

    More recently, Schoemaker and his colleagues evaluated the addition of annual chest radiography, colonoscopy, and computed tomography of the liver to a standard follow up based on clinical examination, faecal occult blood testing, liver function tests, and measurement of the carcinoembyronic antigen, with further investigations as clinically indicated. At five years, fewer patients in the intensive group had died, but the result was not significant. At the cost of 505 additional investigations, annual colonoscopy failed to detect any asymptomatic local recurrences; only one asymptomatic metachronous colon tumour was detected. Six hundred and eight additional liver computed tomograms detected only one asymptomatic patient with liver metastases who might have benefited from liver resection.

    Carcinoembryonic antigen

    Carcinoembryonic antigen concentrations have also been used to predict recurrence. About three quarters of patients with recurrent colorectal cancer have a raised carcinoembryonic antigen concentration before developing symptoms.

    An alternative approach therefore would be to monitor this concentration regularly during follow up and, in those patients showing a rising concentration, undertake second look laparotomy. However, although early non-randomised studies suggested that surgery that was prompted by this method resulted in more potentially curative repeat operations for recurrence, more recent studies have failed to show a survival advantage.

    Carcinoembryonic antigen concentrations have been used to predict recurrence of colorectal cancer, but recent evidence does not support this approach

    Moertel analysed outcome in patients included in trials of adjuvant therapy, according to whether the patient underwent carcinoembryonic antigen testing. Of 1017 patients whose concentrations were monitored, 417 (41%) developed recurrence. A comparison of those patients whose follow up included measurements of carcinoembryonic antigen with those whose follow up did not, failed to show any difference in disease-free survival. Among 29 laparotomies performed solely on the basis of a raised concentration of carcinoembryonic antigen, only one patient remained alive and disease-free after one year.

    Results of “second look” surgery according to measurement of carcinoembryonic antigen (CEA)*

    View this table:

    In the randomised study by Northover and his colleagues, 1447 patients undergoing potentially curative surgery were randomised to an intervention group or a control group. Carcinoembryonic antigen was measured in all patients at frequent intervals. In the intervention group, a rising antigen concentration prompted further investigation, including second look laparotomy, if appropriate.

    Preliminary analysis showed no difference in survival between the two groups. The failure to show a survival advantage in the intervention group may be due to the fact that a rising antigen concentration is a relatively poor predictor of local recurrence; furthermore, even in patients with liver metastases a rising concentration is a relatively late phenomenon.

    Cost effectiveness

    Concern is also increasing about the cost of follow up. A review of the published literature suggests a 28-fold difference in costs between the least intensive and most intensive, published, five year follow up protocols.

    Costs of follow up, suggested by recent study from Italy

    • £2530 per patient over five years

    • £9050 per recurrence detected

    • £39 890 for each case undergoing further surgery

    • £91 190 for each “cured” patient

    Wrong target?

    Clearly, follow up as currently practised is ineffective. Why, therefore, should we continue to follow patients up after apparently curative resection for colorectal cancer? There are several reasons. Firstly, we should do so to provide psychological support and advice; many patients welcome the reassurance that regular check up provides. Secondly, routine follow up facilitates audit of outcome measures after surgery, ensures quality control and facilitates evaluation of trials of new treatments and strategies.

    Figure3

    Contrast enhanced computed tomogram (arterial phase) showing solitary liver metastasis

    There may, however, be a more fundamental reason that current follow up practices are ineffective. On theoretical grounds, attempts to identify potentially resectable local recurrences or metachronous tumours were never likely to have a significant impact on survival. Isolated resectable anastomotic recurrences are uncommon. Most local recurrences arise from residual disease left at the time of surgery and therefore, by definition, are unlikely to be amenable to further curative surgery. Metachronous tumours, although potentially amenable to surgery, are relatively uncommon.

    Wrong intervention?

    In contrast, liver metastases are much more common. Furthermore, these metastases are confined to the liver in about a quarter of patients.

    Comparison of results of trial of early versus delayed chemotherapy in patients with advanced colorectal cancer

    View this table:

    Early chemotherapy was given when patients were asymptomatic; delayed chemotherapy was given when patients were symptomatic. Data from the Nordic Gastrointestinal Tumor Group, 1992.

    Figure4

    Suggested study outline to test three follow up strategies: intensive v minimalist; role of carcinoembyronic antigen; and general practitioner (community) coordinated v hospital coordinated

    Perhaps, therefore, the emphasis should shift towards the early detection of liver metastases. It is worth noting that in contemporary studies of liver resection, mortality is less than 5% and about 35% of patients survive five years. These figures are better than the results obtained after primary surgery for many types of gastrointestinal cancer. Furthermore recent studies have shown that patients with disseminated disease who receive systemic chemotherapy at an asymptomatic stage have higher response rates, better quality of life, and improved survival compared with those in whom the administration of chemotherapy is delayed until symptoms appear. Therefore if liver metastases were diagnosed in more patients at a point at which they were amenable to resection or chemotherapy, more long term survivors might be anticipated.

    To date only two randomised studies have included liver imaging. In both these studies the numbers were small and liver imaging was infrequent. In neither study was a survival advantage noted. However, intensive liver imaging for the first three years after surgery may be more effective: at the Royal Infirmary in Glasgow more than 80% of patients who developed liver metastases as the initial site of recurrence were detected at an asymptomatic stage.

    Hospital or community coordination of follow up?

    Most patients with colorectal cancer are followed up in hospital. Yet overwhelming evidence from previous studies shows that few curable recurrences are detected at routine follow up based on history, physical examination, and routine blood tests. Few patients are followed up by their general practitioners, although good evidence exists that, in other tumours at least, such follow up is as effective (or ineffective) as hospital follow up. Furthermore, provided that general practitioners have access to a “fast track” referral system for patients in whom they suspected recurrent disease, follow up coordinated by general practitioners might offer several advantages. It might be more acceptable to and convenient for patients and might reduce costs.

    Further reading

    • Bruinvels DJ, Stiggelbout AM, Kievit J, Van Houwelingen HC, Habbema JDF, van de Velde CJH. Follow-up of patients with colorectal cancer: a meta-analysis. Ann Surg 1994;219:174-82.

    • Kjeldsen B, Kronberg O, Fenger C, Jorgensen O. A prospective randomised study of follow-up after radical surgery for colorectal cancer. Br J Surg 1997;84:666-9.

    • Mákelá JT, Laitinen SO, Kairaluoma MI. Five year follow-up after radical surgery for colorectal cancer: results of a prospective randomised trial. Arch Surg 1995;130:1062-7.

    • Ohlsson B, Breland U, Ekberg H, Graffner H, Tranberg K. Follow-up after curative surgery for colorectal carcinoma: randomised comparison with no follow-up. Dis Colon Rectum 1995;38:619-26.

    • Schoemaker D, Black R, Giles L, Toouli J. Yearly colonoscopy, liver CT, and chest radiography do not influence 5-year survival of colorectal cancer patients. Gastroenterology 1998;114:7-14.

    Perhaps it is time to reassess follow up. Formal studies to assess the value of these strategies might include:

    • A comparison of the value of intensive versus minimalist follow up

    • A re-evaluation of the role of carcinoembyronic antigen

    • A comparison of the effectiveness of follow up that is coordinated by general practitioners rather than by hospitals.

    Conclusion

    Current methods of follow up, aimed at the early detection and treatment of local recurrence or metachronous tumours, have yet to be shown to be cost effective.

    As liver metastases are common, a protocol that includes regular liver imaging to detect potentially resectable lesions may prove more effective. Further studies are needed to assess the value of this approach in patients undergoing apparently curative resection for colorectal cancer.

    Footnotes

    • Colin McArdle is professor in the university department of surgery at the Royal Infirmary, Edinburgh.

      The ABC of colorectal cancer is edited by D J Kerr, professor at the Institute for Cancer Studies, University of Birmingham; Annie Young, research fellow at the School of Health Sciences, University of Birmingham; and F D Richard Hobbs, professor in the department of primary care and general practice, University of Birmingham. The series will be published as a book by the end of 2000.

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