Colorectal cancer (CRC) remains one of the most common tumour types and a leading cause of cancer death worldwide. The American Cancer Society (ACS) estimates that 148,610 people were diagnosed with, and 55,170 people died of, CRC last year in the US.1 Despite these statistics, mortality from CRC has decreased over the past 30 years, possibly because of better treatment modalities. Until a few years ago, treatment options for CRC patients were limited to 5-fluorouracil (5FU). However, the introduction of two new cytotoxic drugs, irinotecan and oxaliplatin, has resulted in significant progress in the treatment of metastatic CRC (mCRC).2,3 Recently, three novel targeted agents have been approved for the treatment of mCRC: bevacizumab, cetuximab and panitumumab. As a consequence, the armamentarium of treatment options for patients with CRC is rapidly expanding. In spite of these advances, the prognosis for patients with mCRC remains poor, with a five-year survival rate less than 5%. Therefore, new strategies are needed to improve this prognosis. In this article we review the therapeutic options in mCRC.
The Chemotherapy Era
Until a few years ago, 5FU and 5FU in combination with leucovorin (LV) were the treatment options for patients with CRC. Some clinical trials evaluated different schedules and doses of these two drugs, infusional schedules of 5FU and combinations with LV being the most attractive regimens. Nevertheless, the median overall survival (mOS) remained around 12 months.4 Saltz et al.2 demonstrated in a phase III trial with 628 patients that the addition of irinotecan to bolus 5FU/LV (IFL) increased the mOS from 12.6 to 14.8 months (p=0.04). Another study, conducted by Douillard et al. (with an infusional 5FU/LV regimen),5 confirmed this data. The results of these two prospective phase III randomised, controlled, multicentre, multinational clinical trials in patients with previously untreated mCRC served as the basis for US and European approval of irinotecan/5FU/LV for this indication. At the same time, de Gramont et al.3 published the results of a phase III trial which concluded that the combination of infusional FU/LV and oxaliplatin (FOLFOX) prolonged progression-free survival (PFS) (median 9 months versus 6.2 months; p=0.0003) with acceptable tolerability. However, this combination failed to demonstrate a statistically significant increase in OS (median 16.2 months versus 14.7 months; p=0.12). For this reason the FOLFOX regimen was only approved in Europe as first-line treatment in mCRC. With the results of the Goldberg trial in 2004,6 oxaliplatin was approved in the US for the treatment of mCRC. In this study, 795 patients with mCRC were randomised to receive IFL, FOLFOX or irinotecan and oxaliplatin (IROX). The results of the FOLFOX group were significantly superior to the IFL and IROX groups. At that time, two 5FU-based infusional regimens with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) became the most popular schedules used worldwide for the treatment of patients with mCRC.
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