NEW YORKBecause pivotal studies failed to show a survival
advantage, oxaliplatin did not receive FDA approval as first-line therapy
of metastatic colorectal cancer last year.
New US trials may move this drug closer to a regulatory
go-ahead, Daniel G. Haller, MD, of the University of Pennsylvania Cancer
Center, said at the Chemotherapy Foundation Symposium XVIII. A US Intergroup
trial, he said, is comparing the standard treatmentthe Saltz regimen, which
combines fluorouracil (5-FU), leucovorin, and irinotecan (Camptosar)with the
de Gramont regimen of 5-FU, leucovorin, and oxaliplatin. The trial also
includes a third arm of oxaliplatin plus irinotecan without 5-FU.
Oxaliplatin is a platinum derivative that is effective in
cisplatin-resistant cell lines. In phase I trials, oxaliplatin’s
dose-limiting toxicity was neurotoxicity,
primarily peripheral neuropathy that is short-lived and related to cold. No
nephrotoxicity or ototoxicity has been seen.
With oxaliplatin monotherapy, response rates up to 27% have
been reported in chemotherapy-naïve patients, and up to 10% in patients who
previously received a 5-FU-based regimen. "These data are consistent with
those seen with single-agent irinotecan," Dr. Haller said.
A French study that directly compared regimens containing
either oxaliplatin or irinotecan found similar response rates and
progression-free survival for both regimens. These results were reported at the
American Society of Clinical Oncology (ASCO) 2000 annual meeting in New
Dr. Haller noted that a survival advantage may be seen in one
treatment or the other upon longer follow-up.
As reported by de Gramont et al (J Clin Oncol 18:2938-2947,
2000), 5-FU/leucovorin plus oxaliplatin was superior to 5-FU/leucovorin alone
in the primary endpoint of progression-free survival (9.0 months vs 6.2 months,
P = .0003); a significantly improved response rate was also seen (50.7% vs
22.3%, P = .0001).
However, this did not translate into an improvement in overall
survival, which was a median of 16.2 months in the oxaliplatin arm vs 14.7
months in the comparator (P = .12).
Another oxaliplatin trial presented to the FDA in March 2000,
looking at chronomodulated 5-FU and leucovorin with or without oxaliplatin,
showed no significant survival advantage for oxaliplatin.
"Overall survival has been the gold standard for
regulatory approval of oncologic drugs," Dr. Haller said. Thus, results of
the comparative trial of the Saltz and de Gramont regimens are awaited.
Oxaliplatin may also have a role as salvage therapy for
patients who progress on first-line therapy with the Saltz regimen, which is
now being used in 30% to 40% of patients with metastatic colorectal cancer,
according to Dr. Haller. He mentioned two new trials of oxaliplatin as
second-line therapy, both sponsored by Sanofi-Synthelabo Inc, the company that
is developing oxaliplatin. In the first study, patients who have failed the
Saltz regimen will be randomized to the de Gramont bolus/infusion regimen of
5-FU/leucovorin, oxaliplatin alone, or the de Gramont regimen of 5-FU/leucovorin
plus oxaliplatin. In the second study, patients who have failed 5-FU/leucovorin
will be randomized to receive oxaliplatin plus irinotecan or irinotecan alone.
"Oxaliplatin has shown consistent activity as salvage
treatment for patients with colorectal cancer, primarily in patients who have
progressed following 5-FU/leucovorin, not the Saltz regimen," Dr. Haller
said. "It would be of interest to evaluate each of these strategies in a