Colorectal Cancer ____________________________________________________________________________
mucinous adenocarcinoma (33.9% and 58.6%, respectively) or signet-ring cell carcinoma (61.2% and 70.7%) than with adeno- carcinoma (27.6% and 49.9%) [217]. Liver metastases were more frequent in patients with adenocarcinoma (73.0%) or mucinous adenocarcinoma (52.2%) than in those with signet- ring cell carcinoma (31.7%). Peritoneal metastases were more common in patients with signet-ring cell carcinoma (51.2%) or mucinous adenocarcinoma (48.2%) than in those with adenocarcinoma (20.1%) [217]. Metastases to distant lymph nodes occurred in more signet-ring cell carcinoma patients (43.9%) than patients with either mucinous adenocarcinoma (22.3%) or adenocarcinoma (19.9%). Abdominal metastases were more frequent with colon cancer, and extra-abdominal metastases more common with rectal cancer [217]. PROGNOSTIC FACTORS FOLLOWING RESECTION OF LIVER METASTASES Approximately one in three patients who undergo resection for colorectal liver metastases become actual five-year survivors. Of those, approximately half survive 10 years and are considered “cured” of colorectal liver metastases [218]. Surgical resection of colorectal cancer with liver metastases continues to be the most important modality for long-term survival [219]. A mul- tivariate analysis of 1,001 patients who underwent potentially curative resection of liver metastases identified five factors as independent predictors of worse outcome [220]: • Tumor size >5 cm • Disease-free interval less than one year • More than one tumor • Primary lymph-node positivity • CEA level >200 ng/mL Other potential prognostic indicators being investigated include the value of circulating tumor DNA and the level of KRAS mutated circulating cell-free tumor DNA in patients with colorectal liver metastases [221; 222; 223].
COLORECTAL CANCER FIVE-YEAR SURVIVAL RATES BY STAGE
SEER Stage
Five-Year Relative Survival Rate
Colon cancer Localized
91% 73% 13% 63%
Regional Distant
All SEER stages combined
Rectal cancer Distant
13%
Source: [14]
Table 8
after the initiation of new therapy was an independent predic- tor 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 [224]. 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 [225; 226].
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 chemo- therapy regimens were refined through extensive trials. Patients with metastatic colorectal cancer unsuitable for surgery rep- resent 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 colorec- tal cancer. Several additional targeted biologic agents have received FDA approval for metastatic colorectal cancer. As of 2025, 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) [227; 228; 229; 230; 231; 232]. In 2020, pembrolizumab was approved as a first-line treatment for patients with unre- sectable or metastatic microsatellite instability-high (MSI-H)
SURVIVAL Prognostic Factors of Survival by TNM Stage
Patient prognosis is most powerfully associated with clinical and histopathologic stage of colorectal cancer at diagnosis as reflected by the TNM classification and staging. The National Cancer Institute SEER database tracks five-year relative survival rates for colon and rectal cancer, based on how far the cancer has spread; it does not group cancers by AJCC TNM stages. Instead, it groups cancers into localized, regional, and distant stages ( Table 8 ) [14]. 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
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