Baseline Findings of the Italian Multicenter
Randomized Controlled Trial of “Once-Only
Nereo Segnan, Carlo Senore, Bruno Andreoni, Hugo Aste, Luigina Bonelli,
Cristiano Crosta, Roberto Ferraris, Stefano Gasperoni, Angelo Penna, Mauro
Risio, Francesco Paolo Rossini, Stefania Sciallero, Marco Zappa, Wendy S. Atkin
And the SCORE Working Group - Italy
Background: A single sigmoidoscopy examination at around
age 60 years has been proposed as a cost-effective strategy to
prevent colorectal cancer. A multicenter randomized con-
trolled trial, the SCORE trial, is in progress in Italy to esti-
mate the impact of this strategy on colorectal cancer inci-
dence and mortality and the duration of the protective effect.
We present the baseline screening outcomes. Methods: A
questionnaire was mailed to a random sample of 236568
people aged 55–64 years to assess their eligibility for and
interest in screening. Those reporting a history of colorectal
cancer, adenomas, inflammatory bowel disease, recent colo-
rectal endoscopy, or two first-degree relatives with colorectal
cancer were excluded. Eligible, interested respondents were
assigned randomly to the control group (no further contact)
or the intervention group (invitation to undergo sigmoidos-
copy). Screenees with colorectal cancer, polyps larger than
5 mm, three or more adenomas, adenomas 5 mm or smaller
with a villous component of more than 20%, or severe dys-
plasia were referred for colonoscopy. Results: Of the 56532
respondents (23.9% of those invited), 34292 were enrolled
and 17148 were assigned to the screening group. Of those,
9999 attended and 9911 were actually examined by sigmoid-
oscopy. Distal adenomas were detected in 1070 subjects
(10.8%). Proximal adenomas were detected in 116 of 747
(15.5%) subjects without cancer at sigmoidoscopy who then
underwent colonoscopy. A total of 54 subjects was found to
have colorectal cancer, a rate of 5.4 per 1000 (54% of which
were Dukes’ A). The procedures were relatively safe, with
two perforations (one in 9911 sigmoidoscopy exams and one
in 775 colonoscopies) and one hemorrhage requiring hospi-
talization after polypectomy during colonoscopy. The pain
associated with sigmoidoscopy was described as mild or less
than expected by 83.3% of the screenees. Conclusion: Sig-
moidoscopy screening is generally acceptable to recipients
and safe. The high yield of advanced adenomas is consistent
with the projected impact of sigmoidoscopy screening on
colorectal cancer incidence. [J Natl Cancer Inst 2002;94:
Colorectal cancer is the second leading cause of cancer death
in Europe (1). In Italy, mortality rates from the disease have
remained fairly constant over the past decade, with approxi-
mately 17000 deaths per year (2). Based on projections from
past trends, about 40000 new cases were expected in 2000 in
Italy (3). Several observational and intervention studies have
shown consistent and marked reductions in both colorectal can-
cer incidence (4–8) and mortality (9,10) following colorectal
endoscopy and polypectomy. These studies showed a protective
effect of screening only for the colonic segments examined (4–
10) that was maintained for up to 10 years (9). The Minnesota
trial of fecal occult blood testing (11) was the first large trial to
show a reduction of incidence of colorectal cancer following
Affiliations of authors: N. Segnan, C. Senore (Unit of Epidemiology), Centro
per la Prevenzione Oncologica (CPO), Piemonte, Torino, Italy; B. Andreoni
(Unit of Surgery II), C. Crosta (Unit of Gastroenterology), European Institute of
Oncology, Milano, Italy; H. Aste, Department of Oncology, Biology, and Ge-
netics, University of Genova, Italy, and Unit of Gastroenterology and Nutrition,
National Institute for Cancer Research, Genova; L. Bonelli (Unit of Clinical
Epidemology and Trials), S. Sciallero (Unit of Gastroenterology and Nutrition),
National Institute for Cancer Research, Genova; R. Ferraris, Unit of Gastroen-
terology, Mauriziano “Umberto I” Hospital, Torino, Italy; S. Gasperoni, Unit of
Gastroenterology, Infermi Hospital, Rimini, Italy; A. Penna, Fondo “E Tempia,”
Azienda Sanitaria Locale (ASL), 12, Biella, Italy; M. Risio, Unit of Pathology
(IRCC), Candiolo, Torino; F. P. Rossini Unit of Gastroenterology, San Giovanni
AS Hospital, Torino; M. Zappa, Unit of Clinical Epidemology, Centro per lo
Studio e la Prevenzione Oncologia (CSPO), Firenze, Italy; W. S. Atkin, Imperial
Cancer Research Fund, Colorectal Cancer Unit, Harrow, Middlesex, U.K.
Correspondence to: Nereo Segnan, M.D., M.S. Epi, Unita’ di Epidemiologia,
CPO - Piemonte, Azienda Sanitaria Ospedaliero (ASO), “S Giovanni Battista,”
Via S Francesco da Paola 31, 10123 Torino, Italy (e-mail: email@example.com).
See “Notes” following “References.”
© Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 23, December 4, 2002ARTICLES 1763
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The protective effect of endoscopic polipectomy supports the
hypothesis that colorectal carcinomas arise from adenomas, with
an estimated average transition time to malignancy of approxi-
mately 10–15 years (12–14). Based on these findings, it was
estimated that a single sigmoidoscopy screen might be a cost-
effective and feasible strategy for colorectal cancer screening
among individuals at average risk for the disease (15). Two
further observations provide support for the idea that a single
sigmoidoscopy screen may be effective in preventing a consid-
erable proportion of colorectal cancer: the prevalence of distal
adenomas in asymptomatic individuals appears to reach a pla-
teau at around the age of 60 years (15), and data from European
Cancer Registries show that among patients aged 55–74 years
about two thirds of colorectal carcinomas are located in the
rectum or sigmoid colon (16).
A controlled trial of “once-only” sigmoidoscopy screening
for colorectal cancer (the SCORE trial) was undertaken in Italy
as a parallel study to a multicenter trial in the United Kingdom
(17,18). The goal of these trials was to measure the extent of
reduction in colorectal cancer incidence and mortality achieved
by a single screening sigmoidoscopy examination and to deter-
mine both the optimum age interval (i.e., 55–59 or 60–64 years
of age) for screening and the duration of the protective effect of
a single test. The recruitment and screening phases of the
SCORE trial have now been completed. Here we report on re-
sults concerning the neoplasia detection rate and safety and ac-
ceptability of this method of screening.
SUBJECTS AND METHODS
Approval for the study was granted by the local ethics review
committees in each center. Subjects were identified either
through physicians or directly. In Arezzo, Rimini, and Torino,
the target population was selected from the patients of a random
sample of general practitioners drawn from the National Health
Service (NHS) list of those working in the study areas. In Mi-
lano, the patients were selected from the list of all general prac-
titioners who were invited and volunteered to cooperate. In
Genova and Biella, a random sample of individuals in the target
age range was drawn directly from the NHS register. All indi-
viduals aged 55–64 years included in these samples (that is,
resident in the study areas and listed in the NHS lists that pro-
vided their names) were mailed a questionnaire designed to as-
sess their eligibility for and interest in screening, with an ac-
companying letter giving brief information about the
sigmoidoscopy and explaining the rationale for the study. A
prepaid envelope for returning the questionnaire was also pro-
vided. No reminder was sent to nonresponders. Responders were
excluded if they reported a history of colorectal cancer, colorec-
tal polyps, or inflammatory bowel disease had had a colorectal
endoscopy within the previous 2 years; had two or more first-
degree relatives with colorectal cancer; or had a medical condi-
tion that would preclude benefit from screening.
Random Assignment and Invitation for Screening
People who answered that they were probably or definitely
not interested in screening were not contacted again. Eligible
respondents who indicated that they would definitely or prob-
ably undergo screening sigmoidoscopy if it were offered to them
were assigned randomly to the intervention or control group in
a 1:1 ratio. Random assignment was performed in each center
by the local coordinating unit with the use of a computer-
generated allocation algorithm. In Biella, Genova, and Milano,
subjects were assigned randomly on an individual basis; in Mi-
lano the algorithm automatically assigned spouses to the same
arm of the trial. In Arezzo, Rimini, and Torino, a cluster ran-
domization was adopted, with the unit of randomization being
the physician. In these centers, general practitioners were strati-
fied according to the proportion of eligible respondents and then
randomized in a 1:1 ratio within each class of response rate
(ranging from 5% to 35%), based on a computer-generated ran-
dom number sequence.
Subjects assigned to the control group were not contacted.
Subjects assigned to the intervention group were sent a personal
invitation letter, signed by their physician (or by the study co-
ordinator, if the physician refused), with a prescheduled appoint-
ment for a sigmoidoscopy. A leaflet containing a brief descrip-
tion of the procedure and mentioning its possible side effects
was also included. Recipients were asked to call the screening
center to confirm, reschedule, or cancel their appointment.
Those who agreed to a test date were asked to visit their phy-
sician or the screening center to obtain an enema kit. A reminder
letter was mailed to all individuals who did not respond to the
first invitation letter. In Rimini and Torino, a second invitation
was sent to those who did not respond to the first invitation and
to the reminder after 12 months.
Screening was undertaken by specialist gastroenterologists in
hospital endoscopy units. Bowel preparation was limited to a
single enema (133 mL of 22% sodium phosphate) that subjects
were asked to self-administer at home 2 hours before the test. No
dietary restriction was recommended. All patients gave written
informed consent for the screening procedure before it was done.
A 140-cm colonoscope was used in all centers except Genova,
where a sigmoidoscope was used. The aim of the examination
was to advance the endoscope beyond the sigmoid-descending
colon junction under adequate bowel preparation. No sedation
was offered, but it could be administered if the endoscopist
thought it was necessary. The endoscopist recorded on a stan-
dard form information about adequacy of bowel preparation,
reach of the scope, characteristics of detected lesions, visualiza-
tion of other findings, and occurrence of immediate complica-
tions. If the sigmoidoscopy could not be performed because of
inadequate bowel preparation, the screenee was invited to repeat
the test at a later date.
After the examination, the endoscopist gave each patient a
letter explaining the results and reminding the patient of the
limitations of the procedure already mentioned in the leaflet.
Individuals were advised to contact their physician or the en-
doscopy unit if they noticed rectal bleeding or experienced ab-
dominal pain during the first few days after the procedure. Im-
mediately after the exam, all screenees were asked to complete
a short questionnaire administered by a research assistant inde-
pendent of the endoscopy staff, asking about the degree of pain
and embarrassment experienced during the test. Patients were
asked by the interviewer to indicate which of four mutually
exclusive statements best described their experience of pain:
only mild discomfort; I thought it would be worse; I hope it will
not be necessary to repeat the test again; it was the most severe
pain I have ever experienced. Embarrassment was also rated on
a four-level scale: unacceptable, severe, moderate, mild.
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Management of Polyps and Referral for Colonoscopy
The study protocol stipulated that polyps 5 mm or smaller
should be removed during sigmoidoscopy, using the cold snare
technique (19–20). Diathermy snare was not recommended be-
cause it has been associated with an increased risk of compli-
cations (21–22) and because the heating effect of electro-
coagulation may render the specimens difficult to examine (20).
Screenees who had one distal polyp larger than 5 mm, or inad-
equate bowel preparation and at least one polyp, or invasive
colorectal cancer were referred for colonoscopy. In a few cases
the referral to colonoscopy was made by the endoscopist, based
on his or her clinical judgement. Any removed polyp was ana-
lyzed by histologic examination. Colonoscopy was also indi-
cated, on the basis of histologic examination of small polyps
(?5 mm) excised at sigmoidoscopy, for subjects with three or
more adenomas, with one villous or tubulovillous adenoma [vil-
lous component >20% (23)], or with one adenoma with severe
dysplasia. When the colonoscopy could not be completed due to
patient discomfort, a double-contrast barium enema was indi-
cated; when that could not be achieved due to unsatisfactory
bowel preparation the patient was invited to undergo a repeat
colonoscopy within 6 months.
Criteria for colonoscopic surveillance. A follow-up colo-
noscopy was scheduled at 3 years for all patients who, after
being referred for colonoscopy, were found to have colorectal
cancer or “high-risk” adenomas (i.e., one adenoma of ?10 mm
an adenoma with severe dysplasia, an adenoma with villous
component >20%, or three or more adenomas of any type).
Subjects with negative sigmoidoscopy or with other types of
polyps were discharged and offered no further follow-up.
Histologic evaluation. Polyps and cancers were classified
according to World Health Organization criteria (23). Cancer
was defined as the invasion of malignant cells beyond the mus-
cularis mucosae. To avoid inappropriate bowel surgery, slides of
malignant adenomas were reviewed by two pathologists (a con-
sensus diagnosis was reached in case of discordance) to assess
features associated with low risk of lymph nodal metastases (24)
(i.e., low-grade, well, or moderately differentiated lesions; re-
section margin free of cancer; neoplastic embolization absent).
In addition, slides of all cancers and of a sample of adenomas
with severe dysplasia were reviewed blindly by one pathologist
from the U.K. group that was conducting the parallel flexible
sigmoidoscopy screening trial (Professor G. Williams), and one
pathologist from the Italian group (Dr. M. Risio). The classifi-
cation of discordant cases was based on the majority diagnosis
including the original diagnosis.
Polyp size was classified according to the diameter of the
largest polyp recorded by the endoscopist. For the statistical
analysis the largest or the most advanced polyp detected in
each individual was used. Polyps detected at screening sigmoid-
oscopy, including those lesions located beyond the sigmoid-
descending colon junction, were defined as distal polyps.
A complete colonoscopy was reported if the cecum could be
visualized or, in the case of failure, when a second colonoscopy
performed within 6 months of the previous one was able to
visualize the cecum. The combined results of the two colonos-
copies were included in the analysis. Data concerning the per-
formance of colonoscopy, in terms of completion rate and com-
plications, are reported only for those examinations performed
before cancer surgery because colonoscopies performed after
bowel resection may be influenced by clinical and technical
factors that are not directly relevant to a screening context.
Chi-square tests were used to test for statistical significance
in comparisons of proportional parameters. Relative risks (RRs)
with 95% confidence intervals (CIs) computed on the basis of
the normal approximation of the log (RR) distribution using the
Taylor series-derived variance of log (RR) (25) were calculated
to estimate differences in the characteristics of detected lesions
by sex and age. All statistical tests were two-sided and were
considered statistically significant at P<.05. In this interim re-
port, we did not adjust for the hybrid randomization design in the
statistical analysis. As a consequence, the actual P values and
95% CIs may be slightly larger than those presented here. How-
ever, the differences are likely to be small, given the large num-
ber of clusters and their small size.
We planned to enroll 40000 eligible respondents and to
achieve an attendance rate of about 70% in the screening arm.
Assuming the age-specific incidence rates for the period 1988–
1992, as reported in the local cancer registries (26), and a
weighted lead time of screen-detected colorectal cancer
(weighted average) of 3.5 years, the targeted sample size would
give 80% power to detect a 21% reduction in incidence of
colorectal cancer in the intervention group at 6 years that is
statistically significant at the 5% level using a one-sided test
(27). A statistically significant reduction in mortality cannot be
detected before 11 years of follow-up.
Recruitment and Interest-in-Screening Questionnaire
We mailed the interest-in-screening questionnaire to 236568
people, of whom 56532 (23.9%) replied (Fig. 1). Of the 43010
(18.2%; range 14.8%–24.8% in the six trial centers) respondents
who said they would definitely or probably attend screening if
offered it, 4838 (11.2%) were found to be ineligible. Of the
13522 respondents who said they were not interested, 1244
(9.2%) were found to be ineligible (Fig. 1). In total, 34292
people were assigned randomly to one of the two arms (Fig. 1).
Cluster randomization (i.e., by physician) was used in three cen-
ters contributing 17602 patients from the rosters of 507 physi-
cians; the remaining 16690 patients were randomized individu-
ally. Recruitment began in October 1995 and was completed in
Characteristics of subjects assigned to the intervention and to
the control arm (Table 1) were estimated to evaluate the balance
of randomization. Age and sex were well balanced between the
intervention and control arms, as were family history of colo-
rectal cancer and interest in screening. The proportion of people
who had a colorectal endoscopy (colonoscopy or sigmoid-
oscopy) in the past 3–25 years was higher in the intervention arm
than in the control arm (8.6% versus 7.9%).
Compliance and Management of Trial Participants
Of the 17148 subjects randomly assigned to the intervention
arm, 9999 (58.3%) actually attended the endoscopy unit to re-
ceive a sigmoidoscopy exam (Fig. 1). Of the 9558 subjects who
indicated in the interest-in-screening questionnaire that they
would definitely have the test if invited, 6713 (70.2%) attended;
of the 7590 who responded that they would probably have the
test if invited, 3286 attended (43.3%) (P<.001).
Journal of the National Cancer Institute, Vol. 94, No. 23, December 4, 2002ARTICLES 1765
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Attendance rates in the different centers, except for Genova,
ranged from 54.3% to 64.1%. Overall attendance in Genova
(65.5%) was higher than in the other centers because, starting in
December 1996, only subjects who responded that they would
definitely have the test if invited were randomized at that center.
Indeed, low compliance was observed in Genova during the
initial recruitment period among subjects who responded that
they would probably have the test if invited; therefore, such
subjects were no longer randomly assigned. The second invita-
tion, which was mailed after 12 months to subjects who did not
respond to the first invitation and to the mailed reminder, re-
sulted in a 5.8% absolute increase in the attendance rate in
Rimini and Torino.
The sigmoidoscopy could be completed (i.e., reached beyond
the sigmoid-descending colon junction, under adequate bowel
preparation) on a single occasion in 7977 (79.8%) of the 9999
attenders. Among the remaining 2022 subjects, the examination
was terminated because of pain or bowel adhesions in 749 sub-
jects (37.0%), and unsatisfactory bowel preparation resulted in
only partial visualization of the colonic mucosa in another 650
subjects (32.1%). Of these 1399 (749 + 650) patients, 119 were
referred for colonoscopy because a polyp was detected in the
segments examined and the other 1280 subjects were not asked
to return for subsequent tests. The other 623 subjects (30.8%)
had bowel preparation that was so inadequate that no segment of
the bowel mucosa could be visualized; these subjects were all
offered new tests, and 535 (85.9%) attended. The examination
was completed to the descending colon in 468 of these individu-
als. Therefore, a complete sigmoidoscopy to the distal descend-
ing colon was achieved in 8445 (7977 + 468) of the 9999 at-
Out of 9999 screenees, 9911 (7977 + 749 + 650 + 535) were
actually examined, and 88 were not. Of the 9911 subjects who
were examined, there was no evidence of pathology in 8166
(82.4%) (Fig. 2). For 152 additional subjects, a tissue specimen
(?5 mm) was removed and classified by the pathologist as
normal for 96 subjects; the tissue was missed or the sample was
inadequate in the other 56 subjects. Another 741 subjects had
low-risk polyps 5 mm or smaller (i.e., a hyperplastic polyp in
306 subjects and a tubular adenoma in 435 subjects). An addi-
tional 20 patients (19 with clinical evidence of colorectal cancer
and one following perforation) were referred for surgery imme-
diately after sigmoidoscopy. The remaining 832 subjects were
referred for colonoscopy, and 775 (93.1%) of those attended
(Fig. 2). In 638 of the 832 subjects (Fig. 3), the colonoscopy was
indicated based on the characteristics of distal polyps; in 119
cases, referral for colonoscopy followed detection of a small
polyp during an incomplete sigmoidoscopy (this policy was
adopted to avoid a third endoscopic procedure—colonoscopy—
in those people in whom high-risk polyps were detected at the
second sigmoidoscopy); and in 75 cases, referral was based on
the clinical judgement of the endoscopist (e.g., presence of five
or more hyperplastic polyps, blood in the lumen of the intestine,
patients’ self-reported worry about abdominal symptoms, family
history of colorectal cancer, concern about safety of polypecto-
my for patients on anticoagulants).
Among the 775 patients who had a colonoscopy, the exami-
nation could not be completed to the cecum in 188 patients
(24.3%). Of these 188 patients (Fig. 3), 14 had a repeat colo-
noscopy within 12 months, 76 underwent a double-contrast
barium enema, one required surgery following perforation, and
17 refused further investigation; no further assessment was rec-
ommended for the remaining 80 patients. Overall, therefore,
only 17 patients of the 775 who had received colonoscopy were
not adequately assessed (Fig. 3). A subsequent surveillance
colonoscopy (Fig. 2) was indicated for 395 subjects (357 with
high-risk adenomas, 27 with low-risk distal adenomas who har-
bored polyps in the proximal colon that could not be recovered
for histologic examination, and 11 with colorectal cancer treated
Fig. 1. Trial flow diagram. *Because of the low compliance observed in Genova
during the initial recruitment period among subjects who responded that they
would probably have the test if invited, they were no longer randomized at this
center beginning in December 1996.
Table 1. Characteristics of the study population
N ? 17148
N ? 17144
Age at randomization
Interest in screening
Family history of colorectal cancer*
Colorectal endoscopy in the past†
*One first-degree relative with colorectal cancer (people with ?2 first-degree
relatives with colorectal cancer were excluded from randomization.
†Colorectal endoscopy, sigmoidoscopy, or colonoscopy performed between
3 and 25 years before study entry.
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Fig. 3. Trial profile showing indication to colo-
noscopy after screening sigmoidoscopy, and
management of subjects who received colonos-
Fig. 2. Management of trial participants.
Journal of the National Cancer Institute, Vol. 94, No. 23, December 4, 2002ARTICLES 1767
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by endoscopic excision); no further assessment was necessary
for 328 subjects (264 with low-risk polyps, 62 with pathology
deemed not clinically significant, and two with negative endos-
copy who had been referred for colonoscopy based on family
history or detection of blood in the distal colon); and surgery was
indicated for 35 subjects (17 with distal colorectal cancer, seven
with proximal colorectal cancer, 10 with adenomas that were
deemed to be too large for endoscopic excision, and one follow-
Yield of Benign Lesions
The prevalence of distal polyps among the 9911 subjects who
received sigmoidoscopy was 17.6%. Multiple polyps were de-
tected in 477 (4.8%) subjects (279 had two polyps, and 198 had
three or more). Distal adenomas were detected in 1070 (10.8%)
subjects (range, 5.9%–14.7% across the trial centers) (Table 2).
Men showed a statistically significantly higher prevalence than
women of non-neoplastic polyps (RR ? 2.08, 95% CI ? 1.71
to 2.53), adenomas (RR ? 1.64, 95% CI ? 1.46 to 1.85), and
colorectal cancer (RR ? 2.30, 95% CI ? 1.22 to 4.36). Distal
adenomas were detected more frequently among subjects 60
years of age and older than among those younger than 60 years
(RR ? 1.15, 95% CI ? 1.03 to 1.29). Subjects 60 years of age
and older also showed a higher prevalence of advanced adeno-
mas (?10 mm, with villous component >20%, or with high-
grade dysplasia) than those younger than 60 years (RR ? 1.28,
95% CI ? 1.04 to 1.58). The proportion of adenomas with
severe dysplasia or with villous component greater than 20%
also increased with polyp size: it was 9.8% for adenomas smaller
than 10 mm and 45.8% (P<.001) for adenomas 10 mm or larger.
Among the 775 subjects who underwent colonoscopy, the
pathologic examination diagnosed a (distal) cancer in 28 sub-
jects. They were referred to colonoscopy, according to the cri-
teria previously described, because at sigmoidoscopy distal le-
sions, without a manifest clinical appearance of cancer, were
detected. Among the 747 subjects without distal cancer (Table
3), proximal polyps were detected in 174 (23.3%), 116 of whom
were found to have adenomas (range, 3.5%–21.6% across the
trial centers). Men were twice as likely as women to have ad-
vanced adenomas in the proximal colon (RR ? 2.3, 95% CI ?
0.9 to 7.0). No association of pathology with age was observed
for proximal lesions.
There were a total of 54 subjects with colorectal cancer
(Table 4): 47 with a distal cancer, identified among the 9911
subjects who underwent sigmoidoscopy (19 immediately re-
ferred for surgery and 28 referred for colonoscopy), and seven
among the 747 patients without distal cancer who were referred
for colonoscopy. One patient with distal colorectal cancer also
harbored a synchronous malignant lesion in the proximal colon,
another harbored two tumors in the sigmoid colon, and a third
had two tumors at the splenic flexure. Thus, together these pa-
tients contained 57 malignant colorectal tumors: 48 were de-
tected at sigmoidoscopy (18 in the rectum, 28 in the sigmoid
colon, and two in the descending colon), and nine were detected
at colonoscopy (three at the splenic flexure, one in the transverse
colon, one at the hepatic flexure, three in the ascending colon,
and one in the cecum). Twenty-six of the colorectal cancers were
malignant adenomas. The detection rate for colorectal cancer
was 5.4 per 1000 (54/9911), and for 29 of the 54 patients (54%)
the colorectal cancer was classified as Dukes’ A or was judged
to be localized. Indeed, treatment was limited to endoscopic
excision in 11 of 26 cases of malignant adenomas.
Serious Adverse Events of Screening
Three people developed complications requiring hospitaliza-
tion. Among the 9911 subjects who underwent sigmoidoscopy
there was one perforation (0.1 per 1000), and among the 775
subjects who underwent colonoscopy there was one perforation
and one episode of bleeding following polypectomy (both 1.3
per 1000). In addition, one patient was brought to an emergency
room with a peritonitis-like reaction the day after screening sig-
moidoscopy, although his symptoms disappeared within a few
hours; two patients developed glutaraldehyde colitis; one patient
had an allergic reaction to latex gloves; two patients, both re-
ceiving anti-epileptic treatment, suffered seizures that required
medical treatment; 17 patients had self-limited bleeding follow-
ing polypectomy (10 at sigmoidoscopy and seven at colonos-
copy); 49 patients complained of mild vagal reactions (nausea,
feeling faint, or feeling dizzy) (42 at sigmoidoscopy and seven at
colonoscopy); and 24 patients (eight at sigmoidoscopy and 16 at
colonoscopy) complained of abdominal pain. Overall, minor
self-limited complications occurred in 0.6% (60/9911) of pa-
tients who had sigmoidoscopy and in 4% (30/775) of patients
who received colonoscopy.
Of the 9911 people who underwent sigmoidoscopy, 9394
(94.8%) completed the short questionnaire administered imme-
diately after the test. Of these, 60.4% reported mild discomfort
Table 2. Characteristics of screen-detected lesions in the distal colon by sex and age
TotalMen Women Age 55–59Age 60–64
Missed polyp or inadequate sample
Tubular and low-grade dysplasia and size <10 mm
Villous component >20% or high-grade dysplasia and size <10 mm
Tubular and low-grade dysplasia and size ?10 mm
Villous component or high-grade dysplasia and size ?10 mm
1768 ARTICLES Journal of the National Cancer Institute, Vol. 94, No. 23, December 4, 2002
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and 22.9% reported that they found the test to be less painful
than expected. Only 2.0% described the pain as the most severe
they had ever experienced. Women rated the pain as severe (“I
hope it will not be necessary to repeat the test again” or “It was
the most severe pain I have ever experienced”) more often than
men (16.0% versus 7.6 %; P<.001). Only 5.1% of the screenees
found the test more than mildly embarrassing. This proportion
was similar for men and women.
We report the baseline results of a large multicenter random-
ized trial of sigmoidoscopy screening conducted in Italy. The
attendance rate among subjects assigned to the screening arm
was 58.3%. Distal adenomas were detected in 10.8% (1070/
9911) of those receiving sigmoidoscopy. The yield of proximal
adenomas among those without distal cancer who underwent
colonoscopy was 15.5% (116/747). The detection rate for colo-
rectal cancer was 5.4 per 1000 (of which 54% of the cases were
Dukes’ A or localized).
The trial protocol was similar to the one adopted in the U.K.
trial (17). The main differences concerned the randomization
procedure and the criteria for colonoscopy referral. Cluster ran-
domization (i.e., using the physician as the unit of randomiza-
tion) was adopted in three of the six Italian centers to reduce
the probability of contamination in a context of open-access
(i.e., through the physician) endoscopy. In the U.K. trial (17),
a household-based randomization procedure was adopted.
The criteria for colonoscopy referral were the same in the
Italian and U.K. trials, except for the size of distal polyps and the
management of subjects with distal polyps detected at incom-
plete sigmoidoscopy. In Italy, all subjects with distal polyps
larger than 5 mm were referred for colonoscopy to increase the
sensitivity of screening for advanced proximal neoplasia,
whereas in the United Kingdom only patients with distal polyps
larger than 10 mm were referred for colonoscopy. If the same
criteria for “high-risk” distal lesions had been adopted in Italy as
in the United Kingdom, 486 of the 9911 screenees (4.9%) would
have been referred for colonoscopy, instead of 832 (8.4%). Ap-
proximately 49% of this 3.5% difference (i.e., 171 subjects) is
attributable to the different threshold of polyp size. Also, the
Italian trial, but not the U.K. trial, included the option of refer-
ring people with incomplete sigmoidoscopy for colonoscopy
when detecting any distal polyp, and this difference accounted
for about 34% of the additional referrals. In the remaining Italian
cases, referral for colonsocopy was based, as in the U.K. trial, on
the judgement of the endoscopist. Thus, adopting the 10-mm
size threshold would have resulted in 171 fewer colonoscopy
referrals at baseline. Of these 171 patients, 155 underwent colo-
noscopy, and advanced proximal lesions were detected in three
(1.9%). This prevalence is similar to that among men and
Table 3. Number (%) of people with polyps or cancer detected in the proximal colon* and relative risks for men as compared with women
TotalMen Women RR (95% CI)†
Tubulo-villous/villous histology severe dysplasia‡
*Excluding the 47 patients with a distal cancer, identified among the 9911 subjects undergoing sigmoidoscopy (19 immediately referred to surgery and 28 referred
†Relative risk (95% confidence interval [CI]) for men compared with women.
‡Most advanced lesion in subject.
§Any of the following confirmed after pathological analysis of specimens: adenoma 10 mm or larger, tubulo-villous or villous histology, severe dysplasia.
Table 4. Number of patients with colorectal cancer according to method of treatment, Dukes’ stage and TNM* status
Total† T status N status M status
n% T1T2T3N0 N1N2 NxM0/Mx M1
Open abdominal surgery
14 1310 2§
54 26 24 2210 52
*TNM ? tumor–node–metastasis.
†Two men and one woman were detected with two synchronous colorectal cancers, and only one cancer for each is shown on the Table. One man had two Dukes’
C cancers in the sigmoid colon (one pT3, N1, M0; one pT2, N1, M0, not included in the table); one man had two Dukes’ C cancers at the splenic flexure (both pT3,
N2, M1; only one included in the table); one woman had a Dukes’ C cancer in the sigmoid colon, treated by anterior resection (pT2, N1, M0, not included in table)
and a Dukes’ C cancer at the hepatic flexure (pT3, N1, M0; included in the table).
‡Fewer than five nodes were examined; all were negative.
§Fewer than 12 nodes were examined; one, two, or three were positive.
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by guest on June 6, 2013
women without distal polyps who underwent colonoscopy
screening (39). By contrast, advanced neoplasms were found in
the proximal colon in 9.9% of patients with “high-risk” (accord-
ing to the criteria adopted in the U.K. trial) distal adenomas.
Therefore, the lower threshold size for distal adenomas used in
the Italian trial does not appear to have considerably increased
the sensitivity for “high-risk” proximal polyps.
The two-stage recruitment procedure used in all centers in the
Italian trial (i.e., questionnaire to assess interest in and eligibility
for screening followed by randomization of interested and eli-
gible respondents) increased the attendance rate, which was
about 58%, double the 29% uptake rate observed in a pilot study
in Torino (28). However, although this approach increased the
study efficiency, it decreased the degree of coverage of the target
population, at least as compared with the pilot study. The 58%
attendance rate among the 16% of eligible respondents who
expressed an interest in screening resulted in the enrollment of
about 9% of the source population.
We cannot exclude the possibility that these response rates
reflect self-selection of subjects who might have a risk of colo-
rectal cancer different from that in the general population.
Analyses of people recruited in Torino and Genova (data not
shown) indicate that people with higher levels of education had
a higher response rate to the questionnaire than people with
lower levels of education. A higher incidence of colorectal can-
cer has already been documented in people with higher levels of
education compared with people with lower levels of education
(29). However, this selection process should not affect the va-
lidity of the trial, because only eligible responders were entered
into the trial. Also, there is no apparent biologic reason for the
proportional benefit of screening to be different among subjects
who have different risks of colorectal cancer.
Because all subjects targeted for recruitment will be followed
up for colorectal cancer incidence and mortality through re-
gional registries of hospital discharge records, death certificates,
and local cancer registries, we will be able to compare baseline
risks of colorectal cancer among those who did not respond to
the mailed questionnaire with risks among those who were al-
located to the control group of the trial. Therefore, we will be
able to assess the impact of the low response rate to the ques-
tionnaire (23.9%) on the generalizability of the trial findings.
Moreover, because the response rate to the mailed questionnaire
was similar to the observed attendance rate in the pilot phase of
the trial (28), respondents are likely to be representative of the
individuals who would participate in a colorectal cancer screen-
ing program in Italy.
It should also be noted that no mass-media campaign could be
implemented in the trial context, which may partially explain the
low response rate to the questionnaire. However, the cumulative
response rate may be more relevant for evaluating the impact of
a screening strategy based on a single test than compliance with
each single invitation. The 5.8% absolute increase in the pro-
portion of attenders observed in two trial centers (Rimini and
Torino) following an additional invitation mailed to nonre-
sponders after 1 year indicates that repeated invitations might
represent an effective strategy to extend population coverage.
The high detection rate for colorectal cancer may be partially
attributable to the selective enrollment of a high proportion of
subjects who are at increased risk for the disease. However, it
might also reflect the magnitude of the anticipation of the cancer
diagnosis achievable through sigmoidoscopy. Walter and Day
(31) suggest that the ratio of prevalence to incidence can be
considered an estimate of the mean sojourn time. Based on the
observed prevalence in the trial and on incidence data available
from the cancer registries in the study areas (30), we estimate
this ratio to be 4.6, suggesting that, in general, the approach
adopted by the SCORE trial for colorectal cancer screening (sig-
moidoscopy and total colonoscopy for subjects with high-risk
distal adenomas) detects many early-stage malignant lesions.
The high proportion of malignant adenomas, which made up 26
of the 54 (48%) screen-detected colorectal cancers in our study,
supports this hypothesis.
The observed detection rate is consistent with those seen in
studies comparing sigmoidoscopy and fecal occult blood testing
(32–34). Moreover, the detection rate of adenomas 10 mm or
larger or with a villous component of more than 20% (3.7%) was
approximately four times higher than in studies of fecal occult
blood testing screening (using either guaiac or immunochemical
tests) (35–37). This finding is consistent with the expected im-
pact of screening on colorectal cancer incidence because the
estimated conversion rate of these lesions is high (13,38).
The need to repeat sigmoidoscopy in cases of unsatisfactory
bowel preparation is a crucial problem because of the possibility
of undetected lesions and the unwillingness of most patients to
undergo a second sigmoidoscopy examination. About half of the
subjects with incomplete sigmoidoscopy due to unsatisfactory
bowel preparation were not invited to repeat the test. It appears
that physicians offered a repeat sigmoidoscopy examination
only when the reach of the instrument was so limited that they
could not be confident that important lesions had not been
missed. Indeed, the median reach of the instrument in these cases
was 45 cm, and no lesion was detected in the segments examined
(data not shown). Moreover, some patients may well have been
unwilling to repeat the whole screening procedure. In our pilot
study (28), about two thirds of subjects with inadequate bowel
preparation who were offered a new test date did not attend.
Colonoscopy could not be completed to the cecum in about
25% of the patients. The lower completion rate in our screening
setting, as compared with that reported in other studies (33,40),
may be explained by a different attitude of the doctors and
patients in our study. To minimize the risk associated with the
procedure, the endoscopists participating in our study tended to
avoid administering sedation and to interrupt the examination
if patients complained of excess pain. That this approach likely
did not lead to missed cancers seems to be supported by the fact
that no proximal neoplasms were detected among the 76 patients
with incomplete colonoscopy who underwent a double-contrast
barium enema. On the other hand, asymptomatic patients may
have been less motivated to tolerate procedure-related distur-
The acceptability of sigmoidoscopy was satisfactory, with
only 2% of the screenees rating the pain associated with the
procedure as severe, although the test was routinely performed
without sedation. Overall, minor, self-limited complications oc-
curred in about 0.6% of the subjects who received sigmoidos-
copy and about 4% of those who received colonoscopy. The
rates of severe complications compare favorably with those ob-
served in other studies of both examinations (41–45), especially
given that 89% of the subjects in our trial who underwent colo-
noscopy had at least one polyp removed (data not shown). A
recent prospective study (46) suggested that the previous reports,
which were based mainly on patient record reviews, might have
1770 ARTICLES Journal of the National Cancer Institute, Vol. 94, No. 23, December 4, 2002
by guest on June 6, 2013
underestimated the complication rate. In that study, only 15% of
the complications reported by patients interviewed 30 days after
outpatient colonoscopy were known before the interview. Im-
mediate complications were systematically recorded in our study
for all patients before they left the endoscopy unit. Information
on late complications was obtained from physician and endos-
copist reports and by directly contacting all patients referred for
surveillance. We cannot exclude the possibility that, in some
cases, additional minor complications that did not require hos-
pitalization or referral to hospital outpatient clinics occurred in
the days following screening.
A high variability was observed across the trial centers, when
considering a series of performance indicators (e.g., completion
rates of sigmoidoscopy and colonoscopy—which ranged from
81.5% to 98.2% and from 51.8% to 87.1%, respectively—and
detection rates of distal and proximal adenomas, which ranged
from 5.9% to 14.7% and from 3.5% to 21.6%, respectively).
This variability suggests the need to implement quality-control
procedures when planning to use sigmoidoscopy in a large-scale,
population-based screening program. Minimum performance
standards of endoscopic examinations should be established
to achieve adequate levels of accuracy from these screening
In conclusion, the baseline results from the SCORE trial
show that sigmoidoscopy can be an acceptable and safe screen-
ing strategy for colorectal cancer. The high yield of advanced
lesions and early colorectal cancer is consistent with the pro-
jected substantial impact of sigmoidoscopy screening on colo-
rectal cancer incidence and mortality. The positive experience
reported by attenders may contribute to enhance participation
rates of screening programs in the future.
The following are the contributing members of the SCORE Working
Local trial coordinators: P. Ghezzi (Centro Oncologico); T. Galli
(Surgery Unit, Ospedale degli Infermi); A. Cardelli (Gastroenterology
Unit, Ospedale degli Infermi, AUSL, Rimini).
Pathologists: V. Sforza (Pathology Unit, Centro Oncologico,
Arezzo); M. Giudici (Pathology Unit, Ospedale degli Infermi, Biella);
S. Bosari, G. Viale (Pathology Unit, European Institute of Oncology,
Milano); P. Rinaldi (Pathology Unit, Ospedale degli Infermi, AUSL,
Rimini); E. Berardengo (Pathology Unit, Ospedale S Giovanni Antica
Sede, ASO S Giovanni Battista, Torino).
Endoscopists: D. Angioli, A. Agnolucci, P. Ceccatelli (Gastroenter-
ology Unit, Ospedale S Donato, Arezzo). G. Malfitana, A. Azzoni,
F. Ferrero (Gastroenterology Unit, Ospedale degli Infermi, ASL 12,
Biella); V. Pugliese (Unit of Gastroenterology and Nutrition, National
Institute for Cancer Research and Department of Oncology Biology and
Genetics, University of Genova); F. Munizzi, S. Saccomanno (Unit of
Gastroenterology and Nutrition, National Institute for Cancer Research,
Genova); S. Bargiggia (Endoscopy Unit, Sacco Hospital, Milano);
C. Gerosa (Unit of Gastroenterology, S Carlo Hospital, Milano);
G. Minoli (Unit of Gastroenterology, Valduce Hospital, Como);
R. Penagini (Endoscopy Unit, Policlinico Hospital, Milano); A. Prada
(Unit of Gastroenterology, General Hospital, Rho); E. Viale (Endos-
copy Unit, S Raffaele Hospital, Milano); G. Fiori (Unit of Gastroen-
terology, European Institute of Oncology, Milano); A. Arrigoni,
A. Bertone, M. Cavallero, C. Gemme, M. Pennazio, M. Spandre
(Gastroenterology Unit, Ospedale S Giovanni Antica Sede, ASO,
S Giovanni Battista, Torino); G. Babando, F. Coppola, M. Fracchia,
G. Galatola, A. Pera (Gastroenterology Unit, Ospedale Mauriziano
“Umberto I”, Torino).
Research assistants: G. Genta (Fondo “E Tempia,” ASL 12, Biella);
L. Marzona, M. Lotti (Surgery II, European Institute of Oncology and
University of Milano, Milano); O. Giuliani (Gastroenterology Unit,
Ospedale degli Infermi, AUSL, Rimini); D. Brunetti, B. Forlai (Unit of
Epidemiology, CPO, Piemonte, ASO S Giovanni Battista, Torino).
Data managers: M. Forlai (Unit of Epidemiology, CPO, Piemonte,
ASO, S Giovanni Battista, Torino); M. Carloni, C. Crotti (Surgery II,
European Institute of Oncology and University of Milano); S. Bartolini
(Gastroenterology Unit, Ospedale degli Infermi, AUSL, Rimini);
A. Marutti (Fondo “E Tempia,” ASL 12, Biella); A. M. Nicora (Unit
of Clinical Epidemology and Trials, National Institute for Cancer
Research, Genova); L. Frasconi (Centro Oncologico, Arezzo).
Database design: M. Demaria (Epidemiology Unit, ASL5, Grugli-
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Support for the study was provided by a grant from the Italian Association for
Cancer Research (AIRC, 1995–1997), grants from the Italian National Research
Council (CNR, 95.00539.PF39 and 96.00736.PF39). The Istituto Oncologico
Romagnolo (IOR), the Fondo “E Tempia,” the University of Milano, and the
Local Heath Unit ASL1, Torino supported the implementation of the study in
Rimini, Biella, Milano, and Torino, respectively. We are grateful to Professor
Geraint Williams, University of Wales College of Medicine, Cardiff, who re-
viewed the slides of all colorectal cancer cases and of the sample of adenomas
with severe dysplasia. SOFAR s.p.a. provided the enemas for the bowel prepa-
ration. We thank Ms Frederica Gallo for editorial assistance.
1772 ARTICLESJournal of the National Cancer Institute, Vol. 94, No. 23, December 4, 2002
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