Colorectal Cancer

8 Interesting Facts of Colorectal Cancer 

1. Colorectal cancer is a malignant neoplasm of the colon or rectum, most commonly adenocarcinoma; clinical presentation ranges from asymptomatic to imminently life threatening (eg, perforation, obstruction)
2. Often detected by screening or by evaluation of anemia, weight loss, or blood in stool
3. Diagnosis is based on history and physical examination findings, confirmed with colonoscopy, and made conclusive with pathology review of specimen 
4. After tissue diagnosis, additional laboratory tests and imaging are required to assess organ function, guide additional diagnostic measures for staging, and select the best treatment approach 
   • Standard laboratory tests include CBC, carcinoembryonic antigen level, serum chemistry panel, and liver function test 
   • All patients must undergo imaging of chest, abdomen, and pelvis, usually with CT (or MRI for rectal cancer) 
5. Management may include surgical resection, chemotherapy, radiation therapy, or a combination thereof 
   • Regimen is determined by location (colon or rectum), clinical stage, histologic features on biopsy, and presence of comorbidities 
   • Surgery is the keystone of treatment for candidates with acceptable operative risk and resectable disease 
   • Adjuvant chemotherapy is given after surgery to prevent local recurrence or metastasis in patients with more advanced stages 
6. Common complications of colorectal cancer include gastrointestinal bleeding and bowel obstruction or perforation; metastatic disease and treatment-related complications also cause significant morbidity
7. Regular screening for at-risk populations is recommended to identify and remove precancerous polyps 
8. Guidelines vary; however, general consensus is that colonoscopy screening be started at age 45 years and repeat every 10 years until at least age 75 years
   • Recommendations vary for higher-risk populations (eg, people who are Black and those with a familial association) 

Pitfalls

• Incomplete colonoscopy may result in failure to detect primary or synchronous lesions
• In evaluation of abdominal pain on a background of change in bowel habits, CT of abdomen alone (if not followed up with colonoscopy) can miss a diagnosis of colon cancer
• In the presence of coexisting diverticular disease, consider endoscopic evaluation after resolution of acute diverticulitis 

• Colorectal cancer is a malignant neoplasm of the colon or rectum, most commonly adenocarcinoma
• In clinical practice, tumors within 15 cm of the anal verge are typically classified as rectal cancers 

Classification

• TNM staging system
  • Anatomic staging
    • Tumor (T)
      • TX: primary tumor cannot be assessed
      • T0: no evidence of primary tumor
      • Tis: carcinoma in situ; intramucosal carcinoma (involvement of lamina propria with no extension through muscularis mucosae)
      • T1: invades submucosa (through the muscularis mucosae but not into the muscularis propria)
      • T2: invades muscularis propria
      • T3: invades through muscularis propria into pericolorectal tissues
      • T4: invades visceral peritoneum or invades or adheres to adjacent organ or structure
      • T4a: invades through visceral peritoneum
      • T4b: directly invades or adheres to adjacent organs or structures
    • Regional lymph nodes (N)
      • NX: regional nodes cannot be assessed
      • N0: no regional node metastasis
      • N1: 1 to 3 regional nodes are positive (tumor in lymph nodes measuring 0.2 mm or more, or any number of tumor deposits are present and all identifiable lymph nodes are negative)
      • N1a: 1 regional node is positive
      • N1b: 2 or 3 regional nodes are positive
      • N1c: No regional nodes are positive, but there are tumor deposits in subserosa, mesentery, or nonperitonealized pericolic or perirectal/mesorectal tissues
      • N2: 4 or more regional nodes are positive
      • N2a: 4 to 6 regional nodes are positive
      • N2b: 7 or more regional nodes are positive
    • Distant metastases (M)
      • M0: no distant metastasis
      • M1: metastasis to 1 or more distant sites or organs, or peritoneal metastasis is identified
      • M1a: metastasis to 1 site or organ without peritoneal metastasis
      • M1b: metastasis to 2 or more sites or organs without peritoneal metastasis
      • M1c: metastasis to peritoneal surface alone or with other site or organ metastases
  • Prognostic staging according to anatomic staging
    • Stage 0
      • TisN0M0
    • Stage I
      • T1N0M0 or T2N0M0
    • Stage II
      • IIA
        • T3N0M0
      • IIB
        • T4aN0M0
      • IIC
        • T4bN0M0
    • Stage III
      • IIIA
        • T1N1M0, T2N1M0, T1N1cM0, or T2N1cM0
        • T1N2aM0
      • IIIB
        • T3 to T4a, N1 to N1c, M0
        • T2N2aM0 or T3N2aM0
        • T1N2bM0 or T2N2bM0
      • IIIC
        • T4aN2aM0
        • T3N2bM0 or T4aN2bM0
        • T4bN1M0 or T4bN2M0
    • Stage IV
      • IVA
        • Any T, any N, M1a
      • IVB
        • Any T, any N, M1b
      • IVC
        • Any T, any N, M1c

Clinical Presentation

History

• Early stages of colorectal cancer are often asymptomatic
• Most common symptoms are rectal bleeding, abdominal pain, and change in bowel habits 
  • Change in bowel habits include narrowing of stool or diarrhea or constipation that persists longer than a few days; such changes are more commonly associated with lesion in descending colon 
  • Hematochezia
    • More common with lesion in descending colon 
• Other localizing symptoms include rectal pain, tenesmus, nausea, vomiting, and passage of mucus 
  • If present, nausea and/or vomiting may be indicative of a partial or complete large-bowel obstruction due to advanced malignancy
• Nonspecific constitutional symptoms include unintended weight loss, anorexia, and fatigue 
  • Such symptoms are also associated with many other malignancies
• Family history of colon cancer is relevant, including degree of relationship and age of onset in affected family member 

Physical examination

• Findings are usually normal in early stages of disease
• In advanced stages, patients may appear cachectic and debilitated 
• Pallor of skin and conjunctivae (from blood loss anemia) may be evident
  • Anemia is more common with lesion in ascending colon 
• Scleral icterus or frank jaundice may be seen in advanced stages when hepatic metastases are present
• Abdominal examination may find a palpable mass, hepatomegaly, or distention due to colonic obstruction or malignant ascites
• Rectal examination
  • A distal rectal lesion may be reached by digital rectal examination
  • Peritoneal implants in the cul-de-sac may be palpable with metastatic disease
• Metastatic deposits are occasionally evident on palpation of skin or lymph nodes

Causes

• Multifactorial; environment and inheritance play varying roles specific to individual patients
• Most cases are sporadic, involving no apparent underlying genetic predisposition
• In an estimated 12% to 35% of cases, inherited components (typically common polymorphisms) contribute to pathogenesis 
• Approximately 3% to 5% of cases arise from hereditary syndromes that mutate several genes involved in cancer predisposition, causing early onset of disease 

Risk factors and/or associations

Age

• Risk increases with age
  • Most frequently diagnosed in people aged 65 to 74 years 
• Patients with specific genetic syndromes associated with colorectal cancer often present at an earlier age 

Sex

• More common in men than in women 

Genetics

• Family history of colorectal cancer in 1 or more first-degree relatives increases risk approximately 2-fold 
• Specific syndromes associated with susceptibility to colorectal cancer
  • Lynch syndrome (hereditary nonpolyposis colorectal cancer, OMIM #120435)
    • Autosomal dominant disorder of early-onset colorectal cancer (mean age, 45 years) associated with germline mutations in 1 of several mismatch repair genes (ie, MSH2, MLH1, MSH6, PMS2, EPCAM)
    • Lifetime risk of developing colorectal cancer is approximately 66% for men and 43% for women 
    • A subset of patients with hereditary nonpolyposis colorectal cancer is also at higher risk for extracolonic malignancies (eg, endometrial, gastric, pancreatic, biliary, urothelial)
  • Familial adenomatous polyposis (OMIM #175100)
    • Classic case is autosomal dominant, characterized by teenage onset of hundreds to thousands of adenomatous polyps throughout colon; attenuated case is autosomal dominant, is usually identified in patients older than 40 years, and features 10 to 100 adenomas 
      • If condition is left untreated, lifetime risk of developing colorectal cancer is 95% 
      • Both classic and attenuated forms of familial adenomatous polyposis are caused by germline inactivating mutations of APC (WNT signaling pathway regulator)
    • Familial adenomatous polyposis type 2, associated with MUTYH (mutY DNA glycosylase), is an autosomal recessive disorder and phenotypically indistinguishable from attenuated familial adenomatous polyposis; caused by mutations in both copies of MUTYH 
      • Lifetime risk of developing colorectal cancer is approximately 80% 
• Uncommon genetic syndromes associated with development of colorectal cancer
  • Peutz-Jeghers syndrome (OMIM #175200)
    • Autosomal dominant disorder caused by germline mutations in STK11 (serine/threonine kinase 11), characterized by intestinal hamartomatous polyps
    • Lifetime risk of developing colorectal cancer is 39% 
• Juvenile polyposis syndrome (OMIM #174900) 
  • • Autosomal dominant disorder caused by germline mutations in SMAD4 (SMAD family member 4) or BMPR1A (bone morphogenetic protein receptor type 1A), characterized by juvenile polyps, and often presenting by age 20 years
    • Lifetime risk of developing colorectal cancer is approximately 40% 
  • Cowden syndrome (multiple hamartoma syndrome, OMIM #158350) 
    • Autosomal dominant disorder caused by germline mutations in PTEN (phosphatase and tensin homolog); characterized by gastrointestinal polyposis, hamartomas, and increased risk of malignancies in endometrium, breast, and thyroid
    • Hamartomas are commonly found on skin and mucous membranes
    • Estimated lifetime risk of developing colorectal cancer is slightly elevated at 16% 
  • Serrated polyposis syndrome
    • Disorder with no established inheritance characterized by multiple and/or large serrated polyps in colon
    • Estimated lifetime risk of developing colorectal cancer is roughly 50% 
  • Li Fraumeni syndrome
    • Associated with germline mutations in TP53 
    • High lifetime risk of cancers, including breast, soft tissue sarcomas, colon cancer, and brain tumors, occurring at young age 

Ethnicity/race

• Black people are at greater risk of colorectal cancer occurrence and mortality 

Other risk factors/associations

• Risk factors
  • Smoking
  • Use of alcohol
  • Obesity
  • Low physical activity
  • Inflammatory bowel disease (eg, Crohn disease, ulcerative colitis)
  • Diet
    • Low-fiber, high-fat diet may increase risk
    • Red meat consumption may increase risk
• Use of aspirin or NSAIDs reduces risk

Diagnostic Procedures

Primary diagnostic tools

• Start diagnostic workup when colorectal cancer is suspected owing to either a positive screening result or characteristic signs/symptoms
• Diagnosis is based on history and physical examination, confirmed with colonoscopy, and made conclusive with pathology review of specimen 
  • All patients—even those with distal lesions—should undergo visualization of entire colon with colonoscopy owing to possibility of synchronous lesions (incidence may be as high as 10% even in nonhereditary cases) 
    • If full colonoscopy is not possible, consider CT colonography or barium enema 
• After tissue diagnosis, additional laboratory tests and imaging are required to assess organ function, guide additional diagnostic measures for staging, and select the best treatment approach 
  • Standard laboratory tests include CBC, carcinoembryonic antigen level, serum chemistry panel, and liver function test 
  • Selective rather than routine use of preoperative laboratory testing (eg, CBC, liver function tests, coagulation tests) is recommended for evaluation of new patients with colon cancer 
  • All patients must undergo imaging of chest, abdomen, and pelvis, usually with CT (or MRI for rectal cancer)
  • Biopsy (usually fine-needle aspiration) is required to confirm diagnosis of metastatic disease in a suspicious lesion detected by imaging
    • Surgical intervention for staging is indicated only when the area in question cannot be safely biopsied with a needle
  • Patients with rectal cancer should undergo rigid proctoscopy to measure distance from anal verge, along with transrectal (endorectal) ultrasonography and rectal cancer protocol pelvic MRI 
  • For patients who undergo surgical resection, staging is modified postoperatively based on operative findings and histopathology
  • Patients with suspected or proven metastatic disease may also undergo PET-CT (skull base to mid-thigh) if they have potentially surgically curable disease 

Laboratory

• Histopathology of tissue from endoscopically resected polyp or biopsy material
  • Formal diagnosis of colorectal carcinoma is made by microscopic examination of tissue from endoscopically resected polyp or biopsy
    • A malignant polyp is defined as one with cancer invading through muscularis mucosa and into submucosa 
    • Most are adenocarcinomas
  • Parameters that are important to assess include grade, depth of penetration, number of total and positive lymph nodes, status of margins, lymphovascular invasion, perineural invasion, and any tumor deposits 
  • For metastatic disease, tumor tissue is genotyped for RAS family mutations (in KRAS and NRAS) and BRAF mutations 
• CBC
  • Useful in assessing for iron deficiency anemia associated with colorectal cancer
  • Findings of iron deficiency anemia
    • Decreased levels of the following:
      • Ferritin
      • Hemoglobin
      • Hematocrit
      • Mean corpuscular volume
      • Serum iron and iron saturation
    • Elevation in total iron-binding capacity
• Hepatic profile
  • Useful in determining baseline liver function
  • Elevated serum alkaline phosphatase level is nonspecific but may suggest liver metastasis
  • Very high liver transaminase levels may suggest liver metastasis
• Order a serum chemistry panel that includes renal function tests (BUN and creatinine test) 
  • Elevated BUN and creatinine levels indicate renal insufficiency and may warrant a change in standard treatment approach
• Carcinoembryonic antigen level 
  • Is typically assessed before elective surgery for colon cancer (to establish a baseline value) and during surveillance period (to monitor for signs of recurrence) 
    • Increased level has been associated with adverse prognosis in patients with resectable colorectal cancer
    • Useful in determining response to treatment 
    • Not a staging tool per current staging guidelines 

Imaging

• CT of chest, abdomen, and pelvis with IV and oral contrast material
  • Imaging to assess degree of tumor invasion and presence, number, and location of metastases (for staging purposes)
  • Indicated for all patients before surgery
  • Evidence of extramural extension or distant metastasis alters approach to treatment
  • In evaluation of abdominal pain on a background of change in bowel habits, CT of abdomen alone (if not followed up with colonoscopy) can miss a diagnosis of colon cancer
• MRI pelvis, with and without contrast enhancement (rectal cancer protocol)
  • Indications
    • Indicated for patients with rectal cancer
      • MRI is routine for primary staging and restaging of rectal cancer 
  • More accurate than CT in detecting liver metastasis but is rarely used unless the lesions are difficult to characterize on CT 
• Transrectal (endorectal) ultrasonography
  • Recommended in addition to CT for rectal carcinoma staging in all patients 
  • More accurate than CT in determining depth of lesion; T-stage accuracy is far superior to that of CT 
  • Preferred technique for differentiating and staging T1 tumors 

Procedures

• Fiberoptic colonoscopy allows direct visualization of colonic lumen and mucosa so that the endoscopist can identify and localize lesions, obtain biopsy, remove polyps, and detect synchronous neoplasms 
• Requires adequate bowel preparation and conscious sedation 
• Incomplete colonoscopy may result in failure to detect primary or synchronous lesions
• Routine screening and surveillance
• Unexplained gastrointestinal bleeding
  • Hematochezia
  • Melena
  • Fecal occult blood
• Unexplained iron deficiency anemia
• Abnormal findings on CT colonography or other imaging study
• Palliative treatment of bleeding neoplasms
• Inadequate bowel preparation
• Poor tolerance of procedure
• Obstructing lesion
• Serious cardiorespiratory or neurologic comorbidities may increase risk of complications (eg, colonic perforation, adverse sedation events)
• Fulminant colitis 
• Documented acute diverticulitis 
• Bleeding
• Perforation
• Cautery injury; postpolypectomy coagulation syndrome
• Suspicious morphologic features suggest malignant polyps, including: 
  • Irregular contours
  • Central depression
  • Contact bleeding
  • Shape deformity
    • Flat sessile or raised pedunculated polyps
  • Small, regularly spaced papules
  • Abnormal vasculature or surface pattern

Other diagnostic tools

• Flexible sigmoidoscopy in combination with barium enema
  • Gradually being replaced by colonoscopy or CT colonography owing to greater diagnostic yield of these investigations 
• Molecular biomarkers used in clinical decision making
  • All patients with metastatic colorectal cancer should have tumor tissue genotyped for RAS family mutations (in KRAS and NRAS), BRAF mutations, and HER2 amplification 
    • Do not treat patients who have any known KRAS mutation or NRAS mutation with either cetuximab or panitumumab 
    • BRAF V600E mutation makes response to cetuximab or panitumumab unlikely 
  • Universal testing for microsatellite instability and deficient mismatch repair is recommended in all patients with personal history of colon or rectal cancer 
    • Microsatellite instability testing compares the allele patterns of constitutional and tumor DNA extracted from unstained sections from formalin-fixed and paraffin-embedded tissue specimens (after resection or biopsy) using polymerase chain reaction amplification of selected microsatellites
    • Testing for mismatch repair deficiency analyzes expression of proteins involved in the DNA mismatch repair process, using immunohistochemistry
    • Results of microsatellite instability or mismatch repair testing allow for selection of targeted chemotherapy (along with providing prognostic information) 
  • Other biomarkers, such as gene signatures, Immunoscore, and postoperative measurement of circulating tumor DNA, may be of some benefit in determining the risk of recurrence and can be used to further tailor the adjuvant treatment decisions in difficult cases 

Differential Diagnosis

Most common

• Benign conditions
  • Hemorrhoids
    • Presents with rectal bleeding (usually bright red), pain in perianal area, change in bowel habits, and pruritus
    • Distinguishing features may include findings on digital examination, protrusion of swollen blood vessel, and visualization of hemorrhoids on anoscopy or proctosigmoidoscopy
    • Colorectal lesion is excluded by colonoscopy
  • Diverticulitis
    • Presents with onset of persistent pain (commonly in left lower quadrant), nausea, vomiting, fever, and change in bowel habits
    • May appear as a mass similar to colorectal cancer on imaging
    • Differentiating features include mucosal edema and appearance of inflamed diverticula on colonoscopy
      • Colorectal lesion is excluded by colonoscopy
      • Colonoscopy generally must wait for resolution of acute flare up of diverticulitis
  • Irritable bowel syndrome 
    • Presents with chronic symptoms of abdominal pain (usually greater in left lower quadrant) that may increase in severity after a meal; other symptoms include abdominal bloating and feeling of incomplete defecation
      • Distinguishing feature includes satisfying Rome III criteria for diagnosing irritable bowel syndrome
        • Recurrent abdominal discomfort for at least 3 days per month in the past 3 months, plus at least 2 of the following:
          • Onset associated with change in frequency of bowel movement
          • Onset associated with change in form of stool
          • Discomfort relieved by defecation
      • Symptom onset at least 6 months before diagnosis
    • Colorectal lesion is excluded by colonoscopy
  • Inflammatory bowel disease
    • Both Crohn disease and ulcerative colitis may present with abdominal pain, change in bowel habits, blood in stool, weight loss, and anemia
    • Crohn disease may include lesions elsewhere in gastrointestinal tract (eg, oral ulcerations, perianal fistulas)
    • Definitive diagnosis is made by appearance of colonic mucosa (ulcerations and fissures in inflammatory bowel disease, protruding intraluminal lesions in carcinoma) and by histopathology of biopsies
    • Inflammatory bowel disease increases the risk of colorectal carcinoma, thus findings of both may present concurrently
• Malignant conditions
  • Carcinoid tumor
    • Presents with vague abdominal pain and diarrhea; often associated with facial flushing, dyspnea, wheezing, and tachycardia
    • As with colorectal cancer, a mass may be detected on imaging
    • Diagnosis is suggested by extraintestinal serotoninergic symptoms and is confirmed by presence of biochemical markers in urine or plasma, as well as by histopathology of lesion
  • Kaposi sarcoma
    • Presents with nausea, vomiting, and change in bowel habits
    • As with colorectal cancer, a mass may be detected on examination, imaging, or endoscopy
    • Often a history of immunocompromised state (eg, HIV/AIDS, immunosuppression after transplant)
    • Colonoscopy with biopsy confirms diagnosis and excludes colorectal cancer
  • Lymphoma
    • Presents with abdominal pain, change in bowel habits, and night sweats
    • As with colorectal cancer, a mass may be detected on imaging (may not be intraluminal)
    • Diagnostic distinction made by histopathology of primary lesion or regional lymph nodes

Treatment Goals

• General
  • Resectable tumor
    • Complete removal of tumor, major vascular pedicle, and lymphatic drainage basin via surgery
    • Subsequent elimination of residual tumor and/or micrometastasis via adjuvant chemotherapy (indicated for stage III colorectal cancer; may also improve outcomes for high-risk stage II colorectal cancer)
  • Unresectable tumor
    • Preoperative (neoadjuvant) radiotherapy and/or chemotherapy to reduce tumor size and enable curative surgery
    • Subsequent complete removal of tumor via surgical resection
• Metastatic disease (stage IV colorectal cancer)
  • Resectable tumor
    • Surgical cures are possible when metastasis is limited and primary lesion is resectable or becomes resectable after chemotherapy and/or radiotherapy
  • Unresectable tumor
    • Palliative chemotherapy to retard growth
    • Prolong survival
    • Maintain quality of life

Disposition

Admission criteria

Emergency presentations of colorectal cancer, including those with:

• Intestinal obstruction
• Acute gastrointestinal bleeding
• Perforation and peritonitis

In patients who are receiving treatment for colorectal cancer

• Surgical resection of tumor
• Neutropenic fever

Criteria for ICU admission

• Life-threatening complications requiring aggressive monitoring and treatments (eg, perforation with peritonitis and sepsis syndrome, septic shock)

Imaging, chemotherapy, and radiation therapy are done on an outpatient basis

Recommendations for specialist referral

• Refer to gastroenterologist for diagnostic colonoscopy, biopsy, and excision of removable polyps
• Refer to colorectal surgeon or surgical oncologist for surgical removal of lesion and associated nodes
• Refer to medical oncologist for adjuvant or neoadjuvant chemotherapy
• Refer to radiation oncologist for neoadjuvant radiation therapy
• Refer for genetic evaluation/counseling, and possibly detailed risk assessment, those patients in whom a familial syndrome of colorectal cancer is suspected 
  • Personal or family history of known genetic mutation
  • Personal history of more than 10 adenomatous polyps
  • Personal history of 2 or more hamartomatous polyps
  • Personal history of 5 or more serrated polyps proximal to sigmoid colon
  • Family history of 1 or more relatives with polyposis
  • Personal or family history of Lynch syndrome–related cancers

Treatment Options

Management may include surgical resection, chemotherapy, radiation therapy, or a combination thereof 

• Regimen is determined by location (colon or rectum), clinical stage, histologic features on biopsy, and presence of comorbidities 
  • Rectal cancer poses additional considerations owing to the increased surgical complexity of the anatomic position and presence of the sphincter
• Surgery is the keystone of treatment for candidates with acceptable operative risk and resectable disease 
  • For resectable, nonmetastatic colon cancer, the preferred procedure is colectomy with en bloc removal of regional lymph nodes
  • Various surgical approaches may be considered for primary rectal cancer lesions, depending on location and extent of disease
  • Some patients with lesions deemed unresectable at presentation may benefit from neoadjuvant chemotherapy or radiation to shrink the mass to an operable size
• Adjuvant chemotherapy is given after surgery to prevent local recurrence or metastasis in patients with more advanced stages 
• Palliative chemotherapy is given to patients with unresectable disease to prolong survival and improve quality of life 

Stage 0 (carcinoma in situ) and stage I lesions with favorable histopathologic features require no further treatment if completely removed by colonoscopy 

• Lesions with favorable histopathologic features are graded 1 or 2, do not have capillary or lymphatic invasion, and have clear margins
• Perform surgical resection in patients with stage I lesions with unfavorable histopathologic findings; it is also an option for patients with stage I disease in a sessile polyp owing to increased risk of recurrence (versus that of a pedunculated polyp)
• Adjuvant chemotherapy is not recommended

In stages II and III, colon and rectal lesions often must be approached differently owing to inherent difficulties resecting rectal lesions, which benefit from aggressive neoadjuvant chemoradiotherapy to improve resectability and to preserve sphincter

• Colon lesions
  • For patients with local disease (stages II and III) whose primary colon tumor is determined to be operable, complete resection of affected colon and regional lymph nodes is recommended; further (adjuvant) chemotherapy options are based on stage and histologic factors 
    • When indicated, start adjuvant chemotherapy as soon as possible and ideally not more than 8 weeks after surgery 
    • Neoadjuvant therapy with FOLFOX (infusional leucovorin-fluorouracil-oxaliplatin) or CAPEOX (capecitabine-oxaliplatin) is an option for patients with bulky nodal involvement or clinical state T4b disease 
    • Stage II disease
      • May be observed without further treatment 
      • May enter a clinical trial 
      • May elect adjuvant chemotherapy for patients with high-risk stage II disease or those with microsatellite stable disease or microsatellite instability–low disease and no high-risk features; however, most patients will not benefit
        • High-risk features include poorly differentiated histology, invasion of vascular or lymphatic vessels, perineural invasion, bowel obstruction, perforation, inadequate or indeterminate surgical margin, and fewer than 12 nodes having been sampled 
        • Options include FOLFOX (infusional leucovorin-fluorouracil-oxaliplatin), CAPEOX (capecitabine-oxaliplatin), capecitabine, or fluorouracil-leucovorin 
        • Some evidence indicates improved disease-free survival (but not overall survival) 
    • Stage III disease
      • Adjuvant oxaliplatin-based chemotherapy is recommended for 6 months after resection; patients at low risk of recurrence (T1, T2, or T3 and N1) may opt for a shorter duration of 3 months 
        • Preferred regimens include FOLFOX (leucovorin-fluorouracil-oxaliplatin) or CAPEOX (capecitabine-oxaliplatin) 
      • Other options include capecitabine or fluorouracil-leucovorin 
      • Enrollment in a clinical trial may be an appropriate option 
• Rectal lesions
  • Complete surgical excision is the mainstay of curative treatment in patients with resectable lesions 
    • Extent of surgical procedure is determined by clinical stage, distance of lesion from anal verge, and patient’s preferences regarding quality of life (eg, continence, ostomy)
      • Primary surgical approach is total mesorectal excision; transrectal excision is an option for small lesions (less than 3 cm) located within 8 cm of anal verge
  • Stages II and III
    • Most patients are treated with neoadjuvant chemoradiotherapy before surgery, with additional chemotherapy administered either before or after surgery; the optimal schedule has not been determined 
    • Neoadjuvant chemoradiotherapy, compared with radiation therapy alone, reduces the local recurrence rate, although it may not improve overall survival 
      • Neoadjuvant chemoradiotherapy regimens administered before surgery include: 
        • Capecitabine plus concurrent radiation therapy
        • Fluorouracil infusion plus concurrent radiation therapy
        • Fluorouracil-leucovorin plus concurrent radiation therapy
        • Chemotherapy followed by radiation therapy
          • Modified FOLFOX
          • Capecitabine-oxaliplatin
          • Fluorouracil-leucovorin
          • Capecitabine alone
          • Fluorouracil infusion
        • Radiation therapy alone
    • Role of adjuvant (postsurgical) chemotherapy is controversial
      • Generally recommended for patients who did not receive extended neoadjuvant chemotherapy or for patients with stage III disease who also received neoadjuvant therapy; regimens include: 
        • Fluorouracil-leucovorin plus concurrent radiation therapy
        • Fluorouracil infusion plus concurrent radiation therapy
        • Capecitabine plus concurrent radiation therapy
        • Chemotherapy alone
          • Modified FOLFOX
          • CAPEOX (capecitabine-oxaliplatin)
        • Concurrent chemotherapy with radiation therapy 
        • Some oncologists suggest the toxicity of adjuvant therapy may outweigh benefits in patients whose disease was downstaged to pathologic stage I after neoadjuvant therapy; observation after surgery may be more appropriate 
    • Total duration of perioperative therapy should be no longer than 6 months 

Stage IV colorectal cancer

• Prioritize treatment to control symptoms associated with primary tumor 
• In general, medically fit patients with resectable hepatic and/or pulmonary metastases will benefit from curative resection of metastases 
  • Sequence of chemotherapy, resection of primary tumor, and resection of metastases should be individualized and determined by multidisciplinary consensus 
  • Neoadjuvant approaches to systemic chemotherapy before resection may assist in identifying patients who are better candidates for surgery 
• Chemotherapy for metastatic colorectal cancer is often on a continuum beginning with a first line regimen, which frequently requires subsequent adjustment for disease progression or adverse medication effects; duration is determined by the cancer’s response to therapy and by the patient’s quality of life and personal preference 
  • Systemic chemotherapy regimens, often in combination with biologic agents 
    • When recommending combination therapy, consider any 1 of the following first line regimens unless contraindicated: 
      • FOLFOX or modified FOLFOX
      • CAPEOX (capecitabine-oxaliplatin)
      • FOLFIRI (leucovorin-fluorouracil-irinotecan)
        • Some evidence supports that combination therapy improves progression-free survival but not overall survival compared with irinotecan alone 
      • FOLFOXIRI (leucovorin-fluorouracil-oxaliplatin-irinotecan) or FOLFIRINOX (same 4 drugs; usually considered synonymous, although some authors have differentiated the regimens by dosage details)
      • IROX (oxaliplatin-irinotecan)
      • Bolus or infusion fluorouracil-leucovorin
      • Capecitabine
      • Irinotecan
      • Trifluridine-tipiracil
    • FOLFOX is generally used as first line treatment
      • Overall, fewer reported adverse effects except for peripheral neuropathy when treated with FOLFOX compared with FOLFIRI
    • May be used with or without bevacizumab or molecularly targeted therapies 
  • Biologic agents
    • Bevacizumab
      • Bevacizumab in combination with chemotherapy may be offered in the following circumstances: 
        • As an initial treatment regimen
        • As second line therapy when disease has progressed
          • After chemotherapy alone, or
          • After initial therapy that included a bevacizumab-based regimen 
      • Evidence supports measurable improvement in survival among patients with metastatic colorectal cancer 
      • Discontinue at least 28 days before elective surgery and do not administer for a minimum of 28 days after surgery
      • Contraindicated for patients with hemorrhage or recent hemoptysis 
    • Other biologic agents include ramucirumab, regorafenib, and ziv-aflibercept 
    • Some biologic agents are used for lesions with specific molecular biomarkers
      • KRAS, NRAS, BRAF wild type only: cetuximab, panitumumab 
      • MMR/MSI-H: dostarlimab-gxly, pembrolizumab, nivolumab plus ipilimumab 
      • HER2 amplification and RAS family wild types: trastuzumab, pertuzumab, lapatinib, fam-trastuzumab-deruxtecan-nxki 
      • BRAF V600E mutation positive: cetuximab, vemurafenib, panitumumab, dabrafenib, trametinib, encorafenib, binimetinib
      • NTRK gene fusion positive: larotrectinib, entrectinib
    • For patients whose malignancy progresses on the first regimen, a different first line regimen may be instituted 
• Other approaches include surgical resection, percutaneous tumor ablation (radiofrequency, microwave), and localized therapies, such as hepatic intra-arterial infusion or radioembolization for liver metastases and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis

Drug therapy

• Pyrimidine analogues
  • Constitute first line combination regimens; either is sufficient alone for stage II disease (for whom adjuvant chemotherapy is typically not employed) without high-risk features
    • Fluorouracil (usually administered with leucovorin)
    • Capecitabine
• Platins
  • Oxaliplatin
    • May be added to pyrimidine analogues for first line treatment of stage II colorectal cancer with high-risk features and for stages III and IV colorectal cancer (FOLFOX or capecitabine-oxaliplatin regimens)
• Camptothecin analogue
  • Irinotecan
    • Often added to pyrimidine analogues for first line treatment of stage IV disease (FOLFIRI or FOLFOXIRI)
• Biologic response modifiers
  • Used in combination with other agents as first or second line treatment for metastatic disease
    • Bevacizumab
    • Cetuximab
    • Panitumumab
    • Regorafenib 
    • Ramucirumab
    • Ziv-aflibercept
    • Pembrolizumab
    • Nivolumab
    • Ipilimumab
    • Trastuzumab
    • Pertuzumab
    • Lapatinib
    • Vemurafenib
    • Dabrafenib
    • Trametinib
    • Encorafenib
    • Binimetinib
    • Larotrectinib
    • Entrectinib

Nondrug and supportive care

Radiation therapy

• Used preoperatively to decrease local recurrence in those with high-risk rectal and rectosigmoid cancers (stage II or III lesions) 
• Most often used in combination with chemotherapy 
• Combination preoperative radiation therapy with concurrent chemotherapy for locally advanced, nonmetastatic rectal disease reduces local recurrences 
• Following complete clinical response to neoadjuvant radiation treatment, nonoperative management with close surveillance may be considered in patients with rectal cancer who would have a permanent colostomy or inadequate bowel continence after total mesorectal excision 
• Radiation therapy is an option for palliation of bleeding and pain in advanced rectal disease
• Potential complications include radiation proctitis, secondary malignancies, and small-bowel damage 

Colonic stents

• May alleviate some cases of acute large bowel mechanical obstructions, but avoid when possible because colonic stents are temporary measures and preclude use of some chemotherapy regimens
• Recommended primarily for palliation in patients with high risk of surgical mortality. These stents also may be used to decompress distal obstructing lesions that can be operated on subsequently and nonemergently
• Before considering treatment with colonic stents, use CT imaging of abdomen to rule out colonic perforation
• Colorectal surgeon is required to place colonic stents

Procedures

Surgical resection

General explanation

• Surgical removal of tumor; approach depends on location and stage of lesion
• Extent of resection should correspond to lymphovascular drainage of site of colon cancer 
• Resection of adherent or grossly involved adjacent organs should be en bloc 
• Curative resection of rectal cancer also involves removing the blood supply and lymphatics from the origin of the superior rectal artery 
• Synchronous colon cancers may be treated by 2 separate resections or subtotal colectomy 
• Optimal bowel preparation for elective colorectal surgery consists of mechanical bowel preparation in combination with oral antibiotics 
• Laparoscopic approach is associated with reduced morbidity and similar oncological outcomes 

Indication

• Polypectomy via colonoscopy may be sufficient for stage 0 or I colon or rectal lesions if no evidence of high-risk features exists, such as: 
  • Angiolymphatic invasion
  • Positive margin of resection
  • Unfavorable histologic features
• Transanal resection may be performed to remove small (less than 3 cm) rectal lesions located within 8 cm of anal verge 
  • Disadvantage is lack of regional node resection
• Transabdominal resection with total mesorectal excision is advised for other resectable rectal lesions (ie, larger or more proximal stage I lesions, stages II and III lesions) 
  • Transanal total mesorectal excision is a proposed alternative approach; however, this is subject to controversy regarding its technical learning curve, perioperative complications, and the lack of long-term data on oncologic outcomes 
• For resectable, nonmetastatic colon cancer, the preferred procedure is colectomy with en bloc removal of regional lymph nodes 
• Stage IV
  • Surgical resection of primary tumor and all metastasis is ideal but feasible only in a small percentage of patients
  • Colectomy can be used after chemotherapy and/or radiation therapy if curative metastasectomy is either contemplated or deemed necessary to prevent obstruction or other complications
• Laparoscopic and open surgery have similar long-term outcomes (over 3-5 years) and similar rates of locoregional recurrence, disease-free survival, and overall survival 

Contraindications

• Lesion is known to be unresectable

Complications 

• Anastomotic leak
• Gastrointestinal fistula
• Anastomotic hemorrhage
• Postoperative ileus
  • Risk can be reduced by adherence to ERAS protocols (Enhanced Recovery After Surgery), which include limiting use of opioid analgesia, preferring minimally invasive surgical techniques, avoiding routine nasogastric tube placement, and using goal-directed fluid therapy 

Comorbidities

• Diverticular disease
  • In the presence of coexisting diverticular disease, consider endoscopic evaluation after resolution of acute diverticulitis 

Special populations

• Elderly patients may require reduced intensity of chemotherapy and/or radiation therapy 
• High-risk colorectal cancer syndromes
  • Patients with colorectal malignancies associated with a specific mutation (eg, Lynch syndrome, familial polyposis syndrome) may require more extensive surgery, not only to treat the identified lesion but also to curtail evolution of the syndrome 

Monitoring

• Follow‐up strategies vary in terms of timing, frequency, and type of investigations undertaken 
  • Aim of monitoring is to detect recurrences at an early, treatable stage; however, current surveillance with periodic serum carcinoembryonic antigen, radiologic studies, and colonoscopy detects most recurrences late and may not, ultimately, improve long-term outcomes 
    • A Cochrane review reported no overall improvement in survival with intensified follow-up after curative surgery for nonmetastatic colorectal cancer 
  • Certain pathologic and molecular features are associated with an increased risk of recurrence and poorer overall survival and disease-free survival 
    • Additional surveillance beyond what is recommended based on stage alone may be warranted in patients with signet ring cell adenocarcinoma, negative nodes but with lymphovascular or perineural invasion or tumor budding, poorly differentiated tumors, or elevated CEA levels
    • Consider additional surveillance for patients who did not receive guideline-recommended treatment for their cancer
  • Although presence of circulating tumor DNA in peripheral blood may indicate residual tumor or recurrence, it does not currently have an established role in follow-up of colorectal cancer. Studies are underway regarding usefulness in guiding adjuvant therapy following resection and in assisting earlier diagnosis of recurrence 
• Follow-up after curative intent treatment of patients with stage 1 disease
  • Colonoscopy in 1 year
    • If advanced adenoma is found, repeat again in 1 year; if not, repeat in 3 years and then every 5 years
  • Most patients do not require surveillance beyond interval colonoscopy 
    • Surveillance may be considered in selected higher-risk stage I patients including: 
      • Patients with high-risk pathologic features
      • Patients with rectal cancer treated with transanal excision
      • Patients with colon cancer treated with endoscopic resection without subsequent segmental colectomy
      • Patients who did not undergo guideline-based treatment
    • If indicated, surveillance is usually based on the strategy used for stage II patients
• Follow-up after treatment is completed and no signs of disease in patients with stage II or III disease 
  • Interim history and physical examination every 3 to 6 months for 2 years, then every 6 months for an additional 3 years
  • Carcinoembryonic antigen testing at baseline and every 3 to 6 months for 2 years, then every 6 months for an additional 3 years for patients who are candidates for further intervention
  • CT of chest, abdomen, and pelvis every 6 to 12 months for up to 5 years
  • Colonoscopy in 1 year (or in 3-6 months if colonoscopy was not completed initially) 
    • If advanced adenoma is found, repeat again in 1 year; if not, repeat in 3 years and then every 5 years 
  • Proctosigmoidoscopy, in addition to colonoscopy (in patients who underwent proctectomy for rectal cancer) 
  • Patients with identified genetic mutations are often observed more frequently; specific recommendations have been developed for each syndrome 
    • Advise those patients who have mutations that entail higher risk for other malignancies
• Follow-up after curative intent surgery and subsequent adjuvant treatment and no signs of disease in patients with stage IV colorectal cancer 
  • Similar to follow-up for stage II/III with one exception:
    • CT of chest, abdomen, and pelvis every 3 to 6 months in the first 2 years after adjuvant therapy and then every 6 to 12 months up to a total of 5 years
• Follow-up of patients with metastatic disease who continue chemotherapy is determined by the chemotherapy protocol

Complications

• Complications of disease
  • Gastrointestinal bleeding
    • Initial management includes attempts to control the bleeding with nonsurgical approaches
    • When surgery is required, an oncologic resection is performed
  • Intestinal obstruction
    • For patients with obstructing colon cancer and curable disease, initial colectomy or initial endoscopic stent decompression and interval colectomy may be performed
  • Intestinal perforation
    • Resection following established oncologic principles with a low threshold for performing a staged procedure is recommended
  • Metastasis-related complications include fractures, dyspnea, and seizures
• Complications of treatment
  • Chemotherapy
    • Dermatotoxicity
      • Hand-foot syndrome
      • Skin reactions
    • Neurotoxicity
      • Common with oxaliplatin
    • Diarrhea
    • Febrile neutropenia
    • Secondary malignancies
  • Surgery
    • Anastomotic leak
    • Anastomotic hemorrhage
    • Ileus
      • Offer patients a regular diet immediately after elective colorectal surgery 
      • Sham feeding after colorectal surgery is recommended (eg, chewing sugar-free gum for 10 minutes or more 3 to 4 times per day); results in small improvements in gastrointestinal recovery and may be associated with reduction in length of hospital stay 
      • Alvimopan is recommended to speed recovery after open colorectal surgery; its use in minimally invasive surgery is less clear 
    • Gastrointestinal fistula
  • Radiation therapy
    • Nausea, vomiting, and/or diarrhea
    • Loss of appetite
    • Radiation proctitis
    • Small-bowel damage
    • Secondary malignancies

Prognosis

• 5-year survival of colorectal cancer
  • All stages: 64.7%
  • Localized: 90.6%
  • Regional: 72.2%
  • Distant: 14.7%
  • Unstaged: 39%

Screening

At-risk populations

• Patients at average risk
  • Guidelines vary regarding advent, frequency, and method of screening, but most now recommend screening average-risk adults aged 45 to 75 years; individualize screening for adults who are older than 75 years 
    • American Cancer Society, American College of Gastroenterology, and US Preventive Services Task Force recommend that people at average risk of colorectal cancer start regular screening at age 45 years 
    • Multi-Society Task Force on Colorectal Cancer recommends that screening start at age 45 years in people who are Black because they are at higher risk 
    • National Comprehensive Cancer Network guidelines recommend that people at average risk of colorectal cancer start regular screening at age 50 years 
    • Screening in adults aged 76 to 85 years is tailored individually based on overall health status, life expectancy, comorbid conditions, and prior screening results 
    • People who have not had any prior screening may benefit from screening up to age 85 years 
    • Stop screening after age 85 years 
  • There are a variety of colorectal cancer screening tests; select based on risks, benefits, availability, required frequency of testing, and patient preference. Recommended frequency of testing varies 
    • Colonoscopy every 10 years 
    • Alternatives to colonoscopic screening
      • Fecal immunochemical testing every year (preferred) or every 2 years 
      • Fecal immunochemical testing with multitarget DNA testing every 3 years 
      • Highly sensitive guaiac fecal occult blood test every year (preferred) or every 2 years 
      • Flexible sigmoidoscopy every 5 years to every 10 years 
      • Flexible sigmoidoscopy every 10 years plus either of the following:
        • Fecal immunochemical testing (preferred) every year or every 2 years 
        • Guaiac fecal occult blood test every year 
      • CT colonography every 5 years 
      • Colon capsule every 5 years (patients with previously incomplete colonoscopy or lower gastrointestinal bleeding who cannot undergo colonoscopy) 
      • Methylated SEPT9 DNA blood test: interval not established and not recommended routinely for screening but can be considered for patients who decline any other screening methods; not recommended by American College of Gastroenterology 
    • Patients with positive results on any noncolonoscopic colorectal cancer screening require referral for colonoscopy 
  • Recommendations for postcolonoscopy follow-up and polyp surveillance have been published by the US Multi-Society Task Force on Colorectal Cancer 
• Patients at increased risk
  • Strong family history of colorectal cancer
    • Colonoscopy every 3 to 5 years starting at age 40 years, or 5 to 10 years before age of onset in youngest familial case 
  • History of colorectal cancer or sessile serrated polyps
    • Colonoscopy interval varies depending on histopathology characteristics of lesion; in patients with colorectal cancer, follow-up is guided by tumor testing for Lynch syndrome and mismatch repair deficiency 
  • Inflammatory bowel disease (ulcerative colitis or Crohn disease)
    • Colonoscopy with chromoendoscopy or high-definition white light endoscopy beginning 8 to 10 years after diagnosis in patients with inflammatory bowel disease and immediately at diagnosis of primary sclerosing cholangitis. Repeated at 1- to 3-year intervals, according to findings 
  • Past radiation to abdomen or pelvis
    • Colonoscopy screening every 3 to 5 years beginning 5 years after radiation was given or at age 30 years, whichever is later
• Patients at high risk
  • In families with specific genetic syndromes (eg, Lynch syndrome, familial adenomatous polyposis syndrome), screening starts at an early age, is repeated frequently, and may include screening for other associated malignancies; specific recommendations have been established by the American College of Gastroenterology, the European Society for Medical Oncology, the Federation of Spanish Oncology Societies, and the National Comprehensive Cancer Network 

Screening tests

• General
  • Tests vary in accuracy, invasiveness, frequency, and quality of evidence supporting use; a key factor in selection is likelihood of adherence to chosen testing strategy 
  • Recent estimates suggest that screening with fecal immunochemical test every 1 or 2 years, sigmoidoscopy, or colonoscopy, results in similar reductions in colorectal cancer mortality; sigmoidoscopy, colonoscopy, and, to a lesser extent, annual fecal immunochemical testing may reduce incidence of colorectal cancer 
  • Colonoscopy is the most sensitive and specific test for detecting adenomas 10 mm or larger and has most well-established mortality benefits; however, the test is invasive and requires bowel preparation and sedation 
• Colonoscopy
  • Fiberoptic examination of entire colon and rectum
  • Gold standard for screening and for evaluation of positive findings on other (indirect) screening tests (eg, fecal blood test, radiology)
  • Sensitivity is 95%; sensitivity for detection of advanced adenoma 10 mm or larger is 89% to 98% (75%-93% for those 6 mm or larger) 
  • Associated with 68% reduction in mortality 
• Flexible sigmoidoscopy
  • Fiberoptic examination of distal third of colon and rectum
  • Sensitivity for detecting colorectal carcinoma is 95% for area examined and 58% to 75% for entire colon; sensitivity for detecting advanced adenoma is 72% to 86% 
  • Associated with 27% reduction in mortality 
• CT colonography
  • Noninvasive alternative to visualizing entire colon
  • Sensitivity for detecting colorectal carcinoma is 96%; sensitivity for detecting advanced adenoma is 67% to 98% 
  • Unknown effect on mortality 
• Highly sensitive guaiac-based fecal occult blood test
  • Chemical detection of blood (specifically, heme) in stool; series of 3 specimens is recommended
  • False-positives may be caused by ingested animal heme or other foods (eg, peroxidase-rich fruits and vegetables)
  • Associated with reduction in mortality of 16% to 33% 
  • Sensitivity is 52% to 79%; sensitivity for detecting advanced adenoma is 7% 
• Fecal immunochemical testing
  • Specific for human globin
  • Requires only 1 specimen
  • Sensitivity for detecting colorectal cancer is 76% to 95%; sensitivity for detecting advanced adenoma is 27% to 47% 
  • Unknown effect on mortality 
• Multitargeted stool DNA testing (with fecal immunochemical testing)
  • Sensitivity for detecting colorectal cancer is 92%; sensitivity for detecting advanced adenoma is 42%
• Evidence is insufficient to support digital rectal examination or blood tests for methylated SEPT9 DNA as effective primary screening methods 

Prevention

• Primary prevention involves modifying controllable risk factors
  • Physical activity
    • Consistent evidence points to a risk reduction of up to 40% through regular exercise 
  • Maintenance of healthy BMI (less than 35 kg/m²)
    • Abdominal obesity is an independent risk factor 
  • Diet
    • Optimal diet has not been defined
    • High intake of red meats and processed meats appears to be associated with colorectal cancer
    • Conflicting evidence exists about the protective effect of high-fiber diets
    • Conflicting evidence exists about the protective effect of high fruit and vegetable intake; may be greater for distal rather than proximal lesions
  • Dietary supplements
    • Studies on the protective effects of folic acid, calcium, and vitamin D supplements have yielded negative results
    • Use of antioxidants has not been shown to reduce risk
  • Tobacco use is associated with an increased risk of rectal cancers; former smokers have lower risk than active smokers 
  • Alcohol use is associated with increased risk, and higher intake (more than 45 g/day) carries greater risk than lower intake (30-45 g/day) 
• Regular screening for at-risk populations is recommended to identify and remove precancerous polyps 
• Chemoprevention
  • Aspirin
    • Aspirin intake of 75 to 300 mg/day lowers long-term risk and is recommended by the US Preventive Services Task Force for the following populations:
      • Adults aged 50 to 59 years who have life expectancy of at least 10 years, are not at risk for bleeding, and are willing to take aspirin for at least 10 years
      • Adults aged 60 to 69 years who have life expectancy of at least 10 years, are not at risk for bleeding, are willing to take aspirin for at least 10 years, and place higher value on potential benefits (ie, cancer and cardiovascular disease prevention) than harms (eg, bleeding)
    • UK guidelines recommend daily aspirin, to be taken for more than 2 years, to prevent colorectal cancer in people with Lynch syndrome 
  • Conflicting data exist regarding effects of menopausal hormone therapy on risk of colorectal carcinoma; type of hormone therapy influences risk, and any potential protective benefit appears to diminish after discontinuation of therapy 
  • Other agents that have shown some promise in chemoprevention trials include selective cyclooxygenase 2 inhibitors and metformin; however, these are not currently recommended for this indication 

References

ASGE Standards of Practice Committee et al: Role of endoscopy in the staging and management of colorectal cancer. Gastrointest Endosc. 78(1):8-12, 2013