Is colorectal cancer screening by fecal occult blood feasible?

M. Crespi1,+ and D. Lisi2

1National Cancer Institute ‘Regina Elena’, Rome; 2Superior Institute of Health, Rome, Italy

Received 9 August 2001; accepted 10 October 2001.

cancer screening, colorectal cancer, occult blood

Introduction

Colorectal cancer represents the second most frequent neoplasia in mortality statistics of western countries.

In Europe in 1996, there were 213 111 cases and 110 669 deaths from colorectal cancer (Table 1) [1]. The trend in incidence from 1970 projected to 2006 (R. Capocaccia and A. Verdecchia, personal communication) shows a steady increase in all European countries, whereas in the USA there has been a downward trend since 1985 [2]. These differences may be partially explained by the diffusion of endoscopic procedures (colonoscopy) with the related removal of precursor lesions, namely adenomatous polyps. In fact, in a recent report by Lieberman et al. [3], 36.6% of 17 732 average risk subjects invited for a screening colonoscopy had already had a colonic examination performed in the previous 10 years. In addition, a downward trend in colorectal cancer mortality was observed in the USA from 1974 [4], while in Europe mortality has been stable since 1985 (The EUROPREVAL Project).


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Table 1. Colorectal cancer in the European Union (1996), USA and Canada (2000)
 
Reduction in mortality may be achieved by: (i) diagnosis at an earlier stage; or (ii) removal of adenomatous polyps. In fact, it has been demonstrated that the removal of adenomas reduces significantly the incidence of, and therefore mortality from, colorectal cancer [57].

The 5-year survival is strictly related to the stage of the colorectal cancer at presentation. It is 90% in Dukes’ stage A, 50–60% in Dukes’ B, ~35% in stage C1 and <10–15% in stage C2. The ideal screening test is therefore the one that may lead to a downstaging, but also to the identification (and consequent removal), of precursor lesions.

Among the screening tests available are: (i) fecal occult blood testing (FOBT); (ii) flexible sigmoidoscopy (FS); and (iii) colonoscopy. Up to now, only FOBT and FS have been employed in screening programs on asymptomatic populations, while only limited use has been made of colonoscopy.

Fecal occult blood testing

In the present review we examine the efficacy, effectiveness and feasibility of FOBT for screening programs at a national level, in an attempt to address the following questions:

Does the currently available evidence suggest that FOBT has a proven screening effect?
Should FOBT be recommended to the general population as a colorectal cancer screening test?
Should organized FOBT screening programs be established?

FOB tests are non-invasive, acceptable to patients and low cost, and some of them may be made readily available even in the decentralized structures of a health network. The basis of FOBT is that cancer and larger polyps bleed.

The most widely employed FOB test is the one devised by Greegor in 1967 [8], based on the ability of guaiac to detect hemoglobin and its derivatives in fecal samples. Other tests, such as those based on ortho-toluidine or benzidine, have been discontinued because of their toxicity or excessive sensitivity.

The FOB test used in most of the population studies is the guaiac test known as Hemoccult II, requiring two samples from each stool for three consecutive bowel movements. The samples are smeared directly by the subject and the completed test card is then delivered to the reference center or doctor. A recent slightly modified test is the Hemoccult II SENSA, which allows a more clear-cut interpretation of positivity.

The FOB tests based on guaiac pose problems of false-positive and -negative results related to diet. Non-human hemoglobins from meat, as well as other dietary components with peroxidase activity (e.g. spinach), may give false positives, whereas an excess of vitamin C may give false negatives, and therefore dietary restrictions are often applied. In fact though, rare red meat, thought to be the main culprit of false positives, seems to play a minor role: only 0.7% of false-positive results were found with the non-rehydrated test when consumption of red meat was allowed [9, 10]. Several studies have addressed this problem, and some dietary restriction is advisable, possibly limited to one day before the test, as in some of the major randomized studies [11, 12]. The important problem of intermittent bleeding of early lesions is partially overcome by the sampling of three consecutive bowel movements, while false-negative results caused by peroxidase are minimized by delaying the development of the test for at least 3 days [9].

In an attempt to increase sensitivity without a significant loss in specificity, some new FOB tests, based on immunological methods, are entering clinical practice. The most commonly used is Hemeselect, developed by Saito et al. in 1984 [13]. The test is specific for human hemoglobin, and has a high sensitivity and an acceptable specificity, but has a much higher cost than the guaiac test. This fact has lead to the guideline of testing only one or two stool samples, but this does not account for intermittent bleeding [14, 15]. In addition, the development of immunological tests is strictly a labora-tory procedure and requires 12 different steps, which leads to increased costs for laboratory equipment and manpower. In other words, the immunological tests entail a totally different approach and are not suitable for development and interpretation by non-specialist doctors or nurses.

Allison et al. [16] performed three tests [Hemoccult II (HO), Hemeselect (HSel) and Hemoccult II SENSA (HOS)] on a cohort of over 8000 subjects and found that HSel and HOS had greater sensitivity than HO (HO 37.1%; HSel 68.8%; HOS 79.4%), and that the specificity for colorectal cancer was similar for the three tests (HO 97.7%; HSel 94.4%; HOS 86.7%).

The results of randomized controlled trials [11, 12, 17, 18] and non-randomized population studies [19, 20] all use HO as the screening test. A significant reduction in mortality for colorectal cancer has been demonstrated in all studies, ranging from 15% to 33%. The favorable shift in the stage at which cancers are detected and the number of adenomas removed consequent to total colonoscopy and polypectomy, employed as a second level examination, were responsible for the decrease in mortality. In the Minnesota study by Mandel et al. [11], where a long follow-up is available (18 years), a reduction in colorectal cancer incidence was also observed. The results of this study may be unrepresentative, because the sensitivity of the test was enhanced by rehydration and, as a consequence, a large number of subjects were submitted to colonoscopy (36%). The best mortality reduction in their study was achieved with annual repetition of the test. In fact, for those who complied with all the periodic annual tests, the reduction in mortality (45%) was even more striking (S. J. Winawer, personal communication) [see the comparison of rehydrated with non-rehydrated tests for interest (Table 2)].


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Table 2. Comparison of rehydrated and non-rehydrated test in the Minnesota study
 
Discussion

The sensitivity and specificity reported in the different randomized controlled trials (Table 3) varies depending on whether rehydration is used in the test (sensitivity), the test intervals (annual or biennial) and the length of any dietary restrictions (1 or 3 days, or none). With a view to introducing national screening programs, these variables have to be taken into consideration; the most crucial issues in our opinion are the annual testing being carried out on multiple stool samples, and the level of patient compliance with the repetition of the test in the age range 50 to 75 years.


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Table 3. Results of randomized controlled trials
 
We can extract some points for consideration from a meta-analysis of the randomized controlled trials by Towler [4] and several papers by the Memorial Sloan Kettering Cancer Center group led by S. J. Winawer [21]. Rehydration substantially increases the sensitivity of the HO test and leads to a high number of subjects having a colonoscopy. In fact, for each colorectal cancer detected, 6–10 subjects need to be submitted to colonoscopy with the non-rehydrated test, compared with 17–50 with the rehydrated one [4]. Whether this is considered a disadvantage by the individual patient is subject to debate. We are fully convinced that the control of colorectal cancer may be best achieved by persuading average-risk subjects to undergo colonoscopy. The consequent financial burden on health structures is not a problem that doctors should have to consider; it is the role of doctors to advise their patient on the most effective procedure to save or prolong their life. It is the task of health authorities to decide whether this is compatible with the available budget. As colorectal cancer is mostly a problem of developed countries, at least at the moment, it seems reasonable that an appropriate allocation of financial resources may well be possible.

In summary, we fully agree with the recently published Recommendations on Cancer Screening in the European Union when they state that ‘if screening programmes are implemented [for colorectal cancer] they should use faecal occult blood screening test and colonoscopy should be used for the follow-up of test positive cases . . . Other screening methods such as immunological tests, flexible sigmoidoscopy and colonoscopy can at present not be recommended for population screening’ [22].

Footnotes

+ Correspondence to: Director Prevention Cancer & GI Unit, Viale Regina Elena 291, 00161 Roma, Italy. Tel: +39-06-445-2872; Fax: +39-06-493-85147; E-mail: mcrespi@uni.net Back

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