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Colorectal cancer (CRC) is the third most common cancer among men and women and the second leading cause of cancer death in the Western world.1 Nearly 25% of all patients have metastatic disease at initial diagnosis, with a five-year survival rate of less than 10%.1 In addition, despite curative surgery, around 40–50% of these patients will still relapse within three years of primary surgery. Over the last four decades, 5- fluorouracil (5-FU) has been the cornerstone for CRC treatment in both the palliative and the adjuvant setting. The introduction of new cytotoxic drugs such as capecitabine, irinotecan and oxaliplatin, the integration of biological agents such as cetuximab and bevacizumab and the development of new agents acting on novel targets has clearly increased the number of therapeutic options for patients with advanced and metastatic CRC disease.
Systemic Treatment of Metastatic Disease
The incorporation of new chemotherapeutic and biological agents has raised many important questions and challenges concerning the most effective chemotherapy combination, optimal duration of treatment, optimal use of one or two biological agents in combination chemotherapy and the best sequence.
Until the 1990s, the only available drug was 5-FU, with modest activity (response rate [RR] 20–25%, median overall survival [mOS] 13 months) when combined with the biomodulator folinic acid (FA) and delivered as a prolonged infusion2,3 (see Figure 1). More recently, the oral fluoropyrimidine capecitabine has been shown to be as active as bolus 5-FU/FA.4 The first real advance came with the addition of irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) to infusion-based 5-FU/FA with response rates in the 40–50% range and mOS times of 17–19 months5,6 (see Figure 1). The cross-over study, conducted by Tournigand et al., provided evidence for increased OS when patients were exposed sequentially to FOLFIRI followed by FOLFOX (mOS 21.5 months) or to FOLFOX followed by FOLFIRI (mOS 20.6 months).7
In a randomised phase III trial, the triplet combination of irinotecan, oxaliplatin and 5-FU/FA (FOLFOXIRI) was found to be superior to FOLFIRI as first-line treatment with median survival times of 22.6 versus 16.7 months, respectively.8 In contrast to this study, the phase III trial presented by Souglakis et al. failed to demonstrate any superiority of the FOLFOXIRI arm over the FOLFIRI arm.9 Phase II studies with infusional 5-FU/FA and bolus mitomycin-C have shown modest activity with response rates of 12–17% in chemo-resistant CRC patients.
Another important challenge has concerned treatment duration: should patients be treated until disease progression, until maximal response or to only a pre-defined dose-limit? In this respect, the OPTIMOX1 trial showed that a planned interruption of oxaliplatin does not compromise the overall efficacy of the treatment.10 Similarly, a study comparing intermittent FOLFIRI with continuous FOLFIRI administered until disease progression has shown overall survival rates of 16.9 versus 17.6 months, respectively.11 Ongoing trials such as COIN and CONcePT will further evaluate the approach of treatment interruption.