Keywords

Introduction

Colorectal cancer (CRC) is the second most common cancer in Canada, with an estimated 26,900 new cases diagnosed in 2020 [1]. It is also the second leading cause of death from cancer in Canada with an estimated 9700 deaths (5300 men and 4400 women) in 2020 [1, 2]. Although the age-standardized incidence for CRC has been declining in males and females, this decline appears to be confined to older adults as the incidence has been rising in those younger than age 50 [1].

The most common stage of CRC at the time of diagnosis is stage III [1]. There is a strong association between cancer stage at time of diagnosis and survival (Table 6.1).

Table 6.1 Incidence and associated 5-year survival based on stage of colorectal cancer
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The current recommended staging system is the American Joint Committee on Cancer (AJCC) eighth edition.

Screening and Surveillance for Average and High-Risk Patients

Screening

Special Notes

  • There is good quality evidence that population screening using either FOBT or flexible sigmoidoscopy reduces colorectal cancer mortality [4, 5] (Table 6.2).

  • FOBT has been shown to reduce relative risk of CRC mortality by 16% [4, 5].

  • FIT has been shown to have superior sensitivity in detecting CRC and advanced adenoma when compared to gFOBT [6]. It is also anticipated that the reduction in CRC-related death through FIT screening is at least equivalent to that through gFOBT. However, direct comparison between gFOBT and FIT in terms of CRC-related mortality is lacking.

  • A randomized trial from Norway showed that population screening with flexible sigmoidoscopy decreased colorectal cancer mortality (11.7/100,000 deaths per person-years absolute risk reduction) [7].

  • At least four randomized controlled trials and ten observational studies have shown that screening with flexible sigmoidoscopy reduces incidence and mortality in distal, but not proximal colorectal cancer [8].

  • A systematic review and meta-analysis showed decreased mortality for proximal cancers with colonoscopy compared to flexible sigmoidoscopy based on observational data [8].

  • Colonoscopy is recommended by the American College of Gastroenterology for screening, although there are no randomized trials demonstrating a reduction in mortality [9].

  • A population-based study in Ontario of 2,412,077 people demonstrated that the colonoscopy rate was inversely proportional to death from CRC [10]. A case–control study in Ontario has demonstrated a significant association between colonoscopy and fewer deaths from CRC; specifically left-sided cancers [11].

  • Colonoscopy is the most sensitive of available screening options at detecting cancer or polyps and is thus an acceptable modality; however, it is associated with the highest risk and cost.

  • A shorter interval between testing or repeat colonoscopy should be performed if the first colonoscopy is sub-optimal.

  • Quality indicators for colonoscopy:

    • Cecal intubation rate > 90%, adequate bowel preparation, post polypectomy bleeding rate of <0.5%, and perforation rate of <0.1% [12, 13].

    • Polypectomy and adenoma detection rates (ADR) are also important quality indicators. Some studies have suggested ADR ≥ 25% may be associated with lower incidence of interval cancer [14]; however, there is no consensus on what the appropriate target should be [12, 13].

    • There is insufficient evidence to suggest a minimum withdrawal time from the cecum of 6 min improves quality of endoscopy or improves ADR [10, 11]. However, shorter mean withdrawal times have been independently associated with lower ADR [14].

Table 6.2 Screening recommendations
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Surveillance

Special Notes

  • Table 6.3 is adapted from Ontario ColonCancerCheck Guidelines.

  • Patients with multiple colorectal adenomas (>10) should be considered for germline genetic testing of APC, MUTYH, and MMR.

  • Above surveillance interval assumes (1) no family history of CRC in a first-degree relative with an age of onset <60, (2) colonoscopy was complete and adequate, and all visible polyps were completely removed.

Table 6.3 Surveillance of patients with polyps identified at colonoscopy [15]
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Hereditary Colorectal Cancer Syndromes

Lynch Syndrome and Microsatellite Instability

  • Lynch syndrome is the most common hereditary CRC syndrome with a lifetime colorectal cancer risk of 40–80% (Table 6.4). This genetic disease results from mutations in DNA mismatch repair (MMR) genes leading to microsatellite instability (MSI).

  • MSI is identified in approximately 15% of all CRC and is a feature of Lynch syndrome.

  • Majority of cases of MSI are sporadic, due to methylation of an MMR gene, rather than a germline mutation found in Lynch syndrome. Revised Bethesda Guidelines provide criteria for testing of individuals at risk for Lynch syndrome [16].

  • MSI may be screened for in all colorectal cancers via PCR or Immunohistochemistry (IHC) for defective MMR.

Table 6.4 Gene mutations and colorectal cancer risk in hereditary colorectal cancer syndromes
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Revised Bethesda Guidelines

  • CRC diagnosed in a patient < age 50.

  • Synchronous or metachronous CRC or other Lynch-related tumor.

  • CRC diagnosed in a first-degree relative with a Lynch-related tumor, one diagnosed < age 50.

  • CRC diagnosed in two or more first- or second-degree relatives with Lynch-related tumors.

  • CRC with MSI-high (MSI-H) histology in patient < age 60:

    • Tumor infiltrating lymphocytes.

    • Crohn’s-like lymphocytic reaction.

    • Medullary growth pattern.

    • Mucinous/Signet ring differentiation.

Special Notes

  • In stage II patients, IHC testing should be considered as MSI-H status has been shown to predict lack of benefit from fluorouracil-based adjuvant chemotherapy [7, 18].

  • Extracolonic manifestations of Lynch syndrome include cancers of the uterus (30–60%), ovary (4–12%), urinary tract (5–12%), stomach (8–10%), small bowel, pancreas (4%), biliary tract, brain, and skin [15].

  • Testing guidelines based on age and family history miss a significant proportion of patients with MSI-H tumors. Universal testing of patients with CRC is a more sensitive method of identifying MSI-H patients and may be more cost-effective than traditional guidelines [19,20,21].

  • The proposed ASCO/ESMO guidelines suggest (1) universal testing of all patients with CRC or (2) testing of all patients <70 and patients >70 who fulfill any of the revised Bethesda guidelines [19].

  • Tumor testing for MMR deficiency with IHC ± MSI:

    • If loss of MLH1/PMS2 protein expression is observed in the tumor, analysis of BRAF V600E mutation and/or analysis of methylation of the MLH1 promoter should be carried out first to rule out a sporadic case.

    • If tumor is MMR deficient and somatic BRAF mutation is not detected or MLH1 promoter methylation is not identified, testing for germline mutations is indicated.

    • If loss of any of the other proteins (MSH2/MSH6/PMS2) is identified, test for corresponding genes to the absent protein (e.g., MSH2, MSH6, EPCAM, PMS2, MLH1).

    • Full germline testing for Lynch should include DNA sequencing and large re-arrangement analysis.

Polyposis Syndromes

Familial Adenomatous Polyposis (FAP)

  • >100–1000s of adenomas distributed in the colon and rectum at presentation.

  • Accounts for <1% of all CRC cancers. Polyps often manifest in adolescents or young adults.

  • Extracolonic manifestations of FAP: gastric and duodenal polyps, desmoid tumors, thyroid and brain tumors, congenital hypertrophy of the retinal pigmented epithelium (CHRPE), supernumerary teeth, osteomas, and epidermoid cysts.

  • Duodenal/ampullary adenocarcinomas follow CRC as the major cause of cancer death in patients with FAP.

  • Desmoid tumors are found in up to 30% of patients with FAP and are the third most common cause of death in FAP. They peak around age 30 or 2–3 years after surgery. Depending on the location and symptoms, management includes observation (10% resolve spontaneously), medical therapy (NSAIDS, tamoxifen, vinblastine/methotrexate, or chemotherapy), or surgical resection.

Attenuated Familial Adenomatous Polyposis (AFAP)

  • 10–99 colorectal adenomas at presentation, preponderance for right colon. Polyps tend to develop later in life compared to FAP.

MUTYH-Associated Polyposis (MAP)

  • Autosomal recessive inheritance, phenotype characterized by <100 adenomas. Average age of onset mid-50s. Up to 1/3 of biallelic MUTYH-mutation carriers may develop CRC in the absence of colorectal polyposis. Heterozygote individuals are also at a slightly increased risk of CRC (Table 6.4).

Germline Testing for APC and MUTYH [15]

  • Should be considered in all patients with multiple colorectal adenomas (>10).

  • APC germline testing should include DNA sequencing and large re-arrangement analysis.

Management

Primary Localized Colon Cancer

Special Notes

  • Polyps

    • Endoscopic management of sessile and pedunculated polyps is appropriate provided they are removed as a single specimen and lack high-risk features [28,29,30].

    • High-risk features of malignant polyps include poorly differentiated histology, lymphovascular invasion, tumor budding, piecemeal excision, and positive margin [28, 29].

    • Data regarding surveillance following successful endoscopic resection is lacking. Repeat endoscopic evaluation for local recurrence is recommended 3–6 months post resection. There is no defined role for routine imaging (Table 6.5); however, in high-risk patients not undergoing resection, enrollment in a surveillance program may be considered [28,29,30].

    • Given that lymph node involvement has been reported in 5–17% of malignant polyps [28,29,30,31], practice at the University of Toronto has included radiographic staging at diagnosis.

  • Adjuvant Treatment

    • Adjuvant chemotherapy should begin within 8 weeks of surgery. If delayed beyond 12 weeks, there is limited to no clinical benefit [32, 33].

    • The benefit of adjuvant chemotherapy is clearest in patients with stage III disease where ~30% decrease in risk of recurrence and mortality has been demonstrated [34].

    • The role of adjuvant chemotherapy among patients with high-risk stage II disease (perforation, obstruction, nodal harvest <12 nodes, T4, poorly differentiated histology) is more controversial [34].

    • When adjuvant chemotherapy is administered for stage II disease, oxaliplatin is often omitted due to adverse side effects and unclear benefit. Additionally, as noted previously, MIS-H status predicts lack of benefit from fluorouracil-based adjuvant chemotherapy in stage II disease [17, 18].

    • Six months of adjuvant therapy remains the standard of care; however, given the small absolute difference in DFS and the reduced rates of toxicity, adjuvant therapy may be limited to 3 months in patients with T1-T3 and N1 disease [35].

  • Technical Considerations

    • A minimally invasive approach is recommended in all suitable patients. Evidence suggests that the principal benefits are reduction in length of stay and postoperative pain with equivalent oncological outcomes [28, 36,37,38,39,40].

    • Several retrospective studies and one prospective randomized trial have evaluated the use of robotic surgery. While feasibility and safety compared to laparoscopy has been demonstrated, to date there is no convincing evidence to favor the use of robotics over conventional laparoscopic techniques [28, 44,45,46,47].

    • Routine extended lymphadenectomy is not standard of care. At present, no randomized trials have compared complete mesocolic excision surgery to conventional colectomy [28].

    • Quality Indicators:

      • Uninvolved radial resection margin [28, 41].

      • A minimum of 12 lymph nodes in the resected specimen [28, 42, 43].

      • A minimum of 5 cm proximal and distal margins recommended [28, 42, 43].

  • Surveillance

    • If a preoperative assessment was not performed, colonoscopy should be performed within 6 months of surgery or as soon as possible after the completion of adjuvant therapy. Frequency of colonoscopies thereafter should be dictated by the findings [24, 48].

    • Of patients who recur, 80% are within the first 2–2.5 years, and 95% recur by 5 years [48]

    • Any new and persistent or worsening symptoms warrant the consideration of a recurrence.

    • The general practice at the University of Toronto is to perform CT of the chest/abdomen/pelvis every 6 to 12 months for the first 2 years then annually up to 5 years.

    • The American Society of Clinical Oncology (ASCO) 2013 endorsement of CCO practice guidelines suggests considering CT chest/abdomen every 6–12 months for 3 years in patients at a higher risk of recurrence [48].

    • The intensity of postoperative surveillance should depend on the likelihood that additional therapy would be recommended in the setting of recurrent disease.

Table 6.5 Management and surveillance protocol for primary localized colon cancer
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Management of Patient Populations at High Risk for Colon Cancer

Special Notes

  • Lynch syndrome: Segmental resection may be considered in cases of significant comorbidity, advanced age, or advanced disease. Detailed discussion of risk/benefits and need for close endoscopic surveillance should be emphasized if segmental resection is to be performed.

  • FAP: The choice between colectomy + IRA and TPC-IPAA must be balanced with patient age, degree of rectal polyposis, wish to bear children, risk of developing desmoids, and possibly the site of mutation in the APC gene.

  • AFAP/MAP: Preservation of the rectum may be considered when rectal clearance is possible (Table 6.6). The risk of recurrence in rectal stump must be balanced against the alteration in function with proctocolectomy and pelvic pouch.

  • IBD: Nomenclature and management of dysplasia in IBD is evolving. Recent SCENIC [49] guidelines advocate chromoendoscopy for surveillance. Consider referral to an IBD center if dysplasia is identified on random biopsy. Endoscopic management of dysplasia associated mass lesions (DALM) should be done at expert centers.

Table 6.6 Screening, management, and surveillance protocols for high-risk populations
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Locally Advanced Colon Cancer or Locoregional Recurrence

Special Notes

  • Histologically negative margins should be the goal of en bloc resection [50, 51]. Relevant margins should be marked on the specimen by the surgeon.

  • Neoadjuvant chemoradiotherapy may improve resectability and negative margin rates (Table 6.7) [52, 53].

Table 6.7 Management and follow-up of locally advanced/locoregional recurrence
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Colon Cancer with Distant Metastases

Special Notes

  • Resection of the primary tumor should be considered in symptomatic patients or in those with potentially resectable metastatic disease.

  • First-line chemotherapy should be strongly considered in asymptomatic patients with unresectable metastatic disease (Table 6.8).

  • If a synchronous metastasis is resectable, the timing of surgery and chemotherapy should be individualized for each patient. Options include synchronous or staged colectomy with metastasectomy vs. neoadjuvant chemotherapy followed by synchronous or staged colectomy and metastasectomy vs. colectomy followed by chemotherapy and staged metastasectomy or vice versa.

  • Patients with unresected primaries should be followed as up to 20% need surgical resection during the course of their treatment.

  • Bevacizumab administration has been associated with delayed wound healing and GI perforation [54, 58, 59]. The bevacizumab product monograph states it should be discontinued ≥28 days before elective surgery and should not be initiated for ≥28 days after surgery.

  • However, while patients on bevacizumab therapy undergoing surgery have been shown to experience significant morbidity and mortality, the risk of complications has not been detectably associated with time since exposure in population-based studies [59].

  • There may be a survival advantage in resection of the primary tumor in patients with unresectable metastatic disease [60]. Randomized trials investigating this topic are ongoing [61, 62].

Table 6.8 Management and follow-up of colon cancer with distant metastasis
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Landmark Publications (Table 6.9)

Referring to Medical Oncology (See Tables 6.7 and 6.8)

  1. 1.

    High-risk stage II.

  2. 2.

    Stage III, IV.

  3. 3.

    Locally advanced or recurrent disease.

Table 6.9 Summary of landmark publications
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Referring to Radiation Oncology (See Tables 6.7 and 6.8)

  1. 1.

    Consider for locally advanced or recurrent disease.

  2. 2.

    Palliative management of symptomatic lesions with unresectable metastatic disease.

Referring to Multidisciplinary Cancer Conference (MCC)

  1. 1.

    Locally advanced or recurrent disease.

  2. 2.

    Metastatic disease in fit patients (synchronous and metachronous).

Toronto Pearls

  • Neoadjuvant chemoradiotherapy for locally advanced or recurrent colon cancer may improve resectability and negative margin rates. Careful preoperative planning and multidisciplinary approach are necessary to achieve the goal of R0 resection.