Seminars in Oncology Nursing, Vol 25, No 1 (February), 2009: pp 15-31
`
`15
`
`PREVENTION AND SCREENING OF
`GASTROINTESTINAL CANCERS
`
`SUZANNE M. MAHON
`
`OBJECTIVES: This article reviews the current recommendations and data
`supporting various screening and prevention strategies for colorectal cancer
`(CRC) in average and high-risk individuals.
`
`DATA SOURCES: Published research reports, epidemiologic data, and
`published guidelines from professional organizations.
`
`CONCLUSION: Properly applied screening tools can potentially decrease the
`morbidity and mortality associated with CRC.
`
`IMPLICATIONS FOR NURSING PRACTICE: Nurses need to be aware of current
`recommendations for the early detection of CRC so they can provide patients
`with an accurate assessment of risk for developing CRC and education about
`the appropriate CRC screening guidelines.
`
`KEY WORDS: Colorectal cancer, screening, prevention, risk assessment,
`colonoscopy.
`
`T OGETHER, gastrointestinal (GI) cancers
`
`comprise a significant percentage of
`cancers. To date, most efforts
`in
`screening and prevention have been
`directed toward colorectal cancer (CRC), which
`has a high incidence. Recommendations for the
`early detection of CRC have been modified over
`time and there is solid scientific evidence that these
`measures decrease the morbidity and mortality
`
`associated with CRC. More recently, guidelines
`have been released by the American College of
`Gastroenterology (ACG) for screening in patients
`with Barrett’s esophagus, and a Japanese group has
`issued some early guidelines for gastric cancers.1,2
`This article includes an overview of the risk factors
`and early detection strategies for Barrett’s esoph-
`agus and gastric cancer and a detailed discussion
`of risk assessment, prevention, and early detection
`strategies for CRC.
`
`Suzanne M. Mahon, RN, DNSc, AOCNÒ, APNG:
`Clinical Professor, Department of Internal Medicine,
`Clinical Professor, School of Nursing, Saint Louis
`University, St Louis, MO.
`Address correspondence to Suzanne M. Mahon, RN,
`DNSc, AOCNÒ, APNG, 3rd Floor West Pavilion, Saint
`Louis University Cancer Center, 3655 Vista, St. Louis,
`MO 63110; e-mail: mahonsm@slu.edu
`Ó 2009 Elsevier Inc. All rights reserved.
`0749-2081/09/2501-$32.00/0.
`doi:10.1016/j.soncn.2008.10.007
`
`BARRETT’S ESOPHAGUS
`
`Barrett’s esophagus (BE) is a progressive meta-
`plasia of the distal esophagus. It often occurs as
`a result of prolong reflux esophagitis and gastro-
`esophageal reflux. It is considered by many to be
`a precursor to the development of adenocarci-
`noma of the esophagus. The exact prevalence of
`BE in the general population is not known. The
`overall prevalence of BE is estimated to be 1.6%,
`
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`
`

`

`16
`
`S.M. MAHON
`
`with a prevalence rate of 2.3% in those with reflux
`symptoms and 1.4% in those without reflux symp-
`toms.3 Major risk factors for development include
`male sex, advanced age, chronic gastroesophageal
`reflux disease (GERD) and, possibly,
`family
`history. Screening is further complicated by the
`fact that a large number of patients lack reflux
`symptoms and there is not a clear means to iden-
`tify these persons. BE is a histologic diagnosis. An
`esophagogastroduodenoscopy (EGD) is performed
`to obtain tissue samples. Samples are usually
`taken from the distal esophagus just above the
`lower esophageal sphincter, where BE primarily
`occurs. Patients diagnosed with BE should be
`screened regularly with an EGD with biopsy.
`Screening for BE remains controversial because
`of the lack of a clear algorithm for how and whom
`to screen and whether screening has a significant
`impact on mortality.1 Currently esophageal
`capsule endoscopy appears to be a promising tech-
`nique to screen for BE. This video endoscopy is
`accomplished by having the patient swallow
`a small camera about the size of a vitamin capsule.
`The camera emits a light and takes two pictures
`per second as it traverses the GI tract. The pill is
`easily swallowed and transmits the images to
`a recording device worn around the waist. These
`images are then downloaded to a computer where
`they are reviewed by a physician to determine if
`abnormalities are present. It provides a noninva-
`sive means to detect a columnar line esophagus,
`which is suggestive of BE,1 but the expense
`prohibits this test from being utilized routinely.
`Because of these limitations, the ACG does not
`routinely recommend screening for BE in the
`general population.
`Once BE is identified in a patient, there should
`be a discussion regarding the relative strengths
`of surveillance endoscopy and the risk of devel-
`oping esophageal adenocarcinoma, which has
`limited treatment options and poor survival (less
`than 13% 5-year survival rate).1,3 It is recommen-
`ded that persons with GERD be placed on proton
`pump inhibitor therapy to decrease inflammation
`so surveillance is more likely to be effective and
`decrease the cellular changes that result
`in
`dysplasia.3,4 Algorithms are available, depending
`on the degree of dysplasia, to determine the
`interval
`for endoscopy with biopsy. For those
`patients without dysplasia, endoscopy can be per-
`formed every 3 years. Those with low-grade
`dysplasia should have annual endoscopy until no
`dysplasia is detected for 2 years. Patients with
`
`high-grade dysplasia need aggressive and thorough
`surveillance every 3 months.
`Patients diagnosed with BE require education
`on how to manage their disease. They need to be
`aware of the importance of regular endoscopic
`screening and follow-up. Patients should be
`informed to avoid foods and beverages that either
`irritate the esophageal mucosa or decrease lower
`esophageal sphincter pressure. These include
`tomato and citrus-based foods,
`spicy foods,
`onions, garlic, peppermint, chocolate, caffeine,
`and alcohol.4
`
`GASTRIC CANCER
`
`Gastric cancer is a significant problem and
`contributes to 600,000 deaths worldwide,2,5 In
`the United States it accounts for 21,500 new cases
`and 10,880 deaths annually.6 Risk for gastric
`cancer is increased in those with Helicobacter
`pylori (H pylori) infections, and those with certain
`genetic changes that predispose to developing
`gastric cancer. These include persons with a family
`history of gastric cancer as well as persons with
`a known or suspected mutation for hereditary
`nonpolyposis colorectal cancer (HNPCC).5 Other
`persons at risk include those that consume diets
`high in salt, smoked, poorly preserved foods,
`nitrites, and nitrates.
`Persons with a known mutation or suspected
`mutation in their family should be referred to
`a
`genetics
`professional
`for more
`detailed
`evaluation. Genetic testing is readily available
`for HNPCC, and testing
`for diffuse gastric
`cancer is available on a more limited basis.
`Identifying persons with a hereditary predisposi-
`tion is important because this population may
`benefit
`from aggressive
`screening
`including
`gastroduodenoscopy.2
`
`COLORECTAL CANCER
`
`CRC continues to be a significant health
`problem in the United States. There is clear
`evidence that screening is the key to reducing
`the morbidity and mortality associated with this
`disease; when screening is performed consis-
`tently, correctly, and polyps are removed.7 Polyps,
`especially the adenomatous ones, are considered
`to be precursors to CRC. Screening directly
`impacts how early a malignancy is detected and
`long-term survival. The estimated 5-year survival
`
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`

`

`PREVENTION AND SCREENING OF GI CANCERS
`
`17
`
`Probability of Developing Colorectal Cancer
`
`Male
`Female
`
`0123456
`
`Probability
`
`to age 39
`
`40-59
`
`60-69
`
`70+
`
`Age
`
`FIGURE 1. The lifetime probability for males for dev-
`eloping CRC is 5.65 (1 in 18 males) and for females is 5.23
`(1 in 19 females). (Source: American Cancer Society.6)
`
`tives who are more distant than first degree, can
`be considered to be at average risk.7-9
`
`Populations at High Risk
`Approximately 15% to 20% of CRCs occur
`among people at increased risk or high risk
`(approximately twice the average risk).6 People
`who have been diagnosed as having adenomatous
`polyps are clearly at higher risk. A family history
`of either CRC or colorectal adenomas increases
`one’s risk of developing CRC.7 Risk is increased
`for individuals with a family history involving
`first-degree relatives, and is even higher if a first-
`degree relative (parent, sibling, or offspring) has
`had a CRC or an adenomatous polyp diagnosed
`before age 60 years, and/or if more than one
`first-degree relative has been affected at any age.
`Inflammatory bowel disease, which includes
`ulcerative colitis and Crohn’s disease, is a condi-
`tion in which the colon is inflamed over a pro-
`tracted period of time and these conditions have
`an increased risk of developing CRC.9
`
`Hereditary Risk
`Persons with a known hereditary mutation are
`at high risk for developing CRC. The clinical indi-
`cators of hereditary CRC syndromes are shown in
`Table 2. The goal of genetic testing in families is to
`offer appropriate screening guidelines to indi-
`vidual family members by identifying who carries
`the mutation and who does not. For those who
`test positive for a known mutation, screening
`begins at a very early age (such as age 25 for
`HNPCC carriers) and is performed at more
`frequent intervals (annually) throughout their life-
`time. Individuals who test negative for a known
`
`is 90% if the disease is diagnosed while still local-
`ized (confined to the wall of the bowel), but only
`68% for regional disease (lymph node involve-
`ment), and only 10% if distant metastases are
`present.8
`Selection of the appropriate screening interval
`and modality is based on cancer risk assessment.
`Guidelines for CRC cannot be uniformly applied
`to the entire population; some individuals have
`a greater risk of developing CRC than others.
`The most important step in CRC screening is an
`accurate assessment of the risk for developing
`CRC.
`
`Colorectal Cancer Risk Factors
`
`An individual’s risk for CRC is stratified into one
`of three categories. Most of the population has an
`average risk of developing the disease; some have
`a slightly higher risk based on personal risk
`factors. Those with a known or suspected muta-
`tion in a cancer susceptibility gene have a very
`high risk for developing the disease. It is important
`to note that no one has zero or low risk for devel-
`oping CRC.
`
`Population at Average Risk
`The lifetime risk of developing CRC is approxi-
`mately 48.2 cases per 100,000 population.6 Inci-
`dence increases with age (90% of cases occur
`after age 50) and is relatively similar between
`males and females (as shown in Fig. 1). Table 1
`identifies a number of other modifiable and non-
`modifiable risk factors for CRC.
`There are a variety of myths and misconcep-
`tions about CRC that healthcare providers need
`to address. For instance, it is often incorrectly
`assumed there are persons at low risk for CRC.
`At the very minimum, everyone is at average
`risk. Many individuals are surprised to learn that
`some risk factors can be adjusted to reduce the
`risk of developing CRC. When a risk factor can
`be modified,
`individuals should be instructed
`about how to address their particular risk. When
`it cannot be modified, the healthcare provider
`should discuss how this risk factor is considered
`in selecting the appropriate cancer screening
`modality. People may also be confused about their
`risk related to a personal or family history of
`polyps or cancer. Knowing the age of onset can
`help clarify risk. Individuals with a single first-
`degree relative diagnosed with CRC or an adeno-
`matous polyp after age 60, or with affected rela-
`
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`
`

`

`18
`
`S.M. MAHON
`
`TABLE 1.
`Risk Factors for Developing Colorectal Cancer
`
`Risk Factor
`
`Etiologic Basis
`
`Modifiable
`
`Significance
`
`Age
`
`Polyps
`
`As the body ages, all tissues are at
`increased risk for cellular changes
`leading to cancer
`Many polyps progress in an orderly
`fashion from a polyp to malignancy
`over a period of years
`
`No
`
`Probably
`not
`
`90% of colon cancers are diagnosed
`after age 50. Implication for
`screening to begin at age 50
`Polyps need to be removed during
`colonoscopy. Depending on
`findings, interval for screening may
`be decreased
`Risk is higher in those with cancer
`diagnosed before age 60
`
`Screening is probably indicated at
`a younger age and more frequently
`
`Risk increases with the number of
`relatives with adenomatous polyps
`or CRC
`
`Penetrance is nearly 100% and
`accounts for about 1% of all CRC
`Penetrance is 80% to 85% and
`accounts for about 4% of all CRC
`Develop screening programs targeting
`high-risk populations
`
`Risk is decreased in persons who eat
`a diet rich in fruits and vegetables
`
`Risk is increased in inactive persons
`Risk is increased in both men and
`women, but even higher in men
`Risk increases with the number of
`pack years
`Consume no more than 1 alcholic
`beverage per day
`
`Personal history of cancer
`
`Inflammatory bowel
`disease and Crohn’s
`disease
`Family history of CRC
`
`Persons with a mutation
`in FAP
`Persons with HNPCC
`syndromes
`Ethnicity
`
`Dietary factors
`
`Physical inactivity
`Obesity
`
`Smoking
`
`Alcohol use
`
`Type II Diabetes
`
`Same risk factors that led to the first
`cancer can lead to a second CRC in
`another section of the colon
`Associated with dysplasia and
`increased risk of developing CRC
`especially if the disease is long-term
`20% of persons diagnosed with CRC
`have at least one relative with the
`disease which is probably related to
`modifier genes
`Form hundreds of polyps; most start to
`occur about age 20
`Polyp to CRC syndrome is short; often
`occurs before age 40
`African Americans have highest
`incidence and mortality; about 6% of
`Ashkenazi Jews have mutations
`that put them at increased risk
`Risk is increased in persons who
`consume a diet high in red and
`processed meats
`Reason for increased risk is not clear
`Reasons for increased risk is not clear
`
`Carcinogenic substances enter the
`gastrointestinal system
`Those who consume increased
`amounts of alcohol may have lower
`levels of folic acid
`Reason for increased risk is not
`completely understood
`
`No
`
`No
`
`No
`
`No
`
`No
`
`No
`
`Yes
`
`Yes
`Yes
`
`Yes
`
`Yes
`
`Possibly
`
`May be associated with a poorer
`prognosis, once the cancer is
`diagnosed
`
`Abbreviations: CRC, colorectal cancer; FAP, familial adenomatous polyposis gene; HNPCC, hereditary non-polyposis colorectal
`cancer gene.
`Data from Bernard et al,7 American Cancer Society,8 Levin et al,9 and Lynch and de la Chapelle.10
`
`mutation in their family can pursue the screening
`recommendations for those at average risk.
`The most common hereditary CRC syndrome is
`an autosomal dominant syndrome known as
`HNPCC, which accounts for 3% to 5% of all
`CRC.10 It is also associated with endometrial
`cancer, ovarian cancer, gastric cancer, bile duct
`cancer, and small bowel, renal pelvis, and ureter
`cancer.11 The majority of mutations responsible
`for HNPCC occur in four mismatch repair genes,
`
`MSH2, MLH1, PMS2, and MSH6.12 Patients with
`a mutation in MLH1 and MSH2 have an 80% life-
`time risk of developing CRC as compared with
`a 6% risk in the general population. Women with
`mutations in these genes have a 60% lifetime risk
`for developing endometrial cancer and a 12% life-
`time risk for developing ovarian cancer.13
`Persons with HNPCC-related cancers are more
`likely to have poorly differentiated tumors with
`an excess of mucoid and signet-cell features.11
`
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`

`

`PREVENTION AND SCREENING OF GI CANCERS
`
`19
`
`Although not associated with large numbers of
`polyps, persons with HNPCC who do form adeno-
`matous polyps are more likely to do so at an earlier
`age, to develop right-sided colon cancer, and to
`exhibit a rapid progression to malignancy (ie, 1
`to 3 years instead of the 5- to 10-year pattern
`seen in the general population).11,14
`Risk assessment
`is the key to identifying
`families with an HNPCC mutation. There are
`several strategies to consider in identifying these
`patients
`and any suspected family should
`be referred to a genetics professional to identify
`the most cost-effective and efficient strategy
`for genetic testing. The Amsterdam and Bethesda
`criteria (Table 3) assess the number of relatives
`affected by CRC or other HNPCC-related cancers,
`with particular emphasis on the age of onset.10,15,16
`Immunohistochemistry staining can be per-
`formed on tumor tissue from persons who fulfill
`Bethesda criteria to determine the presence or
`absence of MLH1, MSH2, MSH6, and PMS2
`proteins. This can predict a mismatch repair
`defect and thereby avoid unnecessary, expensive,
`and time-consuming DNA analyses.12 If immuno-
`histochemistry is positive for all four proteins in
`a family that fulfills Amsterdam criteria, the next
`strategy to determine if it is appropriate to test
`an individual is to perform an MSI (microsatellite)
`assay on the affected family member’s colorectal
`tumor.10 In HNPCC, mutations in the DNA repair
`
`genes result in a phenomenon known as MSI insta-
`bility. Microsatellites are repeated sequence of
`DNA that are a defined length for each individual.
`Because of the accumulation of errors, these
`sequences can become abnormally longer or
`shorter; this is referred to as MSI.15 An MSI
`high phenotype is reported in 85% to 92% of
`HNPCC colon cancers and approximately 15%
`of sporadic cancers.12 MSI testing is also an
`appropriate
`strategy for Amsterdam-negative
`families who are positive by the Bethesda
`criteria.
`Familial Adenomatous Polyposis (FAP), an auto-
`somal dominant
`trait,
`is
`characterized by
`numerous (usually > 100) adenomatous colon
`polyps and accounts for about 1% of all cases of
`CRC.10 The FAP gene is nearly 100% penetrant,
`so if a person is not treated they will develop
`CRC because of the sheer number of polyps. The
`mean age of cancer onset is 39; although as
`many as 75% will have developed adenomas by
`age 20.17,18 A less severe form of FAP called ‘‘atten-
`uated familial adenomatous polyposis’’ (AFAP) is
`characterized by less than 100 polyps (usually
`about 20) at presentation and later onset of
`CRC. There are over 800 mutations in the APC
`gene associated with FAP.12 Deleterious mutations
`in this tumor suppressor gene result in the prema-
`ture truncation of the APC protein.18,19 There is
`also an autosomal recessive gene on chromosome
`
`TABLE 2.
`Key Indicators of Hereditary Colon Cancer Syndromes
`
`HNPCC
` Personal history of CRC diagnosed before age 50
` Personal history of endometrial cancer diagnosed before age 50
` First-degree relative with CRC before age 50
` Two or more relatives with CRC or an HNPCC-associated cancer (including endometrial, ovarian, gastric, hepatobiliary, small
`bowel, renal pelvis or ureter cancer). One relative must be a first-degree relative of another
` CRC occurring in two or more generations on the same side of the family
` A personal history of CRC and a first-degree relative with adenomas diagnosed before age 40
` An affected relative with a known HNPCC mutation
`FAP
` Patient has a clinical diagnosis of FAP (100 or more polyps)
` Patient has suspected FAP or AFAP (15 to 99 polyps)
` Patient is a first-degree relative of FAP or AFAP patient
` Patient has an affected relative with a known FAP or MYH mutation
` Patient with any number of adenomas in a family with FAP
`
`Abbreviations: CRC, colorectal cancer; HNPCC, hereditary non-polyposis colorectal cancer; FAP, familial adenomatous polyposis.
`NOTE. The presence of one or more of these factors in an individual or family history is suggestive of hereditary risk for CRC and
`warrants further evaluation.
`Data from Lynch and de la Chapelle,10 Vasen et al,16 Balmana et al,17 Calvert and Frucht,18 and Jeter et al.19
`
`Geneoscopy Exhibit 1047, Page 5
`
`

`

`20
`
`S.M. MAHON
`
`TABLE 3.
`Comparison of the Amsterdam and Bethesda Criteria Used in Assessment of Risk for Hereditary Colon Cancer
`
`Amsterdam Criteria
`
`Bethesda Criteria
`
`At least 1 person was diagnosed before age 50
`There are at least 3 relatives with an HNPCC-related cancer
`(large bowel, endometrium, ureter or renal pelvis); does not
`include stomach, ovary brain, bladder, or skin
`
`FAP has been excluded
`
`At least two successive generations are affected
`
`CRC diagnosed in a patient who is less than 50 years of age
`Presence of synchronous, metachronous colorectal, or other
`HNPCC-associated tumors, regardless of age. These
`tumors would include colorectal, endometrial, stomach,
`ovarian, pancreas, ureter and renal pelvis, biliary tract, and
`brain
`CRC with the MSI-High pathology diagnosed in a patient who is
`<60 years of age
`CRC diagnosed in 1 or more first-degree relatives with an
`HNPCC-related tumor, with 1 of the cancers being
`diagnosed under age 50 years
`
`Abbreviations: HNPCC, hereditary non-polyposis colorectal cancer; FAP, familial adenomatous polyposis.
`Data from Umar et al15 and Vasen et al.16
`
`is associated with polyposis.20
`that
`1, MYH,
`Approximately 25% of individuals with FAP have
`a ‘‘de novo mutation,’’ which means they are the
`first person in their family with the hereditary
`mutation for FAP.18 Subsequent generations are
`at risk for inheriting the mutation.
`
`Preventive Measures
`
`Prevention of CRC focuses on two areas. The
`first deals with the modification of risk factors
`when possible. The second area addresses poten-
`tial chemoprevention strategies.
`
`Maintaining a Healthy Body Weight
`The percentage of Americans who are over-
`weight or obese has increased over the past 25
`years. Nearly two thirds (64%) of US adults 20
`years or older met the criteria for overweight or
`obesity in 2000, while 30.5% qualified as obese.21
`The percentage of overweight children and adoles-
`cents has also increased since the late 1980s.
`Educating individuals about ways to achieve
`a healthy body weight is an important nursing
`responsibility. Many individuals know this is
`important, but need encouragement and support
`from a healthcare provider to actually implement
`effective interventions. Excess body fat can be
`reduced by decreasing
`caloric
`intake
`and
`increasing physical activity. For most adults
`a reduction of 50 to 100 calories per day may
`prevent gradual weight gain, whereas a reduction
`of 500 calories or more per day is a common initial
`loss programs.22,23 Research
`goal
`in weight
`suggests that up to 60 minutes of moderate to
`
`vigorous intensity physical activity per day may
`be needed to prevent weight gain, but as much
`as 60 to 90 minutes of moderate intensity physical
`activity per day may help to sustain weight loss for
`previously overweight people. In terms of CRC
`prevention, physical activity causes food to move
`more quickly through the intestine, reducing the
`length of time that the bowel lining is exposed to
`potential carcinogens.21 Therefore, regular phys-
`ical activity and a healthy diet can help decrease
`the risk of CRC.22 This reduction in risk is in-
`tended not only for healthy persons, but also for
`persons who have been diagnosed with colorectal
`ancer. Increased physical activity and a healthy
`diet may reduce the risk of a second primary
`cancer, including CRCs.24
`
`Eating a Healthy Diet
`A diet rich in fruits and vegetables appears to be
`important for cancer risk reduction. Research
`suggests that the body uses certain nutrients in
`vegetables and fruits to protect the body against
`damage to tissues that occurs constantly as a result
`of normal metabolism. Because such damage is
`associated with increased cancer risk, the antiox-
`idant nutrients are thought to protect against
`cancer.22 Antioxidants include vitamin C, vitamin
`E, carotenoids, and many other phytochemicals.
`The amount of fat and fiber in the diet has
`been examined extensively as risk factors associ-
`ated with CRC. A diet high in fiber and low in
`fat, which for adults is 20 to 35 grams of fiber
`per day and about 30% or less of their total daily
`calories from fat, along with limited consump-
`tion of red meat, helps reduce the risk of
`
`Geneoscopy Exhibit 1047, Page 6
`
`

`

`CRC.8 It also is recommended that men and
`women regularly eat fruits and cruciferous vege-
`tables, and consume calcium to decrease the risk
`of CRC.23,24
`Many questions remain concerning nutrition
`and cancer. Epidemiologic studies have shown
`that populations whose diets are high in vegeta-
`bles and fruits and low in animal fat, meat, and/
`or calories have a reduced risk of some of the
`most common types of cancer.22 Until more is
`known about the specific components of diet
`that influence cancer risk, current recommenda-
`tions are to consume a mostly plant-based diet
`that includes at least five servings of vegetables
`and fruits each day, to choose whole-grain carbo-
`hydrate sources over refined sources, and to limit
`saturated fat, alcohol, and excess calories.8
`
`Avoidance of Tobacco and Alcohol Products
`Evidence shows that 12% of CRC deaths are
`attributed to smoking.25 The carcinogens found
`in tobacco increase cancer growth in the colon
`and rectum, and increase the risk of being diag-
`nosed with this cancer.
`Alcohol consumption is also a factor in the diag-
`nosis of CRC, especially at a younger age.
`Increased alcohol intake is also associated with
`increased risk of cancer in the distal colon.
`Regular consumption of alcohol doubles the risk
`of developing CRC; thus limiting alcohol intake
`is recommended.25
`
`Chemopreventive Measures
`CRC chemoprevention has been an active area of
`research; focusing on NSAIDs, aspirin, and COX-1
`and COX-2 inhibitors. Results have been variable.
`Aspirin, an inhibitor of COX-1 and COX-2, has
`been studied in several randomized studies, but
`the effect on CRC prevention is unclear. The US
`Physician’s Health Study (n ¼ 22,071) showed
`that aspirin had no effect on the incidence of polyps
`or colon cancer.26 A different study of aspirin
`combined with folate (n ¼ 1,121) showed that the
`81-mg dose of aspirin prevented recurrence of colo-
`rectal adenomas (19% reduction).27 This study also
`reported a relative-risk reduction of 40% in the 81-
`mg aspirin group for advanced lesions. Analysis of
`the folate intervention is ongoing. This data
`suggests that aspirin may be a potential chemopre-
`ventative agent for CRC.28
`The benefit of NSAIDs in chemoprevention
`has been reported in certain high-risk groups.
`Sulindac reduces MSI in HNPCC cell lines carrying
`
`PREVENTION AND SCREENING OF GI CANCERS
`
`21
`
`MLH1, hMSH2, and MSH6 mutations and in
`persons with FAP.29-31 Individuals with these
`mutations, should be counseled regarding the
`potential benefits of these agents in reducing polyp
`formation.
`The use of COX-2 inhibitors and NSAIDs in the
`primary prevention of sporadic CRC is being
`studied.31,32 To date, none of these agents is rec-
`ommended for prevention in the general popula-
`tion. The United States Prevention Services Task
`Force (USPSTF) currently recommends against
`the routine use of NSAIDs and aspirin for the
`prevention of CRC in persons of average
`risk.33,34 This is based on the premise that these
`agents do not have an effect on the number of
`deaths due to CRC and are associated with poten-
`tial harms, especially in terms of GI bleeding.
`
`Screening Tests for Detection of CRC
`
`Screening remains the single most important
`means to reduce the morbidity and mortality asso-
`ciated with CRC. The most recent guidelines
`change emphasis from a focus on detection to
`one that includes both early detection and preven-
`tion. In addition, they introduce new recommen-
`dations including the incorporation of stool DNA
`testing (sDNA) and virtual colonoscopy. This is
`a major shift from previous guidelines for the early
`detection of CRC. There are many screening test
`options and intervals. For some of the detection
`strategies, the interval guideline is fairly clear
`and for others more research is needed. It also pla-
`ces a tremendous amount of responsibility in the
`hands of the healthcare provider to give patients
`enough education so they can make an informed
`choice about CRC screening. The number of
`choices will undoubtedly be a source of confusion
`for some healthcare providers and much of the
`public. Screening for CRC has been categorized
`into tests that are likely to detect CRC and tests
`that are likely to detect polyps and/or cancers.7
`Table 4 provides a summary of the strengths and
`limitations of screening tests for CRC.
`
`Fecal Occult Blood Tests
`Stool blood tests or fecal occult blood tests
`(FOBT) are one of the more common tools used
`in the detection of CRC. There are two types of
`FOBTs depending on the analysis process. These
`can be guaiac based (gFOBT) or a fecal immuno-
`chemical test (FIT). The premise of using the
`FOBT is that occult blood, although a nonspecific
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`S.M. MAHON
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`finding, may be due to bleeding from a large
`polyp.7 Blood in the stool is a nonspecific finding
`but may originate from CRC or larger (>1 to 2
`cm) polyps. Because small adenomatous polyps
`do not tend to bleed and bleeding from cancers
`or large polyps may be intermittent or simply
`not always detectable in a single sample of stool,
`the proper use of stool blood tests requires annual
`testing that consists of collecting multiple speci-
`mens from consecutive bowel movements while
`following a specific dietary regimen.35
`A significant difference in FOBTs is in the pro-
`cessing. FITs are usually processed in a clinical
`laboratory, whereas gFOBT can be processed
`either in the physician’s office or in a clinical labo-
`ratory. A positive gFOBT or FIT requires a diag-
`nostic workup with colonoscopy to examine the
`entire colon to rule out the presence of cancer or
`advanced neoplasia.
`The gFOBT are the most common FOBT in use
`for CRC screening and the only CRC screening
`test for which there is evidence of efficacy from
`prospective, randomized controlled trials.7 Three
`large, prospective, randomized controlled trials
`with gFOBT have shown that screened patients
`have cancers detected at an early and more
`curable stage than unscreened patients, with
`reductions in CRC mortality of 15% to 33%.37-39
`Usual gFOBT protocol consists of collecting two
`samples from each of three consecutive bowel
`movements at home. Collection of all
`three
`samples is important because test sensitivity
`improves with each additional stool sample.35,36
`The sensitivity and specificity of a gFOBT has
`been shown to be highly variable depending on
`the brand of the test, specimen collection tech-
`nique, number of samples collected per test,
`whether or not the stool specimen is rehydrated,
`and
`variations
`in interpretation,
`screening
`interval, and other factors.40-42
`A significant limitation of the potential of testing
`with gFOBT is that it is commonly performed in
`the doctor’s office as a single-panel test following
`a digital rectal exam. It has been demonstrated
`that sensitivity is only 4.9% for advanced neoplasia
`and only 9% for cancer.42 The accuracy of this
`method is so low that it cannot be considered an
`acceptable measure for CRC screening.7
`The concept of applying an immunochemical
`method to testing stool for occult blood was first
`proposed in the 1970s and commercialization of
`the technology began in the 1980s.7 A limitation
`is that FIT is more expensive than gFOBT. A signif-
`
`icant advantage of FIT is that it detects human
`globin, a protein that along with heme constitutes
`human hemoglobin. Thus, FIT is more specific for
`human blood than guaiac-based tests, which rely
`on detection of peroxidase in human blood and
`also react to the peroxidase that is present in die-
`tary constituents such as rare red meat, crucif-
`erous vegetables, and some fruits. Finally, the
`sample collection for some variants of FIT are
`less demanding of patients than gFOBT, requiring
`fewer samples or less direct handling of stool.
`Despite the physiologic evidence that FIT is
`possibly a better test, it has never been tested in
`a randomized trial where the outcome of interest
`is CRC mortality.7,43
`
`Genetic Testing of Stool
`Adenoma and carcinoma cells that contain
`altered DNA are continuously shed into the colon
`and passed out of the body through feces. Because
`DNA is stable in stool, it can be isolated from
`bacterial DNA found in the feces.44 A limitation
`of this testing is that no single gene mutation is
`present
`in cells shed by every adenoma or
`cancer.45 Thus, a multitarget DNA stool assay is
`required to achieve adequate sensitivity;
`the
`commercial availability of this test is limited.
`The primary benefit of sDNA is that this method-
`ology has acceptable sensitivity for CRC and is
`built upon the concept of detecting molecular
`markers associated with advanced colorectal
`neoplasia. It is not dependent on the detection of
`occult bleeding, which is intermittent and nonspe-
`cific, and it
`requires only a single stool
`collection.46
`
`Flexible Sigmoidoscopy
`Flexible sigmoidoscopy (FSIG) directly exam-
`ines the lumen of the lower half of the colon.
`The endoscope is passed to the transverse colon
`(~ 60 cm). FSIG is performed without sedation
`and with a limited bowel preparation. It is an
`attractive screening tool because it can be
`performed in the office setting by a variety of
`healthcare professionals,
`including nurses with
`