Colon cancer in primary care

Pathophysiology

Colon cancer develops over approximately 10 to 15 years owing to an accumulation of genetic mutations that result in the development of precancerous and subsequently malignant lesions from normal colonic mucosa.⁸ Colon cancer screening aims to detect and remove precancerous lesions prior to transformation into invasive disease. Adenocarcinomas account for 90% of CRCs.⁸ Colon cancer most commonly spreads to the liver and lung but can also spread to the peritoneum and distant lymph nodes.⁹ Colon cancer does not commonly spread to bone or to the brain.

Right-sided versus left-sided tumours. The location of the primary tumour is not only prognostic but also predictive of response to treatment. Right-sided tumours (cecum to hepatic flexure) generally have poorer overall survival compared with left-sided ones.¹⁰ Right-sided tumours typically present with subtle clinical features, such as new-onset anemia, whereas left-sided tumours generally present symptomatically, with bowel habit changes and hematochezia. As a result, right-sided tumours are commonly diagnosed later and are more likely to be metastatic at time of diagnosis.⁸

Workup and staging

Once the diagnosis of colon cancer is made, a complete workup is required to determine stage of the cancer and eligibility for resection. Family physicians should ensure newly diagnosed patients undergo colonoscopy with biopsy of the primary tumour; a complete blood count; a carcinoembryonic antigen test; and baseline computed tomography scans of the chest, abdomen, and pelvis. A positron emission tomography scan is not indicated for preoperative workup.⁷

Staging of colon cancer is based on the American Joint Committee on Cancer TNM (tumour, node, metastasis) classification (Table 1).¹¹ Clinical, pathological, and surgical features can be used to determine poor prognostic CRC, which are high risk and may require more intensive therapy (Box 1).⁶ Stage I cancers (T1 to T2) and most stage II (T3 to T4 without high-risk features [Box 1])⁶ do not routinely receive adjuvant treatment (systemic treatment that follows surgical resection), and therefore ongoing surveillance is often provided by the patient’s family physician.

Molecular diagnostics: tumour biomarkers and mismatch repair genes

Pathology reports will include immunohistochemistry stains assessing the nuclear expression of the mismatch repair (MMR) protein; MMR genes code for proteins involved in the repair of base-base mismatches occurring during DNA replication. Mismatch repair deficient (dMMR) cells lead to an accumulation of DNA replication errors, known as microsatellite instability–high (MSI-H).¹² In contrast, MMR proficient (pMMR) cells or microsatellite stability (MSS) refers to wild-type (or nonmutated) MMR genes. Status of MMR genes affects recommended treatment, so testing for MMR deficiency is now routine for all patients with newly diagnosed CRCs. A tumour that is dMMR or MSI-H can result from somatic mutations (at the cancer cell level) due to methylation of 1 or more MMR genes in the cancer cells. However, in some cases, dMMR or MSI-H can be indicative of germline alterations where the patients’ normal cells are affected, increasing the risk of development of multiple cancers. This condition is known as hereditary nonpolyposis CRC (Lynch syndrome).¹³ Individuals suspected to have hereditary nonpolyposis CRC should be referred to a medical geneticist for assessment.

In the metastatic setting, tumour biomarkers such as KRAS and NRAS, and BRAF mutations are tested to determine whether targeted therapies are indicated. These biomarkers mediate signalling pathways driving growth and proliferation of tumour cells, so therapies directed against these targets can arrest or slow tumour growth.

Treatment of patients with resectable stage I to III colon cancer

Patients with stage I to III CRC are optimally treated with surgical resection upfront, which involves bowel and lymph node dissection (Figure 1). Patients with stage I CRC are typically treated with surgery alone while those with stage II have surgery that may be followed by 3 to 6 months of adjuvant fluoropyrimidine-based (5-fluorouracil or capecitabine) chemotherapy (Box 2)^7,14 if it is MSS or pMMR with high-risk features (Box 1).⁶ Patients with stage II disease that is MSS or pMMR and low risk or dMMR do not require adjuvant treatment. Those with stage III disease will typically be treated with 3 to 6 months of adjuvant chemotherapy after surgery.⁷

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Figure 1.

Summary of treatment for patients with resectable stage I to III colon cancer

Severe fluoropyrimidine-associated toxicity. Some individuals are at increased risk of severe toxicity from fluoropyrimidines, which can be given in an intravenous or infusion (5-fluorouracil) form or orally as capecitabine. Fluoropyrimidines are broken down by the dihydropyrimidine dehydrogenase enzyme. Individuals with variants of the dihydropyrimidine dehydrogenase gene are unable to metabolize this drug adequately and are at increased risk of severe toxicities such as life-threatening inflammation and ulceration of the gastrointestinal system.¹⁴ While these individuals may be given lower doses of the chemotherapy, it is contraindicated in those with severe dihydropyrimidine dehydrogenase deficiency.¹⁵ It is becoming increasingly common to routinely test individuals for this gene prior to commencing treatment.

Management of patients with metastatic disease

Surgical management. In the setting of limited metastatic disease, patients diagnosed with stage IV colon cancer can be evaluated for consideration of surgical resection of liver and lung metastases.⁷ If a patient is deemed to be a good candidate for surgery, then the goal of treatment is to cure.

Patients with metastatic spread limited to the peritoneum may be considered for cytoreductive surgery (peritoneal stripping surgery) in combination with perioperative hyperthermic intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis without extra-abdominal metastases.⁷ Resection of the primary colon tumour is rarely indicated in patients with unresectable metastases.

Systemic treatment for patients with unresectable or metastatic disease. Treatment of metastatic disease depends on the primary tumour location, MMR gene profile of the tumour, biomarker mutations, and prior treatments received. The median overall survival for those with metastatic colon cancer is about 30 months.¹⁶

First-line chemotherapies include FOLFOX (leucovorin, 5-fluorouracil, oxaliplatin), FOLFIRI (leucovorin, 5-fluorouracil, irinotecan), or CAPOX (capecitabine and oxaliplatin).⁷ Meta-analyses of randomized controlled trials have shown similar benefit when comparing first-line FOLFOX with CAPOX for metastatic disease.⁷ Capecitabine is oral, while 5-fluorouracil is delivered as a bolus along with leucovorin followed by a 46-hour infuser. Progression-free survival and median overall survival are similar when comparing FOLFIRI with FOLFOX. Progression-free survival has been estimated at 8.5 months for CAPOX and FOLFIRI and 8 months for FOLFOX.^17,18 Patients continue to take first-line treatment until there is evidence of progression or until treatment intolerance. Following progression, subsequent lines of treatment are considered (Figure 2).

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Figure 2.

Lines of treatment for patients with unresectable or metastatic colon cancer: First-line treatment depends on MMR status and microsatellite stability (MMR deficient vs proficient and MSS vs MSI-H), location of primary tumour (right vs left sided), molecular biomarkers (BRAF and KRAS mutation status), and patient fitness. If there is evidence of progression or treatment intolerance, the patient may be offered subsequent lines of treatment.

Immunotherapy (ie, pembrolizumab) is effective for dMMR or MSI-H tumours and is recommended as first-line therapy in these settings.⁷ Median progression-free survival was found to be significantly longer with pembrolizumab compared with chemotherapy (16.5 vs 8.2 months; P=.0002).¹⁹

Targeted agents are indicated alone or in combination with chemotherapy depending on biomarker status. Some targeted agents include the following:

Bevacizumab: This monoclonal antibody inhibits anti–vascular endothelial growth factor and suppresses tumour angiogenesis. When added to chemotherapy there is benefit in improving overall survival (median survival of 17.9 vs 14.6 months; P=.008).^20-23

Cetuximab and panitumumab: These are epidermal growth factor receptor inhibitors and are indicated in patients with wild-type (ie, nonmutated) KRAS and BRAF genes. Approximately 30% to 50% of colorectal cancers have a mutation in the KRAS gene.⁷ These agents are not effective on tumours with a mutation in either KRAS or BRAF, as inhibition of epidermal growth factor receptor by cetuximab or panitumumab is bypassed.⁷ Treatment with cetuximab or panitumumab can be considered when combined with a BRAF inhibitor, encorafenib.⁷

Regorafenib: This is a receptor tyrosine kinase inhibitor that has antitumour and anti-angiogenic features.²⁴

It has been demonstrated that patients with right-sided tumours have longer overall survival if treated with bevacizumab rather than cetuximab (29.2 months vs 13.7 months; P=.11). However, overall survival was prolonged with cetuximab rather than bevacizumab in individuals with left-sided primary tumours (39.3 months vs 32.6 months; P=.05).²⁵ Therefore, cetuximab or panitumumab should be used for KRAS wildtype left-sided tumours in the first-line setting.