Successes and limitations of targeted cancer therapy in colon cancer.

Constant development of chemotherapy and more recently the introduction of VEGF- and epidermal growth factor receptor (EGFR)-directed agents have improved significantly the treatment of patients with colorectal cancer. In the adjuvant setting, especially for UICC stage III colon cancer patients, fluoropyrimidine in combination with oxaliplatin is usually the standard of care. With some surprise, both VEGF inhibitors (for all patients) and EGFR (for patients with KRAS exon 2 mutant tumors) have failed to improve adjuvant chemotherapy. Also, adding an EGFR antibody to FOLFOX as perioperative treatment in patients with resectable exon 2 KRAS wild-type liver metastases was not successful. However, patients with metastatic disease harboring a RAS wild-type tumor are with no doubt candidates for combination chemotherapy plus an EGFR antibody. In patients with liver-limited disease, metastases may become resectable following intensive chemotherapy (including an EGFR antibody for RAS wild-type disease), which may result in cure or significantly prolonged survival. In the case of RAS wild-type tumors, median survival in patients with unresectable metastases approaches now 3 years if EGFR antibodies are used in the first line. There is little evidence for VEGF inhibitors in patients with RAS wild-type or mutant disease in first-line chemotherapy if combination chemotherapy is considered. VEGF inhibitors, however, are very potent drugs to be combined with chemotherapy for second-line treatment.