The evolving role of oxaliplatin in the management of colorectal cancer.

The introduction of oxaliplatin into the chemotherapy of advanced colorectal cancer has substantially increased the frequency and magnitude of clinical response compared with that achieved using 5-FU/leucovorin, and has extended progression-free and overall survival. Research is now in progress on several fronts to determine how oxaliplatin-based therapy can be optimized. A phase III multicentre trial recently compared the efficacy and safety of the FUFOX regimen, based on high dose infusional 5-FU/leucovorin and 50 mg/m2 oxaliplatin given weekly for 4 weeks in a 5-week cycle (n = 123) with the Mayo clinic 5-FU/leucovorin regimen (n = 129) in the first-line therapy of metastatic disease. The response rate with the FUFOX regimen was 48.3%, more than twice that in the Mayo regimen (22.6%; P < 0.0001) and median survival was 20.4 months, despite the fact that the FUFOX regimen had lower toxicity. The value of high dose oxaliplatin and 5-FU/leucovorin has also been demonstrated in the FOLFOX series of studies, where patients who received more than 85 mg/m2 oxaliplatin per 2-week cycle had double the response rate of patients receiving less than 85 mg/m2. In the FOLFOX7 regimen based on a simplified high dose bolus/infusional regimen of 5-FU/leucovorin (sLV5FU2) plus 130 mg/m2 oxaliplatin, a response rate of over 40% has been achieved in second line therapy. Studies have also compared first-line therapy based on oxaliplatin with irinotecan-based first-line therapy. A large trial coordinated by the North Central Cancer Treatment Group (NCCTG) recently compared the IFL regimen, which is currently the standard irinotecan-based first-line treatment for advanced colorectal cancer in the United States, with oxaliplatin-based treatment using the FOLFOX4 regimen. Compared with irinotecan-based chemotherapy, oxaliplatin was associated with a 30% increase in overall survival (19.5 months vs. 15.0 months; P = 0.0001), a higher response rate (45% vs. 31%, P = 0.002) and lower toxicity. Further studies are investigating how therapy can be optimized over multiple lines. In a phase III two-line study comparing first-line therapy with FOLFOX6 and second line therapy with irinotecan-based therapy (FOLFIRI) (n = 109) with the reverse sequence (n = 111), progression-free and overall survival were comparable whichever regimen was used first, although patient numbers were smaller than in the NCCTG study and less able to detect treatment differences. FOLFOX6 was also more effective than FOLFIRI in second-line therapy. Currently, studies based on FOLFOX7, novel FOLFIRI regimens and sLV5FU2 are in progress to determine how disease control can be sustained in the long-term, and the development of drug resistance delayed, in multiline therapeutic management. In parallel with these studies, two large phase III trials are now investigating the role of oxaliplatin in the adjuvant treatment of nonmetastatic colorectal cancer. The first of these studies, MOSAIC, has already shown a very encouraging 23% decrease in the risk of relapse at 3 years (P = 0.002) with FOLFOX4 compared to LV5FU2.