Colorectal Cancer _ ___________________________________________________________________________
is based on treatment goals, the type and timing of previous therapy, specific efficacy and toxicity profiles, tumor mutational status, and patient preference [230; 266]. The specific chemotherapy agents and combinations used in colon cancer and rectal cancer overlap substantially. The following agents have received FDA approval for use in colorectal cancer [267; 268; 269]. 5-Fluorouracil (5-FU) As discussed, 5-FU has been the foundation of chemotherapy for colorectal cancer for more than four decades. As a single agent, it inhibits tumor cell growth through at least three different mechanisms that ultimately disrupt cellular viability or DNA synthesis, transcription, and replication. Capecitabine Capecitabine is an oral fluoropyrimidine that undergoes a three-step enzymatic conversion to 5-FU, with the last step occurring in the tumor cell. Leucovorin Calcium Leucovorin is a reduced form of folic acid that does not require enzymatic reduction reaction for activation. This agent allows for purine and pyrimidine synthesis, both of which are needed for normal erythropoiesis. Leucovorin counteracts the toxic effects of current standard combination chemotherapy for colorectal cancer and potentiates the effects of 5-FU and its derivatives by stabilizing the binding of the drug’s metabolite to its target enzyme to prolong drug activity. Irinotecan Hydrochloride Irinotecan is inactive in its parent form and is converted by the carboxylesterase enzyme to its active metabolite form SN-38, which is 1,000 times more potent than its parent compound. SN-38 binds to and stabilizes the topoisomerase I-DNA complex and prevents the relegation of DNA after it has been cleaved by topoisomerase I, inhibiting DNA replication. Irinotecan is a current standard therapy for metastatic colon cancer as the combination 5-FU/leucovorin/irinotecan. Oxaliplatin A third-generation platinum-based antineoplastic agent, oxaliplatin is used in combination with 5-FU/leucovorin for metastatic colorectal cancer. As with other platinum compounds, oxaliplatin destroys tumor cells through interaction with DNA to form intra-strand/inter-strand DNA cross-linking that interferes with DNA base pairing, replication, and gene transcription, resulting in cell death [270]. Cetuximab Cetuximab is a partially humanized monoclonal antibody against EGFR that specifically binds to the extracellular domain of EGFRs. The cetuximab-bound EGFR inhibits activation of receptor-associated kinases, which inhibit cell growth, induce apoptosis, and decrease production of matrix metalloproteinase and VEGF. Cetuximab is indicated for
the treatment of KRAS mutation-negative (wild-type), EGFR- expressing metastatic colorectal cancer. Importantly, patients with mutant KRAS tumors may experience worse outcome when cetuximab is added to multiagent chemotherapy regimens containing bevacizumab. Bevacizumab Bevacizumab is a partially humanized monoclonal antibody that binds to VEGF to inhibit angiogenesis. The inhibition of new blood vessel formation denies blood, oxygen, and other nutrients needed for tumor growth. Panitumumab Panitumumab is a fully humanized antibody that binds to EGFR. It is approved by the FDA for use in chemotherapy- refractory metastatic colorectal cancer and is indicated for wild-type KRAS metastatic colorectal cancer. Ziv-Aflibercept Ziv-aflibercept is a novel anti-VEGF molecule that acts as a decoy receptor for VEGF-A, VEGF-B, and placental growth factor. The antiangiogenic mechanism of ziv-aflibercept involves competition with VEGF in the blood and extravascular space to prevent VEGF from interacting with its receptors on endothelial cells. It is indicated for metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin regimen [271]. Regorafenib Regorafenib inhibits multiple tyrosine kinase pathways, including VEGF, and was approved in 2012 for the treatment of metastatic colorectal cancer in patients previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF therapy (e.g., bevacizumab, ziv- aflibercept); and, if KRAS wild type, an anti-EGFR therapy (e.g., cetuximab, panitumumab). Combination Regimens The basis of chemotherapy for the treatment of colon and rectal cancer is combination therapy, with agents identified to work synergistically to manage unresectable lesions and minimize drug resistance. These combinations are generally known by their acronyms ( Table 11 ). RESECTABLE STAGE IV METASTATIC AND RECURRENT COLON AND RECTAL CANCER With recurrent or advanced colon and rectal cancer, treatment is determined by disease location. For patients with locally recurrent or liver- and/or lung-only metastatic disease, surgical resection, if feasible, is the only potentially curative treatment [201]. At any point, symptom emergence from the primary tumor should become the treatment priority in stage IV colorectal cancer [238].
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