REVIEW
U.S. practices for colon cancer screening
Shane E. Hendon and Jack A. DiPalma
Division of Gastroenterology, University of South Alabama College of Medicine, Mobile, AL, USA(Received for publication on July 22, 2005)(Revised for publication on September 12, 2005)(Accepted for publication on September 15, 2005)

Abstract. As the prevalence of gastric carcinoma decreases in Japan, the prevalence of colon cancer
has been increasing. Examination of the screening practices for colon cancer in the United States canoffer insight into practices that may be useful in Japan. This paper will review the epidemiology andrisk factors for colon cancer, the genetics of colon cancer, prevention issues, screening modalities, andcurrent recommendations in U.S. practice. (Keio J Med 54 (4): 179–183, December 2005)
Key words: colon cancer, screening, genetics

Contrast can be made comparing colon cancer in the
United States and gastric carcinoma in Japan. Worldwide, gastric carcinoma is the second leading cause ofcancer death.1 Asian countries have a higher incidenceof gastric cancer than North America. In Japan, the incidence in 2002 of gastric carcinoma in Japanese males
was 57,764 and in females was 37,887. In the U.S., there
were 13,710 cases in males and 8,050 in females.
Even with the high incidence and mortality of gastriccarcinoma in Japan, the overall rate has steadilydecreased since the 1950’s.2 In contrast, the incidenceof colon cancer has steadily been increasing in Japanover the same period. The reason for this changing
epidemiology is not clear but dietary habits have been
implicated.2 The increased consumption of red andprocessed meats with decreased consumption of smokedfoods have contributed to the changes. Recent studies
have shown that high consumption of red meat is associated with an increased risk of colorectal cancer.3
Thus, a more westernized diet may be linked to theincreased incidence of colon cancer in Japan. The incidence for colon cancer in Japan is much lower than forJapanese families in the U.S. and the general U.S. population.4 Gastric carcinoma has exactly the opposite
trend.4
The increase in colon cancer rates in Japan makes
examination of U.S. practices for colon cancer screening worthwhile. This work will address the epidemiology and genetics of colon cancer as it inﬂuences
screening and prevention. It will discuss screening

modalities utilized in the United States and recommended strategies.
Colon Cancer Epidemiology
In 2002, there were approximately one million newcases of colon cancer worldwide with a male to female
ratio of 1.2 : 1.1 There were approximately 529,000
deaths attributed to colon cancer in that same year.1
The ﬁve year survival rate of individuals diagnosed withcolorectal cancer is directly proportional to the stage ofthe cancer when it is identiﬁed. Dukes’ stage A is conﬁned to the mucosa and submucosa. In Dukes’ stage B,
there is progression through the muscularis propria andserosa. For Dukes’ stage C, there is involvement oflymph nodes while in Dukes’ stage D, distant metastases are present. Dukes’ stage A, B, C and D carry a ﬁve
year survival rate of >80%, 60–80%, 30–40%, and 5%
respectively. Colorectal cancer progresses in sequence
from normal mucosa to adenoma, then to severe dysplasia before making the ﬁnal transition into cancer.
These characteristics of colon cancer raise the issue ofscreening.
Screening for colorectal cancer is aimed to detect acurable and prevalent disease. Screening is done on
patients to search for neoplasia without prior evidenceof neoplasia. Patients with positive symptoms or a positive screening test such as fecal occult blood test undergo diagnostic evaluation.
Colorectal cancer is ideal for screening. It is common

Reprints requests to: Dr. Jack A. DiPalma, University of South Alabama, Division of Gastroenterology, 5600 Girby Road, Mobile, AL 36693,
USA, e-mail: jdipalma@usouthal.edu
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Hendon SE and DiPalma JA: U.S. practices for colon cancer screening

and serious. It starts as an identiﬁable and slow growing precursor lesion. Once developed, colon cancer
advances through stages slowly. Early detection cancure.

nosed before the age of 50.
FAP is also an autosomal dominant syndrome characterized by multiple adenomatous polyps. Affectedindividuals may develop adenomatous polyps in thegastric, duodenal, jejunoileal, and colorectal areas.
Individuals may also develop extraintestinal features
including congenital hypertrophy of retinal pigment
epithelium (CHRPE), brain tumors, epidermal cysts,
osteomas, and desmoid tumors. Patients with FAP havean inevitable progression for colon cancer, usually
within 8–10 years.
Genetic mutations involved in the pathogenesis ofcolorectal cancer may be either inherited or acquired.
Inherited mutations are also called germline mutations,indicating that they are present in the initial embryonicgerm cell. A germline mutation will thus also be foundin all daughter cells, and therefore in every cell of
the body. Acquired mutations are also called somatic
mutations and often occur later in life. They are only
present in the cell in which they occur, although if not
repaired, the mutation may be replicated during cell
division and thereby be present in daughter cells. The
mutations that occur as part of colon cancer pathogenesis can be divided into three categories: mutationsof tumor suppressor genes, oncogenes, or DNA repair
genes.6
Tumor suppressor genes normally suppress or control cell growth. When this function is lost through mutation, cell growth becomes uncontrolled, constant, or
constitutive.6 Both alleles of a tumor suppressor geneneeded to be damaged or lost for the gene to be completely lost. Damage or loss occurs in several ways. The
ﬁrst allele can be inherited in a mutated form, as it is in
FAP, or may be somatically mutated, as it is in the setting of sporadic colon cancer. If the second allele
acquires a somatic mutation, gene function is lost. Another common mechanism for loss of the second allele
is called ‘‘loss of heterozygosity’’ (LOH). This is an important mechanism of tumor genesis, although how it
occurs is not completely understood. With LOH, there
appears to be an asymmetric distribution of chromosomal materials during a ﬂawed mitosis. This may resultin loss of the entire normal allele, thereby unmasking
the mutated tumor suppressor genes of that gene’s
normal function. Tumor suppressor genes involved in
the pathogenesis of colorectal cancer include APC, p53,
and a yet to be identiﬁed gene on chromosome 18.6
The normal function on an oncogene, called a protooncogene before it is mutated, is to stimulate cell growth
as part of an intracellular growth-signaling pathway.
Such pathways respond to external growth signals andtransfer the signal to the nucleus through multiple steps.
Only one allele of an oncogene needs to be mutated tocause dysfunction. When this occurs, the growth signal
becomes constant or constitutive, rather than regulated

Who Should Be Screened?
Multiple risk factors have been shown to increase theincidence of colorectal cancer including diet, geography, age, family history, a history of chronic colitis, ahistory of adenomas, and a previous history of colorectal neoplasia.1,3–5 The age-adjusted mortality ishigher in men than in women. However, the lifetime
risk of diagnosis and of death from colorectal cancer
are similar in both sexes.4 Women over 60 years of age
are as likely to develop colorectal cancer as breast cancer. Relatives of individuals with adenomatous polyps
are also at an increased risk for developing colorectal
cancer.5 Patients with newly diagnosed adenomatous
polyps were interviewed regarding the history of colorectal cancer in their patients and siblings.5 In this study,
1199 patients with adenomatous polyps were interviewed. After the exclusion of patients with incomplete
information and patients referred secondary to a family
history of colorectal cancer, there were 1031 patientswith 4246 ﬁrst-degree relatives (1865 parents and 2381
siblings) included. The study used 1411 spouse controls.
The relative risk of developing cancer for ﬁrst-degree
relatives of patients with adenomatous polyps was 1.78
compared with spouse controls.5
Genetics of Colon Cancer
Colon cancer can be classiﬁed as sporadic (75%), familial (20%), and genetic syndromes such as HereditaryNonpolyposis Colorectal Cancer (HNPCC) and Familial Adenomatous Polyposis (FAP) (5%).
HNPCC is an autosomal dominant condition inwhich there is an increased risk of developing colorectal
cancer with an earlier age of onset than sporadic colorectal cancer. HNPCC has a right colon predominanceand affected individuals are at risk of developing otherprimary cancers. Females are at an increased risk ofdeveloping endometrial and ovarian cancer. All individuals are at increased risk for developing otherextracolonic malignancies including keratoacanthomasand sebaceous gland neoplasia, hepatobiliary, stomach,small bowel, and uroepithelial cancers. A thoroughfamily history is essential to help identify families that
may be affected by HNPCC. The Amsterdam Criteria isused to help diagnose patients with HNPCC. To fulﬁll
the Amsterdam Criteria, patients must have 3 or more
relatives with colorectal cancer, one of whom is a ﬁrstdegree relative of the other two, two or more generations affected, and at least one of the relatives diag-Keio J Med 2005; 54 (4): 179–183

and responsive to external stimuli. K-ras is the primary
oncogene involved in the pathogenesis of coloncancer.6
The function of DNA repair genes is to correct DNA
errors that occur either during DNA replication orfrom mutational damage. These genes either repair
DNA error or induce apoptosis if the error cannot be
repaired. Dysfunction of repair genes leads to the accumulation of mutations in daughter cells. Eventuallygenes are affected that are important to colon cancer
tumorigenesis.7
The adenomatous polyposis coli (APC ) gene is a tumor suppressor gene located on the long arm of chromosome 5. It was ﬁrst identiﬁed as the gene mutated in
FAP. It was later determined that this gene plays acritical role in the pathogenesis of colon cancer and is
the ﬁrst gene inactivated in over 80% of colon malignancies.8 This mutation is present even in the smallestof adenomas, with a similar frequency to that seen inlarger adenomas and cancer. This suggest that APC inactivation is an early event. It is now known that themost common order of genetic events is APC gene inactivation, followed by K-ras mutation, chromosome 18
gene inactivation, and ﬁnally p53 inactivation. The benign to malignant change is approximately concurrent
with p53 inactivation.9
The change from normal mucosa to adenoma
involves mucosal hyperproliferation and DNA hypomethylation. Oncogene mutations are involved in an
adenoma changing to severe dysplasia. From this stage,
allelic deletions help progress the dysplasia to cancer.
In the general population, people over the age of
50 are at average risk of developing colorectal cancer.
Individuals with a personal or family history of colorectal cancer or polyps are at moderate risk. Those athigh risk include individuals with a history of Inﬂammatory Bowel Disease (IBD), HNPCC, or FAP.
Prevention of Colon Cancer
Colon cancer is preventable. Primary prevention
involves teaching individuals behavior modiﬁcation andelimination of risk factors. To decrease the risk of colorectal cancer, individuals should increase physicalactivity, eat more vegetables, and consume a diet highin ﬁber and low in fat. Aspirin, NSAID’s and calcium
may also decrease the risk of developing colorectal
cancer.10 Obesity, increased consumption of alcohol,
and increased red meat3,10 may lead to an increase in
the risk of developing colorectal cancer. A diet high in
fat and low in ﬁber may also increase the risk of developing colorectal cancer.10
The secondary prevention involves early tumor detection with proper use of screening, surveillance, anddiagnostic evaluations. Tertiary prevention involves

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decreasing mortality with established tumors by proper
medical management.
Screening Modalities
There are multiple screening options available
including fecal occult blood testing (FOBT), ﬂexible
sigmoidoscopy (FS), barium enema x-ray, and colonoscopy.11–13
Fecal occult blood testing
In a study to test the effectiveness of using FOBT asa screening tool, 46,551 participants age 50 to 80 yearsof age were randomly assigned to be tested annually,biennial, or to a control group.14 The 13 year cumulative mortality from colon cancer per 1000 was 5.88 in
the annually screened group, 8.33 in the biennially
screened group, and 8.83 in the control group. Thus, themortality from colon cancer was decreased by 33% in
the annually screened group compared to the control
group. FOBT offers several advantages as a screening
tool in that it has been proven effective in randomized
trials, it is non-invasive, and cost effective. However,
the mortality reduction is low (15–33%) and the proper
evaluation of a positive test is often inadequate.14
Flexible sigmoidoscopy
Flexible sigmoidoscopy (FS) can also be used as ascreening tool. The procedure can be done in the ofﬁce
without sedation, it is inexpensive and cost-effective, it
has been shown to reduce rectal cancer mortality by
60–70%, and the preparation is much easier on thepatients compared to colonoscopy. However, FS detects
only half of adenomas and 40% of cancers are proximal
to the splenic ﬂexure. Up to 75% of proximal lesion
have no distal lesions that would be identiﬁable by FS.
The test itself is often limited by patient discomfort andpoor preparation.
There is rationale to recommend combining FOBT
and FS by offering FOBT annually and a FS every ﬁve
years.11 This method allows for visualization of the left
colon and provides good sensitivity with FOBT for
proximal cancers that are beyond the reach of FS. Although the combination has never been directly studied
in a randomized trial, a recent study did show that theaddition of a one time FOBT with FS increased thedetection rate of advanced neoplasia from 70% with FS
alone to 76%.15
Barium enema X-ray
Barium enema x-ray examinations (BE) has the
beneﬁt of being cost effective and examining the entire

182

Hendon SE and DiPalma JA: U.S. practices for colon cancer screeningcolon. However, it has never been studied as a screening test. The National Polyp Study showed that BE
missed 50% of adenomas >1 cm.16 The sensitivity forcancer when FOBT was positive was 50–75%. BE also
has poor speciﬁcity and the best interval for testing is
unknown.

reason given by patients for not undergoing screening is‘‘the test was never recommended.’’ Of those offeredtesting, only 4% declined.
The American College of Gastroenterology recommends for patients at average risk, to begin screening atage 50 with FOBT annually and a FS every ﬁve years or
preferably, a colonoscopy every 10 years.13 For patientswith a positive family history of colorectal cancer, acolonoscopy should be done at age 40 or 10 years
younger than the age at which the youngest affected
relative was diagnosed. For those with a single ﬁrstdegree relative that was affected at age >60 years,
a colonoscopy every 10 years should be done. For
patients with 2 or more ﬁrst-degree affected or one ﬁrstdegree relative affected before the age of 60, a colonoscopy should be done every 3–5 years.
Patients with a genetic diagnosis or a clinical diagnosis of HNPCC via Amsterdam Criteria should have acolonoscopy done beginning at age 20–25 or 10 years
prior to the youngest age of colon cancer diagnosis in
the family. Colonoscopy should be done every two
years until the age of 40, then annually. Screening forendometrial, ovarian, pancreatic, gastric, small bowel,
and urinary tract cancers should also be done.
Recommendations differ for special situations include FAP, ulcerative colitis, Crohn’s disease, and pelvic irradiation.
Third, the payors much be convinced that screening
is cost-effective. In the U.S., the cost for colonoscopy
varies widely from institution to institution. It has beenshown that if colonoscopy costs are less than $750, a
one-time colonoscopy is more cost-effective than otherprograms at every level of compliance.18 The incremental cost-effectiveness ratio of screening for colorectal cancer is estimated to cost $6,600 per life year
gained. This compared favorably with the incremental cost-effectiveness ratios of other common medical
practices such as breast cancer screening at $22,000,
heart transplantation at $160,000, and cervical cancer at$250,000.13
Improving the screening tests may also increase
compliance and screening. Colonoscopy compliance
may be improved with better preparation choices. Current gut lavage solutions include polyethylene glycol
electrolyte solutions (PEG-ELS; GoLytely, CoLyte,
Niﬂec) and sulfate-free electrolyte lavage solutions (SFELS; NuLytely; Trilyte). PEG-ELS and SF-ELS are
isotonic, poorly absorbed solutions that pass throughthe GI tract with no net water or electrolyte absorption
or secretion.19 They reach a steady state equilibrium
when given on large volumes at high infusion rates (1.5
1/hr).19 The main complains with lavage solutions are
ﬂavoring and volume. Improving the taste and reducing
the volume consumed may help improve compliance.
Saline laxatives, such as oral sodium phosphate, phos-

Colonoscopy
Colonoscopy can help prevent colon cancer by detection of adenomatous polyps and polypectomy. Colonoscopy allows for visualization of the entire colon so
proximal as well as distal lesions can be identiﬁed. It
also has the best sensitivity of the current screening
methods. The disadvantage of colonoscopy is the cost,
increased risks such as perforation and bleeding, difﬁcult preparation for the patients, and the need forsedation.
When compared, colonoscopy has been shown to bea more effective method of surveillance than double
contrast barium enema.16 After colonoscopic examination with polypectomy, 580 patients underwent surveillance with paired colonoscopy and double control barium enema (DCBE). Out of the 392 cases wherecolonoscopy found polyps, DCBE showed polyps in 139(35%) of those same cases. DCBE accurately detected
34% of adenomas <0.5 cm, 53% of adenomas 0.6 to 1.0
cm, and 48% of adenomas >1.0 cm. Colonoscopy byretesting was found to have missed 20% of adenomas,of which none were >1.0 cm.
Screening Recommendations
Utilization of colorectal cancer screening methods
remains low. In patients without a personal or family
history of colorectal cancer or personal history ofpolyps, 50%, 19.6%, 39.8%, and 17.5% reported everhaving had FOBT, FS, barium enema, and colonoscopy,
respectively.17 Among those with positive family history of colorectal cancer, compliance was greater at
62.9% versus 39.7%.14 In a National Survey of U.S.
residents >50 years of age in 1999, only 33.6% had
undergone sigmoidoscopy or colonoscopy within theprevious 5 years.12
How can utilization of screening tests be increased tohelp make screening more effective? First, the publicmust be convinced of the importance and beneﬁts ofcolorectal cancer screening. There seems to be two important barriers to convincing the public. Most are
afraid to undergo screening for the fear that it will hurt.
They also feel that screening is not needed without
symptoms. Proper patient education is needed to help
overcome these perceptions.
Second, health care providers must offer colorectal
cancer screening to the patients. The most common

Keio J Med 2005; 54 (4): 179–183

phate tablets, magnesium citrate, and magnesium sulfate are also used for colonic preparation.
In Japan, some colonoscopers perform colonoscopy
without sedation. U.S. colonoscopists typically use anarcotic (meperidine or fentanyl) and a sedative (midazolam). Improving sedation and discomfort with theuse of medications such as fentanyl derivatives andpropofol may also help improve colonoscopy compliance.
In the future, virtual colography, capsule colonoscopy, stool-based DNA testing, and chromomagniﬁcation endoscopy show promise as new methods of colorectal cancer screening. These methods are not yet wellenough developed to be offered as routine screening
options.
Summary
The key message is that colon cancer screening has
been proven effective and should be used as standard
medical care. Colon cancer is preventable. Using current screening options and recommendations, physicians can greatly reduce the incidence of colorectal
cancer and improve quality of life. Health care providers must educate patients on not only screening, butpreventative strategies to help reduce the risk of developing colorectal cancer. It is expected that in Japan,
colon cancer screening will become as important as
currently utilized gastric cancer screening modalities.
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