The performance of tests in diagnosing colorectal cancer in adult patients with symptoms varied widely. Sensitivity was consistently high for age ≥50 (range 0.81-0.96, median 0.91) and for the two week referral guideline (range 0.80-0.94, median 0.92), but these lacked specificity (medians 0.36 and 0.42, respectively). These tests are suitable to rule out colorectal cancer at the cost of a high number of patients needing further diagnostic testing. Specificity was consistently high for family history (range 0.75-0.98, median 0.91), weight loss (range 0.72-0.96, median 0.89), and iron deficiency anaemia (0.83-0.95, median 0.92), but all tests lacked sensitivity (medians 0.16, 0.20 and 0.13, respectively). These tests are suitable to rule in colorectal cancer but at the cost of missing a considerable proportion of cases. Only the immunochemical based faecal occult blood tests had both a reasonable sensitivity (range 0.70-1.00, median 0.95) and specificity (range 0.71-0.93, median 0.84).
Diagnostic tests for colorectal cancer in primary care
This review focuses on the diagnostic performance of tests for patients who present with non-acute lower abdominal symptoms in primary care. We found that only a few studies were clearly carried out in primary care populations. We excluded screening studies, which would also include a large proportion of people without symptoms. Screening is useful if early stages of colorectal cancer can be detected, which have a favourable prognosis. In primary care, all colorectal cancer should be diagnosed, and preferably at an early stage. Therefore, it is useful to make a distinction between early stages (Dukes’s A/B)—that is, resectable colorectal cancer—and later stages (Dukes’s C/D). Some of the tests reflect symptoms of later stages, such as weight loss and iron deficiency anaemia, and will therefore not help to identify early stages of colorectal cancer.
When a patient presents to primary care with abdominal symptoms several differential diagnoses can be considered (such as colorectal cancer, irritable bowel syndrome, coeliac disease) and general practitioners should identify patients who should be referred for further diagnosis. Our review focused on colorectal cancer, yet to the clinician a positive test result (such as diarrhoea) leading to a diagnosis of inflammatory disease might be considered a true positive result.
Primary care settings differ between countries, and in only a few countries do general practitioners act as a gatekeeper to specialist clinical care. In other countries specialist care may be directly accessible. Therefore we also included two week referral clinics and secondary care populations with a low prevalence of colorectal cancer, which might reflect populations with a similar spectrum of disease as in primary care and a limited risk of investigation bias. Many studies, both in primary and secondary care settings, however, enrolled a selective population of patients by using the presence of a specific complaint as an inclusion criterion. For example, seven primary care studies investigating the diagnostic performance of signs and symptoms used rectal bleeding as an inclusion criterion. We presented the findings in such a way that differences between settings and populations can be easily identified.
Symptoms and signs
Of the typical symptoms of colorectal cancer, only weight loss had some diagnostic value with a fairly high specificity. This seemed to be translated in clear differences between the probability of colorectal cancer among patients with or without apparent weight loss (positive predictive value v 1−negative predictive value). Other symptoms, including presence of diarrhoea, constipation, change in bowel habit, or abdominal pain, showed poor diagnostic performance.
Studies showed a high degree of heterogeneity. This might be because studies used different definitions to classify self reported symptoms such as change in bowel habit. Furthermore, studies used different inclusion criteria, leading to an increased risk of selection bias in several studies. For example, in seven out of 10 primary care studies that reported on the diagnostic performance of signs and symptoms in symptomatic patients, rectal bleeding was used as inclusion criterion, thereby selecting a higher risk group. It is unlikely that the results of these studies are directly applicable to all primary care patients consulting their general practitioner with lower abdominal signs and symptoms.
Family history showed a high specificity combined with a low sensitivity. Its diagnostic value in primary care is limited, however, because only a small percentage of all cases have a family history. In the UK and other countries patients with a familial link are often referred for genetic assessment instead of immediate investigation with colonoscopy, which often results in a screening advice. The NICE guidelines for colorectal cancer state that there is insufficient evidence for the value of family history in symptomatic patients.73
The few studies in our review that presented information on family history showed heterogeneous results for diagnostic performance. To firmly establish the diagnostic performance of family history in symptomatic patients we need a clear definition for a “positive family history,” which describes the number, age, and degree of affected family members.
Combinations of symptoms and two week referral guidelines
Our results indicate that while the diagnostic performance of individual signs and symptoms is limited, combinations of symptoms improve the sensitivity at the cost of specificity as these symptoms are common in primary care. The two week referral guideline combines symptoms, resulting in a high sensitivity (range 0.80-0.94, median 0.92) and low specificity (0.30-0.56, 0.42).
In their review of the two week referral guideline Hamilton and Sharp6
conclude that rectal bleeding and change in bowel habit have a high predictive value for colorectal cancer, which is in contrast with the conclusion of the review of Ford et al.74
In our review only a few studies reported a significantly higher risk for colorectal cancer among patients reporting one of these symptoms compared with those without the symptom, indicating that the two week referral guideline might provide only limited diagnostic information. Heterogeneity in diagnostic value of a referral guideline could be due to the inclusion of different “tests.” Most favourable combinations of sensitivity and specificity were found for a prediction rule consisting of age, change in bowel habit, and blood in stools (sensitivity 1.0, specificity 0.9), but a study on the external validity of this prediction rule could not confirm these favourable results.72
Our review shows that 12% to 25% (median 14%) of the patients referred by the two week referral guideline were eventually diagnosed with colorectal cancer. Refining the current referral system could help to improve specificity.
We found a low sensitivity for blood tests (haemoglobin, erythrocyte sedimentation rate, white cell count) in detecting colorectal cancer. The median probability of cancer in patients with anaemia (positive predictive value) was only slightly higher than in patients with negative test results, indicating limited diagnostic performance of this test in clinical practice when used as a single test. This is in accordance with the NICE guidelines.73
Despite this, they might provide a useful adjunct to the general medical investigation, with conditions such as iron deficiency anaemia warranting further investigation.6
Faecal occult blood tests
We found relatively good results for diagnostic performance of the faecal occult blood tests, especially for the immunochemical based test, which showed high sensitivity and reasonable specificity in most studies. The probability of colorectal cancer is clearly higher in patients with positive rather than negative findings on the test. These favourable findings for the immunochemical based test contrast with the NICE guideline,73
which states that in patients with abdominal symptoms, the sensitivity, specificity, and positive predictive values of faecal occult blood tests are too low to make these tests helpful.
We did, however, find large heterogeneity in the results of studies on both guaiac based and immunochemical based tests. This might be because of different types of faecal occult blood tests being used in the primary studies. Furthermore, publications often lacked information on dietary restrictions, the definition of a positive test result (cut-off value, number of positive samples), and number of test failures. Not providing a dietary advice has been reported to affect the specificity of guaiac based tests,13
but our review could not confirm this. Overall, analyses both between and within studies showed better diagnostic performance of immunochemical based than guaiac based tests and that guaiac based self tests seemed to perform less well than the regular guaiac based tests.
Subgroup analyses within studies based on small numbers seemed to indicate that immunochemical based tests were more sensitive in detecting early stages of cancer than guaiac based tests.53 58
As early stages have far better prognoses this is an important finding. One of these studies also showed that immunochemical based tests were better than guaiac based tests at detecting colorectal cancer at all sites. 58
These results need confirmation in future, larger studies.
Strengths and weaknesses of our review
We extracted or reconstructed diagnostic data collected from symptomatic patients in primary and interface settings and excluded information from healthy (screening studies) or highly selected diseased controls, thereby preventing limited challenge bias.75
Furthermore, we studied a whole range of diagnostic tools that are available to general practitioners instead of focusing on only one or two tests. We adhered to the most recent guidelines for conducting a diagnostic review as described in the Cochrane Diagnostic Reviewers’ Handbook
We used an extensive search strategy, but by using a methodological filter we might have missed several relevant publications. By reference checking we tried to track down those publications that our search strategy might have failed to identify. Use of a language restriction during the selection phase led to the exclusion of only 0.7% of all citations.
There were quite a few discrepancies in the phase of abstract selection. The first reviewer used a highly sensitive approach and selected all abstracts that could in any way be relevant to the review, with the aim of not missing any relevant papers. The second reviewer subsequently considered all these pre-selected abstracts and excluded those that clearly did not meet the eligibility criteria. Anticipating poor agreement on some items of the QUADAS list,76 77
two reviewers independently assessed all papers for methodological quality and reached consensus by discussing disagreements on individual scores.
The studies of the various tests showed a high degree of clinical heterogeneity, which limited the possibilities for statistical pooling and strong conclusions on diagnostic performance. Reasons for heterogeneity include different definitions of signs and symptoms, variation in executions of tests (such as faecal occult blood tests), and selection of populations based on particular symptoms or complaints.
In subgroup analyses we took into account the generally poor reporting of diagnostic accuracy78
by excluding studies providing insufficient information on the characteristic under study. Finally, we extensively explored many potential sources of heterogeneity, including the adequacy of the reference standard. Because of the small number of studies in the subgroups, we could not use multivariable meta-regression analysis, making it difficult to disentangle the contribution of each source of heterogeneity.
Diagnostic tests as first line investigation in primary care need to be valid, easy to perform, well tolerated by patients, and sensitive, especially in case of serious disease. Our systematic review shows that immunochemical based faecal occult blood tests might prove to be such tests. Evidence is lacking, however, for the diagnostic performance of these tests in primary care populations. We therefore urgently need high quality diagnostic cohort studies enrolling consecutive patients presenting with non-acute abdominal symptoms in primary care. Symptom combinations or two week referral guidelines potentially have diagnostic value, but the performance of the guideline could be improved by standardisation, clear definitions, and the addition of important characteristics of those diagnosed with colorectal cancer but not fulfilling the current guideline.
In future research, cancer location and stage of disease should be an important factor in the analysis, especially as tests that are able to diagnose early stages of colorectal cancer are important tools to reduce the burden of cancer.
What is already known on this topic
- To improve the prognosis of colorectal cancer the diagnosis should be made at an early stage
- An important task for the primary care physician is to identify the patients with an increased risk for colorectal cancer among all those consulting for abdominal symptoms
What this study adds
- The most promising primary care tests in terms of diagnostic performance are combinations of symptoms and faecal occult blood tests, especially immunochemical based tests