International guidelines recommend that blood carcino-embryonic antigen (CEA) levels are measured to detect recurrent colorectal cancer (CRC) as part of an intensive follow-up regimen (Duffy 2013a; Labianca 2010; Locker 2006; NCCN 2013; NICE 2011).
These guidelines are derived from non-randomised studies, and later randomised controlled trials (RCTs) investigating the optimal follow-up strategy following curative CRC resection. Follow-up strategies have been broadly classed as intensive and minimal, but the investigative modalities included in each strategy have varied greatly, with similarities in the composition of intensive and minimal regimens between studies. Jeffery's 2007 Cochrane review (Jeffery 2007) of eight RCTs (Kjeldsen 1997; Makela 1995; Ohlsson 1995; Pietra 1998; Rodriguez 2006; Schoemaker 1998; Secco 2002; Wattchow 2006) showed that when compared to minimal follow-up, an intensive regimen reduces five-year all-cause mortality (odds ratio (OR) 0.73 95% confidence interval (CI) 0.59 to 0.91). As direct comparison of CEA measurement versus no CEA measurement was only possible for recurrence rates using two of these RCTs (OR 0.85 95% CI 0.58 to 1.25) and data on overall mortality were only available from one trial (OR 0.57 05% CI 0.26 to 1.29), the results were not conclusive due to the small numbers. The aim of intensive follow-up is to detect asymptomatic recurrences more amenable to a resection with clear margins. Jeffery's review demonstrated no significant difference in the recurrence rate between investigative strategies, but significantly more curative surgical procedures were conducted for recurrence in the intensive group (OR 2.41 95% CI 1.63 to 3.54) (Jeffery 2007).
The between-study heterogeneity, and the fact that many of the RCTs included in the Cochrane review predate modern approaches to cancer care lead many to caution when applying the meta-analysis to modern-day practice. For others, the advances in chemotherapy, hepatic resection, and multidisciplinary CRC follow-up has led to assertions that the clinical benefits of intensive follow-up will be even greater today (Labianca 2010). Published in 2014, the FACS pragmatic factorial RCT followed 1202 participants from 39 NHS hospitals reporting that those followed up with an intensive regimen had three times the odds of detecting a recurrence amenable to curative resection, that monitoring with CEA combined with a single computed tomography (CT) scan at 12 to 18 months was equally as effective as undertaking regular CT scanning, and that concurrent CEA and CT does not improve accuracy (Primrose 2014).
The absence of a difference in cancer-specific mortality between follow-up approaches has led to suggestions that the psychological support gained from regular medical follow-up, and the associated modifications of diet, lifestyle, and chronic disease management account for the improvement seen in all-cause mortality (Tjandra 2007).
Whilst the optimal combination and frequency of clinic visits, blood tests (including CEA), endoscopy and imaging included in an intensive follow-up regimen remains unclear (Scheer 2009), there is evidence that most recurrences will occur in the first 30 months after primary tumour resection, with almost all occurring within the first five years (Guthrie 2002), that CEA measurement is the most sensitive modality for detecting early recurrent disease (especially liver metastasis) (Duffy 2013a; Tsikitis 2009), that there are an increasing number of well-tolerated effective chemotherapy regimens for recurrent CRC in older populations (Cunningham 2010; Locker 2006), and that primary care follow-up results in similar outcomes to surgical outpatient follow-up (Wattchow 2006). Economic analyses have shown intensive follow-up to be cost-effective (Renehan 2004) and that CEA is the most cost-effective way of detecting recurrent CRC in primary care detecting (Primrose 2014).
There is no consensus on the interpretation of blood CEA results, with substantial variability in clinical practice.
Target condition being diagnosed
Colorectal cancer is globally the third most common cancer accounting for 9.8% of all detected cancers. In 2008, the age-standardised incidence rate was 17.3 cases per 100,000, 30.1 in more developed regions, and 10.7 in less developed regions (Ferlay 2013).
Colorectal adenocarcinoma arises in the colonic mucosa and progressively invades through the layers of bowel wall into surrounding structures leading to peritoneal, neural, lymphatic and haematological metastasis (Gore 1997). This process provides the basis of the internationally recognised TNM staging system (Sobin 2009) and earlier Dukes classification (Dukes 1932). The first site of haematological metastasis is the liver via the portal vein, after which distant metastasis occurs most commonly to the lungs but also the bones and brain (Guthrie 2002). Prognosis is closely related to stage, with higher grade more invasive metastatic tumours having poorer prognosis (Maringe 2013). Approximately two-thirds of patients will present with a primary CRC amenable to radical surgery (+/- adjuvant therapy) (Jeffery 2007).
Following surgery (+/- adjuvant therapy) however, 30% to 50% of patients will develop recurrence (Labianca 2010). The most common site for recurrence is the liver followed by the lungs but can also occur in the abdomen and pelvis (Cunningham 2010; Jeffery 2007). Patients undergoing secondary surgery with curative intent have substantially improved five- and 10-year survival rates with a median survival time of 35.8 to 84.8 months. Surgery for isolated hepatic metastasis improves five-year survival by 36% to 58%, for isolated lung metastasis by 27% to 41%; chemotherapy can prolong life by one to two years, and improve quality of life (Arriola 2006; Cunningham 2010; Tsikitis 2009).
CEA is a relatively simple and low-cost biomarker that can be detected by a blood test. The analysis of CEA in clinical studies utilises the technique of immunoassay in a variety of forms and from a number of different manufacturers. Earlier methods were manual immunoassays such as radio-immunoassay but most laboratories now utilise fully automated non-isotopic methods. The reproducibility of these fully automated methods are, in general, superior to the older manual methods. Unfortunately, the details of the methods used in clinical studies and their analytical performance is often lacking in publications (Wild 2013).
Data from external quality assessment schemes have repeatedly shown good precision for most methods at low CEA concentrations. In 2010 the mean within laboratory precision over a 12-month period at a concentration of 3 µg/L (equivalent to 54 U/L) was < 9% for all major methods. A greater analytical challenge is the difference in method bias (Wild 2013). Despite the availability of an international reference preparation (IRP 73/601) since 1975 and its widespread use in commercial assays since the early 1990’s, method bias may be +/-20% and the degree of this bias may be sample-dependent (Bormer 1991; Laurence 1975). CEA has a complex molecular structure and the antibodies used in the immunoassays recognise different epitopes of the molecule and this is considered to be a major source of the method bias (Bormer 1991). Consequently, the interpretation of data from clinical studies, in particular the use of any particular threshold, whether that is 3, 5 or 7 µg/L, needs to consider the actual method utilised. Due to the good reproducibility but significant method-dependent bias, it is advised that the same assay technique should be used throughout any follow-up period (Duffy 2013a).
CEA is a glycoprotein involved in cell adhesion produced during foetal development. Production usually ceases at birth, but elevated levels can be detected in colorectal, breast, lung and pancreatic cancer, in smokers, and in benign conditions such as cirrhosis of the liver, jaundice, diabetes, pancreatitis, chronic renal failure, colitis, diverticulitis, irritable bowel syndrome, pleurisy and pneumonia (Newton 2011; Sturgeon 2009). It is produced in 90% of CRC and is known to contribute to the malignant characteristics of the tumour, and to have an important role in CRC metastasis (Dallas 2012). CEA levels may rise four and a half to eight months prior to the development of cancer-related symptoms (Goldstein 2005). Depending on the threshold used, the sensitivity of CEA varies depending on the stage of disease; Dukes type A, B, C, and D tumours are reported to be associated with levels of CEA > 5µg/L in 3%, 25% 45% and 65% of cases respectively (Sturgeon 2009). Furthermore, CEA is most sensitive for hepatic and retroperitoneal metastases and least sensitive for local recurrences and peritoneal or pulmonary disease (Scheer 2009).
Because of the variable sensitivity and expression in benign conditions CEA (and all other existing serum biomarkers), fails to meet gold standard criteria for biomarker use and so CEA is not recommended for screening purposes in the general population (Newton 2011). However, it is recommended for use as a preoperative prognostic marker, as a marker of response to chemotherapy (especially for liver metastasis), and as a triage test for diagnosing recurrent CRC (where a rise should lead to further investigation rather than initiation of therapy) (Duffy 2013a; Sturgeon 2009).
Although serial CEA measurements are taken, centres take action on a single CEA level above an absolute threshold level, but there is lack of agreement on the threshold above which action should be taken, or the extent of concentration change that constitutes a clinically significant rise. A threshold between 3 and 7 µg/L is commonly used, some centres look at the difference a pre-operative or post-operative baseline level, some repeat the test before acting, and no guidelines recommend taking into account trend information based on longitudinal CEA measurements.
The most recent meta-analysis includes 20 studies combining diagnostic accuracy data for a range of threshold values (3 to 15 µg/L) measured by a variety of test-kits to investigate the diagnostic value of the absolute level from a single test (Tan 2009). The pooled estimates of diagnostic accuracy were: sensitivity 64% (95% CI 61% to 67%); specificity 90% (89% to 91%); diagnostic OR 18 (12 to 28); and area under the curve (AUC) 0.79 (standard error 0.054). There was a significant degree of heterogeneity reported between studies (Q-value 80.83, P < 0.001) (Tan 2009). When limited to four studies using the 3 µg/L threshold, sensitivity (73% (69 to 77)) increased at the expense of specificity (68% (65 to 72)). Through meta-regression the authors suggest that a cut-off of 2.2µg/L provides the ideal balance between sensitivity and specificity for use in clinical practice (Tan 2009), but this level generates a high level of false-alarms and is implemented by few clinicians: the COST trial used a CEA cut-off of 5µg/L (Tsikitis 2009), and the FACS trial used a threshold of 7µg/L (Primrose 2014). We propose an update of the Tan study (the search was performed in July 2007) using a less conservative search strategy and conducting analyses following the latest Cochrane DTA guidance.
The European Society of Medical Oncology (ESMO) recommend history, physical examination, and CEA determination every three to six months for three years, and every six to 12 months at years four and five, colonoscopy at one year then at every three to five years looking for metachronous adenomas and cancers, a CT scan of the chest and contrast-enhanced ultrasound scan (USS) or CT scan of the abdomen every six to 12 months for the first three years in patients considered higher risk, advising against the use of other laboratory and radiological examinations unless patients have suspicious symptoms (Labianca 2010).
The American Society of Clincal Oncology (ASCO) recommends that CEA is performed every three months for three years in patients with stage II or III disease if the patient is a candidate for surgery or systemic therapy, and that raised CEA levels (> 5µg/L, confirmed by a repeat test) warrants further evaluation for metastatic disease (Locker 2006). Unlike ASCO, ESMO does not specify a threshold nor limit testing to tumour stage but the European Group on Tumour Markers (EGTM) specify CEA measurement at baseline and then every two to three months for three years, then six-monthly for five years in patients with stage II-III disease who would tolerate further surgery or systemic therapy. EGTM recommend that any increase in CEA (confirmed by a repeat test) should trigger further investigations (Duffy 2013a).
NICE recommend follow-up from four to six weeks following curative treatment, for all patients who could tolerate and accept the balance of risk and benefits of further treatment, including CEA measurement at least every six months in the first three years, two CT scans of the chest and abdomen in the first three years, and colonoscopy at one year and five years (NICE 2011).
Once recurrence is suspected patients then undergo further diagnostic testing with usually CT or USS to confirm recurrence (Duffy 2013 ), although the modality used to confirm recurrence varies and can alternatively be clinical assessment, colonoscopy, flexible sigmoidoscopy and barium enema, CT colonography, positron emission tomography–computed tomography (PET-CT), or magnetic resonance imaging (MRI).
As detailed above, CEA is often the first investigative modality to be used within an intensive follow-up regimen.
Role of index test(s)
As a triage test to prompt further investigation for CRC recurrence.
Circulating tumour cells and cytokeratins have been examined as possible biomarkers of CRC recurrence but the studies are few and limited. Ca125 is regarded as an emerging biomarker for use in postoperative follow-up but as yet evidence is limited (Duffy 2013a; Newton 2011). CT imaging is the only other test that meta-analysis suggests has potential to detect metastatic recurrence amenable to resection but CT is less cost-effective than CEA. FACS suggested that concurrent CEA and CT does not improve accuracy (Primrose 2014).
CEA alone is potentially the most cost-effective option to detect CRC recurrence. This DTA review aims to clarify the accuracy of single-measurement blood CEA as a triage test for CRC recurrence. We propose this in the knowledge that serial CEA measures are commonly taken as part of a postoperative monitoring schedules, but have chosen to evaluate the diagnostic accuracy of a single CEA measurement because the clinical decision to investigate further for recurrent CRC is most often based on a single measurement alone.