Consolidation Docetaxel in Advanced NSCLC

CHICAGO—Concurrent chemo-radiotherapy and consolidation docetaxel (Taxotere) achieved an unprecedented 3-year survival rate of 40% in patients with stage IIIB non-small-cell lung cancer (NSCLC) in a phase II trial (SWOG 9504).

"The survival comparison at 3 years of 40% with SWOG 9504 and 18% with SWOG 9019 (as a historical control) are very encouraging. But since these results are in a phase II study, they need to be interpreted with caution," David R. Gandara, MD, said at the Second International Chicago Symposium on Malignancies of the Chest and Head & Neck.

Dr. Gandara, professor of medicine and associate director for clinical research, University of California, Davis, Cancer Center, Sacramento, and chair of the Southwest Oncology Group (SWOG) Lung Committee, explained the hypothesis behind recent SWOG trials for NSCLC: that concurrent chemoradiotherapy plus full-dose consolidation chemotherapy may improve outcomes in patients with locally advanced disease.

Two Potential Designs

"If we look at locally advanced stage III disease as a two-compartment model, where we have to address both the loco-regional disease and the distant metastases, then combination sequential and concurrent chemoradiotherapy may be optimal," he said.

There are two potential designs for optimizing combination chemotherapy and radiotherapy. "The first would be to give full-dose induction chemotherapy followed by concurrent chemoradiation. Depending on the agent, this would sometimes require a marked decrease in the dose of chemotherapy given with radiation," Dr. Gandara said.

The flip side of this coin, he said, would be to give a lower locoregional chemotherapy dose first, followed by full-dose consolidation chemotherapy, the scheme followed in SWOG 9504.

According to Dr. Gandara, SWOG for many years has treated limited small-cell lung cancer on day 1 with radiation therapy and chemotherapy with cisplatin (Platinol) and etoposide (VePesid). This course is followed by two more cycles of the chemotherapeutic agents. "Cisplatin and etoposide are particularly useful because the combination can be given in full dose, even with concurrent continuous radiation therapy," he said.

The current trial, SWOG 9504, investigated taxane sequencing, which meant delivering the taxane not as a second-line treatment but prior to the emergence of clinical drug resistance. "Docetaxel appears to be among the most active agents as secondary treatment for NSCLC. The potential molecular mechanism involving the p53 gene and apoptosis would favor delivering this agent prior to the emergence of clinical drug resistance," Dr. Gandara explained.

In SWOG 9504, a total of 83 patients with pathologically staged IIIB NSCLC received 61 Gy of thoracic radiotherapy (1.8 to 2.0 Gy daily) and concurrent cisplatin 50 mg/m² on days 1, 8, 29, and 36 and etoposide 50 mg/m² on days 1 to 5 and 29 to 33. This regimen was followed by three 21-day cycles of docetaxel: 75 mg/m² on the first consolidation cycle and 100 mg/m² on cycles 2 and 3.

Results of this trial were compared with findings from SWOG 9019, which adhered to the same concurrent chemoradiotherapy paradigm but provided two additional cycles of cisplatin and etoposide as consolidation.

The median survival in SWOG 9019 was 15 months; 34% of patients survived 2 years, and 18% survived 3 years. The median survival in SWOG 9504 is 26 months; 54% of patients have survived for 2 years, and 40% are still alive after 3 years.

Initial analysis of patterns of treatment failure in SWOG 9504 indicate that 31% of patients failed to achieve locoregional control, 9% had local/distant disease, and 45% had distant disease only.

Dr. Gandara nevertheless provided a word of warning about the nature of treatment failures. "There were 15 failures in the brain, of which eight represented isolated brain occurrences. A major issue in all of these trials when long-term survival is being gained is that the brain is a sanctuary site, and we need to find a way to address that."