New oxaliplatin-based combinations in the treatment of colorectal cancer

The synergism between oxaliplatin and 5-fluorouracil (5FU)/leucovorin in the treatment of colorectal cancer raises the prospect of further clinically effective combinations. Phase I/II trials of capecitabine, an oral fluoropyrimidine, plus oxaliplatin have established this combination (XELOX) as an effective treatment for advanced disease, with response rates of over 50% in first line therapy. Phase III studies of XELOX are now in progress, while further studies are investigating the combined use of oxaliplatin and a second oral fluoropyrimidine, UFT, after positive phase I/II results. Studies of combined oxaliplatin and irinotecan treatment have reported response rates varying from 25% to 60% in second-line therapy of treatment resistant metastatic disease, and 42% in first line therapy. The optimum dosing combination of these two agents has yet to be determined however, and in many patients it is likely that greater overall survival will be achieved by using them in successive lines rather than in combination. Clinical studies have also demonstrated clinically significant response rates when oxaliplatin is combined with other agents including raltitrexed and mitomycin C. Alongside these novel chemotherapeutic combinations, a range of biological therapies is now being investigated in combination with oxaliplatin in advanced colorectal cancer. Cetuximab (C225) is a monoclonal antibody that inhibits signalling through the epidermal growth factor receptor (EGFR), a pathway that has been associated with a variety of pathological process in cancer including dysregulated growth, differentiation, angiogenesis, cell motility and cell adhesion. Studies of second-line therapy combining oxaliplatin and cetuximab in advanced disease and in patients with unresectable liver-only metastases are in progress in the United States. A phase I/II study is also investigating the combined use of oxaliplatin and ZD1839 ('Iressa'), a small molecule inhibitor of the EGFR specific tyrosine kinase activating the same pathways. Anti-angiogenesis agents are also being studied intensely. A key angiogenic pathway in the stimulation of tumour growth is the vascular endothelial growth factor (VEGF) pathway, inhibited by the monoclonal antibody bevacizumab. Phase II first line and phase III second line studies of oxaliplatin in combination with bevacizumab are now in progress. Oxaliplatin is being investigated in combination with a number of other classes of biological agent, including the proteasome inhibitor PS-341. The sudden appearance of a wide range of chemotherapeutic and biological agents with activity against colorectal cancer presents many challenges to the current system of clinical trials, given the large number of permutations requiring prospective testing. However, by building upon the encouraging results achieved using oxaliplatin plus 5FU/leucovorin, the introduction of new agents will eventually translate into significantly improved clinical outcomes.