___________________________________________________________________________ Colorectal Cancer
Other Prognostic Factors of Survival Several other factors have shown prognostic significance, including the number of harvested and processed lymph nodes, histologic grade, and evidence of lymphovascular and perineural invasion. In patients with metastatic colorectal cancer, the level of circulating tumor cells measured at baseline after the initiation of new therapy was an independent predictor of survival. In patients with baseline CEA values ≥25 ng/mL, those with low baseline levels of circulating tumor cells (fewer than three) had longer survival, and measurements of both circulating tumor cell number and CEA level at 6 to 12 weeks independently predicted survival [215]. Additionally, an emerging focus in research and literature is the role of host immune-centered factors (e.g., anti-tumor cells in the liver) in the clinical outcomes of colorectal liver metastases [216; 217].
cancer therapy, and the targeted biologic agents cetuximab and panitumumab primarily act through binding EGFR to inhibit downstream signaling [169; 225]. Colorectal tumors that grow beyond 1–2 mm 3 require increased access to oxygen and nutrients and develop neoangiogenesis to enable tumor growth and metastases. Neoangiogenesis originates from complex interactions between pro- and anti- angiogenic factors. Vascular endothelial growth factor (VEGF), the most potent pro-angiogenic factor known to date, is overexpressed in gastrointestinal tumors and is essential for the proliferation and metastases of colorectal cancer [226]. VEGF overexpression is associated with increased tumor vascularity, proliferation, progression, invasion, and metastasis. VEGF binds to and activates one of the three VEGF receptors located on the vascular endothelium. Among the VEGF receptor types, VEGFR-2 is the primary mediator of the mitogenic and angiogenic effects of VEGF, while VEGFR-3 is involved in lymphangiogenesis [218]. Following VEGF binding, VEGF receptors activate several downstream intracellular signal transduction pathways that promote inhibition of apoptosis, degradation of the extracellular matrix to facilitate endothelial cell proliferation and migration to form new blood vessels, and stimulation of mitosis and cytoskeletal changes associated with motility. Colorectal tumors also express VEGF and other proangiogenic factors on their cell surface; their presence is associated with increased vascularity, advanced disease, and poor prognosis [226]. Findings of elevated VEGF levels in patients with metastatic colorectal cancer led to the development and FDA approval of several anti-VEGF agents (i.e., bevacizumab, ramucirumab, regorafenib, and ziv-aflibercept) [222; 223]. In addition to the therapeutic targeting of VEGF, VEGF antagonists have also shown the ability to increase intratumoral delivery of chemotherapeutic agents to improve their antitumor efficacy [217; 218]. Secondary Drug Resistance Patients with chemotherapy-refractory colorectal cancer who initially respond and then become resistant to cetuximab or other monoclonal antibodies have essentially run out of therapeutic options. This emergence of secondary drug resistance within 9 to 18 months of initiation is a major limitation of anti-EGFR therapies. A substantial proportion of patients with colorectal cancer who initially respond to anti-EGFR therapies have, at the time of disease progression, tumors with focal amplification or somatic mutations in KRAS that were undetectable before initiation of anti-EGFR therapy. Drug-resistant KRAS alteration results from pre-existent KRAS mutant and amplified clones and from new mutations arising from ongoing mutagenesis [227]. A mechanism by which KRAS mutation nullifies anti-EGFR therapy involves bypassing the need for upstream EGFR signals to activate downstream oncogenic processes [169; 181]. It is now established that
TREATMENT OF COLON AND RECTAL CANCER
MECHANISM OF CHEMOTHERAPY AND TARGETED THERAPIES
The chemotherapy agent 5-FU entered clinical use for patients with colorectal cancer more than 40 years ago and remains a mainstay of colorectal cancer treatment today. In the mid-1990s, the drugs irinotecan hydrochloride and oxaliplatin became available for colorectal cancer, and standard chemotherapy regimens were refined through extensive trials. Patients with metastatic colorectal cancer unsuitable for surgery represent more than 50% of those diagnosed with disseminated disease, and while they did benefit, the modest increases in life expectancy came with substantial toxicities. These patients, and their overall prognoses, remained poor. The therapeutic outlook improved with introduction of bevacizumab, the first FDA-approved antiangiogenic agent for metastatic colorectal cancer. Several additional targeted biologic agents have received FDA approval for metastatic colorectal cancer. As of 2022, these include cetuximab, capecitabine, panitumumab, ziv-aflibercept, regorafenib, and ramucirumab. Subsequent-line treatment options include pembrolizumab, nivolumab, nivolumab plus ipilimumab, and trifluridine/tipiracil (TAS-102) [218; 219; 220; 221; 222; 223]. In 2020, pembrolizumab was approved as a first-line treatment for patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer [224]. EGFR is a glycoprotein with three primary components: an extracellular ligand binding domain, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase domain. EGFR is activated by ligand binding from EGF or transforming growth factor-alpha, which triggers downstream activation in signaling pathways that facilitate development and progression of colorectal cancer. This critical role of EGFR in oncogenesis has made it an attractive target for colorectal
75
MDFL2626
Powered by FlippingBook