Survival Advantage Seen for Neoadjuvant Docetaxel in Stage III NSCLC, but Study Stirs Criticism

HELSINKI, Finland—A large phase III international study has shown a survival advantage for neoadjuvant chemotherapy with single-agent docetaxel (Taxotere) in selected patients with stage III non–small-cell lung cancer (NSCLC). The analysis of the study, presented at the ASCO meeting, was, however, met with criticism from investigators outside the study.

“The results confirm smaller studies, which taken together indicate that chemotherapy should be included in the standard treatment of patients with locally advanced NSCLC,” said Karin Verena Mattson, MD, of the Helsinki University Central Hospital, Finland.

The study included 277 patients randomly assigned to one of two study arms:

• A neoadjuvant treatment arm consisting of docetaxel (100 mg/m², given over 1 hour IV every 3 weeks for three consecutive cycles) followed by local therapy (surgery or radical radiotherapy);

• An immediate local therapy treatment arm.

The majority of patients in both arms underwent radiotherapy (80%) as the mode of local treatment. In the surgical arm, 71% had a complete resection. The response rate to docetaxel was 26%. Patient characteristics were well balanced in both arms. Most patients had good performance status and squamous cell histology.

Survival Differences

Analyses were performed on both the intent-to-treat population and the full-treatment population, which consisted of those eligible patients who received at least two cycles of docetaxel with either radiotherapy or surgery.

In the randomized intent-to-treat population (n = 274), neoadjuvant docetaxel conferred no additional benefit. Median survival was 15 months for the docetaxel arm and 14 months for the local treatment only arm. One-year survival was about 60% in each arm, Dr. Mattson reported.

In an analysis of the full-treatment group (n = 258), however, there was a highly significant difference in survival in favor of the neoadjuvant arm. Median survival was increased by 7 months, from 14 to 21 months, and there was a 19% increase in absolute 1-year survival, from about 56% to about 75% (P = .0014).

Neoadjuvant therapy also delayed disease progression in the full-treatment population to 15 months vs 8 months for local therapy only (P = .005), Dr. Mattson said.

Febrile neutropenia or infection, without prophylaxis, occurred in 15 patients, and there were two treatment-related deaths. Cumulative nonhematologic toxicities associated with docetaxel were not a problem in this study, as patients received only three cycles, with 81% of patients getting all three cycles.

Concerns about the study were expressed during the discussion period. Investigators from other lung cancer trials questioned the emphasis placed on the results from the full-treatment analysis, rather than the intent-to-treat analysis.

Alan Sandler, MD, of Indiana University at the time of the meeting but now at Vanderbilt University, noted, “The only difference in survival was seen when you included patients who were not dropping off after the first or second cycle of docetaxel. I assume they were dropping off because of disease progression and/or toxicity. I am concerned about the comments regarding benefit.”

Another listener commented that giving therapy that prolongs treatment allows time to “select patients who have occult distant metastases that will appear. If they show metastases, you take them out and it makes your completed treatment look much better.”

Current Results Defended

Dr. Mattson responded that most patients did withdraw due to disease progression, and that about half the progressive disease patients developed metastases.

“If it would be possible to have as many patients as I wanted, I would do this study again and do it differently,” she said. “We were just happy we were able to complete this study. Since 1995, our understanding of the biology of stage III subgroups has improved, and we would not use the same design for all subgroups today.”

She noted that modern staging procedures as well as prognostic and predictive biologic markers now allow for more individualization of treatment in stage III substages.

Furthermore, she said, the analyses are not complete, since 70 patients are still alive. She said she maintained a “positive small hope” that significance will emerge in the intent-to-treat analysis.

The current results, however, “strongly support” the general statement that stage III patients should be considered for combined-modality treatment, Dr. Mattson maintained. “Taxotere, as a single agent, is a good nonplatinum option as a neoadjuvant treatment in this disease and should be studied further in chemotherapy combinations and in concurrent radiation strategies.”

The session’s discussant, Minesh P. Mehta, MD, of the University of Wisconsin, also disagreed with the study conclusions. Preferring to focus on the intent-to-treat analysis, he said, “Taxotere results in negligible benefit that is probably not clinically relevant. The only subgroup where significant differences seemed to appear was in the patients with earlier-stage disease.”