Metastatic Colorectal Cancer
Metastatic colorectal cancer (mCRC) is defined as colorectal carcinoma that has spread beyond the primary site in the colon or rectum to distant organs, most commonly the liver, lungs, peritoneum, and, less frequently, other organs. Pathogenesis involves a multistep process of genetic and epigenetic alterations, including mutations in tumor suppressor genes (such as APC and TP53), activation of oncogenes (e.g., KRAS, BRAF), and dysregulation of cellular signaling pathways that facilitate tumor progression, invasion, and metastasis. The metastatic cascade is characterized by local invasion, intravasation into the vasculature, survival in the circulation, extravasation, and colonization of distant tissues. The health impact of mCRC is profound, as it significantly reduces survival rates and quality of life. Without intervention, median survival is limited, but advances in systemic therapies have improved outcomes. The disease burden is substantial, contributing to high morbidity due to symptoms such as pain, bowel obstruction, cachexia, and organ dysfunction, as well as psychological distress.
Synchronous metastatic colorectal cancer refers to cases in which distant metastases are present at the time of initial diagnosis of the primary colorectal tumor. This type often reflects a more aggressive tumor biology and may be detected during the initial staging workup. Synchronous metastases are most commonly found in the liver, but can also involve the lungs, peritoneum, or other distant sites. The management of synchronous disease often requires a multidisciplinary approach, integrating systemic therapy with possible surgical resection of both primary and metastatic lesions, depending on the extent and resectability of disease.
Metachronous metastatic colorectal cancer is characterized by the development of distant metastases after the initial diagnosis and treatment of localized colorectal cancer, typically occurring months or years following primary tumor resection. This type may result from dormant micrometastatic disease that evades initial detection and later proliferates, or from new metastatic events. Surveillance protocols are critical for early detection. Therapeutic strategies may differ from synchronous disease, with individualized approaches based on timing, location, and burden of metastases, as well as prior treatments.
Liver-dominant metastatic colorectal cancer describes cases in which the majority of metastatic burden is confined to the liver, which is the most frequent site of colorectal cancer dissemination due to portal venous drainage from the colon and rectum. Patients with liver-limited disease may be candidates for potentially curative interventions such as hepatic resection, ablation, or liver-directed therapies in combination with systemic treatment. Prognosis is generally more favorable in selected patients with resectable liver metastases.
Non-liver-dominant metastatic colorectal cancer encompasses cases where metastases are predominantly located in organs other than the liver, such as the lungs, peritoneum, distant lymph nodes, bones, or brain. The clinical course can be more variable, and management is often more challenging due to the diffuse nature of disease and limited surgical options. Systemic therapy remains the cornerstone of treatment, with local interventions considered for selected oligometastatic presentations.
Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer-related death worldwide. Approximately 20–25% of patients present with metastatic disease at the time of initial diagnosis (synchronous metastasis), and an additional 20–35% of patients with initially localized disease will develop metastases later (metachronous metastasis). The incidence of mCRC varies geographically, with higher rates in developed countries, largely attributed to lifestyle factors, dietary habits, and aging populations. In the United States, the overall lifetime risk of developing colorectal cancer is about 4%, with mCRC accounting for a significant proportion of cancer mortality. Five-year survival rates for mCRC remain low, at approximately 14%, compared to over 90% for localized disease. Epidemiological studies have identified risk factors such as age over 50, male sex, family history, hereditary syndromes (e.g., Lynch syndrome, familial adenomatous polyposis), inflammatory bowel disease, obesity, sedentary lifestyle, smoking, and dietary patterns high in red or processed meats.
The diagnosis of metastatic colorectal cancer is based on a combination of clinical evaluation, imaging studies, histopathological confirmation, and molecular profiling. Initial assessment includes a thorough medical history, physical examination, and laboratory investigations such as complete blood count, liver function tests, and measurement of carcinoembryonic antigen (CEA) levels. Imaging modalities are central to staging and include contrast-enhanced computed tomography (CT) scans of the chest, abdomen, and pelvis to identify the extent and distribution of metastatic disease. Magnetic resonance imaging (MRI) is particularly useful for characterizing liver lesions, while positron emission tomography (PET) scans may be employed in selected cases to detect occult metastases or clarify equivocal findings. Colonoscopy is performed to obtain tissue diagnosis of the primary lesion, and biopsy of metastatic sites may be warranted if the diagnosis is uncertain. Histopathological examination confirms adenocarcinoma and provides information on tumor grade. Molecular testing for mutations in KRAS, NRAS, and BRAF, as well as evaluation of microsatellite instability (MSI) or mismatch repair (MMR) status, is recommended to guide therapeutic decisions. The American Joint Committee on Cancer (AJCC) TNM staging system is used for classification, with stage IV indicating distant metastases. Multidisciplinary evaluation is essential to formulate an individualized treatment plan.
Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is utilized in the management of metastatic colorectal cancer to inhibit angiogenesis and is available in several forms, including bevacizumab, bevacizumab-bvzr, bevacizumab-awwb, and bevacizumab-nwgd, each representing either the reference product or biosimilar agents. Encorafenib is an orally administered BRAF inhibitor indicated for use in combination regimens, particularly in patients with BRAF V600E-mutated metastatic colorectal cancer. Fruquintinib is an oral, selective inhibitor of vascular endothelial growth factor receptors (VEGFR) and is employed as a targeted therapy for patients with previously treated mCRC. Binimetinib, a MEK inhibitor, is used in combination with other agents such as encorafenib for patients with specific molecular alterations. Nivolumab is an immune checkpoint inhibitor targeting PD-1 and is indicated for the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, enhancing anti-tumor immune responses. Ramucirumab, a monoclonal antibody directed against VEGFR-2, is administered as an anti-angiogenic agent in combination with chemotherapy for advanced disease. Trifluridine/tipiracil, an oral combination of a nucleoside analog and a thymidine phosphorylase inhibitor, is approved for patients with metastatic colorectal cancer who have been previously treated with standard chemotherapeutic and targeted agents, providing an additional line of therapy.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
| bevacizumab | ||||
| bevacizumab; bevacizumab-bvzr | ||||
| bevacizumab; bevacizumab-awwb | ||||
 | encorafenib (Rec INN; USAN) | 1269440-17-6 | C22 H27 Cl F N7 O4 S | 540.011 |
 | fruquintinib (Rec INN; USAN) | 1194506-26-7 | C21 H19 N3 O5 | 393.393 |
 | binimetinib (Rec INN; USAN) | 606143-89-9 | C17 H15 Br F2 N4 O3 | 441.227 |
| bevacizumab; bevacizumab-nwgd | ||||
| nivolumab (Rec INN; USAN) | 946414-94-4 | |||
| ramucirumab (Prop INN; USAN) | 947687-13-0 | |||
| trifluridine/tipiracil; trifluridine/TPI |
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Metastatic Colorectal Cancer
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