Colorectal carcinoma is the second most common cause of cancer death in the Western world.1 ,2 Traditionally, lower gastrointestinal (GI) symptoms are thought to be more common in those with colorectal carcinoma.3 ,4 However, these symptoms are also prevalent in healthy individuals in the community,5^–13 and in a health service with a limited budget it is not economically feasible to investigate every person who reports them. In the UK, the National Institute for Health and Clinical Excellence (NICE)14 ,15 has published guidelines to assist general practitioners in identifying patients with a high probability of colorectal carcinoma. The presence of so-called “alarm” features, such as rectal bleeding, a change of bowel habit to looser or more frequent stools, iron deficiency anaemia, or a palpable right-sided abdominal mass or rectal mass have been proposed as the optimal method of identifying these individuals, who are required to be seen by a specialist for further assessment and investigation within 2 weeks of referral.

These symptoms and signs have been selected because it is thought that they may predict a diagnosis of colorectal cancer. However, colorectal cancer can present with vague symptoms, or patients may be completely asymptomatic, so expecting clinical features to be highly sensitive is unrealistic. Indeed, this is the rationale for screening of healthy asymptomatic individuals for colorectal cancer in many countries. In addition, as lower GI symptoms are common, many individuals will need to be investigated to detect one case of cancer. Studies that have evaluated the accuracy of clinical features in the diagnosis of colorectal carcinoma have been conflicting, with some suggesting that no single item can be used to identify patients with colorectal cancer accurately, and others reporting that certain individual symptoms or signs, or a combination of both in statistical models, are accurate in this situation.16^–19 All studies have focused on maximising sensitivity, but this may not be appropriate when triaging patients for urgent referral where the doctor wishes to prioritise those with a high likelihood of having malignancy. A better approach to this problem would be to choose clinical features that have a high specificity for the diagnosis of colorectal carcinoma which, if present, would effectively rule the disease in.20

There is currently little in the way of distillation of published evidence to support the recommendations made by current guidelines. We have therefore conducted a systematic review of the literature to identify studies that examine the accuracy of alarm features to ascertain if it is possible, using current available data, to identify subgroups of patients who are likely to have colorectal carcinoma, and therefore require rapid referral for assessment and investigation to exclude this diagnosis.

METHODS

RESULTS

The search strategy identified 11 169 studies of which 205 were possibly relevant to the systematic review and retrieved (fig 1). Of these, 15 studies were eligible for inclusion, evaluating a total of 19 443 patients,16^–19,26^–36 with a pooled prevalence of colorectal carcinoma in all studies of 6% (95% CI 5% to 8%). The prevalence of colorectal carcinoma in individual studies varied from 3% to 14.6%. Polyp detection rates in individual studies, where reported, varied between 7% and 50%. Complete colonic imaging rates for lower GI investigations varied between 56% and 98%. None of the included studies reported on operator experience, in terms of number of previous procedures performed, or withdrawal times for colonoscopy. Only three studies reported the method of bowel preparation,28 ,32 ,35 and only one study reported the quality of bowel preparation achieved,30 which was inadequate in 16% of patients. Other study characteristics are provided in table 1.

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Figure 1 Flow diagram of assessment of studies identified in the systematic review.

Thirteen studies examined the accuracy of alarm features in predicting colorectal carcinoma, one study reported on the accuracy of a statistical model and one study reported on both. Symptom data were collected using a questionnaire in seven studies,17 ,18 ,26 ,27 ,29 ,31 ,34 via clinical history in three studies,16 ,32 ,33 and the method of collection was unclear in the remaining studies. One study used barium enema alone as the lower GI investigation of choice,29 and no study used CT colography alone. Several studies included patients who required endoscopic visualisation of abnormalities detected at barium enema, or who were asymptomatic but undergoing follow-up or surveillance for previous colorectal carcinoma, polyps or inflammatory bowel disease.16 ,27 ,28 ,31 ,33 ,35 ,36 These groups of patients were always excluded from our analyses, as they were not relevant to the clinical question we were addressing.

Rectal bleeding

We identified 14 studies evaluating 19 189 patients,16^–19 ,27^–36 with a pooled prevalence of colorectal cancer of 7% (95% CI 5% to 8%). The pooled prevalence of rectal bleeding in the studies was 49% (95% CI 38% to 59%), the character of which was not specified in 12 of the studies. The pooled positive and negative LRs for rectal bleeding were poor, and there was statistically significant heterogeneity between study results (table 2). The ROC curve indicated that rectal bleeding had a limited accuracy for diagnosing lower GI malignancy, with an area under the curve of 0.60 (fig 2).

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Figure 2 Receiver operating characteristics curve for accuracy of rectal bleeding in predicting colorectal carcinoma. AUC, area under the curve.

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Table 2 Sensitivity, specificity, and positive and negative likelihood ratios of individual symptom items and statistical models

Two studies collected more detailed information on the character of rectal blood loss in 4440 patients,17 ,18 with a pooled prevalence of colorectal cancer of 5% (95% CI 4% to 6%). The pooled prevalence of dark blood loss per rectum was 5% (95% CI 2% to 9%), as distinct from bright red rectal bleeding. The specificity of this symptom was high, which meant that the pooled positive LR was greater than for rectal bleeding of unspecified character (table 2).

DISCUSSION

To our knowledge this is the first systematic review and meta-analysis of the accuracy of alarm features or statistical models in predicting which individuals need urgent investigation to exclude colorectal cancer. The current study suggests that symptoms and signs traditionally thought to have high sensitivity for the diagnosis of colorectal cancer, when taken individually, perform little better than chance alone in differentiating between cancer and other organic and functional lower GI disease. Statistical models, validated in only two studies, were also suboptimal. This is because these models were heavily weighted towards detecting all colorectal cancers, and therefore demonstrated high sensitivity, at the expense of specificity. This aspect of their design means that many individuals would need to be investigated to detect one case of colon cancer, and they are therefore not suitable for triaging patients for urgent referral.

However, the current data also provide additional novel, and clinically more useful, information. The presence of a palpable abdominal mass on examination and a report of dark red rectal bleeding by the patient both had a specificity of >95% for the diagnosis of colorectal carcinoma, because the vast majority of individuals without cancer did not exhibit either of these clinical features. This means that their presence in a patient effectively rules in the diagnosis of colon cancer. These features could therefore have potential value to prioritise access to urgent colonoscopy in the future. The caveat to this is that these features were reported only in secondary care-based studies, and both the spectrum of disease and the doctor making the diagnosis will be different from those encountered in primary care.

There may be ways to improve the utility of other individual alarm features in predicting colorectal cancer. Examples include specifying the amount of weight lost (and over what period of time); the degree of anaemia (and whether there is definite evidence that this is due to iron deficiency); and using more precise definitions of diarrhoea and change in bowel habit based on either stool frequency, form or a combination of the two. Of the seven studies that reported on the presence of anaemia in this meta-analysis, only four stated that this was iron deficiency anaemia,28 ,31 ,32 ,34 and only one of these reported the threshold used to define this.34 Excluding the three studies that did not expand on the term anaemia from the meta-analysis,17 ,27 ,35 so that only studies examining the utility of iron deficiency anaemia were pooled, had little effect on the sensitivity, specificity, or positive and negative LR of anaemia in predicting colorectal carcinoma. However, from table 2 it can be seen that the study providing a precise definition of what constituted iron deficiency anaemia gave the best sensitivity, positive LR and negative LR of these four studies.34 This suggests that definite objective evidence of iron deficiency anaemia may provide greater accuracy in predicting a diagnosis of colorectal carcinoma, rather than anaemia of unspecified type. One study also quantified the degree of weight loss,17 though the positive and negative LRs derived from these data remain disappointing.

Another approach to improve the accuracy of alarm features in predicting underlying colorectal carcinoma might be to combine them. Two of the studies included in this meta-analysis used this approach.19 ,36 However, the sensitivity and positive and negative LRs remained poor. As data reporting was inconsistent between the two studies that combined symptoms, in terms of the individual symptoms that were selected for combination, it was not possible to pool the results for the purpose of this meta-analysis in order to assess the value of this approach further. Doctors often combine other items from the clinical history, such as patient age and any relevant family history, with the patient’s symptoms as part of the diagnostic process,37 and this may improve overall accuracy. This is essentially the approach taken by statistical models, but these are currently suboptimal as they have focused on achieving a high sensitivity, by predicting that between 40% and 50% of patients presenting with lower GI symptoms will have colorectal cancer. A health service with a limited budget would be unable to cope with the demands placed upon it if all these patients were referred for urgent investigation. Future models should concentrate on maximising specificity in order to rule in a diagnosis of colorectal cancer and prioritise urgent referral more effectively.

This systematic review is limited by the quality of the studies included. The majority of the studies identified, while large in several cases, were of poor quality in terms of reporting whether either patient recruitment was consecutive or assessors were blinded. As studies did not routinely report quality assurance data such as quality of bowel preparation, operator experience, withdrawal time for colonoscopy and completion rates, the accuracy of colonoscopy or barium enema as a diagnostic test cannot be assessed as part of the current study. However, even if the quality of the examinations is suboptimal in some of these studies, this is unlikely to account for the disappointing accuracy of most alarm features.

Subgroup analyses conducted according to study setting, type of lower GI investigation used, method of symptom data collection, number of study centres and study sample size failed to have any significant impact on the LRs of individual symptom items, where sufficient studies reported them, and did not reveal any obvious cause for the observed heterogeneity between studies. The poor performance of alarm features in predicting colorectal carcinoma may have been due, in part, to the fact that the majority of included studies were based in secondary care. This could have created a referral bias, whereby primary care doctors preferentially referred only those individuals in whom it was not possible to reach a clear diagnosis, after a comprehensive history and physical examination, to the studies. However, this is unlikely to be a major explanation for the findings of the current study, as the performance of these individual symptoms was no better when only primary care-based studies were included in the meta-analysis. The prevalence of colorectal cancer varied between studies, but in the majority of cases was between 4% and 8%. Three studies reported a prevalence in excess of 10%,27 ,32 ,34 higher than would be expected in a Western population; two of these studies were conducted in Italy.27 ,34 The reasons for this are speculative, but may reflect a degree of selection bias. Eleven of the studies stated that recruitment had been prospective, nine that they had included consecutive patients, only one study specified that investigators were blinded to patient data,29 and in four studies clinical data were collected by the doctor performing the investigative procedure,27 ,31^–33 though the latter would be expected to bias studies towards overestimating the accuracy of alarm features in diagnosing colorectal cancer.

The findings of the current study demonstrate that there is little evidence to support current NICE guidelines on rapid referral for suspected colorectal cancer.14 ,15 The presence of a palpable abdominal mass and dark red rectal bleeding appeared to be the most useful individual clinical features to prioritise access to urgent colonoscopy, due to their high specificity. The latter item is not utilised in current guidelines, but this is an important observation and needs further validation in future studies. Finally, models assessing a combination of features should be developed to focus on specificity rather than sensitivity. These recommendations for research may enable future referral criteria to better identify patients with high likelihood of lower GI malignancy who warrant urgent investigation.