**Colorectal Cancer**

Kouklakis S. Georgios and Asimenia D. Bampali

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53524

**1. Introduction**

#### **1.1. Epidemiology – Clinical presentation-screening**

Colorectal cancer (CRC) is a common and lethal disease. The risk of developing CRC is influenced by both environmental and genetic factors. Colorectal cancer is the third most common cancer worldwide. Clinical symptoms develop late in the course of the disease, and precursor lesions (adenomas) can be easily detected and removed. The disease is a candidate for early detection and prevention by screening. The epidemiology of CRC and risk factors for its development will be discussed here.

**Epidemiology** — CRC incidence and mortality rates vary markedly around the world [1]. Globally, CRC is the third most commonly diagnosed cancer in males and the second in females, with over 1.2 million new cases and 608,700 deaths estimated to have occurred in 2008.Incidence and mortality rates are substantially higher in males than in females [2]. It is the fourth most common cause of cancer death after lung, stomach, and liver cancer. It is more common in developed than developing countries.

In the United States, both the incidence and mortality have been slowly but steadily decreasing. Annually approximately 143,460 new cases of large bowel cancer are diagnosed, of which 103,170 are colon and the remainder rectal cancers. Annually, approximately 51,690 Americans die of CRC, accounting for approximately 9 percent of all cancer deaths [6].

**Incidence** — There is significant geographical variation in age-standardized and cumulative, 0-74 year incidence and mortality rates. Globally, the incidence of CRC varies over 10-fold. The highest incidence rates are in Australia and New Zealand, Europe and North America, and the lowest rates are found in Africa and South-Central Asia [5]. The highest incidence rate of CRC is estimated in the Czech Republic [39-42]. These geographic differences appear to be

attributable to differences in dietary and environmental exposures that are imposed upon a background of genetically determined susceptibility.

Colorectal cancer (CRC) is a disease with a major worldwide burden. The worldwide inci‐ dence of CRC is increasing. In 1975, the worldwide incidence of CRC was only 500,000.In western countries, some of the increase is due to the aging of the population. However, in countries with a low baseline rate of CRC, the incidence is increasing even after age-adjust‐ ment. Prior to 1985, the age-adjusted incidence of CRC in the USA also increased (figure 1). However, since this time the rates have declined an average of −1.6% per year. In the time period 1998–2005, the rate of decline accelerated; −2.8% per year in men and −2.3% per year in women. This reduction has been mainly confined to those of white race and is largely lim‐ ited to a decrease in the incidence of distal cancers. Although the cause of the decrease in incidence is unknown, and may have been influenced by many factors, it is likely that much may be attributable to screening by sigmoidoscopy and colonoscopy. In contrast, the inci‐ dence of proximal cancers has remained relatively stable over the same time period. Cur‐ rently, the overall probability of an individual developing CRC in the USA over a lifetime is

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From a population perspective, age is the most important risk factor for CRC. CRC is pre‐ dominantly a disease of older individuals. 90% of cases are diagnosed over the age of 50. The risk of CRC continues to increase with age (Figure 2). The incidence per 100,000 people age 80–84 is over seven times the incidence in people age 50–54. However, CRC can occur at any

In the USA, the risk of CRC differs by sex. The age-adjusted incidence of CRC is over 40% higher in men than women [8]. Overall, the incidence of CRC in men is 61 per 100,000 males as compared to 45 per 100,000 females. In addition, the ratio of colon to rectal cancer differs by sex; the ratio of colon to rectal cases for women is 3:1 as compared to 2:1 for males.

Race and ethnicity influence CRC risk [20]. Ashkenazi Jewish individuals appear to be at a slightly increased risk of CRC. At least part of this increased incidence may be due to a higher prevalence of the *I1307K* mutation of the adenomatous polyposis gene (*APC*), a mutation that confers an increased risk of CRC development (18–30% lifetime risk). The *I1307K* mutation is found in 6.1% of unselected Ashkenazi Jewish individuals and 28% of Jewish individuals with CRC, while the mutation is rare in other populations. In the USA, the incidence of CRC is higher in African Americans of either sex as compared to white Americans. Asian American/ Pacific Islanders, Native Americans, and Hispanic Americans experience a lower incidence of CRC than Caucasians (Table 1).African Americans have not experienced the substantial reduction in incidence of CRC found to have occurred in whites; prior to 1980 incidence in African Americans was actually lower than in white Americans. In African Americans, the

increased rate of cancer is predominantly due to a higher rate of proximal cancers.

There is substantial geographic variation in the incidence of CRC, with relatively high rates in North America, Western Europe, and Australia and relatively low rates in Africa and Asia (Figure 3) Such observations led to Burkitt's hypothesis; that dietary differences, specifically fiber and fat intake, between populations were responsible for the marked variation in rates of CRC found around the world. Burkitt observed that populations in low-risk areas of the third world had greater stool bulk, a faster colonic transit time, and higher dietary fiber intake

age and the incidence of CRC occurring before age 40 may be increasing.

5.5% in men and 5.1% in women.

In Europe, the incidence of colorectal cancer is increasing, particularly in Southern and Eastern Europe, where rates were originally lower than in Western Europe [7]. In the USA, incidence rose until the mid-1980s but in the last two decades the rates have fallen for both men and women. Countries that have had a rapid 'westernization' of diet, such as Japan, have seen a rapid increase in incidence of colorectal cancer. Consumption of meat and dairy products in Japan increased tenfold between the 1950s and 1990s.

**Figure 1.** Age-adjusted colorectal cancer incidence and death rates in the United States 1975–2006.

Colorectal cancer (CRC) is a disease with a major worldwide burden. The worldwide inci‐ dence of CRC is increasing. In 1975, the worldwide incidence of CRC was only 500,000.In western countries, some of the increase is due to the aging of the population. However, in countries with a low baseline rate of CRC, the incidence is increasing even after age-adjust‐ ment. Prior to 1985, the age-adjusted incidence of CRC in the USA also increased (figure 1). However, since this time the rates have declined an average of −1.6% per year. In the time period 1998–2005, the rate of decline accelerated; −2.8% per year in men and −2.3% per year in women. This reduction has been mainly confined to those of white race and is largely lim‐ ited to a decrease in the incidence of distal cancers. Although the cause of the decrease in incidence is unknown, and may have been influenced by many factors, it is likely that much may be attributable to screening by sigmoidoscopy and colonoscopy. In contrast, the inci‐ dence of proximal cancers has remained relatively stable over the same time period. Cur‐ rently, the overall probability of an individual developing CRC in the USA over a lifetime is 5.5% in men and 5.1% in women.

attributable to differences in dietary and environmental exposures that are imposed upon a

In Europe, the incidence of colorectal cancer is increasing, particularly in Southern and Eastern Europe, where rates were originally lower than in Western Europe [7]. In the USA, incidence rose until the mid-1980s but in the last two decades the rates have fallen for both men and women. Countries that have had a rapid 'westernization' of diet, such as Japan, have seen a rapid increase in incidence of colorectal cancer. Consumption of meat and dairy products in

**Figure 1.** Age-adjusted colorectal cancer incidence and death rates in the United States 1975–2006.

background of genetically determined susceptibility.

4 Colonoscopy and Colorectal Cancer Screening - Future Directions

Japan increased tenfold between the 1950s and 1990s.

From a population perspective, age is the most important risk factor for CRC. CRC is pre‐ dominantly a disease of older individuals. 90% of cases are diagnosed over the age of 50. The risk of CRC continues to increase with age (Figure 2). The incidence per 100,000 people age 80–84 is over seven times the incidence in people age 50–54. However, CRC can occur at any age and the incidence of CRC occurring before age 40 may be increasing.

In the USA, the risk of CRC differs by sex. The age-adjusted incidence of CRC is over 40% higher in men than women [8]. Overall, the incidence of CRC in men is 61 per 100,000 males as compared to 45 per 100,000 females. In addition, the ratio of colon to rectal cancer differs by sex; the ratio of colon to rectal cases for women is 3:1 as compared to 2:1 for males.

Race and ethnicity influence CRC risk [20]. Ashkenazi Jewish individuals appear to be at a slightly increased risk of CRC. At least part of this increased incidence may be due to a higher prevalence of the *I1307K* mutation of the adenomatous polyposis gene (*APC*), a mutation that confers an increased risk of CRC development (18–30% lifetime risk). The *I1307K* mutation is found in 6.1% of unselected Ashkenazi Jewish individuals and 28% of Jewish individuals with CRC, while the mutation is rare in other populations. In the USA, the incidence of CRC is higher in African Americans of either sex as compared to white Americans. Asian American/ Pacific Islanders, Native Americans, and Hispanic Americans experience a lower incidence of CRC than Caucasians (Table 1).African Americans have not experienced the substantial reduction in incidence of CRC found to have occurred in whites; prior to 1980 incidence in African Americans was actually lower than in white Americans. In African Americans, the increased rate of cancer is predominantly due to a higher rate of proximal cancers.

There is substantial geographic variation in the incidence of CRC, with relatively high rates in North America, Western Europe, and Australia and relatively low rates in Africa and Asia (Figure 3) Such observations led to Burkitt's hypothesis; that dietary differences, specifically fiber and fat intake, between populations were responsible for the marked variation in rates of CRC found around the world. Burkitt observed that populations in low-risk areas of the third world had greater stool bulk, a faster colonic transit time, and higher dietary fiber intake

than populations in high-risk, westernized regions. Although such ecological studies are confounded by numerous factors (for example, variations in average life expectancy, cancer detection methods, etc.), environmental factors (most prominently dietary factors) are still considered to have a major role in this disease. This is supported by studies of migrants from low prevalence areas to high prevalence areas. Such studies generally demonstrate that the incidence of CRC in the migrants increases rapidly to become similar and in some cases to exceed the incidence of the high-risk area. Interestingly, there is less variation in the incidence

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**Figure 3.** A Age-Standardized (to the world population) incidence rates of cancer of the large bowel among females,

B Age-standardized (to the world population) incidence rates of cancer of the large bowel among males

of rectal cancer between countries as compared to the incidence of colon cancer.

**Figure 2.** Age-specific SEER incidence rates in the United States 1992–2006.


\*per 100,000 age-adjusted to the 2000 US standard population

**Table 1.** Incidence and mortality rates\* for CRC by site, race and ethnicity, US 2001–2005

than populations in high-risk, westernized regions. Although such ecological studies are confounded by numerous factors (for example, variations in average life expectancy, cancer detection methods, etc.), environmental factors (most prominently dietary factors) are still considered to have a major role in this disease. This is supported by studies of migrants from low prevalence areas to high prevalence areas. Such studies generally demonstrate that the incidence of CRC in the migrants increases rapidly to become similar and in some cases to exceed the incidence of the high-risk area. Interestingly, there is less variation in the incidence of rectal cancer between countries as compared to the incidence of colon cancer.

**Figure 2.** Age-specific SEER incidence rates in the United States 1992–2006.

**African American**

**Table 1.** Incidence and mortality rates\* for CRC by site, race and ethnicity, US 2001–2005

**Asian American and Pacific Islander**

Female 43.2 54.5 35.4 41.2 32.8

Female 15.3 22.4 10.2 14.2 10.8

Incidence Male 58.9 71.2 48.0 46.0 47.3

Mortality Male 22.1 31.8 14.4 20.5 16.5

**American Indian/ Alaska Native**

**Hispanic/ Latino**

**White**

6 Colonoscopy and Colorectal Cancer Screening - Future Directions

\*per 100,000 age-adjusted to the 2000 US standard population

**Figure 3.** A Age-Standardized (to the world population) incidence rates of cancer of the large bowel among females, B Age-standardized (to the world population) incidence rates of cancer of the large bowel among males

The lifetime incidence of CRC in patients at average risk is about 5 percent, with 90 percent of cases occurring after age 50. In the US, CRC incidence is about 25 percent higher in men than in women and is about 20 percent higher in African Americans than in whites. The inci‐ dence is higher in patients with specific inherited conditions that predispose them to the de‐ velopment of CRC.

**1. HereditaryCRCsyndromes** such as: Familial adenomatous polyposis (FAP) and Lynch Syndrome (hereditary nonpolyposis colorectal cancer (HNPCC)) which are the most common of the familial colon cancer syndromes, but together these two conditions

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**a. Familialadenomatouspolyposis(FAP)** and its variants (Gardner's syndrome, Turcot's syndrome, and attenuated adenomatous polyposis coli) account for less than 1 percent of colorectal cancers. In typical FAP, numerous colonic adenomas appear during childhood. Symptoms appear at an average age of approximately 16 years and colonic cancer occurs in 90 percent of untreated individuals by age 45**.** An attenuated form of APC (AAPC) carries a similarly high risk of colon cancer but is characterized by fewer adenomas and

FAP is caused by germline mutations in the adenomatous polyposis coli (APC) gene which is located on chromosome 5. The same gene is involved in the attenuated form of FAP, but the

**b. Lynchsyndrome** — Lynch syndrome is an autosomal dominant syndrome, which is more common than FAP, and accounts for approximately 3 to 5 percent of all colonic adeno‐ carcinomas. The name Lynch syndrome honors the pioneering work of Dr. Henry Lynch in drawing attention to the syndrome. The term Lynch syndrome is now commonly used for families who have been genetically determined to have a disease-causing defect in one of the mismatch repair genes, most commonly hMLH1, hMSH2, hMSH6, or PMS2. As a general rule, patients with Lynch syndrome have a germline mutation in one allele of a MMR gene and the second allele is inactivated in the colorectal cancers by somatic mutation, loss of heterozygosity, or epigenetic silencing by promoter hypermethylation.

The colorectal tumors that develop in patients with Lynch syndrome are characterized by early age of onset and predominance of right-sided lesions [21]. The mean age at initial cancer diagnosis is 48 years, with some patients presenting in their 20s. Nearly 70 percent of first lesions arise proximal to the splenic flexure, and approximately 10 percent will have synchro‐ nous (simultaneous onset of two or more distinct tumors separated by normal bowel) or metachronous cancers (non-anastomotic new tumors developing at least six months after the

Extracolonic cancers are very common in Lynch syndrome, particularly endometrial carcino‐ ma, which may occur in up to 60 percent of female mutation carriers in some families. Other sites at increased risk of neoplasm formation include the ovary, stomach, small bowel,

**2. Personal or family history of sporadic CRCs or adenomatous polyps**

Patients with a personal history of CRC or adenomatous polyps of the colon are at risk for the future development of colon cancer. The clustering of risk in families may be attributed to an inherited susceptibility, common environmental exposures, or a combination of both. The

account for only about 5 percent of CRC cases.

an older average age of cancer diagnosis of 54 years.

sites of the APC gene mutations are different.

hepatobiliary system, brain and renal pelvis or ureter.

initial diagnosis).

**Mortality** — Death rates from CRC have declined progressively since the mid-1980s in the United States and in many other western countries. This improvement in outcome can be attributed, at least in part, to detection and removal of colonic polyps, detection of CRCs at an earlier stage, and more effective treatments, particularly adjuvant therapy. Globally, the United States has one of the highest survival rates from CRC. However, mortality rates con‐ tinue to increase in many countries with more limited resources and health infrastructure, particularly in Central and South America and Eastern Europe [43-44]. African Americans suffer the highest mortality rate from CRC in the USA (Table 1).The reasons for the higher mortality rate are likely multifactorial, including the higher incidence of CRC, and the dif‐ ferences in stage distribution. Differences in incidence, stage distribution and survival of CRC between white and African Americans are in part due to differences in socioeconomic status, screening rates and treatment. However, the differences may also be due to genetic and environmental factors that have yet to be elucidated. The highest mortality rates in both sexes are estimated in Central Europe (20.3/100000 for male patients, 12.1/100000 for female patients), and the lowest in the Middle Africa (3.5 and 2.7 respectively). The majority of deaths of CRC occur in older people, around 80% in people aged 65 and above and almost two-fifths of deaths appear in the group with age over 80.

Because CRC is a survivable cancer, with a 5-year survival rates adjusted for life expectan‐ cy of 64% the prevalence of people living with a diagnosis of CRC in the population is substantial.

Factors that may have contributed to the worldwide variation in colorectal cancer incidence patterns include differences in the prevalence of risk factors and screening practices. Estab‐ lished and suspected modifiable risk factors for colorectal cancer, including obesity, physical inactivity, smoking, heavy alcohol consumption, a diet high in red or processed meats, and inadequate consumption of fruits and vegetables, are also factors associated with economic development or westernization [35]. This partially explains the historically high albeit decreas‐ ing colorectal cancer incidence rates observed in long-standing developed countries such as the United States, Canada, and New Zealand over the past several years [36]. Colorectal cancer screening can also influence colorectal cancer incidence rates. All screening tests including stool blood tests (e.g. fecal occult blood test) and structural screening tests (e.g. sigmoidoscopy and colonoscopy) may increase colorectal cancer incidence rates initially as they detect previously undiagnosed cases.

**Riskfactors**-Although the exact cause for the development of colorectal cancer is not known, there are factors that increase risk for developing adenomas, polyps and cancer. These include numerous suspect factors.

Environmental and genetic factors can increase the likelihood of developing CRC. Although inherited susceptibility results in the most striking increases in risk, the majority of CRCs are sporadic rather than familial. These include:

**1. HereditaryCRCsyndromes** such as: Familial adenomatous polyposis (FAP) and Lynch Syndrome (hereditary nonpolyposis colorectal cancer (HNPCC)) which are the most common of the familial colon cancer syndromes, but together these two conditions account for only about 5 percent of CRC cases.

The lifetime incidence of CRC in patients at average risk is about 5 percent, with 90 percent of cases occurring after age 50. In the US, CRC incidence is about 25 percent higher in men than in women and is about 20 percent higher in African Americans than in whites. The inci‐ dence is higher in patients with specific inherited conditions that predispose them to the de‐

**Mortality** — Death rates from CRC have declined progressively since the mid-1980s in the United States and in many other western countries. This improvement in outcome can be attributed, at least in part, to detection and removal of colonic polyps, detection of CRCs at an earlier stage, and more effective treatments, particularly adjuvant therapy. Globally, the United States has one of the highest survival rates from CRC. However, mortality rates con‐ tinue to increase in many countries with more limited resources and health infrastructure, particularly in Central and South America and Eastern Europe [43-44]. African Americans suffer the highest mortality rate from CRC in the USA (Table 1).The reasons for the higher mortality rate are likely multifactorial, including the higher incidence of CRC, and the dif‐ ferences in stage distribution. Differences in incidence, stage distribution and survival of CRC between white and African Americans are in part due to differences in socioeconomic status, screening rates and treatment. However, the differences may also be due to genetic and environmental factors that have yet to be elucidated. The highest mortality rates in both sexes are estimated in Central Europe (20.3/100000 for male patients, 12.1/100000 for female patients), and the lowest in the Middle Africa (3.5 and 2.7 respectively). The majority of deaths of CRC occur in older people, around 80% in people aged 65 and above and almost

Because CRC is a survivable cancer, with a 5-year survival rates adjusted for life expectan‐ cy of 64% the prevalence of people living with a diagnosis of CRC in the population is

Factors that may have contributed to the worldwide variation in colorectal cancer incidence patterns include differences in the prevalence of risk factors and screening practices. Estab‐ lished and suspected modifiable risk factors for colorectal cancer, including obesity, physical inactivity, smoking, heavy alcohol consumption, a diet high in red or processed meats, and inadequate consumption of fruits and vegetables, are also factors associated with economic

ing colorectal cancer incidence rates observed in long-standing developed countries such as the United States, Canada, and New Zealand over the past several years [36]. Colorectal cancer screening can also influence colorectal cancer incidence rates. All screening tests including stool blood tests (e.g. fecal occult blood test) and structural screening tests (e.g. sigmoidoscopy and colonoscopy) may increase colorectal cancer incidence rates initially as they detect

**Riskfactors**-Although the exact cause for the development of colorectal cancer is not known, there are factors that increase risk for developing adenomas, polyps and cancer. These include

Environmental and genetic factors can increase the likelihood of developing CRC. Although inherited susceptibility results in the most striking increases in risk, the majority of CRCs are

This partially explains the historically high albeit decreas‐

two-fifths of deaths appear in the group with age over 80.

velopment of CRC.

8 Colonoscopy and Colorectal Cancer Screening - Future Directions

substantial.

development or westernization [35].

previously undiagnosed cases.

sporadic rather than familial. These include:

numerous suspect factors.

**a. Familialadenomatouspolyposis(FAP)** and its variants (Gardner's syndrome, Turcot's syndrome, and attenuated adenomatous polyposis coli) account for less than 1 percent of colorectal cancers. In typical FAP, numerous colonic adenomas appear during childhood. Symptoms appear at an average age of approximately 16 years and colonic cancer occurs in 90 percent of untreated individuals by age 45**.** An attenuated form of APC (AAPC) carries a similarly high risk of colon cancer but is characterized by fewer adenomas and an older average age of cancer diagnosis of 54 years.

FAP is caused by germline mutations in the adenomatous polyposis coli (APC) gene which is located on chromosome 5. The same gene is involved in the attenuated form of FAP, but the sites of the APC gene mutations are different.

**b. Lynchsyndrome** — Lynch syndrome is an autosomal dominant syndrome, which is more common than FAP, and accounts for approximately 3 to 5 percent of all colonic adeno‐ carcinomas. The name Lynch syndrome honors the pioneering work of Dr. Henry Lynch in drawing attention to the syndrome. The term Lynch syndrome is now commonly used for families who have been genetically determined to have a disease-causing defect in one of the mismatch repair genes, most commonly hMLH1, hMSH2, hMSH6, or PMS2. As a general rule, patients with Lynch syndrome have a germline mutation in one allele of a MMR gene and the second allele is inactivated in the colorectal cancers by somatic mutation, loss of heterozygosity, or epigenetic silencing by promoter hypermethylation.

The colorectal tumors that develop in patients with Lynch syndrome are characterized by early age of onset and predominance of right-sided lesions [21]. The mean age at initial cancer diagnosis is 48 years, with some patients presenting in their 20s. Nearly 70 percent of first lesions arise proximal to the splenic flexure, and approximately 10 percent will have synchro‐ nous (simultaneous onset of two or more distinct tumors separated by normal bowel) or metachronous cancers (non-anastomotic new tumors developing at least six months after the initial diagnosis).

Extracolonic cancers are very common in Lynch syndrome, particularly endometrial carcino‐ ma, which may occur in up to 60 percent of female mutation carriers in some families. Other sites at increased risk of neoplasm formation include the ovary, stomach, small bowel, hepatobiliary system, brain and renal pelvis or ureter.
