Guaiac-based fecal occult blood (FOB) tests commonly are used in screening programs for colorectal carcinoma. Guaiac is a chemical test for peroxidase activity that is present in both hemoglobin (Hb) and certain foods.1, 2 To improve readability, the guaiac FOB test HemoccultSENSA (HOS) (Beckman-Coulter, Inc., Primary Care Diagnostics, Palo Alto, CA) was introduced.3, 4 This test led to improved sensitivity for significant neoplasia (colorectal carcinoma or adenomas ≥ 1 cm in size), but, conversely, to reduced specificity due to increased false positivity from dietary peroxidases.4–8
The overall impression was that despite its improved sensitivity for significant neoplasia, the high positivity rate of HOS and cumbersome dietary restrictions recommended limited its usefulness as an annual screening test.9, 10 The alternatives considered were to change to or add an immunochemical test specific for human Hb, which also has an additional advantage in that no dietary restrictions are required.6, 8, 9–12 The immunochemical test we evaluated is FlexSure OBT (FS) (Beckman-Coulter, Inc., Primary Care Diagnostics, Palo Alto, CA).
Meanwhile, both experimental studies and clinical experience showed that delaying development of HOS until 3 days after preparing the last FOB card significantly reduced its false positivity rate and improved its specificity.5, 9 This apparently allowed time for the breakdown of dietary vegetable peroxidases.13 Further experience also showed that by this delay in development of HOS of at least 3 but not more than 14 days, dietary restrictions before and during HOS preparation were not required in our population and could be eliminated.14
We examined the comparative usefulness of each test within the framework of an ongoing cumulative evaluation of different FOB tests in an endoscopic screening/follow-up study.5, 9, 15 The objective being to draw conclusions and recommend which FOB test to use for a population-screening program.
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- MATERIALS AND METHODS
To our knowledge, this large comparative study demonstrated for the first time that, even without dietary restrictions, the analytic sensitivity for clinically significant neoplasia of the sensitive guaiac HOS was not significantly different from that of the more specific immunochemical FS test. In addition, the HOS test identified more patients with adenomas, so its sensitivity for any colorectal neoplasia was significantly better than FS, but with significantly less specificity. It also demonstrated the limited clinical value of using a combination of both types of FOBTs.
The main strength of this study is that all the examinees underwent endoscopic examinations. Thus, the estimations of specificity are highly accurate. However, even though the population examined was asymptomatic, they are not at average risk for colorectal neoplasia but mainly at increased risk. Even so, because they were already in a long term screening/follow-up program, they were unlikely now to be harboring clinically significant neoplasia. For this reason, we included a small number of symptomatic persons (3%) to better mimic population screening and to obtain data on relative sensitivity.
The analytic sensitivity of HOS for large adenomas and cancer or even for any neoplasia was as good as or better than with FS. This is surprising because FS is a specific immunochemical test for human Hb and able to detect lower levels of fecal blood than HOS.9 However, this conclusion is based on in vitro studies, in which human blood is mixed with stool before smearing the test card. In vivo, the situation is not the same because the rate and degree of human blood degradation will clearly depend on factors such as transit time, differences between body and room temperature, and the different moisture content of intact stool and air-dried test cards, all of which could all affect the rate of Hb degradation by bacteria. The relatively poor sensitivity of FS for neoplasia in our ambulatory population setting was lower than that reported in symptomatic hospital-based colorectal carcinoma or adenoma cases, by using other immunochemical FOB tests.4, 12, 17 The differences might be related to the type of immunochemical test used and its ability to detect Hb or its products.9
This higher sensitivity of HOS for neoplasia is at the expense of significantly lower specificity than FS. Because FS is specific for human Hb, it has significantly better predictive negative and positive values than HOS. The lower specificity of HOS is unexplained and probably related to unidentified non-Hb sources of fecal peroxidases.
This dilemma, of choosing either FOB test sensitivity or specificity, is most acute when screening large size populations for colorectal carcinoma. In the recently completed randomized population screening studies, the positivity of the guaiac FOB test used (standard Hemoccult) varied from a high 9.8% (due to rehydration) to markedly low values of 0.6–2.1%.18–20 Even with the lowest positivity rates, within a multiyear screening program, there was a significant reduction in large bowel carcinoma mortality. The reduction was highest (33%) when using the most sensitive FOB test annually and so leading to a large number of colonscopic examinations, and lowest (15–18%) when using the less sensitive test biennially. Our one-time test with HOS identified only 50% of clinically significant neoplasia. However, a FOB screening program is not a one-time examination, and only by consistent retesting can the maximum program benefit be obtained.
Ransohoff and Lang noted that a FOB test specificity of less than 95% would lead to an excessive number of colonoscopic examinations.21 Within a population-screening program, this could be an expensive drain on the medical resources and increased iatrogenic morbidity due to the invasive diagnostic procedures. HOS specificity is at the border of this level. The alternative FS has a better specificity but a lower sensitivity for clinically significant neoplasia. Within an annual FOB screening program, a lower one-time test sensitivity might be acceptable by looking at overall program sensitivity, namely, the diagnostic-therapeutic results obtained over a period of some years. It remains to be proven that FS could significantly reduce colorectal carcinoma mortality and at what cost, because the immunochemical test is more expensive than the guaiac FOB tests. There is a favorable experience with a national screening program in Japan, using only an immunochemical test for human Hb, and because of their high intake of dietary peroxidases, it is believed to be better than if a guaiac test were to be used.22
Another possibility that is being considered, to improve the specificity of using HOS and so reduce screening costs, is to combine it with FS, which would only be developed if the HOS was positive, the “two-tier test.”8–11 The assumption is that most significant neoplasia would be identified by a positive HOS test and the false positivity would be reduced by confirmation with FS, a specific test for human Hb. This combination test is being examined prospectively in a population screening trial (Allison JE, personal communication). The analysis of our own results showed that the combination gave a significantly lower sensitivity for any colorectal neoplasm than with HOS alone but markedly improved its specificity. When considering sensitivity only for clinically significant neoplasia (large adenomas and cancer), it was significantly lower than that with HOS alone and FS alone (NS), but with maximum specificity. This was because of the lower sensitivity of FS for large or small adenomas So, we do not see any clinical advantage in this two-tier approach.
One of the disadvantages of HOS is its high sensitivity to dietary peroxidases.9, 13 We and others found that this high positivity could be reduced by delaying its development > 3 days after the FOB test card preparation.13, 14 In our population, this eliminated the need for severe dietary restrictions of almost 1-week duration each year. This is important because it could lead to reduced compliance for annual FOB retesting, which is required to obtain a maximum reduction in colorectal cancer mortality.18–20 This change removes one of the main advantages in using a more expensive human Hb-specific FOB test, which obviously is not sensitive to diet. However, note that our population has a low intake of red meat, which usually is koshered, i.e., the blood has been drained out. So, the recommendation to ignore dietary restriction by changing the timing of FOB test development requires confirmation from other countries having a higher red meat intake.
HOS is the most common FOB test used in Israel and is being considered for use in our National Screening Program, but without routine flexible sigmoidoscopy.23 We had to decide which approach is more practical, either to use the sensitive HOS test, which detects more neoplasia initially at a high cost financially and strain on medical resources, or to use a more gradual approach with the less sensitive but more specific FS annual immunochemical test. Currently, there is not enough long term experience with the immunochemical test to conclude that the program sensitivity will adequately reduce colorectal carcinoma mortality, and at a cost equivalent to, or less than that obtained with a sensitive guaiac test. Because the incidence of colorectal adenomas is lower in Israel than in the U.S. or Europe, and we have well developed endoscopy facilities, the more sensitive HOS test has been chosen.15
In conclusion, within an endoscopic screening program, we have shown that the sensitive guaiac HOS test, without dietary restrictions, had a better sensitivity for colorectal neoplasia than the specific immunochemical FS test. This was done by identifying more adenomas of all sizes. The specificity of HOS although lower than FS was still acceptable for our population screening program.