Four-Drug Regimen Enhances Responses and Increases Survival

MONTPELLIER, France—A 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 11 institutions.

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.”