HERAKLION, GreeceA multicenter phase III study comparing the
triple combination of paclitaxel (Taxol), cisplatin (Platinol), and
etoposide (VePesid) to the double combination of cisplatin and
etoposide as front-line treatment for small-cell lung cancer was
stopped because of eight toxic deaths. Less than a third of the
planned number of patients had been accrued.
All of the deaths occurred among patients receiving the triple-drug
regimen, reported Dimitrios Mavroudis, MD, assistant professor of
medicine in the Department of Medical Oncology, University General
Hospital of Heraklion.
In the three-drug regimen, paclitaxel 175 mg/m² was infused on
day 1, cisplatin 80 mg/m² on day 2, and etoposide 80 mg/m²
on days 2-4, Dr. Mavroudis said. As a prophylactic measure, all
patients on the three-drug regimen received 5 µg/kg G-CSF on
days 5-15. In the two-drug regimen, cisplatin at the same dosage as
in the other treatment arm was given on day 2, while etoposide 120
mg/m² was infused on days 1-3. G-CSF was administered as needed
to patients who developed grade 3 or 4 neutropenia or febrile
neutropenia while treated with the two-drug regimen. Both treatment
cycles were 28 days.
133 Patients Enrolled
Eligibility criteria for the study included having measurable
small-cell lung cancer not previously treated with either
chemotherapy or radiation. Patients with brain metastases were
accepted, Dr. Mavroudis noted, if the condition was stable after
radiation. Adequate organ function was required, he added, and
performance status could be in the range of 0-2. The age range was
set at 18-78 years.
Patients were randomized on the basis of whether their disease was
limited or extensive, their age, and whether they had elevated levels
of lactate dehydrogenase at the time their lung cancer was diagnosed.
As a result of the study protocol, he noted, age, sex ratio,
performance status, and increased lactate dehydrogenase were equally
distributed in the two arms of the study. A little more than
half of the patients, he said, had extensive-stage disease.
The study design called for 230 patients to be treated with each
regimen. At the time the study closed, 133 had been enrolled, 62
randomized to the triplet combination and 71 to the dual. In all, 261
cycles of the three-drug regimen had been administered and 323 of the
Cycle delays and dose reductions due to toxicity were similar in the
two arms of the study, Dr. Mavroudis said, 18 (7%) with three drugs
and 19 (6%) with two. All patients could be evaluated for toxicity,
he said, and 49 of those receiving the three-drug combination and 69
of those on the two-drug regimen were evaluable for response.
Similar Response Rates
Two patients in the triple-drug cohort achieved complete remissions,
and 29 had partial responses, for an overall response rate of 50%,
Dr. Mavroudis reported. Among patients receiving the two-drug
regimen, 3 had complete remissions and 31 had partial responses for
an overall response rate of 48%. The difference was not statistically
significant. Looking at duration of response, median survival,
and 1-year survival, there was no difference between the two
arms, Dr. Mavroudis observed.
Time to disease progression was a little longer with the three-drug
protocol, he noted, with the mean being 7 months compared to 6 months
among those who received only cis-platin and etoposide. Median
survivals were 10.5 months in the three-drug arm and 11.5 months in
the two-drug arm. One-year survival rates were 43% for the three-drug
combination and 45% for the two drug regimen.
Grade 4 neutropenia and grades 3 and 4 thrombocytopenia were
significantly more common with the three-drug regimen, Dr. Mavroudis
reported, and there was a trend toward more febrile neutropenia.
Nonhematologic toxicities, such as grade 3 diarrhea, grades 3 and 4
asthenia, and grade 3 neurotoxicity, were also more frequent.
Causes of Death
Of the eight deaths, four were due to neutropenic sepsis, one to
diarrhea and possible sepsis, and one to stroke with
thrombocytopenia, Dr. Mavroudis stated. One patient died of pneumonia
on day 10 after initial treatment, he noted, and one sudden death for
which a definitive cause was not available occurred on day 7 of the
Based on these results, we concluded that overall, the two
regimens were equally active, Dr. Mavroudis said, acknowledging
that the small number of patients accrued made assessment difficult.
The three-drug regimen, he declared, was definitely
significantly more toxic.
The results contrast with those in an earlier study at M. D. Anderson
Cancer Center, Houston, that achieved a 90% overall response rate
with a combination of paclitaxel, cisplatin, and etoposide. Of the 41
patients in that study, 47% developed grade 4 neutropenia and 9%
febrile neutropenia, and there were two toxic deaths. The paclitaxel
dosage was lower in the US study, Dr. Mavroudis noted, and no
patients with performance status 2 were included.