BOCA RATON, Fla--Docetaxel (Taxotere) is showing promising single-agent activity in non-small-cell lung cancer (NSCLC), said James Rigas, MD, director, Thoracic Oncology Program, Norris Cotton Cancer Center, Dart-mouth-Hitchcock Medical Center (Lebanon, NH).
In the United States, the drug has been approved for use in anthracycline-resistant breast cancer, and in other parts of the world, it is available for use in NSCLC. From the US trial data, Dr. Rigas thinks that its use in the treatment of NSCLC seems warranted.
"We started trials with Taxotere in NSCLC in 1992," Dr. Rigas said at the annual meeting of the Network for Communication and Oncology Research. His talk focused on the phase II trials, which took place in Europe (EORTC) and the United States (Memorial Sloan-Kettering, M.D. Anderson Cancer Center, and the University of Texas Health Sciences Center, San Antonio).
Of the 379 patients enrolled, 291 were chemotherapy-naïve and 88 had failed prior platinum-based chemotherapy regimens. The chemotherapy-naïve patients took part in four single-agent phase II trials (n = 160) and three phase I/II cisplatin(Drug information on cisplatin) (Platinol) combination trials (n = 131). The platinum-resistant patients were enrolled in two single-agent phase II trials.
The criteria for the chemotherapy-naïve patient population were metastatic or locally advanced lung cancer, a contraindication to combined modality therapy, no prior cytotoxicity to chemotherapy, and no radiation within three weeks of starting the trial.
In the single-agent phase II trials, docetaxel(Drug information on docetaxel) was given every 21 days at a dose of 100 mg/m² infused over one hour. The cisplatin/docetaxel combination trials established a standard dosing regimen, given every 21 days, of docetaxel, 75 mg/m² infused over one hour with cisplatin, 75 mg/m².
Antitumor activity was assessed at three weeks by physical examination and x-ray, and at six weeks by CT scan. A follow-up CT scan was given within four to six weeks to confirm the response, Dr. Rigas said.
The response rate in the intent-to-treat analysis for the single-agent phase II trials was 27% (95% confidence interval: 20% to 34%). "This was not a randomized trial," Dr. Rigas commented, "but rather the pooled result of data on all 160 patients treated."
The median survival was nine months with an estimated one-year survival rate of 34%.
The 88 patients who had previously failed a platinum-based regimen showed a response rate of 17% (95% confidence interval: 10% to 27%). The median survival rate was nine months, and one-year survival, 38%.
The 131 patients treated in the phase I/II combination trials had a response rate of 38%, median survival of 10 months, and one-year survival of 40%.
Early into the phase II trials, the researchers began to see that peripheral edema, primarily in the ankles, was a cumulative side effect of the compound. Dexamethasone(Drug information on dexamethasone) premedication was shown to lessen the frequency and severity of fluid retention, infusion-related reactions, and rash.
"The use of corticosteroids has even helped the infusion reactions," Dr. Rigas said. "And if there is an infusion reaction, the infusion can be stopped and restarted in 20 or 30 minutes."
Neutropenia was a significant side effect, with 54% of patients having grade 4 leukopenia and 7.3%, febrile neutropenia. About 3% had grade 4 leukopenia lasting more than seven days.
"A retrospective analysis of multiple variables that may have contributed to the efficacy and toxicity of Taxotere in the trials was possible," Dr. Rigas said, "because the sponsor of the studies, Rhône-Poulenc Rorer, had the insight to make a population pharmacokinetic model for Taxotere."
Model Predicts Neutropenia Risk
This model, based on the blood samples collected during most of the phase II trials, included both the breast cancer and lung cancer trials. From this database, Dr. Rigas said, a combination of liver function abnormalities was identified that predicts which patients are most likely to develop neutropenia and febrile neutropenia.
"This population pharmacokinetic database is the largest study for any oncologic drug developed that I know about," Dr. Rigas said.
He noted that other lung cancer trials are in progress using docetaxel in combination with different agents, including carboplatin(Drug information on carboplatin) (Paraplatin), cisplatin, vinorelbine (Navelbine), gemcitabine(Drug information on gemcitabine) (Gemzar), and irinotecan(Drug information on irinotecan) (Camptosar), as well as thoracic radiation.
Trials of docetaxel as primary chemotherapy for stage III NSCLC are warranted based on its success in early studies, Dr. Rigas believes.