Evolution of Colorectal Cancer Treatment: The Central Role of Oxaliplatin

Oxaliplatin and fluoropyrimidines are synergic combinations very active for the treatment of advanced colorectal cancer and for the adjuvant treatment of stage III colon cancer. Oxaliplatin-based regimens can be further strengthened by the addition of a third component, either a traditional drug such as irinotecan or targeted agents such as anti-vascular endothelial growth factor (VEGF) drugs, bevacizumab and aflibercept, or the anti-epidermal growth factor receptor (EGFR), cetuximab and panitumumab. The availabilty of all these active agents prompted several clinical trials on different lines of treatment of advanced colorectal cancer patients and in the adjuvant setting. Clinical studies involving the administration of anti-EGFR drugs also helped identify mutations in KRAS as a negative marker for the activity of these agents. However, positive selection criteria for targeted agents have not been identified. The results of oxaliplatin-containing regimens are critically presented and discussed in this review. Evolution of Colorectal Cancer Treatment: The Central Role of Oxaliplatin As a single agent, oxaliplatin displays only a marginal activity in the clinic (1), but when administered with fluoruracil (5-FU), the combination is highly synergistic. The best example of this synergism comes from the three-arm phase III trial by Rothenberg et al. (2) in which patients with advanced colorectal cancer, progressing following treatment with irinotecan, 5-FU and leucovorin (LV) were randomised to receive 5-FU-alone, oxaliplatin-alone or the fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) combination of the two drugs. Response rate (ORR) and time-to-progression (TTP) were similarly low in patients allocated to receive either 5-FU-alone (0% ORR; TTP=2.7 months) or oxaliplatin-alone (1.3% ORR; TTP=1.6 months) while better results were observed in the combination arm (9.9% ORR; TTP=4.6 months). In vitro data implicate the downregulation of thymidylate synthase (TS) protein expression by oxaliplatin as a possible molecular mechanism for the observed synergy (3). As front-line treatment, the FOLFOX4 regimen was tested against leucovorin and fluorouracil (LV5FU2) in a randomized study which involved 420 patients, published in 2000 (4). Although patients randomized to receive up-front the combination including oxaliplatin up-front showed a better ORR (50.7% vs. 22.3%) and a longer time-to-progression (9.2 months vs. 6 months), overall survival (OS) was not significantly improved (16.2 vs. 14.7 months). However, the median OS observed in the LV5FU2 arm was about three months longer than that reported in the pre-oxaliplatin era, probably as a result of the introduction of oxaliplatin (or irinotecan) as a second-line treatment. In fact, in the same year, the results of two trials in which patients were randomised to receive a combination of irinotecan and 5-FU or 5-FU-alone were published. 5-FU was given according to different schedules: the weekly bolus infusion according to Roswell Park in the USA (5), weekly prolonged venous infusion (PVI) (the German schedule) or bi-weekly combination of bolus and PVI as in the LV5FU2 in Europe (6). The irinotecan-containing arms performed statistically better regarding all investigated parameters (ORR, TTP and OS). Overall, these data prompted the headto-head comparison of oxaliplatinor irinotecan-containing regimens in five trials (7-11). Looking at the most important parameter, OS, in three studies the two drugs tied, while in the remaining two, the oxaliplatin arms were the winners. Building upon the 5-FU/oxaliplatin cornerstone was the addition of irinotecan in several phase I-II studies (12-23). 423 Correspondence to: Dr. Andrea Bonetti, Department of Oncology, ASL 21 della Regione Veneto, Via Gianella 1-37045 Legnago (Verona), Italy. Tel: +39 0442632624, Fax: +39 0442632469, email: [email protected]