Position Paper
Tumour markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines for clinical use

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Abstract

The aim of this article is to present updated guidelines for the use of serum, tissue and faecal markers in colorectal cancer (CRC). Lack of specificity and sensitivity preclude the use of all existing serum markers for the early detection of CRC. For patients with stage II or stage III CRC who may be candidates for either liver resection or systemic treatment should recurrence develop, CEA should be measured every 2–3 months for at least 3 years after diagnosis. Insufficient evidence exists to recommend routine use of tissue factors such as thymidylate synthase, microsatellite instability (MSI), p53, K-ras and deleted in colon cancer (DCC) for either determining prognosis or predicting response to therapy in patients with CRC. Microsatellite instability, however, may be used as a pre-screen for patients with suspected hereditary non-polyposis colorectal cancer. Faecal occult blood testing but not faecal DNA markers may be used to screen asymptomatic subjects 50 years or older for early CRC.

Introduction

Colorectal cancer (CRC) is the third most common cancer worldwide with an estimated 1 million new cases and a half million deaths each year.1 It is now clear that CRC results from the cumulative effects of sequential genetic alterations in proto-oncogenes, tumour suppressor genes and DNA repair genes (for review, see Ref. [2]). In sporadic CRC, these alterations are acquired, and are likely to be caused by exogenous and endogenous carcinogens. In contrast, in cancer syndromes such as familial adenomatous polyposis (FAP) and hereditary non-polyposis CRC (HNPCC), critical genetic alterations that predispose to malignancy are inherited.3 For example in FAP, a germline mutation in the APC gene which occurs in every cell predisposes to adenomatous polyps, while in HNPCC, mutations in DNA repair genes result in a more rapid accumulation of genetic alterations which increases the risk of polyp formation.

In recent years a multiplicity of markers have been proposed for CRC (for review, see Refs. 4, 5, 6, 7, 8). These markers can be measured in serum, tissue or stools. In 2003, the European Group on Tumour Markers (EGTM) published guidelines on the use of tumour markers in CRC9 (see Table 1 for a summary). These guidelines focussed almost exclusively on serum markers, especially CEA. The aims of this article are to present guidelines on tissue and faecal markers as well as to update the previous EGTM guidelines on serum markers. We also summarise existing published guidelines on genetic testing for inherited susceptibility to CRC. A summary of the updated EGTM guidelines together with the level of evidence10 for their clinical application is outlined in Table 2.

These guidelines should be particularly helpful to surgeons, physicians and nurses involved in the management of patients with CRC and to laboratory personnel undertaking measurement of tumour markers. Their adoption is of course voluntary and the ultimate decision regarding use of any marker should be made by the treating clinician, i.e. the guidelines are intended to aid rather than replace clinical judgement.

Section snippets

CEA in postoperative surveillance

Although the oldest, CEA remains the most widely used serum marker in patients with CRC. EGTM guidelines for the use of CEA in CRC were previously published in 2003 and are summarised in Table 1. The main use of CEA in CRC is in surveillance following curative resection for primary cancer. Five independent meta-analyses have compared outcome in patients undergoing intensive follow-up versus minimal or no follow-up.11, 12, 13, 14, 15 The first 2 of these 2 studies11, 12 included both

Faecal occult blood testing and screening for CRC

Faecal occult blood testing (FOBT) is the most widely used screening modality for CRC.22 Two main types of FOBT exist, i.e. the guaiac test which is based on the peroxidase-like activity (i.e. pseudoperoxidase) of haem in haemoglobin and the immunochemical test which detects the globin moiety in haemoglobin. Of these 2, the guaiac test has been the more widely evaluated. Four randomised trials have shown that screening with the guaiac-based FOBT reduced both the incidence and mortality of CRC

Tissue-based markers

While serum markers are primarily used for postoperative surveillance and stools-based markers are most likely to be used for screening, tissue-based markers have been investigated for potential prognostic and predictive value. The potential prognostic and predictive value of the most widely studied tissue markers in CRC is discussed below.

Tests for susceptibility to CRC

Approximately 15% of CRC are thought to be due to an inherited or familial predisposition.3 The most common hereditary conditions giving rise to an increased risk of CRC are hereditary non-polyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP).

Future work

Guideline articles should not only contain recommendations on existing markers, but should also identify areas requiring further investigation. In the context of tumour markers in CRC, the following topics should be given priority:

  • In order to develop a more accurate screening test for CRC, the existing panel of DNA markers should be expanded to enhance sensitivity. The main focus should be on structurally altered genes that are present in either adenomas with a high predisposition of

Conflict of interest statement

None declared.

Note: The EGTM is an ad hoc group of scientists and physicians from universities, hospitals and the diagnostic industry with an interest in tumour markers.9 One of its main aims is to produce guidelines on the clinical use of tumour markers. All the authors listed are members of the Gastrointestinal Focus group of the EGTM, apart from CS EH-F and PP who were guest authors.

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