Journal of Epidemiology and Community Health 1997;51:453-458

Results of a pilot study of endoscopic screeningof first degree relatives of colorectal cancer

patients in Italy

Laura Colombo, Gianluigi Corti, Filippo Magri, Alessandro Marocchi,Paolo Brambilla, Carla Crespi, Luigi Manieri, Sergio Ghezzi, Daniela Giannone,Luca Merlino, Paolo Mocarelli

AbstractStudy objective-Screening recommenda-tions for colorectal cancer include sig-moidoscopy in asymptomatic, average riskpersons aged 50 and over and colonoscopyevery three to five years in high riskgroups. Little is known about the eligiblepopulation's compliance with endoscopicscreening. This is the first Italian reportofan endoscopic screening programme forcolorectal cancer patients' relatives.Design-In 1986, a pilot project for colo-rectal cancer screening by endoscopy inhigh risk subjects was started in the Desio(Milan, Italy) public health service region.The results obtained after seven years aredescribed.Setting-The names of 536 inhabitantswith colorectal cancer diagnosed betweenJanuary 1975 and December 1984 and theirrelatives' addresses were obtained fromthe Regione Lombardia Health System re-cords and from the municipal registryoffices respectively.Participants-From October 1986 to Oct-ober 1993, 778 first degree relatives aged20-75 were offered colonoscopy.Main results-After seven years, 233(29.9%) had undergone endoscopic ex-amination, mostly up to the splenic flex-ure. Being >60 in age at the start of theprogramme negatively affected par-ticipation (p<0.05). Two cancers were de-tected and adenomatous polyps werefound in another 24 ofthose screened (fre-quencies: 0.9% and 10.3% respectively).Male gender (p<0.05), increasing age inmales (p<0.01), and two or more affectedrelatives in females (p<0.01) positivelyaffected the frequency ofpolyps detection.Conclusion-These results suggest thatabout 30% ofthe eligible population wouldcomply at least with sigmoidoscopicscreening. The coliaboration of familydoctors and more widespread public in-formation about the ability to cure colo-rectal cancer are necessary for bettercompliance.

(JT Epidemiol Community Health 1997;51:453-458)

About 14 000 people die from colorectal cancerevery year in Italy,' and about 56 000 in theUnited States.2 Among the four high mortalitycancers (that is, lung, colorectal, breast, and

prostate), colorectal cancer is the only one thathas become more curable in the past 25 yearsand the progressive stages of this cancer arenow biologically known.34

It has been shown that annual faecal occultblood testing can decrease colorectal cancermortality by 33%,' while sigmoidoscopicscreening can lead to a reduction in mortalityof at least 30-40% 67 and colonoscopy everythree to five years in the high risk populationmight result in a reduction of approximately60-75 %.8 Every year in Italy, therefore, 4000-6000 people could, in theory, survive if screen-ing strategies were successfully applied.

Current screening guidelines for colorectalcancer910 include stool blood testing performedannually and flexible sigmoidoscopy every threeto five years in asymptomatic people over theage of 50 who are at average risk for colorectalcancer. Colonoscopy is recommended for highrisk groups,210 such as siblings of colorectalcancer patients, who are three times more likelyto develop the disease and may account for12-25% of all colorectal cancers.81'Faecal occult blood testing is the only screen-

ing method whose effectiveness has beenproved by a randomised trial.5 It was suggested,however, that part ofthe benefit might be due toa random selection for endoscopic examinationcaused by the low specificity of the methodused,'2 since 38% of the annually screenedparticipants underwent at least one colon-oscopy during the study.5Greenberg and Baron suggested that faecal

occult blood testing should be bypassed andendoscopy should be used directly as a screen-ing tool.'3 Colonoscopy can detect both colo-rectal cancer and adenomatous polyps withhigh accuracy,'4 and colonoscopic removal ofpolyps decreased the expected incidence ofcolorectal cancer by 76-90%, as reported byWinawer et al." Flexible sigmoidoscopy per-mits a 50-60% theoretical detection of colo-rectal cancers and the removal of small polypsin the rectum and the distal part of the largebowel, usually reaching a distance of 40-50 cmfrom the anus.'6 The procedure is simpleenough to be performed by nurses, which re-duces costs.'7 18 Besides the expense, dis-advantages of endoscopic screening includepatient discomfort and the risk of bowel per-foration (about 1.4 per 10 000 sigmoidoscopiesand 2 per 1000 colonoscopies).'920There have been few reports of the feasibility

of endoscopic screening for colorectal cancer

UniversityDepartment ofClinical Pathology,L ColomboA MarocchiP BrambillaC CrespiD GiannoneP Mocarelli

Endoscopy Unit,G CortiF Magri

Associazione MediciDesio,L ManieriS Ghezzi

and Clinical Director'sOfficeL Merlino

Hospital of Desio,20033 Desio, Milan,Italy

Correspondence to:Dr L Colombo,Dipartimento Universitariodi Patologia Clinica,Ospedale di Desio, PiazzaBenefattori 1, 20033 Desio(Milano5, Italia.Accepted for publicationJanuary 1997

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Colombo, Corti, Magri, et al

to date.2"22 The Desio screening programmeis the first Italian report of colorectal cancerscreening based on endoscopy. We report theresults obtained in a group of first degree rel-atives of patients affected by colorectal cancerwho were offered screening, including a com-plete colonoscopic examination, from October1986 on. The aim of the programme was pre-vention of colorectal cancer by locating andremoving adenomatous polyps in subjects athigh risk because of a positive family history,including those who might belong to familiesaffected by familial adenomatous polyposis andhereditary non-polyposis cancer, whose pres-ence in the group could not be excluded onthe basis of available information. For thatreason, although the age at which screeningshould be started, in absence of a genetic syn-drome, is 5-10 years younger than the youngestcancer relative or age 40 years, 20 and 75 yearsof age were chosen respectively as the lowestand highest entry age limit.

MethodsRECRUITMENTThe names of 536 colorectal cancer patientsdiagnosed between January 1975 and De-cember 1984 in the public health service regionof Desio (Unita Socio Sanitaria Locale 63,Desio, Milan, Italy), which has about 130 000inhabitants, were obtained from the officialrecords of the Regione Lombardia Health Sys-tem, which comprehensively registers all hos-pital diagnoses and causes of death. Eachpatient's identity and cancer diagnosis wereverified by examining his/her hospital records.The names and addresses of family members

were obtained from the municipal registryoffices and a file was created, consisting of 802first degree relatives, aged between 20 and 75years, belonging to 355 families.Between October 1986 and October 1993

the relatives were repeatedly invited to undergoa screening protocol that included the col-lection of a personal and family history, faecaloccult blood testing, and colonoscopy. Theprotocol also included a dietary interview witha dietician, measurement of anthropometricalparameters, and 12 blood analyses (results notincluded in the present report).The project was presented to and discussed

at different meetings with the 1 0 family prac-titioners of the public health service region.Their names were obtained from the officialrecords of the Unita Socio Sanitaria Locale 63.They were given literature, material for faecaloccult blood testing, and a list of their patientswho had been included in the screening pro-gramme and whose participation they wererequested to solicit.

In addition to the invitations extended byfamily practitioners, beginning in 1989, thetarget subjects were also invited to participateby a letter that stressed the increased risk ofdisease in consanguineous relatives. These let-ters were sent out three times over a five yearperiod (almost every second year). Moreover,the 355 families were contacted once by phoneand, at their consent, were visited by trained

personnel who explained the aim of the screen-ing programme. Participants were requested tomake an appointment by phone.The family practitioners were kept informed

periodically on the progress of the programme.

PROCEDUREPersonal andfamily historyThe personal and family history of each par-

ticipant were collected by trained medical per-

sonnel, who filled out a questionnaire. Familyhistory investigation included information con-cerning stomach, breast, lung, endometrium,ovary, and urinary tract cancers.

EndoscopyAfter receiving their informed consent, colon-oscopy was performed. The participants were

supplied with full bowel preparation in-structions according to the standard procedurein use at the Desio Endoscopy Unit. In 1987-90, this required a residue-free diet in the 48hours before the examination, together withsaline purgatives and voiding enemas. From1991 on, however, a polyethylene glycol elec-trolyte lavage solution was used. Patients re-

ceived 20 mg of butylscopolamine bromide byintravenous injection before the examination.Analgesic premedication before colonoscopywas not in use at the Desio Endoscopy Unitduring the years of the screening programme.The equipment used was a standard Pentax(160 cm) fiberoptic instrument in the years1987-90 (Pentax -API SpA, Milan, Italy) andan apparatus for video-endoscopy (C 3800 andC 3810, Pentax-API SpA, Milan, Italy) sub-sequently. The examinations were performed'by the same two endoscopists in turn. When a

colonoscopy was incomplete and the subjectwas over 50 in age, a double contrast bariumenema was recommended.

Statistical analysisResults were processed by a SPSS/PC+ pack-age. The X2 test (with the appropriate degreesof freedom) was used to assess the differencesbetween groups; Fisher's exact test (two tailed)was used when the minimum expected fre-quency was less than 5. A p value <0.05 was

regarded as significant.

KEY POINTS* Screening of first degree relatives of colo-rectal cancer patients should include colon-oscopy every three to five years starting atthe age of 40 years.*About 30% of the eligible population inthat high risk group would comply withsigmoidoscopic screening at least.* Compliance was lower in those over 60years at the start of screening, probably dueto fear of a cancer diagnosis and lack ofeducation about prevention.

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536 colorectal cancer -_ 181 without recordedpatients (1975-1984) first degree relatives

355 index cases

802 recorded first degreerelatives (aged 20-75)

778 relatives contacted:*425 males353 females

320 responders (41.1%)

233 endoscopies performed (29.9%)** 121 males (28.5%)** 112 females (31.7%)*

-- 87 faecal occultblood test only

*Percentage of subjects screened versusthose contacted.

Figure 1 Compliance with endoscopic screening forcolorectal cancer in Desio, Italy.

ResultsCOMPLIANCE WITH COLONOSCOPIC SCREENINGAs summarised in figure 1, 778 living, firstdegree relatives of the 355 colorectal neoplasmpatients were contacted. Altogether 425 ofthem were males and 353 were females.

After seven years, 233 subjects from thegroup (29.9%) had complied with the screeningprogramme and had undergone at least oneendoscopy; 87 more persons (11.2%) had hada faecal occult blood test without endoscopy.Consent was greatest in the first two years

(1987-88), when 187 subjects took part inscreening and 108 endoscopies were per-formed. It fell during subsequent recalls-therewere 69 participants in 1989-90 (65 endo-scopies) and 64 in 1991-93 (60 endoscopies).Gender did not affect participation. The mean

age at the first endoscopy was 44.3 in males(range: 26-68; SD: 10.8) and 45.8 in females(range: 23-74; SD: 11.2).Compliance with endoscopic screening in

relation to the age at the beginning of theprogramme was evaluated. Thirty six out of205subjects aged 20-29 at 10/01/1986 (17.6%)underwent endoscopy. Significant differencesin participation were observed in older subjects

Table 1 Compliance with endoscopic screening for colorectal cancer in relation to age atthe start of the programme

Age (y) at start of screening*

30-39 40-49 50-59 60

Screened (no (%)) 71 (39.4) 61 (36.3) 50 (33.1) 15 (20.3)Contribution to X2 (3df) 1.34 0.18 0.07 4.28Not screened (no (%)) 109 (60.6) 107 (63.7) 101 (66.9) 59 (79.7)Contribution to x2 (3df) 0.70 0.10 0.04 2.25Total (no (%)) 180 (100.0) 168 (100.0) 151 (100.0) 74 (100.0)Contribution to X' (3df) 2.04 0.28 0.11 6.53

x2 (3df) = 8.96 p<0.05* Age of first degree relatives at 10/01/1986. Among people aged 20-29, 36 out of 205 subjects(17.6%) took part in the screening.

(table 1), with the highest compliance in theage groups 30-39 and 40-49, lower compliancein the group 50-59, and a drop in people aged60 or older.Education level in the screened group was

compared with that of the general population(about 4 000 000 people) in the province ofMilan, as per the 1991 national census data.2'No significant difference was seen when par-ticipants were stratified by age.

ANATOMICAL SITE REACHED BY ENDOSCOPYColonoscopy was performed up to the caecumin 48 of 223 subjects (20.6%), including thosewho were found positive for colorectal neo-plasms. In the remaining 185 participants(79.4%), the examination was terminated atdifferent bowel sites for the following reasons:* Discomfort which negatively affected patient

compliance (54%),* Poor bowel preparation (40%),* Risk of complications because of technical

difficulties (6%).The transverse colon was reached in 30 sub-

jects (12.9%), the splenic flexure in 99 (42.5%)and the descending colon in 56 (24.0%).

FAECAL OCCULT BLOOD TESTING RESULTSAmong the 233 participants who underwentendoscopic screening, the faecal occult bloodtests yielded 1 true positive (in a subject witha Dukes's A cancer of the transverse colon), 1false positive (in a subject without neoplasms),3 false negatives (in subjects whose endoscopydisclosed adenomatous polyps measuring10 mm in diameter or more), and 228 truenegatives. The subjects with polyps less than10 mm in diameter were not regarded as falsenegatives, even though none of them testedpositive, because their lesions were consideredto be bleeding only intermittently.24 Test sensi-tivity and specificity were 25% and 99% re-spectively.Among the 87 subjects who agreed to un-

dergo faecal occult blood testing but refusedendoscopy, two tested positive with Haem-occult II. One of them underwent an operationfor colon cancer two years later, the other onewas lost to follow up.

THE NEOPLASTIC FINDINGS AT SCREENINGTwo subjects with cancer (frequency=0.9%)and 24 with adenomatous polyps (frequency =10.3%) were found among the 233 screenedparticipants. Twenty seven adenomatouspolyps were found (more than 1 finding persubject). The anatomical site and pathologyof the neoplastic findings are shown in table 2.A Dukes's A cancer of the transverse colon

was found in a subject who also had two tubularpolyps. The polyps were found in the sigmaand descending colon respectively. Carcinoma"in situ" was seen in a 2.5 cm large, villo-tubular adenoma.A single tubular adenoma located in the

ascending colon was found in a participant who

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Colombo, Corti, Magri, et al

Table 2 Anatomical site and pathology of the neoplastic findings* in 26 subjects

Pathology Anatomical site

Rectum Sigma Descending Transverse Ascendingcolon colon colon

Cancer Dukes's A - - - 1Carcinoma in situ 1Villo-tubular adenoma - 5 2Tubular adenoma - 12 7 - 1Total 1 17 9 1 1No of screened subjectst 233 233 177 78 48Frequency (%) 0.4 7.3 5.1 1.3 2.1

* More than 1 finding per subject.t Number of subjects whose corresponding anatomical site was examined.

Table 3 Adenomatous polyps in relation to age andfamily history

Age (y)8 Positive versus screened subjects (%)

1 relative 2 relatives Totalaffected affected

Males20-39 0/40 1/11 (9.1) 1/51 (2.0)40-59 8/44 (18.2) 3/15 (20.0) 11/59 (18.6)60 2/4 (50.0) 4/6 (66.7) 6/10 (60.0)All ages 10/88 (11.4) 8/32 (25.0) 18/120 (15.0)

Females20-39 0/25 0/9 0/3440-59 1/48 (2.1) 5/17 (29.4) 6/65 (9.2)60 0/9 0/3 0/12All ages 1/82 (1.2) 5/29 (17.2) 6/111 (5.4)

* Age of the participants at the time they underwent endoscopy.

had consented to undergo colonoscopy up tothe caecum.

FREQUENCY OF POLYPS IN RELATION TO SEX,AGE, AND FAMILY HISTORYThe subject with Dukes's A cancer was a 56year old man, while the in situ carcinoma was

found in a 31 year old woman. They both hadonly one first degree relative with colorectalcancer.

The influence of gender, age, and familyhistory on the frequency ofadenomatous polypsin the group of participants was investigated(table 3), although the real prevalence of neo-plastic findings could not be calculated becauseof the incompleteness of endoscopic ex-

amination.No cases of familial adenomatous polyposis

were encountered. All the subjects who hadtwo or more colorectal cancer patients in theirfamily history (n= 61) were grouped separatelyfrom those who had only one (n= 170). The

kinship of 15 subjects included not only twoor more members with colorectal cancer butalso two or more members with cancers atother sites (stomach, breast, lung, or ovary).Their eight families did not strictly fulfil therequirements for the clinical diagnosis of her-editary nonpolyposis colorectal cancer, how-ever," so they were not grouped apart.

Polyps were found more frequently in menthan in women (p<0.05). In male subjects a

higher frequency of adenomatous polyps was

associated with increasing age (p<0.0 1). Polypswere more frequently found in subjects withtwo or more relatives affected by colorectalcancer than in subjects who had only one, butthe difference reached a statistical significanceonly for women (p<0.01).

DiscussionAlthough endoscopic screening begins to betaken into account as a promising tool forcolorectal cancer prevention,'82627 its im-plementation poses many problems includingthe cost benefit ratio, the availability of therequired skill and technology, and a good levelof compliance with the proposed procedure bythe target population.The present screening programme addressed

high risk consanguineous relatives of colorectalcancer patients. The prevalence of ad-enomatous polyps found in this group agreedwith that obtained by Rozen in a screeningprogramme for colorectal neoplasm, wheredifferent screening methods (faecal occultblood testing, flexible sigmoidoscopy, colon-oscopy) were used according to the degree ofcancer risk.25

After 7 years of screening, the complianceof the target population was 41.1% for faecaloccult-blood test and 29.9% for endoscopy.The percentages of participants are con-siderably lower than those reported by Steph-enson et al,22 who performed colonoscopy in107 out of 154 (69%) first degree relatives ofcolorectal cancer patients and sigmoidoscopyin 30 out of 64 (47%) spouses. In their pro-gramme, a relatively short time had elapsedsince the index cases' diagnosis of colorectalcancer had been established, a factor that couldhave favourably affected the outcome. Never-theless, the level of compliance with endoscopyachieved in the present screening programmewas close to that reported for sigmoidoscopyin two other studies-31% in the Kaiser multi-phase evaluation study2l and 24% reported byDietrich et al.29Gender did not affect the propensity to un-

dergo screening in this study. However, sig-nificant differences in participation were seenin relation to age. The decrease in compliancerecorded in subjects who were over 60 at thestart of the screening programme is worrisomeas colorectal cancer incidence rates rise withageing.30 Possible explanations for that findingcould be, firstly, better education in main-taining healthy lifestyles in younger people and,secondly, the fear, which could increase withageing, of getting an advanced diagnosis of adisease thought to be incurable.The sensitivity of faecal occult blood testing

by Haemoccult II (without rehydration) rangesfrom 80 to 31% for cancers,5 19 24 and is thoughtto be about 10% for large adenomas."9 Thesensitivity obtained in the Desio screening pro-gramme was rather low, as expected inasymptomatic people, and it is improbable thatthe faecal occult blood test results exerted anypositive influence on the participants' pro-pensity to undergo endoscopic screening. It isremarkable that 2 of the 320 responders, whoconsented to undergo faecal occult blood test-ing but refused endoscopy, persisted in refusingit even though their tests turned out to bepositive.

Difficulties in completing the endoscopic ex-amination up to the caecum were encounteredboth in men and in women; it is probablethat better results would have been achieved if

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analgesic agents had been used, since mostof the examinations were stopped when thepatients judged the discomfort to be un-bearable. Nonetheless, colonoscopy could beperformed in subjects found positive for colo-rectal neoplasms, either immediately or at asecond recall. That was certainly due to thepropensity of endoscopists to complete ex-ploration up to the caecum or not, taking intoaccount that the risk of complications increaseswith the depth of exploration.920 Nevertheless,it also suggests that being aware of personalrisk can positively affect the compliance ofparticipants.During the seven years ofthe Desio screening

programme, one Dukes's A carcinoma and onevillo-tubular adenoma with carcinoma in situwere detected among 233 participants. Boththe neoplasms were in the early stages, as wouldbe expected in a screening programme ofasymptomatic people. Bertazzi et al found 9colorectal cancers per 31 384 person-years inaverage risk men and women aged 20-74 livingin the area north of Milan that includes Desio,31while Ponz de Leon et al reported a total crudeincidence of 52.8 colorectal cancer cases per100 000 person-years in the northern Italy dis-trict ofModena.32 On the basis ofboth authors'data and considering the increase in colorectalcancer risk associated with a family history, theexpected number of carcinomas in the groupthat underwent endoscopic examination variedfrom 0 to 3. Owing to the incompleteness ofcolonic examination, the possibility that can-cers proximal to the splenic flexure had goneundetected cannot be excluded (the continuingfollow up of cancer diagnosis, for the moment,has reached the year 1990).The frequency with which polyps were found

in the Desio group is comparable to the pre-valence reported by Rozen and by Stephensonet a!2522 when corresponding age groups aretaken into account. Other authors,3334 whosedata were based on full bowel colonoscopy,reported higher prevalence rates for ad-enomatous polyps in subjects comparable tothose of the present study for age, gender, andfamily history.Although the real prevalence ofadenomatous

polyps in the Desio group could not be assessed,the findings of the screening programme seemto confirm the data of different authors,28 32 33 35who have reported an increasing prevalencewith ageing, and a higher prevalence of ad-enomatous polyps in males than in females andin subjects with two or more colorectal cancerpatients in their family history than amongthose with only one.35The results of the Desio screening pro-

gramme suggest that about 30% of the eligiblepopulation would consent to undergo colo-rectal cancer screening by endoscopic ex-amination. In other words at least 1000-1500deaths could be prevented in Italy in one year.

Nevertheless, the Desio endoscopic screen-ing results suggest that before colorectal cancerscreening by endoscopy can be successfullyimplemented in a large eligible population,widespread information must be supplied tothe public about the ability to cure colorectal

cancer in its early stages and the benefit ofdetecting adenomatous polyps in order to im-prove the acceptability of such a screeningmethod. An example among cancer preventiontools could be the publicity given to mam-mography in the USA, where the percentageof women who had undergone a mammogramat least once increased from 13-17% in 1978 to74% in 1992.3" As calculated by Ransohoff,27 thecost per life saved by a one time colonoscopicscreening is comparable with that of mam-mographic screening, and the higher curabilityof early colorectal cancer in comparison withbreast cancer3 prompts such an effort.

We thank the family practitioner doctors of the "AssociazioneMedici Desio" for their contribution to the study.Funding: supported by a research grant no 2567/127 from theRegione Lombardia, Milan, ItalyConflicts of interest: none

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