Background: Some non-small-cell lung cancer (NSCLC) patients are unexpectedly diagnosed with stage IIIA-N2 disease at the time of thoracoscopy or thoracotomy. Because of the limited statistical evidence of induction chemotherapy for these patients, it is necessary to develop more profound treatment strategies. Methods: The demographic and clinical characteristics of patients with stage IIIA-N2 NSCLC harboring epidermal growth factor receptor (EGFR) mutations after radical resection were retrospectively reviewed. The patients were divided into 3 groups based on treatment: EGFR tyrosine kinase inhibitors (EGFR-TKIs, erlotinib or gefitinib), adjuvant chemotherapy (docetaxel plus cisplatin), and combination treatment (chemotherapy plus EGFR-TKIs). The effect of adjuvant therapy on survival rate was assessed using univariate and Cox regression analyses. Results: Patients receiving EGFR-TKIs alone showed significantly improved disease-free survival (DFS; p = 0.025) when compared to those receiving chemotherapy alone. Compared to chemotherapy alone, the combination of chemotherapy and EGFR-TKIs resulted did not significantly improve DFS (p < 0.001) and overall survival (OS p < 0.001). The combination of EGFR-TKIs with chemotherapy as adjuvant therapy led to improvements in both DFS (p = 0.116) and OS (p = 0.039) compared to patients receiving a EGFR-TKI monotherapy. Toxicities were mild in the 3 treatment groups. Conclusions: Our study demonstrated that adjuvant EGFR-TKI treatment significantly increased the DFS of patients with stage IIIA-N2 NSCLC when compared with cisplatin-based chemotherapy. The use of EGFR-TKIs and chemotherapy is recommended in the setting of combined-modality therapy.

1.
Arriagada
R
,
Auperin
A
,
Burdett
S
,
Higgins
JP
,
Johnson
DH
,
Le Chevalier
T
, et al.;
NSCLC Meta-analyses Collaborative Group
.
Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data
.
Lancet
.
2010
Apr
;
375
(
9722
):
1267
77
.
[PubMed]
0140-6736
2.
Mountain
CF
.
Revision in the international system for staging lung cancer
.
Chest
.
1997
Jun
;
111
(
6
):
1710
7
.
[PubMed]
0012-3692
3.
Roth
JA
,
Atkinson
EN
,
Fossella
F
,
Komaki
R
,
Bernadette Ryan
M
,
Putnam
JB
Jr
, et al.
.
Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer
.
Lung Cancer
.
1998
Jul
;
21
(
1
):
1
6
.
[PubMed]
0169-5002
4.
NSCLC Meta-analysis Collaborative Group
.
Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data
.
Lancet
.
2014
May
;
383
(
9928
):
1561
71
.
[PubMed]
0140-6736
5.
Kawaguchi
K
,
Yokoi
K
,
Niwa
H
,
Ohde
Y
,
Mori
S
,
Okumura
S
, et al.;
Central Japan Lung Study Group
.
A prospective, multi-institutional phase II study of induction chemoradiotherapy followed by surgery in patients with non-small cell lung cancer involving the chest wall (CJLSG0801)
.
Lung Cancer
.
2017
Feb
;
104
:
79
84
.
[PubMed]
0169-5002
6.
Kim
HK
,
Choi
YS
,
Kim
J
,
Shim
YM
,
Kim
K
.
Outcomes of unexpected pathologic N1 and N2 disease after video-assisted thoracic surgery lobectomy for clinical stage I non-small cell lung cancer
.
J Thorac Cardiovasc Surg
.
2010
Dec
;
140
(
6
):
1288
93
.
[PubMed]
0022-5223
7.
Lee
DH
,
Kim
JB
,
Keum
DY
,
Hwang
I
,
Park
CK
.
Long term survival of patients with unsuspected n2 disease in non-small cell lung cancer
.
Korean J Thorac Cardiovasc Surg
.
2013
Feb
;
46
(
1
):
49
55
.
[PubMed]
2233-601X
8.
Nakanishi
R
,
Osaki
T
,
Nakanishi
K
,
Yoshino
I
,
Yoshimatsu
T
,
Watanabe
H
, et al.
.
Treatment strategy for patients with surgically discovered N2 stage IIIA non-small cell lung cancer
.
Ann Thorac Surg
.
1997
Aug
;
64
(
2
):
342
8
.
[PubMed]
0003-4975
9.
Obiols
C
,
Call
S
,
Rami-Porta
R
,
Trujillo-Reyes
JC
,
Saumench
R
,
Iglesias
M
, et al.
.
Survival of patients with unsuspected pN2 non-small cell lung cancer after an accurate preoperative mediastinal staging
.
Ann Thorac Surg
.
2014
Mar
;
97
(
3
):
957
64
.
[PubMed]
0003-4975
10.
Goldstraw
P
,
Crowley
J
,
Chansky
K
,
Giroux
DJ
,
Groome
PA
,
Rami-Porta
R
, et al.;
International Association for the Study of Lung Cancer International Staging Committee
;
Participating Institutions
.
The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours
.
J Thorac Oncol
.
2007
Aug
;
2
(
8
):
706
14
.
[PubMed]
1556-0864
11.
Yang
CF
,
Kumar
A
,
Gulack
BC
,
Mulvihill
MS
,
Hartwig
MG
,
Wang
X
, et al.
.
Long-term outcomes after lobectomy for non-small cell lung cancer when unsuspected pN2 disease is found: A National Cancer Data Base analysis
.
J Thorac Cardiovasc Surg
.
2016
May
;
151
(
5
):
1380
8
.
[PubMed]
0022-5223
12.
Detterbeck
F
.
What to do with “Surprise” N2?: intraoperative management of patients with non-small cell lung cancer
.
J Thorac Oncol
.
2008
Mar
;
3
(
3
):
289
302
.
[PubMed]
1556-0864
13.
Ettinger
DS
,
Aisner
DL
,
Wood
DE
,
Akerley
W
,
Bauman
J
,
Chang
JY
, et al.
.
NCCN Guidelines Insights: non-small cell lung cancer, version 5.2018
.
J Natl Compr Canc Netw
.
2018
Jul
;
16
(
7
):
807
21
.
[PubMed]
1540-1405
14.
Veeramachaneni
NK
,
Feins
RH
,
Stephenson
BJ
,
Edwards
LJ
,
Fernandez
FG
.
Management of stage IIIA non-small cell lung cancer by thoracic surgeons in North America
.
Ann Thorac Surg
.
2012
Sep
;
94
(
3
):
922
6
.
[PubMed]
0003-4975
15.
Lee
CK
,
Brown
C
,
Gralla
RJ
,
Hirsh
V
,
Thongprasert
S
,
Tsai
CM
, et al.
.
Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis
.
J Natl Cancer Inst
.
2013
May
;
105
(
9
):
595
605
.
[PubMed]
0027-8874
16.
Wu
YL
,
Zhou
C
,
Hu
CP
,
Feng
J
,
Lu
S
,
Huang
Y
, et al.
.
Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial
.
Lancet Oncol
.
2014
Feb
;
15
(
2
):
213
22
.
[PubMed]
1470-2045
17.
Mitsudomi
T
,
Morita
S
,
Yatabe
Y
,
Negoro
S
,
Okamoto
I
,
Tsurutani
J
, et al.;
West Japan Oncology Group
.
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial
.
Lancet Oncol
.
2010
Feb
;
11
(
2
):
121
8
.
[PubMed]
1470-2045
18.
Goss
GD
,
O’Callaghan
C
,
Lorimer
I
,
Tsao
MS
,
Masters
GA
,
Jett
J
, et al.
.
Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study
.
J Clin Oncol
.
2013
Sep
;
31
(
27
):
3320
6
.
[PubMed]
0732-183X
19.
Kelly
K
,
Altorki
NK
,
Eberhardt
WEE
,
O’Brien
MER
,
Spigel
DR
,
Crino
L
, et al.
A randomized, double-blind phase 3 trial of adjuvant erlotinib (E) versus placebo (P) following complete tumor resection with or without adjuvant chemotherapy in patients (pts) with stage IB-IIIA EGFR positive (IHC/FISH) non-small-cell lung cancer (NSCLC): RADIANT results. J Clin Oncol.
2014
; 32(15 suppl): abstr 7501.
20.
Zhong
WZ
,
Wang
Q
,
Mao
WM
,
Xu
ST
,
Wu
L
,
Shen
Y
, et al.;
ADJUVANT investigators
.
Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study
.
Lancet Oncol
.
2018
Jan
;
19
(
1
):
139
48
.
[PubMed]
1470-2045
21.
Kelly
K
,
Altorki
NK
,
Eberhardt
WE
,
O’Brien
ME
,
Spigel
DR
,
Crinò
L
, et al.
.
Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): A Randomized, Double-Blind, Phase III trial
.
J Clin Oncol
.
2015
Dec
;
33
(
34
):
4007
14
.
[PubMed]
0732-183X
22.
Pennell
NA
,
Neal
JW
,
Chaft
JE
,
Azzoli
CG
,
Janne
PA
,
Govindan
R
, et al.
SELECT: A multicenter phase II trial of adjuvant erlotinib in resected early-stage EGFR mutation-positive NSCLC (abstract 7501). J Clin Oncol.
2014
; 32 (15 suppl): abstr 7514.
23.
Yan
H
,
Li
Q
,
Wang
W
,
Zhen
H
,
Cao
B
.
Systems assessment of intercalated combination of chemotherapy and EGFR TKIs versus chemotherapy or EGFR TKIs alone in advanced NSCLC patients
.
Sci Rep
.
2015
Oct
;
5
(
1
):
15355
.
[PubMed]
2045-2322
24.
OuYang
PY
,
Su
Z
,
Mao
YP
,
Deng
W
,
Xie
FY
.
Combination of EGFR-TKIs and chemotherapy as first-line therapy for advanced NSCLC: a meta-analysis
.
PLoS One
.
2013
Nov
;
8
(
11
):
e79000
.
[PubMed]
1932-6203
25.
Li
N
,
Ou
W
,
Ye
X
,
Sun
HB
,
Zhang
L
,
Fang
Q
, et al.
.
Pemetrexed-carboplatin adjuvant chemotherapy with or without gefitinib in resected stage IIIA-N2 non-small cell lung cancer harbouring EGFR mutations: a randomized, phase II study
.
Ann Surg Oncol
.
2014
Jun
;
21
(
6
):
2091
6
.
[PubMed]
1068-9265
26.
Lim
SH
,
Lee
JY
,
Sun
JM
,
Ahn
JS
,
Park
K
,
Ahn
MJ
.
Comparison of clinical outcomes following gefitinib and erlotinib treatment in non-small-cell lung cancer patients harboring an epidermal growth factor receptor mutation in either exon 19 or 21
.
J Thorac Oncol
.
2014
Apr
;
9
(
4
):
506
11
.
[PubMed]
1556-0864
27.
Kim
ST
,
Lee
J
,
Kim
JH
,
Won
YW
,
Sun
JM
,
Yun
J
, et al.
.
Comparison of gefitinib versus erlotinib in patients with nonsmall cell lung cancer who failed previous chemotherapy
.
Cancer
.
2010
Jun
;
116
(
12
):
3025
33
.
[PubMed]
0008-543X
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