**2. Epidemiologic trends in colorectal cancer**

Worldwide CRC is the third most common cancer and fourth most common cause of death. Interestingly this disease affects men and women almost equally (Haggar and Boushey, 2009). In the United States CRC is the third most commonly diagnosed cancer and consti‐ tutes 10% of new cancers in men and women (Society, 2011). In 2011, there were approxi‐ mately 141,120 new cases and it is estimated that 143,460 Americans will be diagnosed with colorectal cancer in 2012 (NIH, 2009). Furthermore it is estimated up to 30% of new cases are found in the general population without known risk factors for this disease (Imperiale et al., 2000). Although there are still approximately one million new cases of CRC diagnosed each year, incidence has been steadily declining over the past 15 years (Bresalier, 2009; Ferlay et al., 2010; Kohler et al., 2011). In the United States mortality from CRC has also declined with a 7% decrease in men and 12% decrease in women between 1980 and 1990 (Jemal et al., 2008). Since 1990 decreases in CRC incidence and mortality have been even more substan‐

© 2013 Mone et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

tial, and is largely attributable to improvements in screening rates (Lieberman, 2010), espe‐ cially the growing use of colonoscopy procedures (Edwards et al., 2010). Nevertheless, important trends remain in the worldwide epidemiology of CRC.

**2.2. Racial and ethnic variations**

**2.3. The gender gap**

blacks at the age of 45 (Cash et al., 2010; Rex et al., 2009).

fied based on gender (Levin et al., 2008).

**2.4. Modifiers of the epidemiologic trends**

There is substantial evidence demonstrating racial disparities in CRC risk particularly for black men. In the USA this group has been found to have 20% higher incidence rate and 45% higher mortality rate from colorectal cancer compared to whites (Jemal et al., 2008; Wallace and Suzuki, 2012). There are also significant differences in life expectancy among blacks compared to whites. While there was a 39% reduction in mortality rate for white men between 1960-2005, during the same period there was a dramatic 28% increase in mortality for black men (Soneji et al., 2010). Of note incidence rates among other racial groups including Hispanics, Asian Amer‐ icans, and American Indians are lower than those among whites. The factors that underlie these differences have not been fully elucidated but most likely encompass both modifiable factors (e.g. smoking, socioeconomic status, body mass index, and cultural beliefs) as well as non-modifiable factors (e.g. race/ethnicity, gender, and genetic predisposition). These findings do suggest there is a need for appropriate risk stratification for CRC and for more aggressive screening in high-risk populations, particularly among blacks in the United States. Such an ap‐ proach has been recommended by both the American College of Gastroenterology as well as the American Society for Gastrointestinal Endoscopy with the suggestion to start screening

Issues in Screening and Surveillance Colonoscopy

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

27

According to SEER 2012 statistics, the overall prevalence of colorectal cancer does not vary substantially between the genders. The lifetime risk of being diagnosed with CRC is similar for men 5.7% and women 5.2%. The lifetime risk of dying from CRC is also similar; 2.3% and 2.1% for men and women respectively (NIH, 2009). Even though annually the new diagno‐ ses of CRC have roughly been equal in men (187,973) and women (185,983), men have high‐ er age-adjusted CRC incidence rates (Abotchie et al., 2012). Women seem have a delay of approximately 7-8 years in the development of advanced polyps (Jaroslaw Regula, 2012; Lie‐ berman et al., 2005). Additionally age adjusted mortality rates can be up to 35-40% higher in men compared to women (CDC, 2011). Gender related disparities are not completely under‐ stood but may be attributable to variations in hormonal exposure (Chlebowski et al., 2004). These biological differences related to sex raise the issue of whether men and women should be screened differently for CRC. However current screening guidelines have not been modi‐

Despite some overall gains, several factors remain that impact the epidemiology of CRC. Advancements in elucidating CRC pathogenesis allow for explanations of the above epide‐ miologic trends and have the potential for more efficient screening and treatment. It is esti‐ mated that up to 70% of CRC cases occur sporadically in individuals with no identifiable risks (Hardy et al., 2000). Factors that predispose individuals to a higher risk for developing CRC include any personal or family history of CRC or adenomatous polyps, inflammatory bowel disease (IBD), and inherited genetic syndromes such as familial adenomatous polypo‐

#### **2.1. Geographic variations in CRC epidemiology**

There is significant diversity in colorectal cancer incidence worldwide. Surprisingly indus‐ trialized nations have a remarkably greater occurrence of CRC accounting for 63% of all cas‐ es. In fact CRC incidence rates range from more than 40 per 100,000 people in the United States, Australia, New Zealand, and Western Europe to less than 5 per 100,000 in Africa and parts of Asia. It is notable that the US is the only country with significantly declining CRC incidence rates for both genders, and this is most likely a reflection of better screening prac‐ tices and early prevention (Jemal et al., 2011).

While there is substantial disparity in CRC occurrence globally, CRC incidence has been in‐ creasing in places previously reporting low rates. For example the number of new CRC di‐ agnoses has been rising in a number of Asian countries that recently transitioned from lowincome to high-income economies. Individuals residing in China, Japan, India, Singapore, and Eastern European countries were previously reported to have the lowest rates of CRC. Countries with the highest incidence rates include Australia, New Zealand, Canada, the United States, and parts of Europe, however incidence has started stabilizing and even de‐ clining in these regions (Haggar and Boushey, 2009; Jemal et al., 2010).

Interestingly CRC incidence seems to have a close association with location. In fact studies show that migrants rapidly acquire the risk patterns for CRC associated with their new sur‐ roundings. For example the incidence rates in Japanese immigrants have been found to sig‐ nificantly increase after moving to the United States. Geographic influence is also evident in a study done in Israel where male Jews of Western descent were found to have a higher like‐ lihood of developing CRC than those born in Africa or Asia. Furthermore environment may be responsible for variations within ethnic groups. This is demonstrated by higher rates of CRC among American Indians living in Alaska than those residing in the Southwest. Inci‐ dence rates among black males were found to range from 46.4 cases per 100,000 individuals in Arizona to 82.4 per 100,000 in Kentucky. In white men rates range from 44.4 per 100,000 in Utah to 68.7 per 100,000 in North Dakota (The Centers for Disease Control and Prevention [CDC], 2011).

The importance of location can also be seen by differences in CRC incidence within specific genders. CRC mortality rates for men are lower in Western states excluding Nevada, and higher in Southern and Midwestern states. These differences in CRC rates may be attributa‐ ble to regional variations in risk factors including diet and lifestyle as well as access to screening and treatment. In fact one study found that up to 43% of colorectal cancers are preventable through diet and lifestyle modifications (Perera P.S., 2012).

#### **2.2. Racial and ethnic variations**

tial, and is largely attributable to improvements in screening rates (Lieberman, 2010), espe‐ cially the growing use of colonoscopy procedures (Edwards et al., 2010). Nevertheless,

There is significant diversity in colorectal cancer incidence worldwide. Surprisingly indus‐ trialized nations have a remarkably greater occurrence of CRC accounting for 63% of all cas‐ es. In fact CRC incidence rates range from more than 40 per 100,000 people in the United States, Australia, New Zealand, and Western Europe to less than 5 per 100,000 in Africa and parts of Asia. It is notable that the US is the only country with significantly declining CRC incidence rates for both genders, and this is most likely a reflection of better screening prac‐

While there is substantial disparity in CRC occurrence globally, CRC incidence has been in‐ creasing in places previously reporting low rates. For example the number of new CRC di‐ agnoses has been rising in a number of Asian countries that recently transitioned from lowincome to high-income economies. Individuals residing in China, Japan, India, Singapore, and Eastern European countries were previously reported to have the lowest rates of CRC. Countries with the highest incidence rates include Australia, New Zealand, Canada, the United States, and parts of Europe, however incidence has started stabilizing and even de‐

Interestingly CRC incidence seems to have a close association with location. In fact studies show that migrants rapidly acquire the risk patterns for CRC associated with their new sur‐ roundings. For example the incidence rates in Japanese immigrants have been found to sig‐ nificantly increase after moving to the United States. Geographic influence is also evident in a study done in Israel where male Jews of Western descent were found to have a higher like‐ lihood of developing CRC than those born in Africa or Asia. Furthermore environment may be responsible for variations within ethnic groups. This is demonstrated by higher rates of CRC among American Indians living in Alaska than those residing in the Southwest. Inci‐ dence rates among black males were found to range from 46.4 cases per 100,000 individuals in Arizona to 82.4 per 100,000 in Kentucky. In white men rates range from 44.4 per 100,000 in Utah to 68.7 per 100,000 in North Dakota (The Centers for Disease Control and Prevention

The importance of location can also be seen by differences in CRC incidence within specific genders. CRC mortality rates for men are lower in Western states excluding Nevada, and higher in Southern and Midwestern states. These differences in CRC rates may be attributa‐ ble to regional variations in risk factors including diet and lifestyle as well as access to screening and treatment. In fact one study found that up to 43% of colorectal cancers are

important trends remain in the worldwide epidemiology of CRC.

clining in these regions (Haggar and Boushey, 2009; Jemal et al., 2010).

preventable through diet and lifestyle modifications (Perera P.S., 2012).

**2.1. Geographic variations in CRC epidemiology**

26 Colonoscopy and Colorectal Cancer Screening - Future Directions

tices and early prevention (Jemal et al., 2011).

[CDC], 2011).

There is substantial evidence demonstrating racial disparities in CRC risk particularly for black men. In the USA this group has been found to have 20% higher incidence rate and 45% higher mortality rate from colorectal cancer compared to whites (Jemal et al., 2008; Wallace and Suzuki, 2012). There are also significant differences in life expectancy among blacks compared to whites. While there was a 39% reduction in mortality rate for white men between 1960-2005, during the same period there was a dramatic 28% increase in mortality for black men (Soneji et al., 2010). Of note incidence rates among other racial groups including Hispanics, Asian Amer‐ icans, and American Indians are lower than those among whites. The factors that underlie these differences have not been fully elucidated but most likely encompass both modifiable factors (e.g. smoking, socioeconomic status, body mass index, and cultural beliefs) as well as non-modifiable factors (e.g. race/ethnicity, gender, and genetic predisposition). These findings do suggest there is a need for appropriate risk stratification for CRC and for more aggressive screening in high-risk populations, particularly among blacks in the United States. Such an ap‐ proach has been recommended by both the American College of Gastroenterology as well as the American Society for Gastrointestinal Endoscopy with the suggestion to start screening blacks at the age of 45 (Cash et al., 2010; Rex et al., 2009).

#### **2.3. The gender gap**

According to SEER 2012 statistics, the overall prevalence of colorectal cancer does not vary substantially between the genders. The lifetime risk of being diagnosed with CRC is similar for men 5.7% and women 5.2%. The lifetime risk of dying from CRC is also similar; 2.3% and 2.1% for men and women respectively (NIH, 2009). Even though annually the new diagno‐ ses of CRC have roughly been equal in men (187,973) and women (185,983), men have high‐ er age-adjusted CRC incidence rates (Abotchie et al., 2012). Women seem have a delay of approximately 7-8 years in the development of advanced polyps (Jaroslaw Regula, 2012; Lie‐ berman et al., 2005). Additionally age adjusted mortality rates can be up to 35-40% higher in men compared to women (CDC, 2011). Gender related disparities are not completely under‐ stood but may be attributable to variations in hormonal exposure (Chlebowski et al., 2004). These biological differences related to sex raise the issue of whether men and women should be screened differently for CRC. However current screening guidelines have not been modi‐ fied based on gender (Levin et al., 2008).

#### **2.4. Modifiers of the epidemiologic trends**

Despite some overall gains, several factors remain that impact the epidemiology of CRC. Advancements in elucidating CRC pathogenesis allow for explanations of the above epide‐ miologic trends and have the potential for more efficient screening and treatment. It is esti‐ mated that up to 70% of CRC cases occur sporadically in individuals with no identifiable risks (Hardy et al., 2000). Factors that predispose individuals to a higher risk for developing CRC include any personal or family history of CRC or adenomatous polyps, inflammatory bowel disease (IBD), and inherited genetic syndromes such as familial adenomatous polypo‐ sis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC). Guidelines recommend ear‐ lier and more aggressive screening for this high-risk population.

ciated with considerable reductions in CRC (Rex et al., 2009; Winawer et al., 1993b), and has

Issues in Screening and Surveillance Colonoscopy

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29

Although it is difficult to identify precisely which adenomas will undergo neoplastic trans‐ formation, there are certain pathologic features that can help predict their level of risk: in‐ creased size ≥10 mm, increased number of 3 or more adenomas, villous histology, and highgrade dysplasia (Alberti et al., 2012; Lieberman et al., 2012). Most adenomas undergo a similar progression to invasive cancer termed the adenoma-carcinoma sequence (Levin et al., 2008; Sano et al., 2009). Given that these cancer precursors are often asymptomatic, there is compelling evidence to support early screening for healthy individuals. In fact the aver‐ age-risk individuals compose 70-75% of the CRC population (Lieberman, 2010). In response to mounting evidence suggesting that screening of average-risk individuals allows for early cancer detection and prevention, CRC guidelines from several organizations were updated

Colonoscopy allows for the direct visualization of the entire colon and for the potential to remove lesions that are identified. Results from the National Polyp Study confirm that colo‐ noscopy and adenoma removal is associated with decreased rates of developing colon can‐ cer in the future (Winawer S.J., 2006) and reduces mortality (Zauber et al., 2012). The finding that mortality is reduced by polypectomy is of major significance because it suggests that colonoscopy can identify a subset of adenomas which can potentially become aggressive cancers and provides further evidence that colonoscopy is in fact the best screening option because of its added benefit of decreased mortality, particularly in individuals at increased risk. In patients with no lesions detected during a screening colonoscopic examination, the interval for follow-up surveillance can be extended to 10 years compared to 5 years for sig‐ moidoscopy (which visualizes only the left side of the colon) along with FOBT every 3 years. The known draw backs to colonoscopy include the need for bowel prep, sedation that may be associated with cardiopulmonary risks, higher cost compared to other methods, associa‐ tion with greater risk of bleeding and perforation, and a miss rate of up to 5% for malignant

While colonoscopy remains the gold standard for CRC prevention, economic constraints and patient attitudes may prevent screening with this technique. In an effort to improve participation alternative tests have been endorsed. There are a range of screening meth‐ ods that are categorized into two major groups, prevention and detection. Prevention tests detect cancer as well as pre-cancerous polyps, and are generally structural exams such as the colonoscopy, flexible sigmoidoscopy, CT colonography, and double-contrast barium enema. Detection tests are only able to identify CRC lesions and consist of fecal tests in‐ cluding the fecal immunochemical test (FIT), fecal occult blood testing (FOBT), and Fecal

Flexible Sigmoidoscopy remains an acceptable alternative to colonoscopy for colorectal can‐ cer screening (Levin et al., 2008; USPSTF, 2008; Winawer et al., 2003; Winawer et al., 1997). Although both screening techniques are similar, sigmoidoscopy requires more frequent

now been demonstrated to have mortality benefit (Zauber et al., 2012).

in 2008 (USPSTF, 2008).

**2.6. CRC prevention tests**

colon lesions.

DNA testing (Rex et al., 2009).

As evidenced by the presence of both modifiable and non-modifiable risk factors, the patho‐ genesis of CRC seems to be influenced by a combination of genetics and the environment. In‐ deed the disease results from the progressive accumulation of both genetic as well as epigenetic changes in the colonic epithelium. Currently genetic tests are available that identify patients with inherited mutations associated with FAP and HNPCC. While this technology is promising, only 2-6% of CRC cases are attributable to common inherited mutations, suggest‐ ing other variables are playing a role in the development of this disease (Winawer et al., 2003).

Some of the environmental influences that have been investigated include the role of Strepto‐ coccus Bovis. Although infections are recognized as a major preventable cause in cancer, an in‐ fectious etiology has not been identified in cases of sporadic CRC, strongly suggesting that more factors are involved in the development of this disease (Boleij and Tjalsma, 2012). Similar to many other cancers, an important common thread in the pathogenesis of CRC is the pres‐ ence of chronic inflammation that is thought to increase the probability of mutagenic events that lead to the production of oxidative species and damage DNA causing genomic instability (Zauber et al., 2008). This is demonstrated by patients with inherited genetic mutations who are found on colonoscopic examination to have chronic inflammatory changes that precede tu‐ mor development (Terzic et al., 2010). This can also be seen in patients colonized with S. Bovis who are found to have inflammatory changes in the bowel wall (Terzic et al., 2010). Further support for an inflammatory basis is found in recent studies showing aspirin and non-steroi‐ dal, anti-inflammatory drugs greatly reduce the risk of CRC (Rothwell et al., 2012).

#### **2.5. Impact of screening on the epidemiology of CRC**

Numerous studies show favorable CRC outcomes if the cancer is identified and treated at an early stage. In fact the 5-year survival rate is greater than 90% if CRC is identified at an early stage. However if the cancer extends beyond the colon, 5-year survival is less than 10% (Col‐ lett et al., 1999). Continuing advances in CRC therapies hold the promise of adequate treat‐ ment for advanced stages of the disease. A recent study in Nature suggests the possibility of helping patients with advanced stage CRC with targeted drugs. This study suggests that there are a finite number of genetic pathways in CRC that can be therapeutically targeted. Although these findings are promising much work is still needed before there will be a cure for CRC (Muzny et al., 2012).

Given the limited effective treatment for advanced CRC, prevention through early detection is paramount. CRC is a model disease for routine population screening since it is prevalent, has a long asymptomatic period, and precancerous lesions can be identified and treated (Pezzoli et al., 2007). Compared to other cancers where the primary goal is early detection of neoplasia, CRC can actually be prevented with detection and removal of cancer precursor lesions (Inadomi et al., 2012). It is estimated that 30% of people over the age of 50 with no history of CRC risk factors harbor adenomatous polyps (Alberti et al., 2012; Pezzoli et al., 2007), and the incidence of these polyps increases with age. Early adenoma resection is asso‐ ciated with considerable reductions in CRC (Rex et al., 2009; Winawer et al., 1993b), and has now been demonstrated to have mortality benefit (Zauber et al., 2012).

Although it is difficult to identify precisely which adenomas will undergo neoplastic trans‐ formation, there are certain pathologic features that can help predict their level of risk: in‐ creased size ≥10 mm, increased number of 3 or more adenomas, villous histology, and highgrade dysplasia (Alberti et al., 2012; Lieberman et al., 2012). Most adenomas undergo a similar progression to invasive cancer termed the adenoma-carcinoma sequence (Levin et al., 2008; Sano et al., 2009). Given that these cancer precursors are often asymptomatic, there is compelling evidence to support early screening for healthy individuals. In fact the aver‐ age-risk individuals compose 70-75% of the CRC population (Lieberman, 2010). In response to mounting evidence suggesting that screening of average-risk individuals allows for early cancer detection and prevention, CRC guidelines from several organizations were updated in 2008 (USPSTF, 2008).

#### **2.6. CRC prevention tests**

sis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC). Guidelines recommend ear‐

As evidenced by the presence of both modifiable and non-modifiable risk factors, the patho‐ genesis of CRC seems to be influenced by a combination of genetics and the environment. In‐ deed the disease results from the progressive accumulation of both genetic as well as epigenetic changes in the colonic epithelium. Currently genetic tests are available that identify patients with inherited mutations associated with FAP and HNPCC. While this technology is promising, only 2-6% of CRC cases are attributable to common inherited mutations, suggest‐ ing other variables are playing a role in the development of this disease (Winawer et al., 2003). Some of the environmental influences that have been investigated include the role of Strepto‐ coccus Bovis. Although infections are recognized as a major preventable cause in cancer, an in‐ fectious etiology has not been identified in cases of sporadic CRC, strongly suggesting that more factors are involved in the development of this disease (Boleij and Tjalsma, 2012). Similar to many other cancers, an important common thread in the pathogenesis of CRC is the pres‐ ence of chronic inflammation that is thought to increase the probability of mutagenic events that lead to the production of oxidative species and damage DNA causing genomic instability (Zauber et al., 2008). This is demonstrated by patients with inherited genetic mutations who are found on colonoscopic examination to have chronic inflammatory changes that precede tu‐ mor development (Terzic et al., 2010). This can also be seen in patients colonized with S. Bovis who are found to have inflammatory changes in the bowel wall (Terzic et al., 2010). Further support for an inflammatory basis is found in recent studies showing aspirin and non-steroi‐

dal, anti-inflammatory drugs greatly reduce the risk of CRC (Rothwell et al., 2012).

Numerous studies show favorable CRC outcomes if the cancer is identified and treated at an early stage. In fact the 5-year survival rate is greater than 90% if CRC is identified at an early stage. However if the cancer extends beyond the colon, 5-year survival is less than 10% (Col‐ lett et al., 1999). Continuing advances in CRC therapies hold the promise of adequate treat‐ ment for advanced stages of the disease. A recent study in Nature suggests the possibility of helping patients with advanced stage CRC with targeted drugs. This study suggests that there are a finite number of genetic pathways in CRC that can be therapeutically targeted. Although these findings are promising much work is still needed before there will be a cure

Given the limited effective treatment for advanced CRC, prevention through early detection is paramount. CRC is a model disease for routine population screening since it is prevalent, has a long asymptomatic period, and precancerous lesions can be identified and treated (Pezzoli et al., 2007). Compared to other cancers where the primary goal is early detection of neoplasia, CRC can actually be prevented with detection and removal of cancer precursor lesions (Inadomi et al., 2012). It is estimated that 30% of people over the age of 50 with no history of CRC risk factors harbor adenomatous polyps (Alberti et al., 2012; Pezzoli et al., 2007), and the incidence of these polyps increases with age. Early adenoma resection is asso‐

**2.5. Impact of screening on the epidemiology of CRC**

for CRC (Muzny et al., 2012).

lier and more aggressive screening for this high-risk population.

28 Colonoscopy and Colorectal Cancer Screening - Future Directions

Colonoscopy allows for the direct visualization of the entire colon and for the potential to remove lesions that are identified. Results from the National Polyp Study confirm that colo‐ noscopy and adenoma removal is associated with decreased rates of developing colon can‐ cer in the future (Winawer S.J., 2006) and reduces mortality (Zauber et al., 2012). The finding that mortality is reduced by polypectomy is of major significance because it suggests that colonoscopy can identify a subset of adenomas which can potentially become aggressive cancers and provides further evidence that colonoscopy is in fact the best screening option because of its added benefit of decreased mortality, particularly in individuals at increased risk. In patients with no lesions detected during a screening colonoscopic examination, the interval for follow-up surveillance can be extended to 10 years compared to 5 years for sig‐ moidoscopy (which visualizes only the left side of the colon) along with FOBT every 3 years. The known draw backs to colonoscopy include the need for bowel prep, sedation that may be associated with cardiopulmonary risks, higher cost compared to other methods, associa‐ tion with greater risk of bleeding and perforation, and a miss rate of up to 5% for malignant colon lesions.

While colonoscopy remains the gold standard for CRC prevention, economic constraints and patient attitudes may prevent screening with this technique. In an effort to improve participation alternative tests have been endorsed. There are a range of screening meth‐ ods that are categorized into two major groups, prevention and detection. Prevention tests detect cancer as well as pre-cancerous polyps, and are generally structural exams such as the colonoscopy, flexible sigmoidoscopy, CT colonography, and double-contrast barium enema. Detection tests are only able to identify CRC lesions and consist of fecal tests in‐ cluding the fecal immunochemical test (FIT), fecal occult blood testing (FOBT), and Fecal DNA testing (Rex et al., 2009).

Flexible Sigmoidoscopy remains an acceptable alternative to colonoscopy for colorectal can‐ cer screening (Levin et al., 2008; USPSTF, 2008; Winawer et al., 2003; Winawer et al., 1997). Although both screening techniques are similar, sigmoidoscopy requires more frequent screenings at 5–year intervals and the benefits are confined to the distal colon only. In addi‐ tion the USPSTF recommends screening with FOBT every 3 years (USPSTF, 2008). Prior studies have demonstrated a significant mortality benefit for the section of the colon exam‐ ined (Wilkins and Reynolds, 2008). A recent study in the NEJM confirmed this data showing that flexible sigmoidoscopy decreases CRC incidence and mortality (Schoen et al., 2012). The advantages of sigmoidoscopy include lower cost, lower risk profile, and need for less bowel preparation compared to colonoscopy. However a major setback for this alternative is that polyp visualization is limited to the distal colon. Studies have shown that up to 30% of pa‐ tients with distal colon cancer also have synchronous proximal lesions that will be missed by sigmoidoscopy (Francois et al., 2006; Imperiale et al., 2000; Lieberman et al., 2000). As such individuals with polyps in the distal colon should undergo follow up with colonosco‐ py given the increased prevalence of synchronous right-sided lesions. Screening only 50% of colon will preclude detection of the lesions in the portion of the colon not within reach of the sigmoidoscope. This test would also not be an appropriate screening tool for women, pa‐ tients over the age of 60, patients with HIV, and African Americans who have a higher like‐ lihood of harboring proximal polyps (Bini et al., 2006; Lieberman et al., 2000; Lieberman et al., 2005; Schoenfeld et al., 2005).

**2.7. CRC detection tests**

Reynolds, 2008).

Fecal occult blood testing (FOBT) is an annual stool test that detects cancer at an early stage. The USPSTF now specifically recommends the high-sensitivity guaiac-based testing (He‐ moccult Sensa) over the standard guaiac-based testing (Hemoccult II) (USPSTF, 2008). Based on the premise that colon cancer intermittently bleeds, the FOBT tests for blood by detecting the peroxidase activity of heme (Lieberman, 2010). Not only is the test economical and con‐ venient, patients with a positive test result have an almost 4 fold increased likelihood having cancer (Winawer et al., 2003). In fact studies have found FOBT reduces mortality by approxi‐ mately 33% over a 10-year period (Lieberman, 2010). Another study reported approximately 20% reduction in mortality when FOBT was compared to controls over an 18-year period (Lieberman, 2010). Supporters of the FOBT question whether invasive measures such as the colonoscopy are harmful given that computer simulated modeling shows similar life-years gained in both tests (Zauber et al., 2008). Furthermore advocates assert that FOBT has the greatest potential for impact at the population level because it is directed at healthy people (Harvard Medical School, 2012). Additionally asymptomatic people may be more willing to

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31

While a case can be made that FOBT has some quantifiable mortality benefits, evidence sug‐ gests that colonoscopy is still the superior screening option. FOBT has many disadvantages. One major drawback of this modality is the high false positive rate because the test is not specific for human blood. In fact the test will not be accurate if patients consume red meat or any other peroxidase containing substances. Additionally three-stool sample are required on separate days (Lieberman, 2010). Single sample FOBT is estimated to miss 95% of CRC (Wil‐ kins and Reynolds, 2008). Furthermore the test must be repeated annually to be effective. In addition to these drawbacks, this test only detects potentially high-risk individuals which means that abnormal test results require subsequent follow up with colonoscopy. Compli‐ ance with all of the aforementioned recommendations is unknown making the effectiveness of the test uncertain. In fact one survey found that up to 30% of doctors recommended inap‐ propriate forms of follow up rendering the FOBT not useful (Nadel et al., 2005). Despite

these drawbacks the FOBT sampling test is still preferable to the no screening option.

Fecal immunochemical testing (FIT) is a newer test that is easier to use and specific for hu‐ mans. This means that the FIT is less susceptible to interference by diet or drugs. This mo‐ dality uses antibodies to detect human blood components such as hemoglobin and albumin in stool samples (School, 2012). This alternative is appealing because it is less invasive than colonoscopy but potentially more accurate than the FOBT. Studies show over 50% sensitivi‐ ty for cancer after using as small an amount as one stool sample (Lieberman, 2010). FIT may be superior to the FOBT given that one study showed higher participation in the FIT group. Participation is key for fecal tests making the previously mentioned study clinically rele‐ vant. However no randomized trials have shown that FIT decreases mortality (Wilkins and

Given that participation may be negatively impacted by hesitation to undergo colonoscopy screening, a recent study investigated whether FIT can serve as a valid screening alternative and no significant differences were found between FIT and colonoscopy in terms of partici‐

participate in a less invasive and generally less inconvenient test.

Double contrast Barium enema allows for visualization of the entire colon and must be com‐ pleted every 5 years. Its high polyp miss rate (as high as 23%), lack of therapeutic interven‐ tion (another procedure is needed to remove detected polyps), and concerns regarding radiation exposure, have limited its use (Toma et al., 2008; Wilkins and Reynolds, 2008).

CT colonography is able to provide information about the entire colon and has been pro‐ posed as a possible screening option for patients who decline conventional colonoscopy. This test is less invasive compared to conventional colonoscopy, is associated with de‐ creased risk of perforation and does not require sedation (Lieberman, 2010). Not only are de‐ tection rates far superior to the barium enema, but CT colonography (CTC) has comparable sensitivity to colonoscopy for polyps 10mm or greater in size (Johnson et al., 2008). However relative to other options, this modality is costly, and has poor sensitivity for polyps less than 7mm (Lieberman, 2010). Due to insufficient evidence for performance metrics this test is cur‐ rently not supported by established guidelines. The United States Preventive Services Task Force expresses additional concern about the impact and extra costs related to following-up extra-colonic findings (USPSTF, 2008). In fact an estimated 27% to 69% of tests performed uncover abnormal extra-colonic findings (Lieberman, 2010). More studies are needed to as‐ sess this procedure's benefits and risks, particularly to determine whether this method may be missing significant lesions.

Capsule Endoscopy provides direct visualization of the colonic mucosa via an ingestible capsule with video cameras at both ends that wireless transmits images to a receiver. Given that bowel motility significantly affects results, this test is not performed regularly and is not supported by current guidelines.

#### **2.7. CRC detection tests**

screenings at 5–year intervals and the benefits are confined to the distal colon only. In addi‐ tion the USPSTF recommends screening with FOBT every 3 years (USPSTF, 2008). Prior studies have demonstrated a significant mortality benefit for the section of the colon exam‐ ined (Wilkins and Reynolds, 2008). A recent study in the NEJM confirmed this data showing that flexible sigmoidoscopy decreases CRC incidence and mortality (Schoen et al., 2012). The advantages of sigmoidoscopy include lower cost, lower risk profile, and need for less bowel preparation compared to colonoscopy. However a major setback for this alternative is that polyp visualization is limited to the distal colon. Studies have shown that up to 30% of pa‐ tients with distal colon cancer also have synchronous proximal lesions that will be missed by sigmoidoscopy (Francois et al., 2006; Imperiale et al., 2000; Lieberman et al., 2000). As such individuals with polyps in the distal colon should undergo follow up with colonosco‐ py given the increased prevalence of synchronous right-sided lesions. Screening only 50% of colon will preclude detection of the lesions in the portion of the colon not within reach of the sigmoidoscope. This test would also not be an appropriate screening tool for women, pa‐ tients over the age of 60, patients with HIV, and African Americans who have a higher like‐ lihood of harboring proximal polyps (Bini et al., 2006; Lieberman et al., 2000; Lieberman et

Double contrast Barium enema allows for visualization of the entire colon and must be com‐ pleted every 5 years. Its high polyp miss rate (as high as 23%), lack of therapeutic interven‐ tion (another procedure is needed to remove detected polyps), and concerns regarding radiation exposure, have limited its use (Toma et al., 2008; Wilkins and Reynolds, 2008).

CT colonography is able to provide information about the entire colon and has been pro‐ posed as a possible screening option for patients who decline conventional colonoscopy. This test is less invasive compared to conventional colonoscopy, is associated with de‐ creased risk of perforation and does not require sedation (Lieberman, 2010). Not only are de‐ tection rates far superior to the barium enema, but CT colonography (CTC) has comparable sensitivity to colonoscopy for polyps 10mm or greater in size (Johnson et al., 2008). However relative to other options, this modality is costly, and has poor sensitivity for polyps less than 7mm (Lieberman, 2010). Due to insufficient evidence for performance metrics this test is cur‐ rently not supported by established guidelines. The United States Preventive Services Task Force expresses additional concern about the impact and extra costs related to following-up extra-colonic findings (USPSTF, 2008). In fact an estimated 27% to 69% of tests performed uncover abnormal extra-colonic findings (Lieberman, 2010). More studies are needed to as‐ sess this procedure's benefits and risks, particularly to determine whether this method may

Capsule Endoscopy provides direct visualization of the colonic mucosa via an ingestible capsule with video cameras at both ends that wireless transmits images to a receiver. Given that bowel motility significantly affects results, this test is not performed regularly and is not

al., 2005; Schoenfeld et al., 2005).

30 Colonoscopy and Colorectal Cancer Screening - Future Directions

be missing significant lesions.

supported by current guidelines.

Fecal occult blood testing (FOBT) is an annual stool test that detects cancer at an early stage. The USPSTF now specifically recommends the high-sensitivity guaiac-based testing (He‐ moccult Sensa) over the standard guaiac-based testing (Hemoccult II) (USPSTF, 2008). Based on the premise that colon cancer intermittently bleeds, the FOBT tests for blood by detecting the peroxidase activity of heme (Lieberman, 2010). Not only is the test economical and con‐ venient, patients with a positive test result have an almost 4 fold increased likelihood having cancer (Winawer et al., 2003). In fact studies have found FOBT reduces mortality by approxi‐ mately 33% over a 10-year period (Lieberman, 2010). Another study reported approximately 20% reduction in mortality when FOBT was compared to controls over an 18-year period (Lieberman, 2010). Supporters of the FOBT question whether invasive measures such as the colonoscopy are harmful given that computer simulated modeling shows similar life-years gained in both tests (Zauber et al., 2008). Furthermore advocates assert that FOBT has the greatest potential for impact at the population level because it is directed at healthy people (Harvard Medical School, 2012). Additionally asymptomatic people may be more willing to participate in a less invasive and generally less inconvenient test.

While a case can be made that FOBT has some quantifiable mortality benefits, evidence sug‐ gests that colonoscopy is still the superior screening option. FOBT has many disadvantages. One major drawback of this modality is the high false positive rate because the test is not specific for human blood. In fact the test will not be accurate if patients consume red meat or any other peroxidase containing substances. Additionally three-stool sample are required on separate days (Lieberman, 2010). Single sample FOBT is estimated to miss 95% of CRC (Wil‐ kins and Reynolds, 2008). Furthermore the test must be repeated annually to be effective. In addition to these drawbacks, this test only detects potentially high-risk individuals which means that abnormal test results require subsequent follow up with colonoscopy. Compli‐ ance with all of the aforementioned recommendations is unknown making the effectiveness of the test uncertain. In fact one survey found that up to 30% of doctors recommended inap‐ propriate forms of follow up rendering the FOBT not useful (Nadel et al., 2005). Despite these drawbacks the FOBT sampling test is still preferable to the no screening option.

Fecal immunochemical testing (FIT) is a newer test that is easier to use and specific for hu‐ mans. This means that the FIT is less susceptible to interference by diet or drugs. This mo‐ dality uses antibodies to detect human blood components such as hemoglobin and albumin in stool samples (School, 2012). This alternative is appealing because it is less invasive than colonoscopy but potentially more accurate than the FOBT. Studies show over 50% sensitivi‐ ty for cancer after using as small an amount as one stool sample (Lieberman, 2010). FIT may be superior to the FOBT given that one study showed higher participation in the FIT group. Participation is key for fecal tests making the previously mentioned study clinically rele‐ vant. However no randomized trials have shown that FIT decreases mortality (Wilkins and Reynolds, 2008).

Given that participation may be negatively impacted by hesitation to undergo colonoscopy screening, a recent study investigated whether FIT can serve as a valid screening alternative and no significant differences were found between FIT and colonoscopy in terms of partici‐ pation (Quintero et al., 2012). Furthermore colonoscopy still detected substantially higher numbers of cancerous polyps. It is difficult from this study to declare that FIT testing is noninferior because of colonoscopy's mortality benefit.

greatest benefit. Several models have been proposed to estimate the costs of various screen‐ ing programs. The 2005 Institute of Medicine comprehensive summary of CRC screening ef‐ fectiveness concluded that all of the screening options are relatively comparable in terms of life-years gained as well as cost when compared with a no-screening option. FOBT was the least costly option, however most modalities are estimated to cost <\$40,000 per life-year saved (Lieberman, 2010; Pignone et al., 2002). However it is difficult to rely on these models alone as they may not be entirely accurate and are not able to account for other factors such as patient compliance. In general cost benefit analysis studies suggest that CRC screening is overall a cost-effective measure and it is estimated that routine screening can save more

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33

Currently the United States Multi-Society Task Force (MSTF) on CRC supports a 10-year inter‐ val between subsequent screening colonoscopies for average risk patients. Case-control and observational studies indicate that the mortality benefit from colonoscopy lasts at least 10 years. However patients who are found to have adenomas on baseline colonoscopy are at in‐ creased risk of developing future adenomas and cancerous lesions (Martinez et al., 2009). Cer‐ tain higher-risk patients can develop cancer as soon as 3-5 years after a colonoscopy. These are termed interval cancers. These patients require a shorter interval between subsequent follow up because this has been shown to reduce colorectal cancer incidence by as much as 66% (Cit‐ arda et al., 2001; Winawer et al., 1993a). Guidelines from the GI consortium panel advocate re‐ peat colonoscopy 5 years after removal of a low-risk polyp and after 3 years if the polyp has higher risk features. The selection of a 3-year screening interval for subsequent follow-up is based on evidence that shows detection of advanced lesions is not improved at 1 year versus 3 years (Winawer et al., 1993b). Further research is still needed to determine whether a single

The use of risk stratification to determine the optimal screening interval is important be‐ cause physicians that refer patients for surveillance at intervals shorter than recommended may be exposing patients to unnecessary risks and costs (Lieberman, 2010). In fact a recent study revealed underuse of colonoscopies in high-risk patients and overuse in low risk pa‐ tients. By ineffective allocation of resources high-risk patients are placed at increased risk for developing cancer. Furthermore optimization of screening is important in light of low screening rates for a preventable cancer. Customized screening recommendations based on risk allows for more streamlined and effective screening leaving resources that can be devot‐ ed to colon cancer education targeting the challenging subset of the population at high risk with poor adherence. Ultimately screening program success depends not only on quality but patient participation (Lieberman et al., 2012). In addition to risk stratification, the MSTF on CRC believes that high-quality baseline examination is key for effective surveillance. In‐ terval cancers have been found to occur more frequently in patients with negative baseline exams. There is evidence to suggest that important lesions are often missed at baseline colo‐ noscopy and it is estimated that up to 17% of 10 mm lesions are missed. This variability in

than 18,800 lives per year (Maciosek et al., 2006; Wilkins and Reynolds, 2008).

negative follow up colonoscopy is sufficient (Lieberman et al., 2012).

**2.10. Surveillance guidelines**

Fecal DNA testing detects a finite number of gene mutations in stool samples associated with colon neoplasia (Alberti et al., 2012). One large prospective trial found stool DNA test‐ ing to have greater sensitivity for cancer than standard FOBT (Imperiale et al., 2004). Fur‐ thermore patients were found to prefer fecal DNA testing to both FOBT and colonoscopy (Wilkins and Reynolds, 2008). However this option is not recommended by current guide‐ lines because of insufficient evidence. Also there have been other studies comparing stool DNA testing to FOBT that suggest this fecal DNA testing does not measure up in terms of cost or efficacy (Lansdorp-Vogelaar et al., 2010).

#### **2.8. Which screening test should be done?**

Each of the aforementioned screening options has strengths and setbacks, however patient adherence to CRC screening remains more critical than the specific method chosen (Vijan et al., 2001). Simply put, the best test is the one that the patient accepts and complies with. De‐ spite mounting evidence that screening is life saving, screening rates remain surprisingly low for this preventable cancer. In fact awareness of the importance of CRC screening has only recently started to approach that of other cancers. Statistics indicate only 24% of Ameri‐ cans have completed the FOBT within the past few years and only 57.1% have ever had a sigmoidoscopy or colonoscopy (Wilkins and Reynolds, 2008). Data from the NHIS, a nation‐ al survey of the general population, shows that only 58.3% of the US population met recom‐ mendations for CRC screening in 2010 (Shapiro et al., 2012). This is increased from 54.5% in 2008. Although there has been progress in the use of CRC testing, 40-50% of individuals over the age of 50 still are not receiving routine screening for colorectal cancer.

It is apparent from these suboptimal screening rates that there is a demand for novel screen‐ ing strategies that are not only effective but also economical and non-invasive. Continued research in this field is ongoing and in a fascinating study published in *Gut*, Citarda et al (Citarda et al., 2001) took steps towards attempting to find this desired formula. Their study is evidence of the increasing knowledge about the molecular properties of cancer. Based on the theory that a specific cancer smell exists, they found that a trained labrador retriever could detect the presence of colorectal cancer with 91% sensitivity and 99% specificity in breath samples and 97% sensitivity and 99% specificity in watery stool samples. Surprising‐ ly the study dog's ability to detect cancer was not confounded by benign colorectal disease, inflammatory bowel disease, or smoking. Even though the routine use of canines for cancer screening is not practical, this study suggests there is potential for future screening tests based on cancer-specific chemical compounds.

#### **2.9. Cost effectiveness of CRC screening**

CRC screening has been found to reduce mortality and to be cost-effective. The challenge remains to make screening affordable and available to individuals who will experience the greatest benefit. Several models have been proposed to estimate the costs of various screen‐ ing programs. The 2005 Institute of Medicine comprehensive summary of CRC screening ef‐ fectiveness concluded that all of the screening options are relatively comparable in terms of life-years gained as well as cost when compared with a no-screening option. FOBT was the least costly option, however most modalities are estimated to cost <\$40,000 per life-year saved (Lieberman, 2010; Pignone et al., 2002). However it is difficult to rely on these models alone as they may not be entirely accurate and are not able to account for other factors such as patient compliance. In general cost benefit analysis studies suggest that CRC screening is overall a cost-effective measure and it is estimated that routine screening can save more than 18,800 lives per year (Maciosek et al., 2006; Wilkins and Reynolds, 2008).

#### **2.10. Surveillance guidelines**

pation (Quintero et al., 2012). Furthermore colonoscopy still detected substantially higher numbers of cancerous polyps. It is difficult from this study to declare that FIT testing is non-

Fecal DNA testing detects a finite number of gene mutations in stool samples associated with colon neoplasia (Alberti et al., 2012). One large prospective trial found stool DNA test‐ ing to have greater sensitivity for cancer than standard FOBT (Imperiale et al., 2004). Fur‐ thermore patients were found to prefer fecal DNA testing to both FOBT and colonoscopy (Wilkins and Reynolds, 2008). However this option is not recommended by current guide‐ lines because of insufficient evidence. Also there have been other studies comparing stool DNA testing to FOBT that suggest this fecal DNA testing does not measure up in terms of

Each of the aforementioned screening options has strengths and setbacks, however patient adherence to CRC screening remains more critical than the specific method chosen (Vijan et al., 2001). Simply put, the best test is the one that the patient accepts and complies with. De‐ spite mounting evidence that screening is life saving, screening rates remain surprisingly low for this preventable cancer. In fact awareness of the importance of CRC screening has only recently started to approach that of other cancers. Statistics indicate only 24% of Ameri‐ cans have completed the FOBT within the past few years and only 57.1% have ever had a sigmoidoscopy or colonoscopy (Wilkins and Reynolds, 2008). Data from the NHIS, a nation‐ al survey of the general population, shows that only 58.3% of the US population met recom‐ mendations for CRC screening in 2010 (Shapiro et al., 2012). This is increased from 54.5% in 2008. Although there has been progress in the use of CRC testing, 40-50% of individuals

It is apparent from these suboptimal screening rates that there is a demand for novel screen‐ ing strategies that are not only effective but also economical and non-invasive. Continued research in this field is ongoing and in a fascinating study published in *Gut*, Citarda et al (Citarda et al., 2001) took steps towards attempting to find this desired formula. Their study is evidence of the increasing knowledge about the molecular properties of cancer. Based on the theory that a specific cancer smell exists, they found that a trained labrador retriever could detect the presence of colorectal cancer with 91% sensitivity and 99% specificity in breath samples and 97% sensitivity and 99% specificity in watery stool samples. Surprising‐ ly the study dog's ability to detect cancer was not confounded by benign colorectal disease, inflammatory bowel disease, or smoking. Even though the routine use of canines for cancer screening is not practical, this study suggests there is potential for future screening tests

CRC screening has been found to reduce mortality and to be cost-effective. The challenge remains to make screening affordable and available to individuals who will experience the

over the age of 50 still are not receiving routine screening for colorectal cancer.

inferior because of colonoscopy's mortality benefit.

32 Colonoscopy and Colorectal Cancer Screening - Future Directions

cost or efficacy (Lansdorp-Vogelaar et al., 2010).

**2.8. Which screening test should be done?**

based on cancer-specific chemical compounds.

**2.9. Cost effectiveness of CRC screening**

Currently the United States Multi-Society Task Force (MSTF) on CRC supports a 10-year inter‐ val between subsequent screening colonoscopies for average risk patients. Case-control and observational studies indicate that the mortality benefit from colonoscopy lasts at least 10 years. However patients who are found to have adenomas on baseline colonoscopy are at in‐ creased risk of developing future adenomas and cancerous lesions (Martinez et al., 2009). Cer‐ tain higher-risk patients can develop cancer as soon as 3-5 years after a colonoscopy. These are termed interval cancers. These patients require a shorter interval between subsequent follow up because this has been shown to reduce colorectal cancer incidence by as much as 66% (Cit‐ arda et al., 2001; Winawer et al., 1993a). Guidelines from the GI consortium panel advocate re‐ peat colonoscopy 5 years after removal of a low-risk polyp and after 3 years if the polyp has higher risk features. The selection of a 3-year screening interval for subsequent follow-up is based on evidence that shows detection of advanced lesions is not improved at 1 year versus 3 years (Winawer et al., 1993b). Further research is still needed to determine whether a single negative follow up colonoscopy is sufficient (Lieberman et al., 2012).

The use of risk stratification to determine the optimal screening interval is important be‐ cause physicians that refer patients for surveillance at intervals shorter than recommended may be exposing patients to unnecessary risks and costs (Lieberman, 2010). In fact a recent study revealed underuse of colonoscopies in high-risk patients and overuse in low risk pa‐ tients. By ineffective allocation of resources high-risk patients are placed at increased risk for developing cancer. Furthermore optimization of screening is important in light of low screening rates for a preventable cancer. Customized screening recommendations based on risk allows for more streamlined and effective screening leaving resources that can be devot‐ ed to colon cancer education targeting the challenging subset of the population at high risk with poor adherence. Ultimately screening program success depends not only on quality but patient participation (Lieberman et al., 2012). In addition to risk stratification, the MSTF on CRC believes that high-quality baseline examination is key for effective surveillance. In‐ terval cancers have been found to occur more frequently in patients with negative baseline exams. There is evidence to suggest that important lesions are often missed at baseline colo‐ noscopy and it is estimated that up to 17% of 10 mm lesions are missed. This variability in adenoma detection rates may be attributable to biologic differences in missed adenomas or disparities in endoscopist proficiency.

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

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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

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,

than the above data suggests, and these groups will be detailed ahead.

focus on screening recommendations for the average-risk group.

**3.1. Distribution of colorectal cancer types**

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