Colorectal Cancer

Definition, Etiology, PathogenesisTop

The development of colorectal cancer (CRC) is a multistep process that requires genetic and epigenetic changes over time. The chromosomal instability pathway, otherwise known as the adenoma-to-carcinoma sequence, is the most common form of genomic instability leading to the development of CRC (75%-85% of cases) through a series of de novo genetic mutations, which results in the transformation of normal colonic mucosa to small adenomas, large adenomas, and then finally carcinomas. The development of CRC can also be due to specific genetic syndromes such as familial adenomatous polyposis (FAP) syndrome, hereditary nonpolyposis colorectal cancer (HNPCC) syndrome (ie, Lynch syndrome), Cowden disease, and Peutz-Jeghers syndrome.

Risk factors for the development of CRC include a personal history of inflammatory bowel disease (IBD), smoking, high nitrate consumption (eg, red meat), and obesity. CRC rarely occurs before the age of 40 years, except in genetically determined polyposis syndromes (0.5%-2% of all CRC cases), where it commonly develops earlier.

Clinical FeaturesTop

The clinical presentation can be variable (frequently symptoms occur late) and is often related to the location of the primary tumor:

1) Right-sided colon cancer: Most commonly abdominal distention, postprandial bloating secondary to obstruction related to tumor growth, or both. Other: anemia, occult bleeding, melena, and abdominal pain.

2) Left-sided colon cancer: Most commonly change in bowel habits (ie, decreased frequency, overflow diarrhea), narrowed-caliber stool, and/or hematochezia. Other: anemia, abdominal pain, and obstructive symptoms if causing complete or partial occlusion of the large bowel lumen.

3) Rectal cancer: Most commonly bright red blood per rectum, narrowed-caliber stool, and/or tenesmus. Other: obstructive symptoms or perineal pain (if extending below the level of the dentate line).

Approximately 20% to 30% of patients may present emergently with obstruction, perforation, and/or hemorrhage.

DiagnosisTop

Diagnostic Tests

1. Laboratory tests:

1) Complete blood count (CBC) can be helpful in identifying iron deficiency anemia and can direct the diagnostic process.

2) Carcinoembryonic antigen (CEA): Low-sensitivity and low-specificity tumor marker for diagnosis but used for post-treatment surveillance. Of note, smokers can have falsely elevated CEA levels.

2. Imaging:

1) Computed tomography (CT) of the chest, abdomen, and pelvis: Staging investigation for all types of CRC.

2) Magnetic resonance imaging (MRI) of the pelvis: Staging investigation for rectal cancers.

3) MRI of the liver: To investigate indeterminate liver lesions or for preoperative planning prior to metastasectomy.

4) Positron emission tomography (PET): No role in staging/preoperative investigations, but can be used for surveillance when there is discordance between symptoms, CEA, and imaging (eg, when CEA titer is rising, but surveillance CT scans are normal). Of note, the result may be falsely negative in the case of cancer with a mucocellular component and falsely positive in patients taking metformin (increases the uptake of 18F-deoxyglucose by the intestinal cells).

3. Histologic examination:

1) Colonoscopy: Allows for tissue diagnosis through biopsy, endoscopic visualization and characterization of the tumor (ie, obstructing/near-obstructing, location), endoscopic localization through endoscopic tattooing, and inspection of the remainder of the colon for synchronous lesions. If patients cannot undergo a complete colonic evaluation preoperatively (ie, due to obstruction, perforation, hemorrhage), they require postoperative colonoscopy within 3 months of the index surgery.

2) Percutaneous liver/lung biopsy: For diagnosis of metastatic disease if imaging is indeterminate.

Diagnostic Criteria

Diagnosis is made based on the histologic examination of the specimen obtained during colonoscopy and then of the entire tumor as part of the surgical specimen; imaging helps determine whether there is evidence of metastatic disease.

Differential Diagnosis

CRC, benign adenoma, large bowel stricture (eg, Crohn disease, ischemic, diverticular), sarcoma, lymphoma, lipoma, endometriosis, solitary rectal ulcer syndrome, hemorrhoids.

ScreeningTop

Detailed description: see Colorectal Cancer Screening.

Screening aims to detect cancer at an early stage as well as to detect and remove polyps considered precancerous—adenomatous and serrated polyps.

The following screening methods should be used:Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Bleijenberg A, Klotz D, Løberg M, et al. Implications of different guidelines for surveillance after serrated polyp resection in United States of America and Europe. Endoscopy. 2019;51(8):750–758. doi:10.1055/a-0916-8598. Epub 2019 Jun 13. PMID: 31195423. Leddin D, Lieberman DA, Tse F, et al. Clinical Practice Guideline on Screening for Colorectal Cancer in Individuals With a Family History of Nonhereditary Colorectal Cancer or Adenoma: The Canadian Association of Gastroenterology Banff Consensus. Gastroenterology. 2018;155(5):1325–1347.e3. doi:10.1053/j.gastro.2018.08.017. Epub 2018 Aug 16. PMID: 30121253. Wolf AMD, Fontham ETH, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin. 2018;68(4):250–281. doi:10.3322/caac.21457. Epub 2018 May 30. PMID: 29846947.

1) Colonoscopy every 10 years in individuals at intermediate risk: Diagnostic (the greatest sensitivity and specificity in the diagnosis of colorectal neoplasms) and therapeutic (allows for removal of polyps).

2) Fecal immunochemical test (FIT) every 2 years (in some jurisdictions every year) in individuals at intermediate risk.

Of note, an individual at intermediate risk is an adult aged >50 years without a personal or family history of CRC or any other condition that predisposes to the development of CRC (eg, IBD, genetic syndromes).

If stool occult blood or polyps are found on sigmoidoscopy, always perform full colonoscopy. Digital rectal examination is not recommended for screening (low sensitivity).

Treatment and PrognosisTop

When planning treatment for CRC, appropriate staging investigations are essential to exclude metastatic disease and determine the extent of locoregional invasion. Surgical resection is the mainstay of treatment of nonmetastatic disease. Endoscopic resection is also possible (in the case of a malignant polyp; such treatment may be sufficient if it is microscopically complete and does not have pathologic features associated with an increased risk of regional lymph node involvement).

Oligometastatic disease may still be amenable to curative-intent surgical resection. Prognosis depends on the stage of the disease: Table 1.

Neoadjuvant therapy (treatment before the main surgical treatment) is used in patients with rectal cancer N1 to N2 T2 to T4 disease threatening the mesorectal fascia and/or invading adjacent structures. Treatment involves either short-course radiotherapy or long-course chemoradiotherapy. Total neoadjuvant therapy (TNT), consisting of radiation and full-dose systemic chemotherapy, may offer a superior treatment response. Decision making should involve multidisciplinary case review and consideration of most recent evidence and best practice.

Metastatic disease: Most commonly systemic chemotherapy prior to surgical intervention for curative intent or palliative systemic chemotherapy.

Surgery: The basic surgical method of treating cancer of the rectum or colon is open, laparoscopic, or robotic resection with adequate resection margins (ie, 5 cm proximally and distally to the primary tumor) and adequate lymphadenectomy (ie, resection of feeding blood vessels with surrounding lymphoid tissue). In the case of nonadvanced (cN0), well-differentiated (G1-G2), and small tumors, local excision using endoscopic methods is acceptable (eg, endoscopic mucosal resection, endoscopic submucosal dissection, transanal minimally invasive surgery).

Surgical treatment may also include hepatectomy and lobectomy for curative intent in selected cases of oligometastatic disease.

Adjuvant Therapy

1. Colon cancer: Chemotherapy may be considered in patients with good and intermediate performance status in the case of metastases to regional lymph nodes or other unfavorable risk factors (pT4 feature, G3 grade disease, insufficient number [ie, <12] of lymph nodes collected or examined, high preoperative CEA titers). It could also be used in the case of increased risk related to surgery (urgent surgery, tumor perforation, anastomotic dehiscence, serious postoperative infectious complications). It most commonly consists of fluorouracil (5-FU) or capecitabine with calcium folinate, and oxaliplatin (in various regimens). Generally, it is suggested to initiate adjuvant chemotherapy within 8 weeks of oncologic resection.

2. Rectal cancer: Indications for systemic adjuvant chemotherapy in patients with rectal cancer are similar to those in patients with colon cancer, with the exception that patients with T2N0 disease who underwent neoadjuvant therapy may also be considered for adjuvant therapy.

Palliative Treatment

Distant metastases: Palliative chemotherapy is initiated in patients with good performance status and incurable stage IV CRC. Chemotherapy regimens most commonly include FU or capecitabine, folinic acid, and irinotecan or oxaliplatin. Bevacizumab may be added as a biologic adjunct to standard chemotherapy regimens. In such cases, it currently remains unclear whether surgical resection of an asymptomatic primary tumor is warranted.Evidence 2Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to observational nature of data and imprecision. Vogel JD, Felder SI, Bhama AR, et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Colon Cancer. Dis Colon Rectum. 2022 Feb 1;65 (2):148-177. doi: 10.1097/DCR.0000000000002323. PMID: 34775402. You YN, Hardiman KM, Bafford A, et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Rectal Cancer. Dis Colon Rectum. 2020 Sep;63(9):1191-1222. doi: 10.1097/DCR.0000000000001762. PMID: 33216491.McCahill LE, Yothers G, Sharif S, et al. Primary mFOLFOX6 plus bevacizumab without resection of the primary tumor for patients presenting with surgically unresectable meta- static colon cancer and an intact asymptomatic colon cancer: definitive analysis of NSABP trial C-10. J Clin Oncol. 2012;30 (26):3223-3228. doi: 10.1200/JCO.2012.42.4044. Epub 2012 Aug 6. PMID: 22869888; PMCID: PMC3434981.

Emergency Presentations

1. Obstruction: There are 3 predominant ways of managing obstructive CRCs in the setting of metastatic disease: resection, diversion (ie, loop ileostomy or loop colostomy), and endoscopic stenting. Data are equivocal as to which approach results in the best overall survival and quality of life (ie, palliation of symptoms). Currently, if the patient is fit for general anesthesia, surgical diversion is the most common approach for these patients given the potential complications associated with stenting (eg, perforation, migration, technical failure).

2. Perforation: Patients initially presenting with perforation have a significantly decreased 5-year disease-free and overall survival. Perforation often occurs in 1 of 2 locations: 1) perforation of the proximally distended large bowel; 2) perforation of the primary CRC. Regardless of location, free perforation often necessitates operative intervention by way of oncologic resection.Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to observational nature of data. Vogel JD, Felder SI, Bhama AR, et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Colon Cancer. Dis Colon Rectum. 2022 Feb 1;65 (2):148-177. doi: 10.1097/DCR.0000000000002323. PMID: 34775402. Pisano M, Zorcolo L, Merli C, et al. 2017 WSES guidelines on colon and rectal cancer emergencies: obstruction and perforation. 2018 Aug 13;13:36. doi: 10.1186/s13017-018-0192-3. eCollection 2018. PMID: 30123315; PMCID: PMC6090779. These patients are much more likely to require a stoma than those not presenting with perforation. Contained perforation may be treated nonoperatively initially or with proximal diversion, but ultimately oncologic resection is advised when the disease is curable. Endoscopic stenting is contraindicated in perforated CRC.

3. Hemorrhage: In the majority of cases, bleeding secondary to CRCs leads to the development of chronic anemia. If patients present with acute gastrointestinal (GI) bleeding and are found to have a hemorrhaging CRC, they are managed similarly to those with lower GI bleeding of another etiology. Endoscopic management is the first-line approach, followed by interventional radiology-guided embolization, and lastly followed by surgical intervention as a final line. In rare circumstances these patients may also receive emergency radiation for hemorrhage control.

Follow-UpTop

After radical surgery for stage II to IV disease, clinical examination and CEA measurement should be performed every 3 to 6 months for the first 3 years, then every 6 to 12 months, up to 5 years after the procedure. The European Society for Medical Oncology (ESMO) recommends thoracic, abdominal, and pelvic CT every 6 to 12 months for the first 3 years, and then every 12 months until the fifth year after surgery. Complete colonoscopy should be performed before surgery or up to 6 months after surgery, another one a year after surgery, then 3 years later (4 years after surgery) and 5 years later (9 years after surgery). These intervals may be altered based on colonoscopy findings.Evidence 4Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity, imprecision, and observational nature of data. Hardiman KM, Felder SI, Friedman G, Migaly J, Paquette IM, Feingold DL; Prepared on behalf of the Clinical Practice Guidelines Committee of the American Society of Colon and Rectal Surgeons. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Surveillance and Survivorship Care of Patients After Curative Treatment of Colon and Rectal Cancer. Dis Colon Rectum. 2021 May;64(5):517-533. doi: 10.1097/DCR.0000000000001984. PMID: 33591043. National Comprehensive Cancer Care Network. NCCN clinical practice guidelines in oncology colon cancer, version 1.2022. Accessed March 23, 2022. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf Willie-Jorgensen P, Syk I, Smedh K, et al. Effect of More vs Less Frequent Follow-Up Testing on Overall And Colorectal Cancer-Specific Mortality in Patients With Stage II Or III Colorectal Cancer: The COLOFOL Randomized Clinical Trial. JAMA. 2018 May 22;319(20):2095-2103. doi: 10.1001/jama.2018.5623. PMID: 29800179; PMCID: PMC6583244. Endoscopic surveillance is usually not offered when patients reach 80 years of age or when comorbidities shorten life expectancy to <5 to 10 years. Surveillance schedules vary significantly according to local and national guidelines. Less intensive surveillance schedules have been advocated over the past several years, with some documents such as the National Cancer Care Network (NCCN) and American Society for Colon and Rectal Surgeons (ASCRS) guidelines, stating that no surveillance is required for stage I disease aside from colonoscopy 1 year following index surgery.

PreventionTop

Acetylsalicylic acid (ASA) ~300 mg/d is the most established medication for chemoprevention of CRC, which offers 20% to 40% relative risk reduction. The recommendations regarding its use differ, but decisive factors may include the perceived risk of bleeding, concomitant cardiovascular risk, and age (ie, a more beneficial effect has been observed at age <70 years).Evidence 5Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due heterogeneity and modelling. Guo CG, Ma W, Drew DA, et al. Aspirin Use and Risk of Colorectal Cancer Among Older Adults. JAMA Oncol. 2021 Mar 1;7(3):428-435. doi: 10.1001/jamaoncol.2020.7338. Dehmer SP, O’Keefe LR, Evans CV, Guirguis-Blake JM, Perdue LA, Maciosek MV. Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: Updated Modeling Study for the US Preventive Services Task Force. JAMA. 2022 Apr 26;327(16):1598-1607. doi: 10.1001/jama.2022.3385. Increasing the consumption of fiberEvidence 6Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due observational data.Park Y, Hunter DJ, Spiegelman D, et al. Dietary fiber intake and risk of colorectal cancer: a pooled analysis of prospective cohort studies. JAMA. 2005 Dec 14;294(22):2849-57. doi: 10.1001/jama.294.22.2849. PMID: 16352792. and physical activityEvidence 7Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due observational data. Shaw E, Farris MS, Stone CR, et al. Effects of physical activity on colorectal cancer risk among family history and body mass index subgroups: A systematic review and meta-analysis. BMC Cancer. 2018 Jan 11;18(1):71. doi: 10.1186/s12885-017-3970-5. PMID: 29325535; PMCID: PMC5763991. also reduces the risk of developing CRC.

TableSTop