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INTRODUCTION: BACKGROUND/EPIDEMIOLOGY

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Metastasis is defined as the spread of malignant cells from a primary tumor to a distant organ. It is estimated that 90% of all cancer deaths are a result of metastasis.1 Colorectal cancer (CRC) can metastasize to regional lymph nodes, liver, lung, or the peritoneal surface, and less frequently to other organs such as ovaries, brain, and bone. While CRC with locoregional lymphatic spread is categorized as stage III disease (5-year overall survival (OS) 70.4%), CRC with spread to distant organs is categorized as stage IV—or metastatic—CRC (CRCm) and carries a significantly worse prognosis (5-year OS 12.3%).2

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Metastasis may be present at the time of diagnosis (synchronous) or may develop after treatment of the primary tumor (metachronous). Synchronous metastases are usually more extensive and portend a poorer prognosis. Metachronous metastases occur in as many as one-third of patients who were treated with apparent success for their primary tumor.

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According to the Surveillance, Epidemiology, and End Results (SEER) database, 20% of CRC patients have metastatic disease at the time of diagnosis.2 Clinical presentation varies significantly, depending on the type and extent of disease spread. Patients with a single metastatic lesion are frequently asymptomatic. Others with more advanced disease involving several organs often present with pain, obstruction, or other debilitating symptoms.

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Although the overall rate of cure is low, aggressive treatment is indicated for most patients with CRCm in order to extend survival and improve health-related quality of life (QOL). Treatment is complex and varies based on patient characteristics and the number, size, and location of metastatic lesions. Given the diversity of the metastatic load, and the multiple potential treatment alternatives (systemic or regional chemotherapy, radiation, surgery, endoscopy, ablation, and others), management of the patient with CRCm must be individualized on a case-by-case basis and developed within the context of a multidisciplinary setting. The goals, priorities, and anticipated course of treatment should be discussed not only with the disease management team but also with the patient and his or her family.

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BIOLOGICAL CONSIDERATIONS

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The development of metastasis is viewed as a continuous process that begins early in tumor formation and evolves as the tumor grows.3 It is thought that, after the initial malignant transformation, the tumor proliferates into a small mass of heterogenous cells with different metastatic potentials. These cells undergo a number of sequential genetic changes, characterized by the activation of oncogenes and inactivation in tumor suppressor genes. As the tumor grows beyond 1 mm in diameter and becomes relatively hypoxic, angiogenesis is initiated.4 Some tumors grow by utilizing other existing blood vessels in nearby tissues.

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The detachment of tumor cells from the primary tumor mass requires the downregulation of cell adhesion molecules that would normally anchor them to other cells and the extracellular matrix. The best characterized alteration involves loss of E-cadherin, a key cell-to-cell adhesion molecule. ...

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