NcXHF

SURGICAL MANAGEMENT OF STAGE IIIA NON–SMALL CELL LUNG CANCER
atrium, or diaphragm when we believe we can perform an R0
resection. Patients with extensive T4 tumors in whom a
complete resection is unlikely are generally poor surgical
candidates. All of these treatment decisions are made as
part of a multidisciplinary care team discussion and with
the agreement of our thoracic oncologists and radiation
oncologists.
MANAGEMENT OF STAGE IIIA WITH N2
MEDIASTINAL INVOLVEMENT
Patients with stage IIIA disease and N2 lymph node involvement
range from those with small tumor foci in a central
node to those with bulky multi-station disease who, therefore,
pose the greatest treatment challenge for thoracic oncologists.
The nature of mediastinal disease portends bad
outcomes and possible microscopically systemic, stage IV
disease. However within this group, surgery can provide defınitive
local control and lead to long-term survival for some
patients. Randomized, controlled trials to evaluate the value
of surgery in N2 disease have been continually plagued by
enrollment diffıculties and many have closed prematurely. In
addition, they have been affected over time by changes in
staging criteria, evolving induction chemotherapy and radiation
trends, and the development of novel chemotherapy
agents.
Early clinical trials, such as the Southwest Oncology Group
(SWOG) 8805 study, demonstrated that patients with initially
unresectable NSCLC could have their tumors downstaged
with induction chemoradiation and ultimately
undergo successful surgical resection. In this trial, patients
whose tumors did not respond to induction treatment or had
positive margins or nodes in the surgical specimen were
given additional chemotherapy and radiation. Patients who
underwent surgery had a median overall survival of 23.6
months versus 22.2 months among patients who only received
chemotherapy and radiation. The 3-year overall survival
with triple-modality treatment was 27% versus 20% in
the chemotherapy and radiation group, respectively. Patients
whose tumors were downstaged to N0 disease after induction
chemoradiation had the best outcomes, with triple-modality
treatment with a 3-year survival rate of 44%. Collectively,
these outcomes demonstrated that a triple-modality treatment
approach was not worse than chemotherapy and radiation
alone and, in certain subgroups of patients, led to
improved survival outcomes.
More recently, two large, randomized clinical trials have
examined the benefıts of surgery in patients with stage IIIA,
N2 NSCLC: the European Organization for Research and
Treatment of Cancer (EORTC) 8941 trial and the North
American Intergroup (INT) 0139 trial. EORTC 8941 compared
surgery and radiation therapy in patients with stage
IIIA N2 disease who responded to induction chemotherapy.
Of 579 enrolled patients, 61% responded to three cycles of
platinum-based induction chemotherapy and, therefore,
were randomly assigned to either radiotherapy or surgery. A
complete surgical resection was achieved in 50% of patients
randomly assigned to surgery. Pneumonectomy was required
in 47% of patients, and the overall operative mortality
rate was 4%. Adjuvant radiotherapy was given to 40% of patients
after surgery. There were no differences in survival between
patients who underwent a surgical resection or
radiotherapy, with a median survival of 16.4 months versus
17.5 months, respectively, and a 5-year overall survival rate of
15.7% and 14.0%, respectively. 12 This trial has been criticized
for inadequate clinical staging, without PET/CT or brain
MRI, which likely led to the inclusion of some patients with
later-stage IIIB and IV disease. In addition, the study reported
a relatively low rate of a complete R0 surgical resection
and a high rate of pneumonectomy, which may reflect
the advanced disease in these patients and account for the
greater morbidity in the surgical arm of the study. 4
As data emerged that concurrent neoadjuvant chemotherapy
and radiation yielded better outcomes than sequential
administration, new randomized, controlled trials were designed
to defıne the role of surgical resections. INT 0139 involved
429 patients with pathologically proven stage IIIA N2
disease who were fırst treated with induction chemotherapy
plus radiation and then randomly assigned to surgery followed
by adjuvant chemotherapy or continued radiation, up
to 61 Gy, followed by more chemotherapy. A complete surgical
resection was achieved in 71% of patients randomly
assigned to surgery. Overall there were no differences between
patients who underwent a complete surgical resection
versus defınitive, full-dose radiation, with median overall
survival times of 23.6 months versus 22.2 months, respectively,
and 5-year survival rates of 27% and 20%, respectively.
However, PFS was signifıcantly improved with surgery (12.8
months vs. 10.5 months; p 0.017). Survival outcomes also
were signifıcantly better in the subgroup of patients whose
tumors were downstaged to N0 by induction chemotherapy,
with a median overall survival time of 34.4 months and a
5-year survival rate of 41% (p 0.0001). 13
Another large trial to include patients with stage IIIA disease
was the Adjuvant Navelbine International Trialist Association
(ANITA) trial, which demonstrated a survival benefıt
with adjuvant chemotherapy in patients who had stage IB to
IIIA, fully resected lung cancer. Among patients who received
adjuvant cisplatin-based chemotherapy and radiation
after surgery, there was a 5-year overall survival rate of 47%
among patients with N2 disease. 14 Similar outcomes have
been reported in single-institution, retrospective studies of
tri-modal therapy in patients with stage IIIA N2 disease. Askoxylakis
et al 15 reported a median survival time of 32
months and 1-, 3-, and 5-year survival rates of 85%, 50%, and
36%, respectively; 32% of patients who underwent an R0 resection
remained disease free at 5 years. 15
These clinical trials have consistently shown that certain
characteristics are good prognostic indicators in stage IIIA
N2 disease. A response to treatment or downstaging of the
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