First-line molecular therapies in the treatment of metastatic colorectal cancer - a literature-based review of phases II and III trials

Introduction: Metastatic colorectal cancer (mCRC) is one of the most common cancers and the second leading cause of cancer worldwide. With the improvement of systemic and operative therapies, median overall survival (mOS) reached 30 months or longer. Here, we will review the use of the anti-vascular endothelial growth factor (VEGF) and anti-epidermal growth factor receptor (EGFR) antibodies in combination with doublet and triplet chemotherapy in patients with borderline and primary unresectable mCRC. Methods: Phases II and III trials were included in investigating chemotherapy in the first-line in combination with an anti-VEGF(R) or anti-EGFR in a cohort of patients with mCRC. Results: The VEGF-antibody bevacizumab has improved progression-free survival (PFS) in several phase III trials in combination with a chemotherapy doublet. More recently, a higher efficacy has been demonstrated in combination with an intensified chemotherapy including 5-fluoropyrimidine (5-FU), oxaliplatin, and irinotecan within the phase III TRIBE study. Similarly, high resectability rates have been shown in the phase II Olivia trial for patients with liver-limited disease with an intensified chemotherapeutic regime. However, this increase in efficacy was accompanied by an increase in toxicity as well. The efficacy of the EGFR-antibodies cetuximab and panitumumab has been shown in several phase III trials, but their use is restricted to patients whose tumors are RAS wildtype (WT). The phase II trials, CELIM and PLANET, demonstrated a favorable long-term survival for patients with initially non-resectable colorectal liver metastases who respond to conversion therapy with EGFR-antibodies and undergo secondary resection. The CLGB and FIRE-3 trials delivered an inconsistent finding whether anti-VEGF or -EGFR treatment is the better option in the first-line setting. However, there is increasing evidence from post hoc analyses of prospective clinical trials that patients with left-sided tumors benefit from EGFR-directed combination therapy in terms of prolongation of OS and PFS compared with limited, if any, benefit for those with right-sided tumors. Conclusion: Both anti-VEGF-and anti-EGFR-directed therapies represent efficient treatment options for patients with mCRC in the first line. For patients with RAS WT, left-sided tumor anti-EGFR-based treatment is recommended. Intensified regimens can be offered initially to unresectable patients in order to achieve resectability at a price of higher toxicity.