VANCOUVER, CanadaA tri-modal regimen integrating
surgical resection with concurrent chemotherapy and radiation (CT/RT) in
non-small-cell lung cancer (NSCLC) continued to show benefits in an updated
analysis of Intergroup Trial 0139 presented at the 10th World Conference on
Lung Cancer plenary session (abstract PL-4). Kathy Albain, MD, who gave the
initial report at ASCO 2003 (abstract 2497), presented the updated results.
"With further follow-up, the significant difference in
progression-free survival is still very solid. There is no weakening of the
strength of the data at this point," said Dr. Albain, of Loyola University
of Chicago’s Cardinal Bernardin Cancer Center.
Surgical resection has yielded encouraging results in
patients with stage IIIA NSCLC and pathologically confirmed N2 nodes (pN2), but
due to increased mortality and morbidity associated with surgery, CT/RT is the
standard of care. Intergroup Trial 1039 was designed to test the value of
resection after induction CT/RT vs full-course CT/RT therapy, in 429 patients
with T1-3, pN2, M0 tumors.
All patients had induction chemoradiation with two cycles
of cisplatin (Platinol) and etoposide and daily radiation to 45 Gy, then were
randomized to either surgical resection (surgery arm) if disease progression
had not occurred or uninterrupted radiotherapy to 61 Gy (CT/RT arm), each
followed by two more courses of chemotherapy.
The median follow-up in this report was 71 months, which
represented an additional 8 months beyond the 63-month data reported at ASCO.
The analysis yielded updated disease-free and overall survival, a new Cox
multivariate model, and revised patterns of failure in 392 evaluable patients
(n = 201 surgery arm; n = 191 CT/RT arm).
Induction chemotherapy was delivered per protocol in 95% to
96% of patients in both arms. Significantly more patients in the surgery arm
did not receive consolidation chemotherapy (42% vs 21%), but RT was delivered
per protocol in significantly more patients in the surgery arm (97% vs 81%).
Toxicities were similar, although more patients died on the
surgery arm. The only difference in grade 3-4 toxicity was more esophagitis in
the CT/RT arm (20% vs 9%). Three deaths occurred on the CT/RT arm during or
after consolidation. In the surgery arm, 14 patients died (10 of postoperative
complications). Twelve deaths followed pneumonectomy, 8 of which were from
acute respiratory distress syndrome.
Updated Survival Analysis
Progression-free survival (PFS) was significantly better for
patients in the surgical arm (P = .03). Median PFS was 13.4 vs 11.8 months, and
3-year PFS was estimated at 28% vs 19% for surgery vs CT/RT, respectively.
Median overall survival was 22 months vs 22.3 months, and 3-year survival was
37% and 34%, respectively, Dr. Albain reported. "The hazard ratios crossed
due to treatment-related deaths for both PFS and overall survival, and the
log-rank P value was not significant," she said.
While early survival favors the CT/RT arm, the curves
superimpose, then cross, and begin to separate at the median survival point of
22 months, she said. By year 3, there is an absolute survival benefit of 3%
favoring the surgery arm, for a 10% proportional risk reduction. However,
confidence intervals are wide and overlap at this point of follow-up. In the
surgical arm, more patients are alive without progression (P = .004),
and more died without progression (P = .007).
"Very little change has occurred in the outcome
endpoints since the ASCO 2003 analysis," she noted. "Progression-free
survival remains significant in favor of surgery, with no difference in overall
survival. The absolute survival improvement with surgery at 3 years is still
small. There is no change in the greater number of patients alive without
progression with surgery, and in the fewer number who died without progression
Patterns of Failure
Overall patterns of failure were still similar between arms.
There was a trend for greater local relapse with CT/RT in the primary site,
nodes, and both (17% with surgery vs 26% with CT/RT; P = .08). The
updated Cox multivariate model for overall survival found the significant
independent predictors of poor outcome to be higher T stage, weight loss less
than 5%, and older age. Performance status and tumor size did not prove
In the analysis of overall survival according to interim
pathologic response data, N0 status continued to predict improved outcome
whether or not there was residual primary tumor. Patients who were T0, N0
(pathological complete response) had a median survival of 36.7 months and a
3-year survival of 52%. Patients who were T0-1, N0 had a median survival of
36.7 months and a 53%
"Progression-free survival is superior for the
trimodality arm with an apparent plateau, but overall survival does not appear
to be statistically different. It is uncertain whether the plateau in median
survival will translate into improved overall survival with longer
follow-up," Dr. Albain concluded.
Discussant Harvey Pass, MD, professor of surgery and
oncology, Karmanos Cancer Institute, Detroit, called Intergroup 0139 "the
most anticipated randomized trial in lung cancer for a long time. It is a
standard for randomized trials in induction therapy and serves as a springboard
for trials we need to plan for the future."
He said that the study confirmed phase II trials showing
that full doses of cisplatin/etoposide could be delivered with radiotherapy and
that pathologic complete responses could be achieved in 18%. "The most
intriguing part of the trial is that downstaging of N2 disease to N0 will occur
in 46% to 48% of patients, and 3-year survival of this group is a phenomenal
53%, which is even better than the 44% we achieved in SWOG 8805," he said.
[In SWOG 8805, 126 patients with pathologically staged IIIA/IIIB disease
received cisplatin plus etoposide concurrent with radiation therapy followed by
Dr. Pass said that results in the surgery arm
"re-amplified the importance of nodal clearance on survival." The
findings do not demonstrate that "everybody should get surgery after
induction," but point to the need to determine which patients will have
nodal downstaging by any induction method. To accomplish this, he said, pre-
and postinduction PET scanning should be used in future trials.
The study still leaves unanswered several questions, such as
whether the N2 downstaging is due to the radiotherapy, the chemotherapy, or the
combination, and what contribution surgery really is making to the outcome.
These questions are difficult because of the heterogeneity of the N2
population, and future studies should stratify these patients, he said.