LOS ANGELES--Adding 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
"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 (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