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Colorectal cancer screening: Results of a 5-year program in asymptomatic subjects at increased risk
Digestive and Liver Disease 39 (2007) 33–39
Alimentary Tract
Colorectal cancer screening: Results of a 5-year program in asymptomatic subjects at increased risk A. Pezzoli a,∗ , V. Matarese a , M. Rubini b , M. Simoni c , G.C. Caravelli a , R. Stockbrugger d , V. Cifal`a a , S. Boccia a , C. Feo e , L. Simone a , L. Trevisani a , A. Liboni e , S. Gullini a a
d
Department of Gastroenterology and GI Endoscopy, University Hospital, Ferrara, Italy b Department of Genetics, University Hospital, Ferrara, Italy c Epidemiological Unit of CNR Institute of Clinical Physiology, Pisa, Italy Department of Gastroenterology and Hepatology, University Hospital, Maastricht, Netherlands e Department of Surgery, University Hospital, Ferrara, Italy Received 8 August 2005; accepted 5 September 2006 Available online 16 October 2006
Abstract Background and aims. The province of Ferrara has one of the highest incidences of colorectal cancer (CRC) in Italy. In January 2000, we set up a colonoscopy screening program focussing on first-degree relatives of CRC patients. We now report the results 5 years after the beginning of the project. Screenees and methods. In October 1999, we started a campaign stressing the usefulness of colonoscopy for the first-degree relatives of CRC patients. Subjects included in the screening program were aged between 45 and 75 years with at least one first-degree relative affected by CRC. They were invited to an interview where a physician suggested colonoscopy as a screening option. Results. In 5 years, 776 subjects were interviewed and 733 (94.4%) agreed to an endoscopic examination (M/F:375/401; mean age 55 years): 562 colonoscopies were performed. Adenomas and cancers were found in 122 (21.7%) and 12 (2.1%) subjects, respectively. Histological examination in 181 persons with lesions (32.8%) showed (most serious lesion quoted) 47 hyperplastic polyps (26% of all lesions), 2 serrated adenomas (1.1%), 68 tubular adenomas (48%), 24 tubulovillous adenomas (13.3%), 9 adenomas with high grade dysplasia (5%) and 12 adenocarcinomas (6.6%). The majority of the cancers were at an early stage (8 Dukes A and 3 Dukes B). Sedation was used in only 42 colonoscopies (7.5%). Conclusions. A colonoscopy-based screening in this selected high-risk population is feasible. Even without sedation subjects readily agreed to the endoscopic procedure. We identified a significant number of advanced neoplasms and cancers at an early stage suggesting that this could be a useful tool in early identification of CRC. © 2006 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Adenoma; Colonoscopy; Colorectal cancer screening; First-degree relatives
1. Background and aim Colorectal cancer (CRC) is the second leading cause of cancer-related death in Western countries [1]. The province of Ferrara has one of the highest incidences of CRC in Italy. In the years 1993–97, data from the local tumour register showed an incidence of 93.4 new cases/year/100.000 inhab∗
Corresponding author. Tel. +39 0532236833; fax: +39 0532236932. E-mail address: [email protected] (A. Pezzoli).
itants and 884 deaths (443 women and 441 men) from CRC [2]. Due to its high prevalence, its long asymptomatic phase and the existence of a treatable precancerous lesion, CRC ideally meets all the criteria for screening. Several screening methods have been evaluated such as faecal occult blood test (FOBT) [3–5], sigmoidoscopy [6,7] and colonoscopy [8] but consensus about the optimal screening strategy has not been completely established in clinical practice. There has been a mounting evidence regarding the
1590-8658/$30 © 2006 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2006.09.001
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A. Pezzoli et al. / Digestive and Liver Disease 39 (2007) 33–39
efficacy of screening with colonoscopy [9,10]. The advantage is that the entire bowel can be visualized, clinically significant lesions can be identified and removed with subsequent reduction of incidence of CRC as shown in the previous data [11]. Nevertheless, it is very difficult to perform a colonoscopy based screening program for the general population and the procedure is not generally well accepted. Since many data have shown that first-degree relatives of patients affected by CRC are at an increased risk [12–13], we designed a screening program that focused on this population using colonoscopy. We report here the results of this program after 5 years of activity.
colonoscopy, we recommended a further colonoscopy at 5year interval and for patients with polyps we suggested a follow up according the American College of Gastroenterology guideline [16,22]. The instrument used for polypectomy was either the biopsy forcep or snare electrocautery depending on the size of the polyp and personal preference of the endoscopist. Anatomic landmarks (ileocoecal valve and appendiceal orifice) were noted to confirm that the coecum had been reached. When the coecum could not be reached, barium enema was suggested, or a second colonoscopic attempt with sedation was scheduled on the basis of clinical judgement. Conscious sedation was only used when requested by the patient or in a second attempt exam.
1.1. Screenees and methods 1.2. Statistical analysis In October 1999, we started an informative campaign underlining the usefulness of colonoscopy for first-degree relatives of CRC patients: meetings with general practitioners and surgeons as well as public conferences were organized; printed booklets were distributed in many medical offices; articles were published in local newspaper; local radio/TV programs were broadcast; interviews and press conferences were organized; finally, a specific web site was activated. Moreover, all patients undergoing surgical intervention for CRC were asked by surgeons to inform their first-degree relatives about the program. The costs of the program were sustained by the hospital. The screening program included subjects aged between 45 and 75 years and with one or more first-degree relatives affected by CRC or with adenomas diagnosed before the age of 60 years as suggested by guidelines and literature [14,15]; when the subjects had more then one first-degree relative with CRC/adenoma, we recorded such information and we considered the index-case to be the one with the lowest age at diagnosis. Potential screenees were invited to an interview, where a physician collected personal and family medical history and suggested colonoscopy as a screening option. When colonoscopy was refused, barium enema or faecal occult blood tests were suggested. The subjects were requested to provide medical documents (if existing) to ensure that there were no contraindications to join the screening program. They were excluded if they had undergone a colonoscopy within the past 3 years, if they had a history of colonoscopic polypectomy, if they had a genetic disorder such as familial polyposis or belonged to hereditary non-polyposis colorectal cancer (HNPCC) families, or if they had a history of ulcerative colitis or Crohn’s disease. All the subjects had to be asymptomatic. All colonoscopies were performed in our unit by experienced endoscopists. Polyethylene glycol lavage solution was used for bowel preparation. During colonoscopy, the number, the location and the size of all polyps were recorded before being removed. Specimens were evaluated by pathologists in order to identify the histological type and degree of atypia of adenoma in each patient; in the case of patients with more than one polyp only the lesion with most severe histology was included in the analysis. For Subjects with a negative
Statistical analysis was performed using the Statistical Package for the Social Sciences (Rel 10.0 SPSS Inc, Chicago 2000). The following routines were used: frequency distribution; chi-square test to assess the association between two dichotomous categorical variables [17]; logistic regression analysis [18] to assess the relationship – by odds ratios (OR) and their 95% confidence interval (CI 95%) – between polyp presence and risk factors such as age (decades), sex, number of first-degree relatives with CRC (one or more) and age of diagnosis (two cut-off limits were used, 55 and 64 years).
2. Results 2.1. Characteristics of the study group Between January 2000 and January 2005, at the Gastroenterology Unit of Ferrara, 776 subjects participated in the study; 375 males (48.3%) and 401 females (51.7%) with a mean age of 55 years (±S.D. 8 years ). 750 subjects had a first-degree relative with CRC and 26 subjects with adenomas diagnosed at an age <60 years. 607 (78.3%) participants had one parent affected by CRC, 157 (20.2%) had a sibling and 12 (1.5%) had a children. The majority, 488 subjects (63%) came from the city of Ferrara, 258 (33.2%) came from the province and 30 (3.8%) from neighbouring provinces (Table 1). The index-cases with CRC had a mean of 6.1 first-degree relatives (range from 1 to 14), out of whom a mean of 3.6 were still alive (range from 1 to 10). From the latter, a mean of 1.2 (range from 1 to 3) participated in the initial interview. Out of all the subjects interviewed in our office 10 (1.3%) refused any type of screening test, 21 (2.7%) chose barium enema and 12 (1.6%) FOBT. 733 (94.4%), agreed to a colonoscopic examination. 2.2. Endoscopic procedures We analyzed 562 colonoscopies performed during the years of screening (the others are still due to be performed or with incomplete data).
A. Pezzoli et al. / Digestive and Liver Disease 39 (2007) 33–39 Table 1 Characteristics of the study group
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Table 3 Histological examination of the 181 lesions found
No of subjects
776
Lesions
Number
%
Sex
375 M, 48.3% 401 F, 51.7%
Mean age
55 years (±S.D. 8 years )
Relative affected by CRC Parents Brother Son
607 subjects (78.3%) 157 subjects (20.2%) 12 subjects (1.5%)
Hyperplastic polyps Adenomas Adenomas Tub-Vill Adenomas serrated Adenomas HGD Adenocarcinomas
47 87 24 2 9 12
26 48 13.3 1.1 5 6.6
Origin of participants Ferrara Province Others
488 subjects (63%) 258 subjects (33.2%) 30 subjects (3.8%)
The coecum was intubated in 478 (85%) colonoscopies. Conscious sedation was carried out in only 42 exams (7.5%). The procedure was generally well tolerated without complications except for one perforation related to polypectomy (0.2%). This patient underwent a surgical operation and was discharged without other complications. 2.3. Endoscopic findings We found polypoid lesions in 181 subjects (33%). Globally, out of 562 subjects who underwent colonoscopy, the prevalence of adenomas was 21.7% (excluding hyperplastic polyps) and overt cancer was 2.2% (Table 2). If we analyse only those patients with a complete colonoscopy (478 patients), the prevalence of adenoma increases to 28% and 2.5% of cancers. If we consider only the advanced neoplasms such as adenomas over 1 cm, those with villous component or high-grade dysplasia and cancers, the percentage decreases to 13.3% (75/562 colonoscopies). Histological examination of the polypoid lesions showed (most severe lesions counted): hyperplastic polyps in 47 cases (26.0%), tubular adenomas were diagnosed in 87 subjects (48%), tubulovillous adenomas in 24 (13.3%), serrated adenomas in 2 (1.1%) and villous adenomas with high grade dysplasia in 9 (5%). In addition, there were 12 adenocarcinomas (6.6%) (Table 3). In 57/122 subjects with adenomas (46.7%), the maximal diameter of the largest polyp was >1 cm. More than one adenoma was found in 40/122 (32.8%) of all patients with adenomas. Adenomas were present in 30.2% of males and in 20.3% of females (P < 0.01).
In 71% of the patients with neoplasms (adenoma or cancer), these were located in the left colon (as far as splenic flexure) and in 29% in the right colon (including one adenocarcinoma). There were eight Dukes A stage cancers, three Dukes B (T3,N0) and one Dukes C (T3,N2). 2.4. Predictive factors for the presence of neoplasms Logistic regression models with the presence of neoplasms (excluding hyperplastic polyps) as a dependent variable together with sex, age, number of first-degree relatives affected by CRC/adenomas, and age at CRC/adenomas diagnosis of the index-case as independent factors, showed that males have highest risk of carrying polyps compared to females (OR 1.7, CI 95% 1.23–2.51). The risk of neoplasm was associated with age increase (OR 1.7, CI 95% 1.39–2.08, for every decade starting from 45 years). Subjects with two or more affected first-degree relatives had no higher risk of carrying neoplasms compared to subjects with only one affected relative (OR 1.4, CI 95% 0.72–2.61). In this study group, a low age at diagnosis of cancer in the index-case was not related to a risk of polyps when a cut-off of 55 years was considered (O.R 1.41,CI 95% 0.81–2.45); however, when a cut-off of 64 years was applied, subjects with index-case diagnosis at ≤64 years showed a significant greater risk for having polyps than those diagnosed at ≥64 (O.R 1.65, CI 95% 1.55–2.36) (Fig. 1). As newer data suggest that hyperplastic polyps may have a malignant potential especially in the populations of subjects with an increased risk of cancer [19,20]; we repeated the same analysis including hyperplastic polyps. The results
Table 2 Prevalence of neoplasm in 562 colonoscopies Findings
Number
%
Negative or hyperplastic polyps Adenomas Adenocarcinomas
428 122 12
76.1 21.7 2.2
Considering only subjects with total colonoscopy(478 pts) Adenomas 28 Asenocarcinomas 2.5
Fig. 1. Predictive factors for the presence of neoplasms.
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A. Pezzoli et al. / Digestive and Liver Disease 39 (2007) 33–39
Fig. 2. Predictive factors for the presence of clinically significant neoplasms.
were similar for every risk factor considered (male sex: O.R. 2.06 CI 1.37–3.11, age O.R. 1.84, CI 1.45–2.35, number of affected relatives O.R. 1.22, CI 0.63–2.35 and age of diagnosis of cancer in the index-case <55 years O.R. 1.13, CI 0.67–1.89, ≥64 years O.R. 1.5, CI 1.0–2.27). These observations support the new hypothesis that different factors may be implicated in the initiation of colorectal cancer especially in subset of high-risk patients [19–20]. Finally, we analyzed the subset of subjects with advanced neoplasms; we found similar associations for all predictive factors considered but with a more significant O.R, most likely due to the limited number of patients (male sex: O.R 2.0, CI 1–3.9, age: O.R 2.2 CI 1.5–3.2, age of diagnosis of cancer in the index-case ≥64 years: O.R 2.3 CI 1.2–4.5, number of first-degree relatives affected: O.R 1.6, CI 0.5–4.9) (Fig. 2).
3. Discussion The high CRC incidence in all Western countries accounts for the mounting interest in screening campaigns and many guidelines have been published [15,21–24]. Nevertheless, the attendance rate in colorectal cancer screening in the population remains low [25,26]. Colon cancer screening implies a complex series of decisions, which comprehends both the choice of the appropriate screening test and also the selection of the subjects who may undergo them. Familial risk of colorectal cancer is a well-known public health issue [27]; for this reason, we tried to determine the feasibility and efficacy of a screening program in firstdegree relatives of CRC patients. Regarding the screening method, we adopted colonoscopy, which is considered by many authors [22] to be the best diagnostic tool. Compliance is an important determinant in effectiveness for all screening programs; we observed a very high compliance with colonoscopy in the subjects who contacted our unit for advice (94.4%). In a previous study [28], 476 first-degree
relatives were contacted by mail and 185 of them (38.9%) consented to undergo a colonoscopy. In another similar study by Colombo et al. [29], participation in endoscopic examination was 29.9%. Unfortunately, we are not able to calculate the exact adhesion rate to the screening program of the population at risk as we do not know the exact number of all first-degree relatives of each index-colon cancer patient. We believe that the high number of patients who agree to undergo colonoscopy in our study group is mainly due to the direct physician–patient contact during the preparatory interview. Moreover, it is to be expected that first-degree relatives will agree to colonoscopy more readily as they are because more susceptible to prevention of CRC as shown by recent data [30]. This was confirmed by our results. We found neoplasms in nearly 22% of subjects; this figure is similar to the results of other studies [28,31–33] although the percentage can range from 8 to 69% [34–37]. We do not have data of a control group at normal risk as the main aim of our project was to study the feasibility of preventing CRC in this particular risk group. Some previous studies have shown that the percentage of adenomas found in first-degree relatives of CRC patients was not significantly higher than that found in the general population >50 years [28–35]; in fact in autopsy studies, the prevalence of adenomas ranges between 20 and 30% and increases with age [38–39], and the American college of Gastroenterology task force have established that the average detection rate of adenomas in non-risk subjects over 50 years, should be about 25%. [40], a percentage similar to the one we found in our increased-risk group of subjects. However, other studies have reported an increased prevalence of polyps in relatives of CRC patients [41,42]. On the other hand we found a high percentage of adenomas with high-grade dysplasia and >1 cm in size, considered to be important risk factors for the development of CRC [43,44]. Similar findings were reported by Pariente et al. [28] and Aitken et al. [35] regarding the prevalence of advanced neoplasm in first-degree relatives of CRC patients. In addition, we found 12 persons with cancer. The number of 12 cancer cases out of 562 subjects (included only subjects aged between 45–75) is a very high incidence compared to the spontaneous rate of 93/100.000 in the general population in the area of Ferrara. It has been suggested that in patients with family history of colorectal cancers, about 30–40% of colon cancers develop in the right colon. [45,46]. We found only 1/12 proximal cancer; probably, this number of cancers is too small to confirm the trend observed in others studies; moreover, we cannot exclude that our low success rate in reaching the caecum (85%) could be responsible for some missing proximal cancers. Although the frequency of total adenomabearers seems not to be excessively high, the proportion of high-risk adenomas appears elevated. We can speculate that genetic factors influence the speed of adenoma growth rather than their number. This hypothesis is also supported by the results of Fossi et al. regarding the time of recurrence of adenomas in first-degree relatives of CRC patients [47]
A. Pezzoli et al. / Digestive and Liver Disease 39 (2007) 33–39
From screenees unwilling to undergo colonoscopy we received the results of only 6/10 FOBT and of 7/21 barium enemas performed; all were negative. We did not include this data in the analysis because the number of subjects and the sensitivity of both the exams in revealing small polyps must be considered very low [48,49]. We tried to identify some predictive factors for the presence of polyps. In previous publications [27,50], the early age of diagnosis of cancer in the index-cases and the number of affected relatives were the considered risk factors for the presence of polyps. Also in the present study the index patient’s age at cancer diagnosis increased the risk of finding adenomas in first-degree relatives when comparison was limited to screenees in whom the diagnosis of cancer in the index-case was obtained at an age of >64 years. Similar findings were obtained by Pariente et al [28]. The number of first-degree relatives did not influence the risk of adenomas in the screenees. This finding, which is discordant with the literature, is difficult to explain; we may hypothesize that the high incidence of cancer in the area of Ferrara has important extrinsic risk factors that could mask the role of hereditary factors, such as they are expressed by the number of relatives affected by colorectal cancer. The advanced age of patients and the male sex are well-known risk factors for neoplasm [39,51,52]. Our data confirm these findings, with a significant increased number of adenomas for every decade of age and for male subjects with respect to females. Our screening program has suffered from some limitations. Above all, it has to be admitted that the number of subjects seen after 5 years was not as high as we expected. We could not estimate the exact number of potential screenees, but a mean of 1.2 relatives per index-case participating is certainly suboptimal. This finding stresses the need for more intensive information about the usefulness of screening campaign among relatives of CRC patients, surgeons, oncologist and last but not the least general practitioners [29,53,54]. Another limitation is that the coecum was intubated in not more that 85% of the colonoscopies. This result is lower than those reported in American studies [9,55] in which the coecum was reached in about 97%. However, in most of those studies, the exams were performed under conscious sedation using intravenous agents. We think that in clinical practice, this high percentage might be difficult to reach. Moreover, we do not routinely use sedation because it is associated with complications, it is a time consuming procedure, increases costs, requires a longer recovery period, and is, at least in our experience, rarely requested by patients. Consequently, sedation was used by us in only 7.5% of the colonoscopies. Moreover, the 85% of coecal intubation rate is similar to that achieved by other European studies [56–58]. We agree that in the future, the ceocal intubation rate should be increased to at least 90%, possibly by more generous application of sedation because of the reported high incidence of proximal cancer in these subjects [45,46] but also in order to increase the compliance to the screening campaign and the follow-up.
37
Colonoscopy remains an invasive procedure that can provoke complications including bleeding, perforation and adverse cardiopulmonary events [59]; we observed only one perforation related to polypectomy a figure similar to those reported in the previous large series of patients [60,61]. New screening methods are now available for the analysis of genetic changes in fecal DNA [62–64] and virtual colonoscopy using abdominal spiral computed tomography [65–67]. However, many doubts remain as to whether these new tools are ready for a widespread application [24,68,69]. Thus, so far primary colonoscopy probably remains an attractive option for all programs that intend to screen for CRC in persons with either normal or increased risk of this condition. In conclusion, our data show that colonoscopy screening in a high-risk population is feasible, effective and well accepted. The high number of advanced neoplasms found suggests that this policy could be efficient in reducing the incidence of CRC. Practice points • Screening colonoscopy in a high risk population is feasible and generally well accepted. • A preliminary interview, with direct physician-patient contact, can increase the compliance rate to colonoscopy. • The attendance rate in screening colonoscopy remains low and should be increased by involving public administration and general practitioners. • First-degree relatives of CRC patients have a high percentage of adenomas with high grade dysplasia and cancer.
Research agenda • Longer follow-up to assess the efficacy of screening-colonoscopy in reducing the incidence and mortality of CRC in increased risk subjects. • Usefulness of sedation in order to increase the compliance to screening colonoscopy. • Comparison of colonoscopy with other new screening methods in this subset of subjects. • To study whether hyperplastic polyps may have a malignant potential in populations of subjects with an increased risk of cancer.
Conflict of interest statement None declared.
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Alimentary Tract
Colorectal cancer screening: Results of a 5-year program in asymptomatic subjects at increased risk A. Pezzoli a,∗ , V. Matarese a , M. Rubini b , M. Simoni c , G.C. Caravelli a , R. Stockbrugger d , V. Cifal`a a , S. Boccia a , C. Feo e , L. Simone a , L. Trevisani a , A. Liboni e , S. Gullini a a
d
Department of Gastroenterology and GI Endoscopy, University Hospital, Ferrara, Italy b Department of Genetics, University Hospital, Ferrara, Italy c Epidemiological Unit of CNR Institute of Clinical Physiology, Pisa, Italy Department of Gastroenterology and Hepatology, University Hospital, Maastricht, Netherlands e Department of Surgery, University Hospital, Ferrara, Italy Received 8 August 2005; accepted 5 September 2006 Available online 16 October 2006
Abstract Background and aims. The province of Ferrara has one of the highest incidences of colorectal cancer (CRC) in Italy. In January 2000, we set up a colonoscopy screening program focussing on first-degree relatives of CRC patients. We now report the results 5 years after the beginning of the project. Screenees and methods. In October 1999, we started a campaign stressing the usefulness of colonoscopy for the first-degree relatives of CRC patients. Subjects included in the screening program were aged between 45 and 75 years with at least one first-degree relative affected by CRC. They were invited to an interview where a physician suggested colonoscopy as a screening option. Results. In 5 years, 776 subjects were interviewed and 733 (94.4%) agreed to an endoscopic examination (M/F:375/401; mean age 55 years): 562 colonoscopies were performed. Adenomas and cancers were found in 122 (21.7%) and 12 (2.1%) subjects, respectively. Histological examination in 181 persons with lesions (32.8%) showed (most serious lesion quoted) 47 hyperplastic polyps (26% of all lesions), 2 serrated adenomas (1.1%), 68 tubular adenomas (48%), 24 tubulovillous adenomas (13.3%), 9 adenomas with high grade dysplasia (5%) and 12 adenocarcinomas (6.6%). The majority of the cancers were at an early stage (8 Dukes A and 3 Dukes B). Sedation was used in only 42 colonoscopies (7.5%). Conclusions. A colonoscopy-based screening in this selected high-risk population is feasible. Even without sedation subjects readily agreed to the endoscopic procedure. We identified a significant number of advanced neoplasms and cancers at an early stage suggesting that this could be a useful tool in early identification of CRC. © 2006 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Adenoma; Colonoscopy; Colorectal cancer screening; First-degree relatives
1. Background and aim Colorectal cancer (CRC) is the second leading cause of cancer-related death in Western countries [1]. The province of Ferrara has one of the highest incidences of CRC in Italy. In the years 1993–97, data from the local tumour register showed an incidence of 93.4 new cases/year/100.000 inhab∗
Corresponding author. Tel. +39 0532236833; fax: +39 0532236932. E-mail address: [email protected] (A. Pezzoli).
itants and 884 deaths (443 women and 441 men) from CRC [2]. Due to its high prevalence, its long asymptomatic phase and the existence of a treatable precancerous lesion, CRC ideally meets all the criteria for screening. Several screening methods have been evaluated such as faecal occult blood test (FOBT) [3–5], sigmoidoscopy [6,7] and colonoscopy [8] but consensus about the optimal screening strategy has not been completely established in clinical practice. There has been a mounting evidence regarding the
1590-8658/$30 © 2006 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2006.09.001
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A. Pezzoli et al. / Digestive and Liver Disease 39 (2007) 33–39
efficacy of screening with colonoscopy [9,10]. The advantage is that the entire bowel can be visualized, clinically significant lesions can be identified and removed with subsequent reduction of incidence of CRC as shown in the previous data [11]. Nevertheless, it is very difficult to perform a colonoscopy based screening program for the general population and the procedure is not generally well accepted. Since many data have shown that first-degree relatives of patients affected by CRC are at an increased risk [12–13], we designed a screening program that focused on this population using colonoscopy. We report here the results of this program after 5 years of activity.
colonoscopy, we recommended a further colonoscopy at 5year interval and for patients with polyps we suggested a follow up according the American College of Gastroenterology guideline [16,22]. The instrument used for polypectomy was either the biopsy forcep or snare electrocautery depending on the size of the polyp and personal preference of the endoscopist. Anatomic landmarks (ileocoecal valve and appendiceal orifice) were noted to confirm that the coecum had been reached. When the coecum could not be reached, barium enema was suggested, or a second colonoscopic attempt with sedation was scheduled on the basis of clinical judgement. Conscious sedation was only used when requested by the patient or in a second attempt exam.
1.1. Screenees and methods 1.2. Statistical analysis In October 1999, we started an informative campaign underlining the usefulness of colonoscopy for first-degree relatives of CRC patients: meetings with general practitioners and surgeons as well as public conferences were organized; printed booklets were distributed in many medical offices; articles were published in local newspaper; local radio/TV programs were broadcast; interviews and press conferences were organized; finally, a specific web site was activated. Moreover, all patients undergoing surgical intervention for CRC were asked by surgeons to inform their first-degree relatives about the program. The costs of the program were sustained by the hospital. The screening program included subjects aged between 45 and 75 years and with one or more first-degree relatives affected by CRC or with adenomas diagnosed before the age of 60 years as suggested by guidelines and literature [14,15]; when the subjects had more then one first-degree relative with CRC/adenoma, we recorded such information and we considered the index-case to be the one with the lowest age at diagnosis. Potential screenees were invited to an interview, where a physician collected personal and family medical history and suggested colonoscopy as a screening option. When colonoscopy was refused, barium enema or faecal occult blood tests were suggested. The subjects were requested to provide medical documents (if existing) to ensure that there were no contraindications to join the screening program. They were excluded if they had undergone a colonoscopy within the past 3 years, if they had a history of colonoscopic polypectomy, if they had a genetic disorder such as familial polyposis or belonged to hereditary non-polyposis colorectal cancer (HNPCC) families, or if they had a history of ulcerative colitis or Crohn’s disease. All the subjects had to be asymptomatic. All colonoscopies were performed in our unit by experienced endoscopists. Polyethylene glycol lavage solution was used for bowel preparation. During colonoscopy, the number, the location and the size of all polyps were recorded before being removed. Specimens were evaluated by pathologists in order to identify the histological type and degree of atypia of adenoma in each patient; in the case of patients with more than one polyp only the lesion with most severe histology was included in the analysis. For Subjects with a negative
Statistical analysis was performed using the Statistical Package for the Social Sciences (Rel 10.0 SPSS Inc, Chicago 2000). The following routines were used: frequency distribution; chi-square test to assess the association between two dichotomous categorical variables [17]; logistic regression analysis [18] to assess the relationship – by odds ratios (OR) and their 95% confidence interval (CI 95%) – between polyp presence and risk factors such as age (decades), sex, number of first-degree relatives with CRC (one or more) and age of diagnosis (two cut-off limits were used, 55 and 64 years).
2. Results 2.1. Characteristics of the study group Between January 2000 and January 2005, at the Gastroenterology Unit of Ferrara, 776 subjects participated in the study; 375 males (48.3%) and 401 females (51.7%) with a mean age of 55 years (±S.D. 8 years ). 750 subjects had a first-degree relative with CRC and 26 subjects with adenomas diagnosed at an age <60 years. 607 (78.3%) participants had one parent affected by CRC, 157 (20.2%) had a sibling and 12 (1.5%) had a children. The majority, 488 subjects (63%) came from the city of Ferrara, 258 (33.2%) came from the province and 30 (3.8%) from neighbouring provinces (Table 1). The index-cases with CRC had a mean of 6.1 first-degree relatives (range from 1 to 14), out of whom a mean of 3.6 were still alive (range from 1 to 10). From the latter, a mean of 1.2 (range from 1 to 3) participated in the initial interview. Out of all the subjects interviewed in our office 10 (1.3%) refused any type of screening test, 21 (2.7%) chose barium enema and 12 (1.6%) FOBT. 733 (94.4%), agreed to a colonoscopic examination. 2.2. Endoscopic procedures We analyzed 562 colonoscopies performed during the years of screening (the others are still due to be performed or with incomplete data).
A. Pezzoli et al. / Digestive and Liver Disease 39 (2007) 33–39 Table 1 Characteristics of the study group
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Table 3 Histological examination of the 181 lesions found
No of subjects
776
Lesions
Number
%
Sex
375 M, 48.3% 401 F, 51.7%
Mean age
55 years (±S.D. 8 years )
Relative affected by CRC Parents Brother Son
607 subjects (78.3%) 157 subjects (20.2%) 12 subjects (1.5%)
Hyperplastic polyps Adenomas Adenomas Tub-Vill Adenomas serrated Adenomas HGD Adenocarcinomas
47 87 24 2 9 12
26 48 13.3 1.1 5 6.6
Origin of participants Ferrara Province Others
488 subjects (63%) 258 subjects (33.2%) 30 subjects (3.8%)
The coecum was intubated in 478 (85%) colonoscopies. Conscious sedation was carried out in only 42 exams (7.5%). The procedure was generally well tolerated without complications except for one perforation related to polypectomy (0.2%). This patient underwent a surgical operation and was discharged without other complications. 2.3. Endoscopic findings We found polypoid lesions in 181 subjects (33%). Globally, out of 562 subjects who underwent colonoscopy, the prevalence of adenomas was 21.7% (excluding hyperplastic polyps) and overt cancer was 2.2% (Table 2). If we analyse only those patients with a complete colonoscopy (478 patients), the prevalence of adenoma increases to 28% and 2.5% of cancers. If we consider only the advanced neoplasms such as adenomas over 1 cm, those with villous component or high-grade dysplasia and cancers, the percentage decreases to 13.3% (75/562 colonoscopies). Histological examination of the polypoid lesions showed (most severe lesions counted): hyperplastic polyps in 47 cases (26.0%), tubular adenomas were diagnosed in 87 subjects (48%), tubulovillous adenomas in 24 (13.3%), serrated adenomas in 2 (1.1%) and villous adenomas with high grade dysplasia in 9 (5%). In addition, there were 12 adenocarcinomas (6.6%) (Table 3). In 57/122 subjects with adenomas (46.7%), the maximal diameter of the largest polyp was >1 cm. More than one adenoma was found in 40/122 (32.8%) of all patients with adenomas. Adenomas were present in 30.2% of males and in 20.3% of females (P < 0.01).
In 71% of the patients with neoplasms (adenoma or cancer), these were located in the left colon (as far as splenic flexure) and in 29% in the right colon (including one adenocarcinoma). There were eight Dukes A stage cancers, three Dukes B (T3,N0) and one Dukes C (T3,N2). 2.4. Predictive factors for the presence of neoplasms Logistic regression models with the presence of neoplasms (excluding hyperplastic polyps) as a dependent variable together with sex, age, number of first-degree relatives affected by CRC/adenomas, and age at CRC/adenomas diagnosis of the index-case as independent factors, showed that males have highest risk of carrying polyps compared to females (OR 1.7, CI 95% 1.23–2.51). The risk of neoplasm was associated with age increase (OR 1.7, CI 95% 1.39–2.08, for every decade starting from 45 years). Subjects with two or more affected first-degree relatives had no higher risk of carrying neoplasms compared to subjects with only one affected relative (OR 1.4, CI 95% 0.72–2.61). In this study group, a low age at diagnosis of cancer in the index-case was not related to a risk of polyps when a cut-off of 55 years was considered (O.R 1.41,CI 95% 0.81–2.45); however, when a cut-off of 64 years was applied, subjects with index-case diagnosis at ≤64 years showed a significant greater risk for having polyps than those diagnosed at ≥64 (O.R 1.65, CI 95% 1.55–2.36) (Fig. 1). As newer data suggest that hyperplastic polyps may have a malignant potential especially in the populations of subjects with an increased risk of cancer [19,20]; we repeated the same analysis including hyperplastic polyps. The results
Table 2 Prevalence of neoplasm in 562 colonoscopies Findings
Number
%
Negative or hyperplastic polyps Adenomas Adenocarcinomas
428 122 12
76.1 21.7 2.2
Considering only subjects with total colonoscopy(478 pts) Adenomas 28 Asenocarcinomas 2.5
Fig. 1. Predictive factors for the presence of neoplasms.
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A. Pezzoli et al. / Digestive and Liver Disease 39 (2007) 33–39
Fig. 2. Predictive factors for the presence of clinically significant neoplasms.
were similar for every risk factor considered (male sex: O.R. 2.06 CI 1.37–3.11, age O.R. 1.84, CI 1.45–2.35, number of affected relatives O.R. 1.22, CI 0.63–2.35 and age of diagnosis of cancer in the index-case <55 years O.R. 1.13, CI 0.67–1.89, ≥64 years O.R. 1.5, CI 1.0–2.27). These observations support the new hypothesis that different factors may be implicated in the initiation of colorectal cancer especially in subset of high-risk patients [19–20]. Finally, we analyzed the subset of subjects with advanced neoplasms; we found similar associations for all predictive factors considered but with a more significant O.R, most likely due to the limited number of patients (male sex: O.R 2.0, CI 1–3.9, age: O.R 2.2 CI 1.5–3.2, age of diagnosis of cancer in the index-case ≥64 years: O.R 2.3 CI 1.2–4.5, number of first-degree relatives affected: O.R 1.6, CI 0.5–4.9) (Fig. 2).
3. Discussion The high CRC incidence in all Western countries accounts for the mounting interest in screening campaigns and many guidelines have been published [15,21–24]. Nevertheless, the attendance rate in colorectal cancer screening in the population remains low [25,26]. Colon cancer screening implies a complex series of decisions, which comprehends both the choice of the appropriate screening test and also the selection of the subjects who may undergo them. Familial risk of colorectal cancer is a well-known public health issue [27]; for this reason, we tried to determine the feasibility and efficacy of a screening program in firstdegree relatives of CRC patients. Regarding the screening method, we adopted colonoscopy, which is considered by many authors [22] to be the best diagnostic tool. Compliance is an important determinant in effectiveness for all screening programs; we observed a very high compliance with colonoscopy in the subjects who contacted our unit for advice (94.4%). In a previous study [28], 476 first-degree
relatives were contacted by mail and 185 of them (38.9%) consented to undergo a colonoscopy. In another similar study by Colombo et al. [29], participation in endoscopic examination was 29.9%. Unfortunately, we are not able to calculate the exact adhesion rate to the screening program of the population at risk as we do not know the exact number of all first-degree relatives of each index-colon cancer patient. We believe that the high number of patients who agree to undergo colonoscopy in our study group is mainly due to the direct physician–patient contact during the preparatory interview. Moreover, it is to be expected that first-degree relatives will agree to colonoscopy more readily as they are because more susceptible to prevention of CRC as shown by recent data [30]. This was confirmed by our results. We found neoplasms in nearly 22% of subjects; this figure is similar to the results of other studies [28,31–33] although the percentage can range from 8 to 69% [34–37]. We do not have data of a control group at normal risk as the main aim of our project was to study the feasibility of preventing CRC in this particular risk group. Some previous studies have shown that the percentage of adenomas found in first-degree relatives of CRC patients was not significantly higher than that found in the general population >50 years [28–35]; in fact in autopsy studies, the prevalence of adenomas ranges between 20 and 30% and increases with age [38–39], and the American college of Gastroenterology task force have established that the average detection rate of adenomas in non-risk subjects over 50 years, should be about 25%. [40], a percentage similar to the one we found in our increased-risk group of subjects. However, other studies have reported an increased prevalence of polyps in relatives of CRC patients [41,42]. On the other hand we found a high percentage of adenomas with high-grade dysplasia and >1 cm in size, considered to be important risk factors for the development of CRC [43,44]. Similar findings were reported by Pariente et al. [28] and Aitken et al. [35] regarding the prevalence of advanced neoplasm in first-degree relatives of CRC patients. In addition, we found 12 persons with cancer. The number of 12 cancer cases out of 562 subjects (included only subjects aged between 45–75) is a very high incidence compared to the spontaneous rate of 93/100.000 in the general population in the area of Ferrara. It has been suggested that in patients with family history of colorectal cancers, about 30–40% of colon cancers develop in the right colon. [45,46]. We found only 1/12 proximal cancer; probably, this number of cancers is too small to confirm the trend observed in others studies; moreover, we cannot exclude that our low success rate in reaching the caecum (85%) could be responsible for some missing proximal cancers. Although the frequency of total adenomabearers seems not to be excessively high, the proportion of high-risk adenomas appears elevated. We can speculate that genetic factors influence the speed of adenoma growth rather than their number. This hypothesis is also supported by the results of Fossi et al. regarding the time of recurrence of adenomas in first-degree relatives of CRC patients [47]
A. Pezzoli et al. / Digestive and Liver Disease 39 (2007) 33–39
From screenees unwilling to undergo colonoscopy we received the results of only 6/10 FOBT and of 7/21 barium enemas performed; all were negative. We did not include this data in the analysis because the number of subjects and the sensitivity of both the exams in revealing small polyps must be considered very low [48,49]. We tried to identify some predictive factors for the presence of polyps. In previous publications [27,50], the early age of diagnosis of cancer in the index-cases and the number of affected relatives were the considered risk factors for the presence of polyps. Also in the present study the index patient’s age at cancer diagnosis increased the risk of finding adenomas in first-degree relatives when comparison was limited to screenees in whom the diagnosis of cancer in the index-case was obtained at an age of >64 years. Similar findings were obtained by Pariente et al [28]. The number of first-degree relatives did not influence the risk of adenomas in the screenees. This finding, which is discordant with the literature, is difficult to explain; we may hypothesize that the high incidence of cancer in the area of Ferrara has important extrinsic risk factors that could mask the role of hereditary factors, such as they are expressed by the number of relatives affected by colorectal cancer. The advanced age of patients and the male sex are well-known risk factors for neoplasm [39,51,52]. Our data confirm these findings, with a significant increased number of adenomas for every decade of age and for male subjects with respect to females. Our screening program has suffered from some limitations. Above all, it has to be admitted that the number of subjects seen after 5 years was not as high as we expected. We could not estimate the exact number of potential screenees, but a mean of 1.2 relatives per index-case participating is certainly suboptimal. This finding stresses the need for more intensive information about the usefulness of screening campaign among relatives of CRC patients, surgeons, oncologist and last but not the least general practitioners [29,53,54]. Another limitation is that the coecum was intubated in not more that 85% of the colonoscopies. This result is lower than those reported in American studies [9,55] in which the coecum was reached in about 97%. However, in most of those studies, the exams were performed under conscious sedation using intravenous agents. We think that in clinical practice, this high percentage might be difficult to reach. Moreover, we do not routinely use sedation because it is associated with complications, it is a time consuming procedure, increases costs, requires a longer recovery period, and is, at least in our experience, rarely requested by patients. Consequently, sedation was used by us in only 7.5% of the colonoscopies. Moreover, the 85% of coecal intubation rate is similar to that achieved by other European studies [56–58]. We agree that in the future, the ceocal intubation rate should be increased to at least 90%, possibly by more generous application of sedation because of the reported high incidence of proximal cancer in these subjects [45,46] but also in order to increase the compliance to the screening campaign and the follow-up.
37
Colonoscopy remains an invasive procedure that can provoke complications including bleeding, perforation and adverse cardiopulmonary events [59]; we observed only one perforation related to polypectomy a figure similar to those reported in the previous large series of patients [60,61]. New screening methods are now available for the analysis of genetic changes in fecal DNA [62–64] and virtual colonoscopy using abdominal spiral computed tomography [65–67]. However, many doubts remain as to whether these new tools are ready for a widespread application [24,68,69]. Thus, so far primary colonoscopy probably remains an attractive option for all programs that intend to screen for CRC in persons with either normal or increased risk of this condition. In conclusion, our data show that colonoscopy screening in a high-risk population is feasible, effective and well accepted. The high number of advanced neoplasms found suggests that this policy could be efficient in reducing the incidence of CRC. Practice points • Screening colonoscopy in a high risk population is feasible and generally well accepted. • A preliminary interview, with direct physician-patient contact, can increase the compliance rate to colonoscopy. • The attendance rate in screening colonoscopy remains low and should be increased by involving public administration and general practitioners. • First-degree relatives of CRC patients have a high percentage of adenomas with high grade dysplasia and cancer.
Research agenda • Longer follow-up to assess the efficacy of screening-colonoscopy in reducing the incidence and mortality of CRC in increased risk subjects. • Usefulness of sedation in order to increase the compliance to screening colonoscopy. • Comparison of colonoscopy with other new screening methods in this subset of subjects. • To study whether hyperplastic polyps may have a malignant potential in populations of subjects with an increased risk of cancer.
Conflict of interest statement None declared.
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