HERAKLION, GreeceA multicenter phase III study comparing the triple combination of paclitaxel(Drug information on paclitaxel) (Taxol), cisplatin(Drug information on cisplatin) (Platinol), and etoposide(Drug information on 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 two-drug regimen.
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 third cycle.
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.