NEW YORKIn a phase I/II study combining gemcitabine (Gemzar)
and oxaliplatin, French investigators saw a 47% objective response rate among
evaluable patients with advanced non-small-cell lung cancer (NSCLC).
Thierry Le Chevalier, MD, chief, Department of Medicine,
Institut Gustave-Roussy, Villejuif, reported at the Chemotherapy Foundation
Symposium XVIII that 13 of the 28 evaluable patients with stage III/IV NSCLC
had a major response and 8 others had stable disease. Disease progression
occurred in 7 patients. Of the 9 patients with ovarian cancer, 3 showed an
The outpatient study tested six different dosage combinations
in 35 lung cancer patients and 9 with ovarian carcinoma. The dosages ranged
from 800 mg/m2 gemcitabine and 70 mg/m2 oxaliplatin every 2 weeks to 1,500
mg/m2 gemcitabine and 85 mg/m2 oxaliplatin every 2 weeks. The highest level
tested turned out to be the maximum tolerated dose and is recommended for
On days 1 and 14 of the 28-day treatment cycles, patients
received a 30-minute infusion of gemcitabine followed by a 2-hour infusion of
oxaliplatin. Treatment can be completed in 3 hours, Dr. Le Chevalier noted. The
schedule was based on laboratory studies that had shown better in vitro
activity of the combination when gemcitabine was given before oxaliplatin, he
explained. In preclinical studies, he noted, oxaliplatin showed a broader
spectrum of activity than cisplatin (Platinol), which has long been used in
doublet therapy in NSCLC.
Both gemcitabine and oxaliplatin have clinical activity against
lung and ovarian cancer. "Their mechanism of action and resistance are
distinct," he said. "In the preclinical studies, we showed a
synergistic activity between gemcitabine and oxaliplatin and at least an equal
or better synergistic effect of the gemcitabine-oxaliplatin combination,
compared with the gemcitabine-cisplatin combination."
All lung cancer patients were evaluable for acute toxicity and
29 for chronic toxicity, he said. There was no dose-limiting toxicity at the
time of the first cycle. Nonhematologic toxicity consisted mainly of nausea and
vomiting in a small proportion of patients and asthenia in 18% of all cycles,
he said. Transient grade 3 asthenia, observed in 2% of the cycles, was
responsible for treatment delay in one patient. One patient experienced a grade
2 flu-like syndrome.
Hematologic toxicity was not a major occurrence. "Even at
the highest dose," Dr. Le Chevalier said, "most patients didn’t
experience a major neutropenia." Grade 3 neutropenia, he reported,
occurred in only 3 of 55 cycles of treatment at the highest dose levels. Grade
3 thrombocytopenia was seen in one patient.
The toxicity profile in the ovarian carcinoma group was similar
to that of the lung cancer patients.
At the three highest doses, he said, "we saw several grade
2-3 neurotoxicities; some of those patients are still under treatment, and the
assessment for that is not finished." Of the five patients who received
five cycles, four developed grade 3 neurotoxicity and were withdrawn from the
study for that reason.
Treatment was delayed in 7 of the total 125 cycles in the lung
cancer group. In six instances, the delay was caused by grade 1, 2, or 3
thrombocytopenia, and in one case the reason was transient asthenia. "Most
patients," Dr. Le Chevalier observed, "could get the treatment right
at the time set by the protocol."
Gemcitabine-oxaliplatin is generally well tolerated, Dr. Le
Chevalier concluded. "The complete and partial responses seen with this
combination suggest it could be compared to the classical gemcitabine-cisplatin
doublet in advanced NSCLC," he said.