HELSINKI, FinlandA large phase III international study has
shown a survival advantage for neoadjuvant chemotherapy with
single-agent docetaxel (Taxotere) in selected patients with stage III
nonsmall-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
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.
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
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
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
The sessions 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.