Rectal Cancer

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Practice Essentials

Rectal cancer is a disease in which cancer cells form in the tissues of the rectum; colorectal cancer occurs in the colon or rectum. Adenocarcinomas comprise the vast majority (98%) of colon and rectal cancers; more rare rectal cancers include lymphoma (1.3%), carcinoid (0.4%), and sarcoma (0.3%).

The incidence and epidemiology, etiology, pathogenesis, and screening recommendations are common to both colon cancer and rectal cancer. The image below depicts the staging and workup of rectal cancer.



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Diagnostics. Staging and workup of rectal cancer patients.

Signs and symptoms

Bleeding is the most common symptom of rectal cancer, occurring in 60% of patients. However, many rectal cancers produce no symptoms and are discovered during digital or proctoscopic screening examinations.

Other signs and symptoms of rectal cancer may include the following:

See Presentation for more detail.

Diagnosis

Perform physical examination with specific attention to the size and location of the rectal tumor as well as to possible metastatic lesions, including enlarged lymph nodes or hepatomegaly. In addition, evaluate the remainder of the colon.

Examination includes the use of the following:

Screening tests

Screening tests may include the following:

Laboratory studies

Routine laboratory studies in patients with suspected rectal cancer include the following:

Imaging studies

If metastatic (local or systemic) rectal cancer is suspected, the following radiologic studies may be obtained:

See Workup for more detail.

Management

A multidisciplinary approach that includes surgery, medical oncology, and radiation oncology is required for optimal treatment of patients with rectal cancer. Surgical technique, use of radiotherapy, and method of administering chemotherapy are important factors. 

Considerations with respect to surgical technique include the intent of surgery (curative or palliative), restoration of bowel function, and preservation of anal continence and genitourinary functions. Ideally, the intent is achievement of a cure, because the risk of pelvic recurrence is high in patients with rectal cancer, and locally recurrent rectal cancer has a poor prognosis.

Surgery

Radical resection of the rectum is the mainstay of therapy. The choice of surgical procedure is based on the size, location, extent, and grade of the rectal carcinoma. Operative management of rectal cancer may include the following:

Adjuvant medical management

Adjuvant medical therapy may include the following:

Pharmacotherapy

Chemotherapy for rectal cancer may be given preoperatively or postoperatively, either alone or in combination with radiation therapy. The following agents may be used in the management of rectal cancer:

See Treatment and Medication for more detail.

Background

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  in both men and women in the United States.[1]

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.[2, 3]

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.[2]

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

Anatomy

The surgical definition of the rectum differs from the anatomical definition. Surgeons define the rectum as starting at the level of the sacral promontory. The National Comprehensive Cancer Network (NCCN) bases its definition on magnetic resonance imaging (MRI) results, stating that "the rectum lies below a virtual line from the sacral promontory to the upper edge of the symphysis as determined by MRI."[4] 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.

European Society for Medical Oncology (ESMO) guidelines define rectal cancer as cancer located within 15 cm of the anal verge.[5] ESMO guidelines categorize rectal cancers as low, medium, or high, according to the distance of their distal edge from the anal verge. Location, based on rigid proctoscopy or flexible endoscopy, is as follows: 

In contrast, tumor location based on MRI, which uses anorectal junction rather than anal verge as a landmark, is as follows[5] :

Tumor location within the rectum can influence treatment decisions.[5]  For example, NCCN lines list tumor location within 8 cm of the anal verge as one of the criteria for use of transanal local resection.[4]

Computed tomography or MRI 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] :

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 radiologicallt.[6]  On imaging, the sigmoid take-off is where the sigmoid sweeps away from the sacrum, with ventral projection in the axial plane and/or horizontal projection in the sagittal plane.[7] 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, 8]

Pathophysiology

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 vast majority of colorectal cancers are adenocarcinomas.  Colonic adenomas precede adenocarcinomas. Approximately 10% of adenomas will eventually develop into adenocarcinomas. This process may take up to 10 years.[2]  The adenoma-carcinoma sequence is well described in the medical literature.[2]

Three pathways to colon and rectal carcinoma have been described:

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.[9]

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.[2, 10] A separate carcinogenic pathway is also described in inflammatory bowel disease (IBD). Chronic inflammation such as in ulcerative colitis can result in genetic alterations that lead to dysplasia and carcinoma formation.[2]

Etiology

Colorectal cancer appears to be multifactorial in origin and includes environmental factors and a genetic component. 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 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.[11]

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.[12, 13]

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.[12]

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.[14] 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.[15] 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).[16]

Tobacco

Smoking, particularly when started at a young age, increases the risk of colorectal cancer.[17] 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.[18]

Cholecystectomy

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.[2]

Family and personal history

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.[19]

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 on 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.[20]

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):

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[21] :

Another strategy is so-called universal screening, in which all individuals newly diagnosed with colorectal cancer undergo either microsatellite instability (MSI) or immunohistochemistry (IHC) tumor 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.[21]

Inflammatory bowel disease

The malignant pathway in individuals with inflammatory bowel disease 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.

 

Epidemiology

United States

Colon and rectal cancer is the third most common cancer in both females and males. The American Cancer Society (ACS) estimates that 107,320 new cases of colon cancer and 46,950 new cases of rectal cancer will occur in 2025—27,950 cases of rectal cancer in men and 19,000 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 52,900 deaths from colorectal cancer are expected to occur in 2025.[1]

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 2012 to 2021, incidence rates decreased by about 1% per year overall, but rates in persons younger than 50 years increased by 2.4% per year and rates in those age 50-64 increased by 0.4% per year.[1]  Currently, adults born circa 1990 have quadruple the risk of rectal cancer compared with those born circa 1950.[22]  

The overall death rate from colorectal cancer has also been falling, decreasing 57% from 1970 to 2022—from 29.2 to 12.6 per 100,000, respectively—because of changing patterns in risk factors, increased screening, and improvements in treatment. During the past decade, the death rate declined by 1.7% per year. As with incidence rates, however, the decrease in overall mortality masks the rise in death rates in adults younger than 55 years, which have increased by about 1% per year since the mid-2000s.[1]  

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 42% of cases in those age 20 to 49 years and 38% in those 50 to 64 years of age. In individuals age 65 and older, rectal cancer accounts for 24% of colorectal cancer cases; the proximal colon is the most common colorectal cancer site in that age group, accounting for 47% of cases.[23]

International

An estimated 729,833 new cases of rectal cancer occurred worldwide in 2022, making it the eighth most common cancer. Incidences varied considerably by country, with high rates in Europe and Australia–New Zealand, and low rates in western and middle Africa and south-central Asia.[24]

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).[25] However, the incidence of colorectal cancer among people younger than 50 years is increasing much faster in Whites than in Blacks (2% vs 0.2% per year, respectively).[23]

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.[26]

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.[27]  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).[25]  

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.[2]  In the United States, the incidence rates of colorectal cancer increased by more than 2% per year in adults younger than age 50 from 2012 to 2021, largely because of increases in rectal cancer.[1]

Incidence rates of colorectal cancer in persons younger than 50 years have also increased 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.[23]

A study by Sung et al that examined colorectal cancer incidence trends in younger adults versus older adults in 50 countries and territories found that from 2013 to 2017, early-onset colorectal cancer (diagnosed at ages 25 to 49 years) increased in 27 countries. The greatest annual increases occurred in New Zealand (3.97%), Chile (3.96%), Puerto Rico (3.81%), and England (3.59%). In 14 of those 27 countries and territories, rates in older adults were either stable or decreased.[28]

Mortality/morbidity

The American Cancer Society estimates that in 2025, colorectal cancer will account for 9% of cancer deaths in men and 8% in women, making it the third and fourth most common cause of cancer deaths, respectively. In the US, mortality rates have been decreasing in both sexes for the past 2 decades. The 5-year relative survival rate is 65% for colorectal cancer; however, for patients who are diagnosed with localized disease, the 5-year survival rate is 91.1%.[25]

Prognosis

The 5-year relative survival rates for colorectal cancer based on SEER stage are as follows[25] :

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.[29]

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%.[30]  Factors that influence the development of recurrence include the following:

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.

Patient Education

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.[31]  Survivors should also receive education on the possible benefits of secondary prevention with dietary changes (see Treatment/Diet) and aspirin (see Treatment/Prevention).

 

History

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 signs or symptoms and are discovered during screening examinations.

Bleeding is the most common sign of rectal cancer, occurring in 60% of patients. Bleeding often is mistakenly 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. Occult bleeding is detected via a fecal occult blood test (FOBT) in 26% of all cases.

Change in bowel habits develops 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.

Abdominal pain is present in 20% of 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. Pelvic pain is a late symptom, usually indicating nerve trunk involvement, and is present in 5% of all cases.

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.  Other manifestations include emergencies such as peritonitis from perforation (3%) or jaundice, which may occur with liver metastases (< 1%).

The rising rates of colon and rectal cancer in persons younger than 50 years has prompted research in this population. A matched case-control study of 5075 incident colorectal cancers in patients younger than 50 years identified abdominal pain, rectal bleeding, diarrhea, and iron deficiency anemia within three months to two years before diagnosis as red-flag clinical manifestations in this age group. The presence of any one of those clinical manifestations was associated with 1.94-fold higher risk; any two, with 3.59-fold higher risk, and three or more, with 6.52-fold higher risk. The risk associations were stronger in younger patients and with rectal versus colon cancer.[32]

Physical Examination

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.

Laboratory Studies

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 gastrointestinal (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.



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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.[33] 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%.

Screening for Colon and Rectal Cancer

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:

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. U.S. Preventive Services Task Force (USPSTF) guidelines give a grade A recommendation for screening of the average-risk population beginning at age 50 years and ending at age 75 years; however, in view of the rising rate of early-onset colorectal cancer, the USPSTF gives a grade B recommendation for screening adults aged 45 to 49 years.[37]  However, current American Cancer Society and National Comprehensive Cancer Network guidelines recommend starting screening in all average-risk patients at age 45 years.[38, 39]

Indications for screening in patients at average risk for colon and rectal cancer include the following:

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:

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

Screening recommendations by risk factor are as follows:

Staging

Dukes Classification

In 1932, the English pathologist Cuthbert E. Dukes introduced a staging system for rectal cancer. His system divided tumor classification into three stages, as follows:

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

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:

Regional lymph nodes (N) include the following:

Distant metastasis (M) include the following:

Table 1. Comparison of AJCC Definition of TNM Staging System to Dukes Classification.



View Table

See Table

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

Rectal cancer lexicon

An updated rectal cancer lexicon from the Society of Abdominal Radiology’s Colorectal and Anal Cancer Disease-Focused Panel provides information on primary tumor and nodal staging. The lexicon includes discussions of cT staging in low-rectal cancers, definitions for cT4b and cM1a disease, definitions for mesorectal fascia (MRF) involvement, evaluation of lymph nodes versus tumor deposits, and staging of lateral lymph nodes.[42]

Approach Considerations

A multidisciplinary approach that includes surgery, medical oncology, and radiation oncology is required for optimal treatment of patients with rectal cancer.[43, 44]  See the image below.



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

Determination of the optimal treatment plan for a patient with rectal cancer involves a complex decision-making process. Considerations with respect to surgical technique include the intent of surgery (curative or palliative) and preservation of anal continence and genitourinary functions. The choice of surgical procedure is based 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.

Ideally, the intent is 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.[45]

Factors influencing sphincter and organ preservation in patients with rectal cancer can be described as follows[45] :

The following factors are associated with difficult sphincter preservation:

Patients with the following may be candidates for local excision:

Disadvantages of abdominoperineal resection include the following:

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.

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

Neoadjuvant Therapy

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

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.[46, 47] 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.[48]

The disadvantages of preoperative RT include the following:

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.[49] The authors recommend preoperative chemoradiation therapy in patients with large bulky cancers and with obvious nodal involvement.[46]

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).[50]

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[4, 44] :

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.[51]  

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).[52]

Guidelines from the American Society of Colon and Rectal Surgeons include the following recommendations on this topic[53] :

Transanal Excision

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%.[45, 54]

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.[55]

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%.[29]

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.[54]

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.[56] 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.[56]

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.[45, 56, 57]

Endocavitary Radiation

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%.[54]

Transanal Endoscopic Microsurgery and Transanal Minimally Invasive Surgery

Transanal endoscopic microsurgery (TEM) involves the use of a special operating proctoscope that distends the rectum with insufflated carbon dioxide, which allows the passage of dissecting instruments for lesion excision. This method can be used on lesions located higher in the rectum and even in the distal sigmoid colon.

TEM offers several advantages over conventional transanal excision. It provides better exposure and visualization than standard transanal excision and affords access to lesions higher in the rectum. It is associated with less morbidity and quicker recovery time than a radical transabdominal approach. 

The major limitations of TEM have been that it requires expensive, highly specialized equipment and has a steep learning curve. Accordingly, it should be performed only by skilled and experienced surgeons.

Transanal minimally invasive surgery (TAMIS) was developed to address some of the limitations of TEM.[58] It requires minimal setup time, and its use of existing laparoscopic cameras and instruments offers a lower-cost alternative to TEM. Nonetheless, the learning curve appears to be generally comparable. 

A comparison of TEM (n = 53) with TAMIS (n = 68) for resection of intraluminal rectal tumors showed that although resection margins, lesion grade, and invasion depth were comparable for the two approaches, median operating time was significantly shorter for TAMIS (45 vs 65 min) and the postoperative readmission rate was significantly lower (4.4% vs 17%).[59]

Robotic TAMIS (R-TAMIS) has been proposed as a potential alternative to both TEM and standard TAMIS.[60] In a case series by Schwab et al that compared the three techniques, R-TAMIS tended to be faster than TEM and TAMIS and to be more likely to result in negative surgical margins.[61]

Indications

TEM has become accepted as a curative operation for large rectal polyps that are not amenable to colonoscopic resection,[62] and it may be used in selected patients with rectal cancer—typically, anatomically accessible lesions localized to the bowel wall (T1N0).[63]

Definitive treatment of T2 or T3 rectal lesions with TEM has not been recommended. However, a study by González et al, which examined surgical and long-term oncologic outcomes of TEM for treatment of T2-3 rectal cancer after chemoradiotherapy and complete clinical response, found TEM to be oncologically safe and effective in this setting.[64] The use of TEM as palliative surgery for advanced rectal lesions is also acceptable for patients with comorbid conditions and disseminated disease who are otherwise unfit for more radical surgery.{ref124 }

A meta-analysis comparing TEM with endoscopic submucosal dissection (ESD) for the treatment of rectal tumors found that the two procedures are similar with regard to the rates of resection, adverse events, and recurrence; however, both the procedure time and the duration of hospitalization were shorter with ESD.[65]  An international collaborative study by Kim et al found ESD to be safer and more cost-effective than TEM for the treatment of early rectal cancer.[66]

An approach that combines TEM with ESD (TEM-ESD) has been described.[67]

Sphincter-Sparing Procedures

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.[68]

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.[69]  

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.[70]

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.[46]

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.[35, 57, 46]

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.[35]

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.[57]   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.[71]

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).[35] 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.[35]

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.[72]

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 identified high tumor location and low carcinoembryonic antigen (CEA) level after chemoradiation therapy as independent predictive factors for pCR.[73]

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.[46]

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.[46]

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.[74] 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 is longer, 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.[75]  

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.[76]  

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.[77]  

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.[35, 78]



View Table

See Table

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.[46]

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.[35, 46]  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.[79]

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.[80]

Adjuvant Therapy

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.[81]

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.[46]

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 is typically based on 5-fluorouracil (5-FU), or the 5-FU prodrug capecitabine, in combination with adjuncts such as levamisole and leucovorin.[4] See Table 3, below.

Table 3. Common Chemotherapeutic Regimens for Colon and Rectal Cancer



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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.[4] 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.[82]

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

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.[83]

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.[84]

Trifluridine/t/ipiracil

The US Food and Drug Administration (FDA) has approved trifluridine/tipiracil (Lonsurf), as monotherapy and in combination with bevacizumab, for metastatic colorectal cancer in adults previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti–vascular endothelial growth factor (VEGF) biologic therapy; and, if RAS wild-type, an anti–endothelial growth factor receptor (EGFR) therapy. Trifluridine is a nucleoside analog that inhibits cell proliferation by incorporating into DNA and interering with DNA synthesis; tipiracil inhibits the metabolism of trifluridine.

Efficacy and safety for trifluridine/tipiracil monotherapy were evaluated in the phase III RECOURSE trial, an international, randomized, double-blind study involving 800 patients with previously treated metastatic colorectal cancer. Patients had received chemotherapy with a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and—for patients with KRAS wild-type tumors—cetuximab or panitumumab. Median overall survival was 7.1 months with trifluridine/tipiracil vs 5.3 months with placebo (P < 0.001). The progression-free survival was 2 months with trifluridine/tipiracil vs 1.7 months with placebo.[85]

Approval for combination therapy with bevacizumab was based on the results from the phase III SUNLIGHT trial, in which 246 patients received either trifluridine/tipiracil plus bevacizumab (combination group) or trifluridine/tipiracil alone (FTD–TPI group). The median overall survival was 10.8 months in the combination group and 7.5 months in the FTD–TPI group (P < 0.001). The median progression-free survival was 5.6 months in the combination group and 2.4 months in the FTD–TPI group (P< 0.001).[86]

Biologic therapy

In unresectable and metastatic rectal cancer, biologic agents are used in combination with chemotherapy

Bevacizumab

Bevacizumab, a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF), inhibits tumor angiogenesis. It is indicated for first-line or second-line treatment of metastatic colorectal carcinoma in combination with 5-FU-based chemotherapy.

Cetuximab

Cetuximab, a recombinant humanized monoclonal antibody that binds specifically to EGFR, is recommended as part of combination therapy (eg, with FOLFOX or FOLFIRI) for unresectable metastatic colorectal carcinoma.[4] Cetuximab should not be used in patients with the KRAS mutation.[87] 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.[88]

Panitumumab

Panitumumab is a monoclonal antibody for EGFR. In patients with metastatic colorectal cancer that is wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test) it is indicated in combination with FOLFOX as first-line treatment, and as monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. It is also indicated for use in combination with sotorasib for the treatment of KRAS G12C-mutated metastatic colorectal carcinoma, as determined by an FDA-approved test, in patients who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.[89]

Programmed cell death 1 inhibitors

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.[90]  The PD-1 inhibitor dostarlimab has also demonstrated benefit in dMMR rectal cancer[91] and has FDA approval for second-line use in this setting.[92]

HER2-directed treatment

In 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.[93]

Fruquintinib

Fruquintinib (Fruzaqla), a selective and potent oral inhibitor of VEGFR 1, 2, and 3, was approved by the FDA in November 2023 for adults with metastatic colorectal cancer who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy.

Approval was based on results of the FRESCO and FRESCO-2 trials.[94, 95] Overall survival (OS) was the major efficacy outcome in both trials. In FRESCO-2, median OS was 7.4 months in the fruquintinib group versus 4.8 months in the placebo group (hazard ratio [HR] 0.66, P < 0.0001).[95] In FRESCO, median OS was 9.3 months and 6.6 months, respectively (HR 0.65, P < 0.001).[94]

Encorafenib

In December 2024 the FDA granted accelerated approval for the BRAF inhibitor encorafenib, in combination with cetuximab and mFOLFOX6, for first-line treatment of BRAF V600E mutation–positive metastatic colorectal cancer. Approval was based on results of the active-controlled, open-label BREAKWATER trial, in which the objective response rate with this regimen was 61%, as compared with 40% in the control arm, in which patients received mFOLFOX6, FOLFOXIRI, or CAPEOX, each with or without bevacizumab. Median duration of response was 13.9 versus 11.1 months, respectively.[96]

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 rates of distant metastasis and overall recurrence but not local recurrence.[97]

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.[98]  

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).[99]

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) that, 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.[100]

Diet

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.[101]

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.[101]  

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.[101]

Prevention

Randomized, controlled trials of daily aspirin use (designed to study prevention of vascular events) showed that aspirin reduced incidence and mortality due to colorectal cancer, after a delay of 8–10 years.[102]  Benefit appears unrelated to aspirin dose.[103]  

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.[104]  

Nevertheless, the National Comprehensive Cancer Network (NCCN) considers that the evidence is unclear whether the use of aspirin for primary prevention reduces the incidence or mortality of colorectal cancer. However, the NCCN supports consideration of aspirin use for prevention in patients with Lynch syndrome.[39]

Secondary prevention

Preclinical and epidemiologic studies have suggested that statins may have antineoplastic properties. A systematic review and meta-analysis concluded that statin use after diagnosis of colorectal cancer improved overall survival, although not disease-free survival.[105]

Aspirin use after the diagnosis of colorectal cancer has also been associated with improved survival in these patients.[106]  NCCN guidelines recommend considering aspirin use, 325 mg daily, for secondary prevention.[4]

Long-Term Monitoring

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.[107] This includes the following:

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[4] :

Guidelines Summary

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

Guidelines on familial risk have been issued by the following organizations:

Guidelines on postpolypectomy surveillance have been issued by the following organizations:

Guidelines on surgical treatment of rectal cancer have been issued by the following organizations:

Guidelines on adjuvant and neoadjuvant therapy have been issued by the following organizations:

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

Guidelines on molecular testing in metastatic disease were issued by the following organizations:

Surgical Treatment

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.[119]

Additional recommendations include the following[119] :

Guidelines from the European Society for Medical Oncology (ESMO) include the following recommendations on management of local and locoregional rectal cancer[120] :

Adjuvant Therapy

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.[4]

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.[4]

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:

Follow-up Care in Stage II and III Colorectal Cancer

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

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).[118, 121, 4, 117] The frequency of the surveillance testing differs as shown in the table below.

Table. 1



View Table

See Table

In 2016, the US Multi-Society Task Force on Colorectal Cancer issued guidelines on colonoscopy after colorectal cancer resection, which included the following recommendations[107] :

Molecular Testing in Metastatic Disease

 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[122] :

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[116] :

 

Medication Summary

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.

As with colon cancer, standard chemotherapy for rectal cancer is with 5-fluorouracil (5-FU), or the 5-FU prodrug capecitabine, in combination with adjuncts such as levamisole and leucovorin. 

In unresectable and metastatic rectal cancer, biologic agents are used in combination with chemotherapy. Biologic agents used in both first-line and second-line therapy include bevacizumab and encorafenib. Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, in combination with chemotherapy is indicated in patients with positive or negative resectable synchronous metastases, as well as those with unresectable synchronous metastases. Encorafenib, a BRAF inhibitor, is used in combination with cetuximab and mFOLFOX6 for first-line treatment of BRAF V600E mutation-positive metastatic rectal cancer. Other biologic agents are used in second-line therapy.

 

 

 

Fluorouracil (5-FU, Fluorouracil, Adrucil)

Clinical Context:  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.

Capecitabine (Xeloda)

Clinical Context:  Oral agent that is converted to 5-FU in the body.

Vincristine (Vincasar PFS, Oncovin)

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

Leucovorin (Wellcovorin)

Clinical Context:  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)

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

Oxaliplatin (Eloxatin)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  Recombinant human IgG2 kappa monoclonal antibody that binds to human epidermal growth factor receptor (EGFR). In patients with metastatic colorectal cancer that is wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test), it is indicated in combination with FOLFOX as first-line treatment, and as monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. It is also indicated for use in combination with sotorasib for the treatment of KRAS G12C-mutated metastatic colorectal carcinoma, as determined by an FDA-approved test, in patients who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

Tucatinib (Tukysa)

Clinical Context:  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.

Trifluridine/tipiracil (Lonsurf)

Clinical Context:  Trifluridine is a thymidine-based nucleoside analog that incorporates into DNA, interferes with DNA synthesis, and inhibits cell proliferation. Tipiracil increases trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase. The combination product is indicated, as a single agent or in combination with bevacizumab, for metastatic colorectal cancer in patients previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

Fruquintinib

Clinical Context:  Fruquintinib is a selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. It is indicated for metastatic colorectal cancer (mCRC) in adults who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy.

Encorafenib (Braftovi)

Clinical Context:  BRAF inhibitor; indicated for treatment of BRAF V600E mutation–positive metastatic rectal cancer. Used first-line in combination with cetuximab and mFOLFOX6, and second-line in combination with cetuximab.

Sotorasib (Lumakras)

Clinical Context:  Forms irreversible, covalent bond with unique cysteine of KRAS G12C, locking the protein in an inactive state that prevents downstream signaling without affecting wild-type KRAS. Indicated for use in combination with panitumumab for the treatment of KRAS G12C-mutated metastatic colorectal carcinoma, as determined by an FDA-approved test, in patients who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

Class Summary

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

What is rectal cancer?What are the common signs and symptoms of rectal cancer?How is a physical exam performed in suspected rectal cancer?Which lab studies are indicated in the workup of suspected rectal cancer?Which screening tests are used in suspected rectal cancer?Which imaging studies are used in the workup of metastatic rectal cancer?What is the approach to the treatment of rectal cancer?What are the surgical options for the treatment of rectal cancer?What are the options for medical management of rectal cancer?Which drugs are recommended by the NCCN for the treatment of rectal cancer?How common is rectal cancer and what are the most common types?What is the anatomy of the rectum in relation to rectal cancer?What is the pathophysiology of rectal cancer?What are the pathways to colon and rectal cancer?What is the epidemiology of rectal cancer in the US?What is the international incidence of rectal cancer?What is the incidence of rectal cancer by race?Is rectal cancer more common in men or women?What is the incidence of rectal cancer by age?What are the overall 5-year survival rates for rectal cancer?How common is the recurrence of rectal cancer and what is the prognosis?What educational information is available for patients with rectal cancer?What is the mortality of rectal cancer?What is the role of aspirin in the reduction of cancer death rates?What is the clinical history of rectal cancer?How is a physical exam conducted in suspected rectal cancer?What causes rectal cancer?Which dietary habits contribute to the development or prevention of rectal cancer?What is the role of alcohol in the development of rectal cancer?What is the role of tobacco in the development of rectal cancer?What is the relationship between cholecystectomy and rectal cancer?Which hereditary factors increase the risk of rectal cancer?What is the role of familial adenomatous polyposis (FAP) in the development of rectal cancer?What causes hereditary nonpolyposis colorectal cancer (HNPCC) (Lynch syndrome), and who is at risk?What is the malignant pathway of rectal cancer in patients with ulcerative colitis or Crohn disease?Which lab studies are indicated in the workup of rectal cancer?What is the purpose of screening for colon and rectal cancer?What are the screening options for colon and rectal cancer?When is screening for colon and rectal cancer indicated in average-risk patients?What are the screening options and regimens for colon and rectal cancer?What are the advantages of the different colon and rectal cancer screening tests?When is screening for colon and rectal cancer indicated in high-risk patients?When is surveillance for colon and rectal cancer indicated?What are the screening recommendations for rectal cancer by risk factor?Which histopathologic features of rectal cancer are associated with a poor outcome?What are the stages of rectal cancer according to the Dukes Classification?What are the subdivisions of Dukes Classification stages B and C in rectal cancer?What is the role of the tumor, node, metastasis (TNM) system in rectal cancer?What are the TNM system tumor classifications in rectal cancer?What are the TNM system node classifications in rectal cancer?What are the TNM system metastasis classifications in rectal cancer?How do the Dukes Classification and the TNM staging system for rectal cancer compare?What are the 5-year survival rates for rectal cancer according to the tumor, node, metastasis (TNM) system?What are the approach considerations in the treatment of rectal cancer?Which factors influence sphincter and organ preservation in patients with rectal cancer?When is sphincter preservation difficult in the treatment of rectal cancer?When is local excision indicated in the treatment of rectal cancer?What are disadvantages of abdominoperineal resection in the treatment of rectal cancer?What is the role of neoadjuvant therapy in the treatment of rectal cancer?What is the role of transanal excision in the treatment of rectal cancer?What is the role of endocavitary radiation in the treatment of rectal cancer?What are the sphincter-sparing surgical options the treatment of in rectal cancer?What are indications for low anterior resection (LAR) in the treatment of rectal cancer?What are indications for total mesorectal excision (TME) in the treatment of rectal cancer?How effective is mesorectal excision (TME) in the treatment of rectal cancer?When is coloanal anastomosis (CAA) indicated in the treatment of rectal cancer?What is the role of laparoscopic resection in the treatment of rectal cancer?When is abdominal perineal resection (APR) indicated in the treatment of rectal cancer?How is an abdominal perineal resection (APR) performed in the treatment of rectal cancer?How is liver metastasis treated in patients with rectal cancer?What dietary recommendations are indicated in the treatment of rectal cancer?What are the USMSTF guidelines for long-term monitoring of patients with rectal cancer?What are the NCCN guidelines for long-term monitoring of patients with rectal cancer?What is the role of transanal endoscopic microsurgery (TEM) in the treatment of rectal cancer?What are the options for adjuvant care in the treatment of rectal cancer?What is the role of adjuvant radiation therapy in the treatment of rectal cancer?How effective is postoperative radiation therapy in the treatment of rectal cancer?What is the role of intraoperative radiation therapy in the treatment of rectal cancer?What is the role of adjuvant chemotherapy in the management of rectal cancer?Which chemotherapeutic agents are used in the treatment of rectal cancer?What is the role of biologic therapy in the treatment of rectal cancer?What is the role of adjuvant chemoradiation in the treatment of rectal cancer?What is the role of radioembolization in the treatment of rectal cancer?What is the indicator of response to neoadjuvant therapy for rectal cancer on MRI??What are the ESMO guidelines on surgery for rectal cancer?What are the NCCN guidelines on adjuvant therapy regimens for rectal cancer?What are the NCCN guidelines on adjuvant therapy for stage II or stage III rectal cancer?What are the guidelines on follow-up care for survivors of stage II and stage III rectal cancer?What are the USMSTF guidelines on colonoscopy after rectal cancer resection?What are the recommendations on gene mutation testing in metastatic colorectal carcinoma (mCRC)?Which organizations have issued guidelines on rectal cancer screening?What are the risk factors and ACS/USMSTF/ACR guidelines for rectal cancer screening?Which tests are recommended to detect adenomatous polyps and cancer?Which tests are recommended to detect rectal cancer?What are the updated 2018 ACS colorectal screening guidelines?What are USPSTF guidelines on rectal cancer screening?What are the stool-based tests used in rectal cancer screening and their recommended intervals?What are the direct visualization tests used in rectal cancer screening and their recommended intervals?What are the ACP recommended strategies for rectal cancer screening?What are the ACG guidelines for rectal cancer screening?What are NCCN screening recommendations for patients at increased risk of rectal cancer?Which syndromes associated with rectal cancer are addressed in the NCCN guidelines?When is further evaluation indicated for high-risk syndromes in rectal cancer screening?When is testing for Lynch syndrome (HNPCC) indicated in patients with rectal cancer?What are the guidelines for testing in familial risk-rectal cancer?What are the colonoscopy findings and associated recommended follow up in patients at risk for rectal cancer?What are the US Multi-Society Task Force on Colorectal Cancer guidelines on postpolypectomy surveillance of rectal cancer?What are recommended surveillance intervals for patients with serrated lesions and risk for rectal cancer?What are the BSG/ACPGBI/PHE guidelines on postpolypectomy surveillance of rectal cancer?What are the guidelines for surveillance of patients with familial adenomatous polyposis (FAP) and risk for rectal cancer?What are the recommendations for surveillance of patients with attenuated familial adenomatous polyposis (FAP) and risk for rectal cancer?What is the role of genetic testing in patients with familial adenomatous polyposis (FAP) and risk for rectal cancer?In addition to genetic counseling, what are the recommendations for surveillance and treatment of patients with familial adenomatous polyposis (FAP) and risk for rectal cancer?What are the ASCRS guidelines on surgery for rectal cancer?What are the goals of drug treatment in rectal cancer?Which medications in the drug class Antineoplastic agents are used in the treatment of Rectal Cancer?

Author

Burt Cagir, MD, FACS, Associate Regional Dean and Professor of Surgery, Geisinger Commonwealth School of Medicine; Director, General Surgery Residency Program, Executive Director, Donald Guthrie Foundation for Research and Education, Guthrie Robert Packer Hospital; Medical Director, Guthrie/RPH Skills and Simulation Lab; Associate in Surgery, Guthrie Robert Packer Hospital and Corning Hospital

Disclosure: Nothing to disclose.

Coauthor(s)

Gabriel O Ologun, MD, Resident Physician, Department of Surgery, Guthrie Robert Packer Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

N Joseph Espat, MD, MS, FACS, Harold J Wanebo Professor of Surgery, Assistant Dean of Clinical Affairs, Boston University School of Medicine; Chairman, Department of Surgery, Director, Adele R Decof Cancer Center, Roger Williams Medical Center

Disclosure: Nothing to disclose.

Additional Contributors

Douglas R Trostle, MD, MBA, FACS, Chairman of Surgery, The Guthrie Clinic

Disclosure: Nothing to disclose.

Elwyn C Cabebe, MD, Associate Medical Director, Stanford Cancer Networks; Medical Director, Stanford Cancer Center South Bay (CCSB); Medical Director of Oncology Quality, Stanford Medical Partners

Disclosure: Nothing to disclose.

Philip Schulman, MD, Chief, Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center

Disclosure: Nothing to disclose.

Acknowledgements

Elizabeth Cirincione, MD Director of Colon and Rectal Surgery, Department of Surgery, Nassau University Medical Center

Disclosure: Nothing to disclose.

Wendy Hu, MD Consulting Staff, Department of Hematology/Oncology and Bone Marrow Transplantation, Huntington Memorial Medical Center

Wendy Hu, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Blood and Marrow Transplantation, American Society of Hematology, and Physicians for Social Responsibility

Disclosure: Nothing to disclose.

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Diagnostics. Staging and workup of rectal cancer patients.

Diagnostics. Staging and workup of rectal cancer patients.

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

Diagnostics. Staging and workup of rectal cancer patients.

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

Rectal Cancer Stages TNM Staging Duke Staging 5-Year Survival
Stage IT1-2 N0 M0A>90%
Stage IIAT3 N0 M0B60%-85%
BT4 N0 M060%-85%
Stage IIIAT1-2 N1 M0C55%-60%
BT3-4 N1 M035%-42%
CT1-4 N2 M025%-27%
Stage IVT1-4 N0-2 M15%-7%
Resection Margins Proximal Resection Margin Distal Resection Margin
Ideal Margins 5 cm or more2 cm or more
Minimally acceptable margins 5 cm or more0.5-1 cm 
Regimen Frequency Schedule
FOLFOXEvery 2 weeksOxaliplatin 85 mg/m2 day 1



Leucovorin 200 mg/m2 day 1



5-Fluorouracil (5-FU) 400 mg/m2 IV bolus day 1 and 2



5-FU 600 mg/m2 IV infusion day 1 and 2 (22 hours)



FOLFOX 4Every 2 weeks



(Four cycles)



Oxaliplatin 85 mg/m2 day 1



Leucovorin 200 mg/m2 day 1



5-FU 400 mg/m2 IV bolus day 1 and 2



5-FU 2400 mg/m2 IV infusion day 1 (46 hours)



mFOLFOX 6Every 2 weeks



(Four cycles)



Oxaliplatin 85 mg/m2 day 1



Leucovorin 400 mg/m2 day 1



5-FU 400 mg/m2 IV bolus day 1 and 2



5-FU 1200 mg/m2 IV infusion day 2 days



CapeOxEvery 3 weeksOxaliplatin 130 mg/m2 day 1



Capecitabine 1000 mg/m2 PO BID for 14 days



FOLFIRIEvery 2 weeksIrinotecan 165 mg/m2 day 1



Leucovorin 200 mg/m2 day 1



5-FU 400 mg/m2 IV bolus day 1 and 2



5-FU 600 mg/m2 IV infusion day 1 and 2 (22 hours)



FOLFOXIRIEvery 2 weeksIrinotecan 180 mg/m2 day 1



Oxaliplatin 85 mg/m2 day 1



Leucovorin 200 mg/m2 day 1



5-FU 3200 mg/m2 IV infusion day 1 and 2 (48 hours)



BevacizumabEvery 2 weeks



with chemotherapy



5-10 mg/kg IV
CetuximabWith chemotherapy400 mg/m2 IV day 1, then 250 mg/m2 IV weekly
Parameter Organization
ESMO (2013)[121] ASCO (2013)[118] NCCN (2019)[4] ASCRS (2015)[117]
History and physical examEvery 3-6 mo for 3 y, then every 6 -12 mo at 4 and 5 yEvery 3-6 mo for 3 y, then every 6 mo to 5 yEvery 3-6 mo for 2 y, then every 6 mo to 5 yEvery 3-6 mo for 2 y, then every 6 mo to 5 y
CEAEvery 3-6 mo for 3 y, then every 6 -12 mo at 4 and 5 yEvery 3 mo for 3 y*Every 3-6 mo for 2 y, then every 6 mo to 5 yEvery 3-6 mo for 2 y, then every 6 mo to 5 y
Chest CT*Every 6-12 mo for first 3 yEvery 1 y for 3 yEvery 6-12 mo to 5 yEvery 1 y for 5 y
Colonoscopy**At y 1 after surgery, and every 3-5 y thereafterAt 1 y, then every 5 y, dictated by the findings on the previous colonoscopyAt 1 y, 3 y, and 5 y if negativeAt y 1 after surgery, and every 3-5 y dictated by the findings on the first postoperative examination.
Abdominal CT*Every 6-12 mo for first 3 yEvery 1 y for 3 yEvery 6-12 mo to 5 yEvery 1 y for 5 y
ESMO = European Society of Medical Oncology; ASCO = American Society of Clinical Oncology; NCCN = National Comprehensive Cancer Network; American Society of Colon and Rectal Surgeons = ASCRS CEA = carcinoembryonic antigen; CT = computed tomography * For patients at high risk for recurrence (eg, lymphatic or venous invasion, or poorly differentiated tumors). **Colonoscopy should be performed 3-6 mo postoperatively if preoperative colonoscopy was not done, due to an obstructing lesion; otherwise, colonoscopy in 1 y; if abnormal, repeat in 1 year; if no advanced adenoma (ie, villous polyp, polyp >1 cm, or high-grade dysplasia), repeat in 3 y, then every 5 y.