American Association for Clinical Chemistry
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NACB - Scientific Shorts
NACB - Scientific Shorts (formerly NACB Blog)
By Callum Fraser, PhD
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Screening the asymptomatic population for significant colorectal neoplasia, that is, cancer and advanced adenomatous polyps (sometimes called high-risk or significant), has generated significant interest over recent years with national or regional pilots or programs being set up in all over the world.
There are a number of modalities available for screening and appropriate evidence-based guidelines for application of these are available in many countries. There are differences in approaches between countries, but use of fecal tests is widespread.  The advantages and disadvantages of the traditional guaiac-based fecal occult blood test (gFOBT) and the newer fecal immunochemical test (FIT, sometimes called the immunochemical fecal occult blood test or iFOBT) have been described recently (1) and are discussed in a presentation available in the AACC Lecture Library (2).

Due to its many advantages, the use of automated FIT, in which the fecal hemoglobin (F-Hb) concentration is estimated, is becoming widespread and seen by many as the current method of choice, at least for large structured screening programs.  However, most pilots and programs use this approach simply as a qualitative investigation, deciding a single cut-off F-Hb concentration to divide the screened population into two classes, those who do and those do not warrant further investigation, usually bowel visualization.  Often the cut-off recommended by the manufacturer is used.  However, it has been suggested that this approach could be bettered (3) since available technology allows quantitation of the F-Hb concentration.

Research has shown that F-Hb concentration increases as disease becomes more serious, from the normal through non-advanced polyps, through advanced polyps to cancer, although there is overlap between these four groups (4,5).  Interestingly, F-Hb concentrations in individuals with hyperplastic polyps, hemorrhoids, and diverticular disease appear to be similar to those in people with normal colonoscopy. Thus, F-Hb concentration does seem related to stage of colorectal neoplastic disease.

Moreover, it has been demonstrated that gender and age affect F-Hb concentrations (6).  Men have higher concentrations than women and older people have higher concentrations than younger people. Recently, it has been stated that such findings mean that there is a need for more tailored screening strategies (7).  It might be that different cut-off F-Hb concentrations should be used as the criteria for further investigation for different groups.  After all, laboratories commonly use gender and age stratified reference values when these are warranted on objective grounds.

There are many publications on the clinical outcomes of screening pilots and programs using quantitative FIT with a single cut-off F-Hb concentration.  In addition, data are available on how outcomes vary with different cut-off F-Hb concentrations and the number of fecal samples analysed. However, until recently, little information was available on the risk of developing colorectal neoplasia in people with “negative” F-Hb concentrations.   An important recent study by Chen et al (8) investigated baseline F-Hb concentration as a predictor of incident colorectal neoplasia.  44324 participants with negative findings at the first investigation with quantitative FIT were followed up to find cases. Then, the association between the F-Hb concentration and risk of colorectal neoplasia was examined. In these participants, quantitative F-Hb concentration at first screening did predict subsequent risk of incident colorectal neoplasia. Chen et al stated that, during follow-up, risk stratification based on F-Hb concentration could help clinicians and suggested a number of strategies for this (8).  Firstly, F-Hb concentration at baseline could provide a means for determining risk: low, intermediate, high-risk and extremely high-risk groups could be defined, which would allow individually tailored screening strategies to be developed. For example, high-risk subjects could be offered subsequent screening at shorter intervals. Similarly, the inter-screening interval for participants with lower F-Hb concentrations could be lengthened to reduce the number of false positive tests and avoid unnecessary colonoscopy.  Secondly, using baseline F-Hb concentration as a predictor of incident colorectal neoplasia could provide a basis for participants to be educated about their own risk, which might then encourage uptake at subsequent screenings. Thirdly, a baseline F-Hb concentration measure of risk could be combined with the findings of subsequent colonoscopy to reduce the number of interval cancers and false positives by again adopting different inter-screening intervals as a result of this combined information.

These recent data on associations between F-Hb concentration and (1) disease stage, (2) demographic characteristics including gender and age, and (3) future risk for the individual should influence the design of screening programs using quantitative FIT.  However, this necessary evolution can only occur if the estimated F-Hb concentrations are used as quantitative data. Unfortunately, this seems currently to be rarely considered or done or even allowed by regulation.  Specialists in laboratory medicine could play a key role in promoting the better use of quantitative F-Hb analyses.

 

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About the Author
Callum Fraser, PhD
Callum Fraser, PhD 
 

References
1.  Fraser CG. Fecal occult blood tests. Life savers or outdated colorectal screening tools? Clin Lab News 2011:37(3):8-10. swww.aacc.org/publications/cln/2011/march/Pages/FecalOccult.aspx
2.  AACC Lecture Library. Colon cancer: The role of fecal tests – 2011

3.  Fraser CG. Screening for colorectal neoplasia with faecal tests, Lancet Oncol 2011;12:516-7.
4.  Levi Z, Rozen P, Hazazi R, et al. A quantitative immunochemical fecal occult blood test for colorectal neoplasia. Ann Intern Med 2007;146:244–55.
5.  Fraser CG, Mathew CM, McKay K, Carey FA, Steele RJ.  Automated immunochemical quantitation of haemoglobin in faeces collected on cards for screening for colorectal cancer. Gut 2008;57:1256-60.
6.  Brenner H, Haug U, Hundt S.  Sex differences in performance of fecal occult blood testing.  Am J Gastroenterol 2010;105:2457-64.
7.  Khalid-de Bakker CA, Jonkers DM, Sanduleanu S, et al. Test performance of fecal occult blood testing and sigmoidoscopy compared with colonoscopy screening for colorectal advanced adenoma. Cancer Prev Res 2011 Jul 12. Epub ahead of print
8.  Chen L-S, Yen A M-F, Chiu S H-Y, Liao C-S, Chen H-H. Baseline immunochemical faecal occult blood test (iFOBT) concentration as a predictor of incident colorectal neoplasia: longitudinal follow-up of a Taiwanese population-based colorectal cancer screening cohort. Lancet Oncol 2011;12:551-8.