Colorectal cancer is the second leading cause of cancer related death in men and women, accounting for 8.7% of all cancer-related deaths in the United States.1 With an estimated incidence of 151,030 new cases as well as a mortality rate of 52,580 patients annually, it continues to remain a substantial source of morbidity and mortality.2 The American Cancer Society's estimates 106,180 new cases of colon cancer and 44,850 new cases of rectal cancer in 2022. While its incidence and mortality have generally decreased, most likely due to improved screening practices and more-effective systemic therapies, 5-year survival rate for metastatic colorectal cancer is still quite low at 14%.1

The main treatment goal in metastatic colorectal cancer (mCRC) is to extend life as well as maintain the quality of life. Systemic therapy remains the mainstay treatment in patients with metastatic colorectal cancer who are not candidates for definitive surgical resection. Over the past few decades, significant progress has been made in improving overall survival, owing mainly to the development of new active agents against mCRC.

The treatment regimen for mCRC includes chemotherapy with fluoropyrimidines (5-Fluorouracil, 5-FU) based regimen in combination with platinum compound oxaliplatin (FOLFOX) or topoisomerase I inhibitor irinotecan (FOLFIRI) or both (FOLFOXIRI). These regimens are now combined with biologic agents targeted against vascular endothelial growth factor (anti-VEGF) such as bevacizumab, epithelial growth factor receptor (anti-EGFR) such as cetuximab and panitumumab, human epidermal growth factor receptor 2 (HER2) such as trastuzumab, and multikinase inhibitors such as regorafenib (Figure 1). With advances in molecular characterization of CRC as well as new insights into its genetic heterogeneity, the role of immunotherapy using immune checkpoint inhibitors targeting PD-1 such as pembrolizumab and nivolumab has been expanding in the treatment of mCRC.

Compared to the overall survival of around 11-12 months in the era of treatment with 5-FU alone, median survival in patients with mCRC is now approximately 3 years with 5-year survival rate trending upwards.3,4 These promising improvements in outcomes further demonstrate the efficacy of the current treatment. In this review, we aim to delineate the current treatment modalities for mCRC as well as discuss advances in systemic chemotherapy and immunotherapy.