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Centre Rene Gauducheau
Colorectal cancer ranks as the third leading type of cancer in Europe and the USA, representing 10% of all cancers.(1) One in 25 people in Western countries has been or will be affected by this malignancy, and 50% of newly diagnosed patients will progress to metastatic disease. The treatment of metastatic colorectal cancer (mCRC) has largely benefited from the development of new drugs and new therapeutic concepts, such as oral chemotherapy and targeted biotherapy. There are now five agents used for the treatment of mCRC: 5-fluorouracil (5-FU) or 5-FU oral prodrugs such as capecitabine; irinotecan; oxaliplatin; and two new biological agents, bevacizumab and cetuximab.
Development of schedules with 5-FU in association with irinotecan or oxaliplatin
Before the 1990s, 5-FU appeared to be the only useful chemotherapeutic agent against colorectal cancer. Efforts to improve the efficacy of 5-FU led to the development of many variations in the mode of administration – from intravenous bolus to continuous infusion – in order to optimise the therapeutic index of the drug. The 1990s saw the introduction of irinotecan and oxaliplatin. Three pivotal trials validated the 5-FU-based regimens with oxaliplatin or irinotecan in mCRC. In the Saltz trial, patients were treated with bolus 5-FU/leucovorin (LV), either alone or combined with irinotecan (IFL regimen).(2) In the Douillard trial, patients received bolus and infusional 5-FU/LV (LV5FU2) alone or with irinotecan.(3) The response rates in the irinotecan arm were 39% and 35% in the first and the second study, respectively. For both studies, the difference was statistically significant compared with the 5-FU/LV arm (21% and 22%, respectively). Median survivals were also significantly increased (14.8 months vs 12.6 months; 17.4 vs 14.1 months). The third pivotal phase III study conducted by de Gramont et al compared LV5FU2 with LV5FU2 plus oxaliplatin (FOLFOX4).(4) FOLFOX4 was superior, showing an objective response rate of 50% (versus 22.3% with LV5FU2), a progression-free survival of nine months (versus 6.2 months) and a nonsignificant difference in overall survival. Based on these three pivotal trials, 5-FU-based regimens with irinotecan or oxaliplatin were recommended in first-line mCRC. However, the IFL regimen using bolus 5-FU was dropped after the publication of the N9741 intergroup trial.(5) Indeed, compared with IFL, FOLFOX4 prolonged time to progression (8.7 months vs 6.9 months; p=0.001), overall survival (19.5 months vs 15 months; p=0.0001) and also increased response rate (45% versus 31%; p=0.002).
An additional trial compared infusional 5-FU/LV plus irinotecan (FOLFIRI) with FOLFOX6 followed by a crossover after progression.(6) Overall survival was not significantly different between the two groups (20.4 months and 21.5 months, respectively). The conclusion reached in this trial was that a two-line chemotherapy strategy with doublets is suitable for a majority of patients, providing median survival of more than 20 months.
Development of new cancer agents:targeted biotherapy
Angiogenesis is an essential physiological mechanism in tumour growth, invasion and metastasis. The clinical impact of bevacizumab (Avastin), a recombinant human monoclonal antibody (rhuMAb) VEGF (vascular endothelial growth factor), was established in two phase III trials in mCRC. The first study evaluated the nonoptimal IFL regimen with or without bevacizumab. Time to progression and survival were significantly enhanced with bevacizumab (10.6 vs 6.2 months; and 20.3 months vs 15.6 months, respectively).(7) The second trial enrolled 828 patients who had failed previous therapy with both irinotecan and 5-FU.(8) Patients were randomly assigned to receive FOLFOX with or without bevacizumab or bevacizumab alone. The bevacizumab arm was discontinued early because of inefficacy. This study confirmed that the FOLFOX regimen with bevacizumab improved time to progression (7.4 months vs 5.5 months) and overall survival (12.5 months vs 10.7 months).
Cetuximab (Erbitux), an investigational mouse/human chimeric monoclonal antibody, targets the epidermal growth factor receptor (EGFR). Cetuximab is approved for patients who have been previously treated with irinotecan-based chemotherapy. This approval is supported by the results of the pivotal BOND study.(9) Out of 329 patients with mCRC refractory to irinotecan, 218 received a combination of cetuximab with irinotecan and 111 were treated with cetuximab alone. The response rates with cetuximab/irinotecan or cetuximab alone were 23% and 11%, respectively. Median time to progression was prolonged from 1.5 months to 4.1 months. Following these data, a randomised phase II study compared bevacizumab and cetuximab with or without irinotecan in patients with irinotecan-refractory mCRC.(10) Bevacizumab and cetuximab produced an objective response rate of 20% and a median time to progression of 5.6 months. Adding irinotecan increased these values to 37 % and 7.9 months, respectively.
Real progress has been made during 20 years of systemic therapy for mCRC, from the initial use of 5-FU alone to polychemotherapy regimens, such as 5-FU/LV/irinotecan or 5-FU/LV/oxaliplatin to allow a median survival of 20 months. In addition, two biological agents are approved for the treatment of mCRC: bevacizumab in first line with IV 5-FU based-regimen and cetuximab in second or third line after failure of irinotecan.
Figure 1 summarises the treatment options for patients with mCRC. At this time, regimens such as infusional 5-FU plus oxaliplatin plus bevacizumab, or cetuximab plus chemotherapy, are not validated in first-line mCRC. Thus, other possibilities are offered when irinotecan is prescribed in first intention. In addition, irinotecan plus cetuximab has to be prescribed after failure of irinotecan. Figure 2 represents the new therapeutic strategy, introducing cetuximab or bevacizumab with oxaliplatin in first intention. In all these proposed protocols, infusional 5-FU could be replaced by an oral prodrug of 5-FU, such as capecitabine, providing better tolerance and convenience. Nevertheless, if optimal strategy is not clearly identified, the high efficacy of available regimens allows considering local procedures for metastatic lesions (surgery or radiofrequency) after initial systemic therapy. Thus, a multidisciplinary approach is essential in the treatment of patients with mCRC.