LOS ANGELES--Adding oxaliplatin(Drug information on oxaliplatin) (Eloxatine) to a bimonthly regimen of leucovorin and 5-fluorouracil (5-FU) in colorectal cancer patients "substantially enhanced the regimens activity with little increase in toxicity," Aimery de Gramont, MD, Hospital Saint-Antoine, Paris, reported at ASCO. "The study confirms the good activity and excellent tolerability of the bimonthly leucovorin/5-FU schedule," he said.
The standard first-line US treatment for patients with advanced colorectal cancer has been the NCCTG (North Central Cancer Treatment Group)/Mayo Clinic regimen in which patients receive leucovorin and a bolus plus IV infusion of 5-FU over several hours as outpatients for 5 days every 4 to 5 weeks.
However, last year, Dr. de Gramonts bimonthly regimen of leucovorin and a bolus plus IV infusion of 5-FU given over 2 days was shown to have efficacy superior to that of the NCCTG/Mayo regimen.
The bimonthly regimen, Dr. de Gramont said, requires hospitalization for a higher-dose 5-FU bolus and initiation of a programmable infusion pump that goes home with the patient. Both response rate (32.6% vs 14.5% Mayo) and progression-free survival (27.6 weeks vs 22.0 weeks) favored the de Gramont regimen, according to last years report.
"The bimonthly regimen is clearly less toxic," Dr. de Gramont said in an interview after his ASCO presentation of the new trial in which oxaliplatin was added. He emphasized that avoiding the significant diarrhea and mucositis of the Mayo regimen is very important for patients. [See also article.]
In the new multicenter phase III trial, 420 colorectal cancer patients with unresectable metastases were randomized to the bimonthly regimen (leucovorin 200 mg/m² as a 2-hour infusion followed by 5-FU 400 mg/m² bolus and 600 mg/m² IV infusion on days 1 and 2 every 2 weeks), with or without oxaliplatin, 85 mg/m² as a 2-hour IV infusion on day 1.
Response rates in the 409 patients with evaluable disease were 51.2% for the bimonthly regimen with oxaliplatin vs 22.6% for the bimonthly regimen alone, a significant difference. Progression-free survival was significantly longer for the regimen including oxaliplatin (median, 37.9 weeks vs 26.4 weeks for the bimonthly regimen alone). Survival analysis is not complete; however, no overall survival benefit is apparent at this time, he said.
Overall, side effects were acceptable, Dr. de Gramont said, with moderate increases in the usual 5-FU toxicities and frequent asymptomatic neutropenia, which imposed dose reductions or cycle delays. More grade 3 neurosensory tox-icities were reported among patients on oxaliplatin, including late paresthesia (usually after 4 to 6 cycles), which could be severe but was never life-threatening.
Discussion of the Results
ASCO session discussant Mace L. Rothenberg, MD, of Vanderbilt University, said that oxaliplatin appears to be substantially non-cross-resistant with cisplatin(Drug information on cisplatin) (Platinol) and demonstrates activity in tumor cell lines resistant to cisplatin. "While oxaliplatin has been commercially available in France for more than a year, it is only now entering clinical trials in the United States," he said.
Although there is a higher incidence of grade 3 neurosensory toxicity with oxaliplatin, he noted that in this study grade 3 neurosensory toxicity was defined as a difficulty rather than an inability to perform fine motor skills, eg, a patient must look to button his shirt but is still able to do so.
Dr. Rothenberg praised the trial for its good design, saying it had adequate size and power to detect a clinically meaningful difference in survival. "Notably," he said, "this and other trials of 5-FU/leucovorin and oxaliplatin report some of the longest progression-free and overall survivals of any multicenter trial of metastatic colorectal cancer."
He noted that about 20% of patients in the leucovorin/5-FU group with tumor progression had gone on to second-line treatment with the oxaliplatin-containing regimen, which may have obscured an overall survival advantage.