Department of Surgery, New York Medical College, Valhalla, NY, USA and Division of Epidemiology and Biostatistics, European Institute of Oncology Milan, Italy
Received 9 August 2001; accepted 10 October 2001.
Key words: colorectal cancer, fecal occult blood, screening
Introduction
With an estimated life-time cumulative incidence of around 5%, and an overall long-term mortality of about 40% to 50%, colorectal cancer (CRC) adds greatly to the burden of cancer for both patients and health providers. We now know that nearly all CRC arises from pre-existing polyps, implying that detection and removal of these premalignant lesions would have an enormous impact on CRC.
In high-risk countries, incidence and mortality rates have demonstrated only minor changes during the past decade, raising the question: why dont we screen for this potentially preventable cancer? Table 1 lists some basic background information concerning fecal occult blood testing (FOBT).
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If FOBT has no impact on CRC mortality, then obviously it should not be recommended as a screening procedure. However, even if there is evidence that FOBT reduces CRC mortality, it does not necessarily imply that the procedure should be recommended for the general population without consideration of other issues.
Does FOBT reduce the burden of colorectal cancer?
The impact of FOBT on CRC mortality can best be assessed by studying data from randomized controlled clinical trials, comparing Hemoccult screening with no screening. Data from such trials are now available from four countries: Denmark [1], Sweden [2], USA [3], and the UK [4]. Trial participants were randomly assigned to either the screening group, which was generally with un-rehydrated slides, or to a control group. Participants in the screened group were asked to avoid meat or medications known to interfere with the test prior to the screening procedure. Those participants with a positive test were then re-examined either by colonoscopy or by sigmoidoscopy and barium enema with air contrast.
The results of these four randomized controlled trials as well as one other controlled non-randomized trial [5] have been carefully studied and published as a review in the Cochrane Library [6]. The total number of subjects enrolled in the four randomized controlled trials was more than 300000truly an impressive number. Average follow-up periods ranged from 7.8 to 13 years, providing ample time to determine the impact of screening. The overall results of the meta-analysis showed a reduction in CRC mortality of 16% [95% confidence interval (CI) 7% to 23%]. After adjusting for attendance, the overall mortality reduction was 23% (95% CI 11% to 43%)
Although there are additional ongoing studies or studies not included in this review, the published results of this meta-analysis are likely to be unchallenged for the foreseeable future. The results suggest that FOBT screening for CRC, carried out under the ideal conditions of a research environment, are likely to reduce deaths from CRC.
Should we recommend wide-scale FOBT for the general population
The best available current evidence implies that FOBT saves lives in persons enrolled in randomized clinical trials. Based on these findings, should we therefore recommend large scale application of FOBT to the general population? Listed below are the main reasons why FOBT should NOT be used as a screening test.
Other available screening tests
To overcome some of the perceived shortcomings associated with FOBT screening, several newer modalities should be considered.
Flexible sigmoidoscopy
This procedure can be performed alone or in combination with FOBT. Even though it has proven to be cost effective [10], it will probably be replaced by colonoscopy. One advantage is that the procedure can be performed by physicians who are not qualified to perform colonoscopy or by specially trained nurses and other allied health professionals. Use of well trained non-medical doctors would lower the costs of the examination.
Although a considerable number of CRCs are located within the range of modern instruments, the major disadvantage of flexible sigmoidoscopy is that it cannot detect lesions located above the reach of the instrument. This is a significant drawback, especially since the frequency of right sided colonic cancers appears to be increasing [11].
Colonoscopy
This is the screening procedure preferred by most gastroenterologists. When performed by a competent practitioner, colonoscopy has several advantages: (i) it visualizes the entire colon; (ii) suspicious lesions can be biopsied; and (iii) adenomatous polyps can be removed prior to their malignant transformation. In many ways, colonoscopy can be considered the gold standard for prevention of CRC.
There are several disadvantages of colonscopy as a screening tool. The results of controlled randomized trials are not available to allow us to draw firm conclusions about the advantages and disadvantages of the procedure. Careful cleansing of the colon is unpleasant, burdensome, but essential before colonoscopy can be performed. Although the procedure has a low risk, perforations do occur perhaps once or twice per 1000 procedures [12, 13]. Predictably, gastroenterologists are reluctant to publish adverse results, so the true perforation rates might be somewhat higher. Finally, cost is a major consideration, especially if we consider using colonoscopy to screen large population groups. Nevertheless, because of the problems associated with FOBT, colonoscopy needs careful evaluation as a potentially valuable screening tool [14, 15].
Radiological procedures
Barium enema with air contrast was one of the earliest methods suggested to diagnose CRC. Its use as a diagnostic and screening tool has gradually been replaced by colonoscopy, which has the obvious advantage of combining diagnosis with biopsy and or excision of visualized lesions.
Virtual colonoscopy is a new technique combining radiological examination of the colon with either spiral computed axial tomography where air is used as the contrast agent, or with magnetic resonance imaging, using a small amount of a paramagnetic contrast agent. The advantage of virtual colonoscopy is that it eliminates invasive instrumentation of the colon. The interpretation may be observer dependent, and, obviously, any detected lesions will require conventional colonoscopy as an additional procedure.
DNA stool examination
Detecting altered DNA in the stool has been suggested as a promising screening test [16]. Although inconceivable prior to the discovery of PCR-based technology, CRC has been diagnosed from altered DNA extracted from stool. In one pilot study, sensitivity was 91% for cancer and 82% for polyps 1 cm or larger in diameter, with a specificity of 93%. In the study by Dong and co-workers, three genetic markers discovered in the stool detected 35 (71%) of 51 patients with CRC. The stool DNA test detected 92% of those tumors where there was an alteration in any one of the three genes included in the screening panel [17].
The cost of the requisite laboratory work is still high, but would hopefully be reduced in large-scale screening tests. If so, and if the reported sensitivity and specificity can be confirmed in larger studies, then this screening procedure holds great promise as an alternative to FOBT. In the future, it would be ideal if DNA testing could be incorporated into the so-called smart toilet (Matsushita Electric Industrial, Osaka, Japan), which can already test for sugar in the urine.
Table 2 summarizes the major advantages and disadvantages of several available screening procedures for CRC.
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Fecal occult blood testing, when evaluated in large-scale long-term randomized controlled trials, reduces mortality from CRC by 16%. As yet, no other CRC screening procedure has been shown to have comparable results. It is appealing because the initial costs are low, the test is widely available, and FOBT does not pose an immediate risk to the screened population. All of these characteristics support FOBT as a screening procedure.
However, before adopting this seemingly appropriate screening procedure, we must consider multiple unresolved questions. There is no evidence that FOBT will be as effective if widely employed in a large population as it appears to be in carefully supervised clinical trials. It is not particularly effective in detecting polypsthe major precursor of CRC; colonoscopy is a much better choice. Compliance cannot be expected to be more than 50%, immediately limiting the effectiveness of FOBT. The predictive value of a positive test is no more than 10%, meaning that most screen-positive individuals will be subjected to additional tests, as well as considerable psychological stress. Finally, even though FOBT is inexpensive, the predicted volume of confirmatory tests will generate high costs per actual life saved. For all these reasons we should proceed with extreme caution before applying FOBT to large population groups
Footnotes
+ Correspondence to: Department of Surgery, New York Medical College, Valhalla, NY 10595, USA. Tel: +1-914-594-4260; Fax: +1-914-594-4576; E-mail: lowenfel@nymc.edu
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