Procedurefor Drawing a Lot of Blood
Keywords
- 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 don't we screen for this potentially preventable cancer?' Table 1 lists some basic background information concerning fecal occult blood testing (FOBT).
Table 1 Basic considerations for fecal occult blood testing in persons with colorectal cancer (CRC)
| Estimated percentage of population ≥ age 55 a USA figures. | 21–22% |
| Age-standardized incidence CRC a USA figures. | |
| Males | 39.6/100000/year |
| Females | 28.1/100000/year |
| Compliance rates | |
| Clinical trials | >60% [ 6.
Screening for colorectal cancer using the faecal occult blood test, hemoccult.
|
| General population | 35–50% [ 18.
A critical analysis of the largest reported mass fecal occult blood screening program in the United States.
|
| Sensitivity | 50% [ 8.
Should all people over the age of 50 have regular fecal occult-blood tests? Postpone population screening until problems are solved.
|
| Specificity | 98% [ 8.
Should all people over the age of 50 have regular fecal occult-blood tests? Postpone population screening until problems are solved.
|
| Predictive value of positive FOBT | 5–10% [ 8.
Should all people over the age of 50 have regular fecal occult-blood tests? Postpone population screening until problems are solved.
|
| Estimated number needing screening to prevent one CRC death | 1173 [ 6.
Screening for colorectal cancer using the faecal occult blood test, hemoccult.
|
| Estimated cost per prevented CRC death | $250000–350000 [ 19.
Cost-effectiveness model for colon cancer screening.
|
- Open table in a new tab
For several decades, FOBT has been available to detect and thereby potentially reduce the frequency of this prevalent cancer. The test is safe, inexpensive, and can be performed without sophisticated equipment. FOBT detects tumors throughout the large bowel, although it may be less effective for picking up small right-sided cancers. Given the attractiveness of the procedure: 'why should there be a debate about it's role in the prevention of CRC?' The continuing controversy about the usefulness of this screening test requires a discussion of two related issues:
- 1
Does FOBT reduce CRC mortality?
- 2
Should we recommend FOBT as a population screening test for the general population?
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 [
], Sweden [
2.
- Kewenter J.
- Brevinge H.
- Engaras B.
- et al.
Results of screening, rescreening, and follow-up in a prospective randomized study for detection of colorectal cancer by fecal occult blood testing. Results for 68,308 subjects.
- Crossref
- PubMed
- Scopus (255)
- Google Scholar
], USA [
], and the UK [
4.
- Hardcastle J.D.
- Thomas W.M.
- Chamberlain J.
- et al.
Randomised, controlled trial of faecal occult blood screening for colorectal cancer. Results for first 107,349 subjects.
- Abstract
- PubMed
- Scopus (309)
- Google Scholar
]. 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 [
] have been carefully studied and published as a review in the Cochrane Library [
6.
- Towler B.P.
- Irwig L.
- Glasziou P.
- et al.
Screening for colorectal cancer using the faecal occult blood test, hemoccult.
- Google Scholar
]. The total number of subjects enrolled in the four randomized controlled trials was more than 300000—truly 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.
- •
Randomized FOBT trials began about three decades ago. Since then newer procedures have been developed which may be more suitable for the prevention and detection of CRC. Indeed, the large number of available screening tests suggests dissatisfaction with FOBT.
- •
It has been difficult to show a reduction in all-cause mortality as a result of FOBT. The probable explanation is that a reduction of 15% to 20% in mortality of a disease that afflicts only ∼5% of the population will have a limited impact on overall mortality.
- •
Not all CRCs bleed, explaining why FOBT testing has a low sensitivity for the detection of CRC—probably no more than ∼50%. The sensitivity for the detection of polyps is even lower. The implication is that FOBT will miss about half of all malignant large bowel tumors and most polyps. It will undoubtedly detect some polyps, explaining why in an extremely long follow-up period, there does appear to be some reduction in the incidence of CRC [
]. But detection of polyps is likely to be a chance event, related to the increased exposure of the FOBT screened population to procedures that visualize the colon.
- •
Specificity issues. The specificity of FOBT is high—around 98%. However, if FOBT is used as a screening procedure for the general population—say, all persons over age 50—the predictive value of a positive test is no more than 5% to 10% [
8.
- Simon J.B.
Should all people over the age of 50 have regular fecal occult-blood tests? Postpone population screening until problems are solved.
- PubMed
- Google Scholar
]. Therefore most patients who test positive will require an expensive, uncomfortable, confirmatory procedure such as colonoscopy that does carry a slight risk of colonic perforation.
- •
Compliance issues. Collecting stool for FOBT is an unpleasant task, explaining why even in the ideal setting of a randomized trial, no more than two thirds of participants are compliant. Compliance rates are much lower outside of randomized trials.
- •
Cost issues. FOBT by itself is relatively inexpensive, but a positive test requires an additional much more expensive test, which will usually be negative. There are substantial costs associated with any of the confirmatory tests, and with time lost from work. Most cost estimates exclude legal costs from procedure-related colonic perforations: these could be substantial [
]. CRC is rare in younger individuals, commonest in older persons who are most likely to die from competing causes, even if their CRC is successfully diagnosed by FOBT and treated. The overall mortality reduction from population screening with FOBT will be small—perhaps about eight or nine fewer deaths per 10000 individuals offered screening over a 10 year period [
6.
- Towler B.P.
- Irwig L.
- Glasziou P.
- et al.
Screening for colorectal cancer using the faecal occult blood test, hemoccult.
- Google Scholar
]. Although FOBT screening programs have proven to be cost-effective, the costs will be high, probably requiring diversion of a considerable proportion of health workers from other tasks. Should we allocate so much effort to FOBT? If resources are limited, would it not be more appropriate to fund projects such as control of smoking, alcohol, and substance abuse, or injury control? For the same investment the results in terms of potential years of life saved might be much greater if we apply preventive strategies to conditions that are more prevalent in younger individuals.
- •
Adequacy of follow-up. Not all screen-positive persons will decide to proceed with recommended additional follow-up studies. For those that do, we may not have an adequate number of trained, competent gastroenterologists to safely carry out the increased volume of procedures.
- •
Any type of screening procedure has a better chance of detecting slower growing, potentially less aggressive tumor types. FOBT may be ineffective against the subset of highly malignant tumors with rapid growth and high likelihood of early metastasis.
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 [
], 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 [
].
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 [
,
13.
- Ettersperger L.
- Zeitoun P.
- Thiefin G.
Colonic perforations complicating colonoscopy. Apropos of 15 consecutive cases observed over 16 years.
- PubMed
- Google Scholar
]. 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.
- Helm J.F.
- Russo M.W.
- Biddle A.K.
- et al.
Effectiveness and economic impact of screening for colorectal cancer by mass fecal occult blood testing.
- Crossref
- PubMed
- Google Scholar
,
].
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 [
]. 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 [
].
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.
Table 2 Advantages and disadvantages of available screening modalities
| Procedure | Advantages | Disadvantages |
| Fecal occult blood testing | Has reduced mortality from colorectal cancer (CRC) in controlled randomized clinical trials | Low sensitivity. Poor compliance. Generates large volume of confirmatory tests |
| Flexible sigmoidoscopy | Accurate for detection of cancers and polyps in the rectosigmoid area—commonest site for CRC. Reduces CRC deaths in case–control studies | Misses lesions above 50 cm. Randomized trials not currently available |
| Barium enema | Usually possible to visualize entire colon | Diagnostic procedure. Any detected polyps would require colonoscopy—an additional invasive procedure |
| Colonoscopy | Currently regarded as the 'gold standard' for diagnosis of polyps and CRC. Most accurate currently available procedure | Cost. Inconvenience. Occasional colonic perforation |
| Virtual colonoscopy | Less invasive than colonoscopy | Has never been tested in controlled clinical trials. Any lesions detected would require 'real' colonoscopy |
| DNA stool examination | New modality; non-invasive, good sensitivity and specificity | Results only available from small research studies |
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Conclusions
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 polyps—the 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
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Article Info
Publication History
Accepted: October 10, 2001
Received: August 9, 2001
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DOI: https://doi.org/10.1093/annonc/mdf074
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© 2002 European Society for Medical Oncology. Published by Elsevier Inc.
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