Faecal occult blood tests eliminate, enhance or update?

Personal View Faecal occult blood tests eliminate, enhance or update? Callum G Fraser Scottish Bowel Screening Centre Laboratory, Kings Cross, Dundee DD3 8EA, UK Email: callum.fraser@nhs.net Abstract Traditional guaiac-based faecal occult blood tests (FOBT) are commonly performed investigations in laboratories, wards, clinics and general practices. Although there is much evidence that use of FOBT in asymptomatic population screening programmes for colorectal (bowel) cancer does reduce mortality, there is little, if any, evidence of the value of FOBT in symptomatic individuals. In contrast, recent evidence-based guidelines are unequivocal that most of those presenting with symptoms should have bowel visualization and that the only laboratory test required is the full blood count. Moreover, recent literature shows that there are significant problems in sample collection for FOBT and in analysis of FOBT. In view of these facts, it is suggested that FOBT be ceased in all clinical settings except in asymptomatic population screening programmes. An alternative to elimination of FOBT would be laboratory-led improvement of knowledge on the appropriateness of requests, the FOBT used, the quality of FOBT sample collection and the standard of analysis, but this would require significant efforts and resources, which probably could be better spent elsewhere. A favoured option is that FOBT be replaced by faecal immunochemical tests since these undoubtedly have many clinical and laboratory advantages and fewer problems in both performance and interpretation. Ann Clin Biochem 2008; 45: 117 121. DOI: 10.1258/acb.2008.007223 Introduction Faecal occult blood tests (FOBT) are the most frequently done gastrointestinal investigations in UK laboratories. 1 In addition, if Scotland is representative of UK practice, then many more FOBT are performed in wards, clinics and primary care. 2 Because of the planned or already launched colorectal (bowel) cancer screening programmes in the UK and elsewhere, there has been much publicity in the media on the use of faecal tests. There is evidence, at least anecdotal, that requests to laboratories for FOBT are increasing. However, all tests in the repertoire of laboratory medicine should be evidence based and this Personal View discusses the pros and cons of this analysis and the recent literature that has impacted upon the evidence base. The evidence for faecal occult blood tests in screening There is overwhelming evidence that the use of a FOBT in asymptomatic populations as a screening test for bowel cancer reduces mortality. This is documented in a recent systematic review 3 that concluded: We identified nine articles concerning four randomised controlled trials and two controlled trials involving over 320,000 participants with follow-up ranging from 8 to 18 years. Combined results from the four eligible RCT show that participants had a 16% reduction in the relative risk of colorectal cancer mortality. However, by definition, screening is the investigation of the apparently healthy. FOBT performed outside screening programmes in laboratories, wards, clinics and general practices are likely to be done on those with one or more symptoms of bowel cancer. The evidence against faecal occult blood tests in investigation of the symptomatic There appears to be no real evidence regarding the use of FOBT in patients with symptoms. However, current guidelines are unambiguous. Scottish Intercollegiate Guideline Network 67 states: Although faecal occult blood testing is an effective means of population screening, it is too insensitive to be used in guiding investigation of symptomatic patients. 4 National Institute for Health and Clinical Excellence Guideline CG27 states: In patients for whom the decision to refer has been made, no examinations or investigations other than those referred to earlier (abdominal and rectal examination, Annals of Clinical Biochemistry 2008; 45: 117 121

118 Annals of Clinical Biochemistry Volume 45 March 2008 full blood count) are recommended as this may delay referral. 5 Recent Scottish referral guidelines for suspected cancer are clear with regard to investigations: No examinations or investigations other than abdominal and rectal examination and full blood count are recommended. 6 Furthermore, these particular guidelines are explicit with regard to FOBT, stating: FOBT is not indicated and should not influence decisionmaking in symptomatic patients. 6 Furthermore, guidelines for the management of iron deficiency anaemia (IDA) from the British Society of Gastroenterology state: Faecal occult blood testing is of no benefit in the investigation of IDA. 7 Thus, although there are best practice guidelines for primary care that suggest other approaches, in particular proposing that lower-risk patients who would not require urgent referral should be considered for FOBT, 8 the clear consensus of national guidelines is that FOBT is not indicated in symptomatic patients and should not influence decision-making. However, it is important to note that these guidelines are concerned with the use of the traditional guaiac-based FOBT. These detect the haem moiety of haemoglobin using the pseudo-peroxidase activity of haem; haem releases oxygen from hydrogen peroxide in the developer and this reacts with the colourless guaiac in the paper component of the FOBT to form a blue colour. 9 Problems with faecal occult blood tests in sample collection Because FOBT are based on pseudo-peroxidase activity, they are not analytically specific for human haemoglobin. In consequence, many factors might affect results, including diet and drugs. For example, animal haemoglobin and myoglobin in red meat, fruits and vegetables high in peroxidase activity and aspirin or other medication that may cause gastrointestinal bleeding, all of which allegedly give falsepositive results, and high doses of vitamin C, which give false-negative results. 9 Thus, traditionally, it is deemed necessary for individuals undertaking FOBT to undertake dietary and drug restriction for three days before collecting the two specimens from each of three faeces required for the usual FOBT. It might be that the need for dietary restriction would discourage some from undertaking the test. In addition, diet has changed over recent years with less red meat and more poultry, fruit and vegetables being consumed. 10 More objectively, the results of a meta-analysis show that dietary restriction may not be necessary for FOBT of traditional analytical detection limit since this did not appear to affect positivity rates. 11 Moreover, in the follow-up of participants with equivocally positive FOBT in the second pilot screening round carried out in England, one year was done with dietary restriction and a second year without: positivity rates were not different. 12 Potential interference from plant peroxidases can be simply eliminated by making sure that the faeces on the FOBT are dried for at least 48 h before analysis. 13 Further, although there is older literature on blood loss in faeces caused by aspirin and other drugs, recent studies have stated that low-dose aspirin does not result in positive FOBT results 14 and that aspirin and non-steroidal antiinflammatory drug use were not risk factors for a falsepositive FOBT result. 15 It has been the practice in many health-care institutions to screen admissions, particularly emergency surgical admissions, with a digital rectal examination (DRE) and perform FOBT on the faeces collected. A considerable number of recent studies have examined the utility of this procedure. Typical conclusions are that a single FOBT with DRE obtained faeces is a poor screening method for colorectal neoplasia and cannot be recommended 16 and that specimens collected at the time of DRE are not suitable for FOBT. 17,18 A further common theme of recent work, mainly done in the US health-care setting, is that this test is not well done in hospital practice 19 and it would be preferable to identify patients who are appropriate candidates for bowel screening at the time of hospital discharge and to advise them about the appropriate performance of FOBT at home. 20 Problems with faecal occult blood tests in analysis Analysis of FOBT does seem simple to the uninitiated. However, the reading of the subtle colour changes seen on positive samples is not without difficulty, especially when done by the inexperienced. One study has raised concerns that clinical errors are being made solely because of problems in interpretation. 21 This is a particular worry since many FOBT are currently done in wards, clinics and general practices. It could be more than cogently argued that these FOBT should be classified as point-of-care tests (since the definition is an analytical test undertaken by a member of the health-care team or a non-medical individual in a setting distinct from a normal hospital laboratory) and the appropriate guidelines, such as those provided by the Royal College of Pathologists, should be followed. 22 In addition, it is highly unlikely that faeces are allowed to dry before testing in situations outside laboratories and the problem of false-positive results due to plant peroxidases may occur. 13 Samples are often sent to laboratories for FOBT analysis in the traditional faecal collecting pots with spoons. This poses real problems in that bacterial degradation of the pseudo-peroxidase activity of haem in moist faeces is significant. False-negative results are likely when there is a delay between passing the faeces and smearing samples on to the FOBT. This problem can only be prevented by collecting samples directly onto the guaiac paper in the FOBT and allowing the samples to dry. 23

Fraser. Faecal occult blood tests 119 Options for the future Eliminate? Since national guidelines state that FOBT is of no value in the investigation of patients with symptoms of bowel cancer or with IDA and there are major problems in both sample collection and analysis, the evidence strongly supports the view that FOBT should be eliminated from the repertoire of laboratories and should be ceased in wards, clinics and general practices as an investigation of those with symptoms of bowel disease. Enhance? If elimination of traditional FOBT was considered a step too far at this time, an at least theoretical alternative would be to enhance the performance of FOBT through laboratories undertaking the following mandatory steps: selecting the appropriate FOBT, since there is evidence 1 that certain of the currently available methods have very poor analytical performance in External Quality Assessment; educating all users and health-care professionals that FOBT should not be done on patients with symptoms by promulgating the relevant sections of published guidelines and enlightening them that FOBT on samples obtained by DRE has been clearly shown to be inappropriate; taking a lead role in improving practice across all sites at which FOBT analyses are done and including FOBT in the point-of-care repertoire, with all the training, quality management and other requirements that are necessary prerequisites to fulfil current recommendations, guidelines and accreditation standards; ensuring that recent literature evidence is translated into practice by promulgating, not only the clinical guidelines on investigation of the symptomatic [which should cut down the workload per se], but also the evidence that (1) dietary restriction is not required for commonly used FOBT of usual analytical detection limit; (2) two samples from each of three faeces are the basis for the evidence of the value of FOBT and provide the documented clinical sensitivity and specificity; (3) samples must be collected on the FOBT rather than in pots and tubes; (4) samples must be allowed to dry on the FOBT for at least 48 h and (5) analysis must be done by well-trained personnel in suitable environments with, for example, good lighting and lack of blue-coloured objects or surrounds. Given the major efforts and considerable resources that would undoubtedly be required to undertake all these activities, elimination of the use of FOBT in the symptomatic seems much preferred on the basis of the published guidelines and evidence. Update? All of the discussion to this point refers to guaiac-based FOBT. However, over recent years, there has been a huge interest in, and much work done on, faecal immunochemical tests (FIT), sometimes called ifobt. These tests are based on the use of monoclonal or polyclonal antibodies raised against the globin moiety of human haemoglobin, detecting intact human haemoglobin or its very early degradation products. 9 The significant benefits of FIT have been summarized 9,24 27 and include the following: greater clinical sensitivity, more disease being detected; easier to collect since only one or two samples are generally required; some FIT formats encourage uptake of the test; no dietary interference is encountered and the question of dietary restriction is eliminated since FIT detect the globin of human haemoglobin; more specific for lower gastrointestinal bleeding due to digestion of blood in the upper gastrointestinal tract before faeces are formed; very simple and reliable qualitative analysis using test cassettes; advocated in modern guidelines for bowel screening, 28 although there are no randomized controlled trials and these are deemed unnecessary by many since FIT are clearly superior to FOBT. FIT do have some disadvantages, mainly that they have lower clinical sensitivity than FOBT and are more expensive by a factor of approximately 10-fold. Most of the work done on FIT is concerned with application of this newer technology in screening settings. There are many studies from throughout the world using different approaches with, inter alia, a variety of number of samples, analytical detection limits, populations, algorithms, etc. Indeed, screening programmes in a number of countries, including Japan, Australia and Italy, already use FIT as the first-line screening test and pilot studies under way in other countries are also trialling this approach. 29 In addition, studies on FIT have informed the Scottish Bowel Screening Programme and a two-tier reflex FOBT/FIT screening algorithm in which equivocally positive FOBT individuals undertake a FIT rather than a FOBT has been adopted. 30 These studies will not be discussed here any further since they deal with the asymptomatic except to say that all conclude with statements similar to the bottom line of a recently published study, 31 that is: the FIT has high sensitivity and specificity for detecting left-sided colorectal cancer, and it may be a useful replacement for the FOBT. It is also important to note that quantitative FIT on small analytical systems has now become increasingly available giving the quality, speed and many other advantages of automation. In addition, it is becoming widely suggested that the use of quantitative FIT, unlike FOBT and qualitative FIT for which the analytical detection limit is set by the manufacturer, will allow the detection limit, and thereby the positivity rate, and in consequence the colonoscopy resource required, to be set by the laboratory. 32 A good

120 Annals of Clinical Biochemistry Volume 45 March 2008 example of this approach is provided in a recently published French study that concludes: Evidence in favour of the substitution of FOBT by FIT is increasing, the gain being more important for high risk adenomas than for cancers. The automated reading technology allows choice of the positivity rate associated with an ideal balance between sensitivity and specificity. 33 Finally, the role of FIT in the investigation of the symptomatic, that is, patients with some clinical suspicion of bowel disease, is of considerable current interest. Evidence is rapidly growing that FIT have significant merits in such situations, in large part due to the many advantages outlined above. For example, a recent study from Israel 34 investigated 1000 consecutive ambulatory patients, some of whom were at increased risk for colorectal neoplasia and others who were symptomatic. It was concluded that FIT have good sensitivity and specificity. Most importantly, it was clearly demonstrated again that, challenging dogma, faecal haemoglobin increased in a clinically important and statistically significant way as the colonoscopy went from normal to low-risk adenoma to high-risk adenoma to cancer. FIT may have other invaluable uses in directing colonoscopy to those who would most benefit. For example, an Australian study has shown that a one-off FIT within a colonoscopy-based surveillance programme had a participation rate of nearly 50% and appeared to detect additional pathology, especially in patients with a past history of colonic neoplasia. 35 Thus, current work supports the thesis that the resources currently expended on FOBT might be better spent on FIT if laboratories do wish to provide an up to date faecal occult blood analytical technique of potential use in the assessment of the symptomatic patient. Certainly, education of users would be required since FOBT and FIT are not simply interchangeable (and here the FIT terminology would seem to have many advantages over the use of ifobt), but the advantages of FIT over FOBT do seem considerable. In addition, current opportunities would seem to abound for laboratory professionals to add to the rapidly growing evidence base for the correct application of FIT in a variety of clinical situations. REFERENCES 1 Duncan A, Hill PG. A review of the quality of gastrointestinal investigations performed in UK laboratories. Ann Clin Biochem 2007;44:145 58 2 Fraser CG. Faecal Occult Blood Tests Eliminate or Improve! See www. acbscot.org.uk/science/fobt.html 3 Hewitson P, Glasziou P, Irwig L, Towler B, Watson E. Screening for colorectal cancer using the faecal occult blood test, Hemoccult. Cochrane Database Syst Rev 2007;24:CD001216 4 SIGN. Management of Colorectal Cancer. SIGN, 2003. See www.sign.ac.uk/ pdf/sign67.pdf 5 NICE. Clinical Guideline 27. 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