Rectal Cancer

Colon and rectal cancer incidence was negligible before 1900. The incidence of colorectal cancer rose dramatically following economic development and industrialization. Currently, colorectal cancer is the third most common cancer and the third leading cause of cancer deaths in both males and females in the United States.[2]

Adenocarcinomas comprise the vast majority (98%) of colon and rectal cancers. Other rare rectal cancers, including carcinoid (0.4%), lymphoma (1.3%), and sarcoma (0.3%), are not discussed in this article. Squamous cell carcinomas may develop in the transition area from the rectum to the anal verge and are considered anal carcinomas. Very rare cases of squamous cell carcinoma of the rectum have been reported.[3, 4]

Approximately 20% of colorectal cancers develop in the cecum, another 20% in the rectum, and an additional 10% in the rectosigmoid junction. Approximately 25% of colon cancers develop in the sigmoid colon.[3]

The incidence and epidemiology, etiology, pathogenesis, and screening recommendations are common to both colon cancer and rectal cancer. These areas are addressed together.

The surgical definition of the rectum differs from the anatomical definition; surgeons define the rectum as starting at the level of the sacral promontory, while anatomists define the rectum as starting at the level of the 3rd sacral vertebra. Therefore, the measured length of the rectum varies from 12 cm to 15 cm. The rectum differs from the rest of the colon in that the outer layer consists of longitudinal muscle. The rectum contains three folds, namely the valves of Houston. The superior (at 10 cm to 12 cm) and inferior (at 4 cm to 7 cm) folds are located on the left side and the middle fold (at 8 cm to 10 cm) is located at the right side.

National Comprehensive Cancer Network guidelines define rectal cancer as cancer located within 12 cm of the anal verge by rigid proctoscopy.[1] This definition was developed by the Dutch Colorectal Cancer Group study, which found that the risk of recurrence of rectal cancer depends on the location of the cancer. Univariate sub-group analyses showed that the treatment effect for surgery alone vs preoperative radiotherapy plus surgery was not significant in patients whose cancer (TNM stage I to IV) was located between 10.1 cm and 15 cm from the anal verge.[5]

Computed tomography or magnetic resonance imaging is the most common modality to define the anatomic rectum. The variations in the definition of anatomic rectum result in variations in the treatment options, most importantly determining whether neoadjuvant chemoradiotherapy is indicated.  Neoadjuvant therapy has significant consequences in the functional and oncologic outcomes of patients. 

The following features are used to define the rectum apart from the sigmoid colon[6] :

• The sacral promontory
• The third valve of Houston
• The coalescence of tenia of sigmoid
• The transition from sigmoid mesocolon to mesorectum
• Loss of appendiceal epiploicae
• Anterior peritoneal reflection 

In order to standardize treatment of colorectal cancer, an international group of colorectal experts established a consensus definition of the anatomic rectum, using the Delphi technique. This consensus meeting came up with new terminology, the sigmoid takeoff, which defines the junction of sigmoid colon and rectum and the junction of sigmoid mesocolon and mesorectum radiographically.[6]  Although there are many publications on this topic in the literature, all rectal surgeons should familiarize themselves with the Delphi consensus article, as well as "The 'Holy Plane' of rectal surgery", which defines an optimal dissection plane around rectal tumors in terms of the pelvic fascia.[6, 7]

The mucosa in the large intestine regenerates approximately every 6 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.

The significant portions of colorectal carcinomas are adenocarcinomas. The adenoma-carcinoma sequence is well described in the medical literature.[3]  Colonic adenomas precede adenocarcinomas. Approximately 10% of adenomas will eventually develop into adenocarcinomas. This process may take up to 10 years.[3]

Three pathways to colon and rectal carcinoma have been described:

• Adenomatous polyposis coli ( APC) gene adenoma-carcinoma pathway
• Hereditary nonpolyposis colorectal cancer (HNPCC) pathway
• Ulcerative colitis dysplasia

The APC adenoma carcinoma pathway involves several genetic mutations, starting with inactivation of the APC gene, which allows unchecked cellular replication at the crypt surface. With the increase in cell division, further mutations occur, resulting in activation of the K-ras oncogene in the early stages and p53 mutations in later stages. These cumulative losses in tumor suppressor gene function prevent apoptosis and prolong the cell's lifespan indefinitely. If the APC mutation is inherited, it will result in familial adenomatous polyposis syndrome.

Histologically, adenomas are classified in three groups: tubular, tubulovillous, and villous adenomas. K-ras mutations and microsatellite instability have been identified in hyperplastic polyps. Therefore, hyperplastic polyps may also have malignant potential in varying degrees.[8]

The other common carcinogenic pathway involves mutation in DNA mismatch repair genes. Many of these mismatched repair genes have been identified, including hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6. Mutation in mismatched repair genes negatively affects the DNA repair. This replication error is found in approximately 90% of HNPCC and 15% of sporadic colon and rectal cancers.[3, 9] A separate carcinogenic pathway is also described in inflammatory bowel disease (IBD). Chronic inflammation such as in ulcerative colitis can result in genetic alterations which then lead into dysplasia and carcinoma formation.[3]

United States

Colon and rectal cancer is the third most common cancer in both females and males. The American Cancer Society (ACS) estimates that 106,970 new cases of colon cancer and 46,050 new cases of rectal cancer will occur in 2023; 27,440 cases of rectal cancer are expected in men and 18,610 in women. For estimates of deaths, the ACS combines colon and rectal cancers, because many deaths from rectal cancer are misclassified as due to colon cancer on death certificates; approximately 52,550 deaths from colorectal cancer are expected to occur in 2023.[2]

The incidence of colorectal cancer has generally declined since the mid-1980s. The decrease has accelerated since 2000, thanks largely to greater use of screening. However, the overall trend is driven by older adults (who have the highest rates) and masks the situation in younger adults, who have experienced rising incidence rates since at least the mid-1990s. From 2011 to 2019, incidence rates decreased by about 1% per year in adults 50 and older, but rates in persons younger than 50 years have increased by 1%-2% per year since the mid-1990s f.[2]  Currently, adults born circa 1990 have quadruple the risk of rectal cancer compared with those born circa 1950.[10]  

The overall death rate from colorectal cancer has also been falling, decreasing 56% from 1970 to 2019—from 29.2 to 12.8 per 100,000, respectively—because of changing patterns in risk factors, increased screening, and improvements in treatment. From 2015 to 2019, the death rate declined by almost 2% per year. As with incidence rates, however, the decrease in overall mortality masks the rise in death rates in adults younger than 55 years.[2]

Tumor site tends to vary by patient age. In those aged younger than 65 years, the rectum is the most common site of colorectal cancer, accounting for 37% of cases in those under age 50 years and 36% in those 50 to 64 years of age. In individuals age 65 and older, rectal cancer accounts for 23% of colorectal cancer cases; the proximal colon is the most common site, accounting for 49% of cases.[11]

International

Although the incidence of colon and rectal cancer varies considerably by country, an estimated 1,931,590 cases occurred worldwide in 2020. High incidences of colon and rectal cancer cases are identified in the US, Canada, Japan, parts of Europe, New Zealand, Israel, and Australia. Low colorectal cancer rates are identified in Algeria and India. The majority of colorectal cancers still occur in industrialized countries.[12]

Increases in colorectal cancer in persons younger than 50 years has also been in many other high‐income countries aside from the US, including Australia, Canada, Germany, and the United Kingdom. In Austria, however, where opportunistic screening has been used in individuals aged 40 years and older since the 1980s, rates of colorectal cancer are increasing in those aged 20 to 39 years but decreasing in those age 40 to 49 years.[11]

Race

The incidence of colorectal cancer tends to be higher in Western nations than in Asian and African countries; however, within the United States, differences in incidence exist among Whites, Blacks, and Asians: the rate of new cases per 100,000 population is highest in Blacks (52.4 in men, 38.6 in women), then Whites (43.5 in men, 33.3 in women), then Hispanics (41.1 in men, 29.0 in women). In the US, Black men have the highest mortality (22.3 per 100,000 population) and Asian/Pacific Islander women and Hispanic women have the lowest mortality (7.7 and 8.5 per 100,000 population, respectively).[13] However, the incidence of colorectal cancer among people younger than 50 years is increasing much faster in Whites than in Blacks (2% vs 0.5% per year, respectively).[11]

A study by Yothers et al found that Black patients with resected stage II and stage III colon cancer had worse overall and recurrence-free survival compared with White patients who underwent the same therapy.[14]

A study of racial disparities in mortality rates between Black and White individuals with colorectal cancer by Robbins et al showed earlier and larger reductions in death rates for Whites from 1985-2008.[15]  This racial disparity could be decreased with greater education to the Black population regarding colorectal cancer prevention and access to treatment, including colonoscopies and polypectomies.

Sex

The incidence of colorectal malignancy is slightly higher in males than in females. The overall age-adjusted incidence of colorectal cancer in all races was 43.4 per 100,000 for males and 32.8 per 100,000 for females in 2015-2019, yielding a male-female ratio of 1.32:1. Mortality rates for colorectal cancer in 2016-2020 were also higher in males (15.7 per 100,000) than in females (11.0 per 100,000).[13]  

Age

The incidence of colorectal cancer starts to increase after age 35 and rises rapidly after age 50, peaking in the seventh decade. More than 90% of colon cancers occur after age 50. However, cases have been reported in young children and adolescents.[3]  The incidence rates of colorectal cancer increased by about 2% per year in adults younger than age 55 from 2006 to 2015, largely because of increases in rectal cancer.[2]

The American Cancer Society estimates that in 2023, colorectal cancer will account for 9% of cancer deaths in men and 8% in women. In the US, mortality rates have been decreasing in both sexes for the past 2 decades. The 5-year relative survival rate is 65.1% for colorectal cancer; however, for patients who are diagnosed with localized disease, the 5-year survival rate is 90.9%.[13]

A review of eight trials by Rothwell et al found that allocation to aspirin reduced death caused by cancer. Individual patient data were available from seven of the eight trials. Benefit was apparent after 5 years of follow-up. The 20-year risk of cancer death was also lower in the aspirin group for all solid cancers. A latent period of 5 years was observed before risk of death was decreased for esophageal, pancreatic, brain, and lung cancers. A more delayed latent period was observed for stomach, colorectal, and prostate cancer. Benefit was only seen for adenocarcinomas in lung and esophageal cancers. The overall effect on 20-year risk of cancer death was greatest for adenocarcinomas.[16]

A study by Banks et al showed the benefit of aspirin in preventing colon adenocarcinoma among patients with hereditary risk of colorectal cancer. In a study of 861 patients, 600 mg of aspirin daily for a mean of 25 months substantially reduced cancer incidence after 55.7 months among carriers of hereditary colorectal cancer. Further studies are needed to determine the ideal dosage and duration.[17]

In a review of 51 randomized controlled trials, Rothwell et al found that aspirin reduced the short-term incidence of cancer and the short- and long-term risk of cancer death. The authors conclude that their results support the use of daily aspirin for cancer prevention.[18]

The 5-year relative survival rates for colorectal cancer based on SEER stage are as follows[13] :

• Localized - 90.9%
• Regional - 72.8%
• Distant - 15.1%
• Unknown - 40.5%
• All stages - 65.1%

A review of 111,453 patients in the National Cancer Data Base who were diagnosed with early-stage (T1N0 or T2N0) rectal cancer from 1998 to 2010 found that increasing age, male sex, higher comorbidity score, and positive or unknown final surgical margins were associated with poorer long-term adjusted overall survival.[19]

Recurrence of rectal cancer, which usually develops in the first year after surgery, carries a poor prognosis. Recurrence may be local, distant, or both; local recurrence is more common in rectal cancer than in colon cancer. Reported rates of local recurrence have ranged from 3.7% to 50%.[20]  Factors that influence the development of recurrence include the following:

• Surgeon variability
• Grade and stage of the primary tumor
• Location of the primary tumor (eg, low rectal cancers have higher rates of recurrence
• Ability to obtain negative margins

Surgical therapy may be attempted for recurrence and includes pelvic exenteration or abdominal perineal resection in patients who had a sphincter-sparing procedure. Radiation therapy generally is used as palliative treatment in patients who have locally unresectable disease.

A study by Thong et al found that survivors of rectal cancer may benefit from increased focus, both clinical and psychological, on the possible long-term morbidity of treatment and its effects on health.[21]

For patient education resources, see Rectal Cancer.

All patients should undergo a complete history (including a family history) and assessment of risk factors for the development of rectal cancer. Many rectal cancers produce no symptoms and are discovered during digital or proctoscopic screening examinations.

Bleeding is the most common symptom of rectal cancer, occurring in 60% of patients. Bleeding often is attributed to other causes (eg, hemorrhoids), especially if the patient has a history of other rectal problems. Profuse bleeding and anemia are rare. Bleeding may be accompanied by the passage of mucus, which warrants further investigation.

Change in bowel habits is present in 43% of patients; change is not evident in some cases because the capacity of a rectal reservoir can mask the presence of small lesions. When change does occur it is often in the form of diarrhea, particularly if the tumor has a large villous component. These patients may have hypokalemia, as shown in laboratory studies. Some patients experience a change in the caliber of the stool. Large tumors can cause obstructive symptoms. Tumors located low in the rectum can cause a feeling of incomplete evacuation and tenesmus.

Occult bleeding is detected via a fecal occult blood test (FOBT) in 26% of all cases. Abdominal pain is present in 20% of the cases. Partial large-bowel obstruction may cause colicky abdominal pain and bloating. Back pain is usually a late sign caused by a tumor invading or compressing nerve trunks. Urinary symptoms may also occur if the tumor is invading or compressing the bladder or prostate.

Malaise is a nonspecific symptom and present in 9% of rectal cancer cases. Bowel obstruction due to a high-grade rectal lesion is rare, occurring in 9% of all cases. Pelvic pain is a late symptom, usually indicating nerve trunk involvement, and is present in 5% of all cases. Other manifestations include emergencies such as peritonitis from perforation (3%) or jaundice, which may occur with liver metastases (< 1%).

Physical examination is performed with specific attention to size and location of rectal cancer in addition to possible metastatic lesions, including enlarged lymph nodes or hepatomegaly. The remainder of the colon is also evaluated.

Digital rectal examination (DRE) provides an opportunity to readily detect abnormal lesions. The average finger can reach approximately 8 cm above the dentate line. Rectal tumors can be assessed for size, ulceration, and presence of any pararectal lymph nodes. Fixation of the tumor to surrounding structures (eg, sphincters, prostate, vagina, coccyx and sacrum) also can be assessed. DRE also permits a cursory evaluation of the patient's sphincter function. This information is necessary when determining whether a patient is a candidate for a sphincter-sparing procedure. Rigid proctoscopy is also performed to identify the exact location of the tumor in relation to the sphincter mechanism.

The etiology of colorectal cancer is unknown, but colorectal cancer appears to be multifactorial in origin and includes environmental factors and a genetic component. Diet may have an etiologic role, especially diet with high fat content. 

A cohort study by Tabung et al that followed 121,050 adults for 26 years found that in both men and women, intake of proinflammatory diets (replete in red, processed, and organ meat, for example) was associated with a significantly higher risk of developing colorectal cancer. Risk was especially high in overweight and obese men and, paradoxically, in lean women. Risk was also increased in men and women who do not drink alcohol.[22, 23]

Approximately 75% of colorectal cancers are sporadic and develop in people with no specific risk factors. The remaining 25% of cases occur in people with significant risk factors—most commonly, a family history or personal history of colorectal cancer or polyps, which are present in 15-20% of all cases. Other significant risk factors are certain genetic predispositions, such as hereditary nonpolyposis colorectal cancer (HNPCC; 4-7% of all cases) and familial adenomatous polyposis (FAP, 1%); and inflammatory bowel disease (IBD; 1% of all cases).

Diet

A high-fat, low-fiber diet is implicated in the development of colorectal cancer. Specifically, people who ingest a diet high in saturated animal fats and highly saturated vegetable oils (eg, corn, safflower) have a higher incidence of colorectal cancer. The mechanism by which these substances are related to the development of colorectal cancer is unknown.

Saturated fats from dairy products do not have the same carcinogenic effect, nor do oils containing oleic acid (eg, olive, coconut, fish oils). Omega-3 monounsaturated fatty acids and omega-6 monounsaturated fatty acids also appear to be less carcinogenic than unsaturated or polyunsaturated fats. In fact, epidemiologic data suggest that high fish consumption may provide a protective effect against development of colorectal cancer. Long-term diets high in red meat or processed meats appear to increase the risk of distal colon and rectal cancers.[24, 25]

The ingestion of a high-fiber diet may be protective against colorectal cancer. Fiber causes the formation of a soft, bulky stool that dilutes carcinogens; it also decreases colonic transit time, allowing less time for harmful substances to contact the mucosa. The decreased incidence of colorectal cancer in Africans is attributed to their high-fiber, low–animal-fat diet. This favorable statistic is reversed when African people adopt a western diet. Findings of a meta-analysis of 22 studies with a total of 2,876,136 subjects suggest that dietary fiber intake could be a protective factor against rectal cancer with a clinically relevant reduction in rectal cancer risk.[24]

Increased dietary intake of calcium appears to have a protective effect on colorectal mucosa by binding with bile acids and fatty acids. The resulting calcium salts may have antiproliferative effects, decreasing crypt cell production in the mucosa. A double-blind placebo-controlled study showed a statistically significant reduction in the incidence of metachronous colorectal adenomas.[26] Other dietary components, such as selenium, carotenoids, and vitamins A, C, and E, may have protective effects by scavenging free-oxygen radicals in the colon.

Alcohol

Alcohol intake of more than 30 g daily has been associated with increased risk of developing colorectal carcinoma, with risk of rectal cancer greater than that of colon cancer. Risk appears greater with beer than with wine.[27] Specifically, Kabat et al found that daily beer consumption of 32 ounces or more increases the risk of rectal cancer in men (odds ratio 3.5).[28]

Tobacco

Smoking, particularly when started at a young age, increases the risk of colorectal cancer.[29] Possible mechanisms for tumor development include the production of toxic polycyclic aromatic amines and the induction of angiogenic mechanisms due to tobacco smoke.

A study by Phipps et al found that smoking is also associated with increased mortality after colorectal cancer diagnosis, especially among patients with colorectal cancer with high microsatellite instability.[30]

Following cholecystectomy, bile acids flow freely, increasing exposure to the degrading action of intestinal bacteria. This constant exposure increases the proportion of carcinogenic bile acid byproducts. A meta-analysis by Giovannucci et al revealed an increased risk of proximal colon carcinoma following cholecystectomy. Although a large number of studies suggest the increased risk of proximal colon cancer in patients following cholecystectomy, the data are not compelling enough to warrant enhanced screening in this patient population.[3]

The relative risk of developing colorectal cancer is increased in the first-degree relatives of affected patients. For offspring, the relative risk is 2.42 (95% confidence interval [CI]: 2.20-2.65); when more than one family member is affected, the relative risk increases to 4.25 (95% CI; 3.01-6.08). If the first-degree family member is younger than 45 years at the time of diagnosis, the risk increase is even higher.[31]

Regarding the personal history of colorectal cancer or polyps: Of patients with colorectal cancer, 30% have synchronous lesions, usually adenomatous polyps. Approximately 40-50% of patients have polyps on a follow-up colonoscopy. Of all patients who have adenomatous polyps discovered via a colonoscopy, 29% of them have additional polyps discovered on a repeat colonoscopy one year later. Malignancy develops in 2-5% of patients. The risk of cancer in people who have had polyps removed is 2.7-7.7 times that of the general population.[32]

Familial adenomatous polyposis (FAP)

FAP is an autosomal dominant inherited syndrome that results in the development of more than 100 adenomatous polyps and a variety of extra-intestinal manifestations. The defect is in the APC gene, which is located on chromosome 5 at locus q21. The disease process causes the formation of hundreds of intestinal polyps, osteomas of bone, desmoid tumors, and, occasionally, brain tumors. Individually, these polyps are no more likely to undergo malignant transformation than are polyps in the general population. The increased number of polyps, however, predisposes patients to a greater risk of cancer. If left untreated, colorectal cancer develops in nearly 100% of these patients by age 40. Whenever the hereditary link is documented, approximately 20% of FAP cases are found to be caused by spontaneous mutation.

Hereditary nonpolyposis colorectal cancer

HNPCC, or Lynch syndrome, is an autosomal dominant inherited syndrome that occurs because of defective mismatch repair genes located on chromosomes 2, 3, and 7. Patients have the same number of polyps as the general population, but their polyps are more likely to become malignant. These patients also have a higher incidence of endometrial, gastric, thyroid, and brain cancers.

The revised Amsterdam criteria are used to select at-risk patients (all criteria must apply):

• Three or more relatives who are diagnosed with an HNPCC-associated cancer (colorectal, endometrium, small bowel, ureter, or renal pelvis)
• One affected person is a first-degree relative of the other two
• One or more cases of cancer are diagnosed before age 50 years
• At least two generations are affected
• FAP has been excluded
• Tumors have undergone a pathology review

The National Comprehensive Cancer Network (NCCN) guidelines discuss various strategies for identifying patients who should undergo testing for HNPCC. One approach is to test patients with any of the following[33] :

• Personal history of colorectal, endometrial, or other Lynch syndrome–associated cancer
• Suspicious family history
• ≥5% risk of having a mismatch repair (MMR) gene pathogenic variant, based on predictive models (PREMM5,11 MMRpro, MMRpredict)

Another strategy is so-called universal screening, in which all individuals newly diagnosed with colorectal cancer have either microsatellite instability (MSI) or immunohistochemistry (IHC) testing for absence of 1 of the 4 DNA MMR proteins. An alternative is to test all patients with colorectal cancer diagnosed before age 70 years, and test those 70 years and older only if they meet the Bethesda criteria for colorectal cancer. The primary method for detecting HNPCC in tumor tissue from biopsied or surgically resected specimens is with either immunohistochemistry or microsatellite instability testing. The NCCN guidelines also indicate that genetic counseling is not necessary before “routine tumor testing” at a center.[33]

The malignant pathway in these patients does not involve any adenoma-carcinoma sequence. Cancer risk increases with duration of disease. After 10 years, the incidence of colorectal cancer in ulcerative colitis (UC) is approximately 1% per year. Patients should be evaluated for dysplastic changes via an annual colonoscopy. Dysplasia is a precursor of cancer and when present, the risk of cancer is 30%.

The incidence of colorectal cancer in patients with Crohn disease is 4-20 times greater than that of the general population. Cancer occurs in patients with disease of at least 10 years' duration. The average age at cancer diagnosis, 46-55 years, is younger than that of the general population. Cancers often develop in areas of strictures and in de-functionalized segments of intestine. In patients with perianal Crohn disease, malignancy is often present in fistulous tracts. Patients with Crohn colitis should undergo the same surveillance regimen as those with UC.

Routine laboratory studies should include a complete blood count (CBC); serum chemistries, including liver and kidney function tests; and a carcinoembryonic antigen (CEA) test. A cancer antigen (CA) 19-9 assay, if available, may also be useful to monitor the disease.

Screening CBC may demonstrate a hypochromic, microcytic anemia, suggesting iron deficiency. The combined presence of vitamin B12 or folate deficiency may result in a normocytic or macrocytic anemia. All men and postmenopausal women with iron deficiency anemia require a GI evaluation.

Liver function tests are usually part of the preoperative workup. The results are often normal, even in patients with metastases to the liver.

Perform a CEA test in all patients with rectal cancer. A baseline level is obtained before surgery and a follow-up level is obtained after surgery. If a previously normalized CEA begins to rise in the postoperative period, this suggests possible recurrence. A CEA level higher than 100 ng/mL usually indicates metastatic disease and warrants a thorough investigation. The steps of the workup are outlined in Figure 1.

Diagnostics. Staging and workup of rectal cancer patients.

Fecal immunochemical tests appear to be accurate for detecting colorectal cancer. In a meta-analysis that examined 8 different brands of fecal immunochemical tests (FITs), Lee and colleagues found that FITs had high accuracy, high specificity, and moderately high sensitivity for the detection of colorectal cancers.[34, 35] The meta-analysis, which included 19 studies with sample sizes ranging from 80 to 27,860, showed that FITs had sensitivity of 0.79, specificity of 0.94, a positive likelihood ratio of 13.10, and a negative likelihood ratio of 0.23. The overall diagnostic accuracy of FITs was 95%.

The process of malignant transformation from adenoma to carcinoma takes several years. The purpose of screening is to eradicate potential cancers while they are still in the benign stage of the adenoma-carcinoma sequence. Screening also increases the likelihood of discovering existing cancers while they are still in the early stage.

Screening techniques

Screening techniques include the following:

• Guaiac-based fecal occult blood test (FOBT): Perform FOBT yearly by testing 2 samples from each of 3 consecutive stools. If any of the 6 sample findings is positive, recommend that the patient have the entire colon studied via colonoscopy or flexible sigmoidoscopy. FOBT has significant false-positive and false-negative rates.

• Stool DNA screening (SDNA): SDNA screening is done using polymerase chain reaction of sloughed mucosal cells in stool. This test evaluates for genetic alterations that lead to the cancer formation. Compared with no testing, SDNA testing is cost effective and has high sensitivity for invasive cancer.

• Fecal immunochemical test (FIT): Fecal immunochemical testing uses a monoclonal antibody assay to identify human hemoglobin. This test is more specific for lower GI tract lesions. The presence of the globin molecule is indicative of bleeding in the colon and rectum because the globin molecule is broken down during passage through the upper GI tract. This test is probably the wave of the future in fecal occult blood testing and may serve as screening in certain populations. FIT has comparable sensitivity for the detection of proximal and distal advanced neoplasia.[36]

• Rigid proctoscopy: Rigid proctosigmoidoscopy can be performed without an anesthetic, allows direct visualization of the lesion, and provides an estimation of the size of the lesion and degree of obstruction. This procedure is used to obtain biopsies of the lesion, assess ulceration, and determine the degree of fixation. Rigid proctoscopy has proved to be a highly reproducible method of determining the level of rectal cancer and does not depend on the operator and on the technique. Therefore, it gives an accurate measurement of the distance of the lesion from the anal verge; the latter is critical in deciding which operation is appropriate. The anal verge should be used as preferred landmark because the lowest edge of the rectal cancer and the anal verge can be visualized simultaneously during rigid proctoscopy evaluation. In conclusion, the level of rectal cancer must be confirmed by rigid proctoscopy.[37]

• Flexible sigmoidoscopy (FSIG): Perform this test every 5 years. Biopsy any lesions identified, and perform a full colonoscopy. With flexible sigmoidoscopy, lesions beyond the reach of the sigmoidoscope may be missed. FSIG introduces significant variability for the level of rectal cancer and level of rectum itself. Therefore, FSIG should not be used to determine the level of the rectal cancer.[37] Screening with flexible sigmoidoscopy is associated with significant decreases in the incidence of colorectal cancer (in both the distal and proximal colon) and in colorectal cancer mortality (distal colon only).[38]

• Combined glucose-based FOBT and flexible sigmoidoscopy: Theoretically, the combination of these two tests may overcome the limitations of each test.

• Double-contrast barium enema (DCBE): Although barium enema is the traditional diagnostic test for colonic polyps and cancer, the United States Preventive Services Task Force (USPSTF) did not consider barium enema in its 2008 update of colorectal cancer screening recommendations. The USPSTF noted that barium enema has substantially lower sensitivity than modern test strategies and has not been studied in trials of screening trials; its use as a screening test for colorectal cancer is declining.[39]

• CT colonography (CTC): Virtual colonoscopy (CTC) was introduced in 1994. After bowel preparation, the thin-cut axial colonic images are gathered in both prone and supine positions with high-speed helical CT scanner. Then, the images are reconstituted into a 3-dimensional replica of the entire colon and rectum. This provides a good visualization of the entire colon, including the antegrade and retrograde views of the flexures and haustral folds. Because this is a diagnostic study, patients with positive findings should undergo colonoscopic evaluation the same day.

• Fiberoptic flexible colonoscopy (FFC): FFC is recommended every 5-10 years. Colonoscopy allows full visualization of the colon and excision and biopsy of any lesions. The likelihood is extremely low that a new lesion could develop and progress to malignancy between examinations.

Average-risk screening

People who are asymptomatic, younger than 50 years, and have no other risk factors are considered at average risk for developing colorectal cancer. Screening of the average-risk population should begin at age 50 years and end at age 75 years.[39] Indications for screening in patients at average risk for colon and rectal cancer include the following:

• No symptoms and age 50-75 years
• No symptoms, but requesting screening
• Change in bowel habits
• Rectal and anal bleeding
• Unclear abdominal pain
• Unclear iron deficiency anemia

A French study found that even in patients with no personal or family history of colorectal polyps or cancer, starting colonoscopy screening at age 45 instead of age 50 can be valuable. In a prospective study that included 6027 consecutive screening colonoscopies, Karsenti et al found that for the 515 patients age 45 to 49 years, the average polyp detection rate was 26% and the average neoplasia detection rate was nearly 4%. By comparison, for the 4438 patients older than 50 years, the average polyp detection rate exceeded 35% and the average neoplasia detection rate exceeded 5%. Both rates were markedly lower in the 1076 study patients age 44 years and younger.[40]

The US Multi-Society Task Force on Colorectal Cancer (USMSTF) has endorsed various cost-effective screening regimens. Screening options for the detection of adenomatous polyps and cancer for asymptomatic adults 50 years and older include FSIG every 5 years, colonoscopy every 10 years, DCBE every 5 years, or CTC every 5 years. Testing options that primarily detect cancer in asymptomatic adults 50 years and older include annual glucose-based FOBT with high test sensitivity for cancer; annual FIT with high test sensitivity for cancer; or SDNA with high test sensitivity for cancer, although the optimal interval for SDNA is uncertain.

Each screening test has unique advantages. They have been shown to be cost-effective and have associated risks and limitations. Ultimately, patient preferences and availability of testing resources guide the selection of screening tests.

The main disadvantage of the structural tests is their requirement for bowel preparation. The primary advantage of structural tests is that they can detect polyps as well as cancer. Conscious sedation is usually used for colonoscopy. FSIG is uncomfortable, and screening benefit is limited to sigmoid colon and rectum. Risks for colonoscopy, DCBE, and CTC may rarely include perforation; colonoscopy may also be associated with bleeding. Positive findings on FSIG, DCBE, and CTC usually result in referral for colonoscopy.

The advantages of the stool tests are that they are noninvasive, do not require bowel preparation, can be done in the privacy of the patient's home, and are more readily available to patients without adequate insurance coverage or local resources.

In the United States, colon and rectal cancer screening rates have been averaging between 50% and 60%. Brounts and colleagues studied colorectal cancer screening in the Military Healthcare System. In this study, overall screening rates were lower in minority groups than in whites. Also, overall lower screening rates were identified in patients younger than 65 years. Although ethnicity-related, gender-related, and age-related disparities were observed, screening rates were improved in this equal-access health care system when compared with national averages.[41]

Screening of high-risk patients

A patient's family history or personal history may indicate increased risk for colorectal cancer. Patients at high risk for colon and rectal cancer due to family history who should be included in surveillance programs include those with the following:

• Family history of colon and rectal cancer
• First-degree relative with adenoma aged younger than 60 years
• Genetic cancer syndromes
• Hereditary nonpolyposis colorectal cancer (HNPCC)
• Familial adenomatous polyposis (FAP)

Patients at high risk for colon and rectal cancer due to personal history who should be included in surveillance programs includes the following:

• Personal history of inflammatory bowel disease (IBD)
• Personal history of adenomas
• Personal history of colon or rectal cancer

Screening recommendations by risk factor are as follows:

• First-degree relative affected: Offer family members the same screening tests as the general population; however, begin the screening at age 40 years rather than age 50 years. These people often undergo colonoscopy as their initial screening test, particularly if the relative was diagnosed with cancer at a young age.

• Family history of FAP: Genetic counseling and genetic testing are recommended to determine whether the person is a gene carrier. Current tests are approximately 80% accurate. In the remaining 20%, the mutation cannot be identified. Genetic testing is useful only if the test result is positive or if the test is a true negative (ie, mutation present in other family members are not identified in the patient being tested). Flexible sigmoidoscopy should be offered to known gene carriers and persons with an indeterminate carrier status every year to look for polyps. When polyposis develops, consider colectomy.

• Family history of HNPCC: Genetic counseling and genetic testing should be offered to individuals whose family histories meet the Amsterdam criteria (see Causes, above). Patients with documented HNPCC should undergo colonoscopy every 1-2 years when 20-40 years of age and every year when older than 40 years. Since these cancers tend to be located on the right side of the colon, flexible sigmoidoscopy is not recommended.

• Personal history of adenomatous polyps: Patients who have adenomatous polyps removed during colonoscopy should have a repeat examination at 1 to 3 years. If the findings of this examination are normal, follow up at 5 years.

• Personal history of colorectal cancer: Patients who have colorectal cancer and undergo resection for cure should have a repeat colonoscopy after 1 year. If this examination reveals no abnormalities, follow up at 3 years. In the absence of disease, perform colonoscopy every 5 years thereafter.

• Personal history of IBD: Surveillance colonoscopy is performed to look for dysplasia as a marker for colorectal cancer in patients with long-standing IBD. These patients should undergo colonoscopy every 1-2 years after 8 years of diffuse disease or after 15 years of localized disease. Random biopsies are performed at specific intervals throughout the colon and rectum. Colectomy is recommended when dysplasia is present.

Histopathologic features such as poor differentiation, lymphovascular and/or perineural invasion, T4 tumor stage, and clinical findings such as obstruction or perforation, and elevated preoperative CEA levels are all associated with increased recurrence rates and worse survival.

Dukes Classification

In 1932, Cuthbert E. Dukes, a pathologist at St. Mark Hospital in England, introduced a staging system for rectal cancer. His system divided tumor classification into three stages, as follows:

• Those limited to the rectal wall (Dukes A)
• Those that extend through the rectal wall into extra-rectal tissue (Dukes B)
• Those with metastases to regional lymph nodes (Dukes C).

This system was modified by others to include subdivisions of stages B and C, as follows:

• Stage B was divided into B1 (tumor penetration into muscularis propria) and B2 (tumor penetration through muscularis propria).
• Stage C was divided into C1 (tumor limited to the rectal wall with nodal involvement) and C2 (tumor penetrating through the rectal wall with nodal involvement).
• Stage D was added to indicate distant metastases

Tumor, Node, Metastasis (TNM) System

This system was introduced in 1954 by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (IUAC). The TNM system is a universal staging system for all solid cancers that is based on clinical and pathologic information. Each category is independent.

Neither the Dukes nor the TNM system includes prognostic information such as histologic grade, vascular or perineural invasion, or tumor DNA ploidy. TNM staging of rectal cancer correlates well with 5-year survival rates of patients with rectal cancer (see the TNM stage–dependent 5-year survival rate for rectal carcinomas).

TNM classification for cancer of the colon and rectum (AJCC)

Primary tumor (T) includes the following:

• TX - Primary tumor cannot be assessed or depth of penetration not specified
• T0 - No evidence of primary tumor
• Tis - Carcinoma in situ (mucosal); intraepithelial or invasion of the lamina propria
• T1 - Tumor invades submucosa
• T2 - Tumor invades muscularis propria
• T3 - Tumor invades through the muscularis propria into the subserosa or into non-peritonealized pericolic or perirectal tissue
• T4 - Tumor directly invades other organs or structures and/or perforates the visceral peritoneum

Regional lymph nodes (N) include the following:

• NX - Regional lymph nodes cannot be assessed
• N0 - No regional lymph node metastasis
• N1 - Metastasis in 1-3 pericolic or perirectal lymph nodes
• N2 - Metastasis in 4 or more pericolic or perirectal lymph nodes
• N3 - Metastasis in any lymph node along the course of a named vascular trunk

Distant metastasis (M) include the following:

• MX - Presence of metastasis cannot be assessed
• M0 - No distant metastasis
• M1 - Distant metastasis

Table 1. Comparison of AJCC Definition of TNM Staging System to Dukes Classification. (Open Table in a new window)

The TNM stage–dependent 5-year survival rate for rectal carcinomas is as follows:

• Stage I - 90%
• Stage II - 60-85%
• Stage III - 27-60%
• Stage IV - 5-7%

A multidisciplinary approach that includes surgery, medical oncology, and radiation oncology is required for optimal treatment of patients with rectal cancer.[42]  See the image below.

Staging and treatment. Rectal cancer treatment algorithm (surgery followed by adjuvant chemotherapy and radiotherapy). Initial stages are Endorectal ultrasound staging (uT).

Determination of the optimal treatment plan for a patient with rectal cancer involves a complex decision-making process. Strong considerations should be given to the intent of surgery, possible functional outcome, and preservation of anal continence and genitourinary functions. The timing of surgical resection is dependent on the size, location, extent, and grade of the rectal carcinoma. The number of lymph nodes removed (12 or more; minimum, 10) at the time of surgery impacts staging accuracy and prognosis.

The first step involves achievement of cure, because the risk of pelvic recurrence is high in patients with rectal cancer and locally recurrent rectal cancer has a poor prognosis. Functional outcome of different treatment modalities involves restoration of bowel function with acceptable anal continence and preservation of genitourinary functions. Preservation of both anal and rectal reservoir function in treatment of rectal cancer is highly preferred by patients. Sphincter-saving procedures for rectal cancer are now considered the standard of care.[43]

Factors influencing sphincter and organ preservation in patients with rectal cancer can be described as follows[43] :

• Surgeon training
• Surgeon volume
• Use of neoadjuvant chemoradiotherapy

The following factors are associated with difficult sphincter preservation:

• Male sex
• Morbid obesity
• Preoperative incontinence
• Direct involvement of anal sphincter muscles with carcinoma
• Bulky tumors within 5 cm from the anal verge

Patients with the following may be candidates for local excision:

• Lesions located in low rectum (within 8-10 cm)
• Lesions occupying less than one third of the rectal circumference
• Mobile exophitic or polypoid lesions
• Lesions less than 3 cm in size
• T1 lesions
• Low-grade tumor (well or moderately differentiated)
• Negative nodal status (clinical and radiographic)

Disadvantages of abdominoperineal resection include the following:

• Need for permanent colostomy
• Significantly higher short-term morbidity and mortality
• Significantly higher long-term morbidities
• Higher rate of sexual and urinary dysfunction

Except for stage I rectal cancer, neoadjuvant and adjuvant chemotherapy and radiation therapy are standard aspects of treatment. Chemotherapy is with combination regimens, along with biologic agents in metastatic cases.

Because biologic therapy with programmed death 1 (PD-1) inhibitors has proved effective in metastatic rectal cancer that is mismatch repair deficient, Cercek et al conducted a prospective phase 2 study of the PD-1 inhibitor dostarlimab in 12 patients with mismatch repair–deficient stage II or III rectal adenocarcinoma. Dostarlib was administered every 3 weeks for 6 months. All 12 patients had a clinical complete response, and none underwent chemoradiotherapy or surgery. During follow-up ranging from 6 to 25 months, no cases of progression or recurrence had been reported.[44]

To view a multidisciplinary tumor board case discussion, see Memorial Sloan Kettering e-Tumor Boards: Newly Diagnosed With Moderately Differentiated Rectal Adenocarcinoma.

Preoperative radiation therapy (RT) has many potential advantages, including the following:

• Tumor down-staging
• An increase in resectability, possibly permitting the use of a sphincter-sparing procedure
• A decrease in tumor viability, which may decrease the risk of local recurrence

A further advantage of preoperative RT is that radiation works better in well-oxygenated tissues. Postoperatively, tissues are relatively hypoxic as a result of surgery and may be more resistant to radiotherapy. In addition, if patients have postoperative complications, initiation of adjuvant therapy may be delayed.

Preoperative RT also minimizes the radiation exposure of small bowel loops due to pelvic displacement and adhesions following surgery.[45, 46] In a study of patients with locally advanced rectal cancer, a higher dose of radiation delivered using an endorectal boost increased major response in T3 tumors by 50% without increasing surgical complications or toxicity.[47]

The disadvantages of preoperative RT include the following:

• Delay in definitive resection
• Possible over-treatment of early-stage (stage I and II) rectal cancer
• Possible loss of accurate pathologic staging
• Increased postoperative complications and morbidity and mortality rates secondary to radiation injury

Preoperative RT decreases the risk of tumor recurrence in patients with stage II or III disease; however, this does not translate into a decrease in distant metastases or an increase in survival rate. Some recent reports cite an increase in survival; however, this is still the minority opinion.

In sum, preoperative RT may be effective in improving local control in localized rectal cancer but is only of marginal benefit in attainment of improved overall survival; it does not diminish the need for permanent colostomies, and it may increase the incidence of postoperative surgical infections; it also does not decrease the incidence of long-term effects on rectal and sexual function.[48] The authors recommend preoperative chemoradiation therapy in patients with large bulky cancers and with obvious nodal involvement.[45]

A study by Cassidy et al found that elimination of neoadjuvant radiation therapy for select patients with stage II and III rectal adenocarcinoma is associated with worse overall survival. In their review of 21,707 patients with clinical T2N1 (cT2N1), cT3N0, or cT3N1 rectal cancers in the National Cancer Data Base, the 5‐year actuarial overall survival rate was 75% for patients who received neoadjuvant chemoradiotherapy versus 67.2% for those who received neoadjuvant multiagent chemotherapy (P < 0.01).[49]

Neoadjuvant long-course RT plus radiation sensitization with a fluoropyrimidine (eg, capecitabine, fluorouracil), followed by a treatment break of approximately 8 weeks before surgical excision and concluding with adjuvant chemotherapy, has been a standard of care in rectal cancer. Other options for neoadjuvant treatment include the following[1, 42] :

• Short-course RT
• Chemotherapy (eg, with FOLFOX [leucovorin calcium (folinic acid), fluorouracil, oxaliplatin] or CapeOX [capecitabine plus oxaliplatin])
• Short-course RT followed by chemotherapy

The randomized RAPIDO trial found that at 3-year follow-up, patients receiving short-course RT (5x5 Gy), then chemotherapy with CapeOX or FOLFOX4 followed by total mesorectal excision (TME) had a disease-related treatment failure rate of 23.7%, compared with 30.4% in patients who received neoadjuvant capecitabine-based chemoradiotherapy followed by TME and optional adjuvant chemotherapy.[50]  

For locally advanced rectal cancer, a newer standard of care is total neoadjuvant therapy (TNT), which consists of induction chemotherapy (eg, with CapeOX or modified FOLFOX6 [mFOLFOX6]) followed by chemoradiation therapy and then TME. In a retrospective cohort analysis of patients with locally advanced (T3/4 or node-positive) rectal cancer, the cohort that received TNT (n = 308) had higher rates of complete response and were more likely to have temporary ileostomy reversed within 15 weeks of proctectomy, compared with the cohort that received the standard regimen of neoadjuvant chemoradiation therapy, surgery, and planned adjuvant chemotherapy (n = 320).[51]

The local transanal excision of rectal cancer is reserved for early-stage cancers in a select group of patients. The lesions amenable for local excision are small (< 3 cm in size), occupying less than a third of a circumference of the rectum, preferably exophytic/polypoid, superficial and mobile (T1 and T2 lesions), low-grade tumors (well or moderately differentiated) that are located in low in the rectum (within 8 cm of the anal verge). There should also be no palpable or radiologic evidence of enlarged mesenteric lymph nodes. The likelihood of lymph node involvement in this type of lesion ranges from 0-12%.[43, 52]

A study by Peng et al found that local excision in early-stage rectal cancer may result in high local recurrence rates. The authors recommend limiting the use of this procedure to highly selected groups of patients, specifically those with a tumor size of 2.5 cm or smaller.[53]

Local excision is increasingly used to treat stage I rectal cancers despite its inferiority to total mesorectal excision, which is the current standard of care. In a study of all rectal cancer patients in the National Cancer Data Base from 1998 through 2010, researchers found that local excision was used to treat 46.5% of the patients with T1 tumors and 16.8% of those with T2 tumors. For patients with T1 cancer, local excision rates increased from 39.8% in 1998 to 62.0% in 2010. For patients with T2 cancers, rates increased from 12.2% to 21.4%.[54, 19]

Preoperative endorectal ultrasound should be performed. If nodes are identified as suggestive of cancer, do not perform transanal excision. The lesion is excised with the full thickness of the rectal wall, leaving a 1-cm margin of normal tissue. The defect is usually closed; however, some surgeons leave it open. Unfavorable pathologic features such as positive resection margins, lymphovascular invasion, lymph node metastasis, perineural invasions, and recurrent lesion at follow-up evaluations mandate salvage resection. Usually, an abdominal perineal resection or proctosigmoidectomy with coloanal anastomosis is performed as a salvage resection following failure of local excision.[52]

The advantages of local excision include rapid recovery, minimal effect on sphincter function, and relatively low perioperative morbidity and mortality. Recovery is usually rapid. The 5-year survival rate after transanal excision ranges from 65-100% (these figures include some patients with T2 lesions). The local recurrence rate ranges from 0-40%. Patients with lesions that display unfavorable histologic features but are excised completely may be treated with adjuvant radiation therapy.

Cancer recurrence following transanal excision of early rectal cancer has been studied by Weiser et al.[55] Failures due to transanal excision are mostly advanced local disease and are not uniformly salvageable with radical pelvic excision. These patients may require extended pelvic dissection with en bloc resection of adjacent pelvic organs such as the pelvic side wall with autonomic nerves, coccyx, prostate, seminal vesicle, bladder, vagina, ureter, ovary, and uterus. The long-term outcome in patients with recurrent rectal carcinoma who undergo radical resection is less favorable than expected, relative to the early stage of their initial rectal carcinoma.[55]

In summary, the treatment of T1 and T2 rectal cancers continues to be challenging. Local excision is associated with higher rate of recurrence, especially in T2 lesions. Ultimately, 15-20% of patients may experience recurrence. When local recurrence is detected, patients usually have advanced disease, requiring extensive pelvic excisions. Therefore, strict selection criteria are essential when considering local excision. All patients should be informed of the risk of local recurrence and the lower cure rates associated with recurrence.[43, 55, 56]

This radiotherapy method differs from external-beam radiation therapy in that a larger dose of radiation can be delivered to a smaller area over a shorter period. Selection criteria for this procedure are similar to those for transanal excision. The lesion can be as far as 10 cm from the anal verge and no larger than 3 cm. Endocavitary radiation is delivered via a special proctoscope and is performed in an operating room with sedation. The patient can be discharged on the same day.

A total of 6 applications of high-dose (20 to 30 Gy), low-voltage radiation (50kV) is given over the course of 6 weeks. Each radiotherapy session produces a rapid shrinkage of the rectal cancer lesion. An additional booster dose can be given to the tumor bed. The overall survival rate is 83%, although the local recurrence rate is as high as 30%.[52]

Transanal endoscopic microsurgery is another form of local excision that uses a special operating proctoscope that distends the rectum with insufflated carbon dioxide and allows the passage of dissecting instruments. This method can be used on lesions located higher in the rectum and even in the distal sigmoid colon. Transanal endoscopic microsurgery has not come into wide use yet because of a significant learning curve and a lack of availability.

Procedures are described that use the traditional open technique. All of these procedures, except the perineal portions, can also be performed using laparoscopic techniques, with excellent results. Laparoscopic surgery offers the advantages of faster recovery time and less pain, compared with open surgery. The nuances of the laparoscopic technique used are beyond the scope of this discussion.

A study by Li et al found that laparoscopic and open surgery for middle and lower rectal cancer are associated with similar long-term outcomes. The study shows the value of technical experience when performing laparoscopic surgery and encourages the use of this surgery by experienced teams.[57]

Long-term results from the UK Medical Research Council trial of laparoscopically assisted versus open surgery for colorectal cancer showed no differences between groups in overall or disease-free survival or recurrence rates.[58]  

In an international randomized, open-label trial (COlorectal cancer, Laparoscopic or Open Resection II [COLOR II]) involving 1044 patients with localized solitary rectal cancer located within 15 cm from the anal verge, comparison of the locoregional recurrence rate at 3 years showed no significant differences between the laparoscopic and open-surgery groups (5% in both). Disease-free-survival (74.8% and 70.8%, respectively), overall survival (86.7% and 83.6%), and rate of complications also showed no significant differences.[59]

Low anterior resection (LAR)

LAR is generally performed for lesions in the middle and upper third of the rectum and, occasionally, for lesions in the lower third. Because this is a major operation, patients who undergo LAR should be in good health. They should not have any preexisting sphincter problems or evidence of extensive local disease in the pelvis.

Patients will not have a permanent colostomy but should be informed that a temporary colostomy or ileostomy may be necessary. They also must be willing to accept the possibility of slightly less-than-perfect continence after surgery, although this is not usually a major problem.

Other possible disturbances in function include transient urinary dysfunction secondary to weakening of the detrusor muscle. This occurs in 3-15% of patients. Sexual dysfunction is more prominent and includes retrograde ejaculation and impotence. In the past, this has occurred in 5-70% of men, but more recent reports indicate that the current incidence is lower.[45]

The operation entails full mobilization of the rectum, sigmoid colon, and, usually, the splenic flexure. Mobilization of the rectum requires a technique called total mesorectal excision (TME). TME involves sharp dissection in the avascular plane that is created by the envelope that separates the entire mesorectum from the surrounding structures. This includes the anterior peritoneal reflection and Denonvilliers fascia anteriorly and preserves the inferior hypogastric plexus posteriorly and laterally. TME is performed under direct visualization. Mesorectal spread can occur by direct tumor spread, tumor extension into lymph nodes, or perineural invasion of tumor.[37, 56, 45]

TME yields a lower local recurrence rate (4%) than transanal excision (20%), but it is associated with a higher rate of anastomotic leak (11%). For this reason, TME may not be necessary for lesions in the upper third of the rectum. The distal resection margin varies depending on the site of the lesion. A 2-cm margin distal to the lesion must be achieved. For the tumors of the distal rectum, less than 5 cm from the anal verge, the minimally accepted distal margin is 1 cm in the fresh specimen. Distal intra-mural spread beyond 1 cm occurs rarely. Distal spread beyond 1 cm is associated with aggressive tumor behavior or advanced tumor stage.[37]

The procedure is performed with the patient in the modified lithotomy position with the buttocks slightly over the edge of the operating table to allow easy access to the rectum.[56]   A circular stapling device is used to create the anastomosis. A double-stapled technique is performed. This entails transection of the rectum distal to the tumor from within the abdomen using a linear stapling device. The proximal resection margin is divided with a purse-string device.

After sizing the lumen, the detached anvil of the circular stapler is inserted into the proximal margin and secured with the purse-string suture. The circular stapler is inserted carefully into the rectum, and the central shaft is projected through or near the linear staple line. Then, the anvil is engaged with the central shaft, and, after completely closing the circular stapler, the device is fired. Two rings of staples create the anastomosis, and a circular rim or donut of tissue from the proximal and distal margins is removed with the stapling device.

According to a study by Maurer et al, the introduction of TME has resulted in an impressive reduction of local recurrence rates. TME appears to have improved survival in patients without systemic disease.[60]

The anastomotic leak rate with this technique ranges from 3-11% for middle-third and upper-third anastomosis to 20% for lower-third anastomosis. For this reason, some surgeons choose to protect the lower-third anastomosis by creating a temporary diverting stoma. This is especially important when patients have received preoperative radiation therapy. The rate of stenosis is approximately 5-20%. A hand-sewn anastomosis may be performed; if preferred, the anastomosis is performed as a single-layer technique. The leak and stenosis rates are the same.

In R0 resection, the inferior mesenteric artery (IMA) should be excised at its origin, but this rule is not mandated by available supportive evidence. Patients with non–en-bloc resection, positive radial margins, positive proximal and distal margin, residual lymph node disease, and incomplete preoperative and intra-operative staging would not be considered to have complete resection of cancer (R0 resection).[37] Patients with R1 and R2 resection are considered to have an incomplete resection for cure. Incomplete R1 and R2 resection does not change the TNM stage but affects the curability.[37]

In a 2012 multicenter, randomized controlled trial, mesorectal excision with lateral lymph node dissection was associated with a significantly longer operation time and significantly greater blood loss than mesorectal excision alone.[61]

A study by Han et al analyzing factors that might be predictive of pathologic complete response (pCR) in patients with stage II and III rectal cancer undergoing TME after preoperative chemoradiation indentified high tumor location and low carcinoembryonic antigen (CEA) level after chemoradiation therapy as independent predictive factors for pCR.[62]

Colo-anal anastomosis (CAA)

Very distal rectal cancers that are located just above the sphincter occasionally can be resected without the need for a permanent colostomy. The procedure is as already described; however, the pelvic dissection is carried down to below the level of the levator ani muscles from within the abdomen. A straight-tube coloanal anastomosis (CAA) can be performed using the double-stapled technique, or a hand-sewn anastomosis can be performed transanally.[45]

The functional results of this procedure have been poor in some patients, who experience increased frequency and urgency of bowel movements, as well as some incontinence to flatus and stool. An alternative to the straight-tube CAA is creation of a colonic J pouch. The pouch is created by folding a loop of colon on itself in the shape of a J. A linear stapling or cutting device is inserted into the apex of the J, and the stapler creates an outer staple line while dividing the inner septum. The J-pouch anal anastomosis can be stapled or hand sewn.

An alternative to doing the entire dissection from within the abdomen is to begin the operation with the patient in the prone jackknife position. The perineal portion of this procedure involves an intersphincteric dissection via the anus up to the level of the levator ani muscles. After the perineal portion is complete, the patient is turned to the modified lithotomy position and the abdominal portion is performed. Either a straight-tube or colonic J-pouch anal anastomosis can be created; however, both must be hand sewn.[45]

The advantages of the J pouch include decreased frequency and urgency of bowel movements because of the increased capacity of the pouch. A temporary diverting stoma is performed routinely with any coloanal anastomosis.

Laparoscopic Rectal Resections

The first laparoscopic colectomy study was published in 1991 by Jacobs et al. It included 20 cases, mostly right and sigmoid colectomies but only one low anterior rectal resection and one abdominal perineal resection.[63] In the succeeding decades, minimally invasive rectal procedures, including radical proctectomy, became a well-accepted practice for rectal cancers. Compared with open resection, laparoscopic proctectomy is associated with earlier return of bowel function and faster overall recovery. However, operating room time, and laparoscopic resections should be performed by experienced surgeons.

In 2012, Trastulli et al compared open and laparoscopic rectal resection for cancer in a meta-analysis of nine randomized clinical trials that included1544 patients. In the study, patients who underwent laparoscopic rectal resection experienced shorter hospital stay; earlier return of bowel function; reduced intraoperative blood loss; and less postoperative bleeding, late intestinal adhesion obstruction, and late morbidity. Intra-operative and late oncological outcomes were similar in the two groups.[64]  

The COLOR-II trial, a European multi-center, randomized phase III noninferiority study, concluded that in the hands of skilled surgeons, the safety, resection margins, and completeness of rectal resection are similar with laparoscopic and open proctectomy. In both the laparoscopic group (n=739) and the open proctectomy group (n=364), 10% of patients had positive circumferential margins (< 2 mm). Morbidity and mortality within 20 days after surgery were similar in both groups. The laparoscopic surgery group had less blood loss, earlier return of bowel function, and shorter duration of hospital stay, but laparoscopic surgeries took longer.[65]  

However, another multi-center randomized trial (ACOSOG Z6051), conducted in patients with stage II and III rectal cancer in the United States and Canada, failed to support the noninferiority of laparoscopic resection for rectal cancer. A successful rectal resection—defined as a tumor-free circumferential radial margin larger than 1 mm and complete total mesorectal resection—was identified in 81.7% of 220 laparoscopic rectal resection cases and 86.9% of 222 open resection cases, which did not meet the study's criterion for noninferiority. Conversion from laparoscopic resection to open rectal resection occurred in 11% of the patients. Operative time was significantly longer for laparoscopic procedures than for open proctectomy.[66]  

Abdominal Perineal Resection (APR)

APR is performed in patients with lower-third rectal cancers. APR should be performed in patients in whom negative margin resection (see Table 2, below) will result in loss of anal sphincter function. This includes patients with involvement of the sphincters, preexisting significant sphincter dysfunction, or pelvic fixation, and sometimes is a matter of patient preference.

Table 2. Acceptable Minimal Distal and Proximal Resectional Margins for Rectal Cancer. ^{[37, 67]} (Open Table in a new window)

A 2-team approach is often used, with the patient in modified lithotomy position. The abdominal team mobilizes the colon and rectum, transects the colon proximally, and creates an end-sigmoid colostomy. The perineal team begins by closing the anus with a purse-string suture and making a generous elliptical incision. The incision is carried through the fat using electrocautery. The inferior rectal vessels are ligated and the anococcygeal ligament is divided. The dissection plane continues posteriorly, anterior to the coccyx to the level of the levator ani muscles.

Then, the surgeon breaks through the muscles and retrieves the specimen that has been placed in the pelvis. The specimen is brought out through the posterior opening, and the anterior dissection is continued carefully. Care must be taken to avoid the prostatic capsule in the male and the vagina in the female (unless posterior vaginectomy was planned). The specimen is removed through the perineum, and the wound is irrigated copiously. A closed-suction drain is left in place, and the perineal wound is closed in layers, using absorbable sutures. During this time, the abdominal team closes the pelvic peritoneum (this is not mandatory), closes the abdomen, and matures the colostomy.[45]

In patients who have rectal cancer with adjacent organ invasion, en bloc resection should be performed in order to not compromise cure. This situation is encountered in 15% of rectal cancer patients. The urinary bladder is the organ most commonly involved in locally advanced rectal carcinoma. Extended, en bloc resection may involve partial or complete cystectomy.[37, 45]  In women, rectal carcinoma also commonly invades the uterus, adnexa, and posterior vaginal wall.

Treatment of colorectal cancer with liver metastasis

Chemotherapeutic regimens for liver metastasis including systemic and intrahepatic administration have only had limited benefit. Systemic chemotherapy had 18-28% response rates. However, one meta-analysis found that carefully selected patients with metastatic colorectal cancer may benefit from preoperative chemotherapy with curative intent.[68]

It is well accepted that liver resections in selected patients are beneficial. Overall, 5-year survival rates following surgical resection of liver metastasis vary from 20-40%. A study by Dhir et al found that among patients undergoing hepatic resection for colorectal metastasis, a negative margin of 1 cm or more had a survival advantage.[69]

Although radical resection of rectum is the mainstay of therapy, surgery alone has a high recurrence rates. The local recurrence rate for rectal cancers treated with surgery alone is 30-50%. Rectal adenocarcinomas are sensitive to ionizing radiation. Radiation therapy can be delivered preoperatively, intraoperatively, or postoperatively and with or without chemotherapy.

Tumor stage, grade, number of lymph node metastases, lymphovascular involvement, signet cell appearance, achievement of negative radial margins, and distance from the radial margin are important prognostic indicators of local and distant recurrences. Low anterior (LAR) or abdominal-perineal resection (APR) in conjunctions with total mesorectal excision (TME) should be performed for optimal surgical therapy.

A study by Margalit et al found that patients older than 75 years had difficulty tolerating combined modality chemotherapy to treat rectal cancer. They required early termination of treatment, treatment interruptions, and/or dose reductions.[70]

Intraoperative radiation therapy

Intraoperative radiation therapy is recommended in patients with large, bulky, fixed, unresectable cancers. The direct delivery of high-dose radiotherapy is believed to improve local disease control. Intraoperative radiation therapy requires specialized, expensive operating room equipment, limiting its use.

Adjuvant radiation therapy

The advantages of postoperative radiation therapy include immediate definitive resection and accurate pathologic staging information before beginning ionizing radiation. The disadvantages of postoperative radiation therapy include possible delay in adjuvant radiation therapy if postoperative complications ensue; no effect on tumor cell spread at the time of surgery; and the decreased effect of radiation in tissues with surgically-induced hypoxia. Published randomized trials suggest that preoperative or postoperative radiation therapy appears to have a significant impact on local recurrence but does not increase survival rates.[45]

Adjuvant chemotherapy

Chemotherapy options for rectal cancer have greatly expanded in recent years, but the efficacy of chemotherapy remains incomplete and its toxicities remain substantial. Combination therapy with use of as many drugs as possible is needed for maximal effect against rectal cancer.[1] See Table 3, below.

Table 3. Common Chemotherapeutic Regimens for Colon and Rectal Cancer (Open Table in a new window)

The most useful chemotherapeutic agent for colorectal carcinoma is 5-fluorouracil (5-FU), an antimetabolite. Fluorouracil is a fluorinated pyrimidine, which blocks the formation of thymidylic acid and DNA synthesis. Clinically, it offers good radiosensitization without severe side effects, although diarrhea can be dose limiting and, if severe, life-threatening. 5-FU has been used in conjunction with radiation (combined modality) therapy before surgery (neoadjuvant), as well as after surgery.

Stage I (T1-2, N0, M0) rectal cancer patients do not require adjuvant therapy due to their high cure rate with surgical resection. High-risk patients, including those with poorly differentiated tumor histology and those with lymphovascular invasion, should be considered for adjuvant chemotherapy and radiotherapy.

National Comprehensive Cancer Network (NCCN) guidelines recommend FOLFOX (folinic acid [leucovorin], 5-FU, and oxaliplatin) or CapeOx (capecitabine plus oxaliplatin) as reasonable for patients with high-risk or intermediate-risk stage II disease; however, FOLFOX is not indicated for good- or average-risk stage II rectal cancer.[1] FOLFOX is associated with neuropathy, and one long-term study confirmed that although overall neurotoxicity did not significantly increase after a median of 7 years, rates of specific neurotoxicity (numbness and tingling of the hands and feet) remained elevated.[71]

Use of FOLFOX or FOLFIRI (folinic acid, 5-FU, and irinotecan) is recommended in treatment of patients with stage III or IV disease.

Biologic therapy

Cetuximab, a recombinant humanized monoclonal antibody that binds specifically to the epithelial growth factor receptor (EGFR), is recommended as part of combination therapy (eg, with FOLFOX or FOLFIRI) for unresectable metastatic rectal cancer.[1] Cetuximab should not be used in patients with the KRAS mutation.[72] In addition, a study by Maughan et al found that cetuximab added to oxaliplatin-based chemotherapy has no confirmed benefit in patients with advanced colorectal cancer.[73]

In randomized phase III studies, panitumumab, a monoclonal antibody for EGFR, combined with FOLFOX4 or FOLFIRI significantly improved progression-free survival when compared with FOLFOX4 or FOLFIRI alone in patients with metastatic colorectal cancer and wild-type KRAS status.[74, 75]

Simkens et al found that patients with a high body mass index (BMI) had better overall survival on chemotherapy regimens than those with a low BMI. This effect was not seen in patients receiving chemotherapy and targeted therapy; the authors suggest that a possible decreased efficacy of bevacizumab in obese patients may account for the discrepancy.[76]

A study by Boisen et al in patients with metastatic colorectal cancer reported significantly better outcomes with first-line CapeOx plus bevacizumab in patients whose primary tumors originated in the rectum and sigmoid colon. For patients treated with CapeOx only, no association between primary tumor location and outcome was found.[77]

Pembrolizumab, a monoclonal antibody to programmed cell death–1 protein (PD-1), gained accelerated approval from the US Food and Drug Administration (FDA) in 2017 for unresectable or metastatic colorectal cancer that has tested positive for microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) and has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. In 2020, the FDA extended the indications for pembrolizumab to include first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer.[78]

In January 2023, the FDA granted accelerated approval of tucatinib (a tyrosine kinase inhibitor for HER2) in combination with trastuzumab (an anti-HER2 monoclonal antibody) for treatment of RAS wild-type HER2-positive unresectable or metastatic colorectal cancer in patients who progressed after treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Approval was based on results from the open-label, multicenter MOUNTAINEER study (n=84), in which tucatinib in combination with trastuzumab yielded an overall response rate of 35% (3.6% complete response; 35% partial response), with a median duration of response of 12.4 months.[79]

Statins

Preclinical and epidemiological studies have suggested that statins may have antineoplastic properties. Nevertheless, a study by Ng et al found that statin use during and after adjuvant chemotherapy did not result in improved disease-free survival, recurrence-free survival, or overall survival in patients with stage III colon cancer.[80]

Adjuvant chemoradiation therapy

Patients with locally advanced rectal cancer (T3-4, N0, M0 or any T, N1-2, M0) should receive primary chemotherapy and radiotherapy. The combination of preoperative radiation therapy and chemotherapy with fluorouracil improves local control, distant spread, and survival. The basis of this improvement is believed to be the activity of fluorouracil as a radiosensitizer. Surgical resection can be done 4 to 10 weeks after completion of chemotherapy and radiotherapy.

A meta-analysis of neoadjuvant long-course chemoradiotherapy followed by total mesorectal excision for locally advanced rectal cancer concluded that waiting for a minimum of 8 weeks from the end of chemoradiotherapy to surgical excision increases pathological complete response (pCR) and downstaging rates, and improves recurrence-free survival without compromising surgical morbidity. With longer intervals, the odds ratio (OR) for pCR was 1.41 (95% confidence interval [CI] 1.30-1.52; P <   0.001) and the OR for tumor downstaging was 1.18 (95% CI 1.05-1.32; P = 0.004). The increased rate of pCR translated to reduced distant metastasis and overall recurrence but not local recurrence.[81]

A study by Ebert et al of colorectal cancer genetics and treatment found a link between hypermethylation of transcription factor AP-2 epsilon (TFAP2E) and clinical nonresponsiveness to chemotherapy in colorectal cancer.[82]

Radioembolization

The FDA has approved yttrium-90 resin microspheres (SIR-Spheres) for the treatment of unresectable metastatic liver tumors from primary colorectal cancer in combination with adjuvant intra-hepatic artery chemotherapy with floxuridine.

A prospective, multicenter, randomized phase III study by Hendlisz et al compared the addition of yttrium-90 resin to a treatment regimen of fluorouracil 300 mg/m2 IV infusion (days 1-14 every 8 wk) with fluorouracil IV alone. Yttrium-90 was injected intra-arterially into the hepatic artery. The addition of radioembolization with yttrium-90 significantly improved time to liver progression and median time to tumor progression.[83]  

However, improvement in liver disease control has not translated to a benefit in overall survival. Three multicenter randomized, phase III trials—FOXFIRE, SIRFLOX, and FOXFIRE-Global—have evaluated the efficacy of combining first-line chemotherapy with selective internal radiotherapy  using yttrium-90 resin microspheres in patients with metastatic colorectal cancer with liver metastases. A combined analysis of those trials found that overall survival was not significantly different in patients who received FOLFOX chemotherapy plus selective internal radiotherapy (n=554) compared with those who received FOLFOX only (n=549).[84]

Response to treatment indicator

A retrospective study conducted by Santiago and colleagues found the split scar sign was a simple morphologic pattern visible on restaging magnetic resonance (MR) high-resolution T2-weighted imaging (T2-WI) which, although not sensitive, is very specific for the identification of sustained complete responders after neoadjuvant therapy in rectal cancer. The split scar sign consists of an area of low signal on the inner wall of the rectum at the site of the tumor, corresponding to fibrosis of the submucosa, with a layer of intermediate signal intensity, representing the muscularis propria, immediately deeper in the wall of the rectum. In tumors that have breached the muscularis propria, there may also be an outermost layer of low-signal perirectal fibrosis.

Because the split scar sign is visible on high-resolution T2-weighted MR imaging, it does not require any changes to standard protocol.  At first restaging pelvic MR imaging (mean: 9.1 weeks after the end of radiotherapy), the split scar sign identified patients who sustained a complete response with very high specificity (0.97) and positive predictive value (0.93-0.94).  The split scar sign has the potential to improve patient selection for "watch-and-wait" after neoadjuvant therapy in rectal cancer.[85]

In a prospective cohort study that included 1575 healthcare professionals with stage I to III colorectal cancer, Song et al found that rates of colorectal cancer (CRC)–specific mortality and overall mortality were lower in patients who had higher intake of dietary fiber, especially from cereals. Survival rates were higher in patients who increased their fiber intake after diagnosis from levels before diagnosis, and in patients reporting higher intake of whole grains.[86, 87]

After multivariable adjustment, each 5 g increment in daily fiber intake was associated with a 22% decrease in CRC-specific mortality and a 14% decrease in all-cause mortality. In patients who increased their fiber intake after diagnosis, each 5 g increase in daily fiber intake was associated with 18% lower CRC-specific mortality. The relationship between fiber intake after diagnosis and CRC-specific mortality  reached a maximum at approximately 24 g/d, beyond which no further mortality reduction was found.[86, 87]

Evaluation of the source of fiber showed that cereal fiber was associated with lower CRC-specific mortality (33% per 5-g/d increment) and all-cause mortality (22%); vegetable fiber was associated with 17% lower all-cause mortality but not with significantly lower CRC-specific; no association was found for fruit fiber. Whole grain intake was associated with lower CRC-specific mortality (28% decrease in risk per 20-g/day increment), although this beneficial association fell to 23% after adjusting for fiber intake.[86, 87]

US Multi-Society Task Force on Colorectal Cancer guidelines recommend local surveillance with flexible sigmoidoscopy or endoscopic ultrasound (EUS) every 3−6 mo for the first 2−3 y after surgery in patients at increased risk for local recurrence.[88] This includes the following:

• Patients with localized rectal cancer who have undergone surgery without total mesorectal excision
• Patients who have undergone transanal local excision (ie, transanal excision or transanal endoscopic microsurgery) or endoscopic submucosal dissection
• Patients with locally advanced rectal cancer who did not receive neoadjuvant chemoradiation and then surgery using total mesorectal excision techniques

The task force also advises that all patients who have undergone curative resection of rectal cancer should receive their first surveillance colonoscopy 1 y after surgery (or 1 y after clearing perioperative colonoscopy).

The National Comprehensive Cancer Network recommends the following surveillance measures[1] :

• History and physical examination every 3–6 mo for 2 y, then every 6 mo for a total of 5 y
• Carcinoembryonic antigen (CEA) assays every 3–6 mo for 2 y, then every 6 mo for a total of 5 y for T2 or greater lesions
• Chest/abdominal/pelvic CT:  every 6–12 mo for a total of 5 y for stage II and III; every 3–6 mo for 2 y, then every 6–12 mo for a total of 5 y for stage IV
• Colonoscopy in 1 y; if no preoperative colonoscopy was performed, due to obstructing lesion, colonoscopy in 3–6 mo; if advanced adenoma is found, repeat in 1 y; if no advanced adenoma, repeat in 3 y, then every 5 y
• Proctoscopy (with EUS or MRI) every 3–6 mo for the first 2 y, then every 6 mo for a total of 5 y (for patients treated with transanal excision only)
• PET-CT scan is not routinely recommended

Guidelines Contributor: Elwyn C Cabebe, MD Physician Partner, Valley Medical Oncology Consultants; Medical Director of Oncology, Clinical Liason Physician, Cancer Care Committee, Good Samaritan Hospital

Guidelines on colorectal screening have been issued by the following organizations:

• American Cancer Society (ACS), US Multi-Society Task Force on Colorectal Cancer, and American College of Radiology
• U.S. Preventive Services Task Force (USPSTF)
• American College of Physicians (ACP)
• American College of Gastroenterology (ACG)
• National Comprehensive Cancer Network (NCCN)

While all the guidelines recommend routine screening for colorectal cancer and adenomatous polyps in asymptomatic adults, they differ with regard to frequency of screening and age at which to discontinue screening, as well as the preferred screening method. Although the customary age for starting screening in persons at average risk has been 50 years, the increasing incidence of colorectal cancer in younger people has prompted several organizations to lower the recommended starting age to 45 years. For high-risk patients, the recommendations differ regarding the age at which to begin screening, as well as the frequency and method of screening.

American Cancer Society (ACS), US Multi-Society Task Force on Colorectal Cancer, and American College of Radiology

A joint guideline developed by the American Cancer Society, US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology recommends that screening for colorectal cancer and adenomatous polyps start at age 50 years in asymptomatic men and women.[89]

In addition, individuals with any of the following colorectal cancer risk factors should undergo colonoscopy at an earlier age and more frequently than average risk individuals:

• Family history of colorectal cancer or polyps
• Family history of a hereditary colorectal cancer syndrome such as familial adenomatous polyposis (FAP) or hereditary non-polyposis colon cancer (HNPCC)
• Personal history of colorectal cancer
• Personal history of chronic inflammatory bowel disease (ulcerative colitis or Crohn disease)
• Screening options for average risk adults consist of tests that detect adenomatous polyps and cancer, and tests that primarily detect cancer. Any one of these tests can be used for screening.

Tests that detect adenomatous polyps and cancer, and their recommended frequency, include the following:

• Flexible sigmoidoscopy every 5 years
• Colonoscopy every 10 years
• Double-contrast barium enema every 5 years
• Computed tomographic (CT) colonography every 5 years

Tests that primarily detect cancer, and their recommended frequency, include the following:

• Annual guaiac-based fecal occult blood test (FOBT) with high test sensitivity for cancer
• Annual fecal immunochemical test (FIT) with high test sensitivity for cancer
• Stool DNA test with high sensitivity for cancer, interval uncertain

American Cancer Society update

In May 2018 the ACS revised its colorectal screening guidelines, advising that regular screening for people at average risk start at age 45 years.[90]  Additional ACS recommendations include the following:

• For people in good health and with a life expectancy of more than 10 years, regular colorectal cancer screening should continue through the age of 75.
• People ages 76 through 85 should make a decision with their medical provider about whether to continue screening, based on their own personal preferences, life expectancy, overall health, and prior screening history.
• People over 85 should discontinue colorectal cancer screening.          

U.S. Preventive Services Task Force (USPSTF)

The USPSTF recommends that screening for colorectal cancer start at age 50 years and continue until age 75 years (A recommendation). For adults aged 76 to 85 years, the decision to screen should be individualized, taking into account the patient’s overall health and prior screening history (C recommendation).[39]

The USPSTF advises that screening is more likely to benefit older patients who have never been screened than those who have undergone screening, and is more likely to benefit patients who are healthy enough to undergo treatment for colorectal cancer treatment and who do not have other medical conditions limiting their life expectancy.[39]

The USPSTF does not recommend colorectal cancer screening for adults older than 85 years.[39]

The USPSTF notes that colorectal screening is substantially underused. As part of a strategy to increase screening rates, the guidelines provide a range of screening options rather than a ranking of tests.

Stool-based screening tests and intervals are as follows:

• Guaiac-based fecal occult blood test (FOBT), every year
• Fecal immunochemical test (FIT), every year
• FIT-DNA, every 1 or 3 years

Direct visualization screening tests and intervals are as follows:

• Colonoscopy, every 10 years
• Computed tomographic (CT) colonography, every 5 years
• Flexible sigmoidoscopy, every 5 years
• Flexible sigmoidoscopy with FIT; sigmoidoscopy every 10 years, with FIT every year

American College of Physicians (ACP)

In 2015, the American College of Physicians recommended that average-risk adults aged 50 to 75 years should be screened for colorectal cancer by one of the following strategies[91] :

• Annual high-sensitivity FOBT or FIT
• Flexible sigmoidoscopy every 5 years
• High-sensitivity FOBT or FIT every 3 years plus flexible sigmoidoscopy every 5 years
• Colonoscopy every 10 years

Interval screening with fecal testing or flexible sigmoidoscopy in adults having 10-year screening colonoscopy is not recommended. Average-risk adults younger than 50 years, older than 75 years, or with an estimated life expectancy of less than 10 years should not be screened. 

American College of Gastroenterology (ACG)

American College of Gastroenterology (ACG) 2021 guidelines recommend colorectal cancer screening in average-risk individuals of age 50 to 75 years, and suggest screening in average-risk individuals of age 45 to 49 years. The ACG recommends colonoscopy and FIT as the primary modalities for colorectal cancer screening.[92]  Further ACG suggestions regarding colorectal cancer screening include the following:

• Initiate colorectal cancer screening with a colonoscopy at age 40 or 10 years before the youngest affected relative, whichever is earlier, in individuals in whom a first-degree relative has had colorectal cancer or an advanced polyp before age 60 years or in whom two or more first-degree relatives have had colorectal cancer or an advanced polyp at any age; perform interval colonoscopy every 5 years.
• Consider genetic evaluation in individuals with a higher familial colorectal cancer burden (higher number and/or younger age of affected relatives).
• In individuals in whom a first-degree relative has had colorectal cancer or an advanced polyp at age 60 years or older, initiate colorectal cancer screening at age 40 or 10 years before the youngest affected relative, then resume screening according to average-risk screening recommendations.
• In individuals with a second-degree relative with colorectal cancer or an advanced polyp, follow average-risk colorectal cancer screening recommendations.
• Decide whether to continue screening beyond age 75 years on an individualized basis.
• In individuals unable or unwilling to undergo colonoscopy or FIT, consider screening with flexible sigmoidoscopy, multitarget stool DNA test, CT colonography, or colon capsule.
• Do not use the Septin 9 methylated DNA test Septin 9 for screening.

The ACG guidelines note that colonoscopy is the only screening modality that is both diagnostic and therapeutic. All others are two-step approaches: a positive test requires a follow-up colonoscopy. Despite that limitation, the ACG suggests that, "in some instances the 'best' screening test can be considered the one that is acceptable to the patient and gets completed."[92]

National Comprehensive Cancer Network (NCCN)

The National Comprehensive Cancer Network (NCCN) has released separate guidelines for average-risk and high-risk individuals.[93, 33]  For average individuals, the recommendations are nearly identical to those of the joint American Cancer Society (ACS), US Multi-Society Task Force on Colorectal Cancer, and American College of Radiology. However, in 2021 the NCCN lowered the age for starting screening in average-risk individuals from 50 years to 45 years.[93]

The NCCN guidelines provide screening recommendations for patients at increased risk due to a personal or family history of any of the following[33] :

• > 10 adenomatous polyps
• ≥2 hamartomatous polyps
• ≥5 serrated polyps proximal to the sigmoid

The guidelines also specify recommendations for patients with the following high-risk syndromes[33] :

• Lynch syndrome
• Familial adenomatous polyposis (FAP)
• Attenuated familial adenomatous polyposis (AFAP)
• MUTHYH-associated polyposis
• Peutz-Jeghers syndrome (PJS)
• Juvenile polyposis syndrome (JPS)
• Serrated polyposis syndrome (SPS)
• No syndrome, but familial risk present

Individuals meeting one or more of the following criteria should receive further evaluation for high-risk syndromes:

• Individuals meeting the revised Bethesda Guidelines (Lynch syndrome)
• Family members meeting Amsterdam criteria (Lynch syndrome)
• Individuals with more than 10 adenomas detected ( MUTYH)
• Individuals with multiple GI hamartomatous polyps (PJS and JPS)
• Family members with a known high-risk syndrome associated with colorectal cancer, with or without a known mutation
• Individuals with a desmoid tumor

Screening for Familial Risk

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Guidelines for Lynch syndrome screening have been developed by the National Cancer Institute (Bethesda guidelines) and the NCCN.[33]

The American Gastroenterological Association recommends testing all patients with colorectal cancer for Lynch syndrome; the tumor should be tested for MSI or with immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 proteins.[94]

The European Society for Medical Oncology (ESMO) guidelines for familial risk-colorectal cancer [95] , which have been endorsed by the American Society of Clinical Oncology (ASCO)[96]  includes the following recommendations:

• Tumor testing for DNA mismatch repair (MMR) deficiency with immunohistochemistry for MMR proteins and/or MSI should be assessed in all patients with colorectal cancer. As an alternate strategy, tumor testing should be carried out in individuals with CRC younger than 70 years, or those older than 70 years who fulfill any of the revised Bethesda guidelines

• If loss of MLH1/PMS2 protein expression is observed, analysis of BRAF V600E mutation or analysis of methylation of the MLH1 promoter should be conducted to rule out a sporadic case. If tumor is MMR deficient and somatic BRAF mutation is not detected or MLH1 promoter methylation is not identified, testing for germline mutations is indicated.

• If loss of any of the other proteins (MSH2, MSH6, PMS2) is observed, germline genetic testing should be carried out for the genes corresponding to the absent proteins (eg, MSH2, MSH6, EPCAM, PMS2, or MLH1).

• Full germline genetic testing for Lynch syndrome should include DNA sequencing and large rearrangement analysis.

The American College of Gastroenterology recommendations are in general agreement with ESMO.[97]

Revised Bethesda guidelines for Lynch syndrome and microsatellite instability

Because cancers with MSI account for approximately 15% of all colorectal cancers, in 1996 the National Cancer Institute developed the Bethesda guidelines for the identification of individuals with HNPCC who should be tested for MSI. These guidelines were most recently revised in 2002.[98]

A 2020 update of US Multi-Society Task Force on Colorectal Cancer guidelines provides recommendations on postpolypectomy surveillance. The recommendations assume high-quality baseline colonoscopy, defined as meeting all the following criteria[99] :

• Adequate bowel preparation
• Performance by a colonoscopist with adequate adenoma detection rate
• Complete examination to the cecum
• Attention to complete polyp excision

Screening colonoscopy findings and recommended scheduling of surveillance colonoscopy are as follows[99] :

• Normal colonoscopy, or  < 20 hyperplastic polyps < 10 mm: 10 years
• 1–2 adenomas < 10 mm: 7–10 years
• 3–4 adenomas < 10 mm: 3–5 years
• 5–10 adenomas, adenoma ≥10 mm, or adenoma with villous component or high-grade dysplasia: 3 years
• More than 10 adenomas: 1 year, with consideration for genetic testing based on adenoma burden, age, and family history
• Piecemeal resection of adenoma ≥20 mm: 6 months, then 1 year later, then 3 years after the second examination
• 1–2 sessile serrated polyps (SSPs) < 10 mm: 5–10 years
• 3–4 SSPs < 10 mm or hyperplastic polyp ≥10 mm: 3–5 years
• 5–10 SSPs, SSP ≥10 mm, SSP with dysplasia, or traditional serrated adenoma:  3 years

In 2020, the British Society of Gastroenterology (BSG), the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and Public Health England (PHE) released joint guidelines for surveillance after polypectomy and colorectal cancer resection. According to the guidelines, the criteria for high-risk for future colorectal cancer (CRC) following polypectomy comprise either of the following[100] :

• Two or more premalignant polyps, including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia)  or
• Five or more premalignant polyps

Patients who meet the high-risk criteria should undergo a single surveillance colonoscopy at 3 years.  Patients who have undergone CRC resection should have a colonoscopy at 1 year post-surgery and every 3 years thereafter.[100]

Patients who do not meet high-risk criteria postpolypectomy should participate in national bowel screening when invited. For patients who are more than 10 years younger than the national bowel screening lower age limit, colonoscopy may be considered after 5 or 10 years and individualized to age and other risk factors.

The American College of Gastroenterology has published guidelines for surveillance of patients who have had adenomas detected and removed at colonoscopy.[99]

These patients should have more frequent followup, as they are at increased risk for developing metachronous adenomas or colon cancer.

Colonoscopy findings and recommended scheduling of followup colonoscopy are as follows:

• No polyps – 10 years
• Small (< 10 mm) hyperplastic polyps in rectum or sigmoid – 10 years
• 1–2 small (< 10 mm) tubular adenomas – 5- 10 years
• 3–10 tubular adenomas – 3 years
• 10 adenomas – < 3 years
• One or more tubular adenomas ≥10 mm – 3 years
• One or more villous adenomas – 3 years
• Adenoma with high-grade dysplasia – 3 years

For serrated lesions, recommended surveillance intervals are as follows:

• Sessile serrated polyp(s) < 10 mm with no dysplasia – 5 years
• Sessile serrated polyp(s) ≥10 mm with no dysplasia – 3 years
• Sessile serrated polyp with dysplasia – 1 year
• Traditional serrated adenoma – 1 year
• Serrated polyposis syndrome – 1 year

The European Society of Medical Oncology offers the following recommendations for surveillance of patients with familial adenomatous polyposis (FAP)[95] :

Classic FAP

• Colon and rectum: Sigmoidoscopy (or colonoscopy) every 1 to 2years, starting at age 10 to 11 years and continued lifelong in mutation carriers. Once adenomas are detected, annual colonoscopy until colectomy. Surgery is indicated if there are large numbers of adenomas, including adenomas showing a high degree of dysplasia.

• Gastroduodenal adenomas: Gastroduodenal endoscopy starting when colorectal polyposis is diagnosed or at age 25 to 30 years, whichever comes first. Surveillance intervals are based on the Spigelman stage.

• Thyroid cancer:  Consider annual cervical ultrasonography starting at age 25 to 30 years.

• Desmoid tumors: Consider baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan in presence of risk factors (positive family history for desmoids and site of the mutation in APC).

Attenuated FAP

• Colon and rectum: Colonoscopy every 1 to 2 years, starting at age 18 to 20 years and continued lifelong in mutation carriers. Once adenomas are detected, colonoscopy should be carried out annually.

• Gastroduodenal adenomas: Gastroduodenal endoscopy starting when colorectal polyposis is diagnosed or at age 25 to 30 years, whichever comes first. Surveillance intervals are based on the Spigelman stage.

• Thyroid cancer: Annual cervical ultrasonography may be considered, starting at age 25 to 30 years.

• Desmoid tumors: A baseline CT scan or MRI should be considered if risk factors (positive family history for desmoids and site of the mutation in APC).

The American Society of Colon and Rectal Surgeons recommends that patients with familial adenomatous polyposis (FAP) or with personal or family risk factors for FAP be referred to center registries and genetic counselors with experience in the multidisciplinary management of these individuals.[101]

Additional recommendations include:

• Prophylactic colectomy or proctocolectomy should be routine; the frequency and type of surgery should depend on the severity of the polyposis phenotype
• Use of chemoprevention as primary therapy is not recommended
• Small tubular adenomas with mild dysplasia can be kept under surveillance, but adenomas with severe dysplasia must be removed
• Duodenectomy or pancreaticoduodenectomy is recommended for persistent or recurrent severe dysplasia in the papilla or duodenal adenomas
• Clinically inert tumors should be treated with sulindac or not treated at all
• Slowly growing or mildly symptomatic tumors may be treated with less toxic regimens such as sulindac and tamoxifen or with vinblastine and methotrexate
• Rapidly growing tumors need aggressive therapy with either very-high-dose tamoxifen or antisarcoma-type chemotherapy
• Radiation is an option if collateral damage is not a major concern

The American Society of Colon and Rectal Surgeons (ASCRS) defines rectal cancer as cancer located within 15 cm of the anal verge by rigid proctoscopy. ASCRS 2013 revised management guidelines and practice parameters recommend that patients with low-risk, early-stage rectal cancer be treated with primary surgical therapy. Treatment of locally advanced or high-risk disease should include neoadjuvant radiation or chemoradiation followed by surgery.[102]

Additional recommendations include the following[102] :

• Local excision for T1 tumors absent high risk factors
• Total mesorectal excision (TME) for curative resection of tumors of the middle and lower thirds of the rectum
• In the absence of clinical involvement, extended lateral lymph node dissection (LLND) is not necessary in addition to TME
• For tumors of the upper third of the rectum, a tumor-specific mesorectal excision should be used.
• For T4 rectal cancers, resection of involved adjacent organs should be performed with an en bloc technique.
• Oophorectomy is advised for grossly abnormal ovaries or contiguous extension of a rectal cancer, but routine prophylactic oophorectomy is not necessary
• Laparoscopic TME has comparable outcomes with open TME

Guidelines from the European Society for Medical Oncology (ESMO) include the following recommendations on management of local and locoregional rectal cancer[103] :

• Local excisional procedures such as transanal endoscopic microsurgery are appropriate as a single modality for early cancers (cT1N0 without adverse features such as G3, V1, L1).

• Local radiation therapy (brachytherapy or contact therapy—Papillon technique) may also be used as an alternative to local surgery, alone or combined with chemoradiotherapy.

• More advanced tumors up to and including cT2c/T3a/b should be treated with radical TME surgery because of higher risks of recurrence and the higher risk of mesorectal lymph node involvement. TME (ie, meticulous excision of all the mesorectal fat, including all lymph nodes) is the standard of care for surgery.

• For patients with locally advanced rectal cancer (LARC), treatment decisions regarding neoadjuvant therapy should be based on preoperative, MRI-predicted circumferential resection margin (≤1 mm), extramural vascular invasion, and more advanced T3 substages (T3c/T3d), which define the risk of both local recurrence and/or synchronous and subsequent metastatic disease. For resectable cancers, where there is no indication on MRI that surgery is likely to be associated with either an R2 or an R1 resection, standard TME should achieve a curative resection. The use of short-course preoperative radiotherapy or short-course preoperative radiotherapy aims to reduce local recurrence.

• The selection of preoperative approach in LARC is based more on the multidisciplinary team's decision regarding the risk of a  positive circumferential resection margin at TME. If the circumferential resection margin and/or R0 resection status are predicted to be at risk, chemoradiotherapy is advised. Otherwise, either short-course preoperative radiotherapy or chemoradiotherapy can be administered. For chemoradiotherapy, continuous intravenous infusions of 5-FU or oral capecitabine are recommended rather than bolus 5-FU [I, A].

• Preoperative radiation therapy or chemoradiotherapy reduces the rate of local recurrence without improvement of overall survival for mid/low stage II/III rectal cancers but is associated with significantly worse intestinal and sexual function after surgery.

• Upper rectal cancers (>12 cm from the anal verge) above the peritoneal reflection do not benefit from short-course preoperative radiotherapy or chemoradiotherapy and should be treated as colon cancer.

• With short-course preoperative radiotherapy in resectable cancers where downstaging is not required, ‘immediate’ surgery is recommended to take place within 7 days from the end of neoadjuvant treatment, and ideally within 0–3 days if the patient is ≥75 years (< 10 days from the first radiation fraction).

• Postoperative chemoradiotherapy could be selectively used in patients with unexpected adverse histopathological features after primary surgery (eg, positive circumferential resection margin, perforation in the tumor area, incomplete mesorectal resection, extranodal deposits or nodal deposits with extracapsular spread close to the mesorectal fascia), or in other cases with high risk of local recurrence if preoperative radiation therapy has not been given.

National Comprehensive Cancer Network (NCCN) guidelines advise that adjuvant therapy regimens for rectal cancer should include both concurrent chemotherapy/radiotherapy and adjuvant chemotherapy. Preferably, perioperative treatment should be given for a total of approximately 6 months.[1]

According to the NCCN, patients with stage I (T1-2, N0, M0) rectal cancer without high-risk features do not require adjuvant therapy due to the high cure rate with surgical resection. High-risk patients, including those with positive margins, sm3 invasion (submucosal invasion to the lower third of the submucosal level), poorly differentiated tumor histology and those with lymphovascular invasion, should be considered for adjuvant chemotherapy and radiotherapy.[1]

The NCCN guidelines recommend combination therapy with infusional fluorouracil, folinic acid, and oxaliplatin (FOLFOX) as reasonable for patients with high-risk or intermediate-risk stage II disease; however, FOLFOX is not indicated for good- or average-risk stage II rectal cancer. Adjuvant chemotherapy is encouraged for eligible patients with stage III disease.

For the majority of patients with stage II or stage III rectal cancer, the NCCN recommends the use of ionizing radiation to the pelvis along with adjuvant chemotherapy. Either of the two following sequences of therapy may be used:

• Chemoradiation therapy preoperatively and chemotherapy postoperatively
• Chemotherapy followed by chemoradiation therapy, followed by resection

Guidelines on follow-up care for survivors of stage II and stage III colorectal cancer were issued by the following organizations:

• Cancer Care Ontario endorsed by American Society of Clinical Oncology (ASCO)
• European Society of Medical Oncology (ESMO)
• National Comprehensive Cancer Network (NCCN)
• American Society of Colon and Rectal Surgeons (ASCRS)

All four guidelines agree that patients with resected colon cancer (stage II and III) should undergo regular surveillance for at least 5 years following resection, and that surveillance should include regular reviews of medical history, physical examination, and carcinoembryonic antigen assays, as well as colonoscopy and abdominal and chest computed tomography (CT).[104, 105, 1, 106] The frequency of the surveillance testing differs as shown in the table below.

Table. 1 (Open Table in a new window)

In 2016, the US Multi-Society Task Force on Colorectal Cancer issued guidelines on colonoscopy after colorectal cancer resection, which included the following recommendations[88] :

• Patients with colorectal cancer (CRC) should undergo high-quality perioperative clearing with colonoscopy. The procedure should be performed preoperatively, or within a 3- to 6-mo interval after surgery in the case of obstructive CRC. The goals of perioperative clearing colonoscopy are detection of synchronous cancer and detection and complete resection of precancerous polyps.
• Patients who have undergone curative resection of either colon or rectal cancer should receive their first surveillance colonoscopy 1 yr after surgery (or 1 yr after the clearing perioperative colonoscopy).
• Patients with localized rectal cancer who have undergone surgery without total mesorectal excision, those who have undergone transanal local excision (ie, transanal excision or transanal endoscopic microsurgery) or endoscopic submucosal dissection, and those with locally advanced rectal cancer who did not receive neoadjuvant chemoradiation and then surgery using total mesorectal excision techniques, are at increased risk for local recurrence. In these situations, it is suggested that patients undergo local surveillance with flexible sigmoidoscopy or endoscopic ultrasound (EUS) every 3−6 mo for the first 2−3 yr after surgery. These surveillance measures are in addition to recommended colonoscopic surveillance for metachronous neoplasia.
• In patients with obstructive CRC precluding complete colonoscopy, CT colonography (CTC) is recommended as the best alternative to exclude synchronous neoplasms. Double-contrast barium enema is an acceptable alternative if CTC is not available.

 In 2015, the American Society for Clinical Pathology (ASCP), the College of American Pathologists (CAP), the Association for Molecular Pathology (AMP), and the American Society of Clinical Oncology (ASCO) issued a provisional clinical opinion regarding gene mutation testing to predict response to anti–epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy in patients with metastatic colorectal carcinoma (mCRC). Among the recommendations are the following[107] :

• RAS mutational testing of colorectal carcinoma tissue should be performed in a Clinical Laboratory Improvement Amendments–certified laboratory for patients who are being considered for anti-EGFR therapy

• Analysis should include KRAS and NRAS codons 12 and 13 of exon 2; 59 and 61 of exon 3; and 117 and 146 of exon 4.

• Anti-EGFR MoAb therapy (currently cetuximab and panitumumab) should only be considered for treatment of patients with mCRC who are identified as having tumors with no mutations detected after extended RAS mutation analysis

The 2016 European Society of Medical Oncology (ESMO) guidelines for the management of patients with mCRC concur with the ASCP/CAP/AMP/ASCO RAS mutational testing recommendations above. Additional recommendations include[108] :

• Tumor  BRAF mutation status should be assessed alongside the assessment of tumor  RAS mutation status for prognostic assessment (and/or potential selection for clinical trials)

• Dihydropyrimidine dehydrogenase (DPD) testing before 5-FU administration remains an option but is not routinely recommended 

• UGT1A1 phenotyping remains an option and should be carried out in patients with a suspicion of UGT1A1 deficiency as reflected by low conjugated bilirubin and in patients where an irinotecan dose of >180 mg/m2 per administration is planned 

• Thymidylate synthase (TS) activity and TSER genotyping are not recommended for use in clinical practice

• ERCC1 expression for treatment decisions involving the use of oxaliplatin is not recommended outside of clinical trial

Pharmacotherapy in rectal cancer involves the use of multiple chemotherapy agents in combination regimens, often given together with radiation therapy. Chemotherapy is given before surgery to down-stage the tumor and help induce remission, and after surgery to prevent recurrences.

In metastatic rectal cancer, biologic agents are used in combination with chemotherapy. Biologic agents used in Bevacizumab in combination with chemotherapy is indicated in patients with positive or negative resectable synchronous metastases. For colon and rectal cancer, bevacizumab in combination with chemotherapy is also indicated in patients with unresectable synchronous metastases.

FOLFOX is not indicated for good-risk or average-risk stage II patients. In patients in whom 5-fluorouracil treatment has failed, capecitabine should be avoided. Patients who experience no benefit from bevacizumab regimens should avoid continuing the therapy. Cetuximab should not be replaced with panitumumab. Patients with KRAS mutations should not be treated with cetuximab or panitumumab, as these mutations confer resistance to epidermal growth factor receptor (EGFR) inhibitors.

Class Summary

These agents inhibit cell growth and proliferation. They are generally used in combination regimens.

Fluorouracil (5-FU, Fluorouracil, Adrucil)

Blocks methylation of deoxyuridylic acid to thymidylic acid, thereby interfering with DNA synthesis. Dose is body-weight dependent and varies with specific protocol in which patient is involved.

Vincristine (Vincasar PFS, Oncovin)

Mechanism of action uncertain. May involve decrease in reticuloendothelial cell function or increase in platelet production. It is mitotic spindle inhibitor.

Leucovorin (Wellcovorin)

Potentiates effects of fluorouracil. Reduced form of folic acid that does not require enzymatic reduction reaction for activation. Allows for purine and pyrimidine synthesis, both of which are needed for normal erythropoiesis.

Given just prior to fluorouracil.

Irinotecan (Camptosar, Camptothecin-11, CPT-11)

Inhibits topoisomerase I, inhibiting DNA replication and, consequently, cell proliferation.

Oxaliplatin (Eloxatin)

A platinum-based antineoplastic agent used in combination with an infusion of 5-fluorouracil (5-FU) and leucovorin for the treatment of metastatic colorectal cancer in patients with recurrence or progression following initial treatment with irinotecan, 5-FU, and leucovorin. It forms interstrand and intrastrand Pt-DNA crosslinks that inhibit DNA replication and transcription. The cytotoxicity is cell-cycle nonspecific.

Cetuximab (Erbitux)

Recombinant human/mouse chimeric monoclonal antibody that specifically binds to the extracellular domain of human epidermal growth factor receptors (EGFR, HER1, c-ErbB-1). Cetuximab-bound EGF receptor inhibits activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased production of matrix metalloproteinase and vascular endothelial growth factor. Indicated for treating irinotecan-refractory, EGFR-expressed, metastatic colorectal carcinoma. Treatment is preferably combined with irinotecan. May be administered as monotherapy if irinotecan is not tolerated.

Bevacizumab (Avastin)

Indicated as a first-line treatment for metastatic colorectal cancer. Murine-derived monoclonal antibody that inhibits angiogenesis by targeting and inhibiting vascular endothelial growth factor (VEGF). Inhibiting new blood vessel formation denies blood, oxygen, and other nutrients needed for tumor growth. Used in combination with standard chemotherapy.

Panitumumab (Vectibix)

Recombinant human IgG2 kappa monoclonal antibody that binds to human epidermal growth factor receptor (EGFR). Indicated to treat colorectal cancer that has metastasized following standard chemotherapy.

Tucatinib (Tukysa)

Tucatinib is a tyrosine kinase inhibitor of HER2. In vitro and in vivo, tucatinib inhibits the antitumor activity of HER2-expressing tumor cells and inhibits the growth of HER2-expressing tumors. The combination of tucatinib with trastuzumab showed an increase in antitumor activity  in vitro and in vivo. The FDA granted accelerated approval for tucatinib in combination with trastuzumab for adults with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed after treatment with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy.