MONTPELLIER, FranceA four-drug regimen produced better outcomes
in patients with extensive small-cell lung cancer than the commonly
used combination of etoposide (VePesid) and cisplatin (Platinol), a
French multicenter study showed.
The 1-year survival rate in the phase III trial was 40% for patients
receiving epirubicin (Ellence) and cyclophosphamide (Cytoxan) as well
as etoposide and cisplatin, according to Jean-Louis Pujol, MD,
department of thoracic oncology, Montpellier University.
The 18-month survival rate for patients in the four-drug group, he
added, was 18%. In contrast, the 1-year survival rate for patients
receiving only etoposide and cisplatin was 29%, and the 18-month
survival rate was 9%. These differences were statistically
significant, Dr. Pujol noted.
Under the study protocol, etoposide 100 mg/m² was administered
on days 1-3 and cisplatin 100 mg/m² on day 2 in both regimens.
The four-drug regimen also included cyclophosphamide 400 mg/m²
on days 1-3 and epirubicin 40 mg/m² on day 1. Treatment cycles
were repeated every 28 days, and the protocol specified a total of
six cycles per patient.
All With Extensive Disease
Eligibility criteria called for patients younger than 75 years of age
with histologically proven small-cell lung cancer classified as
extensive and with performance status between 0 and 2. A total of 226
patients were enrolled in the study from March 1996 to March 1999 at
Of these, 109 were randomized to receive etoposide and cisplatin and
117 to the four-drug regimen. Three in each group turned out to be
ineligible, and one assigned to the two-drug regimen was lost to
follow-up. Analysis showed no statistical differences in the
groups pretreatment characteristics such as performance status
and age. All analyses were on an intent-to-treat basis,
Dr. Pujol said.
The 76% objective response rate with the four-drug regimen was
significantly higher than the 61% achieved with etoposide and
cisplatin, Dr. Pujol noted. The complete response rate for the
four-drug therapy was 21% vs 13% for the other regimen, but that
difference was not statistically significant. Six courses of
chemotherapy were completed by 64% of the patients receiving the four
drugs, compared to 53% of those assigned two drugs. One reason for
the difference, Dr. Pujol observed, was that more patients on the
two-drug regimen discontinued therapy because of progressive disease,
32% vs 9% with the four-drug course.
More Toxicity With Four Drugs
Toxicity, however, was a more frequent problem with the four-drug
regimen. The overall rate was 15% with this combination and 5% with
the two drugs. Myleosuppression was clearly more severe with
four drugs than two, Dr. Pujol reported.
In particular, febrile neutropenia was more frequently
observed, occurring in 70% of the patients receiving four
drugs, compared with 18% of those in the two-drug group. No
differences were observed regarding nonhematological toxicities such
as nausea and vomiting, Dr. Pujol added.
The toxic death rate was 9% in the four-drug arm and 5.5% in the
other group. The difference was not statistically significant, Dr.
Pujol said. Most of the deaths occurred in the first year of the
study, he noted, and current knowledge of how to use the therapy
might reduce the risk. Some deaths, he indicated, were related to
radiation pneumonitis, but radiation therapy is now avoided after the
long treatment with epirubicin.
At Montpellier University Hospital and many of the other institutions
participating in the trial, the four-drug regimen is now standard for
advanced small-cell lung cancer. The study, he said, led to the
conclusion that it yields a higher response rate and better survival
than etoposide and cisplatin without any detrimental effect on
the quality of life during therapy.