Metastatic colorectal cancer (CRC) remains a significant health problem as the second leading cause of cancer death in the United States and the fourth most frequently diagnosed cancer. Despite improvements in some age groups, its incidence has actually been increasing in patients younger than 50 years. The cause of this trend is currently unknown.


CRC’s presenting symptoms most often include a change in bowel habits, rectal bleeding, abdominal discomfort, anemia, or unexplained weight loss. The American Cancer Society recommends average risk screening to start at age 45; colonoscopy is preferred because it is the most sensitive test available. 

Full staging with computed tomography (CT) scan of the chest, abdomen, and pelvis; carcinoembryonic antigen test; and consultation with an interprofessional team are crucial. Additional testing may be considered for clarifying CT findings or surgical planning, such as magnetic resonance imaging or positron-emission tomography scan. Discussion of family history and consideration of referral to a risk assessment program,may be appropriate. The majority of patients with metastatic CRC cannot be cured, although a subset with liver- or lung-isolated disease is potentially curable with surgery and additional chemotherapy. RAS mutation and microsatellite status testing are crucial at diagnosis. 


For patients with surgically inoperable metastatic disease, fluorouracil (5-FU) was the primary treatment. This has changed since 2000, with the approval of irinotecan, oxaliplatin, and three humanized monoclonal antibodies that target the vascular endothelial growth factor VEGF and epidermal growth factor receptor EGFR. Regorafenib is an orally active inhibitor of angiogenic tyrosine kinases (including the VEGF receptors 1, 2, and 3) as well as several other membrane-bound and intracellular kinases that are involved in normal cellular function and in pathologic processes. 

Another oral option is trifluridine-tipiracil (TAS-102), an oral cytotoxic agent that consists of the nucleoside analog trifluridine (a cytotoxic antimetabolite that inhibits thymidylate synthetase and, after modification within tumor cells, is incorporated into DNA, causing strand breaks) and tipiracil (a potent thymidine phosphorylase inhibitor that inhibits trifluridine metabolism and has antiangiogenic properties as well). 

 Newer data suggest that the first line of treatment may vary depending on whether a patient has a right- or left-sided colon tumor. Right-sided colon cancers include tumors in the cecum, ascending, hepatic flexure, and transverse colon, and left-sided colon tumors include splenic flexure, descending, sigmoid and rectosigmoid colon. Significant differences exist in epidemiology, histology, genetic expression, and molecular profiles between right-sided colon cancer and left sided colon cancer. Patient preferences, including treatment schedule and consideration of side effects and goals, must also be taken into consideration when strategizing their treatment plan. 

Genetic Testing and Immunotherapy

Use of predictive biomarkers has been significant in metastatic CRCtreatment planning and prognostication. Mutations in RAS oncogenes (KRAS, NRAS) are present in approximately 35%–45% of patients with metastatic disease, which results in constitutive activation of the RAS-RAF-ERK pathway and resistance to anti-EGFR therapy. Activating mutations in RAF, particularly BRAF V600E, are present in 5%–10% of colon cancers and portend a poor prognosis. The addition of vemurafenib, an oral BRAF kinase inhibitor, to a regimen of irinotecan and cetuximab may result in prolongation of progression free survival and a high disease control rate.  

Approximately 4%–9% of metastatic CRCs display microsatellite instability caused by a genotype with mismatch repair deficiency. Immune checkpoint inhibitors, including pembrolizumab and nivolumab, have been approved for this indication.