Screening Guidelines for Colorectal Cancer 0 . KRONBORG Dept. of Surgical Gastroenterology, Odense University Hospital, Odense. Denmark
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Kronborg 0. Screening guidelines for colorectal cancer. Scand J Gastroenterol 1992;27 Suppl 192:123129. A review is given of methods and rcsults of screening for colorectal cancer in average-risk and high-risk groups. Possible methods are digital rectal exploration, endoscopic examination, barium enemas, faecal occult blood tests, tumour markers like carcinoembryonic antigen, Ca-19-9, and others, and gene markers. Final results of large randomized population studies with faecal occult blood tests are expected within the next few years, but it will probably be necessary to add flexible sigmoidoscopy to achieve a major reduction in mortality from colorectal cancer in average-risk persons. Recommendations for screening in high-risk groups are proposed, but strong support for these guidelines are still missing, an exception being first-degree relatives of individuals with familial adenomatous polyposis; the other highrisk groups include members of hereditary non-polyposis colorectal cancer families, relatives of patients with sporadic colorectal cancer, patients with colorectal adenomas. patients with previous colorectal cancer. and patients with inflammatory bowel disease.
Key words: Colonoscopy; colorectal cancer; hereditary disease; inflammatory bowel disease; polyps; screening Ole Kronborg, M. D . Dept. of Surgical Gastroenterology, Odense University Hospital, DK-5000 Odense. Denmark ~
Colorectal cancer is one of the most frequent cancers in the EEC, with 130,000 new cases diagnosed and 90,000 deaths occurring every year. Neither mortality from colorectal cancer nor the incidence of the disease has shown any major reduction during the past decade in Europe. The incidence of colonic cancer has been steadily increasing, whereas that of rectal cancer has tended to decrease. Five years after the diagnosis of colorectal cancer no more than one-third of patients are still alive. The treatment is mainly surgical, but some benefit has been suggested from adjuvant chemotherapy in recent trials, whereas adjuvant radiotherapy does not influence mortality. Primary prevention of colorectal cancer is seldom possible. Screening results in the detection and treatment of early cancers and possible precursors, and it is hoped that a reduction in mortality will be achieved. Different methods of screening have been suggested as well as different target populations, including average-risk and high-risk groups. This review describes methods and results and presents suggested guidelines for screening and recommendations for further research. METHODS Digital rectal exploration detects no more than 10% of colorectal cancers and is an unpleasant experience, both of which makes it unsuitable as a screening method. Rigid sigmoidoscopy (25 cm) may detect 25% of the cancers but is also unpleasant and carries a small risk of intestinal perforation. There is some evidence from uncontrolled studies
that deaths from rectal cancer may be reduced by sigmoidoscopic surveillance (1.2). Furthermore, rigid sigmoidoscopy has been included in a multiphasic health screening controlled trial, demonstrating a reduction in mortality from colorectal cancer. However, this finding may have been due to pure chance (3). Flexible sigmoidoscopy (60 cm) is more attractive, since more than half of the cancers are located within the reach of this instrument, which is less uncomfortable than rigid sigmoidoscopy. However, the costs are substantial, and the compliance in a study of 2416 individuals was no more than 45% (4). No controlled studies have been published. Full colonoscopy has the highest sensitivity and specificity for neoplasia but is unpleasant to the individual, is not easy to perform, carries a risk of perforation, and is expensive; it should therefore not be considered as a tool for screening average-risk groups. Double-contrast barium enema (DCBE) has a lower sensitivity and specificity than colonoscopy and is unsuitable for the same reasons as colonoscopy. Tumour markers, such as carcinoembryonic antigen (CEA) and Ca 19-9, have a low sensitivity and specificity; other antigens and enzymes have been studied, but so far no markers have been found suitable for mass screening (5,6). Recently, gene markers have been introduced for high-risk groups with a genetic disposition to colorectal cancer. Faecal occult blood tests (FOBT) are widely used for screening, but even the most commonly used guaiac test, Hemoccult-I1 (H-II), detects n o more than 50-70% of the
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cancers, depending on how often it is performed. However, Table I. Randomized trials with Hemoccult-I1 in Europe the specificity is satisfactory for screening, and the test is Year of Age groups Test group, Control group, n (years) n easy to perform, without inconvenience to the individual, initiation and inexpensive. The sensitivity may be increased by rehy1982 13.744 60-64 13,759 Goteborg drating the slides before adding the developer but not with- Nottingham 1983 78,000 50-74 78,000 30,968 1985 45-74 30,970 out loss in specificity. This drawback may to some extent be Funen 47,000 1988 45-74 47,000 compensated for by repeating the test with dietary restric- Burgundy tions in those with a positive test. Unfortunately, bleeding from colorectal cancer varies, may be intermittent, is related to the site of the tumour, and blood is not equally distributed in faeces. The H-I1 test is not specific for human haemo- Table 11. Predictive values of Hemoccult-I1 globin, but dietary restrictions may increase both sensitivity PV-pos for cancer, PV-pos for adenoma, 70 '%I and specificity, and duplicate stool sampling is recommended over 3 consecutive days. The slides contain test areas, 1st 2nd 3rd 2nd 3rd 1st specially treated to yield negative and positive result (blue scr. scr. scr. scr. scr. scr. colour) for quality control. Other guaiac tests are available 5 4 17 18 (7), but H-I1 is the only one that has been extensively Goteborg Nottingham 10 8 12 43 22 50 evaluated. Subjects with positive tests are referred for full Funen 17 8 16 40 48 36 7 colonoscopy or, less optimally, flexible sigmoidoscopy and Burgundy 24 DCBE. More complex tests for a faecal occult blood include immunochemical tests, which are specific for human haemoglobin and are more sensitive for the detection of cancer other societies or unions. Furthermore, randomization was (8,9). However, they are more expensive and not so suitable performed after informed consent, making the study of for an office procedure. The same is true for immuno- no value for estimating any reduction in mortality from chemical tests detecting human albumin in faeces. The Hae- colorectal cancer in the general population. No mortality moquant test is a quantitative test based on fluorescence of figures have been published, even though 16 years have haeme-derived porphyrin (10). Comparison of H-11, Haem- passed since the beginning of the study (15). occult-SENSA, which is a more sensitive guaiac test, HemeIn Europe four randomized population studies with HSELECT (immunochemical test), and Haemoquant has con- I1 were initiated during the eighties (Table I). The most firmed that sensitivity for bleeding is higher for the immu- important interim results have been published in a recent nochemical tests, whereas the specificity for cancer detection review (16). may still be highest for the guaiac tests (11). The FECAThe Goteborg Study includes persons aged between 60 enzyme immunoassay (EIA) test, which is a combined and 64 years, and the test group has been subdivided in two chemical test with enhanced sensitivity for haemoglobin and equally large subgroups with rehydrated H-I1 and unhyan immunologic test, may also have too low a specificity drated H-I1 (17). Compliance was 66% during the first for screening of average risk subjects (12). Increasing the screening, and the overall positivity rate of H-I1 was 3.8%. sensitivity of FOBTs by extending the number of days of During rescreening 16-22 months later all tests were rehytesting may reduce the compliance in mass screening. drated, and 6.4% became positive, but with a low predictive value for colorectal cancer and possible precursor adenomas (Table 11). Cancers detected per 1000 screened were 1.9 AVERAGE RISK during the initial and 2.4 at the second screening. H-I1 Risk of colorectal cancer increases with age, beginning at was repeated in those with positive tests and no apparent age 40 years and increasing more sharply at 50 years (13). bleeding source detected by flexible sigmoidoscopy and Those at risk by virtue of age only are considered at average DCBE. Colonoscopy was performed when positivity perrisk for the disease. In Western Germany eight million sisted (no more than 50 of 205 persons). More cancers and people were screened with Hemoccult-I1 from 1977 to 1979, adenomas were detected when using rehydration. The Dukes but no more than a case control study has been set up to stage distribution of cancers was more favourable than evaluate possible benefits from this strategy (14). among controls, but the size of the study is too small to In 1975 a randomized trial began in Minnesota to evaluate evaluate a possible reduction in mortality from colorectal the effect of screening with H-I1 in a population of 48,000 cancer and has therefore been doubled. The Nottingham Study initially had a low compliance, individuals. It would thereby be possible to avoid lead time and length time bias, but unfortunately the population was increasing to above 50% after an explanatory letter from the selected from among participants of the American Cancer general practitioner. H-I1 without rehydration is offered Society program for prevention examinations and also from every 2 years. Since 1985 subjects with a positive test have
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Table 111. Cancers and adenomas in the Nottingham and Funen studies (no. of patients) Nottingham
Cancer Dukes A
Dukes C + D
Total no.
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Adenoma
Funen
Test group offered screening (71,277)
Control group
Test group offered screening (30,970)
Control group
(71,413)
98 (29%) 139 (42%) 334 483
33 (13%) 134 (51%) 26 I 130
52 (27%) 72 (38%) 190 232
15 (9%) 85 (51%) 166 109
been asked to repeat the test over a 6-day period, while excluding from their diets red meats and vegetables rich in peroxidase. Colonoscopy is used for evaluating positive tests. More early cancers have been found in the test group, and the number of cancers and adenomas is higher than in controls (Table 111). Interval cancers (in persons with falsenegative H-11) have been more frequent in the lower part of the rectum and the right side of the colon, which might be explained by insufficiently haemolysed blood in the former and a total breakdown of haematin during the passage of blood in the latter cases. The large yield of adenomas suggests the possibility of obtaining a reduction in the incidence of colorectal cancer. However, some carcinomas may develop without preceding adenomas. The authors are 80% confident of detecting a reduction in mortality from colorectal cancer of at least 23% (18). The Funen Study began in 1985 (16). Three biannual screenings have been performed with the fourth beginning in August 1991. The compliance is high, 67% having performed the initial screening. The second was done by 91% of those completing the first test, and the third by 95% of the latter. Dietary restrictions have been used from the beginning, and all those with known colorectal cancer and adenomas were excluded before randomization. A positive H-I1 is followed by colonoscopy. The number of advanced cancers tends to be lower in the test group (those performing the H-I1 plus non-responders) than among controls (Table 111). Hopefully, this difference will be more pronounced over the next few years, making a reduction in mortality from colorectal cancer possible. The Nottingham and Funen studies are similar in design, and a meta-analysis may be performed. The Danish study has an unbiased death review committee, which defines the cause of death whenever doubt exists as to whether colorectal cancer may be the cause. The interim resuls from the Danish study suggest that mortality from colorectal cancer may be reduced by 20%, but the final verdict may not be reached before 1996, and the statistical power is no more than 0.70 (19). The Burgundy Study is based on randomization of different towns and administrative distsicts, in contrast to the other studies, which are based on the random sampling of individuals (20). The compliance during the first screening was
(30,968)
52%, and the further examination of subjects with a positive H-I1 was completed in no more than 80%. The predictive value of a positive test was rather low (Table 11). No dietary restrictions were used. The first rescreening began in 1990. Mortality figures are necessary before any cost benefit and effectiveness can be calculated. Preliminary results suggest that overall hospital costs will be the same when comparing test groups and controls (21,22), but there will be an initial increase of costs. The total costs of a screening program are related to the age of participants compliance, positivity rate, intervals of screening, and methods of further examination in subjects with a positive test. However, other costs should be considered, including diagnostic and therapeutic complications, and a false security to persons with interval cancers. Also, there is a risk of overtreatment by detecting small cancers in elderly people, who would have died from other causes before the colorectal cancer became symptomatic. Interval cancers do not seem to have a worse stage distribution than controls, according to the Funen study, suggesting that false security will not compromise the survival of interval cases compared with that of controls. Screening for colorectal cancer does not seem to influence the risk of suicide (19). However, all possible drawbacks make it necessary to demonstrate in randomized trials that screening of subjects who are at average risk of colorectal cancer results in a reduction of mortality from colorectal cancer. Before this has been achieved, population screening cannot be recommended (13,16,23). Individual subjects asking to be screened may be offered Hemoccult-11, the chance of finding early cancer and large adenoma being higher than among those not being screened. A colonoscopy every 3-5 years, after the age of 50, will probably achieve a major reduction of the risk of dying from colorectal cancer, but it is expensive and not completely without risk of complications. Final results are needed from the randomized population trials, before an approach to population screening can be recommended to governments.
HIGH RISK First-degree relatives of individuals with familial adenomatous polyposis, including Gardner’s syndrome (FAP),
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should be screened with rigid or preferably flexible sigmoidoscopy from the age of 10 years, with intervals of 1-2 years until at least 40 years and even 10-20 years longer in those families with a history of high age for adenoma formation. It is unnecessary to perform colonoscopy or DCBE. Duodenal carcinoma occurs more frequently than in the general population, but it is not known whether firstdegree relatives will benefit from screening with upper GI endoscopy. Other extracolonic manifestations such as epidermal cysts may be the first clinical sign of FAP. The disease is an autosomal dominant and results in colorectal cancer in all affected individuals, if left untreated. In the near future screening of first-degree relatives can be limited to FAP gene-positive individuals and non-DNAinformative families (24). FAP is treated by colectomy with ileorectal anastomosis or colectomy with rectal mucosectomy and ileoanal anastomisis. The former makes it necessary to screen the rectal remnant for the rest of the patient’s life, with removal of any new polyps. The risk of rectal cancer is 5 1 0 % . The Leeds Castle Polyposis Group (25) has introduced a set of rules for polyposis registries, making international clinical research easier. The prophylaxis should be organized by national or regional registries. In a Danish study the survival of FAP patients after 10 years was 93% in call-up patients, compared with only 40% in probands (26). The hereditary non-polyposis colorectal cancer (HNPCC) family has histologically verified colorectal adenocarcinoma in at least three members within two generations, and one member must be a first-degree relative of the two others. The diagnosis of colorectal cancer should have been made before the age of 50 years in at least one member. These criteria were agreed on by The International Collaborative Group on HNPCC in 1990. The syndrome has an autosomal dominant mode of inheritance and includes the original Lynch syndromes (27,28). Five per cent of colorectal cancers are believed to belong to HNPCC families, which is 10-20 times that of FAP. Other characteristics include multiple colorectal cancers, with predominantly right-sided location and carcinomas in other organs, especially the endometrium and breast. Unfortunately, it is not possible at present to screen for HNPCC with gene markers. It has been recommended that full colonoscopy be performed every 2 years and FOBTs every year from age 25, or beginning 5 years before the age of the earliest colorectal cancer in the family (29). However, it must be emphasized that at least 50% of the family members will not develop colorectal cancer. The increased risk of cancer of the endometrium and breast suggests screening by endometrial sampling and mammography. Treatment of HNPCC should probably be colectomy with ileorectal anastomosis with lifelong surveillance of the rectal stump. Furthermore, additional hysterectomy has been suggested in postmenopausal women. Relatives of patients with sporadic colorectal cancer have a threefold increase in the risk of developing colorectal
cancer (30). The risk is highest for index cases who are diagnosed at a young age. Approximately one-fourth of patients with apparent sporadic colorectal cancer have a history of colorectal cancer in a first-degree relative. Individuals with two first-degree relatives with colorectal cancer may have a lifetime risk of one in six (31), which is two to three times higher than in those with only one first-degree relative affected. Accordingly, a less intensive screening program has been suggested in the latter; that is, annual FOBTs and flexible sigmoidoscopy every 3-5 years beginning at age 40 years, whereas individuals with two first-degree relatives should have colonoscopy instead of sigmoidoscopy (29). However, detection of any adenomas by sigmoidoscopy should always be followed by complete colonoscopy because of the high rate of synchronous lesions. No randomized clinical trials have been published supporting the recommendations made. Mathematical models suggest that the mortality from colorectal cancer may be reduced by no more than 25% using Hemoccult-I1 alone, whereasendoscopymayachieve reductionsof up to85% (32). The HNPCC syndrome should be suspected when three or more first-degree relatives have colorectal cancer and when one has colorectal cancer at an age younger than 30 years. Patients with colorectal adenomas probably have an increased risk of developing colorectal cancer, but the magnitude of the relative risk is uncertain, compared with that in the general population. Most adenomas are small and symptomless, and it is estimated that no more than 5-10% will proceed to cancer. Adenomas are present in one-third of individuals above the age of 55 years (33). Radiologic studies of patients with colorectal polyps of at least 1 cm in diameter, which for some reason were not removed, suggest that the lifetime risk of developing colorectal cancer is 2 5 4 0 % (34). The figures are open to heavy criticism, since it is not known how many of the polyps contained colorectal cancer when first detected by roentgenography. Nevertheless, following the introduction of flexible endoscopy, it has become widespread practice to obtain a clean colon in patients with adenomas, and to follow up these patients with colonoscopy or flexible sigmoidoscopy and DCBE at intervals of 1-4 years (35,36). The effect of varying the intervals between follow-up examinations has been investigated in large randomized studies (35,37), and it may be possible to reduce mortality from colorectal cancer in adenoma patients compared with a matched normal population. However, this advantage is to some extent compromised by complications from follow-up examinations with or without polypectomy (38). Also, it is not known to what extent the incidence of colorectal cancer may be reduced by endoscopic surveillance with removal of all polyps. Recommendations for adenoma surveillance include early follow-up with colonoscopy (3 months) after piecemeal polypectomy and removal of multiple adenomas whenever the endoscopist is not confident that the colon has been
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cleaned of all polyps. The optimal long-term intervals between examinations have not been determined but should probably be within 2-4 years, patients with previous villous adenomas and multiple adenomas having the shortest intervals. Patients with previous colorectal cancer have an increased risk of getting a new metachronous colorectal cancer, but the relative risk is difficult to estimate. Colonoscopy was not available before 1970, and publications before 1970 present figures of 2-5%, which may be too high because of many overlooked synchronous tumours. However. more recent publications, in which perioperative colonoscopy has been used, suggest similar figures for metachronous cancer (39) but higher figures for synchronous cancer. The number of metachronous cancers is related to the frequency of postoperative colonoscopic surveillance and removal of adenomas perioperatively and during follow-up. Estimation of the risk of metachronous cancer may also have been incorrect before 1970 because of less effective tools for surveillance (40). Two large randomized trials are underway to estimate the possible benefits from surveillance after radical surgery for colorectal cancer using tumour markers and endoscopy (41,42). The Danish two-arm study compares, among other factors, an intensive colonoscopic program with no more than colonoscopy every 5 years, all patients being subjected to initial perioperative colonoscopy (42). The preliminary results suggest that more metachronous early cancers may be detected by frequent colonoscopy, but it is still not known whether a reduction in mortality from colorectal cancer can be achieved. Recurrence of the first cancer is detected more often during intensive clinical follow-up (43), but the prognosis is poor, and it has not been proved that mortality will be reduced. Accordingly, no intensive surveillance program can be recommended at present, and colonoscopy should probably not be done more frequently than every 5 years. Most local recurrences develop within 2 years, and the English multicentre trial (41) will evaluate the questionable use of frequent CEA measurements to detect recurrence at a favourable stage. Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer beginning after the first 10 years. The risk is higher in patients with pancolitis than in those with left-sided disease and is higher in ulcerative colitis than in Crohn’s disease (44). The exact risk is difficult to estimate because of surgical intervention in patients with severe symptoms but is probably at least five times higher than in the normal population (45). However, colorectal cancer in ulcerative colitis amounts to no more than a small fraction of the total incidence of colorectal cancer. Dysplasia of the intestinal mucosa may be a better marker in ulcerative colitis than in Crohn’s disease (46), but it has not been demonstrated that patients with severe dysplasia at endoscopic biopsy will benefit more from colectomy than those
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having surgery, because of symptomatic colorectal cancer (47). It has been suggested that patients with long-standing ulcerative colitis and possibly also Crohn’s disease may benefit from colonoscopic surveillance with multiple biopsies every 1-2 years (45,48). The diagnosis of severe dysplasia is to some extent compromised by both inter- and intraobserver variation, and the frequency of coexistent carcinoma may vary from 5% to 40% (47), being highest in combination with dysplasia in a mass lesion. Most authors then suggest colectomy. Dysplasia without a mass lesion requires shorter intervals between colonoscopic surveillance (3-6 months); furthermore, intervals should possibly be shorter with the increasing disease duration, but recommendations are not based on solid evidence from randomized trials. Such trials would have to be undertaken as multicentre studies, and it is questionable whether they ever will take place. It must be realized that detection of colorectal cancer in patients with IBD will cost at least the same as detection of colorectal cancer in average-risk individuals, but the stage distribution of the cancer may not be favourable (49). THE FUTURE Screening of average-risk individuals with Hemoccult-I1 may result in a reduction of mortality from colorectal cancer, but FOBTs have several drawbacks making it attractive to evaluate the addition of flexible sigmoidoscopy , as long as the search for more specific tumour markers has not been successful. The yield of adenomas by screening with Hemoccult-I1 and subsequently sigmoidoscopy makes it possible to perform intervention studies to evaluate the influence of dietary factors on the risk of new adenomas and/or growth of adenomas left behind. Such studies are underway, and provided that the adenoma-carcinoma sequence is true for most cancers, this is a step towards primary prevention of colorectal cancer. Assuming that a reduction in mortality is obtained, several other problems remain unsolved: the organisation of population screening, physician education and training in endoscopic procedures, and evaluation of cost effectiveness and cost-benefit, all of which would be necessary before any mass screening could be introduced. It should be possible to reduce the burden of screening for FAP by organizing more registries in different countries and selecting gene-positive individuals. Clinicians should be aware of the importance of anamnestic information about family history, making it possible to diagnose HNPCC and plan colonoscopic screening of the family members. However, it is not known how often screening should be performed, and it is hoped that The International Collaborative Group will take steps towards a prospective trial to optimize the use of our limited resources. The lack of randomized trials in first-degree relatives of patients with
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sporadic colorectal cancer is apparent, but resources should also b e used within gene technology, since genetic susceptibility t o colorectal cancer may b e higher than originally thought. Progress in the study of inherited genetics may also identify individuals with adenomas and those who are likely t o progress to colorectal cancer (50). Until then. the guidelines from major surveillance trials must b e followed. The value of follow-up after curative surgery for colorectal cancer has not been established but gives an opportunity for intervention studies evaluating risk of metachronous neoplasia. The benefit of screening for neoplasia in patients with IBD still is a matter of controversy, and n o randomized trials have been published. More specific markers than the presence of dysplasia in biopsy specimens will be needed. REFERENCES 1. Hertz REL, Deddish MR, Day E. Value of periodic exam-
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plified plan for follow-up of patients with colon and rectal cancer supported by prospective studies of laboratory and radiologic results. Surgery 1987: 102:70-87. 44. Weedon DD. Shorter RG. Ilstrup DM. Huizcnga KA. Taylor WF. Crohn's disease and cancer. N Engl J Med 1973;289: IOYY103.
liams CB. Precancer and cancer in extensive ulcerative colitis: findings among 401 patients over 22 years. Gut 1990:31:80(t-h. 49. Gyde S. Screening for colorectal cancer in ulcerative colitis: dubious benefits and high costs. Gut IYYO;31:1089-92. 50. Winawer SJ, O'Brien MJ. Waye J D . et al. Risk and surveillance of individuals with colorectal polyps. W H O Bulletin OMS
cinoma of the large intestine and intestinal polyps. Proc R Soc Med 1967;60:208-11. 41. Northover JMA. Carcinoembryonic antigen and recurrent colorectal cancer. Gut 1986;27: 1 17-22. 42. Kronborg 0, Fenger C . Deichgraeber E. Hansen L. Follow-up after riidical surgery for colorectal cancer. Design of a randomizcd study. Scand J Gastroenterol 1988; 23 Suppl 149:159-
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Kronborg 0. Screening guidelines for colorectal cancer. Scand J Gastroenterol 1992;27 Suppl 192:123129. A review is given of methods and rcsults of screening for colorectal cancer in average-risk and high-risk groups. Possible methods are digital rectal exploration, endoscopic examination, barium enemas, faecal occult blood tests, tumour markers like carcinoembryonic antigen, Ca-19-9, and others, and gene markers. Final results of large randomized population studies with faecal occult blood tests are expected within the next few years, but it will probably be necessary to add flexible sigmoidoscopy to achieve a major reduction in mortality from colorectal cancer in average-risk persons. Recommendations for screening in high-risk groups are proposed, but strong support for these guidelines are still missing, an exception being first-degree relatives of individuals with familial adenomatous polyposis; the other highrisk groups include members of hereditary non-polyposis colorectal cancer families, relatives of patients with sporadic colorectal cancer, patients with colorectal adenomas. patients with previous colorectal cancer. and patients with inflammatory bowel disease.
Key words: Colonoscopy; colorectal cancer; hereditary disease; inflammatory bowel disease; polyps; screening Ole Kronborg, M. D . Dept. of Surgical Gastroenterology, Odense University Hospital, DK-5000 Odense. Denmark ~
Colorectal cancer is one of the most frequent cancers in the EEC, with 130,000 new cases diagnosed and 90,000 deaths occurring every year. Neither mortality from colorectal cancer nor the incidence of the disease has shown any major reduction during the past decade in Europe. The incidence of colonic cancer has been steadily increasing, whereas that of rectal cancer has tended to decrease. Five years after the diagnosis of colorectal cancer no more than one-third of patients are still alive. The treatment is mainly surgical, but some benefit has been suggested from adjuvant chemotherapy in recent trials, whereas adjuvant radiotherapy does not influence mortality. Primary prevention of colorectal cancer is seldom possible. Screening results in the detection and treatment of early cancers and possible precursors, and it is hoped that a reduction in mortality will be achieved. Different methods of screening have been suggested as well as different target populations, including average-risk and high-risk groups. This review describes methods and results and presents suggested guidelines for screening and recommendations for further research. METHODS Digital rectal exploration detects no more than 10% of colorectal cancers and is an unpleasant experience, both of which makes it unsuitable as a screening method. Rigid sigmoidoscopy (25 cm) may detect 25% of the cancers but is also unpleasant and carries a small risk of intestinal perforation. There is some evidence from uncontrolled studies
that deaths from rectal cancer may be reduced by sigmoidoscopic surveillance (1.2). Furthermore, rigid sigmoidoscopy has been included in a multiphasic health screening controlled trial, demonstrating a reduction in mortality from colorectal cancer. However, this finding may have been due to pure chance (3). Flexible sigmoidoscopy (60 cm) is more attractive, since more than half of the cancers are located within the reach of this instrument, which is less uncomfortable than rigid sigmoidoscopy. However, the costs are substantial, and the compliance in a study of 2416 individuals was no more than 45% (4). No controlled studies have been published. Full colonoscopy has the highest sensitivity and specificity for neoplasia but is unpleasant to the individual, is not easy to perform, carries a risk of perforation, and is expensive; it should therefore not be considered as a tool for screening average-risk groups. Double-contrast barium enema (DCBE) has a lower sensitivity and specificity than colonoscopy and is unsuitable for the same reasons as colonoscopy. Tumour markers, such as carcinoembryonic antigen (CEA) and Ca 19-9, have a low sensitivity and specificity; other antigens and enzymes have been studied, but so far no markers have been found suitable for mass screening (5,6). Recently, gene markers have been introduced for high-risk groups with a genetic disposition to colorectal cancer. Faecal occult blood tests (FOBT) are widely used for screening, but even the most commonly used guaiac test, Hemoccult-I1 (H-II), detects n o more than 50-70% of the
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cancers, depending on how often it is performed. However, Table I. Randomized trials with Hemoccult-I1 in Europe the specificity is satisfactory for screening, and the test is Year of Age groups Test group, Control group, n (years) n easy to perform, without inconvenience to the individual, initiation and inexpensive. The sensitivity may be increased by rehy1982 13.744 60-64 13,759 Goteborg drating the slides before adding the developer but not with- Nottingham 1983 78,000 50-74 78,000 30,968 1985 45-74 30,970 out loss in specificity. This drawback may to some extent be Funen 47,000 1988 45-74 47,000 compensated for by repeating the test with dietary restric- Burgundy tions in those with a positive test. Unfortunately, bleeding from colorectal cancer varies, may be intermittent, is related to the site of the tumour, and blood is not equally distributed in faeces. The H-I1 test is not specific for human haemo- Table 11. Predictive values of Hemoccult-I1 globin, but dietary restrictions may increase both sensitivity PV-pos for cancer, PV-pos for adenoma, 70 '%I and specificity, and duplicate stool sampling is recommended over 3 consecutive days. The slides contain test areas, 1st 2nd 3rd 2nd 3rd 1st specially treated to yield negative and positive result (blue scr. scr. scr. scr. scr. scr. colour) for quality control. Other guaiac tests are available 5 4 17 18 (7), but H-I1 is the only one that has been extensively Goteborg Nottingham 10 8 12 43 22 50 evaluated. Subjects with positive tests are referred for full Funen 17 8 16 40 48 36 7 colonoscopy or, less optimally, flexible sigmoidoscopy and Burgundy 24 DCBE. More complex tests for a faecal occult blood include immunochemical tests, which are specific for human haemoglobin and are more sensitive for the detection of cancer other societies or unions. Furthermore, randomization was (8,9). However, they are more expensive and not so suitable performed after informed consent, making the study of for an office procedure. The same is true for immuno- no value for estimating any reduction in mortality from chemical tests detecting human albumin in faeces. The Hae- colorectal cancer in the general population. No mortality moquant test is a quantitative test based on fluorescence of figures have been published, even though 16 years have haeme-derived porphyrin (10). Comparison of H-11, Haem- passed since the beginning of the study (15). occult-SENSA, which is a more sensitive guaiac test, HemeIn Europe four randomized population studies with HSELECT (immunochemical test), and Haemoquant has con- I1 were initiated during the eighties (Table I). The most firmed that sensitivity for bleeding is higher for the immu- important interim results have been published in a recent nochemical tests, whereas the specificity for cancer detection review (16). may still be highest for the guaiac tests (11). The FECAThe Goteborg Study includes persons aged between 60 enzyme immunoassay (EIA) test, which is a combined and 64 years, and the test group has been subdivided in two chemical test with enhanced sensitivity for haemoglobin and equally large subgroups with rehydrated H-I1 and unhyan immunologic test, may also have too low a specificity drated H-I1 (17). Compliance was 66% during the first for screening of average risk subjects (12). Increasing the screening, and the overall positivity rate of H-I1 was 3.8%. sensitivity of FOBTs by extending the number of days of During rescreening 16-22 months later all tests were rehytesting may reduce the compliance in mass screening. drated, and 6.4% became positive, but with a low predictive value for colorectal cancer and possible precursor adenomas (Table 11). Cancers detected per 1000 screened were 1.9 AVERAGE RISK during the initial and 2.4 at the second screening. H-I1 Risk of colorectal cancer increases with age, beginning at was repeated in those with positive tests and no apparent age 40 years and increasing more sharply at 50 years (13). bleeding source detected by flexible sigmoidoscopy and Those at risk by virtue of age only are considered at average DCBE. Colonoscopy was performed when positivity perrisk for the disease. In Western Germany eight million sisted (no more than 50 of 205 persons). More cancers and people were screened with Hemoccult-I1 from 1977 to 1979, adenomas were detected when using rehydration. The Dukes but no more than a case control study has been set up to stage distribution of cancers was more favourable than evaluate possible benefits from this strategy (14). among controls, but the size of the study is too small to In 1975 a randomized trial began in Minnesota to evaluate evaluate a possible reduction in mortality from colorectal the effect of screening with H-I1 in a population of 48,000 cancer and has therefore been doubled. The Nottingham Study initially had a low compliance, individuals. It would thereby be possible to avoid lead time and length time bias, but unfortunately the population was increasing to above 50% after an explanatory letter from the selected from among participants of the American Cancer general practitioner. H-I1 without rehydration is offered Society program for prevention examinations and also from every 2 years. Since 1985 subjects with a positive test have
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Table 111. Cancers and adenomas in the Nottingham and Funen studies (no. of patients) Nottingham
Cancer Dukes A
Dukes C + D
Total no.
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Adenoma
Funen
Test group offered screening (71,277)
Control group
Test group offered screening (30,970)
Control group
(71,413)
98 (29%) 139 (42%) 334 483
33 (13%) 134 (51%) 26 I 130
52 (27%) 72 (38%) 190 232
15 (9%) 85 (51%) 166 109
been asked to repeat the test over a 6-day period, while excluding from their diets red meats and vegetables rich in peroxidase. Colonoscopy is used for evaluating positive tests. More early cancers have been found in the test group, and the number of cancers and adenomas is higher than in controls (Table 111). Interval cancers (in persons with falsenegative H-11) have been more frequent in the lower part of the rectum and the right side of the colon, which might be explained by insufficiently haemolysed blood in the former and a total breakdown of haematin during the passage of blood in the latter cases. The large yield of adenomas suggests the possibility of obtaining a reduction in the incidence of colorectal cancer. However, some carcinomas may develop without preceding adenomas. The authors are 80% confident of detecting a reduction in mortality from colorectal cancer of at least 23% (18). The Funen Study began in 1985 (16). Three biannual screenings have been performed with the fourth beginning in August 1991. The compliance is high, 67% having performed the initial screening. The second was done by 91% of those completing the first test, and the third by 95% of the latter. Dietary restrictions have been used from the beginning, and all those with known colorectal cancer and adenomas were excluded before randomization. A positive H-I1 is followed by colonoscopy. The number of advanced cancers tends to be lower in the test group (those performing the H-I1 plus non-responders) than among controls (Table 111). Hopefully, this difference will be more pronounced over the next few years, making a reduction in mortality from colorectal cancer possible. The Nottingham and Funen studies are similar in design, and a meta-analysis may be performed. The Danish study has an unbiased death review committee, which defines the cause of death whenever doubt exists as to whether colorectal cancer may be the cause. The interim resuls from the Danish study suggest that mortality from colorectal cancer may be reduced by 20%, but the final verdict may not be reached before 1996, and the statistical power is no more than 0.70 (19). The Burgundy Study is based on randomization of different towns and administrative distsicts, in contrast to the other studies, which are based on the random sampling of individuals (20). The compliance during the first screening was
(30,968)
52%, and the further examination of subjects with a positive H-I1 was completed in no more than 80%. The predictive value of a positive test was rather low (Table 11). No dietary restrictions were used. The first rescreening began in 1990. Mortality figures are necessary before any cost benefit and effectiveness can be calculated. Preliminary results suggest that overall hospital costs will be the same when comparing test groups and controls (21,22), but there will be an initial increase of costs. The total costs of a screening program are related to the age of participants compliance, positivity rate, intervals of screening, and methods of further examination in subjects with a positive test. However, other costs should be considered, including diagnostic and therapeutic complications, and a false security to persons with interval cancers. Also, there is a risk of overtreatment by detecting small cancers in elderly people, who would have died from other causes before the colorectal cancer became symptomatic. Interval cancers do not seem to have a worse stage distribution than controls, according to the Funen study, suggesting that false security will not compromise the survival of interval cases compared with that of controls. Screening for colorectal cancer does not seem to influence the risk of suicide (19). However, all possible drawbacks make it necessary to demonstrate in randomized trials that screening of subjects who are at average risk of colorectal cancer results in a reduction of mortality from colorectal cancer. Before this has been achieved, population screening cannot be recommended (13,16,23). Individual subjects asking to be screened may be offered Hemoccult-11, the chance of finding early cancer and large adenoma being higher than among those not being screened. A colonoscopy every 3-5 years, after the age of 50, will probably achieve a major reduction of the risk of dying from colorectal cancer, but it is expensive and not completely without risk of complications. Final results are needed from the randomized population trials, before an approach to population screening can be recommended to governments.
HIGH RISK First-degree relatives of individuals with familial adenomatous polyposis, including Gardner’s syndrome (FAP),
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should be screened with rigid or preferably flexible sigmoidoscopy from the age of 10 years, with intervals of 1-2 years until at least 40 years and even 10-20 years longer in those families with a history of high age for adenoma formation. It is unnecessary to perform colonoscopy or DCBE. Duodenal carcinoma occurs more frequently than in the general population, but it is not known whether firstdegree relatives will benefit from screening with upper GI endoscopy. Other extracolonic manifestations such as epidermal cysts may be the first clinical sign of FAP. The disease is an autosomal dominant and results in colorectal cancer in all affected individuals, if left untreated. In the near future screening of first-degree relatives can be limited to FAP gene-positive individuals and non-DNAinformative families (24). FAP is treated by colectomy with ileorectal anastomosis or colectomy with rectal mucosectomy and ileoanal anastomisis. The former makes it necessary to screen the rectal remnant for the rest of the patient’s life, with removal of any new polyps. The risk of rectal cancer is 5 1 0 % . The Leeds Castle Polyposis Group (25) has introduced a set of rules for polyposis registries, making international clinical research easier. The prophylaxis should be organized by national or regional registries. In a Danish study the survival of FAP patients after 10 years was 93% in call-up patients, compared with only 40% in probands (26). The hereditary non-polyposis colorectal cancer (HNPCC) family has histologically verified colorectal adenocarcinoma in at least three members within two generations, and one member must be a first-degree relative of the two others. The diagnosis of colorectal cancer should have been made before the age of 50 years in at least one member. These criteria were agreed on by The International Collaborative Group on HNPCC in 1990. The syndrome has an autosomal dominant mode of inheritance and includes the original Lynch syndromes (27,28). Five per cent of colorectal cancers are believed to belong to HNPCC families, which is 10-20 times that of FAP. Other characteristics include multiple colorectal cancers, with predominantly right-sided location and carcinomas in other organs, especially the endometrium and breast. Unfortunately, it is not possible at present to screen for HNPCC with gene markers. It has been recommended that full colonoscopy be performed every 2 years and FOBTs every year from age 25, or beginning 5 years before the age of the earliest colorectal cancer in the family (29). However, it must be emphasized that at least 50% of the family members will not develop colorectal cancer. The increased risk of cancer of the endometrium and breast suggests screening by endometrial sampling and mammography. Treatment of HNPCC should probably be colectomy with ileorectal anastomosis with lifelong surveillance of the rectal stump. Furthermore, additional hysterectomy has been suggested in postmenopausal women. Relatives of patients with sporadic colorectal cancer have a threefold increase in the risk of developing colorectal
cancer (30). The risk is highest for index cases who are diagnosed at a young age. Approximately one-fourth of patients with apparent sporadic colorectal cancer have a history of colorectal cancer in a first-degree relative. Individuals with two first-degree relatives with colorectal cancer may have a lifetime risk of one in six (31), which is two to three times higher than in those with only one first-degree relative affected. Accordingly, a less intensive screening program has been suggested in the latter; that is, annual FOBTs and flexible sigmoidoscopy every 3-5 years beginning at age 40 years, whereas individuals with two first-degree relatives should have colonoscopy instead of sigmoidoscopy (29). However, detection of any adenomas by sigmoidoscopy should always be followed by complete colonoscopy because of the high rate of synchronous lesions. No randomized clinical trials have been published supporting the recommendations made. Mathematical models suggest that the mortality from colorectal cancer may be reduced by no more than 25% using Hemoccult-I1 alone, whereasendoscopymayachieve reductionsof up to85% (32). The HNPCC syndrome should be suspected when three or more first-degree relatives have colorectal cancer and when one has colorectal cancer at an age younger than 30 years. Patients with colorectal adenomas probably have an increased risk of developing colorectal cancer, but the magnitude of the relative risk is uncertain, compared with that in the general population. Most adenomas are small and symptomless, and it is estimated that no more than 5-10% will proceed to cancer. Adenomas are present in one-third of individuals above the age of 55 years (33). Radiologic studies of patients with colorectal polyps of at least 1 cm in diameter, which for some reason were not removed, suggest that the lifetime risk of developing colorectal cancer is 2 5 4 0 % (34). The figures are open to heavy criticism, since it is not known how many of the polyps contained colorectal cancer when first detected by roentgenography. Nevertheless, following the introduction of flexible endoscopy, it has become widespread practice to obtain a clean colon in patients with adenomas, and to follow up these patients with colonoscopy or flexible sigmoidoscopy and DCBE at intervals of 1-4 years (35,36). The effect of varying the intervals between follow-up examinations has been investigated in large randomized studies (35,37), and it may be possible to reduce mortality from colorectal cancer in adenoma patients compared with a matched normal population. However, this advantage is to some extent compromised by complications from follow-up examinations with or without polypectomy (38). Also, it is not known to what extent the incidence of colorectal cancer may be reduced by endoscopic surveillance with removal of all polyps. Recommendations for adenoma surveillance include early follow-up with colonoscopy (3 months) after piecemeal polypectomy and removal of multiple adenomas whenever the endoscopist is not confident that the colon has been
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cleaned of all polyps. The optimal long-term intervals between examinations have not been determined but should probably be within 2-4 years, patients with previous villous adenomas and multiple adenomas having the shortest intervals. Patients with previous colorectal cancer have an increased risk of getting a new metachronous colorectal cancer, but the relative risk is difficult to estimate. Colonoscopy was not available before 1970, and publications before 1970 present figures of 2-5%, which may be too high because of many overlooked synchronous tumours. However. more recent publications, in which perioperative colonoscopy has been used, suggest similar figures for metachronous cancer (39) but higher figures for synchronous cancer. The number of metachronous cancers is related to the frequency of postoperative colonoscopic surveillance and removal of adenomas perioperatively and during follow-up. Estimation of the risk of metachronous cancer may also have been incorrect before 1970 because of less effective tools for surveillance (40). Two large randomized trials are underway to estimate the possible benefits from surveillance after radical surgery for colorectal cancer using tumour markers and endoscopy (41,42). The Danish two-arm study compares, among other factors, an intensive colonoscopic program with no more than colonoscopy every 5 years, all patients being subjected to initial perioperative colonoscopy (42). The preliminary results suggest that more metachronous early cancers may be detected by frequent colonoscopy, but it is still not known whether a reduction in mortality from colorectal cancer can be achieved. Recurrence of the first cancer is detected more often during intensive clinical follow-up (43), but the prognosis is poor, and it has not been proved that mortality will be reduced. Accordingly, no intensive surveillance program can be recommended at present, and colonoscopy should probably not be done more frequently than every 5 years. Most local recurrences develop within 2 years, and the English multicentre trial (41) will evaluate the questionable use of frequent CEA measurements to detect recurrence at a favourable stage. Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer beginning after the first 10 years. The risk is higher in patients with pancolitis than in those with left-sided disease and is higher in ulcerative colitis than in Crohn’s disease (44). The exact risk is difficult to estimate because of surgical intervention in patients with severe symptoms but is probably at least five times higher than in the normal population (45). However, colorectal cancer in ulcerative colitis amounts to no more than a small fraction of the total incidence of colorectal cancer. Dysplasia of the intestinal mucosa may be a better marker in ulcerative colitis than in Crohn’s disease (46), but it has not been demonstrated that patients with severe dysplasia at endoscopic biopsy will benefit more from colectomy than those
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having surgery, because of symptomatic colorectal cancer (47). It has been suggested that patients with long-standing ulcerative colitis and possibly also Crohn’s disease may benefit from colonoscopic surveillance with multiple biopsies every 1-2 years (45,48). The diagnosis of severe dysplasia is to some extent compromised by both inter- and intraobserver variation, and the frequency of coexistent carcinoma may vary from 5% to 40% (47), being highest in combination with dysplasia in a mass lesion. Most authors then suggest colectomy. Dysplasia without a mass lesion requires shorter intervals between colonoscopic surveillance (3-6 months); furthermore, intervals should possibly be shorter with the increasing disease duration, but recommendations are not based on solid evidence from randomized trials. Such trials would have to be undertaken as multicentre studies, and it is questionable whether they ever will take place. It must be realized that detection of colorectal cancer in patients with IBD will cost at least the same as detection of colorectal cancer in average-risk individuals, but the stage distribution of the cancer may not be favourable (49). THE FUTURE Screening of average-risk individuals with Hemoccult-I1 may result in a reduction of mortality from colorectal cancer, but FOBTs have several drawbacks making it attractive to evaluate the addition of flexible sigmoidoscopy , as long as the search for more specific tumour markers has not been successful. The yield of adenomas by screening with Hemoccult-I1 and subsequently sigmoidoscopy makes it possible to perform intervention studies to evaluate the influence of dietary factors on the risk of new adenomas and/or growth of adenomas left behind. Such studies are underway, and provided that the adenoma-carcinoma sequence is true for most cancers, this is a step towards primary prevention of colorectal cancer. Assuming that a reduction in mortality is obtained, several other problems remain unsolved: the organisation of population screening, physician education and training in endoscopic procedures, and evaluation of cost effectiveness and cost-benefit, all of which would be necessary before any mass screening could be introduced. It should be possible to reduce the burden of screening for FAP by organizing more registries in different countries and selecting gene-positive individuals. Clinicians should be aware of the importance of anamnestic information about family history, making it possible to diagnose HNPCC and plan colonoscopic screening of the family members. However, it is not known how often screening should be performed, and it is hoped that The International Collaborative Group will take steps towards a prospective trial to optimize the use of our limited resources. The lack of randomized trials in first-degree relatives of patients with
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sporadic colorectal cancer is apparent, but resources should also b e used within gene technology, since genetic susceptibility t o colorectal cancer may b e higher than originally thought. Progress in the study of inherited genetics may also identify individuals with adenomas and those who are likely t o progress to colorectal cancer (50). Until then. the guidelines from major surveillance trials must b e followed. The value of follow-up after curative surgery for colorectal cancer has not been established but gives an opportunity for intervention studies evaluating risk of metachronous neoplasia. The benefit of screening for neoplasia in patients with IBD still is a matter of controversy, and n o randomized trials have been published. More specific markers than the presence of dysplasia in biopsy specimens will be needed. REFERENCES 1. Hertz REL, Deddish MR, Day E. Value of periodic exam-
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