**3. When to start screening?**

As with any effective screening technique, the most important issue is always *when* to start offering the test. Although the lifetime risk of CRC is estimated to be 6%, we now under‐ stand that the chance of developing the disease increases with age. In the United States the annual incidence of CRC in people of ages 50 to 54 was found to be approximately double that found in individuals ages 45 to 49 (Imperiale et al., 2000). A successful screening test, if used on 100% of the population has the potential to save many more lives than if the test is used on only a portion of the population. However given limited medical resources, strate‐ gic optimization is necessary for maximum impact. Current recommendations support ini‐ tiation of screening at age 50 for average risk men and women with earlier screening recommended for high-risk populations (Levin et al., 2008; Rex et al., 2009; USPSTF, 2008; Winawer et al., 2003). In addition to identifying optimal timing for initiation, the goals of screening have shifted to focus on cancer prevention rather than simply cancer detection (Winawer et al., 2003). As a result recent guidelines from the American College of Gastroen‐ terology (ACG) and USPSTF now endorse colonoscopy as the preferred modality for screen‐ ing (Rex et al., 2009; USPSTF, 2008).

Screening guidelines must be tailored to maximize benefit while minimizing cost to both the individual and society as a whole (Rembold, 1998). The term "number needed to screen" is defined as the amount of people needed to be screened over a timed duration to prevent one death or adverse event. Many studies have looked at the cost-effectiveness of colon cancer screening with the three most common methods (i.e. fecal occult blood annually, sigmoido‐ scopy every 5 years, colonoscopy every 10 years - all beginning at age 50 and stopping at age 85). Current estimates range from \$6,000 – \$11,900 spent for every year of life gained (Maciosek et al., 2006; Telford et al., 2010). In contrast, studies on the cost effectiveness of screening mammography estimate roughly \$58,000 spent for every one year of life gained (Stout et al.). Many experts suggest that a screening policy should result in expenditure of \$50,000 or less per year of life gained. Thus, it is clear that colon cancer screening makes sense medically and financially. The question of when colon cancer screening should begin and end remains, and is a complex one. While colon cancer is typically a disease of the mid‐ dle age to elderly, there are many groups of high-risk patients that need screening much ear‐ lier than current guidelines. The remainder of this section will attempt to elucidate screening strategies in low-risk, average-risk, and high-risk groups.

It is important to emphasize that colon cancer is a diverse entity with many paths leading to a common endpoint, carcinoma. The adenoma-carcinoma sequence can encompass a multi‐ tude of genetic mutations that lead to the eventual progression to cancer (i.e. mismatch re‐ pair genes, tumor suppressor genes, base excision repair genes, micro-satellite genes). No single mutation results in adenocarcinoma, but as mutations compile, a carcinoma eventual‐ ly develops. For the majority of colon cancers, there is a significant amount of time between development of an adenoma and its progression to a malignant lesion. The time interval for progression is often determined by type of adenoma found. Current studies estimate that the dwelling time for a tubular adenoma is roughly 26 years, 9 years for tubulovillous ade‐ noma, and 4 years for a villous adenoma (with an overall annual transition rate of 2.2%) (Chen et al.). It is this significant window period of detection time that allows screening for colon cancer to be so incredibly effective, and thus important to optimize timing and fre‐ quency of screening. While these concepts hold true for the majority of colon cancers, not all cancers are created equal. Certain high-risk groups progress to cancer much more rapidly than the above data suggests, and these groups will be detailed ahead.

#### **3.1. Distribution of colorectal cancer types**

adenoma detection rates may be attributable to biologic differences in missed adenomas or

As with any effective screening technique, the most important issue is always *when* to start offering the test. Although the lifetime risk of CRC is estimated to be 6%, we now under‐ stand that the chance of developing the disease increases with age. In the United States the annual incidence of CRC in people of ages 50 to 54 was found to be approximately double that found in individuals ages 45 to 49 (Imperiale et al., 2000). A successful screening test, if used on 100% of the population has the potential to save many more lives than if the test is used on only a portion of the population. However given limited medical resources, strate‐ gic optimization is necessary for maximum impact. Current recommendations support ini‐ tiation of screening at age 50 for average risk men and women with earlier screening recommended for high-risk populations (Levin et al., 2008; Rex et al., 2009; USPSTF, 2008; Winawer et al., 2003). In addition to identifying optimal timing for initiation, the goals of screening have shifted to focus on cancer prevention rather than simply cancer detection (Winawer et al., 2003). As a result recent guidelines from the American College of Gastroen‐ terology (ACG) and USPSTF now endorse colonoscopy as the preferred modality for screen‐

Screening guidelines must be tailored to maximize benefit while minimizing cost to both the individual and society as a whole (Rembold, 1998). The term "number needed to screen" is defined as the amount of people needed to be screened over a timed duration to prevent one death or adverse event. Many studies have looked at the cost-effectiveness of colon cancer screening with the three most common methods (i.e. fecal occult blood annually, sigmoido‐ scopy every 5 years, colonoscopy every 10 years - all beginning at age 50 and stopping at age 85). Current estimates range from \$6,000 – \$11,900 spent for every year of life gained (Maciosek et al., 2006; Telford et al., 2010). In contrast, studies on the cost effectiveness of screening mammography estimate roughly \$58,000 spent for every one year of life gained (Stout et al.). Many experts suggest that a screening policy should result in expenditure of \$50,000 or less per year of life gained. Thus, it is clear that colon cancer screening makes sense medically and financially. The question of when colon cancer screening should begin and end remains, and is a complex one. While colon cancer is typically a disease of the mid‐ dle age to elderly, there are many groups of high-risk patients that need screening much ear‐ lier than current guidelines. The remainder of this section will attempt to elucidate screening

It is important to emphasize that colon cancer is a diverse entity with many paths leading to a common endpoint, carcinoma. The adenoma-carcinoma sequence can encompass a multi‐ tude of genetic mutations that lead to the eventual progression to cancer (i.e. mismatch re‐ pair genes, tumor suppressor genes, base excision repair genes, micro-satellite genes). No single mutation results in adenocarcinoma, but as mutations compile, a carcinoma eventual‐

disparities in endoscopist proficiency.

34 Colonoscopy and Colorectal Cancer Screening - Future Directions

**3. When to start screening?**

ing (Rex et al., 2009; USPSTF, 2008).

strategies in low-risk, average-risk, and high-risk groups.

The vast majority (70-75%) of colorectal cancers develop in sporadic (nonhereditary) fashion and no risk factors are identified in the individuals. The next most common form (15-20%) occurs in those with a family history of colon cancer (excluding known cancer syndromes). Hereditary Non-polyposis colorectal cancer (i.e. Lynch Syndrome) makes up roughly 3-8%. Familial Adenomatous Polyposis 1%, and Colitis Associated Cancer (i.e. Inflammatory Bow‐ el Disease) also 1% (Winawer et al.). Keeping these figures in mind, colon cancer screening has the largest absolute impact on average-risk individuals. As such, the next section will focus on screening recommendations for the average-risk group.

#### **3.2. Approach to average-risk individuals**

As mentioned before, colon cancer is a disease of the middle age to elderly. According to a review by the National Cancer Institute conducted from 2005-2009, the median age at time of diagnosis of a colorectal cancer is 69. Thus, if we extrapolate from the data provided pre‐ viously (~2% annual transformation from adenoma to carcinoma), we can see that it makes sense to exclude the younger population from screening tests. In fact, the most recent USPSTF recommendations support the initiation of colon cancer screening in average-risk individuals at age 50 (Grade A Recommendation) (USPSTF). These recommendations were made based in part on the results of two microsimulation models (MISCAN and SimCRC models) that incorporated current data on colon cancer incidence and adenoma progression, and simulated the natural history of colon cancer in a large population. The models then es‐ timated the life-years gained if screening colonoscopy was performed vs. no screening at all. Further data analysis detailed age to begin screening, age to stop screening, and time inter‐ vals between screening. The models concluded that the optimal age to initiate screening is 50 (when compared to ages 40 and 60). Of note, one simulation showed better outcomes when screening was initiated at age 40, however the alternate simulation did not corrobo‐ rate the data. The Task Force concluded, "Because the evidence for both adenoma preva‐ lence at age 40 and the duration of the adenoma-carcinoma sequence is weak, we restricted further analysis to start ages of 50 and 60." This led to the recommendation of initiating screening at age 50. Regarding interval time period between colonoscopy, the authors re‐ viewed data on 5-year, 10-year, and 20-year intervals. They concluded, as could be expected, shorter intervals resulted in more life-years gained (their primary endpoint). However, when comparing 5-year to 10-year, there was only a modest increase in life years gained when compared to the corresponding increase in colonoscopies performed. 20-year intervals resulted in significantly less life-years gained, so was not considered optimal. While these authors agree with the recommendations by the USPSTF for average-risk individuals, it is important that practitioners further tailor their screening strategies based on several addi‐ tional factors. As mentioned, 75% of colon cancers occur in average-risk individuals, thus representing a large absolute number of persons. As such, there is much variability and as‐ sociated risks among the average-risk population.

Study Research Group concluded similarly that increasing BMI is associated with increased risk of colon cancer, and particularly noted a higher risk among women with an increased waist-to-hip ratio (Martinez et al., 1997). It is now widely accepted that obesity, and particu‐ larly central obesity, is an independent risk factor for the development of colon cancer. Sev‐ eral theories have been proposed as to why exactly this clear association exists. For now, the most supported theory proposes that insulin resistance (along with hyperinsulinemia and increased Insulin-like Growth Factor-1) plays a large role in this relationship. In fact, a re‐ cent meta-analysis has concluded that Diabetes Mellitus is itself an independent risk factor for colon cancer. Even after controlling for physical activity, smoking, and obesity, the au‐ thors found an increase in relative risk among those with Diabetes Mellitus of 1.43 and 1.35 in men and women, respectively (both statistically significant) (Yuhara et al., 2011). Patho‐ physiologically, both insulin and IGF-1 are involved in cell proliferation and regulation of apoptosis and it is enough to recognize that states with elevated levels of both hormones have been clearly linked to increased risk for colon cancer. Additionally, multiple studies have looked at the effect of physical activity and its influence on colon cancer. These studies and their respective meta-analyses have shown clearly an inverse relationship between physical activity and colon cancer. Among data taken from the group exhibiting the highest level of exercise, one study showed a 50% reduction in lifetime colon cancer risk (Colditz et al., 1997). Thus, an important conclusion can be reached based on the data reviewed as well as others: obese, sedentary individuals are at higher risk for colon cancer. While the USPSTF guidelines do not currently reflect this information for screening recommendations, clini‐ cians most certainly can make use of it to provide patient-centered care. Patients should be counseled regarding overall health and the potential for primary prevention of colon cancer

Issues in Screening and Surveillance Colonoscopy

http://dx.doi.org/10.5772/53111

37

The next most common modifiable risk factors a clinician is likely to encounter is tobacco and/or alcohol use, both clearly linked with colon cancer. Multitudes of studies have been undertaken in the last two decades examining the potential link between cigarette smoking and colorectal cancer. A meta-analysis from 2009 conducted by Liang et al examined 36 such studies (Liang et al., 2009). The results of the analysis showed a clear association between age of initiation of tobacco use, amount smoked per day, and total duration of tobacco use. Data showed a relative-risk of 1.38 for an increase in 40-cigarretes per day, 1.20 for an in‐ crease of 40 years total duration, and 1.51 for an increase of 60-pack years. Interestingly, they also noted a predilection for rectal cancer over colon cancer when analyzing incidence of site-specific carcinoma. Next, studies emerging over the last decade have begun to note in‐ creases in risk for colorectal cancer even in light to moderate alcohol use. A pooled analysis of 8 cohort studies involving nearly 490,000 men and women was published in the Annals of Internal Medicine in 2004. Data showed, when compared with non-drinkers, a relative-risk of 1.41 (CI 1.16-1.72) in individuals who consumed 45g of daily alcohol (roughly three drinks) (Cho et al., 2004). There was no statistically significant correlation among daily con‐ sumption of 30-44g/daily. More recently, a meta-analysis from 2011 from the Annals of On‐ cology examined 27 cohort studies and 34 case-control studies (Fedirko et al., 2011). They also concluded a strong association between alcohol consumption and colorectal cancer risk. The association was strongest among heavy drinkers, relative-risk 1.82 if >100g/day. Surpris‐

via improved dieting and exercise habits.

Factors that increase the risk for colorectal cancer or are protective have been identified. While these factors have not been incorporated into the USPSTF Guidelines, knowledge about their existence and influence on overall risk may be helpful in directing clinicians to‐ ward screening colonoscopy practices. Additionally, and some may argue more important‐ ly, clinicians must take into account a patient's expected adherence to their colonoscopy recommendations. Will the patient have regular and predictable access to a skilled gastroen‐ terologist? Will they be willing to comply with frequent colonoscopy should their risk fac‐ tors or findings require it? A new concept known as once in a lifetime screening with colonoscopy is being proposed as an effective technique in some groups. Knowledge of risk factors can be especially helpful in these cases, in which a clinician can strongly encourage adherence to recommendations based on each individual's risk factors. Additionally, it is important to note that the following discussion applies only to individuals classified as aver‐ age-risk, and excludes those with a family history, diagnosed genetic condition, and Inflam‐ matory Bowel Disease. These groups will be discussed separately.

#### **3.3. Modifiable CRC risk factors**

To date, several modifiable risk factors have been clearly linked with the development of colorectal carcinoma. Starting from the 10,000-foot view, many of the risk factors can be col‐ lectively grouped under the heading of total energy balance (i.e. caloric intake vs. caloric ex‐ penditure). Numerous studies have shown a clear link between Body Mass Index and resultant risk of colon cancer. For example, investigators looked at the lifetime incidence of colon cancer among the Framingham Cohort in Massachusetts, and divided the group by age group to a 30-54 year old group and a 55-79 year old group. They then looked at the overall incidence of colon cancer among the groups, and related the information to average Body Mass Index. In the 55-79 year old group, they separated the cohort into BMI >30 and BMI <30 groups. They noticed a significant 2.4 fold increased risk for the development of co‐ lon cancer for those with a BMI >30 (95% CI: 1.5-3.9) (Moore et al., 2004). Interestingly, the same study also analyzed the results with relation to waist size measurement. As BMI can be notoriously misleading, especially among males, the authors pursued this alternate meas‐ ure for further support. They concluded that central adiposity (defined as a waist size >39 inches), was associated with a two-fold increase in risk for colon cancer. They further noted that the risk increased linearly with increases in waist size. This data has been replicated among many other studies, in both men and women. A large study by the Nurses' Health Study Research Group concluded similarly that increasing BMI is associated with increased risk of colon cancer, and particularly noted a higher risk among women with an increased waist-to-hip ratio (Martinez et al., 1997). It is now widely accepted that obesity, and particu‐ larly central obesity, is an independent risk factor for the development of colon cancer. Sev‐ eral theories have been proposed as to why exactly this clear association exists. For now, the most supported theory proposes that insulin resistance (along with hyperinsulinemia and increased Insulin-like Growth Factor-1) plays a large role in this relationship. In fact, a re‐ cent meta-analysis has concluded that Diabetes Mellitus is itself an independent risk factor for colon cancer. Even after controlling for physical activity, smoking, and obesity, the au‐ thors found an increase in relative risk among those with Diabetes Mellitus of 1.43 and 1.35 in men and women, respectively (both statistically significant) (Yuhara et al., 2011). Patho‐ physiologically, both insulin and IGF-1 are involved in cell proliferation and regulation of apoptosis and it is enough to recognize that states with elevated levels of both hormones have been clearly linked to increased risk for colon cancer. Additionally, multiple studies have looked at the effect of physical activity and its influence on colon cancer. These studies and their respective meta-analyses have shown clearly an inverse relationship between physical activity and colon cancer. Among data taken from the group exhibiting the highest level of exercise, one study showed a 50% reduction in lifetime colon cancer risk (Colditz et al., 1997). Thus, an important conclusion can be reached based on the data reviewed as well as others: obese, sedentary individuals are at higher risk for colon cancer. While the USPSTF guidelines do not currently reflect this information for screening recommendations, clini‐ cians most certainly can make use of it to provide patient-centered care. Patients should be counseled regarding overall health and the potential for primary prevention of colon cancer via improved dieting and exercise habits.

shorter intervals resulted in more life-years gained (their primary endpoint). However, when comparing 5-year to 10-year, there was only a modest increase in life years gained when compared to the corresponding increase in colonoscopies performed. 20-year intervals resulted in significantly less life-years gained, so was not considered optimal. While these authors agree with the recommendations by the USPSTF for average-risk individuals, it is important that practitioners further tailor their screening strategies based on several addi‐ tional factors. As mentioned, 75% of colon cancers occur in average-risk individuals, thus representing a large absolute number of persons. As such, there is much variability and as‐

Factors that increase the risk for colorectal cancer or are protective have been identified. While these factors have not been incorporated into the USPSTF Guidelines, knowledge about their existence and influence on overall risk may be helpful in directing clinicians to‐ ward screening colonoscopy practices. Additionally, and some may argue more important‐ ly, clinicians must take into account a patient's expected adherence to their colonoscopy recommendations. Will the patient have regular and predictable access to a skilled gastroen‐ terologist? Will they be willing to comply with frequent colonoscopy should their risk fac‐ tors or findings require it? A new concept known as once in a lifetime screening with colonoscopy is being proposed as an effective technique in some groups. Knowledge of risk factors can be especially helpful in these cases, in which a clinician can strongly encourage adherence to recommendations based on each individual's risk factors. Additionally, it is important to note that the following discussion applies only to individuals classified as aver‐ age-risk, and excludes those with a family history, diagnosed genetic condition, and Inflam‐

To date, several modifiable risk factors have been clearly linked with the development of colorectal carcinoma. Starting from the 10,000-foot view, many of the risk factors can be col‐ lectively grouped under the heading of total energy balance (i.e. caloric intake vs. caloric ex‐ penditure). Numerous studies have shown a clear link between Body Mass Index and resultant risk of colon cancer. For example, investigators looked at the lifetime incidence of colon cancer among the Framingham Cohort in Massachusetts, and divided the group by age group to a 30-54 year old group and a 55-79 year old group. They then looked at the overall incidence of colon cancer among the groups, and related the information to average Body Mass Index. In the 55-79 year old group, they separated the cohort into BMI >30 and BMI <30 groups. They noticed a significant 2.4 fold increased risk for the development of co‐ lon cancer for those with a BMI >30 (95% CI: 1.5-3.9) (Moore et al., 2004). Interestingly, the same study also analyzed the results with relation to waist size measurement. As BMI can be notoriously misleading, especially among males, the authors pursued this alternate meas‐ ure for further support. They concluded that central adiposity (defined as a waist size >39 inches), was associated with a two-fold increase in risk for colon cancer. They further noted that the risk increased linearly with increases in waist size. This data has been replicated among many other studies, in both men and women. A large study by the Nurses' Health

sociated risks among the average-risk population.

36 Colonoscopy and Colorectal Cancer Screening - Future Directions

matory Bowel Disease. These groups will be discussed separately.

**3.3. Modifiable CRC risk factors**

The next most common modifiable risk factors a clinician is likely to encounter is tobacco and/or alcohol use, both clearly linked with colon cancer. Multitudes of studies have been undertaken in the last two decades examining the potential link between cigarette smoking and colorectal cancer. A meta-analysis from 2009 conducted by Liang et al examined 36 such studies (Liang et al., 2009). The results of the analysis showed a clear association between age of initiation of tobacco use, amount smoked per day, and total duration of tobacco use. Data showed a relative-risk of 1.38 for an increase in 40-cigarretes per day, 1.20 for an in‐ crease of 40 years total duration, and 1.51 for an increase of 60-pack years. Interestingly, they also noted a predilection for rectal cancer over colon cancer when analyzing incidence of site-specific carcinoma. Next, studies emerging over the last decade have begun to note in‐ creases in risk for colorectal cancer even in light to moderate alcohol use. A pooled analysis of 8 cohort studies involving nearly 490,000 men and women was published in the Annals of Internal Medicine in 2004. Data showed, when compared with non-drinkers, a relative-risk of 1.41 (CI 1.16-1.72) in individuals who consumed 45g of daily alcohol (roughly three drinks) (Cho et al., 2004). There was no statistically significant correlation among daily con‐ sumption of 30-44g/daily. More recently, a meta-analysis from 2011 from the Annals of On‐ cology examined 27 cohort studies and 34 case-control studies (Fedirko et al., 2011). They also concluded a strong association between alcohol consumption and colorectal cancer risk. The association was strongest among heavy drinkers, relative-risk 1.82 if >100g/day. Surpris‐ ingly, they even found a statistically significant increase in relative-risk to 1.07 for individu‐ als drinking one alcoholic beverage per day (10g/day), which throws into question the current recommendations of the USDA (two drinks or less daily for men, one drink or less daily for women). Interestingly, even stronger associations were noted in studies examined the Asian population (specifically Japanese men). Clearly, there is a link between both tobac‐ co and alcohol use and risk of colorectal cancer. Over the next few years, additional studies and meta-analyses will likely emerge further elucidating just which populations are at risk and what usage levels are most harmful. For now, clinicians should clearly state that tobacco use and even light daily alcohol ingestion increases their likelihood of developing colorectal cancer. As the current data suggests only a modest increase in relative-risk, this information may be more pertinent among individuals with additional risk factors. Clinicians should certainly take a patient's tobacco and alcohol use into account when determining how fre‐ quent they will advise screening colonoscopies.

trials geared toward cardiovascular effects), it can likely be expected that clearer relation‐ ships between NSAID type, dosing, and duration will be elucidated. As it is not officially recommended by the USPSTF, clinicians are not currently advocating for NSAID use as pri‐ mary prevention. However, a large portion of those at greatest risk for developing colorectal cancer (i.e. middle-age to elderly) are already on Aspirin for its cardiovascular benefits. Thus, clinicians can take this fact into account when assessing an individual's colorectal can‐ cer risk. Again, there is no current recommendation to decrease screening intervals in pa‐ tients on Aspirin therapy, however, when taken collectively with other risk factors,

Issues in Screening and Surveillance Colonoscopy

http://dx.doi.org/10.5772/53111

39

Another common protective measure a clinician may encounter regards the use of postmenopausal hormonal therapy. Again, as early as the 1980s, studies emerged showing an unexpected link between hormonal therapy and colorectal cancers. As in many other associ‐ ations, the exact mechanism by which estrogen/progestin can inhibit cancer development is unknown. However, speculations on its pathophysiology are under active investigation. Re‐ searchers hypothesize that hormonal therapy can alter levels of bile acids, Insulin-Like Growth Factor-1, and IGF Binding Protein-3. Moreover, estrogen receptors have been found on colonic epithelial cells, and it is unclear if this may also provide a route of protection. Nevertheless, numerous studies (one of which will be described below) have shown the in‐ verse relationship between hormonal therapy and colon cancer risk. In a prospective study of nearly 57,000 women (taken from the Breast Cancer Detection Demonstration Project) published in 2009, Johnson et al looked at hormonal therapy (including estrogen alone, com‐ bination with progestin, and duration of therapy) and its relation to colon cancer incidence (Johnson et al., 2009). Results are astoundingly clear that hormonal therapy is protective against colon cancer. The results were as follows: ever users of unopposed estrogen RR 0.83 (95% CI, 0.70-0.99), current users unopposed estrogen >10 years RR 0.74 (95% CI, 0.56-0.96). The results among estrogen + progestin users showed an even stronger relationship: estro‐ gen + progestin RR 0.78 (95% CI, 0.6-1.02), estrogen + sequential progestin RR 0.64 (95% CI, 0.43-0.95), and strongest effect with 2-5yr use of estrogen + sequential progestin RR 0.52 (95% CI, 0.32-0.87). Similar studies conducted by the WHI (Women's Health Initiative) have shown similar results for estrogen + progestin therapy, but not estrogen therapy alone. Inter‐ estingly, they also noted that although the frequency of cancer was less in the hormonal group, the cancers were detected at later stages (increased lymph node involvement and metastatic disease) (Chlebowski et al., 2004). So, as before, we have clear evidence of a pro‐ tective measure against colon cancer. Unfortunately, the same WHI trial showed an increase in myocardial infarction, stroke, dementia, pulmonary emboli, and breast cancer among hor‐ monal therapy users. As such, there have been no widespread recommendations for pri‐ mary prevention of colorectal cancer by means of hormonal therapy. However, clinicians may encounter women who are on hormonal therapy. While estrogen therapy alone may not have clear benefits, estrogen + progestin therapy has repeatedly shown to be of benefit in prevention of colorectal cancer. In fact, based on the results of the first-mentioned study, risk was decreased by a staggering 25-46%. Taking this information into account, assuming no additional risk factors exist, and clinician may be able to tailor their screening colonosco‐

clinicians may further tailor how aggressive they wish to be with screening.

py frequency toward a less aggressive and frequent approach.

#### **3.4. Protective measures against CRC**

Just as risk factors have been identified, there are also several clear factors that are protective against colon cancer. Physical activity was discussed earlier, thus will not be repeated here, but suffice it to mention again that it is highly protective against colon cancer. Moreover, the medical community already advocates daily exercise for a multitude of other health bene‐ fits, and the fact that it also protects against colon cancer would not alter a clinician's man‐ agement of colonoscopy screening. However, several studies have clearly shown a protective relationship between common pharmaceuticals and colon cancer. Both Aspirin and Non-steroidal anti-inflammatory drugs have been shown to decrease the incidence of colon cancer. Studies from as early as the 1980s began to show a relationship between antiinflammatory medications and colon cancer. Initial studies performed on patients with Rheumatoid Arthritis, as they were often on chronic NSAID therapy, were the first to show this relationship in the 1980s. Further studies conducted in patients on long-term aspirin therapy showed similar results. The exact mechanism by which anti-inflammatory medica‐ tions provide this protective benefit currently remains unknown. Several hypotheses exist which primarily center on COX-1 and COX-2 inhibition, as they are known to promote in‐ flammation, tumorigenesis, and angiogenesis. In a study published in the Lancet in 2007 by Flossman et al, British researchers pooled data from two large Aspirin trials in the UK (Brit‐ ish Doctors Aspirin Trial, UK-TIA Aspirin Trial) (Flossmann and Rothwell, 2007). Among patients with complete compliance for 5 years or more of aspirin therapy, they found a stat‐ istically significant relative-risk of 0.26 (CI 0.12-0.56). The effect was less substantial among non-compliant patients, but nevertheless protective (RR 0.37). It is important to note in this study, as in many other studies, the protective benefit was most clearly seen after a latency period of at least 10 years. Moreover, study data pooled from trials related to cardiovascular protection often have used differing doses of aspirin (or NSAIDs). At this time, no clear dose, duration of therapy or type of NSAID has shown to be of greatest benefit in primary colorectal cancer chemoprevention. As such, the USPSTF has not recommended NSAIDS as a primary preventive measure for colorectal cancer. As more and more studies specifically geared and powered toward colorectal carcinoma prevention (as opposed to data analysis of trials geared toward cardiovascular effects), it can likely be expected that clearer relation‐ ships between NSAID type, dosing, and duration will be elucidated. As it is not officially recommended by the USPSTF, clinicians are not currently advocating for NSAID use as pri‐ mary prevention. However, a large portion of those at greatest risk for developing colorectal cancer (i.e. middle-age to elderly) are already on Aspirin for its cardiovascular benefits. Thus, clinicians can take this fact into account when assessing an individual's colorectal can‐ cer risk. Again, there is no current recommendation to decrease screening intervals in pa‐ tients on Aspirin therapy, however, when taken collectively with other risk factors, clinicians may further tailor how aggressive they wish to be with screening.

ingly, they even found a statistically significant increase in relative-risk to 1.07 for individu‐ als drinking one alcoholic beverage per day (10g/day), which throws into question the current recommendations of the USDA (two drinks or less daily for men, one drink or less daily for women). Interestingly, even stronger associations were noted in studies examined the Asian population (specifically Japanese men). Clearly, there is a link between both tobac‐ co and alcohol use and risk of colorectal cancer. Over the next few years, additional studies and meta-analyses will likely emerge further elucidating just which populations are at risk and what usage levels are most harmful. For now, clinicians should clearly state that tobacco use and even light daily alcohol ingestion increases their likelihood of developing colorectal cancer. As the current data suggests only a modest increase in relative-risk, this information may be more pertinent among individuals with additional risk factors. Clinicians should certainly take a patient's tobacco and alcohol use into account when determining how fre‐

Just as risk factors have been identified, there are also several clear factors that are protective against colon cancer. Physical activity was discussed earlier, thus will not be repeated here, but suffice it to mention again that it is highly protective against colon cancer. Moreover, the medical community already advocates daily exercise for a multitude of other health bene‐ fits, and the fact that it also protects against colon cancer would not alter a clinician's man‐ agement of colonoscopy screening. However, several studies have clearly shown a protective relationship between common pharmaceuticals and colon cancer. Both Aspirin and Non-steroidal anti-inflammatory drugs have been shown to decrease the incidence of colon cancer. Studies from as early as the 1980s began to show a relationship between antiinflammatory medications and colon cancer. Initial studies performed on patients with Rheumatoid Arthritis, as they were often on chronic NSAID therapy, were the first to show this relationship in the 1980s. Further studies conducted in patients on long-term aspirin therapy showed similar results. The exact mechanism by which anti-inflammatory medica‐ tions provide this protective benefit currently remains unknown. Several hypotheses exist which primarily center on COX-1 and COX-2 inhibition, as they are known to promote in‐ flammation, tumorigenesis, and angiogenesis. In a study published in the Lancet in 2007 by Flossman et al, British researchers pooled data from two large Aspirin trials in the UK (Brit‐ ish Doctors Aspirin Trial, UK-TIA Aspirin Trial) (Flossmann and Rothwell, 2007). Among patients with complete compliance for 5 years or more of aspirin therapy, they found a stat‐ istically significant relative-risk of 0.26 (CI 0.12-0.56). The effect was less substantial among non-compliant patients, but nevertheless protective (RR 0.37). It is important to note in this study, as in many other studies, the protective benefit was most clearly seen after a latency period of at least 10 years. Moreover, study data pooled from trials related to cardiovascular protection often have used differing doses of aspirin (or NSAIDs). At this time, no clear dose, duration of therapy or type of NSAID has shown to be of greatest benefit in primary colorectal cancer chemoprevention. As such, the USPSTF has not recommended NSAIDS as a primary preventive measure for colorectal cancer. As more and more studies specifically geared and powered toward colorectal carcinoma prevention (as opposed to data analysis of

quent they will advise screening colonoscopies.

38 Colonoscopy and Colorectal Cancer Screening - Future Directions

**3.4. Protective measures against CRC**

Another common protective measure a clinician may encounter regards the use of postmenopausal hormonal therapy. Again, as early as the 1980s, studies emerged showing an unexpected link between hormonal therapy and colorectal cancers. As in many other associ‐ ations, the exact mechanism by which estrogen/progestin can inhibit cancer development is unknown. However, speculations on its pathophysiology are under active investigation. Re‐ searchers hypothesize that hormonal therapy can alter levels of bile acids, Insulin-Like Growth Factor-1, and IGF Binding Protein-3. Moreover, estrogen receptors have been found on colonic epithelial cells, and it is unclear if this may also provide a route of protection. Nevertheless, numerous studies (one of which will be described below) have shown the in‐ verse relationship between hormonal therapy and colon cancer risk. In a prospective study of nearly 57,000 women (taken from the Breast Cancer Detection Demonstration Project) published in 2009, Johnson et al looked at hormonal therapy (including estrogen alone, com‐ bination with progestin, and duration of therapy) and its relation to colon cancer incidence (Johnson et al., 2009). Results are astoundingly clear that hormonal therapy is protective against colon cancer. The results were as follows: ever users of unopposed estrogen RR 0.83 (95% CI, 0.70-0.99), current users unopposed estrogen >10 years RR 0.74 (95% CI, 0.56-0.96). The results among estrogen + progestin users showed an even stronger relationship: estro‐ gen + progestin RR 0.78 (95% CI, 0.6-1.02), estrogen + sequential progestin RR 0.64 (95% CI, 0.43-0.95), and strongest effect with 2-5yr use of estrogen + sequential progestin RR 0.52 (95% CI, 0.32-0.87). Similar studies conducted by the WHI (Women's Health Initiative) have shown similar results for estrogen + progestin therapy, but not estrogen therapy alone. Inter‐ estingly, they also noted that although the frequency of cancer was less in the hormonal group, the cancers were detected at later stages (increased lymph node involvement and metastatic disease) (Chlebowski et al., 2004). So, as before, we have clear evidence of a pro‐ tective measure against colon cancer. Unfortunately, the same WHI trial showed an increase in myocardial infarction, stroke, dementia, pulmonary emboli, and breast cancer among hor‐ monal therapy users. As such, there have been no widespread recommendations for pri‐ mary prevention of colorectal cancer by means of hormonal therapy. However, clinicians may encounter women who are on hormonal therapy. While estrogen therapy alone may not have clear benefits, estrogen + progestin therapy has repeatedly shown to be of benefit in prevention of colorectal cancer. In fact, based on the results of the first-mentioned study, risk was decreased by a staggering 25-46%. Taking this information into account, assuming no additional risk factors exist, and clinician may be able to tailor their screening colonosco‐ py frequency toward a less aggressive and frequent approach.

A clinician may also encounter questions from a patient regarding diet recommendations. While a healthy, balanced diet high in non-processed, low animal fat calories is always recom‐ mended, there has been non conclusive data regarding diet and its relation to colorectal cancer. As such, the decision on when to initiate and how often to perform screening colonoscopies should not be influenced by a patient's diet. It is possible that more clear relationships will be clarified in the future, but for now, data displaying strong associations does not exist.

tablished. Data may eventually and conclusively show that colorectal cancer appears earlier and is more aggressive in African-Americans. In the meantime, these authors would argue

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Finally, in the average-risk population, the issue of access to colonoscopy need always re‐ main in the back of a clinician's mind. Many patients may not have access due to socioeco‐ nomic or geographic barriers, or simply they may choose not to undergo screening based on underlying psychological barriers or misconceptions regarding colon cancer and/or colono‐ scopy. As mentioned previously, many organizations are working toward colon cancer and screening awareness, however clinicians must keep public unawareness as part of their screening practice. If a patient presents at age 45 and there is concern for eventual adherence

As mentioned previously, the next largest group of the population diagnosed with colon cancer involves those with a family history (excluding individuals with a known colorectal cancer syndrome). This group makes up ~15-20% of all diagnoses. Currently, there are mul‐ tiple efforts and studies looking into what exactly confers this higher risk among individuals with a positive family history of colon cancer. At this time, it remains unclear what genetic and/or environmental factors are involved in the pathogenesis, however, it is abundantly clear that patients with 1st degree relatives diagnosed with colon cancer, are at a significantly higher risk of developing colon cancer themselves. In fact, in one of the seminal studies pub‐ lished on the topic from the New England Journal Of Medicine, individuals with one 1st-de‐ gree relative with colon cancer were found to have a 1.7 fold increase in their own risk for colon cancer (Rex et al., 2009). This risk increased further as the number of diseased 1st-de‐ gree relatives increased as well. Further, they found that the increased risk was irrespective of location of diagnosed tumor in the relative (i.e. proximal vs. distal site of malignancy). As such, the American College of Gastroenterology revised its guidelines regarding individuals with a positive family history. If an individual has a 1st degree relative that was diagnosed with colon cancer before the age of 60 (or 2 or more relatives with colon cancer or advanced adenomas irrespective of age at diagnosis), they are considered to have a positive family his‐ tory. If a patient is identified as having a positive family history, they should then begin co‐ lonoscopy screening at age 40 (or 10 years before the youngest age of diagnosis), and they should have an interval follow-up colonoscopy every 5 years. According to these recom‐ mendations, 2nd-degree relatives or relatives diagnosed >60 years of age are not considered

While the exact genetic predisposition for the majority of colon cancer remains unknown, there are several well-known (and identifiable) cancer syndromes that a clinician must take into account when making colon cancer screening advice. The most common of these is Familial Adenomatous Polyposis. It affects roughly 1 in 5,000-7,000 individuals and confers a 100% risk of eventual colorectal cancer, with the average age at diagnosis 40 (Bussey et al.,

for earlier age at initiation of screening and more frequent screening intervals.

to the screening guidelines at age 50, he/she should be screened at age 45.

**3.5. Risk associated with family history of CRC**

as a conferring a positive family history.

**3.6. Polyposis syndromes**

The next question that must be answered is what role should gender and race/ethnicity of a patient play in a clinician's screening colonoscopy recommendations? According to the most recent data from the Center for Disease Control (CDC) males have a higher incidence of col‐ orectal cancer vs females (52.7 vs. 39.7/100,000) (Prevention). The highest incidence is found in African American males (62/100,000), followed by Caucasian males (51.5/100,000). His‐ panics, Asians, and Native American/Alaskan Native groups all had a lower incidence than the comparative African-American and Caucasian groups in both the male and female cate‐ gories. When comparing death rates from colorectal cancer by race, again males have an overall higher rate vs. females (20.2 vs 14.1/100,000).(NIH, 2009) African-American males displayed the highest rate at 29.8/100,000, and African-American Females the next highest rate at 19.8/100,000. The remainder of the groups showed death rates below the average of respective male and female groups analyzed. Compiling the above data, it is evident that African-Americans are most affected by colorectal cancer in comparison to other race/ethnic‐ ities. In fact, a study examining 5-year survival rates among Caucasians vs. African-Ameri‐ cans (among all stages of colorectal cancer) revealed a staggering difference of 64% vs. 52% (Ries). Initially, arguments were made postulating that perhaps the African-American com‐ munity rate of screening colonoscopy was much lower, thus accounting for the higher inci‐ dence and mortality rate. According to the CDC data on screening rates, Caucasians are most screened at 66.2% and African-Americans are next most screened at 62.9% (Rim S.H., 2011). The lowest screening rate is found in the Hispanic population at 51.2%. While Afri‐ can-Americans have a higher mortality rate from colorectal cancer, it is clear that it is not solely due to inadequate screening, as African-Americans have much higher screening rates than Hispanics, yet also a much higher mortality rate. A study examining this finding con‐ cluded that African-Americans are more likely to be diagnosed at an earlier age and present at later stages of disease, as compared to Caucasians, however this data has not been consis‐ tently replicated (Chien et al., 2005). Another study postulated that socioeconomic status and access to medical care may be partially involved in this mortality discrepancy (Wudel et al., 2002). This study found that African-Americans are more likely to be treated at city hos‐ pital vs university hospitals (which are associated with better outcomes). However, when comparing survival data even among Caucasians and African-Americans at each type of hospital, African-Americans fared worse. Another study has pointed to type of care offered (i.e. adjuvant chemotherapy and radiation) as a potential factor (Govindarajan et al., 2003). This study found that African-Americans are treated less with both chemotherapy and radi‐ ation therapy vs. Caucasian patients. It is still unclear why exactly African-Americans are more often diagnosed and more often killed by colorectal cancer. Regardless of the reason, it is clear that there is a difference that needs to be addressed. It seems that while the reasons are being elucidated, more aggressive screening among African-Americans needs to be es‐ tablished. Data may eventually and conclusively show that colorectal cancer appears earlier and is more aggressive in African-Americans. In the meantime, these authors would argue for earlier age at initiation of screening and more frequent screening intervals.

Finally, in the average-risk population, the issue of access to colonoscopy need always re‐ main in the back of a clinician's mind. Many patients may not have access due to socioeco‐ nomic or geographic barriers, or simply they may choose not to undergo screening based on underlying psychological barriers or misconceptions regarding colon cancer and/or colono‐ scopy. As mentioned previously, many organizations are working toward colon cancer and screening awareness, however clinicians must keep public unawareness as part of their screening practice. If a patient presents at age 45 and there is concern for eventual adherence to the screening guidelines at age 50, he/she should be screened at age 45.

#### **3.5. Risk associated with family history of CRC**

A clinician may also encounter questions from a patient regarding diet recommendations. While a healthy, balanced diet high in non-processed, low animal fat calories is always recom‐ mended, there has been non conclusive data regarding diet and its relation to colorectal cancer. As such, the decision on when to initiate and how often to perform screening colonoscopies should not be influenced by a patient's diet. It is possible that more clear relationships will be

The next question that must be answered is what role should gender and race/ethnicity of a patient play in a clinician's screening colonoscopy recommendations? According to the most recent data from the Center for Disease Control (CDC) males have a higher incidence of col‐ orectal cancer vs females (52.7 vs. 39.7/100,000) (Prevention). The highest incidence is found in African American males (62/100,000), followed by Caucasian males (51.5/100,000). His‐ panics, Asians, and Native American/Alaskan Native groups all had a lower incidence than the comparative African-American and Caucasian groups in both the male and female cate‐ gories. When comparing death rates from colorectal cancer by race, again males have an overall higher rate vs. females (20.2 vs 14.1/100,000).(NIH, 2009) African-American males displayed the highest rate at 29.8/100,000, and African-American Females the next highest rate at 19.8/100,000. The remainder of the groups showed death rates below the average of respective male and female groups analyzed. Compiling the above data, it is evident that African-Americans are most affected by colorectal cancer in comparison to other race/ethnic‐ ities. In fact, a study examining 5-year survival rates among Caucasians vs. African-Ameri‐ cans (among all stages of colorectal cancer) revealed a staggering difference of 64% vs. 52% (Ries). Initially, arguments were made postulating that perhaps the African-American com‐ munity rate of screening colonoscopy was much lower, thus accounting for the higher inci‐ dence and mortality rate. According to the CDC data on screening rates, Caucasians are most screened at 66.2% and African-Americans are next most screened at 62.9% (Rim S.H., 2011). The lowest screening rate is found in the Hispanic population at 51.2%. While Afri‐ can-Americans have a higher mortality rate from colorectal cancer, it is clear that it is not solely due to inadequate screening, as African-Americans have much higher screening rates than Hispanics, yet also a much higher mortality rate. A study examining this finding con‐ cluded that African-Americans are more likely to be diagnosed at an earlier age and present at later stages of disease, as compared to Caucasians, however this data has not been consis‐ tently replicated (Chien et al., 2005). Another study postulated that socioeconomic status and access to medical care may be partially involved in this mortality discrepancy (Wudel et al., 2002). This study found that African-Americans are more likely to be treated at city hos‐ pital vs university hospitals (which are associated with better outcomes). However, when comparing survival data even among Caucasians and African-Americans at each type of hospital, African-Americans fared worse. Another study has pointed to type of care offered (i.e. adjuvant chemotherapy and radiation) as a potential factor (Govindarajan et al., 2003). This study found that African-Americans are treated less with both chemotherapy and radi‐ ation therapy vs. Caucasian patients. It is still unclear why exactly African-Americans are more often diagnosed and more often killed by colorectal cancer. Regardless of the reason, it is clear that there is a difference that needs to be addressed. It seems that while the reasons are being elucidated, more aggressive screening among African-Americans needs to be es‐

clarified in the future, but for now, data displaying strong associations does not exist.

40 Colonoscopy and Colorectal Cancer Screening - Future Directions

As mentioned previously, the next largest group of the population diagnosed with colon cancer involves those with a family history (excluding individuals with a known colorectal cancer syndrome). This group makes up ~15-20% of all diagnoses. Currently, there are mul‐ tiple efforts and studies looking into what exactly confers this higher risk among individuals with a positive family history of colon cancer. At this time, it remains unclear what genetic and/or environmental factors are involved in the pathogenesis, however, it is abundantly clear that patients with 1st degree relatives diagnosed with colon cancer, are at a significantly higher risk of developing colon cancer themselves. In fact, in one of the seminal studies pub‐ lished on the topic from the New England Journal Of Medicine, individuals with one 1st-de‐ gree relative with colon cancer were found to have a 1.7 fold increase in their own risk for colon cancer (Rex et al., 2009). This risk increased further as the number of diseased 1st-de‐ gree relatives increased as well. Further, they found that the increased risk was irrespective of location of diagnosed tumor in the relative (i.e. proximal vs. distal site of malignancy). As such, the American College of Gastroenterology revised its guidelines regarding individuals with a positive family history. If an individual has a 1st degree relative that was diagnosed with colon cancer before the age of 60 (or 2 or more relatives with colon cancer or advanced adenomas irrespective of age at diagnosis), they are considered to have a positive family his‐ tory. If a patient is identified as having a positive family history, they should then begin co‐ lonoscopy screening at age 40 (or 10 years before the youngest age of diagnosis), and they should have an interval follow-up colonoscopy every 5 years. According to these recom‐ mendations, 2nd-degree relatives or relatives diagnosed >60 years of age are not considered as a conferring a positive family history.

#### **3.6. Polyposis syndromes**

While the exact genetic predisposition for the majority of colon cancer remains unknown, there are several well-known (and identifiable) cancer syndromes that a clinician must take into account when making colon cancer screening advice. The most common of these is Familial Adenomatous Polyposis. It affects roughly 1 in 5,000-7,000 individuals and confers a 100% risk of eventual colorectal cancer, with the average age at diagnosis 40 (Bussey et al., 1978). These individuals should begin screening colonoscopy in adolescence (usually started 10-12 years old), and this should be repeated annually. Ultimately these patients should re‐ ceive prophylactic colectomy. Another such polyposis includes Attenuated Adenomatous Polyposis. As opposed to FAP (which involves hundreds to thousands of polyps diffusely spread throughout the colon), AAP is an oligopolyposis and typically involves <100 polyps. These polyps are more often right-sided and with a flat morphology. Patient's typically be‐ gin to have polyps appear in the 4th-5th decade of life and an average age of diagnosis of cancer at age 55 (Knudsen et al., 2003). Roughly 69% of patients with APP will eventually develop colon cancer. These patients should begin screening colonoscopy at age 25 and this should be repeated annually. Less common genetic polyposes a clinician may encounter in‐ volve: MUTYH-Associated Polyposis, Peutz-Jeghers Syndrome, and Juvenile Polyposis Syn‐ drome. MUTYH-Associated Polyposis is an autosomal recessive cancer syndrome (heterozygotes with one affected allele are at increased risk, but homozygotes show the larg‐ est increase in risk). Variations in phenotype have been described, from hundreds to thou‐ sands of polyps distributed throughout the colon. Lifetime prevalence of colon cancer is reported at 80% (Jenkins et al., 2006). These individuals should begin annual screening at age 18-20. Clinicians may also encounter Peutz-Jeghers Syndrome, which is an autosomal dominant disorder characterized by numerous hamartomatous polyps throughout the co‐ lon. These individuals carry a 39% lifetime risk of colon cancer and should have colonosco‐ py screening every 2-3 years beginning in their late teen years (McGarrity and Amos, 2006). Finally, pediatric clinicians may encounter Juvenile Polyposis, which is an autosomal domi‐ nant condition characterized by numerous polyps throughout the gastrointestinal tract. These individuals are often brought to the attention of a physician following an intestinal obstruction or gastrointestinal bleed as a consequence of the numerous polyps. These pa‐ tients carry a 10-38% lifetime colon cancer risk and should be screened annually beginning at age 15 (Howe et al., 1998; Jass et al., 1988).

is related to the severity of disease (in both Ulcerative Colitis, and Crohn's Disease). The cu‐ mulative risk of colon cancer among patients with ulcerative colitis (U.C.) is thought to be roughly 2% after 10-years of disease, and up to 18% after 30-years of disease (Eaden et al., 2001). Although Crohn's Disease (C.D.) classically involves the small intestine, it can also in‐ volve the large bowel, which confers an increased risk of colon cancer as well. Crohn's pa‐ tients with large intestinal involvement carry an 8.3% risk of colon cancer after 30 years of disease (Canavan et al., 2006). Currently, the recommendation is to begin screening both U.C. and C.D. patients 8-10 years post-diagnosis, and institute 1-2 year screening intervals.

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As touched on previously, equally important to the initiation of an effective screening pro‐ gram involves the optimal age to finish the screening process. The question could be posed: "Why stop screening at all if it is an effective means to prevent morbidity and mortality from colon cancer?" However several factors should be considered including the fact that colonoscopy is not entirely without risk. The known complications associated with colono‐ scopy (e.g. bleeding, perforation, infection, diverticulitis), occur particularly in the elderly population. Furthermore, and especially true with regard to colorectal cancer screening, there exists a potentially long latency period from adenoma to carcinoma which may take years and even decades in some individuals. Elderly patients with an adenoma seen on screening may, and oftentimes do, perish as a result of other disease processes. Finally, lim‐ ited resources must also be taken into account. Each and every colonoscopy takes a concert‐ ed effort from a skilled colonoscopist and their support staff, and the required financial means on the part of the patient and/or government. As such it is necessary to establish evi‐ dence-based guidelines on when patients can safely stop colon cancer screening. The follow‐ ing section will delve further into this topic and the current recommendations for age at

In general, colonoscopy is a relatively safe, well-tolerated procedure by patients. The majori‐ ty of patients will never experience any complications, even if undergoing multiple colonos‐ copies throughout their lifetime. There are, however, significant and life-threatening complications that can occur. Although rare, given the enormous number of colonoscopies performed annually, it is important to be cognizant of the associated complications. In 2010, an analysis was released tracking complications rates among 18 large studies and involving over 685,000 colonoscopies (Ko and Dominitz, 2010). The most common complication seen was lower gastrointestinal bleeding, at roughly 0.1-0.6%. Fortunately, the far majority of these were not mortal bleeds. However, as most colonoscopies are undertaken in the outpa‐ tient setting, gastrointestinal hemorrhage can develop into a life-threatening event very quickly in a non-monitored setting. Next most common, bowel perforation posed a risk of less than 0.3% (Ko and Dominitz, 2010). These most often occur following barotrauma or mechanical trauma to the bowel wall. Again, although exceedingly rare, a perforated bowel

**4. When to stop screening?**

which to stop screening.

**4.1. Complications from screening colonoscopy**

#### **3.7. Non-polyposis syndromes**

The most common hereditary colon cancer syndrome is Lynch Syndrome, or Hereditary Non-Polyposis Colorectal Cancer. This too is an autosomal dominant condition, which is characterized by numerous, proximal adenomas. Affected individuals carry a 48-68% risk of colon cancer by age 60, with the majority being diagnosed between age 40-50 (Mecklin et al., 2007). Even more importantly, adenomas associated with HNPCC are typically more ag‐ gressive and advance to carcinoma quicker than would be otherwise expected. As such, these individuals should begin screening at age 20, and this should be repeated every 1-3 years.

#### **3.8. CRC risk associated with Inflammatory Bowel Disease**

Nearly every clinician is sure to encounter a patient afflicted with Inflammatory Bowel Dis‐ ease (IBD). As such, it is important to recognize that these patients carry an increased risk for colon cancer, and they cannot be treated as average-risk individuals. The entity is refer‐ red to as Colitis-Associated Cancer, or CAC, and the resultant risk of eventual colon cancer is related to the severity of disease (in both Ulcerative Colitis, and Crohn's Disease). The cu‐ mulative risk of colon cancer among patients with ulcerative colitis (U.C.) is thought to be roughly 2% after 10-years of disease, and up to 18% after 30-years of disease (Eaden et al., 2001). Although Crohn's Disease (C.D.) classically involves the small intestine, it can also in‐ volve the large bowel, which confers an increased risk of colon cancer as well. Crohn's pa‐ tients with large intestinal involvement carry an 8.3% risk of colon cancer after 30 years of disease (Canavan et al., 2006). Currently, the recommendation is to begin screening both U.C. and C.D. patients 8-10 years post-diagnosis, and institute 1-2 year screening intervals.
