Comparing Fecal Immunochemical Tests: Improved Standardization Is Needed

Abstract

See “Lower risk of advanced neoplasia among patients with a previous negative result from a fecal test for colorectal cancer,” by Denters MJ, Deutkom M, Bossuyt PM, et al, on page 497. See “Lower risk of advanced neoplasia among patients with a previous negative result from a fecal test for colorectal cancer,” by Denters MJ, Deutkom M, Bossuyt PM, et al, on page 497. The fecal immunochemical test (FIT) for hemoglobin has had a long and hard journey to acceptance in the US Proof of FIT superiority over the traditional guaiac fecal occult blood tests was first demonstrated in an average risk American population in 19961Allison J.E. Tekawa I.S. Ransom L.J. et al.A comparison of fecal occult-blood tests for colorectal-cancer screening.N Engl J Med. 1996; 334: 155-159Crossref PubMed Scopus (529) Google Scholar; however, the US has been slow to embrace a technology that has clear analytical, operational, and clinical advantages. American opinion leaders, the media,2Cram P. Fendrick M.A. Inadomi J. et al.The impact of a celebrity promotional campaign on the use of colon cancer screening: the Katie Couric effect.Arch Intern Med. 2003; 163: 1601-1605Crossref PubMed Scopus (332) Google Scholar and some US colorectal cancer (CRC) guidelines have consistently reinforced the philosophy that colonoscopy every 10 years, beginning at age 50 years, is the preferred screening strategy.3Rex D. Johnson D.A. Anderson J.C. et al.Guidelines for colorectal cancer screening 2009.Am J Gastroenterol. 2009; 104: 739-750Crossref PubMed Scopus (1175) Google Scholar Some experts have suggested that FIT is a nonspecific marker for screen relevant neoplasia4Osborn N.K. Ahlquist D.H. Stool screening for colorectal cancer: molecular approaches.Gastroenterology. 2005; 128: 192-206Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar or is less effective than structural examinations of the colon for CRC prevention.5Levin B. Lieberman D.A. McFarland et al.Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology.Gastroenterology. 2008; 134: 1570-1595Abstract Full Text Full Text PDF PubMed Scopus (1704) Google Scholar Until recently, there have been few US studies evaluating the clinical effectiveness of FIT6Allison J.E. The imperative of equal funding for studies that evaluate any of the evidence-based, guideline-recommended colorectal cancer screening tests.Clin Gastroenterol Hepatol. 2009; 7: 1269-1271Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar; however, across Europe and in some non-European countries, these studies have provided a sound evidence base upon which population screening programs for CRC are being developed and implemented. The strength of this evidence is apparent in the recently published European Guidelines for Quality Assurance in Colorectal Cancer Screening and Diagnosis, where FIT is recommended as the test of choice for population-based screening.7Segnan N. Patnick J. von Karsa L. European guidelines for quality assurance in colorectal cancer screening and diagnosis. Publications Office of the European Union, Luxembourg2010http://screening.iarc.fr/doc/ND3210390ENC.pdfGoogle Scholar FIT are very specific markers of screen relevant neoplasia8Levi Z. Rozen P. Hazazi R. et al.A quantitative immunochemical fecal occult blood test for colorectal neoplasia.Ann Intern Med. 2007; 146: 244-255Crossref PubMed Scopus (284) Google Scholar, 9Park D. Ryu S. Kim Y. et al.Comparison of guaiac-based and quantitative immunochemical fecal occult blood testing in a population at average-risk undergoing colorectal cancer screening.Am J Gastroenterol. 2010; 105: 2017-2025Crossref PubMed Scopus (257) Google Scholar and many studies including the one in this issue of Gastroenterology show that in only one round they identify approximately one third of the advanced adenomas present in an average risk, asymptomatic population and thus have the ability to prevent CRC as well as decrease mortality from it.10Morikawa T. Kato J. Yamaji Y. et al.A comparison of the immunochemical fecal occult blood test and total colonoscopy in the asymptomatic population.Gastroenterology. 2005; 129: 422-428Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar, 11Allison J.E. Sakoda L.C. Levin T.R. et al.Screening for colorectal neoplasms with new fecal occult blood tests: update on performance characteristics.J Natl Cancer Inst. 2007; 99: 1462-1470Crossref PubMed Scopus (317) Google Scholar, 12Denters M.J. Deutkom M. Bossuyt P.M. et al.Lower risk of advanced neoplasia among patients with a previous negative result from a fecal test for colorectal cancer.Gastroenterology. 2012; 142: 497-504Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar A recent editorial suggested that a noninvasive, effective, and inexpensive screening test for CRC could mean less harm to patients, more participation by underscreened groups, fewer opportunity costs to the healthcare system, and a lower overall cost for CRC screening.13Harris R. Kinsinger L.S. Less is more: not “going the distance” and why.J Natl Cancer Inst. 2011; 103: 1726-1728Crossref PubMed Scopus (8) Google Scholar The Denters et al12Denters M.J. Deutkom M. Bossuyt P.M. et al.Lower risk of advanced neoplasia among patients with a previous negative result from a fecal test for colorectal cancer.Gastroenterology. 2012; 142: 497-504Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar study in this issue describes FIT performance in a program of biennial testing over 2 screening rounds. It confirms the findings of other studies that FIT identifies advanced adenomas, elicits better participation than guaiac FOBT, and that second-round participation increases in those previously screened (86%). The study shows that a negative first-round test reduces the odds of a diagnosis of advanced neoplasm at 2 years and that the advanced neoplasms uncovered in the second screening round are much more likely to be advanced adenomas and early stage cancers rather than incurable cancers. We agree with the authors that this study’s limitations include both the number of rounds reported and the quality of the preparation for colonoscopy. More detailed information and further research are needed from established population screening programs on participant acceptance, interval cancers, and advanced adenomas after multiple rounds of FIT screening both annually and biennially. The poor quality of the colonoscopy preparation in this study is a problem highlighted by US endoscopy societies14Rex D. Petrini J.L. Baron T.H. et al.Quality indicators for colonoscopy.Am J Gastroenterol. 2006; 101: 873-885Crossref PubMed Scopus (45) Google Scholar, 15Lieberman D. Nadel M. Smith R.A. et al.Standardized colonoscopy reporting and data system: report of the Quality Assurance Task Group of the National Colorectal Cancer Roundtable.Gastrointest Endosc. 2007; 65: 757-766Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar as one reason that screening colonoscopy has been shown to be strongly associated with fewer deaths from left-sided but not from right-sided CRC.16Baxter N.N. Goldwasser M.A. Paszat L.F. et al.Association of colonoscopy and death from colorectal cancer.Ann Intern Med. 2009; 150: 1-8Crossref PubMed Scopus (1065) Google Scholar, 17Lakoff J. Paszat L.F. Saskin R. et al.Risk of developing proximal versus distal colorectal cancer after a negative colonoscopy: a population-based study.Clin Gastroenterol Hepatol. 2008; 6: 1117-1121Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 18Singh H. Nugent Z. Demers A.A. et al.The reduction in colorectal cancer mortality after colonoscopy varies by site of the cancer.Gastroenterology. 2010; 139: 1128-1137Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar CRC screening programs require “high-confidence colonoscopy,” defined as excellent preparation, slow withdrawal, and complete polypectomies. A further weakness of this study and many similar ones is that the results cannot be easily compared with other studies that use different FIT products or even the same FIT but with different hemoglobin cutoff concentrations. As this and other FIT reporting limitations are more widely recognized, we hope they can be addressed by professionals in academia and industry working together to agree on a standardized approach to nomenclature, measurement, and results reporting. Constancy of nomenclature aids understanding and transference of ideas across time and geography. Recommendations that we propose for names and abbreviations include two names for the guaiac test—namely, the guaiac FOBT (usual analytical sensitivity) and high-sensitivity FOBT—and “FIT” not “iFOBT” should be the name used to identify the measurement of hemoglobin concentration in feces using the very different immunochemical methodology. Evaluation of test performance across studies requires consistency in reporting results. FIT come in 2 formats: Qualitative (positive/negative) and quantitative (measured hemoglobin concentration). There are many FIT products available from a range of manufacturers, but they vary in several key aspects. Qualitative FIT express cutoff hemoglobin concentrations using a range of units and they have no requirement for commonality in methodologic principles or standardization procedures. The quoted cutoff concentrations for a positive test result differ between products and consequently are not necessarily comparable. Quantitative FIT provide a numeric result and the opportunity to assign a concentration at which a test is designated “positive.” In doing so, it determines the referral rate for colonoscopy and the clinical characteristics of the screening program. Currently, this all important numerical value is not comparable across different FIT products and this limits the value of FIT research and carries the potential of misleading those who may not be aware of this problem. There are other issues of standardization of FIT. We must understand and document how specific the test is for measuring intact human hemoglobin and what else it might be measuring (hemoglobin degradation products or hemoglobin variants). We need an understanding of fecal hemoglobin stability in the devices used to transport samples to the laboratory, and to be able to compare data for one product with others under a range of storage conditions. Finally, we need to express the concentrations that FIT measures consistently to enable important studies like that of Denters et al to be compared with others. Consistency in reporting requires FIT concentrations expressed as the quantity of hemoglobin present in feces not in the collection or measurement solution as is currently the custom. The current approach presents us with results that cannot be compared because they are unique to a specific product design, to its sample collection system, and to the volume of buffer used to preserve the sample. In summary, the numerical results obtained by FIT cannot be compared across different products because:•There are differences in method principle, reagents and reporting units;•The tests do not use a hemoglobin calibrant that is traceable to an international reference preparation with concentration assigned by a high order method;•Analytical sensitivity and specificity are dependent on the characteristics of antibody reagents;•The mass of feces collected by any of the available FIT and the volume of buffer contained in the collection device are specific and therefore analytical results based on hemoglobin concentration in the buffer (ng Hb/mL buffer) cannot be compared directly with results from other FIT; and•The preservatives contained in the buffer used in many FIT collection devices vary in their effectiveness. A study by Brenner et al19Brenner H. Haug U. Hundt S. Intertest agreement and quantitative crossvalidation of immunochromatographical fecal occult blood tests.Int J Cancer. 2010; 127: 1643-1649Crossref PubMed Scopus (44) Google Scholar of six qualitative FIT illustrates the nature of the problem. These investigators reported that the positivity rates of the six tests varied widely. Clinical sensitivity and specificity for advanced neoplasms also varied widely but were closely related to the positivity rate. Table 1 presents the observed positivity, sensitivity, and specificity for advanced neoplasms of six FIT devices alongside manufacturers' quoted cutoff hemoglobin concentration (ng Hb/mL buffer) as documented by Hundt et al.20Hundt S. Haug U. Brenner H. Comparative evaluation of immunochemical fecal occult blood tests for colorectal adenoma detection.Ann Intern Med. 2009; 150: 162-169Crossref PubMed Scopus (300) Google Scholar If the cutoff concentrations had been derived and expressed similarly in units of micrograms of hemoglobin per gram of feces, which takes both mass of feces collected and the volume of buffer in the collection device into account, then a low cutoff would always render a high positivity rate (and indeed be the most sensitive and least specific) and vice versa. These data demonstrate inappropriate comparisons across FIT devices.Table 1Positivity, Sensitivity, and Specificity for Advanced Neoplasia and Manufacturer's Quoted Cutoff Hemoglobin Concentrations (ng Hb/mL) for Six Qualitative FITFITPositivity (%)Sensitivity (%)Specificity (%)Manufacturer's quoted hemoglobin cutoff (ng Hb/mL buffer)A6.429.896.750B11.030.592.940C22.353.281.810D24.156.082.040E35.059.670.250F46.873.458.825 Open table in a new tab We can only identify the most appropriate FIT and achieve the maximum benefit from FIT screening by ensuring comparability of results over time, geography, and method. Establishment of internationally agreed FIT standards is now a priority as this test becomes central to the development of international screening programs. Standardization will bring analytical comparability to measured concentrations and the units used for reporting, and it will bring traceability to the hemoglobin solutions used to calibrate tests. The time has come to bring order to FIT measurement and to the literature that is demonstrating its clinical efficacy. We strongly urge the international community, including clinical researchers, academic laboratory chemists, and manufacturers to work together to develop common standards for the performance and reporting of FIT to achieve this goal. Lower Risk of Advanced Neoplasia Among Patients With a Previous Negative Result From a Fecal Test for Colorectal CancerGastroenterologyVol. 142Issue 3PreviewConsecutive rounds of fecal occult blood tests (FOBTs) are used to screen for colorectal cancer (CRC); they detect precursor lesions and early-stage disease. We assessed whether the positivity rate and the positive predictive values (PPVs) for advanced neoplasia and CRC decrease with repeated testing by using fecal immunochemical tests (FITs). Full-Text PDF