Colonoscopy Principles and Practice - part 3 doc

Upper gastrointestinal cancer in a population-based screening program with fecal occult blood test for colorectal cancer.. Screening for colorectal cancer with fecal occult blood test- i

in 10%; 22.5% of the procedures showed a normal colon[12] One study reported an overall yield of 74% in 43patients with IBD, including one nonneoplastic stenosis,but no cancer and no polyps (S Morini, personal com-munication) Within the context of the EPAGE study, weassessed, in 6004 patients undergoing colonoscopy, thediagnostic yield of findings other than IBD in patientswith known ulcerative colitis and known Crohn’s dis-ease (EPAGE study 2002, unpublished results) In 201patients with known ulcerative colitis, we found cancer

in 1%, adenomas in 3.5%, nonadenomatous polyps in2.0%, and diverticulosis in 0.5% In the 158 patients withknown Crohn’s disease, cancer was found in 0.6%, ade-nomas in 1.3%, nonadenomatous polyps in 1.3%, anddiverticulosis in 0.6%

Diagnostic yield of routine ileoscopy

Intubation of the ileum is not routinely performed ing colonoscopy Ileal intubation is one way to indicatecompleteness of the procedure A skilled endoscopistcan inspect the terminal ileum in about 90% of cases

dur-in which such examdur-ination is needed [1] In practice,ileoscopy is not routinely performed A recent Europeanmulticenter trial in 6004 patients undergoing colono-scopy found that ileoscopy was performed in 29.6% ofcolonoscopies reaching the cecum [138]

Cancer Adenoma IBD

Fig 11.14 Diagnostic yield of colonoscopy in patients with

abdominal pain or altered bowel habit Data from 12 studies

(six prospective studies), 3252 patients.

IBD in most patients We recently studied the yield of

colonoscopy in 1144 patients, among whom was a subset

of 40 patients with known IBD IBD was present in 65%,

another form of colitis (infectious) in 2.5%, and stenosis

Table 11.8 Diagnostic yield of colonoscopy in patients with abdominal pain or altered bowel habit.

Number of Cancer Adenoma Inflammatory Diverticula Stricture

De Bosset et al [12] Prospective

symptoms

results; change in bowel habit

symptoms; polyp or mass > 1 cm

and/or change in bowel habit

negative FOBT

pain; change in bowel habit

FOBT, fecal occult blood test; NS, not stated.

* Excluding data from Liebermann et al [132].

Chapter 11: Diagnostic Yield of Colonoscopy by Indication 125

adenomas greater than 1 cm in diameter Furthermore,barium enema was falsely positive in 14% In a largenonrandomized controlled trial [88] in 21 000 patientsaged over 40 years, barium enema missed 25% of thelesions found at colonoscopy

Insufficient procedural competence and experience

on the part of the endoscopist may decrease the value

of colonoscopy [145] Even in expert hands, there is asignificant miss rate of polyps Rex and colleagues [146]performed two colonoscopies on the same day (back-to-back colonoscopy) in 183 patients randomly assigned

to the same or another endoscopist The overall miss rate of adenomas was 24%; it was 27% for adenomas

≤ 5 mm, 13% for adenomas 6–9 mm, and 6% for mas≥ 1 cm Although considered as the gold standard

adeno-in the diagnostic armamentarium of colonic disease, the performance characteristics of colonoscopy are notoptimal, even in the hands of an expert operator andunder ideal conditions

The quality and diagnostic reliability of the procedureare further dependent on several other factors Muchemphasis has been placed on the duration of colonoscopyand in particular on the time needed to reach the cecum.Overall duration may be significant with respect to pro-cedural efficiency in a context of cost constraints, waitinglists at endoscopy units, and the need for endoscopistsand endoscopes However, it is not acceptable that anoverly rapid endoscopic technique should render theprocedure less tolerable or reduce its diagnostic reliab-ility Withdrawal time seems to be more critical for diag-nostic yield, particularly colonic distension, adequatesuctioning and cleaning, and adequate time spent exam-ining the colon The quality of withdrawal is critical forthe detection rate of adenomas [147] In fact, it has been shown very recently that individual endoscopists’

In one study in 138 consecutive colonoscopies,

ileo-scopy revealed a diagnosis in eight patients (6%) In

half of these patients, the diagnosis was made based

on ileoscopy alone The yield of ileoscopy was 2.7% in

asymptomatic patients undergoing screening

colono-scopy and 29% in patients complaining of diarrhea [139]

Another prospective study in 295 consecutive patients

[140] reported macroscopic abnormalities of the ileum in

4 of 213 patients (1.8%) in whom ileoscopy was possible,

one-quarter of whom also had abnormal histology of the

ileal mucosa (0.5%) However, this study did not

indic-ate patient symptoms Ileoscopy is obviously

particu-larly useful in patients with symptoms suggesting IBD

in order to exclude isolated ileal disease or to facilitate

the differential diagnosis between Crohn’s disease and

ulcerative colitis [141] Furthermore, ileoscopy seems to

be indicated in patients with chronic diarrhea, especially

in HIV-positive patients [142]

Diagnostic reliability of colonoscopy

Colonoscopy is more sensitive than barium enema and

allows biopsies and endoscopic therapy The sensitivity

of barium enema and colonoscopy for diagnosing

colo-rectal cancer was 84% and 95% in a recent retrospective

study [143] A controlled and blinded comparison of

both procedures was made in the National Polyp Study

where 580 patients underwent 862 paired examinations

[144] Barium enema detected a polyp in only 39% of

cases in which a polyp was subsequently found during

colonoscopy, and in only 48% in patients with advanced

40

30 35

25

10 15 20

Fig 11.15 Diagnostic yield of colonoscopy in patients with

abdominal pain or altered bowel habit: (a) EPAGE; (b) all

studies.

up after cancer resection, and positive FOBT have a highdiagnostic yield (Fig 11.16) In contrast, nonbleedingcolonic symptoms (diarrhea, abdominal pain, alteredbowel habit) and surveillance after polypectomy have alower yield of cancer (Fig 11.16) Incidence rates of colo-rectal cancer increase consistently with age Patient age

is thus an important predictor of colorectal cancer inpatients referred for colonoscopy

The yield in the detection of adenomas is less pendent on the indications than the detection of cancer,due to the high prevalence of polyps found in screeningcolonoscopies or in patients with nonspecific symptoms.The adenoma detection rate is highest in the follow-up

de-of polyps, follow-up de-of cancer, in patients with positiveFOBT (Fig 11.16), and in nonemergency lower gastroin-testinal bleeding (see Fig 11.2) IBD is a relatively com-mon finding in hematochezia and diarrhea

Although diagnostic yield is important, it must bekept in mind that colonoscopy may also be beneficial topatients if it excludes a clinically relevant lesion by con-ferring reassurance

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–

–

– –

– –

Cancer Polyp

Acute lower

GI bleeding

Non-acute lower GI bleeding

Iron deficiency anemia

F up polyp

F up cancer

FOBT pos Diarrhea Non-specific

colonic symptoms

Fig 11.16 Diagnostic yield of colonoscopy by indication.

Chapter 11: Diagnostic Yield of Colonoscopy by Indication 127

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itself should be the preferred screening test [8], othershave argued that it should be one of several screeningoptions [4,7,9]

This chapter reviews the rationale for consideringcolonoscopy as a primary screening test in average-riskpopulations and discusses implementation issues includ-ing compliance, resources, and cost

Rationale for screening

Screening with colonoscopy should be considered in thecontext of other screening tests For each test we shouldask the following questions

1 What is the likelihood that the test will detect the target lesion (advanced adenoma or early cancer)?

2 Are there programmatic issues, such as need forrepeat testing, which impact effectiveness?

3 What are the potential harms?

Fecal occult blood test

Three randomized controlled trials have compared population screening using the fecal occult blood test(FOBT) with no screening [11–13] Although there weredifferences in study methods, the findings are consistentacross all the studies Cancers are detected at earlierstages in screened compared with unscreened subjects,and this translates into significant mortality reduction of15–33% over time [11–13] Rehydration of FOBT slidesincreases sensitivity but reduces specificity, so thatmany more patients will receive colonoscopy for false-positive results over time In the Minnesota study [11],38% of subjects in the FOBT arm received colonoscopyduring the first 13 years of the study One analysis hassuggested that some of the benefit of the FOBT could

be explained by random assignment to screening noscopy [14]

colo-In the Veterans Affairs (VA) Cooperative Study

[15], average risk subjects (n= 2885) had both one-time rehydrated FOBT and screening colonoscopy FOBT waspositive in 50% of patients with cancer, consistent withother studies [16,17] However, among patients withadvanced neoplasia without invasive cancer (defined asadenoma with high-grade dysplasia or villous histology,

Introduction

Colorectal cancer (CRC) is the second leading cause of

cancer death in North America and western Europe [1]

As populations live longer due to advances in medicine

and public health, rates of CRC are likely to increase

The biology of CRC offers an opportunity for both early

detection and prevention Most cancers evolve from

pre-malignant adenomas over a period of many years;

spread of malignancy from the colon to sites outside the

colon likewise occurs over years Screening of

asymp-tomatic populations has demonstrated that cancers can

be detected at early, more curable stages compared with

unscreened controls Furthermore, studies have

demon-strated that detection and removal of premalignant

adenomas can prevent incident cancers [2,3] Therefore,

if screening tests could identify patients with high-risk

adenomas, many cancers could be prevented, mortality

reduced, and the burden of caring for patients with

can-cer diminished If the target of screening is the advanced

adenoma, we should ask: how effectively do screening

tests identify patients with advanced adenomas?

There is consensus that colonoscopy should be the

preferred screening test for individuals known to have

higher than average risk [4] Higher-risk categories

include individuals with familial hereditary syndromes

(familial polyposis, hereditary nonpolyposis CRC),

chronic colitis due to ulcerative colitis or Crohn’s

dis-ease, and a family history of CRC in a first-degree

relat-ive Patients with a personal history of adenoma or

cancer should receive colonoscopic surveillance, and are

not considered part of a screening cohort

Recent studies [5,6] have raised questions about

whether colonoscopy should also be a preferred

screening test in average-risk individuals The

perform-ance characteristics of several screening modalities in

average-risk populations have been scrutinized by the

United States Preventive Services Task Force (USPSTF)

and by expert multidisciplinary panels [4,7–10] All the

expert panels strongly recommend that population

screening should begin for average-risk individuals at

age 50 years They have noted that colonoscopy is more

effective than other screening tests for polyp detection

Although some experts have argued that colonoscopy

Chapter 12 Screening Colonoscopy:

Rationale and Performance

David Lieberman

Colonoscopy Principles and Practice

Edited by Jerome D Waye, Douglas K Rex, Christopher B Williams

Copyright © 2003 Blackwell Publishing Ltd

reduce CRC mortality, particularly from tumors in thedistal colon An important limitation is that a large por-tion of the colon is not examined at sigmoidoscopy Ifmost patients with advanced neoplasia in the proximalcolon had index adenomas in the distal colon, whichwould lead to complete colonoscopy, then sigmoido-scopy would be a sensitive screening test.

Two screening colonoscopy studies reported the ings of complete colonoscopy, and estimated the poten-tial findings of screening sigmoidoscopy in average-risksubjects [5,6] Advanced neoplasia was more likely to befound in the distal colon (55% in the Indiana study; 53%

find-in the VA study) Both studies found that more than 50%

of patients with advanced proximal neoplasia (beyondthe reach of the sigmoidoscope) would not have beenidentified with sigmoidoscopy, even assuming that anyindex adenoma would lead to colonoscopy In addition,both studies found that as average-risk subjects age, theyare more likely to harbor advanced proximal neoplasiaand that these are less likely to be identified with sigmoi-doscopy alone

Sigmoidoscopy is able to detect advanced adenomasand early cancers in the area examined The key limita-tion of sigmoidoscopy is that a large portion of the colon

is not examined; some patients with advanced proximalneoplasia would go undetected There is also concernthat with increasing age, sigmoidoscopy may be lesseffective

Combined flexible sigmoidoscopy and FOBT

The American Cancer Society has long recommendedscreening with both FOBT and flexible sigmoidoscopybeginning at age 50 years [9], among other options.Intuitively, this combined approach should have agreater impact on CRC mortality than either test alone

In one study [23], patients were offered sigmoidoscopywith or without FOBT Although the patients were notrandomly assigned to groups, the groups were com-parable Follow-up was irregular and compliance withfollow-up testing poor During the 9-year follow-up, 144cases of CRC were found but only 28 were actuallydetected through screening The major finding was thatpatients screened with both FOBT and sigmoidoscopyhad better long-term survival after detection of cancercompared with controls, suggesting a benefit from evalu-ation of positive screening tests The overall mortalityrate of the two groups was similar

In the VA Cooperative Study [15], combined screeningwith one-time FOBT and sigmoidoscopy would haveidentified 76% of patients with advanced neoplasia, onlyslightly better than sigmoidoscopy alone (70%) Withincreasing age, there was a trend for decreasing efficacy

of the combined screening approach Modeling [24–26]has suggested that the combined approach could be

or tubular adenoma ≥ 1 cm), FOBT was positive in only

21.6% Moreover, it is likely that if rehydration had not

been used, the positive rate would have been lower

These results suggest that one-time FOBT has serious

lim-itations for detection of high-risk adenomas If FOBT is

to be used for screening, a program of repeat screening

must be developed Compliance with repeat screening is

poor There is some concern that patients may be falsely

reassured after a negative test, and not return for repeat

testing [7] If the FOBT is positive, there is consensus that

patients should undergo complete colonoscopy This

represents a second step during which compliance can

break down

These studies support the hypothesis that population

screening of average-risk subjects could reduce CRC

mortality FOBT is a poor test for detection of advanced

adenomas Although there is some evidence that

screen-ing with FOBT can lead to reduction in cancer incidence

(due to polyp detection and removal) [3], this reduction

is modest The need for frequent repeat testing and

appropriate follow-up of positive tests with colonoscopy

represent important program limitations

Flexible sigmoidoscopy

There is evidence from two case–control studies [18,19]

that exposure to sigmoidoscopy is associated with a

reduction in colon cancer mortality, in that portion of

the colon examined In these studies, patients with death

due to CRC were ascertained and an age-matched

control group without CRC was used for comparison

Selby and colleagues [18] compared 261 patients with

fatal rectosigmoid cancers (within reach of the

sigmoi-doscope) to 868 age- and sex-matched controls; 8.8% of

cases had sigmoidoscopy compared with 24.2% of

con-trols, suggesting that endoscopic sigmoid screening

could reduce the risk of fatal cancers within the range

of the sigmoidoscope (odds ratio 0.41) Moreover, the

benefit remained strong even when the most recent

examination was 9–10 years earlier Newcomb and

col-leagues [19] found similar results Both studies did

not find that sigmoidoscopy reduced the likelihood of

fatal cancers of the right colon, perhaps because such

tumors would not be readily detected with

sigmoi-doscopy Muller and Sonnenberg [20] reported another

case–control study in a VA population to determine the

impact of either sigmoidoscopy or colonoscopy on CRC

risk Compared with controls, patients with CRC were

less likely to have had prior endoscopic examinations

of the colon (odds ratio 0.51 for colon cancer; 0.55 for

rectal cancer) Two ongoing randomized trials using

flexible sigmoidoscopy will report findings in the next

few years [21,22]

These case–control data provide compelling

evid-ence that screening sigmoidoscopy could substantially

Chapter 12: Screening Colonoscopy: Rationale and Performance 133

The case for screening with colonoscopyRationale

Colonoscopy can examine the entire colon in more than90–95% of procedures, if performed by a fully trainedendoscopist Polypectomy can be performed at the sametime Given these obvious advantages, we should ask:why not perform screening colonoscopy?

Arguments against screening with colonoscopy

General criteria for screening tests applied to the tion are summarized in Table 12.1 Colonoscopy is aninvasive and expensive test The risk of perforation, seri-ous bleeding, and cardiopulmonary events is low whenperformed by experienced endoscopists (0.3–0.5%), but

popula-if applied to the general population could account forconsiderable morbidity [29] If only 5–6% of the adultpopulation will develop CRC during life, most patientswill not benefit from colonoscopy Ideal screening wouldtarget colonoscopy at the patients most likely to haveadvanced neoplasia or cancer, and would not employ

an expensive invasive test to populations with a ively low pretest probability of disease However, theideal simple test has been elusive Lacking the perfectlysensitive and adequately specific noninvasive screeningtest, screening with colonoscopy is now recommended

relat-as a screening option by all expert panels in the USA,though not in Canada, Europe, or Australia

Arguments for screening with colonoscopy

Relative to other screening tests, there is substantial evidence that colonoscopy is very accurate for detection

of significant neoplasia In two tandem colonoscopystudies, in which patients had two colonoscopies per-formed during the same session, the miss rate for polypsgreater than 1 cm was less than 10% [30,31] Since thesestudies were performed by experts, it is possible that inclinical practice more lesions are missed by less expertendoscopists Specificity for detection of neoplasia ap-proaches 100%, because biopsies are usually obtainedthat confirm the histologic presence of neoplasia

The ability to prevent incident cancers or reduce mortality with primary screening colonoscopy has neverbeen tested in a clinical trial However, there are severallines of indirect evidence which endorse the potentialeffectiveness of colonoscopy First, the FOBT trials allrecommended colonoscopy as the follow-up test after

a positive FOBT It was colonoscopy which identified the early cancers that led to a survival advantage inscreened populations Lang and Ransohoff [14] per-formed a posthoc analysis of the Minnesota FOBT study,

in which 38% of subjects in the screened group received

more effective and less costly than other screening

approaches if tests are performed programmatically and

on a regular basis, as is recommended (annual FOBT and

sigmoidoscopy every 5 years) However, the models

require assumptions about compliance with initial

test-ing and follow-up colonoscopy after positive tests,

which may not be realistic in clinical practice

Radiographic colon imaging with barium, computed

tomography and magnetic resonance imaging

No large studies have evaluated colon imaging with

barium in an average-risk population The USPSTF rates

barium as “unknown” with regard to effectiveness

in reducing incidence and mortality from CRC, and

only “fair” with regard to ability to detect cancer and

advanced neoplasia The National Polyp Study found

that the sensitivity of barium studies for detection of

polyps larger than 1 cm was 48% [27]

The data on computed tomography or magnetic

resonance imaging of the colon are preliminary and

the technology is still evolving The range of

sensitiv-ity for large polyps is 40–96%, suggesting wide

vari-ation in either skill or technique Currently, no review

panel has recommended screening with these

modal-ities, although they have captured the attention of the

public

Possible future tests

There are other screening modalities that show promise

When specific gene mutations were identified in patients

with familial polyposis (adenomatous polyposis coli

gene on chromosome 5) and hereditary nonpolyposis

CRC (mismatch repair gene mutations), there was great

hope that molecular genetics would provide a simple

blood test to risk-stratify otherwise average-risk

sub-jects Such screening was touted to the public in the New

York Times in the 1990s The reality of genetic testing to

date has been sobering, but there has been recent

pro-gress Several groups have identified genetic mutations

in stool samples If tumors slough cells with genetic

mutations into the bowel lumen and if these mutations

can be identified, it may be possible to select individuals

for colonoscopy based on the stool profile This “needle

in a haystack” approach is complicated by the fact that

there is no single mutation which identifies all high-risk

patients New tests that search for several of the most

common genetic alterations associated with CRC are

under study [28] With the development of the Human

Genome Project has come the science of proteomics:

understanding of the relationship of a gene mutation to

specific protein product If altered protein products are

circulating in the blood, it may be possible to screen

patients with blood tests

regarding accuracy, compliance, and harms The clusion of the most recent analyses is that colon cancerincidence could be reduced by 58–86% and that CRCmortality could be reduced by 64–90% [32].

con-Patient acceptance

Patient acceptance of colonoscopy as a screening test

is unknown Colonoscopy is well accepted when mended for evaluation of other positive screening testsand other gastrointestinal symptoms In the VA Cooper-ative Study, nearly two-thirds of eligible subjects whowere offered colonoscopy completed the examination.The VA population may not be generalizable, but thisstudy does demonstrate that good compliance can beobtained when procedures are fully explained Accept-ance of sigmoidoscopy is estimated to be 25–50% [33].Although acceptance of one-time FOBT may exceed 75%,compliance with repeat FOBT is poor A colonoscopyscreening program may require only one or two exam-inations in a lifetime, a factor that may enhance programperformance compared with other programs requiringfrequent repeat testing and colonosocopic follow-up ofpositive screening tests

recom-Benefits/ harms

The largest study to report complications of colonoscopy

is VA Cooperative Study 380 [29] Serious complications,definitely attributed to colonoscopy, occurred in 0.3%

of patients receiving screening colonoscopy The mostcommon serious complications were serious bleeding

colonoscopy over 13 years of study They attributed

much of the mortality reduction to high rates of

colo-noscopy, with only a portion of benefit derived from

performance of FOBT In the follow-up of the Minnesota

study, the subsequent incidence of CRC was reduced in

patients who had been screened, a benefit attributed by

the authors to colonoscopy with polypectomy [3] The

second line of evidence is extrapolated from the case–

control studies of sigmoidoscopy These studies found a

significant reduction in fatal colon cancers in that

por-tion of the colon examined There was no reducpor-tion in

mortality from proximal colon cancers [18] It is logical to

assume that if more colon is examined, the benefit could

be extended to as much of the colon as can be examined

The third line of evidence comes from the National

Polyp Study [2], in which patients underwent complete

colonoscopy with polypectomy and were followed over

the next 5 years When compared with reference

popula-tions, the incident rates of CRC were reduced by 76–90%

in the study subjects Although the comparison groups

differed from the study subjects, the marked reduction

in expected incidence is compelling Finally, a case–

control study in the VA population found that patients

diagnosed with CRC were less likely to have had prior

colonoscopy compared with patients without CRC [20]

The risk reduction of 53% for colon cancer and 39% for

rectal cancer was significant These studies provide

com-pelling indirect evidence that screening colonoscopy

could be effective, i.e reduce colon cancer mortality and

incidence

Several investigators have modeled colon cancer

screening and evaluated a broad range of assumptions

Table 12.1 Criteria for population-based screening test.

5–6% risk in adults

Second most common cause of cancer death

Asymptomatic phase during which screening could detect disease Yes

Imaging requires preparation, but is low risk Colonoscopy invasive, with higher risk Screening test is inexpensive Costs are similar for all screening programs

Tests are sensitive enough to detect disease at curable phase Yes for all tests

Colonoscopy more sensitive than other tests Tests are specific (high false-positive rates increase cost if patients have Nearly 100% for endoscopic tests

Poor specificity for imaging studies Available health services for diagnostic follow-up of positive tests Uncertain if there are enough fully trained endoscopists Therapy during asymptomatic phase will favorably alter natural history Yes

FOBT, fecal occult blood test.

Chapter 12: Screening Colonoscopy: Rationale and Performance 135

They assumed that some patients would have comorbidconditions which would preclude screening, somewould have examinations to evaluate symptoms, and alarge number would be noncompliant In a “best-case” scenario, 60% of the population would be compliant with screening Therefore, rather than a stampede toscreening colonoscopy, the demand may more closelyresemble a traffic jam If traffic patterns are understood,most traffic jams have engineering solutions To offercolonoscopy services with existing resources, Rex andLieberman made several recommendations

endoscopy units are not efficient with regard to roomscheduling and turnover Endoscopists could developopen-access systems for screening of otherwise healthyindividuals, and use physician extenders to obtain con-sent and perform initial history and physical examina-tions Support personnel could handle much of thepostprocedure follow-up with patients who do not havecomplex pathology

of colonoscopy procedures are performed for lance of prior adenomas (D Lieberman, unpublisheddata from the Clinical Outcomes Research Initiative[CORI] database) Based on the VA Cooperative Study[5], more than 70% of patients found to have adenomas

surveil-at screening will have only small (< 1 cm) tubular adenomas The Indiana colonoscopy study found that65% of patients with neoplasia had only small tubularadenomas [6] Data from the National Polyp Study [35]suggest that these patients may have a low risk of seriouspathology at surveillance examinations Extending theinterval for surveillance of patients with low-risk lesionscould shift considerable resources towards screening.Rex [36] estimated that screening will have a greateryield than surveillance (64 colonoscopies to detect onecancer for screening average-risk male vs 317 colono-scopies to detect one cancer in postpolypectomy surveil-lance) If specialists in gastroenterology spend more timeperforming colonoscopy and less with flexible sigmoi-doscopy, this will allow some resource shifting Thistrend is currently observed in the CORI database, whichshows a significant decline in sigmoidoscopy as a frac-tion of endoscopic practice by gastrointestinal specialists(D Lieberman, unpublished data)

In summary, existing resources can be provided moreefficiently and selectively to increase the capacity forscreening colonoscopy (or colonoscopy to evaluate otherpositive screening tests)

Cost

Several recent analyses of colon screening costs havereached similar conclusions: screening with any of therecommended tests is cost-effective relative to other

and myocardial infarction or serious arrhythmia Most

of the serious complications occurred in association with

polypectomy The serious complication rate of a

diag-nostic colonoscopy was 0.1% Less serious

complica-tions were common, including vasovagal events (5.4%),

transient oxygen desaturation (4.4%), abdominal pain

requiring termination of the procedure (0.9%), and minor

gastrointestinal bleeding that did not require

hospital-ization or intervention (0.2%) Since these procedures

were performed by experts, it is not known if

complica-tions would be more common in community practice

Studies are currently underway to measure 30-day

com-plication rates in diverse clinical practice settings

Resources

The algorithm of every CRC screening program

even-tually leads to colonoscopy to evaluate positive tests

Public and provider awareness of the benefits of colon

screening has increased over the past few years A

Gallup poll in 1998 indicated that nearly 90% of the

pub-lic was aware of the potential benefits of colon screening

In March 2000, a prominent television personality had a

screening colonoscopy performed on her program, with

the goal of diminishing public fear of the test An

aggress-ive public education campaign followed the program

Despite this increased public awareness, compliance

with screening has been poor: only 30–40% of the

age-eligible population have had the recommended

screen-ing However, there are indications that this may improve

over the next few years In 1998, the Department of Health

and Human Services added colon screening with FOBT

or sigmoidoscopy as a Medicare benefit for

average-risk individuals, and colonoscopy for individuals with

a positive family history In July 2001, the federal

gov-ernment extended the benefit to include colonoscopy

screening for all Healthcare systems such as the

Depart-ment of Veterans Affairs have initiated annual reminders

to primary providers to encourage FOBT Health

main-tenance organizations like Kaiser have enrolled all

age-eligible patients into flexible sigmoidoscopy screening

programs The National Cancer Institute and the Centers

for Disease Control are dedicating resources to study

strategies which will improve compliance

By 2000, most gastrointestinal practices in the USA

were confronted with increased demand for colonoscopy

services During this same time period of the late 1990s,

there was a decline in the number of gastrointestinal

fellowship positions in the USA The shifting demand

for colonoscopy and the decline in newly trained

en-doscopists has raised concerns about whether there are

sufficient resources to provide colonoscopy screening to

the general population

Rex and Lieberman [34] examined some of the

assumptions that underlie the demand for services

by colon cancer screening, then the benefit may not offsetharm For example, let us assume that a hypotheticalindividual would have died from CRC at age 80 years Ifhis colon cancer is prevented by screening but he has

a myocardial infarction and dies at age 80, is there abenefit? Although society is spared the cost of caring for

a patient with cancer, would the resources spent forscreening have been better spent on some other form ofhealthcare? These are difficult questions to answer inclinical trials The modeling analyses are helpful becausethey account for all causes of death, and consistentlyshow that there is a benefit from screening A clinicaltrial to resolve this issue would require 10–20 years,large numbers of patients, and an enormous budget

As in other areas of medicine, we may lack precise information for medical decision-making As new databecome available from the VA Study follow-up and theCONCeRN trial [43] in women, they can be incorporatedinto the models and reduce areas of uncertainty

The appropriate timing for screening colonoscopy

is uncertain and has implications for cost, resource ization, and benefit Imperiale and colleagues [44] foundthat detection of serious pathology is uncommon inasymptomatic persons aged 40–49 years who hadscreening colonoscopy Ness and colleagues [39] foundthat screening colonoscopy at age 50–54 years would becost-effective compared with no screening The VACooperative Study data showed that the prevalence

util-of any advanced pathology in men aged 50–59 years was 5.7%, and few had cancer Only 2% had advancedproximal neoplasia and most of these patients would have been detected with sigmoidoscopy [5] In contrast,4.9% of patients aged 60–69 years and 5.9% of patientsaged 70–74 years had advanced proximal neoplasia Less than half of these patients would have been detectedwith sigmoidoscopy Therefore, a strategy of screening sigmoidoscopy during the sixth decade followed bycomplete colonoscopy at age 60 years might be a cost-effective screening strategy in men

Expert groups have recommended that colonoscopyscreening be performed at 10-year intervals, basedlargely on the expected natural history of progression ofcolonic neoplasia There has not been a study evaluating

a 10-year interval Rex and colleagues [45] performedfollow-up colonoscopy at 5.5 years in 154 average-riskpersons who had a negative baseline colonoscopy; onlyone patient had an adenoma greater than 1 cm Thesedata suggest that a 6-year interval is quite safe Would anegative screening colonoscopy at age 60 years identify alow-risk person who does not need further screening?These data are crucial to decision-making about when

to stop screening The VA Cooperative Study will follow its population for 10 years, and will provide some pro-gnostic information in men who have had a baselinescreening colonoscopy For now, there is some uncer-tainty about the appropriate screening interval

medical interventions, and could even be cost-saving

if large numbers of cancers can be prevented [24–26,

37–41] The analyses show that various screening tests

are quite similar in programmatic costs over life, roughly

$20 000 per life-year saved The analysis of these studies

by the USPSTF stated that the current evidence is

insuf-ficient to determine the most effective or cost-effective

strategy for screening [32]

Important assumptions in these analyses include the

rate of cancer prevention and the cost of cancer care

In the USA, the cost of care for patients with CRC

prob-ably exceeds $50 000 [42] This cost includes diagnostic

studies, cancer surgery, chemotherapy or radiation

therapy, postcancer surveillance, and end-of-life care if

detection is late As the cost of cancer care increases,

averting this cost by detection and removal of advanced

adenomas will probably result in cost-saving In each

model, colonoscopy results in the greatest potential for

cancer prevention because of the highly accurate

detec-tion and removal of adenomas

If cost differences between the screening tests are

small, why are many insurers reluctant to include

colonoscopy screening as a benefit to their clients? From

the standpoint of the insurer, screening is a large

invest-ment with potential downstream benefit If cancers are

averted, then the cost of cancer care can be reduced,

although this benefit may not be realized for many years

If individuals change insurance coverage frequently, the

insurer may not wish to make a large “up-front”

invest-ment for a downstream benefit that may occur after the

individual is no longer covered by the insurer Among

the screening test options, colonoscopy would represent

the largest up-front investment If we approach the

screening from a societal point of view (a lifetime,

single-payer system), an effective cancer prevention program

would be a worthwhile investment

Screening colonoscopy:

areas of uncertainty

Colonoscopy screening has not been studied in a

clin-ical trial Therefore, the balance of benefits and harms

remains uncertain Although there is little doubt that

colonoscopy is beneficial in the evaluation of other

positive screening tests (FOBT, sigmoidoscopy,

imag-ing), it is uncertain if whole-population colonoscopy

screening would necessarily confer the degree of

bene-fit that would justify the risk and resource utilization

For colonoscopy to be effective, the examinations will

need to be accurate and complete, and performed with

minimal risk The overall success rate and risk of

colono-scopy in community practice is unknown and requires

study Future advances in colonoscopy technology may

improve success rates and reduce risk

The “holy grail” of screening is mortality reduction

Some may argue that if all-cause mortality is not reduced

Chapter 12: Screening Colonoscopy: Rationale and Performance 137

4 Winawer SJ, Fletcher RH, Miller L et al Colorectal cancer screening: clinical guideline and rationale Gastroenterology

1997; 112: 594–642.

5 Lieberman DA, Weiss DG, Bond JH et al Use of

colonoscopy to screen asymptomatic adults for colorectal

cancer N Engl J Med 2000; 343: 162–8.

6 Imperiale TF, Wagner DR, Lin CY, Larkin GN, Rogge JD, Ransohoff DF Risk of advanced proximal neoplasms in asymptomatic adults according to the distal colorectal

findings N Engl J Med 2000; 343: 169–74.

7 Pignone M, Rich M, Teutsch SM, Berg AO, Lohr KN Screening for colorectal cancer in adults at average risk: a summary of the evidence for the US Preventive Services

Task Force Ann Intern Med 2002; 137: 132–41.

8 Rex DK, Johnson DA, Lieberman DA, Burt RW, Sonnenberg

A Colorectal cancer prevention 2000: screening

recommen-dations of the American College of Gastroenterology Am J Gastroenterol 2000; 95: 868–77.

9 Smith RA, von Eschenbach C, Wender R et al American Cancer Society guidelines for early detection of cancer CA Cancer J Clin 2001; 51: 38–75.

10 American Society for Gastrointestinal Endoscopy lines for colorectal cancer screening and surveillance.

Guide-Gastrointest Endosc 2000; 51: 777–82.

11 Mandel JS, Bond JH, Church TR et al Reducing mortality from colorectal cancer by screening for fecal occult blood N Engl J Med 1993; 328: 1365–71.

12 Kronborg O, Fenger C, Olsen J, Jorgensen OD, Sondergaard

O Randomised study of screening for colorectal cancer

with faecal occult blood test Lancet 1996; 148: 1467–71.

13 Hardcastle JD, Chamberlain J, Robinson MHE et al.

Randomised, controlled trial of faecal occult blood

screen-ing for colorectal cancer Lancet 1996; 148: 1472–7.

14 Lang CA, Ransohoff DF Fecal occult blood screening for colorectal cancer Is mortality reduced by chance selection

for screening colonoscopy? JAMA 1994; 271: 1011–3.

15 Lieberman DA, Weiss DG, for the Veterans Affairs Cooperative Study Group 380 One-time screening for col- orectal cancer with combined fecal occult-blood test and

examination of the distal colon N Engl J Med 2001; 345:

555–60.

16 Allison JE, Feldman R, Rekawa IS Hemoccult screening in detecting colorectal neoplasm: sensitivity, specificity, and

predictive value Ann Intern Med 1990; 112: 328–33.

17 Ahlquist DA, Wiend HS, Moertel CG et al Accuracy of fecal

occult blood screening for colorectal neoplasia A

prospect-ive study using Hemoccult and HemoQuant tests JAMA

1993; 269: 1262–7.

18 Selby JV, Friedman GD, Quesenberry CP Jr, Weiss NS A case-control study of screening sigmoidoscopy and mortal-

ity from colorectal cancer N Engl J Med 1992; 326: 653–7.

19 Newcomb PA, Norfleet RG, Storer BE, Surawicz TS, Marcus

PM Screening sigmoidoscopy and colorectal cancer

mortal-ity J Natl Cancer Inst 1992; 84: 1572–5.

20 Muller AD, Sonnenberg A Prevention of colorectal cancer

by flexible endoscopy and polypectomy: a case-control

study of 32,702 veterans Ann Intern Med 1995; 123: 904–10.

21 Atkin WS, Hart A, Edwards R et al Uptake, yield of

neopla-sia, and adverse effects of flexible sigmoidoscopy screening.

Will screening colonoscopy likely be replaced by new

methods of screening? This is an important question

because of resource utilization If society determines

that screening colonoscopy should be offered to

every-one, significant resources will need to be dedicated to

provide endoscopy services and train endoscopists If

colonoscopy is subsequently replaced, then there will

be issues of excess capacity and wasted resources The

ideal screening test of the future will target colonoscopy

precisely at those patients most likely to develop

can-cer If a genetic or biologic marker could successfully

risk-stratify patients, colonoscopy may only need to be

offered to the 10–20% of the population who develop

high-risk lesions For patients with sporadic CRC, this

ideal test remains in the distant future In the best-case

scenario, once a marker was identified, years of testing

would likely precede widespread acceptance Imaging

studies are not likely to provide precise targeting

be-cause they will identify patients with advanced and

non-advanced lesions Unless clinicians are willing to ignore

small polyps found on imaging studies, these tests are

not likely to reduce the need for colonoscopy services

Therefore, for the next generation, colonoscopy will be

the most accurate test for assessing risk and enhancing

prevention

Summary

CRC screening with colonoscopy in average-risk

popu-lations could have a significant impact on CRC

incid-ence and mortality [32] Advantages over other forms

of screening include the ability to examine the entire

colon and remove pathology during the examination

Uncertainties exist about the application of the

proced-ure in practice Would completion rates and

complica-tion rates be similar to those reported from clinical trials?

Further study is needed in community practice Would

one or two examinations during a lifetime be sufficient

if they are negative? Are there sufficient resources to

provide colonoscopy to large populations? Despite these

questions, there is little doubt that colonoscopy

screen-ing would have a large impact on CRC incidence and

mortality Until selective screening can be targeted at

those individuals most likely to develop CRC,

colono-scopy screening may offer the most effective means for

reducing mortality

References

1 American Cancer Society Cancer Facts and Figures Atlanta:

American Cancer Society, 2002.

2 Winawer SJ, Zauber AG, Ho MN et al Prevention of

colorec-tal cancer by colonoscopic polypectomy N Engl J Med 1993;

329: 1977–81.

3 Mandel JS, Church TR, Bond JH et al The effect of fecal

occult-blood screening on the incidence of colorectal cancer.

N Engl J Med 2000; 343: 1603–7.

35 Winawer SJ, Zauber AG, O’Brien MJ et al Randomized

com-parison of surveillance intervals after colonoscopic removal

of newly diagnosed adenomatous polyps N Engl J Med

1993; 328: 901–6.

36 Rex DK Colonoscopy: a review of its yield for cancers and

adenomas by indication Am J Gastroenterol 1995; 90: 353–

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37 Lieberman DA Cost-effectiveness model for colon cancer

screening Gastroenterology 1995; 109: 1781–90.

38 Sonnenberg A, Delco F, Inadomi JM Cost-effectiveness of

colonoscopy in screening for colorectal cancer Ann Intern Med 2000; 133: 573–84.

39 Ness RM, Holmes AM, Klein R, Dittus R Cost-utility of time colonoscopy screening for colorectal cancer at various

of colorectal cancer screening and surveillance guidelines

for average-risk adults Int J Technol Assess Health Care 2000;

16: 799–810.

42 Taplin SH, Barlow W, Urban N et al State, age, comorbidity, and direct costs of colon, prostate and breast cancer care J Natl Cancer Inst 1995; 87: 417–26.

43 Schoenfeld P, Cash B, Dobhan R et al Colorectal neoplasia

screening with colonoscopy in average-risk women at regional Naval medical centers: the CONCERN trial.

Gastrointest Endosc 2002: 55: A99.

44 Imperiale TF, Wagner DR, Lin CY, Larkin GN, Rogge JD, Ransohoff DF Results of screening colonoscopy among

persons 40–49 years of age N Engl J Med 2002; 346: 1781–

5.

45 Rex DK, Cummings OW, Helper DJ et al 5-year incidence

of adenomas after negative colonoscopy in asymptomatic

average-risk persons Gastroenterology 1996; 111: 1178–81.

23 Winawer SJ, Flehinger BJ, Schottenfeld D, Miller DG.

Screening for colorectal cancer with fecal occult blood

test-ing and sigmoidoscopy J Natl Cancer Inst 1993; 85: 1311–18.

24 Wagner JL, Tunis S, Brown M et al Cost effectiveness of

col-orectal cancer screening in average-risk adults In: Young

GP, Rozen P, Levin B, eds Prevention and Early Detection of

Colorectal Cancer London: WB Saunders, 1996: 321–56.

25 Frazier AL, Colditz GA, Fuchs CS, Kuntz KM

Cost-effectiveness of screening colorectal cancer in the general

population JAMA 2000; 284: 1954–61.

26 Vijan S, Hwang EW, Hofer TP, Hayward RA Which colon

cancer screening test? A comparion of costs, effectiveness

and compliance Am J Med 2001; 111: 593–601.

27 Winawer SJ, Stewart ET, Zauber AG et al A comparison of

colonoscopy and double-contrast barium enema for

surveil-lance after polypectomy N Engl J Med 2000; 342: 1766–72.

28 Ahlquist DA, Skoletsky JE, Boynton KA et al Colorectal

cancer screening by detection of altered human DNA in

stool: feasibility of a multitarget assay panel Gastroenterology

2000; 119: 1219–27.

29 Nelson DB, McQuaid KR, Bond JH et al Procedural success

and complications of large-scale screening colonoscopy.

Gastrointest Endosc 2002; 55: 307–14.

30 Rex DK, Cutler CS, Lemmel GT et al Colonoscopic miss

rates of adenomas determined by back-to-back

colono-scopies Gastroenterology 1997; 112: 24–8.

31 Hixson LS, Fennerty MB, Sampliner RE, McGee D, Garewal

H Prospective study of the frequency and size distribution

of polyps missed by colonoscopy J Natl Cancer Inst 1990; 82:

1769–72.

32 Pignone M, Saha S, Hoerger T, Mandelblatt J

Cost-effective-ness analyses of colorectal cancer screening: a systematic

review for the U.S Preventive Services Task Force Ann

Intern Med 2002; 137: 96–104.

33 Ransohoff DF, Sandler RS Screening for colorectal cancer N

Engl J Med 2002; 346: 40–4.

34 Rex DK, Lieberman DA Feasibility of colonoscopy

screen-ing: discussion of issues and recommendations regarding

implementation Gastrointest Endosc 2001; 54: 662–7.

Effectiveness of screening is measured in terms of life-years saved through prevention of colorectal cancerand improved survival by detecting cancer at earliercancer stages The cost-effectiveness of colonoscopy orother alternatives for screening is calculated as the aver-age costs per life-years saved (average cost-effectivenessratio, ACER) Rather than calculate an absolute value,cost-effectiveness is frequently calculated in comparisonwith other strategies The marginal or incremental cost-effectiveness ratio (ICER) corresponds to the additionalcosts needed to spend in order to save one additionallife-year in comparison with another strategy In math-ematical terms:

[13.1]where the indices 1 and 2 refer to the first and secondmedical strategy, respectively, compared with eachother Frequently, the cost-effectiveness of prevention iscompared with a strategy of no cancer prevention or noscreening

It has been argued that in making a decision, a policy-maker could rely directly on the various cost-effectiveness ratios published in the medical literature[2] The outcome of CEA is heavily dependent on thetypes of variables considered by the analysis and theassumptions built into the decision model Despite mul-tiple efforts at standardization, no two diseases are alikeand submit to similar types of cost analyses If one trulytries to include all factors that contribute to the manage-ment of a disease and tally even its most remote implica-tions, the actual medical question becomes diluted by alarge variety of nonmedical issues, such as cab fare to thehospital or patient placement in a nursing home QALY

is an effectiveness parameter that does not apply to alldiseases and that does not provide a reliable measure forall medical achievements, e.g in treating dental cavit-ies, managing irritable bowel syndrome, or just ruling

Colonoscopy has a wide range of clinical applications,

from its use as the primary diagnostic tool for all colonic

diseases to a treatment modality in an ever-increasing

variety of clinical indications In each instance, the use of

colonoscopy is governed by the interplay between its

medical effectiveness and costs, as well as the

availabil-ity of other competing medical options A large portion

of the clinical use of colonoscopy is still focused on the

diagnosis and prevention of colorectal cancer and this

chapter deals with the cost-effectiveness of colonoscopy

in the prevention of colorectal cancer

The primary goal of any medical intervention relates

to medical success rather than inexpensive management

Cost is only of secondary relevance compared with the

primary concerns about the most efficacious prevention,

diagnosis, or therapy Costs become relevant if assessed

in conjunction with medical effectiveness In

compar-ing two competcompar-ing management options, four potential

scenarios can arise If the first option is cheaper and

bet-ter than the second option, the decision in its favor is

easy The decision against the first option is similarly

easy if the first option is more expensive and worse than

its alternative option It is the mixture of medically better

but more expensive or medically worse but less

expens-ive outcomes that are difficult to decide unequivocally

Ideally, comparison of cost-effectiveness ratios would

provide a means for comparison of such options [1,2]

General principles of cost-effectiveness

analyses

In cost-effectiveness analyses (CEA), one calculates the

ratio of costs per effectiveness of the medical

inter-vention [1,2] The effectiveness is measured in terms of

quality adjusted life-years (QALY) gained through the

intervention Health-related quality of life (HRQL) is

measured on a scale between 0 (death) and 1 (perfect

health) and is used as a multiplier for life-years to adjust

for the different values of lifetime spent in various

disease states A low cost-effectiveness ratio indicates

a highly cost-effective medical intervention with low

investment costs per yield The general use of CEA and

Chapter 13 Cost-effectiveness of Colonoscopy Screening

Amnon Sonnenberg

Colonoscopy Principles and Practice

Edited by Jerome D Waye, Douglas K Rex, Christopher B Williams

Copyright © 2003 Blackwell Publishing Ltd

ally small when compared with their potential benefit.For instance, a single colonoscopy costing $1000 can save

a life worth, say, $1 000 000 However, the relativelyinexpensive test must be applied multiple times to alarge population of subjects in order to gain a benefit inone or few patients In other words, colonoscopies mayneed to be performed 1000 times before one single can-cer case is detected in a timely fashion to save a singlelife On one hand, this balance may shift in disfavor ofscreening if the screening procedure itself results in life-threatening and costly complications On the otherhand, if screening is associated not only with life-savingmeasures in one patient but also with extended life inanother case and prevention of cancer altogether in yetanother set of patients, the balance may shift yet again,this time in favor of screening

To avoid the contentious issue of assigning a ary value to human life, health economists have largelyabandoned cost–benefit analyses and resorted to CEA.Instead of translating medical benefits into costs, the endresult is usually measured in terms of QALY, life-yearssaved, or some other outcome parameter indicating theeffectiveness of screening The investment in screeningand its potential risks and adverse effects are still meas-ured as monetary cost Cost lends itself to be used as the common denominator for the multitude of hetero-geneous entities touched upon by the analysis It is awidely used means of measurement and people are intimately familiar with its meaning and ubiquitousapplicability These items include, among others, cost ofthe screening procedure and its potential complications,costs of cancer care, and absenteeism from work

monet-The tree in Fig 13.1 represents only a crude tion of the issues involved in screening In Fig 13.2, theinitial tree is expanded to depict in more detail otherpotential events and outcomes associated with screen-ing Besides screening, the option of nonscreening isadded as a lower branch to the tree The results of screen-ing are broken down into true and false Lastly the moredetailed outcomes differentiate between patients who

presenta-do and presenta-do not fully benefit from prevention It is obviousthat even this tree is far from complete and that it could

be expanded much further, e.g by considering theinfluence of repeat screening procedures, the concom-itant or subsequent use of different screening tests, orpatient noncompliance with the screening procedure

Cost-effectiveness of decennial colonoscopy

The decision tree shown in Fig 13.2 becomes an helpful instrument when tackling decision problemsthat involve many screening options, test outcomes, andtherapies The tree is difficult to appreciate and thereader is overwhelmed by the amount of detail It is also

un-out the presence of a serious disease with a negative

test Although costs were initially introduced only as an

accounting trick to make the heterogeneous variety of

social and medical items commensurable, their

intro-duction into the analysis has brought economists into

the fray who harbor a completely different set of

inter-ests from physicians

Economists are primarily concerned with scarcity of

resources and the maximization of resource utilization

Although in many CEA the focus has shifted from a

medical to an economic perspective, physicians may still

misread them to provide guidance on the best

med-ical management From the perspective of a physician,

medical arguments should prevail over economic

argu-ments Costs are only relevant to a physician as a

gen-eral way of accounting for the large variety of otherwise

incommensurable quantities that may bear on a medical

decision CEA are helpful and most reliable when

striv-ing to compare different medical management

strat-egies, such as fecal occult blood testing vs colonoscopy

or repeat vs single colonoscopy If done properly,

comparative CEA subject all management options to a

similar set of constraints, assumptions, and costs CEA

are less suited to providing absolute measures of

cost-effectiveness or general guidance about the actual

imple-mentation of a particular medical strategy

Small costs in a great many as opposed

to great effects in a small few

At least in principle, the decision for or against

screen-ing is governed by a rather simple balance: the end result

must justify the initial investment in screening The

risks and costs of screening affect the entire population,

whereas the preventive measures benefit only a small

fraction of the population (Fig 13.1) This interplay

between the entire population and a subfraction prone to

develop cancer adds the perspective of probability to the

analysis The costs of the screening procedure are

usu-Benefit of prevention

Cost of

screening

No benefit Few positives

Many negatives

Fig 13.1 Decision tree demonstrating the general principles of

screening The costs of screening are accrued in the entire

population, whereas its benefits affect only a minority of

patients.

Chapter 13: Cost-effectiveness of Colonoscopy Screening 141

cer is equal to the screening interval The population ineach state is also subject to the annual age-specific deathrate of the US population

The transition probabilities built into the model aretaken from the literature, including a 40% mortality fromcolorectal cancer, a 75% efficacy of colonoscopy in pre-venting colorectal cancer, and a 1% annual incidence rate

of colorectal adenomas In a set of sensitivity analyses

less well suited for handling the impact of decisions and

events that occur repetitively and change over time, such

as surveillance colonoscopy after polypectomy,

time-dependent decline in compliance, or age-related rise in

cancer incidence The transition from polyp to cancer

and the time-dependent evolution of cancer are better

modeled by a Markov process [3] In a Markov process,

medical events are modeled as transitions of patients

among a set of predefined health states, the occurrence

of each transition being governed by a probability value

(Fig 13.3) The circles in Fig 13.3 symbolize the

vari-ous health states, while the arrows symbolize transition

probabilities among them The time frame of the

ana-lysis is divided into equal increments of 1 year, during

which patients may cycle from one state to another

The initial population comprises 100 000 subjects aged

50 years who at the start are offered screening

colono-scopy Depending on the initial compliance rate, subjects

undergo a colonoscopy or enter the pool of

noncom-pliant persons After a normal colonoscopy (without

adenomatous polyp), subjects enter a new state labeled

“status post colonoscopy.” In subjects compliant with a

repeat screening, a colonoscopy is scheduled every 10

years In the case of an adenomatous polyp, surveillance

colonoscopy is repeated every 3 years until

adenomat-ous polyps are no longer found Subjects in any Markov

state can develop colorectal cancer, the probability

being given by the age-specific incidence rate The

likeli-hood of developing cancer is reduced in subjects after a

normal colonoscopy or after polypectomy, depending

on the rate of preventive efficacy assigned to the

pro-cedure The length of time for which colonoscopy plus

polypectomy provide protection against colorectal

can-Screening

Cure

Extended life True positive

compliant

Non-CRC Death

3 yrs

polyp

scopy

Colono-10 yrs no polyp

s/p colono- scopy

Fig 13.2 Expanded decision tree of

screening The arrows symbolize

transitions that are associated with

costs.

Fig 13.3 Markov state diagram of screening for colorectal

cancer (CRC) by repeat colonoscopy The arrows symbolize transitions between the various states Noncompliant, subjects noncompliant with repeat colonoscopy s/p, status post.

From the age of 50–64 years and after the age of 75 years,subjects are exposed to the age-specific incidence rate ofcolorectal cancer without any potential protection fromcolonoscopy and polypectomy The smaller fraction

of cancers prevented by a single screening colonoscopy

is associated with fewer life-years saved The ACER

of a single colonoscopy is $55 400 Compared with noscreening, a single colonoscopy represents an extremelycost-effective screening strategy of less than $3000 perlife-year saved

Flexible sigmoidoscopy

The cost-effectiveness of screening by flexible doscopy is modeled similarly to screening by decennialcolonoscopy (Fig 13.4) [3] Instead of colonoscopy, the simulation is started with 100 000 subjects beingoffered screening through flexible sigmoidoscopy Thetransitions out of this initial state depend on whether apolyp is found during sigmoidoscopy After a normal(negative) flexible sigmoidoscopy without adenomatouspolyps, subjects stay in the pool waiting for the nextscreening sigmoidoscopy in 5 years The remainder ofthe model is similar to that of colonoscopy Besides thestates shown in Fig 13.4, the actual model was simulatedwith an additional status to account for noncompliantpatients regarding repeat flexible sigmoidoscopies orfollow-up colonoscopies after a positive flexible sigmoi-doscopy About 45% of all polyps are within the reach offlexible sigmoidoscopy [11–13] According to the model,screening by flexible sigmoidoscopy prevents 34% of allcolorectal cancers Although the investments in screen-ing with flexible sigmoidoscopy reduce the number of

sigmoi-these values are varied over a wide range The costs

for medical, surgical, and diagnostic services represent

the average payments allowed for each service by the

U.S Health Care Finance Administration The costs

also include the possibility of hospitalization for

bleed-ing or perforation after colonoscopy with or without

polypectomy and cost estimates for the medical care of

subjects with colorectal cancer The costs accrue every

time subjects pass through transitions that are associated

with healthcare utilization Effectiveness is measured in

terms of life-years that accumulate in subjects who stay

alive after each cycle The number of life-years saved

through screening corresponds to the difference in

life-years lost from cancer-related deaths between two

Markov models with and without screening All future

costs arising from screening or care of colorectal cancer

and all future life-years saved through screening are

dis-counted at an annual rate of 3% [4]

The ACER of colonoscopy every 10 years is $28 000

per life-year saved The ICER of colonoscopy compared

with no screening amounts to $11 000 per life-year

saved In comparison with other medical interventions,

such ACER and ICER values are considered quite

cost-effective and colonoscopy appears a strategy

worth-while pursuing [5] More frequent colonoscopies, e.g

every 5 instead of 10 years, increase the ACER and ICER

of cancer prevention by making the screening procedure

more costly Changes in the surveillance interval after

polypectomy exert only a small influence without

affect-ing the relative differences among competaffect-ing screenaffect-ing

programs Any decrease in the efficacy of colonoscopy

plus polypectomy in preventing colorectal cancer also

increases the ACER and ICER of colonoscopy

Cost-effectiveness of alternative

screening procedures

Single colonoscopy

Although repeat colonoscopies every 5–10 years

repres-ent the most effective screening strategy for colorectal

cancer, it has not been widely used because of its

asso-ciated high costs and relatively low patient compliance

To escape these shortcomings, some authors have

sug-gested a one-time only screening colonoscopy after age

50 [6–9] In a previous study it was shown that the best

period to schedule a single colonoscopy lies between

65 and 70 years of age [9] At this age a balance is

achieved between a declining life expectancy (leading to

a reduced impact of any life-saving measures) and a

ris-ing incidence of colorectal cancer Screenris-ing by a sris-ingle

colonoscopy at age 65 is modeled similarly to screening

by multiple colonoscopies, as shown by Fig 13.3 [10]

However, no repeat colonoscopy is scheduled after the

initial colonoscopy or after a successful polypectomy

FS

compliant

Non-CRC Death

5 yrs

3 yrs

No polyp FS

10 yrs polyp

scopy

Colono-Fig 13.4 Markov state diagram of screening for colorectal

cancer (CRC) by flexible sigmoidoscopy (FS) s/p, status post.

Chapter 13: Cost-effectiveness of Colonoscopy Screening 143

rise in costs (from baseline $3.50) to $7 or $14 raises the ICER of FOBT in comparison with no screening to

$12 600 or $18 400, respectively An increase in both test sensitivity and specificity reduces the ICER Within thebroad ranges tested in the sensitivity analysis, their over-all influence on the ICER does not exceed $2000 Becausescreening based on flexible sigmoidoscopy or FOBT bothdepend on colonoscopy as their final arbiter, shortening

of the interval between repeat colonoscopies also ders these two screening strategies more expensive andless cost-effective Similarly, any decrease in the efficacy

ren-of colonoscopy plus polypectomy in preventing tal cancer increases the ACER and ICER of other screen-ing methods as well

colorec-Under base case conditions, patient compliance withthe screening program is assumed to be perfect Since theinitial compliance determines how many persons enterthe screening program, it influences the overall number

of cancers prevented and the total costs in a linear ion However, the initial compliance rate does not affectthe cost-effectiveness ratio of any individual program

fash-A decrease in compliance associated with test tion results in higher costs per life-year saved FOBT

repeti-is particularly sensitive to changes in compliance withrepeat testing because it is done more frequently thancolonoscopy Only a slight decrease in compliance withrepeat FOBT increases its ICER (compared with noscreening) far above the ICER of colonoscopy A lowcompliance with colonoscopy following a positive FOBTalso renders the initial FOBT less efficacious and in-creases its associated costs per saved life-year Because itdepends on several types of patient compliance, screen-ing by FOBT is generally far more sensitive to changes incompliance than a colonoscopy screening program

CEA comparison of competing screening strategies

Table 13.1 illustrates a comparison of various analysesthat use variations of a similar Markov process to estim-ate the cost-effectiveness of competing strategies to prevent colorectal cancer in the general population Allanalyses assume perfect compliance and do not includecosts or quality adjustment of the life years saved Ashighlighted in the previous sections, all values shown

in Table 13.1 can easily be shifted upward or downward

by assuming a set of more or less favorable costs and prevention outcomes Based on the limited evidenceprovided by the analyses, the ACERs of all six medicalinterventions fall between $28 000 and $82 000 Whencompared with no prevention, single colonoscopy, FOBT,and decennial colonoscopy are associated with the small-est ICER and appear the most cost-effective strategies.Compared with no screening, a single colonoscopyrepresents a very cost-effective screening strategy of less

colonoscopies used for screening, an ACER of $74 000

and an ICER of $36 500 compared with no screening

make this strategy far more expensive than any strategy

using colonoscopy Screening by flexible sigmoidoscopy

is most sensitive to the costs of the procedure itself The

only way to salvage sigmoidoscopy as a screening

pro-cedure would be to offer it at very low cost Currently,

flexible sigmoidoscopy costs $400, compared with $695

for a simple colonoscopy and $1004 colonoscopy plus

polypectomy If the cost of flexible sigmoidoscopy drops

below a threshold of $170, its ICER (compared with no

screening or with screening using fecal occult blood test)

makes it a cost-effective alternative to colonoscopy as

a secondary screening procedure Moreover, if polyps

can be removed during flexible sigmoidoscopy without

need for a follow-up colonoscopy, this strategy also

becomes a cost-effective screening alternative

Fecal occult blood test

In prospective trials the fecal occult blood test (FOBT)

was shown to reduce colorectal cancer-related mortality,

on average by 18% [14] Since it also appears to be a

cheap test, it has been suggested that it would represent

a cost-effective alternative for screening colorectal

can-cer [6,15–18] In our own analysis, its cost-effectiveness

was assessed using a Markov process very similar to the

one shown in Fig 13.4 for flexible sigmoidoscopy [3] In

the case of FOBT, the lower two states of Fig 13.4

repres-ent “FOBT” and “status post FOBT.” The simulation is

started with 100 000 subjects being offered screening

through FOBT The transitions out of the initial FOBT

state depend on whether the test is negative or positive

After a negative FOBT, subjects stay in the pool waiting

for the test repetition in a year’s time In case of a positive

FOBT, subjects undergo a colonoscopy After a negative

colonoscopy, FOBT is abandoned for a period of 10

years In addition to many similar transition

probabilit-ies from the previous models, the present Markov

pro-cess assumes a 40% sensitivity and 97.5% specificity of

FOBT for colorectal cancer

Compared with no intervention, screening by FOBT

prevents 16% of all colorectal cancers In detecting

earlier cancer stages, FOBT leads to an additional 2%

reduction in mortality beyond cancer prevention alone

Compared with no screening, only $9700 (ICER) are

spent to save one additional life-year FOBT represents

a relatively cost-effective option when compared with

no screening

The outcome of the simulation is mostly influenced by

the costs of the FOBT itself and the test characteristics

The baseline cost of $3.50 for the FOBT may be overly

optimistic because it does not include any cost for

phy-sician visit and test management The ICER of FOBT is

linearly dependent on the costs of delivering the test A

(CT) or magnetic resonance imaging (MRI) to create and three-dimensional scans of the colon Advancedimaging software creates axial and reformatted two-dimensional images of the colon, as well as simulatedendoluminal images When computer-generated endo-luminal images are displayed at a fast rate of 15–30/s,virtual colonoscopy provides the illusion of travelingthrough the colon For both techniques the bowel needs

two-to be cleansed in the same way as for a barium enema

or colonoscopy The colon is then inflated with a singlecontrast of gas or a water-based enema Both techniqueshave been reported to yield a sensitivity over 75% and

a specificity over 90% in detecting colorectal cancer and polyps of 10 mm or more in size [19–21] Using CT

or MRI colonography for screening of colorectal cancerwould reduce the number of colonoscopies This costsaving is gained at the expense of exposing all subjectswith suspected polyps or cancers to two procedures, i.e.colonography plus colonoscopy In principle, screen-ing CT or MRI colonography is associated with a similarsituation as all other screening procedures whose find-ings need to be followed by a subsequent colonoscopy.After a positive FOBT, for instance, a colonoscopy isneeded to assess the colon for the presence of neoplasm

In the USA, polyps found during flexible sigmoidoscopyresult inevitably in a colonoscopy administered for poly-pectomy and to evaluate the remainder of the colon

than $3000 per life-year saved Repeat decennial

colono-scopies could save two to three times more lives than

a screening program based on a single colonoscopy If

third-party payers are able to provide the financial

re-sources and subjects are willing to participate, a

screen-ing program comprisscreen-ing repeat colonoscopies represents

the better yet more expensive alternative Under tighter

economic conditions with only limited funds available

for cancer screening, a single colonoscopy between the

age of 65 and 70 years offers a relatively cheap and highly

cost-effective means of screening for colorectal cancer

The ICER of colonoscopy compared with no screening

amounts to $11 000 per life-year saved, which is only

slightly higher than the ICER of FOBT Colonoscopy is

also associated with a relatively modest ICER when

com-pared as an add-on to FOBT alone, i.e $11 400 per

life-year saved In screening using flexible sigmoidoscopy,

the costs saved on colonoscopies are partly offset by the

additional expenses for two procedures in all patients

with distal polyps and the higher expenses for cancer

care among patients with missed proximal cancers

Costs of inconclusive tests and

colonoscopy as the final arbiter

Computer-assisted colonography is a new technique

that uses data generated from computed tomography

Table 13.1 Outcomes of competing programs to prevent colorectal cancer.

Numbers in the table relate to a cohort of 100 000 persons aged 50 and followed on average for 28.5 years until the time of death Future life-years saved and future costs were discounted using an annual rate of 3%.

ACER, average cost-effectiveness ratio; CRC, colorectal cancer; FOBT, fecal occult blood test; ICER, incremental

cost-effectiveness ratio.

Chapter 13: Cost-effectiveness of Colonoscopy Screening 145

tion of subjects with normal findings For instance,expecting 30% of all subjects at age 50 years to harbor

polyps and a colonoscopy to cost $1000, P= 70% and thealternative procedure < $700

The usefulness of this type of threshold analysisrelates to the fact that it can be similarly applied to manydifferent screening techniques that require a colonoscopy

as a follow-up test for their positive results As ated above, such screening techniques include FOBT, flexible sigmoidoscopy, and newer stool tests for tumor-specific DNA sequences It needs to be kept in mind that threshold analysis represents a rather crude, back-of-the-envelope type of calculation that ignores, forinstance, the different costs associated with simplecolonoscopy vs polypectomy and the impact of false-positive or false-negative outcomes of the alternative testprocedure Of course, the analysis could be refined byusing more detailed assumptions or one could use amore detailed Markov modeling, as done previously toassess the cost-effectiveness of flexible sigmoidoscopy

indic-or FOBT [3] Using a Markov process, we also did notfind (MRI or CT) colonography to be a cost-effectivemethod that could presently compete with colonoscopy[24] However, it is conceivable that further refine-ments and simplifications of the technique will lower its costs and render it a cost-effective alternative in thefuture

Surveillance and prevention in ulcerative colitis

Patients with long-standing extensive ulcerative colitisharbor an increased risk of developing colorectal cancer[25–28] After 40 years about 30% of all patients withpancolitis have developed colorectal cancer [25–28],compared with a 6% cumulative risk over lifetime forsuch cancer in the general population [29] Because of theincreased risk of cancer, surveillance colonoscopy inlong-standing pancolitis has been widely recommended[30–32] The rationale of surveillance colonoscopy is todetect cancer at an early stage when treatment is morelikely to be curative Little evidence exists, however, thatsurveillance is truly efficacious and cost-effective in preventing deaths from colorectal cancer Considering the obstacles to a clinical resolution, one can again usethe techniques of medical decision analysis to assess the feasibility and usefulness of surveillance However, the values of ACER or ICER would provide little guidance

to the clinician, since no other comparative measures ofprevention are available to put such parameters in per-spective Instead of expressing the outcome of a simula-tion in terms of ACER or ICER, a threshold analysis

is used similarly to the example given above [33] Theanalysis tries to answer the following question: Howhigh does the cumulative probability of colorectal cancer

Newer tests designed to screen stool specimens for a

vari-ety of cancer-related genes face a similar need for

colono-scopy as final arbiter in the case of a positive finding [22]

In Fig 13.5, this medical scenario is modeled as a

simple decision tree A threshold analysis is used to

determine the probability of a normal finding, i.e no

colorectal polyps or cancers that would render

screen-ing with colonography the less expensive approach [23]

The decision between colonoscopy or another screening

alternative is symbolized by the small filled square on

the left-hand side The upper branch representing the

screening alternative to colonoscopy has two possible

outcomes, both governed by chance The alternative test

can reveal a normal finding or a neoplasm The

prob-abilities associated with these two outcomes are P and

1 – P respectively In the case of a normal finding, no

fur-ther testing is necessary In the case of a positive test

out-come, a subsequent colonoscopy becomes necessary The

lower decision branch representing screening

colono-scopy results in the same two outcomes and probabilities

as in the upper branch but with different implications

No further diagnostic work-up is needed in case of

neo-plasm or any other positive finding In summary, the

decision tree weighs the higher costs of a colonoscopy

against the savings obtained through a cheaper

alternat-ive procedure with the occasional need to perform two

procedures in patients with positive findings For the

upper branch to cost less than the lower branch:

Alternative+ (1 – P) × Colonoscopy < Colonoscopy

[13.2]

Simple algebraic manipulations yield:

In essence, any alternative test procedure needs to cost

less than colonoscopy multiplied by the expected

frac-Negative: $0 Alternative

Fig 13.5 Decision tree for calculating the threshold

probability when a test becomes a viable alternative to

colonoscopy Both procedures (colonoscopy or its alternative)

are associated with the same two potential outcomes, i.e.

negative vs positive finding A positive finding of the

alternative procedure needs to be followed by an additional

colonoscopy.

against surveillance It has only two possible outcomesgoverned by the probability of developing cancer In thecase of cancer, the outcome is identical to that of a missedcancer as a consequence of FN surveillance tests With-out cancer, the outcome is identical to the outcome associated with TN surveillance tests, i.e life unaffected

$1000= $17 000 Using the human capital approach, thevalue of life is equated with the average annual earningsmultiplied by the life expectancy, i.e life= 34 × $25 000 =

$850 000 The HRQL after proctocolectomy is assumed

to be 95% compared with 100% of an unoperated healthyindividual A recent study reported a cancer mortalityrate of 15% (mort1) in a population with surveillance asopposed to 45% (mort2) in a population without surveil-lance [34] The sensitivity of colonoscopy in detectingpremalignant lesions and preventing cancer-relateddeath is estimated as TP= 80%, while the specificity isestimated as TN= 60% based on data taken from Con-nell and colleagues [35]

need to be for biannual surveillance to be more beneficial

than nonsurveillance?

This question is translated into the decision tree

shown in Fig 13.6 Its structure is explained

proceed-ing from left to right and from top to bottom The filled

square on the left-hand side symbolizes the initial

decision for or against surveillance The chances for or

against the development of colorectal cancer are denoted

as P and 1 – P respectively In the case of cancer,

surveil-lance colonoscopy plus histology can yield true-positive

(TP) or false-negative (FN) test results Cancers

pre-vented or detected as a consequence of surveillance are

associated with proctocolectomy The mortality (mort1=

15%) reflects the impact of cancers that cannot be

pre-vented through surveillance and proctocolectomy The

life gained becomes reduced by the impaired HRQL

after proctocolectomy The final outcomes of TP and FN

surveillance tests are quite similar, except for the higher

mortality rate (mort2= 45%) associated with cancers

missed during surveillance Colonoscopy in patients

without dysplasia can yield true-negative (TN) or

false-positive (FP) tests Life and its quality remain unaffected

by TN surveillance procedures FP tests lead to an

un-necessary proctocolectomy and a reduction in HRQL

The main lower branch of the tree represents the decision

CRC, Timely operation life x HRQL x (1-mort1)

$850,000

c

No CRC, unneeded operation life x HRQL

$807,500

d

CRC, late operation life x HRQL x (1-mort2)

$444,125

e

No CRC life

$850,000

f

FP TN

No surveillance

Surveillance

P

40% Fig 13.6 Decision tree for threshold

analysis of surveillance in patients

with ulcerative colitis P, cumulative

probability of developing colorectal cancer (CRC); TP, true-positive (sensitivity); FN, false-negative; TN, true-negative (specificity); FP, false- positive results of surveillance colonoscopy; HRQL, health-related quality of life (95%); mort1(15%) and mort2(45%), cancer-related mortality

in patients with and without surveillance respectively.

Chapter 13: Cost-effectiveness of Colonoscopy Screening 147

TP= 70% The resulting threshold value P = 45% lies

outside the cumulative lifetime risk of the patient to everdevelop colorectal cancer The second set of assumptions

is by no means extreme and seems to fall well within areasonable range that might be expected by a widely dis-tributed surveillance program

As these examples show, one can conceive ilarly reasonable sets of assumptions that result either

sim-in excessively high or low thresholds Based on one’s preferences, one can use the decision analysis to do both, defend or refute the usefulness of surveillancecolonoscopy To narrow down the possible range of eachassumption built into the decision analysis, a better set

of data would be needed that can only be obtainedthrough clinical studies More refined decision modelscan be envisaged that account for the time-dependentdevelopment of dysplastic lesions and their multisteptransition into cancer [37] Instead of comparing the two main branches of Fig 13.6, one can compare the outcome of two separate Markov chains that simulatethe age- and time-dependent occurrence of colorectalcancer Such more complicated models also consider thetransition from dysplasia to cancer, the expendituresarising from medical and surgical therapy, as well as theindirect costs of surveillance However, a more detailedmodel provides a similar answer as the present thresh-old analysis, i.e the argument in favor or against sur-veillance depends on the assumptions built into themodel, for which definitive data are lacking [37] Thedecision analysis shows which factors are most relevantfor the success of a surveillance program, but fails to pro-vide a clear-cut answer as to whether such a programwould be truly beneficial

Limitations of CEA

The decision for or against screening and prevention ofcolorectal cancer depends on many partly interrelatedfactors These factors include:

• family history of adenomatous polyps and cancer;

• patient demographics;

• presence of other comorbid conditions;

• incidence and prevalence of colorectal polyps;

• progression of various polyp types and other malignant conditions to cancer;

pre-• sensitivity and specificity of competing diagnostictechniques;

• invasiveness and risks of various diagnostic modalities;

• surgical success at different disease stages;

• adverse effects, disability, and mortality from surgery;

• effectiveness of other treatments;

• availability of medical interventions;

• medical and nonmedical costs;

• natural history, including mortality, of colorectal cancer

For surveillance to be the preferred management

strat-egy, the upper main branch of the decision tree should

result in a higher yield than the lower main branch:

– Surveillance+ P · TP · a + P · FN · b + (1 – P) ·

TN · c + (1 – P) · FP · d ≥ P · e + (1 – P) · f [13.4]

where a–f are used as short forms to indicate the various

outcomes The cost for surveillance enters the equation

with a minus sign, as opposed to the plus sign associated

with the benefit of life-years saved Equation 13.4 can be

solved for the probability value of P:

[13.5]

Although the formula may look daunting, the P-value

is readily calculated on a spreadsheet A probability of

P= 16% is obtained using the values introduced in the

preceding paragraph This P-value suggests that if the

probability for developing cancer exceeds 16%,

surveil-lance would represent a decision preferred over no

surveillance In the present example of a 45-year-old

patient with a 10-year history of ulcerative colitis, the

cumulative probability of developing cancer over the

patient’s remaining lifetime of 34 years equals:

P= 10 years × 0.5% + 10 years × 1.0% + 14 years

Considering the high risk of developing colitis-related

cancer, biannual surveillance appears to be the better

medical decision to make Since the 36% probability

of developing cancer exceeds the threshold P-value of

16%, surveillance becomes the preferred management

strategy The strength of the argument in favor of

sur-veillance is directly proportional to the threshold value

A low threshold value would argue strongly in favor

of surveillance Vice versa, a high threshold value that

exceeds the lifetime probability of developing cancer

would speak against the use of surveillance colonoscopy

Since the value of life appears as variable in the final

outcomes of all six branches in the decision tree shown

in Fig 13.6, the actual costs calculated by the human

capital approach exert little influence on the outcome of

the analysis The cost of surveillance pales in comparison

with the benefit of life-years saved Therefore,

vari-ations in the cost of surveillance also exert relatively little

influence on the threshold probability However, the

outcome of the analysis very much depends on the other

assumptions built into the model It has been suggested,

for instance, that HRQL remains largely unaffected by

proctocolectomy [36] Increasing HRQL from baseline

95% to 100% halves the threshold value from baseline

16% to 8% In the baseline analysis shown in Fig 13.6,

the following set of values were chosen: mort1= 15%,

HRQL= 95%, TP = 80% Slight variations lead to a

second set of values, such as mort1= 25%, HRQL = 85%,

and present their outcomes as definitive answers to gering medical problems They restrict the ranges tested

lin-in the sensitivity analyses or avoid polin-intlin-ing out ables that shift the model out of balance The investig-ators make their results appear more conclusive thanthey really are and advertise them as mathematicallyderived rigorous evidence for or against a particularmedical strategy Various medical specialists and theirprofessional organizations pursue a political and eco-nomic agenda Gastroenterologists, for instance, areinterested in studies that confirm the relevance associ-ated with endoscopic procedures, whereas radiologistswant to emphasize the benefit of their imaging tech-niques, and generalists want to preserve the use of FOBTand flexible sigmoidoscopy as screening methods acces-sible to the nonspecialist Rather than look at details ofthe analysis, CEA are often accepted based on their out-come alone and whether they succeed in confirming a set of preconceived notions However, medical decisionanalyses are generally less suitable for implementing

vari-a specific policy, but more suitvari-able for highlightingwhich variables are important in influencing the med-ical decision or its outcome It needs to be kept in mindthat models only serve as guidance for assessing thepotential outcome of a medical strategy Economic anddecision models do not obviate the primacy of clinicaldata gathered through controlled clinical trials

Summary

In comparing two competing screening strategies, thefollowing scenarios may arise If one strategy is cheaperand more effective than the alternative one, the decision

in favor of the cheaper and more effective strategy ismade easy The mixtures of more effective but moreexpensive or less effective but less expensive outcomesare sometimes difficult to decide without a formal cost-effectiveness analysis However, physicians should notmisread a cost-effectiveness analysis as guidance towardthe best medical strategy Compared with no screening,

a single colonoscopy represents a very cost-effectivescreening strategy of less than $3000 per life-year saved.Repeat decennial colonoscopies save two to three timesmore lives than a screening program based on a singlecolonoscopy The ICER of decennial colonoscopy com-pared with no screening amounts to $11 000 per life-yearsaved Colonoscopy is also associated with a relativelymodest ICER when used in addition to FOBT, i.e

$11 400 per life-year saved In screening using flexiblesigmoidoscopy, the costs saved on colonoscopies arepartly offset by the additional expenses for two proced-ures in all patients with distal polyps and the higherexpenses for cancer care among patients with missedproximal cancers Economic and decision models aregenerally unreliable in predicting the exact outcomes

Many of these parameters do not remain constant but

vary as the patient ages and the disease progresses For

instance, the sensitivity and specificity of all screening

methods improve as the disease progresses from a small

mucosal lesion, to polyp, to small and eventually large

cancer [38,39]

For the vast majority of associations, sufficiently

reli-able data do not exist Different factors contribute

differ-ently to the disease and its prevention Medical decision

analysis helps to weigh the contribution of these factors

and to choose between competing management options

Because the available evidence is often crude or

incom-plete, economic and medical decision analyses have to

include many assumptions in their models Although

the individual assumption may have a small margin of

error, the sheer multitude of assumptions built into a

model can render its overall outcome susceptible to large

variations Even if the influence of individual factors is

known and clinically well established, their interaction

and joint influence often remain untested and unknown

For instance, it is known that colonoscopy is a good

tech-nique for diagnosing colon cancers and removing

polyps, but less conclusive evidence exists that these

single achievements actually prevent cancers or

cancer-related deaths [40–42] Even if screening colonoscopy

prevented deaths from colorectal cancer, it would still

remain to be proven that such a strategy actually saved

lives and extended life expectancy [43,44] It may well

be that patients who are saved from death through

colo-rectal cancer soon succumb to other diseases Screening

itself could be associated with untoward medical or

social effects that, in the final balance, completely negate

its seemingly obvious benefits [45]

In the review process of decision analyses submitted

for publication, reviewers almost invariably suggest

additions that make already complex models even more

complicated and difficult to appreciate The inclusion of

many less relevant side issues distract from the few

important associations Unfortunately, simple models

are often misjudged as being primitive or inconclusive

rather than transparent, insightful, or elegant There is a

general failure among medical reviewers to understand

that instead of painting a detailed picture of reality, ideal

models are supposed to contain a simplified and

con-densed representation of a medicine that focuses on the

few essential parameters It does not help the clinician

to have the complexity of his or her medical reality be

replaced by the black box of an overly complicated

model whose conclusions have to be taken at face value,

because the model has become too large and too detailed

to fit the confinements of a journal article Even experts

may find it difficult to disentangle the intricacies of

indi-vidual models and compare their outcomes [46]

To publish their decision analyses investigators are

forced to oversell the relevance of their modeling efforts

Chapter 13: Cost-effectiveness of Colonoscopy Screening 149

17 Frazier AL, Colditz GA, Fuchs CS, Kuntz KM iveness of screening for colorectal cancer in the general

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18 Ransohoff DF, Sandler RS Screening for colorectal cancer

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19 Hara AK, Johnson CD, Reed JE et al Detection of colorectal

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20 Schoenenberger AW, Bauerfeind P, Krestin GP, Debatin JF Virtual colonoscopy with magnetic resonance imaging: in

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21 Royster AP, Fenlon HM, Clarke PD, Nunes DP, Ferrucci JT.

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22 Ahlquist DA, Skoletsky JE, Boynton KA et al Colorectal

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23 Pauker SG, Kassirer JP The threshold approach to clinical

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24 Sonnenberg A, Delcò F, Bauerfeind P Is virtual colonoscopy

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25 Gyde SN, Prior P, Allan RN et al Colorectal cancer in

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26 Gilat T, Fireman Z, Grossman A et al Colorectal cancer in

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29 Ries LAG, Kosary CL, Hankey BF, Millaer BA, Harras A,

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30 Choi PK, Kim WH Colon cancer surveillance Gastroenterol Clin North Am 1995; 24: 671–87.

31 Bauer WM, Lashner BA Inflammatory bowel disease and

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Gastroentero-of a specific screening policy, but more suitable for

demonstrating which variables are most important in

influencing its expected result Models can only guide in

comparing the potential outcomes of competing

stra-tegies, but they do not obviate the primacy of clinical

data gathered through controlled clinical trials

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colonoscopy for screening of colorectal cancer be

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679–83.

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Chejfec G Use of colonoscopy to screen asymptomatic

adults for colorectal cancer N Engl J Med 2000; 343: 162–

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Ransohoff DF Risk of advanced proximal neoplasms in

asymptomatic adults according to the distal colorectal

findings N Engl J Med 2000; 343: 169–74.

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C A systematic review of the effects of screening for

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justifiable? Postgrad Med 1997; 102: 49–62.

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two- to three-fold increased risk of colon cancer pared to control or population incidence [4–6] Further-more, the age of the patient at the time of diagnosis andthe number of affected relatives affects the degree of risk

com-If the patient is diagnosed when older than 55 years, the risk to first-degree relatives is approximately double that of the general population This risk is three-fold ifthe patient is between 45 and 55 years and four-fold

if younger than 45 years at the time of diagnosis [7].Likewise, if two first-degree relatives have colorectalcancer, the risk increases by three- to four-fold

The risk of colorectal cancer is also increased in ives of a person with colon adenomas, as demonstrated

relat-by the National Polyp Study The risk in siblings andparents of a patient with any adenomatous polyp was1.78 (95% CI, 1.18–2.67) Again, the age of the person

at the time of adenoma diagnosis was also important.The risk of CRC increased to 2.59 (95 CI, 1.46–4.58) if the polyp was diagnosed at a less than 60 years of age compared to an age greater than 60 years [8] In

another study by Pariente et al [9], the odds ratio for

all adenomas in first-degree relatives of colon cancerpatients compared with controls was 1.5 (95% CI,1.0–2.4) However, if high-risk adenomas (villous com-ponent or size ≥ 1 cm) were considered, the odds ratioincreased to 2.6 (95% CI, 1.3–5.1)

Although there is clearly an increased chance of developing CRC in persons with a family history, thespecific factors involved in this risk are incompletelyunderstood Hereditary factors certainly predispose todeveloping CRC and are probably a major determin-ant However, environmental exposures significantlyinterplay with the hereditary tendency to develop CRC.Hereditary factors appear to make one more susceptible

to the deleterious effects of certain exposures

Which factors and how much each contributes tofamilial tendency have only partially been elucidated.Environmental exposures of adult life are unlikely to bemajor determinants of familial CRC risk, although theyare certainly important to overall colon cancer patho-genesis Studies of spouses of persons with CRC, forexample, show no increased risk of CRC [10] By con-trast, an analysis of cohorts of twins in three Nordiccountries emphasizes the importance of inheritance in

Introduction

Colorectal cancer (CRC) is the second most common

cause of cancer-related mortality, with approximately

57 100 deaths annually in the USA The lifetime risk

for CRC is about 6% in both males and females [1]

The causes of colon cancer are heterogeneous and

include several environmental and heritable factors

Undoubtedly, a complex interaction between these two

categories ultimately determines risk The majority of

cancers occurs in patients with no family history and

are defined as sporadic cases However, roughly 10–

25% of patients have familial colon cancer as defined by

their positive family history In addition, several

well-characterized hereditary syndromes have been

iden-tified that confer a higher risk for colorectal cancer

Although such syndromes account for only a small

per-centage of CRC cases (1–3%), the genetic and molecular

mechanisms involved have contributed immensely to

our understanding of cancer pathogenesis in general

The clinician, especially the primary care physician and

gastroenterologist, should have a fundamental

under-standing of familial colon cancer, including

heredit-ary CRC syndromes For this select group of patients,

screening recommendations for CRC and overall

man-agement are distinct from those of the general

popu-lation Furthermore, the hereditary syndromes have

unique phenotypes with additional clinical

manifesta-tions, including other types of malignancies Genetic

testing is available for many of these syndromes and

offers another tool for the clinician to identify this subset

of patients and their families

Familial colon cancer

A family history of colon cancer is a significant risk

factor for the subsequent development of CRC [2]

Several studies have established the risk of CRC in

relat-ives of a patient with colon cancer, and have

demon-strated that clustering of cases within families occurs

frequently The risk in a first-degree relative of a person

with CRC is approximately the same at the age of 40 as

it is for someone in the general population at the age of

50 [3] First-degree relatives of persons with CRC have a

Chapter 14 Hereditary Colorectal Cancer

Robert F Wong, Scott Kuwada & Randall W Burt

Colonoscopy Principles and Practice

Edited by Jerome D Waye, Douglas K Rex, Christopher B Williams

Copyright © 2003 Blackwell Publishing Ltd

mendations are given in several consensus statements.

In 1997 a multidisciplinary expert panel, composed ofrepresentatives from several organizations, includingthe American Gastroenterological Association (AGA),the American College of Gastroenterology (ACG), theAmerican Society for Gastrointestinal Endsocopy (ASGE),the American Society of Colon and Rectal Surgeons(ASCRS), and the American Cancer Society (ACS), estab-lished clinical practice guidelines for both CRC screen-ing in the general population as well as those with

a familial risk [17] Recently, the panel established new criteria [17a] For those with a family history of CRC orpolyps, the panel makes specific screening recommenda-tions for other family members depending on who isaffected (first-degree, second-degree relatives, etc.), howmany relatives are affected and at which ages For thosewith at least two first-degree relatives with CRC or a single first-degree relative with CRC or adenomatouspolyps diagnosed before the age of 60 years, the panelrecommends a colonoscopy every 5 years, starting at theage of 40 years or 10 years younger than the earliest case

in the family (whichever comes first) Double-contrastbarium enema is another possible option for screening,but the preferred method is colonoscopy If a first-degreerelative is diagnosed with CRC or adenomatous polyps

at age 60 years or older, the screening recommendationsare the same as those persons at average risk for devel-oping CRC, but beginning at age 40 years This is also therecommendation for those with two second-degree relat-ives affected with CRC Finally, the panel recommendsthe same screening for CRC as the average-risk popula-tion in those with second- or third-degree relatives withCRC

The ACS also has separate recommendations [18] Inthose persons with a first-degree relative with CRC oradenomatous polyps diagnosed before age 60 years or

if two or more first-degree relatives had CRC at any age, full examination of the colon should begin at age

40 years or 10 years before the youngest case The mostrecent United States Preventive Services Task Force(USPSTF) guidelines give a strong recommendation thatall average-risk men and women receive CRC screen-ing starting at age 50 years They add that early agescreening in those with affected first-degree relatives is

“reasonable” [18a] They note that the best evidence forcolon cancer screening comes from fecal occult blood test(FOBT) and sigmoidoscopy studies, but that the com-bination of these two, as well as colonoscopy and bariumenema are also reasonable screening approaches in view

of the characteristics of these procedures and presentevidence Other groups have made recommendations,but they are similar to both the multidisciplinary expertpanel and the ACS Table 14.1 outlines a composite of the recommended screening interval and ages of imple-mentation for familial colon cancer

the propensity to develop CRC In this cohort, colon

cancer was only 1 of 3 cancers to show a significant

influence by hereditary factors; the remaining 25 cancers

appeared to have minimal, if any, contribution from

inheritance, and were presumably more dependent on

environmental exposures [11] The study found that

inheritance was part of the pathogenesis of colon cancer

in 36% of all colon cancer cases Exposure of family

members to common or the same environmental factors

accounted for only 8% of familial cases

According to several kindred studies, the common

familial risk probably arises from several low to

moder-ately penetrant susceptibility alleles [12,13] Several

genes and chromosomal loci have already been

demon-strated to be involved in the inherited predisposition

to CRC Houlston and Tomlinson [13a] performed a

pooled analysis on 50 studies to clarify the impact of

individual polymorphisms on cancer risk, and were able

to identify three potential candidate alleles that confer an

increased susceptibility These polymorphisms include

the adenomatous polyposis coli (APC-I1307K) variation,

the Harvey Ras-1 variable number tandem repeat

poly-morphism (HRAS1-VNTR), and certain alleles of the

methylenetetrahydrofolate reductase (MTHFR) gene.

The APC-I1307K mutation is a mutation in the APC gene

found in 6% of the general Ashkenazi Jewish

popula-tion, 12% of this population with CRC, and 29% with

CRC and a family history of colon cancer APC-I1307K

mutation predisposes to a milder degree of CRC risk

compared to that observed in persons with familial

adenomatous polyposis, which also arises from APC

mutations This mutation predisposition appears to give

rise to a phenotype of CRC that is similar to sporadic

cases aside from a mild to moderate increased risk

[14–16]

Genetic testing is available for the APC-I1307K

muta-tion in a person of Ashkenazi Jewish decent with a

fam-ily history of CRC Other than this specific population

and the established hereditary syndromes (see below),

no other routine genetic testing exists to identify persons

at risk for colon cancer Therefore, the clinician must be

aware of those at higher risk based on their family

his-tory, so effective CRC screening can be implemented

Screening recommendations for persons with a family

history of CRC differ from those for the general

popula-tion; they are more aggressive and begin at younger

ages It must be understood that these

recommenda-tions are not based on prospective controlled studies

with mortality endpoints since no studies have yet been

performed Based on ethical considerations and the

identification of higher risk in families with colon cancer,

such future studies may not be accomplished

Recommendations for CRC screening in the setting

of familial colon cancer are based on known risk and the

known effectiveness of screening modalities The

recom-Chapter 14: Hereditary Colorectal Cancer 153

chromosome 5 (5q21-q22) [23–28] Different APC tions can result in different clinical manifestations asnoted below Over 825 germline mutations have beenidentified [29] About one-third of newly diagnosedcases not belonging to a known FAP family representspontaneous or new APC mutations [19]

muta-The APC gene has 15 exons, coding for 2844 aminoacids and a 311.8-kDa protein Exon 15 comprises overthree-quarters of the coding region The APC proteincontrols cell proliferation through signalling pathwaysinvolved in apoptosis, cell proliferation, colonocytemigration, and, perhaps, chromosomal stability

Interestingly, the location of the mutation within the APC gene bears on the phenotype of the disease.Depending on the specific mutation, patients can pres-ent with differences in polyp burden, location, age ofpresentation, and extracolonic manifestations In attenu-ated FAP (AAPC), mutations are found in the extreme

5′ part of the gene, in exon 9 or in the far 3′ end [30–38].The most frequent mutation in FAP involves codon 1309.Persons with mutations at this location tend to present at

an average age of 20 years, compared to 10 years later inthose with mutations between codons 168 and 1580(excluding 1309) [39] Those with mutations 3′ to codon

168 and 5′ to codon 1580 present at an average age of 52years Furthermore, extracolonic manifestations associ-ate to some degree with the mutation location Congenitalhypertrophy of the retinal pigment epithelium (CHRPE)

is observed with mutations between codons 463 and

1387 [40], while it tends to be absent when the mutation

is between codons 1444 and 1578 [41,42] Thyroid cancer

is associated with mutations in the 5′ end of exon 15.Studies have also found desmoid tumors to be associ-ated with mutations in specific exons [43]

Clinical presentation

Gastrointestinal manifestations

Currently, most patients with FAP are diagnosed at anasymptomatic stage of their disease due to screening

Inherited syndromes of colon cancer

Although technically considered familial cases, CRC

developing in the setting of inherited syndromes

repres-ents a unique situation as there is a better understanding

of the pathogenesis, genetics, and molecular biology

involved Furthermore, these genetic syndromes have a

significant association with several benign and

malig-nant extraintestinal manifestations Unlike the more

com-mon familial colon cancers, genetic testing is available

and allows for more effective screening of families at risk

Familial adenomatous polyposis

Epidemiology

Familial adenomatous polyposis (FAP) is a

well-characterized genetic condition with first reports in the

literature in 1861 and 1873 [19,20] It is the most common

of the polyposis syndromesaa heterogeneous group

of disorders characterized by multiple gastrointestinal

polyps occurring in the lumen of the gut The hallmark

of FAP is the propensity to develop hundreds to

thou-sands of adenomatous colon polyps with an inevitable

occurrence of CRC if not treated The prevalence of

FAP varies between 1 in 6850 and 1 in 31 250 (2.29–3.2

cases per 100 000 persons) [19,21,22], with both genders

affected equally Historically, FAP accounted for about

0.5% of all CRC cases [21], although currently this

num-ber is likely to be lower, probably due to improved

screening and prevention of CRC development [22]

Variants of FAP include Gardner’s syndrome, about

two-thirds of Turcot’s syndrome families, and

attenu-ated adenomatous polyposis coli (AAPC), also referred

to as attenuated FAP (AFAP)

Etiology

FAP occurs in families as an autosomal dominant

condi-tion Disease-causing mutations occur in the

adeno-matous polyposis coli gene (APC) on the long arm of

Table 14.1 Colon cancer screening recommendations for persons with familial risk.

Second- or third-degree relative with colorectal cancer Same as average risk*

First-degree relative with colon cancer or adenomatous Same as average risk, but begin at age 40 years

polyps diagnosed at age ≥ 60 years

Two or more first-degree relatives with colon cancer, Colonoscopy every 5 years,† beginning at age 40 years or 10 years younger

or a single first-degree relative with colon cancer or than the earliest diagnosis in the family, whichever comes earlier

adenomatous polyps diagnosed at an age < 60 years Double-contrast barium enema may be substituted, but colonoscopy is preferred

* Colonoscopy may be considered, even starting at a younger age, depending on the number and age of second- and/or third-degree relatives with colon cancer.

† An interval of 3–5 years is given by some organizations to allow for families with more severe familial risk

39 years Eighty-seven per cent will develop cancer bythe age of 45 years, and 93% by the age of 50 years.Although uncommon before adolescence, CRC has beendescribed in FAP cases as young as 9 years of age [46].Most FAP colon cancers (84%) are distal to the splenicflexure, which is similar to the distribution of sporadiccancers Synchronous (41%) and metachronous (7%)tumors occur often Average life expectancy after thediagnosis of colonic malignancy is 2.6 years The risk forCRC correlates with polyp burden Persons with over

1000 polyps are at a 2.3-fold higher risk of CRC pared to those with less than 1000 polyps [47]

com-Polyps also develop in other parts of the intestinal tract Gastric polyps occur in 23–100% of FAPpatients and are usually nonneoplastic fundic glandpolyps [48–51] On endoscopic examination, gastricpolyps are multiple and sessile, 1–5 mm in size, the samecolor as the surrounding mucosa, and located in the gas-tric fundus and corpus (Fig 14.2) They can coalesce toform a matted, irregular mucosal surface Histologically,the polyps consist of simple hyperplasia of the fundicglands with microcysts They rarely cause symptomsand rarely progress to malignancy However, about 10%

gastro-of FAP patients develop adenomatous polyps in thestomach, typically in the antrum and less so in the bodyand fundus [49,52] The lifetime risk of gastric adenocar-cinoma is 0.6%, probably as a consequence of adenomat-ous gastric polyps

Often of more clinical significance in FAP are denal polyps, including ampullary polyps (Fig 14.3).About 50–90% of FAP patients will develop adenomat-ous polyps in the duodenum [51], which are often small (1–5 mm), numerous, and located throughout the duodenum, especially in the second and third portions.Some patients have polyps in the periampullary areaonly Like colon polyps, duodenal polyps show an adenoma–carcinoma progression and can have villous

duo-efforts If symptoms do develop, 66% of patients already

have cancer Typical symptoms include rectal bleeding

(79%), diarrhea (70%), and abdominal pain (40%), which

are uncommon in patients with polyps alone

A clinical diagnosis of FAP can be made when a

patient has 100 or more colonic adenomatous polyps, or

less than 100 if the patient has an immediate relative

with FAP [19] Typically, a person will present with

an average of 1000 polyps in fully expressed FAP and

sometimes up to 5000 In early disease development

and AAPC, the polyp number can be significantly less

Polyps usually begin to appear in the second or third

decade of life, with an average age of polyp occurrence

at 15.9 years (range 8–34) as assessed by prospective

rigid sigmoidoscopy [44] The average age of diagnosis,

when the patient presents with symptoms, is 35.8 years

(range 4–72) [19]

The typical adenomatous polyp in FAP is small In

fact, even in fully developed cases, more than 90% of

polyps are less than 5 mm and less than 1% are larger

than 1 cm Polyps can carpet the entire colonic mucosa

(Fig 14.1) or occur as more distinct, larger lesions They

are distributed throughout the colon, although there

is a slight distal predominance Histopathologic

exam-ination of polyps is indistinguishable from sporadic

adenomas There can be villous and tubulovillous

archi-tecture, but this is seen far less commonly than tubular

adenomas A unique feature of FAP that is not seen in

the general population is the finding of adenomatous

epithelial cells in a single crypt called microadenomas

[19] Microadenomas are often found in the biopsy

spe-cimens of normal-appearing, flat mucosa Budding of

dysplastic epithelium is also seen as well as aberrant

crypt foci, which are identified by staining the colonic

wall with methylene blue [45]

Untreated FAP will inevitably progress to

adenocar-cinoma of the colon The average age of CRC diagnosis is

Fig 14.1 Multiple pedunculated and sessile polyps seen on

colonoscopy in a patient with FAP.

Fig 14.2 Numerous sessile polyps in the gastric corpus in a

patient with known FAP.

Chapter 14: Hereditary Colorectal Cancer 155

teeth, unerupted teeth, dentigerous cysts, and odontomas[58–60] Again, these can precede the development

of polyposis The incidence of these dental ities in FAP is 17%, compared to 1–2% in the generalpopulation

abnormal-Desmoid tumors are benign fibrous growths with anincidence in FAP of 3.6–20% [61–63] The relative risk ofdesmoid tumors in FAP compared to the general popu-lation is 825 and occurs at an average age of 28–31 years[64] They may be the first manifestation of disease and,

in some families, may be the only finding of FAP Otherthan the location of the APC mutation, other risk factorsinclude a family history of desmoids, female gender, andosteomas [65] Although considered benign, desmoidtumors are a significant cause of morbidity and mortal-ity Mortality from the tumors is 10–50% with a 10-yearsurvival rate of 63%; they are a common cause of death inthose who have had prophylactic colectomy Desmoidtumors in FAP consist of monoclonal growths of hyper-proliferative fibroblastic cells Tumors are most common

in the abdomen, both intraabdominally and within theabdominal wall [62,63] The most common symptom

is abdominal pain, though only a third of tumors causepain They do not metastasize; however, tumors cangrow and compress structures, such as nerves, bloodvessels, and hollow organs, and can erode into bones.Surgery can stimulate the development and growth ofdesmoid tumors [66]

Congenital hypertrophy of the retinal pigment epithelium (CHRPE), also called pigmented ocular fundus lesions, are dark round areas of pigment of theretina [67], ranging in size from 0.1 to 1.0 disk diameters.They are best seen on slit-lamp examination Bilaterallesions or multiple lesions (> 4) are relatively specific forFAP (94–100%), but only have a sensitivity of 58–84%.CHRPE can be the earliest clinical manifestation of FAP

Adrenal adenomas [68,69] are also more common inFAP than in the general population, with an incidence

of 7% and 13% in two studies [70,71] Functioning adenomas and adenocarcinoma have both been reported,although the association with FAP is unclear Manage-ment is identical to that in the general population

Cutaneous lesions in FAP consist of epidermoid cysts, sebaceous cysts, lipomas, and fibromas [58,72–76].Epidermoid cysts often occur before puberty and mayprecede the development of polyposis Nasal angio-fibromas have also been reported in FAP patients [77]

Extragastrointestinal malignancies

Several malignancies not affecting the gastrointestinaltract have been associated with FAP Hepatoblastoma is

an important malignancy in children with FAP The risk

is 800-fold higher than that of the general population

architecture and high-grade dysplasia The Spigelman

staging system [53] evaluates the severity of duodenal

polyposis

Duodenal cancer usually occurs in the periampullary

region and exhibits a lifetime incidence of 3–5% [19,51]

Cancer occurs at an average age of 45–52 years (range

17–81 years) and is one of the leading causes of death in

FAP patients who have had a prophylactic colectomy

The typical periampullary location of adenomas and

cancers may be related to bile or pancreatic secretions

[51,52] Unlike the case with colonic polyps, the severity

and presence of duodenal adenomas has not been

con-sistently shown to relate to the location of the APC gene

mutation [51]

Small bowel adenomas can also occur and concentrate

in the proximal jejunum (50% of cases) or distal ileum

(20% of cases) [54] Patients can also develop adenomas

in the distal ileum after colectomy Younger patients can

develop prominent lymphoid follicles of the distal

ileum, which must be differentiated histologically from

adenomas Small bowel cancer is uncommon in any of

these situations

Although the frequency of lesions is unknown,

adeno-mas and cancer can develop in the gallbladder, biliary

tree, and pancreas [48,54–56]

Extraintestinal manifestations

FAP also has several important extraintestinal

mani-festations Osteomas are benign lesions of bones that

often occur in the skull and mandible The lesions appear

as radiopaque lucencies on plain radiographs and are

of little clinical importance, except for occasional

cos-metic concerns Osteomas can appear in children before

the development of polyposis, but can develop later in

life as well [57,58] Several dental abnormalities have

also been described in FAP, including supernumerary

Fig 14.3 Characteristic ampullary tumor in a patient with

known FAP.

Genetic testing

Genetic testing for hereditary syndromes serves as avaluable method for screening individuals and theirfamilies at high risk for disease Informed consent is anessential component of genetic testing, and the patient orhis/her representative must understand the rationale,meaning, and limitations of testing, including implica-tions for screening and treatment Genetic counselingboth before and after testing should be available

Most of the inherited syndromes of colon cancer now have available genetic tests Commonly, these tests use peripheral leucocytes for obtaining DNA Anincreasing number of laboratories are offering such genetic tests, and a website lists these available labor-atories (http://www.genetests.org/) The AmericanGastroenterological Association (AGA) has establishedguidelines for genetic testing in hereditary colon cancer[88] Testing should be utilized in two specific situations:(i) to confirm the diagnosis in an individual clinicallysuspected of having the disease, and (ii) in at-risk familymembers In a particular family, the affected membershould be tested first to identify the mutation and thenother family members should be screened for that spe-cific mutation The accuracy of this method is near 100%when a germline mutation is identified in the index case When no mutation can be identified in the affectedmember, additional family members should not undergogenetic testing However, they should still be consideredhigh risk and have appropriate management and screening If no affected family member is available in apedigree suspected of harboring the disease, familymembers can be tested, although the likelihood of anuninformative result is high In this circumstance, fail-ure to identify a mutation cannot exclude the diagnosis,and family members must still undergo suggested can-cer screening

An APC mutation can be found in 80–90% of FAP ilies [89] Generally, individuals with the typical polypburden of FAP, suspected AAPC, or a first-degree relat-ive of a person with known FAP or AAPC should beoffered testing Several methodologies exist for geneticscreening and include protein truncation testing (PTT),linkage analysis, and DNA sequencing When sequenc-ing is used, single-strand conformation polymorphismtesting (SSCP) or similar methods are often employed tonarrow the area where sequencing should be done.Sequencing is becoming the preferred method because

fam-of its accuracy With sequencing, once a germline tion is identified, other family members can be tested for the same mutation Since the accuracy of testing is

muta-so high once a germline APC mutation is identified in

a particular family, only those who test positive needappropriate screening for FAP Genetic testing should

be delayed until age 10–12 years, given the potential

psy-[78,79] and usually develops within the first 5 years of

life with a male predominance Thyroid cancer affects

2% of FAP patients [80], with a relative risk of 7.6

com-pared to the general population The average age of

diagnosis is 28 years (12–62 years) and there is a female

predominance [81] The characteristic histology is

papil-lary cancer Pancreatic cancer has also been found to

be higher in the FAP population with a relative risk of

4.46 [81] compared to the general population

Variants of FAP

Attenuated adenomatous polyposis coli (AAPC)

As the name implies, less polyp burden and later

onset of disease characterizes AAPC Usually, there are

an average of 30 colonic polyps, though the number

can vary widely in different families [36–38,82] In

some families, polyp burden can be minimalamaking

the diagnosis difficult without genetic testingabut in

others, the number can approach those in typical FAP

Polyps have a more proximal distribution in the colon

CRC develops, on average, at age 50 years with a lifetime

risk of 80% [37] Unlike, colonic polyps, upper

gastroin-testinal polyps are not attenuated [35,36,83]

Gardner’s syndrome

The term Gardner’s syndrome is mostly of historic

interest, though it is still commonly used Gardner’s

syn-drome is characterized by typical FAP, but with a high

propensity to develop extracolonic growths, especially

osteomas, fibromas, and epidermoid cysts [59] With the

discovery of the APC gene, it was realized that FAP and

Gardner’s syndrome both resulted from mutations of

that gene Again, the location of the mutation in the APC

gene has an important role in the tendency to develop

extracolonic growths [84]

Turcot’s syndrome

About two-thirds of Turcot’s syndrome patients have

germline mutations in the APC gene, giving rise to

poly-posis as well as central nervous system (CNS) tumors

[85] The other third arise from germline mutations in

the DNA mismatch repair genes and are a variant of

hereditary non-polyposis colorectal cancer (HNPCC)

The CNS tumors in patients with germline APC

muta-tions are typically medulloblastoma-type, anaplastic

astrocytomas, or ependymomas [86,87] By contrast,

in patients with germline DNA mismatch repair gene

mutations, the tumors are usually glioblastoma

multi-forme [87] The relative risk of CNS tumors in FAP is

92-fold [86], and 40% of families with CNS malignancy

have more than one family member with tumors