Is colorectal cancer screening by fecal occult blood feasible?
2002; Elsevier BV; Volume: 13; Issue: 1 Linguagem: Inglês
10.1093/annonc/mdf070
ISSN1569-8041
Autores Tópico(s)Genetic factors in colorectal cancer
ResumoIntroductionColorectal 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.Ferlay J, Bray F, Sankila R, Parkin DM. EUCAN: Cancer Incidence, Mortality and Prevalence in the European Union 1996. version 3.1. IARC CancerBase No. 4. Lyon: IARC Press [on-line] 1999; http://www.dep.iarc.fr/eucan/eucan.htm (29 September 2000, date last updated).Google Scholar]. 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.US Department of Health and Human Services SEER surveillance, epidemiology, and end results. US Department of Health and Human Services.National Cancer Institute. April 2000; Google Scholar]. 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.Lieberman D.A. Weiss D.G. Bond J.H. et al.Use of colonoscopy to screen asymptomatic adults for colorectal cancer. Veterans Affairs Cooperative Study Group 380.N Engl J Med. 2000; 343: 162-168Crossref PubMed Scopus (1601) Google Scholar], 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.Winawer S.J. Fletcher R.H. Miller L. et al.Colorectal cancer screening: clinical guidelines and rationale.Gastroenterology. 1997; 112: 594-642Abstract Full Text Full Text PDF PubMed Scopus (1822) Google Scholar], while in Europe mortality has been stable since 1985 (The EUROPREVAL Project).Table 1Colorectal cancer in the European Union (1996), USA and Canada (2000)Males 110 025, females 103 086Males 55 134, females 55 535PopulationCasesASR (E)ASR (W)DeathsASR (E)ASR (W)European Union213 11144.4629.67110 66921.8813.93Austria505647.8032.39266723.4315.23Belgium597345.4130.05310622.5014.16Denmark320048.0231.97206129.0118.48Finland203132.5221.8396414.979.62France32 75746.0531.0616 05020.7913.05Germany57 75353.5435.4630 46027.0617.11Greece305322.0814.55158510.956.87Ireland169149.1933.2689625.0116.11Italy31 79640.9427.5815 75019.1812.31Luxembourg23348.2131.4110821.4313.58The Netherlands876550.2033.59417622.8814.65Portugal530044.7830.21261621.2213.67Spain18 09636.7624.6410 12519.5112.51Sweden500339.2625.92248118.3911.76United Kingdom32 40442.2027.8717 62422.0114.11USA147 971–35.5159 596–13.89Canada16 635–35.226857–13.99–, not available. Open table in a new tab 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 [5.Winawer S.J. Zauber A.G. Ho M.N. et al.Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup.N Engl J Med. 1993; 329: 1977-1981Crossref PubMed Scopus (3862) Google Scholar, 6.Citarda F. Tomaselli G. Capocaccia R. et al.Efficacy in standard clinical practice of colonoscopic polypectomy in reducing colorectal cancer incidence.Gut. 2001; 48: 812-815Crossref PubMed Scopus (611) Google Scholar, 7.Mandel J.S. Church T.R. Bond J.H. et al.The effect of fecal occult-blood screening on the incidence of colorectal cancer.N Engl J Med. 2000; 343: 1603-1607Crossref PubMed Scopus (1230) Google Scholar].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 testingIn 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.Greegor D.H. Diagnosis of large-bowel cancer in the asymptomatic patient.JAMA. 1967; 201: 943-945Crossref PubMed Scopus (158) Google Scholar], 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.Rozen P. Knaani J. Samuel Z. Performance characteristics and comparison of two immunochemical and two guaiac fecal occult blood screening tests for colorectal neoplasia.Dig Dis Sci. 1997; 42: 2064-2071Crossref PubMed Scopus (47) Google Scholar, 10.Macrae F.A. St John D.J. Caligiore P. et al.Optimal dietary conditions for Hemoccult testing.Gastroenterology. 1982; 82: 899-903Abstract Full Text PDF PubMed Scopus (116) Google Scholar]. 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.Mandel J.S. Bond J.H. Church T.R. et al.Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study.N Engl J Med. 1993; 328: 1365-1371Crossref PubMed Scopus (2897) Google Scholar, 12.Hardcastle J.D. Chamberlain J.O. Robinson M.H.E. et al.Randomised controlled trial of faecal-occult-blood screening for colorectal cancer.Lancet. 1996; 348: 1472-1477Abstract Full Text Full Text PDF PubMed Scopus (2415) Google Scholar]. 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.Rozen P. Knaani J. Samuel Z. Performance characteristics and comparison of two immunochemical and two guaiac fecal occult blood screening tests for colorectal neoplasia.Dig Dis Sci. 1997; 42: 2064-2071Crossref PubMed Scopus (47) Google Scholar].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.Saito H. Tsuchida S. Kakizaki R. et al.An immunochemical fecal occult blood test for mass screening of colorectal cancer by reversed passive hemagglutination (RPHA).Jap J Gastroenterol. 1984; 81: 2831Google Scholar]. 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.Nakama H. Kamijo N. Fujimori K. et al.Relationship between fecal sampling times and sensitivity and specificity of immunochemical fecal occult blood tests for colorectal cancer: a comparative study.Dis Colon Rectum. 1997; 40: 781-784Crossref PubMed Scopus (22) Google Scholar, 15.Nakama H. Yamamoto M. Kamijo N. et al.Colonoscopic evaluation of immunochemical fecal occult blood test for detection of colorectal neoplasia.Hepatogastroenterology. 1999; 46: 228-231PubMed Google Scholar]. 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.Allison J.E. Tekawa I.S. Ransom L.J. Adrain A.L. A comparison of fecal occult-blood tests for colorectal cancer screening.N Engl J Med. 1996; 334: 155-159Crossref PubMed Scopus (523) Google Scholar] 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.Mandel J.S. Bond J.H. Church T.R. et al.Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study.N Engl J Med. 1993; 328: 1365-1371Crossref PubMed Scopus (2897) Google Scholar, 12.Hardcastle J.D. Chamberlain J.O. Robinson M.H.E. et al.Randomised controlled trial of faecal-occult-blood screening for colorectal cancer.Lancet. 1996; 348: 1472-1477Abstract Full Text Full Text PDF PubMed Scopus (2415) Google Scholar, 17.Kronborg O. Fenger C. Olsen J. et al.Randomised study of screening for colorectal cancer with faecal-occult-blood test.Lancet. 1996; 348: 1467-1471Abstract Full Text Full Text PDF PubMed Scopus (2175) Google Scholar, 18.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.Scand J Gastroenterol. 1994; 29: 468-473Crossref PubMed Scopus (259) Google Scholar] and non-randomized population studies [19.Winawer S.J. Flehinger B.J. Schottenfeld D. Miller D.G. Screening for colorectal cancer with fecal occult blood testing and sigmoidoscopy.J Natl Cancer Inst. 1993; 85: 1311-1318Crossref PubMed Scopus (359) Google Scholar, 20.Faivre J. Arveux P. Milan C. et al.Participation in mass screening for colorectal cancer results of screening and rescreening from the Burgundy study.Eur J Cancer Prev. 1991; 1: 49-55Crossref PubMed Scopus (74) Google Scholar] 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.Mandel J.S. Bond J.H. Church T.R. et al.Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study.N Engl J Med. 1993; 328: 1365-1371Crossref PubMed Scopus (2897) Google Scholar], 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)].Table 2Comparison of rehydrated and non-rehydrated test in the Minnesota studyRehydrated (%)Unhydrated (%)Positivity9.82.4Sensitivity92.280.8Specificity90.497.7Positive predictive value2.25.6 Open table in a new tab DiscussionThe 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.Table 3Results of randomized controlled trialsMandel et al. [11.Mandel J.S. Bond J.H. Church T.R. et al.Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study.N Engl J Med. 1993; 328: 1365-1371Crossref PubMed Scopus (2897) Google Scholar]Hardcastle et al. [12.Hardcastle J.D. Chamberlain J.O. Robinson M.H.E. et al.Randomised controlled trial of faecal-occult-blood screening for colorectal cancer.Lancet. 1996; 348: 1472-1477Abstract Full Text Full Text PDF PubMed Scopus (2415) Google Scholar]Kronborg et al. [17.Kronborg O. Fenger C. Olsen J. et al.Randomised study of screening for colorectal cancer with faecal-occult-blood test.Lancet. 1996; 348: 1467-1471Abstract Full Text Full Text PDF PubMed Scopus (2175) Google Scholar]Kewenter et al. [18.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.Scand J Gastroenterol. 1994; 29: 468-473Crossref PubMed Scopus (259) Google Scholar]Type of test82.5% rehydratedNon-rehydratedNon-rehydratedMostly rehydratedFrequency of testAnnual and biennialBiennialBiennial18 monthsDietary restrictionYes, 24 hNo, only for retestYes, 3 daysYes, 2 daysSensitivity81% non-rehydrated64% non-rehydrated46% non-rehydratedOverall 81%92% rehydratedPositive predict value5.6% non-rehydrated1st screen 9.9%1st screen 17.7%1st screen (mostly non-rehydrated) 5%2.2% rehydrated2nd screen 11.9%2nd screen 8.4%2nd screen (all rehydrated) 4.2%3rd screen 16.3%4th screen 10.8%5th screen 10.2%Reduction in mortalityAnnual 33%15%18%––, not available. Open table in a new tab We can extract some points for consideration from a meta-analysis of the randomized controlled trials by Towler [4.Winawer S.J. Fletcher R.H. Miller L. et al.Colorectal cancer screening: clinical guidelines and rationale.Gastroenterology. 1997; 112: 594-642Abstract Full Text Full Text PDF PubMed Scopus (1822) Google Scholar] and several papers by the Memorial Sloan Kettering Cancer Center group led by S. J. Winawer [21.Towler B. Irwig L. Glasziou P. et al.A systematic review of the effects of screening for colorectal cancer using the fecal occult blood test, hemoccult.BMJ. 1998; 317: 559-565Crossref PubMed Scopus (427) Google Scholar]. 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.Winawer S.J. Fletcher R.H. Miller L. et al.Colorectal cancer screening: clinical guidelines and rationale.Gastroenterology. 1997; 112: 594-642Abstract Full Text Full Text PDF PubMed Scopus (1822) Google Scholar]. 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.Lynge E. Recommendations on cancer screening in the European Union. Advisory Comittee on Cancer Prevention.Eur J Cancer. 2000; 36: 1473-1478Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar]. IntroductionColorectal 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.Ferlay J, Bray F, Sankila R, Parkin DM. EUCAN: Cancer Incidence, Mortality and Prevalence in the European Union 1996. version 3.1. IARC CancerBase No. 4. Lyon: IARC Press [on-line] 1999; http://www.dep.iarc.fr/eucan/eucan.htm (29 September 2000, date last updated).Google Scholar]. 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.US Department of Health and Human Services SEER surveillance, epidemiology, and end results. US Department of Health and Human Services.National Cancer Institute. April 2000; Google Scholar]. 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.Lieberman D.A. Weiss D.G. Bond J.H. et al.Use of colonoscopy to screen asymptomatic adults for colorectal cancer. Veterans Affairs Cooperative Study Group 380.N Engl J Med. 2000; 343: 162-168Crossref PubMed Scopus (1601) Google Scholar], 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.Winawer S.J. Fletcher R.H. Miller L. et al.Colorectal cancer screening: clinical guidelines and rationale.Gastroenterology. 1997; 112: 594-642Abstract Full Text Full Text PDF PubMed Scopus (1822) Google Scholar], while in Europe mortality has been stable since 1985 (The EUROPREVAL Project).Table 1Colorectal cancer in the European Union (1996), USA and Canada (2000)Males 110 025, females 103 086Males 55 134, females 55 535PopulationCasesASR (E)ASR (W)DeathsASR (E)ASR (W)European Union213 11144.4629.67110 66921.8813.93Austria505647.8032.39266723.4315.23Belgium597345.4130.05310622.5014.16Denmark320048.0231.97206129.0118.48Finland203132.5221.8396414.979.62France32 75746.0531.0616 05020.7913.05Germany57 75353.5435.4630 46027.0617.11Greece305322.0814.55158510.956.87Ireland169149.1933.2689625.0116.11Italy31 79640.9427.5815 75019.1812.31Luxembourg23348.2131.4110821.4313.58The Netherlands876550.2033.59417622.8814.65Portugal530044.7830.21261621.2213.67Spain18 09636.7624.6410 12519.5112.51Sweden500339.2625.92248118.3911.76United Kingdom32 40442.2027.8717 62422.0114.11USA147 971–35.5159 596–13.89Canada16 635–35.226857–13.99–, not available. Open table in a new tab 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 [5.Winawer S.J. Zauber A.G. Ho M.N. et al.Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup.N Engl J Med. 1993; 329: 1977-1981Crossref PubMed Scopus (3862) Google Scholar, 6.Citarda F. Tomaselli G. Capocaccia R. et al.Efficacy in standard clinical practice of colonoscopic polypectomy in reducing colorectal cancer incidence.Gut. 2001; 48: 812-815Crossref PubMed Scopus (611) Google Scholar, 7.Mandel J.S. Church T.R. Bond J.H. et al.The effect of fecal occult-blood screening on the incidence of colorectal cancer.N Engl J Med. 2000; 343: 1603-1607Crossref PubMed Scopus (1230) Google Scholar].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.
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