In the United States, colorectal cancer is the third leading cause of cancer death, with 106,180 new diagnoses of colon cancer, 44,850 new diagnoses of rectal cancer, and 52,580 deaths projected for 2022 [7]. From 2014 to 2018, colorectal cancer incidence rates declined by 3.7% per year in adults 55 years of age and older, increased by about 2.0% per year in adults 50 to 55 years of age, and increased by 1.5% per year in individuals younger than 50 years of age—a trend that began in the mid-1990s for unknown reasons [8]. The death rate has decreased by 56%, from 29.2 per 100,000 in 1970 to 12.8 in 2019, primarily due to earlier detection. From 2015 to 2019, the death rate declined by about 2% per year [8].

Trends in the United States suggest a disproportionally higher incidence and death from colorectal cancer in Black/African American patients than in White patients. Asian/Pacific Islander individuals have the lowest incidence and mortality from colorectal cancer [9]. The incidence of colorectal cancer is higher in men than in women, with the annual rate in men ranging from 34.4 per 100,000 for Asian/Pacific Islanders to 50.4 per 100,000 for African Americans. The annual incidence rate in women ranges from 24.6 per 100,000 in Asians/Pacific Islanders to 43.9 per 100,000 in American Indian/Alaska Natives. The annual age-adjusted mortality rates for men and women are 16.0 and 11.3 per 100,000, respectively [9].

Trends in the United States suggest a disproportionally higher incidence and death from colorectal cancer in Black/African American patients than in White patients. Asian/Pacific Islander individuals have the lowest incidence and mortality from colorectal cancer [9]. The incidence of colorectal cancer is higher in men than in women, with the annual rate in men ranging from 34.4 per 100,000 for Asian/Pacific Islanders to 50.4 per 100,000 for African Americans. The annual incidence rate in women ranges from 24.6 per 100,000 in Asians/Pacific Islanders to 43.9 per 100,000 in American Indian/Alaska Natives. The annual age-adjusted mortality rates for men and women are 16.0 and 11.3 per 100,000, respectively [9].

Approximately 4.2% of Americans will be diagnosed with colorectal cancer at some point in their lifetime. Of those diagnosed, 50% will die from the disease. The overall five-year survival rate is 65.7% [10]. Cancer stage at diagnosis strongly influences duration of survival. With colon and rectum cancer, the five-year survival is approximately 91% in patients diagnosed with localized cancer, 72% with limited regional extension, and 14% with distant metastases [13]. Despite advances in surgical techniques and adjuvant therapy, the modest survival improvements in patients with advanced neoplasm provide the rationale for implementing primary and secondary preventive approaches to reduce morbidity and mortality from colorectal cancer [1,2,3].

For most people, the dominant risk factor for colorectal cancer is increasing age. As noted, risk increases dramatically after 50 years of age. Other nonmodifiable factors, such as family history of colorectal cancer, personal history of colorectal cancer or high-risk adenomas, genetic predisposition, and inflammatory bowel disease, also elevate the risk of colorectal cancer [14]. There are also modifiable factors that increase (or decrease) an individual's risk of colorectal cancer, including alcohol use, cigarette smoking, diet, and physical activity.

Obesity, defined as a body mass index (BMI) ≥30, has been consistently associated with increased incidence and mortality from colorectal cancer, particularly in men. Compared with BMI <22, the risk of colorectal cancer increases with a BMI >28.5 by 60% in men and 30% in women. A BMI ≥30 increases the overall risk of colorectal cancer by 45%. The mechanism of increased vulnerability to colorectal cancer in obese patients is not known but may involve the elevated release and bioavailability of growth factors, insulin, and insulin-like growth factor 1. Heightened risk in obese patients appears to be mitigated by high levels of physical activity [21,22].

BMI is associated with risk of colorectal adenomas and colorectal cancer, but few studies have accrued large enough sample sizes to allow stratified analyses. Evaluation of pooled data from 8,213 participants in seven prospective studies found higher BMI was significantly associated with most histologic characteristics of metachronous adenomas in men, but not in women. The researchers concluded that body mass may affect colorectal carcinogenesis at comparatively early stages, particularly in men [23].

A study of 11,598 survivors of incident primary colorectal cancer examined the effect of obesity on risk of developing a second obesity-associated cancer (e.g., postmenopausal breast, kidney, pancreas, esophageal adenocarcinoma, endometrium). Compared with colorectal cancer survivors of normal prediagnostic BMI, the risk of developing a second obesity-associated cancer was increased 39% in overweight patients and 47% in obese patients [24]. This compares to the risk for developing a first primary obesity-associated cancer, which was increased by 18% in overweight persons and 61% in obese persons. The authors state that colorectal cancer survivors who were overweight or obese before diagnosis had an increased risk of second obesity-associated cancers relative to normal-weight survivors. Elevated risk of developing a second cancer in colorectal cancer survivors is more likely the result of the increased prevalence of overweight and obesity rather than increased susceptibility [24].

Researchers have associated a common mutation in colorectal cancer with elevated risk of metabolic disease. APC is a tumor-suppressor gene that indirectly regulates cell proliferation by encoding a protein called beta-catenin. APC inactivation by mutation leads to loss of beta-catenin function, which results in unchecked cellular replication and other processes that drive progression to malignant phenotype. Activation of the Wnt signaling pathway, normally mediated by beta-catenin, also occurs. Beta-catenin-Wnt signaling is involved in glucose metabolism and metabolic diseases such as obesity and type 2 diabetes. Using a molecular pathologic epidemiology database, researchers found that risk of beta-catenin-negative colorectal cancer was significantly higher with greater BMI and lower with increased physical activity level. Risk of beta-catenin-positive colorectal cancer was unrelated to BMI or physical activity level [25].

A sedentary lifestyle has been associated with an increased risk of colorectal cancer, although this finding has not been consistent [14]. More consistent is the association between regular physical activity and a decreased incidence of colon but not rectal cancer, with an estimated 22% to 27% risk reduction [26,27,28,29].

Colon cancer rates are high in populations with high total fat intakes and are lower in those consuming less fat [30]. On average, fat comprises 40% to 45% of total caloric intake in high-incidence Western countries; in low-risk populations, fat accounts for only 10% of dietary calories [31]. Several case-control studies have explored the association of colon cancer risk with meat or fat consumption as well as protein and energy intake [32]. Positive associations with meat consumption or fat intake have been found frequently but have not always achieved statistical significance [33]. One hypothesis is that heterocyclic amines formed when meat or fish are cooked at high temperatures may contribute to the increased risk of colorectal cancers associated with meat consumption observed in epidemiologic studies [34,35].

Despite evidence from case-control studies of a protective effect, results from a large prospective study found no difference in the risk of colorectal cancer between women in the highest quintile group compared with the lowest quintile group with respect to dietary fiber, after adjusting for age, known risk factors, and total energy intake [36]. One study evaluated the associations between dietary fiber, fat, and colorectal cancer risk in the Women's Health Initiative prospective cohort, which included 134,017 women [37]. During a mean 11.7 years follow-up (1993–2010), 1,952 incident cases of colorectal cancer were identified. When fiber and fat intake were assessed individually, the authors found a modest trend toward lower cancer risk with increased intakes of total fiber, suggesting a mild protective effect of higher fiber intake on risk of colorectal cancer, but not when combined with intake of dietary fats [37]. Results of a pooled analysis of 3,209 participants combined from two trials indicate that men may experience more benefit from dietary fiber than women [38].

Overall, results from more rigorously designed randomized controlled trials have washed out findings of significant correlation in earlier studies that linked higher fruit and vegetable consumption with lower rates of colorectal cancer. Diets low in fat and meat and high in fiber, fruits, and vegetables started as an adult do not appear to reduce the risk of colorectal cancer by a clinically important degree [37,39].

There is evidence that vitamin D may be an important cofactor in immune protection against colorectal cancer risk. A large, population-based case-control study, derived from the Nurses' Health Study and Health Professionals Follow-Up Study, found a significant association between plasma vitamin D level and colorectal cancer risk according to the degree of local antitumor immune response. The study consisted of 318 colorectal cancer cases and 624 matched controls. Subjects were divided into three groups based on the median plasma vitamin D level (tertile I 19.0 ng/mL, tertile III 37.4 ng/mL) and analyzed according to the degree of lymphocytic immune reactivity within and surrounding the tumor. Subjects in the highest vitamin D tertile were seen to have a significantly lower risk of developing colorectal cancer subtype showing an intense intratumoral cellular immune reaction. This association was not found for tumor subtypes characterized by a poor intratumoral immune response. The authors discuss possible mechanisms and conclude that these observations support a role for vitamin D in cancer immunoprevention through tumor-host interaction [45].

A 2015 prospective observational study published the first-ever results of cyclooxygenase-2 (COX-2) inhibitor and aspirin use as adjuvant therapy following resection in patients with stage III colon cancer. All patients received standard adjuvant chemotherapy with fluorouracil (5-FU) plus leucovorin with or without irinotecan. In the aspirin arm of 799 patients, 75 (9.4%) used aspirin during and after chemotherapy. In the COX-2 inhibitor arm of 843 patients, 59 (7.5%) used celecoxib or rofecoxib after completing chemotherapy. Both groups had a median follow-up of 6.5 years [50]. Among patients taking aspirin (vs. no aspirin), recurrence-free survival (i.e., time period until tumor recurrence, death with recurrence, or development of a new invasive colon cancer) was increased by 49%, disease-free survival (i.e., time period until tumor recurrence, occurrence of a new colon cancer, or death from any cause) was increased by 32%, and overall survival (i.e., time period until death from any cause) was increased by 37%. Adjusted hazard ratios were censored at five years to minimize misclassification from non-cancer death and showed increases in disease-free survival by 39% and overall survival by 52% (vs. no aspirin). Patients taking a COX-2 inhibitor (vs. no COX-2 inhibitor) found increases in recurrence-free survival by 47%, disease-free survival by 40%, and overall survival by 50%. Censor of survival data at five years found disease-free survival increased by 53% and overall survival by 74% [50].

Although this study was not designed to identify the optimal dose and duration of aspirin or COX-2 inhibitors for protection against colorectal cancer, the data suggest a dose-response relationship in aspirin with increased frequency, while any dose of COX-2 inhibitors was associated with benefit. The statistically significant associations between aspirin and COX-2 inhibitor use and reduced colon cancer recurrence and mortality found in this study will continue to be evaluated [50].

Celecoxib, rofecoxib, and aspirin share a similar mechanism of action in colon (and presumably rectal) cancer involving COX-2 inhibition. COX synthesizes the conversion of arachidonic acid to prostaglandins. Prostaglandins mediate tumor growth by altering stem cell gene expression, hypermethylating genes involved in proliferation and differentiation, promoting angiogenesis and Wnt/CTNNB1 signaling, and inhibiting apoptosis. Thus, suppression of prostaglandin synthesis through COX inhibition interferes with the processes involved in tumor promotion and growth [50,51].

Long-term follow-up data from two large studies initiated in the 1980s found that ≥300 mg aspirin daily taken for five or more years was associated with a 37% overall reduction in colorectal cancer risk. In subjects who remained adherent to the protocol for 5 or more years, those randomized to aspirin were found to have a 40% risk reduction in colorectal cancer mortality after 20 years and absolute risk reduction from 3.1% to 1.9% relative to those receiving placebo. Mortality reduction was primarily from the effect of aspirin on proximal colon cancer. These findings were serendipitous, because the research was designed to examine the protective effects of aspirin against cardiovascular events [52,53].

Prospective studies have demonstrated significant reduction in colorectal cancer among regular aspirin users [54]. In a randomized controlled trial of 861 persons with Lynch syndrome, primary colorectal cancer developed in 4.2% of patients taking daily aspirin 600 mg, compared with 6.9% in those receiving daily placebo (mean follow-up: 55.7 months). Time to first colorectal cancer was increased 37% with aspirin versus placebo; with regression analysis incorporating multiple primary events, aspirin led to a 44% reduction in colorectal cancer incidence. In subjects completing at least two years of intervention, time to first colorectal cancer was increased 59% and incidence of colorectal cancer was reduced 63%. Adverse events did not differ between aspirin and placebo groups during the intervention [55]. A planned 10-year follow-up to this trial (the double-blind, randomised CAPP2 trial) included 861 patients with Lynch syndrome from 43 international centers worldwide. The participants were randomly assigned to receive either 600-mg aspirin daily (427 participants) or placebo (434 participants). Cancer outcomes were monitored for at least 10 years from recruitment; some of the participants (i.e., English, Finnish, and Welsh participants) were monitored for up to 20 years. The primary endpoint was development of colorectal cancer [56]. Forty (9%) of the aspirin group developed colorectal cancer compared with 58 (13%) of the placebo group. Noncolorectal Lynch syndrome cancers were reported in 36 participants who received aspirin and 36 participants who received placebo. Adverse events between the aspirin and placebo groups were similar [56]. Likewise, a randomized controlled trial of patients with a history of adenomas or colorectal cancer found a statistically significant 21% reduction in risk of adenoma recurrence in patients randomized to aspirin (versus placebo) [57].

A prospective cohort study examined the effects of aspirin in participants following a diagnosis of colorectal cancer. Regular use of aspirin after colorectal cancer diagnosis was associated with a 29% increase in colorectal cancer-specific survival and a 21% increase in overall survival [58]. In the long-term Nurses' Health Study and the Health Professional Follow-up Study, 964 patients diagnosed with rectal or colon cancers were evaluated. In those with PI3K-mutant colorectal cancer, regular use of aspirin was associated with a 46% increase in overall survival [59].

The benefit of aspirin in prevention of colorectal cancer is not apparent until 10 years after aspirin therapy is started and is most effective when started between 50 and 59 years of age. Because of the time required before a reduced incidence in colorectal cancer is realized, persons 60 years of age and older are less likely to realize a benefit [60]. Additionally, aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with potentially serious adverse effects that should be considered when determining the risk-benefit ratio [57]. Aspirin use can result in excessive bleeding, gastrointestinal bleeds, and hemorrhagic stroke. The estimated average increased risk of upper gastrointestinal complications was 10 to 30 per 1,000 people over a 10-year period, with men on the higher end and women on the lower end. Risk increases with age [60].

While no studies have assessed adenoma or colorectal cancer risk reduction with use of NSAIDs in the general (and presumably average-risk) population, multiple lines of evidence from epidemiologic studies, observational cohort studies, and randomized controlled trials have consistently affirmed the association between NSAID use and a 30% to 50% reduction in adenomatous polyps, incident disease, and death from colorectal cancer [57,61,62,63]. In one study, patients with familial adenomatous polyposis (FAP) who were followed over four years of treatment with NSAIDs showed a trend in reduction in adenoma incidence and statistically significant reductions in polyp number and size. A 34% reduction in adenoma recurrence risk and a 55% reduction in advanced adenoma incidence were found in patients with a history of adenomas [57].

The NSAIDs sulindac and celecoxib have been shown in randomized controlled trials to induce adenoma regression in patients with FAP, which, together with supportive preclinical data, led the U.S. Food and Drug Administration (FDA) to approve celecoxib for patients with FAP in 1999. However, in 2011, the FDA requested Pfizer voluntarily withdraw the FAP indication for celecoxib, because the company never fulfilled a condition for approval requiring postmarketing evaluation to verify clinical benefit, which Pfizer did [64]. Despite the change of celecoxib use in FAP to off-label status and withdrawal of regulatory approval, several health insurance companies have codified the use of celecoxib in FAP as an authorized indication [65].

The consistently positive findings of NSAID benefit in suppressing the development of adenomas and improving recurrence-free, disease-free, and overall survival in patients with histories of adenomas and colon cancer has posed a dilemma for researchers and clinicians, given the known toxicity profile. NSAID-related morbidity is fairly common and potentially serious and includes upper gastrointestinal bleeding, renal dysfunction, and serious cardiovascular events such as myocardial infarction, heart failure, and hemorrhagic stroke. Among other findings, use of NSAIDS increases the risk of serious cardiovascular events by 50% to 60% [61,66].

The Women's Health Initiative (WHI) randomized participants to estrogen plus progestin or placebo. At a mean follow-up of 11.6 years, women receiving active hormone therapy had a 28% lower risk of colorectal cancers [67]. However, in the hormone therapy group, colorectal cancers that developed were significantly more likely to exhibit lymph node involvement and higher stages (regional and distant) compared with those in the placebo group. Deaths from colorectal cancers in the active group were somewhat higher, but the difference from placebo was not statistically significant [67]. A meta-analysis of cohort studies observed a 14% risk reduction for incidence of colorectal cancer associated with combined hormone therapy [68].

Conjugated equine estrogens do not improve incidence or survival in invasive colorectal cancer [67]. Definite harms have been established in using combined estrogen plus progestin hormone in postmenopausal women. The WHI trial found increased risks of invasive breast cancer, coronary heart disease events, and thromboembolic events [67,69].

Findings suggestive of heritable colorectal cancer risk are termed "red flags" and direct the healthcare provider to probe further. One red flag is a personal history of colon cancer diagnosed before 60 years of age or endometrial cancer diagnosed before 50 years of age [87,88]. Early age at diagnosis suggests that genetic factors are playing a strong role in the development of disease.

A family history of colon or endometrial cancer diagnosed before 50 years of age is another red flag. Early age at diagnosis of cancer in a closely related family member suggests that genetic factors are playing a role in the development of disease, and these factors can be passed on to other relatives. If multiple family members have been diagnosed with colorectal cancer, or other Lynch/hereditary nonpolyposis colorectal cancer (HNPCC)-related cancers, this strongly suggests genetic factors are increasing individual cancer risks, especially among first-degree relatives [87,88].

One to two polyps in a lifetime is common, but more than 10 in a lifetime is unusual and suggests genetic contribution. Polyposis is associated with increased colorectal cancer risk. In addition, diagnosis of two or more Lynch/HNPCC-associated cancers suggests an inherited mutation, increasing the overall risk for cancer in different organs.

Past diagnosis of Lynch/HNPCC, FAP, or other inherited cancer syndrome in a family member is another risk factor. Many of these conditions are inherited in a dominant pattern, but not everyone who inherits gene mutations for these conditions develops cancer. Therefore, a diagnosis of HNPCC in a grandparent may be relevant to the patient.

Of total colorectal cancer cases, 75% are due to sporadic disease without apparent inherited origin, 10% to 30% are due to familial risk factors, and 5% to 6% are due to heritable genetic mutations. The absolute risk of colorectal cancer by 79 years of age is [90,91]:

Heritable gene mutations that confer elevated risk of colorectal cancer broadly cluster into two groups: stability genes, including mutations in DNA mismatch repair (MMR) genes responsible for Lynch syndrome, and tumor suppressor genes, including APC gene mutations responsible for FAP. Lynch syndrome and FAP account for the vast majority of heritable colorectal cancer cases and 5% to 6% of all colorectal cancer cases [95]. The absolute risks for colorectal cancer in mutation carriers of hereditary colorectal cancer syndromes are [95]:

Risk of extracolonic malignancy is greatest for endometrial cancer. At least one female member in about half of all Lynch syndrome pedigrees is affected, and 50% of women with an MMR gene mutation present with endometrial cancer as first malignancy. Patients with Lynch syndrome have an elevated risk of several other cancers. Risk of extracolonic tumor development by 70 years of age in Lynch syndrome is shown below, with prevalence rate ranges reflecting differences between specific MMR mutations [97]:

The extent of macroscopic and histologic inflammation is associated with increased risk of colorectal cancer, which can develop in areas of endoscopically normal but histologically active colitis. Colorectal cancer can occur in areas where colitis has remitted or where histologic findings show inactive colitis such as crypt distortion in the absence of active inflammation. Lack of endoscopic inflammation at the time of neoplastic detection does not mean absence of inflammation in the area before neoplastic development, and risk of neoplasia is not increased in mucosa that has never been inflamed. Thus, histologic instead of macroscopic evidence of tissue changes from inflammatory bowel syndrome serves as a more accurate determinant for assessing colorectal cancer risk. In the context of surveillance, extent of disease should be defined histologically [118].

As noted, the United States is the only developed country experiencing declining incidence rates of colorectal cancer, despite the increase in colorectal cancer risk factors such as obesity [4]. Increasingly widespread colorectal cancer screening is believed to be the root of this seeming paradox.

Colorectal cancer is a serious disease but in many cases is preventable, and its incidence, mortality, and financial burden to society make it an important healthcare concern. The usually long and often asymptomatic premalignant natural history and the clinical features of colorectal cancer make the malignancy amenable to prevention by screening. Colonoscopy has become the dominant screening approach, and optical (versus computed tomography [CT] or "virtual") colonoscopy has the advantage of providing cure via polypectomy during the session [119].

With screening colonoscopy, a colonoscope (a thin tube with a light and video camera on one end connected to a display monitor) is inserted through the rectum and guided through the length of the colon for observation on the monitor screen. Instruments to remove polyps and obtain biopsy are inserted through the rectum as needed [131]. Colonoscopy allows direct visualization of the colonic mucosa, lesion biopsy, and polyp removal over the entire colon. The sensitivity and specificity for colorectal cancer and advanced adenomas are very high, and colonoscopy is the confirmatory test used with all other screening approaches when positive findings occur [120].

Colonoscopy may fail to detect as many as 6% of colorectal malignancies, and the miss rate for adenomas smaller than 1 cm has ranged from 12% to 17% [132]. This is largely the result of high inter-operator variability in adenoma detection rate. Greater awareness of this hazard from inadequate colonoscopy performance has led to heightened emphasis on training and continuous quality assurance of endoscopists [120]. In addition, colonoscopy is an invasive procedure, requires an invasive bowel cleansing, is time-consuming and uncomfortable, and thus possesses several characteristics that negatively affect patient acceptance as a first-line screening test [120].

Clinically significant complications that require medical intervention are rare and include perforation, bleeding, and cardiovascular events. Complication rates may increase in older patients [133,134]. More than 85% of serious colonoscopy complications occur during polypectomy, and a study of 97,000 colonoscopies found polypectomy associated with a seven-fold increase in risk of bleeding or perforation [135]. Up to 33% of patients report one or more minor, transient gastrointestinal symptoms after colonoscopy, and a review of 12 studies involving 57,742 colorectal cancer screening colonoscopies in average-risk patients found the aggregate rate of serious complications was 2.8 per 1,000 procedures [134,136].

The adequacy of pre-procedure bowel cleansing merits special attention because this patient factor is strongly associated with colonoscopy success. Up to 20% to 25% of colonoscopies are attempted in patients with inadequate bowel preparation, leading to diminished adenoma detection rates, longer procedural time, lower cecal intubation rates, and increased electrocautery risk [138,139,140].

Cecal Intubation. Cecal intubation involves advancing the colonoscope beyond the ileocecal valve, allowing the colonoscopist to visualize the medial wall of the cecum between the ileocecal valve and the appendiceal orifice. Cecal intubation is essential for optimal colonoscopy because many colorectal neoplasms are harbored in the proximal colon, including the cecum, and low cecal intubation rates are linked to higher rates of interval proximal colon cancer [143]. Colonoscopists should be able to intubate the cecum in ≥95% of screening colonoscopies in healthy adults. Photography of the cecum is mandated to verify intubation [142].

Adenoma Detection. Missed adenoma detection is strongly associated with failure to prevent colorectal cancer during multi-year follow-up colonoscopy trials, and most interval colorectal cancers are due to missed lesions and incomplete polypectomy. The marked variation in colonoscopist adenoma detection rates within practice groups, and the essential role of adenoma detection in colorectal cancer prevention led to adenoma detection as a performance target [144,145,146]. The examination is considered adequate if detection of polyps >5 mm is unimpeded.

In screening colonoscopies of asymptomatic, average-risk persons, a minimum adenoma detection target rate of 25% is recommended. Adenoma detection rates of less than 25% indicate that performance improvement steps should be initiated. Adenoma detection rate is considered the primary measure of mucosal inspection quality and is the single most important quality measure in colonoscopy. Colonoscopists with high adenoma detection rates clear colons better, and patients with precancerous lesions are brought back earlier for their next colonoscopy. Colonoscopists with low adenoma detection rates fail to identify patients with precancerous lesions and multiple lesions, placing these patients at elevated risk for cancer from inappropriately long intervals between colonoscopy [142].

Withdrawal Time. The time taken to remove the colonoscope after cecum intubation (excluding time for biopsies or polypectomy) is termed withdrawal time, and colonic mucosa should be carefully examined for polyps during scope withdrawal. The recommended colonoscope withdrawal time should be at least six minutes in colorectal cancer screening of patients without previous bowel surgery (when no biopsies or polypectomies are performed) [142]. Numerous studies have demonstrated increased detection of significant neoplastic lesions in colonoscopic examinations with an average withdrawal time of at least six minutes, and longer withdrawal time is associated with higher detection rates [147,148,149].

Colorectal lesions and adenomatous polyps tend to bleed, and the resulting presence of hemoglobin in stool that is detectable even with intermittent or minimal bleeding formed the basis for gFOBT use in colorectal cancer screening. Hemoglobin is used as a biomarker for detecting blood in stool with guaiac, which identifies peroxidase-like activity that characterizes hemoglobin. However, gFOBT cannot discriminate human from nonhuman or intact from partially digested hemoglobin and is being phased out of clinical use. This results in detection of blood from ingested meat and upper airway and gastrointestinal bleeding as well as colorectal lesions. The low specificity of gFOBT requires confirmatory colonoscopy to validate positive findings [159].

iFOBT was developed to detect intact human hemoglobin originating from colorectal tissue. Unlike gFOBT, it does not detect hemoglobin from nonhuman dietary sources or partly digested human hemoglobin originating from the upper respiratory or gastrointestinal tract [160]. The sDNA variation of FOBT incorporates markers of DNA mutation that detect molecular genetic changes associated with colorectal cancer gene mutations shed into the stool [161].

There are three broad pathways by which colorectal carcinoma develops [169]:

Colorectal lesions present as a broad spectrum of neoplasms that range from benign growths to invasive tumors. Most colorectal cancers develop slowly over years, typically beginning as non-cancerous polyps on the inner lining of the colon or rectum. Some, but not all, polyps develop into cancer, and the risk of malignant progression is influenced by polyp type. Colorectal lesions are classed into three groups [173]:

Adenomas may reflect an innate or acquired tendency of the colon to form tumors. Benign and malignant tissue occurs within colorectal tumors, and 20-year follow-up of patients with adenomas has found a 25% malignancy rate in adenoma sites. Removal of adenomatous polyps is linked with reduced colorectal cancer incidence and represents the foundation of primary colorectal cancer prevention [170].

The transition from normal epithelium to adenoma to carcinoma is associated with acquired molecular events. The mucosa in the large intestine regenerates roughly every six days. Crypt cells migrate from the base of the crypt to the surface, where they undergo differentiation and maturation and ultimately lose the ability to replicate. As noted, most colorectal carcinomas are adenocarcinomas. Adenomas precede adenocarcinomas, with roughly 10% of adenomas eventually developing into adenocarcinomas during a process that occurs over up to 8 to 10 years with sporadic colorectal cancers. Dysplastic adenomas progress to colorectal malignancies through a multistep process involving inactivation of a variety of tumor-suppressor and DNA-repair genes and simultaneous activation of oncogenes. Colonic epithelial cells are selectively vulnerable to the transformation from normal colonic epithelium to adenomatous polyp to invasive carcinoma [171,177,178].

Anemia is present in close to 90% of patients with right-sided colon cancer at the time of diagnosis [190].

Practice guideline recommendations for imaging to stage colorectal cancer have been published by the American Society of Colon and Rectal Surgeons (ASCRS) and by Cancer Care Ontario [188,200]. They recommend contrast-enhanced CT of the chest, abdomen, and pelvis should be performed in all patients with colon cancer (unless contraindicated) to estimate disease stage and identify metastases. If local excision is considered for low rectal cancer (0–5 cm from the anal verge), transrectal ultrasonography is preferred over MRI to improve discrimination between T1 and T2 lesions. For upper rectal cancers (10–15 cm above the anal verge), whereby the mesorectal fascia is not threatened, MRI is not considered superior to pelvic CT.

Specific clinical features associated with worse prognosis are [211]:

The standard treatment options for colon cancer are [201]:

Unlike in rectal cancer, the role of adjuvant radiation therapy is poorly defined in colon cancer treatment. Radiation therapy has no current adjuvant role following curative resection but may have a potential role in patients with residual disease [220]. If used, radiation fields should include the tumor bed, as defined by preoperative radioimaging or surgical clips. Radiation should be given in doses of 45–50 Gy in 25 to 28 fractions; the dose in the small bowel should be no greater than 45 Gy [220]. Neoadjuvant chemoradiotherapy that includes 5-FU should be delivered concurrently to aid resectability. Conformal external beam radiation is preferred; intensity-modulated radiation therapy should be limited to unique clinical situations. Intraoperative radiation therapy should be considered in T4 or recurrent cancer [220].

The greater toxicity concerns with pelvic irradiation of rectal cancer involve potential late-onset morbidity. Relative to patients receiving surgical resection alone, those with additional radiation therapy treatment have shown increased risks of chronic bowel problems, sphincter dysfunction, sexual dysfunction, and elevated risk of surgical morbidity [258].

Ziv-aflibercept is a novel anti-VEGF molecule that acts as a decoy receptor for VEGF-A, VEGF-B, and placental growth factor. The antiangiogenic mechanism of ziv-aflibercept involves competition with VEGF in the blood and extravascular space to prevent VEGF from interacting with its receptors on endothelial cells. It is indicated for metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin regimen [271].

With recurrent or advanced colon and rectal cancer, treatment is determined by disease location. For patients with locally recurrent or liver- and/or lung-only metastatic disease, surgical resection, if feasible, is the only potentially curative treatment [201]. At any point, symptom emergence from the primary tumor should become the treatment priority in stage IV colorectal cancer [238].

Stage IV colon cancer denotes distant metastatic disease, and therapeutic options for stage IV and recurrent disease include [201]:

As with colon cancer, surgical resection is the only potentially curative treatment for patients with locally recurrent, liver-only, or lung-only metastatic rectal cancer [201]. Patients with limited pulmonary metastasis and patients with both pulmonary and hepatic metastasis may also be considered for surgical resection, with five-year survival possible in highly selected patients [273,274]. The presence of hydronephrosis associated with recurrence appears to be a contraindication to surgery with curative intent [275].

Hepatic metastases are considered suitable for resection based on the following criteria [201]:

Hepatic intra-arterial chemotherapy with floxuridine for liver metastases has shown higher overall response rates but no consistent improvement in survival compared with systemic chemotherapy [201]. In one trial, patients receiving curative liver resection were randomized to combined hepatic intra-arterial floxuridine and dexamethasone plus systemic 5-FU/leucovorin or to systemic 5-FU/leucovorin alone. Combined therapy improved two-year progression-free survival (57% vs. 42%) and overall survival (86% vs. 72%) but not median survival (72.2 vs. 59.3 months) [326].

A meta-analysis of randomized trials of fluoropyrimidine systemic therapy found no survival advantage. Furthermore, hepatic intra-arterial therapy is associated with increased local toxic effects, including liver function abnormalities and fatal biliary sclerosis [327].

Anti-EGFR agents have a specific adverse effect profile primarily involving skin toxicities. Electrolyte abnormalities also occur with these agents, especially magnesium-wasting syndrome. Cetuximab is associated with an infusion reaction caused by the immunogenicity of the chimeric antibody. The most prominent adverse effects of anti-EGFR agents are skin lesions (e.g., acneiform eruption, paronychial inflammation) and hair abnormalities (including a marked increase in the length of eyelashes). These are sometimes dose-limiting complications that, while not fatal, can greatly interfere with patients' quality of life. The development of skin toxicities (particularly more intense reactions) has actually been associated with better outcomes of cetuximab and panitumumab. Preliminary evidence shows benefit with use of a pre-emptive prophylactic skin treatment regimen of skin moisturizers, sunscreen, topical steroids, and doxycycline [225].

Outcomes from several large clinical trials were pooled and analyzed and demonstrated that following resection of the primary tumor, 85% of colon cancer recurrences occur within three years and 95% occur within five years. These results underscored the importance of regular surveillance for a minimum of five years following the resection of stage II and III colon cancer [335]. Accordingly, several professional organizations have published updated practice recommendations for surveillance of patients with resected stage II and III colon cancer. The recommendations by the ASCO, the NCCN, and the joint European Society of Medical Oncology and Japanese Society of Medical Oncology (ESMO/JSMO) are broadly similar but differ on some parameters (Table 12) [335,338].

Measurement of the serum glycoprotein CEA as a tumor marker for colorectal cancer has been used to help guide patient management and follow-up. Serum CEA testing is not valuable in screening for colorectal cancer because of its low sensitivity and specificity [340]. Use of postoperative CEA testing is usually limited to patients who may benefit from further intervention, including [339]: