Title: Immunochemical Fecal Occult Blood Tests. Date: June 15, 2007

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1 Title: Immunochemical Fecal Occult Blood Tests Date: June 15, 2007 Context and policy issues: Colorectal cancer is the third most prevalent cancer, after breast and lung cancer in women, and prostate and lung cancer in men. 1 The 2005 issue on screening for colorectal cancer from Health Canada estimated 17,600 cases diagnosed per year, with approximately 6,500 Canadians dying from colorectal cancer. 2 Colorectal cancer develops over a period of at least 10 years. 2 Two-thirds of the cancers are found in the large intestine and one-third in the rectum. The symptoms include: 1) fatigue and weakness; 2) change in bowel habit; 3) stool streaked or mixed with blood; 4) discomfort or pain in the lower abdomen. Symptoms of colorectal cancer are usually investigated by examining the stool for evidence of blood using Fecal Occult Blood Test (FOBT). If positive, further tests such as colonoscopy are followed. The Canadian Task Force on Preventive Health Care < recommends that all Canadians of over 50 years should have an FOBT every one or two years. Two types of FOBT are available: the guaiac-based test and the immunochemicalbased tests. Table 1 shows some guaiac and immunochemical FOBT approved by Health Canada, and there may be others available in Canada. Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information on available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 Table 1: Health Canada approved screening tests (Please note that this may not be a complete list due to the lack of a complete listing of trade names) Immunochemical tests: 3 Device name First issue date License number Hemoccult ICT devices One-step fecal occult blood test Clearview ultra FOB test Guiac tests: 3 Device name First issue date License number Hemoccult ii Hemoccult ii sensa Hemoccult ii sensa elite Hemoccult sensa Coloscreen/coloscreen es, coloscreen iii Hema-screen lab pack The guaiac-based tests use spatulas to collect specimens from 3 stools that are not in contact with toilet bowl water. 4 A chemical developer reacts with the peroxidase activity of the heme portion of hemoglobin. Dietary and drugs rich in peroxidase activity are often restricted with guaiac tests. Dietary restrictions led to the hypothesis that decreased compliance may have an effect on population screening. The guaiac-based tests are usually low in specificity. The immunochemical tests use brush to collect specimens from 1 to 3 stools, depending on the kits, while in the toilet bowl water. 4 The tests employ an antibody to detect the globin portion of human hemoglobin, and have high sensitivity and specificity. The antibody-based tests are more expensive, but much simpler to use than the chemical-based tests. This report provides evidence of the comparative effectiveness and cost-effectiveness of immunochemical tests and guaiac tests. The selection criteria include health technology assessments, systematic reviews/meta-analyses, randomized controlled trials, and economic studies. Research questions: 1. What is the comparative clinical effectiveness/efficacy of guaiac fecal occult blood tests compared to immunochemical fecal occult blood tests for colorectal carcinoma screening? 2. What is the comparative cost effectiveness of guaiac fecal occult blood tests compared to immunochemical fecal occult blood tests for colorectal carcinoma screening? 3. What is the comparative clinical effectiveness across immunochemical fecal occult blood tests for colorectal carcinoma screening? Immunochemical FOB Tests 2

3 Methods: A limited literature search was conducted on key health technology assessment resources, including PubMed, the Cochrane Library (Issue 2, 2007), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, EuroScan, international HTA agencies, and a focused Internet search. Results include articles published between 2002 and the present, and are limited to English language publications only. Internet links are provided, where available. Summary of findings: From the limited search, we identified two health technology assessments, two systematic reviews, one randomized controlled trial (RCT), and four economic studies. a) Health technology assessments The 2005 report of New Zealand Health Technology Assessment (NZHTA) addressed the effectiveness and cost-effectiveness of population screening for colorectal cancer. 5 It is reported that there was limited definitive evidence regarding the superiority of immunochemical test performance over the guaiac tests. However, evidence from cross-sectional studies suggested that only the HemeSelect, an immunochemical test, performs as well as, or better than, the guaiac tests (HOII and HOS). The report also states that good evidence showed the simplified testing process of the immunochemical test Insure encouraged more participants to complete the FOB screening tests. Only the cost-effectiveness of the guaiac-based screening was reported (i.e., less than $20,000 per life year saved), while that of the immunochemical FOB test was uncertain due to the lack of RCT data and the uncertainty of the economic models that relied heavily on assumptions. The 2004 report of the Medical Advisory Committee in Australia addressed the effectiveness and cost-effectiveness of FOB testing for population health screening. 6 FOB tests, in general, for colorectal cancer screening were safer than diagnostic colonoscopy. However, no safety data were reported regarding the performance of different FOB tests. For clinical effectiveness, the report concluded that the measures of sensitivity and specificity of the FOB tests varied considerably between studies conducted in different populations. The estimates of these measures differed significantly between different tests of the same class. Thus, relative findings for any individual pairs of guaiac and immunochemical tests cannot be generalized. For cost-effectiveness, the incremental cost per life year gained of HemeSelect (immunochemical) was $3172 in comparison with Hemoccult (guaiac), and $21,533 for Hemoccult SENSA in comparison with HemeSelect. Both Immunochemical FOB Tests 3

4 HemeSelect and Hemoccult SENSA are therefore likely to be cost-effective with respect to its comparators by commonly accepted standards at a costeffectiveness threshold of $50,000 per life year saved. However, there was no apparent class effect in determining the relative cost-effectiveness of different FOB tests. b) Systematic reviews/meta-analyses The 2004 assessment of the Blue Cross and Blue Shield Medical Advisory Panel evaluated the performance of immunochemical FOB tests in general. In addition, they evaluated specific immunochemical FOB tests in comparison to standard guaiac-based FOB tests. 4 It also assessed patient compliance with immunochemical versus guaiac FOB tests. The conclusions were as follows.. The evidence on clinical performance of immunochemical FOB tests compared to guaiac FOB tests was limited and was insufficient for drawing conclusions. It was not possible to draw conclusions regarding the dietary restrictions on patient compliance with FOB testing. There was insufficient evidence to permit conclusions regarding the use of immunochemical FOB testing and health outcomes for colorectal cancer screening. Thus, the immunochemical FOB testing for colorectal cancer screening did not meet the Blue Cross and Blue Shield Association Technology Evaluation Center criteria. The 2002 report conducted by WHO (World Health Organization) and OMED (World Organization for Digestive Endoscopy) reviewed the published data on the performance of different FOB tests for colorectal cancer. 7 It also provides recommendations for their use in screening. Of the quaiac tests, Hemocult SENSA had the highest sensitivity. Its high positivity rate resulted in a high rate of colonoscopy. Other tests of this class were Hemocult II and rehydrated Hemocult. Of the immunochemical tests, Flexure OBT and Immudia Hem Sp (one of the HemeSelect ) had acceptable performance and were easier to use, but expensive Other tests of this class were OC-Hemodia, Monohaem, Iatro-Hemocheck, LA Homochaser. The report recommended the use of guaiac tests in ideal circumstances (e.g., excellent dietary compliance and adequate colonoscopy capability), because it is more sensitive, less expensive, but less specific. However, the choice of FOB tests should be tailored to suit target population, taking into account colonoscopy capability, willingness to comply with dietary restrictions and ability to pay for the cost of FOB test. The immunochemical test may be preferable in improving participation in the screening when dietary and drug restrictions are removed. Immunochemical FOB Tests 4

5 c) Randomized controlled trial The study by Cole et al 8 investigated patient participation in colorectal cancer screening by testing for blood products in feces using technologies that removed dietary restrictions (i.e., immunochemical tests) and simplify fecal sampling (i.e., tests that used brush sampling) in comparison with guaiac test. Three cohorts of 606 participants between 50 and 69 years were randomly assigned to Hemoccult SENSA (guaiac-based), FlexSure OBT (immunochemical based) and InSure (immunochemical-based). The Hemoccult and Flexsure groups were instructed to sample three stools using a spatula, while the InSure cohort sampled two stools using a brush. The Hemoccult cohort was asked to restrict certain foods and drugs having high peroxidase. The study received InSure test kits and financial support from Enterix Inc. The quality of the study was ranked 1 (low) according to the criteria put forth by Jadad. With respect to elimination of diet and drug restrictions, the participation rate in those offered FlexSure OBT was significantly higher than that in those offered Hemoccult SENSA (30.5% versus 23.4%, p=0.007). With respect to simplified stool sampling, the participation rate in those offered InSure was significantly higher than that in those offered FlexSure OBT (39.6% versus 30.5%, p=0.002). With respect to combining of elimination of diet and drug restrictions and simplified stool sampling, the participation rate in those offered InSure was significantly higher than that in those offered Hemoccult SENSA (39.6% versus 23.4%, p<0.001). Thus, the brush-sampling of immunochemical FOB test achieved the best participation rates by simplifying sampling and removing the need for restrictions of diet and drugs. d) Economic studies The observational study of Li et al 9 evaluated the efficacy and cost of an immunochemical FOB test (Hemosure, IFOBT), and compared it with a guaiacbased test (CFOBT). A hypothetical sequential method (SFOBT), in which the IFOBT was used to confirm the CFOBT was also evaluated. Participants were Chinese patients (n=324) and were symptomatic with various clinical indications for colonoscopy. Each patient submitted three consecutive stool samples. Tests were carried out with either first two consecutive samples (two-sample setting) or all three samples (three-sample setting). The Wanhua-Puman Biol. Tech Ltd Company provided IFOBT kits for the study. It was found that, with three sample setting, SFOBT and IFOBT had favorable specificity for colorectal cancer detection over CFOBT (94.2% and 89.2% vs. 75.5%, p<0.05), with similar sensitivity (93.8% and 95.9% vs 95.9%, p>0.05). With two-sample setting, IFOBT had a higher sensitivity (87.8% vs 77.5%, p<0.05) and specificity (96.4% vs 88.5, p<0.05)) than CFOBT. Immunochemical FOB Tests 5

6 Based on those findings, the relative cost per cancer detected with two-sample IFOBT appears to be better than other protocols. The observational study of Levi et al 10 compared the efficacy and costs of guaiac (GFOBT, Hemoccult SENSA) and immunochemical (IFOBT, OC-MICRO ) FOB tests for identifying colorectal cancer. The study retrospectively evaluated a group of patients (n=151), who had consecutive GFOBT and IFOBT tests before colonoscopy examination. The patients had high risk of colorectal neoplasia. The industry provided the instruments and reagents for the immunochemical test. The sensitivity of both FOB tests were identical (75%) for significant colorectal neoplasia, but the IFOBT had significant higher specificity than GFOBT (94% vs. 34%, p<0.01). Four times more colonoscopies were needed with GFOBT than with IFOBT. The cost per significant neoplasia was $612 for IFOBT versus $2965 for GFOBT. It concluded that the IFOBT (OC-MICRO ) maintains the high sensitivity of the GFOBT (Hemoccult SENSA ), but significantly reduces the colonoscopy burden and screening costs. The study by Berchi et al 11 was a cost-effectiveness analysis of 20 years of biennial colorectal cancer screening in France with an automated reading immunochemical test (Magstream, one of the HemeSelect products) in comparison with a guaiac test (Hemoccult ). A transitional probabilistic model and results obtained from screening program run in Calvados and other studies were used. It was found that the use of Magstream costs 59 euros more than Hemoccult per individual. The incremental cost-effectiveness ratio (ICER) for the use of Magstream was 2980 euros per life year saved. It concluded that using an immunochemical test could increase the effectiveness of colorectal cancer screening at a reasonable cost for society. The study by van Ballegooijen et al 12 was a cost-effectiveness analysis of FOB tests (i.e., Hemoccult II, a guaiac test versus immunochemical tests). The study was a report to the Agency for Healthcare Research and Quality. It reviewed the literature of the guaiac and immunochemical tests for different test characteristics to establish test performance levels of sensitivity and specificity, and used a micro-simulation model to describe the natural history of the adenoma carcinoma sequence and the impact of screening on reducing colorectal cancer incidence and mortality. The Hemoccult II and Hemoccult SENSA were considered as bases cases. Assumptions were realized to sensitivity, specificity, and compliance of different FOB tests since the evidence about the relative specificity and sensitivity of ifobt in comparison to Hemoccult II was highly uncertain. It was found that Hemoccult II was the most cost-effective ($1,071 per life year gained) in comparison with other cancer screening modalities. The immunochemical tests (IFOBT) had a cost effectiveness ratio of no more than $4,500 per life year saved, even with cost per test of $28. Immunochemical FOB Tests 6

7 At the cost per test of $28 for IFOBT and $4.50 for Hemoccult II, the incremental cost effectiveness ratio (ICER) for IFOBT was $11,000 per additional life year saved assuming a specificity of 98%, and $21,000 per additional life year saved assuming a specificity of 95% for IFOBT. If the IFOBT tests maintain the high specificity (98%) and increase sensitivity to 70%, then a unit cost level of $13.00 would provide a comparable costeffectiveness to Hemoccult II at $4.50 per unit cost. Thus, both guaiac and immunochemical tests appears to be cost-effective for reducing colorectal cancer incidence and mortality. Conclusions and implications for decision or policy making: There were no randomized controlled trials investigating the clinical effectiveness of the immunochemical tests in comparison with the guaiac tests, nor in comparison with themselves. Two included health technology assessments had difficulties generalizing between the two types of tests since the performance of the tests varied within each class, as well as depending on the study population. The 2004 assessment of the Blue Cross and Blue Shield Medical Advisory Panel stated that the evidence on clinical performance of immunochemical tests compared to guaiac tests was limited and was insufficient for drawing conclusions. The 2002 joined report by WHO and OMED recommended the use of guaiac tests in circumstances with high compliance and colonoscopy availability, since the tests are less expensive, more sensitive, but less specific. One RCT showed that the participation rates in screening for colorectal cancer were highest with brush-sampling immunochemical test. From the economic perspective, the immunochemical tests appear to be equal or better than the guaiac tests. Although the simpler method of administration of immunochemical FOB tests may result in higher compliance as indicated by the study by Cole et al, 8 the direct cost of these tests are higher compared to guaiac FOB tests. However, several economic analyses indicate that immunochemical FOB tests appear to be equal to or better than the guaiac FOB tests. Prepared by: Khai Tran, MSc, PhD, Research Officer Amanda Hodgson, MLIS, Information Specialist Health Technology Inquiry Service (HTIS) htis@cadth.ca Toll free phone: Immunochemical FOB Tests 7

8 References: 1. McLeod RS. Screening strategies for colorectal cancer: a systematic review of the evidence. Can J Gastroenterol 2001;15(10): Screening for colorectal cancer. Ottawa: Health Canada; Available: (accessed 2007 Mar 9). 3. Medical devices active license listing [database online]. Ottawa: Medical Devices Bureau, Therapeutic Products Directorate, Health Canada; Available: (accessed 2007 Jan 12). 4. Immunochemical versus guaiac fecal occult blood tests. Technol Eval Cent Asses Program Exec Summ 2004;19(5):1-3. Available: 5. Kerr J, Broadstock M, Day P, Hogan S. Effectiveness and cost-effectiveness of population screening for colorectal cancer: systematic review of the literature [NZHTA report]. Christchurch (NZ): New Zealand Health Technology Assessment; 2005 (accessed 2007 May 23). 6. Faecal occult blood testing for population health screening: assessment report. Canberra, ACT: Medical Services Advisory Committee; MSAC reference 18 (accessed 2007 May 23). 7. Young GP, St John DJ, Winawer SJ, Rozen P. Choice of fecal occult blood tests for colorectal cancer screening: recommendations based on performance characteristics in population studies: a WHO (World Health Organization) and OMED (World Organization for Digestive Endoscopy) report. Am J Gastroenterol 2002;97(10): Cole SR, Young GP, Esterman A, Cadd B, Morcom J. A randomised trial of the impact of new faecal haemoglobin test technologies on population participation in screening for colorectal cancer. J Med Screen 2003;10(3): Li S, Wang H, Hu J, Li N, Liu Y, Wu Z, et al. New immunochemical fecal occult blood test with two-consecutive stool sample testing is a cost-effective approach for colon cancer screening: results of a prospective multicenter study in Chinese patients. Int J Cancer 2006;118(12): Levi Z, Hazazi R, Rozen P, Vilkin A, Waked A, Niv Y. A quantitative immunochemical faecal occult blood test is more efficient for detecting significant colorectal neoplasia than a sensitive guaiac test. Aliment Pharmacol Ther 2006;23(9): Immunochemical FOB Tests 8

9 11. Berchi C, Bouvier V, Reaud JM, Launoy G. Cost-effectiveness analysis of two strategies for mass screening for colorectal cancer in France. Health Econ 2004;13(3): Van Ballegooijen M, Habbema JD, Boer R, Zauber AG. A comparison of the costeffectiveness of fecal occult blood tests with different test characteristics in the context of annual screening in the medicare population. Bethesda (MD): Agency for Healthcare Research and Quality; Immunochemical FOB Tests 9