Cancer Treatment Communications 5 (2016) 22–25

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Cancer Treatment Communications

journal homepage: www.elsevier.com/locate/ctrc

Resection is safe for patients with stage IIIA NSCLC undergoing

multimodality therapy
Entela B. Lushaj, Walker Julliard, Traci Bretl, Abbasali Badami, Ryan Macke, Justin Blasberg,
James Maloney n
Division of Cardiothoracic Surgery, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, CSC Madison, WI 53792, United States

art ic l e i nf o a b s t r a c t

Article history: Background: Controversy continues regarding the optimal therapy for stage IIIA non-small cell lung
Received 1 September 2015 cancer (NSCLC). Improved survival has been shown in patients undergoing multimodality therapy that
Received in revised form includes surgical intervention.
7 December 2015
Methods: Stage IIIA NSCLC demographics, post-treatment survival, complications and survival rates were
Accepted 17 December 2015
compared with stage I and stage II NSCLC.
Results: Mean age for patients from all groups was over 60 years (p¼0.66). They had similar BMI
Keywords: (p¼ 0.35) and the majority of the patients in all groups were females (p¼ 0.51). Lobectomy was the most
Lung used procedure in all three groups; 93% in patients with stage I NSCLC, 73% and 76% in patients with
Cancer
stage II and IIIA, respectively (po0.001). Video-assisted thoracoscopic surgery (VATS) was used in 69% of
Surgery
lobectomies in patients with stage I NSCLC, 37% in stage II and 65% of lobectomies in patients with IIIA
Stage IIIA
NSCLC (p o0.001). More stage IIIA patients had prolonged ventilation ( 424 h; 3%) than patients in stage
I (o 1%) and stage II (0%; p ¼0.032). Median hospital length of stay was 3 days for stage II and IIIA
patients and 2 days for patients with stage I (po 0.001). Overall survival rate for stage IIIA patients at 1-,
3- and 5-years was 85%, 55% and 48%, respectively.
Conclusions: Pulmonary resection as an initial therapy or following neoadjuvant radiation and che-
motherapy is safe for patients with stage IIIA NSCLC. Locally advanced disease does not confer increased
risk of perioperative morbidity or mortality in our study population.
& 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction cancer. Furthermore, there is a theoretical increase in risk of sur-

Lung cancer remains the number one cause of cancer mortality
among both men and women worldwide [1]. The majority of lung
cancer patients treated with surgical resection have stage I/II non-
small cell lung cancer (NSCLC) [2]. Stage IIIA lung cancer re-
presents a locally advanced form of lung cancer that is difficult to
successfully treat and is a heterogeneous group of cancer pheno-
types. Given the amount of local invasion and possible mediastinal
involvement, traditional approaches to treatment of IIIA lung
cancer involved definitive chemoradiotherapy [3,4] without sur-
gical resection. Due to poor survival and high local recurrence
rates, a trimodality approach of chemotherapy, radiation therapy,
and surgery was adopted [5–8]. However, there has been poor
acceptance of surgical resection in stage IIIA lung cancer world-
wide [9]. This is due in part to the limited number of studies that
have evaluated the role of surgical resection in stage IIIA lung
n
Corresponding author.
E-mail address: maloney@surgery.wisc.edu (J. Maloney).
gery in patients with locally advanced cancer.
In an effort to assess the risk benefit ratio for long term sur-
vival, here we examine whether surgical resection could be safely
performed in IIIA NSCLC patients. To this end, a prospectively
collected database was analyzed and retrospectively reviewed.
2. Methods
We retrospectively reviewed prospectively collected institu-
tional Society of Thoracic Surgeons (STS) data of all consecutive
patients who were treated at our institution for stage I, II or IIIA
(7th edition [10]) non-small cell lung cancer (NSCLC) between 01/
2007 and 12/2014. Demographics, complications and post-treat-
ment survival rates were assessed. Survival was calculated from
the date of surgery. PET/CT and brain MRI were used for clinical
staging. PET/CT and brain MRI findings were confirmed with EBUS,
mediastinoscopy or VATS staging. The presence of limited, non-
bulky N2 disease did not necessarily alter therapy in patients we
thought were appropriate for surgical resection followed by

http://dx.doi.org/10.1016/j.ctrc.2015.12.002
2213-0896/& 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 E.B. Lushaj et al. / Cancer Treatment Communications 5 (2016) 22–25 23

adjuvant therapy. A multidisciplinary decision (surgery, oncology
and radiation oncology) was involved in decision making pre-
operatively for surgical treatment of IIIA patients. Surgery was
advocated in patients with a single or 2 station non-bulky ade-
nopathy. Surgery was not considered in patients with bulky multi-
station adenopathy. Performance status of the patient was also
taken into consideration in decision making. The concern was to
give less than definitive chemo-radiation with induction therapy
when intended surgery is no longer therapeutically possible be-
cause of performance status or failure to respond. This study was
approved by our Institutional Review Board. A waiver of the need
to obtain consent from unidentified patients was approved.
2.1. Statistical analysis
Continuous variables are represented as mean 7standard de-
viation, and categorical variables are represented as number and
percentage. Continuous variables were compared using t-test.
Categorical variables were compared using the chi-square test. The
Kaplan-Meier survival method was used to assess overall survival.
Log-rank tests were used to assess statistical significance in sur-
vival differences between the groups. All analyses were performed
using the IBM SPSS statistical software program (IBM SPSS Sta-
tistics for Windows, Version 21.0. Armonk, NY: IBM Corp).
3. Results
3.1. Demographic profiles
Between 01/2007 and 12/2014, 240 patients were diagnosed
with clinical stage I NSCLC, 71 patients were diagnosed with
clinical stage II and 119 with clinical stage IIIA NSCLC, who un-
derwent surgical intervention, at our institution. A detailed de-
scription of the type of stage IIIA disease is shown in Table 1
supplement. Median follow-up time was 23 months (interquartile
range (IQR) 10, 54 months) from date of surgery for all stage
groups. Preoperative patient characteristics of patients with stage
I, II and IIIA are shown in Table 1. Mean age for patients from all
groups was over 60 years (p ¼0.66). No difference was seen in
their BMI (p ¼0.35) and the majority of the patients in all groups
were females (p ¼0.51). No difference was seen in the forced ex-
piratory volume (FEV1) predicted (p ¼0.23) between all groups.
Patients with stage I and IIIA had a significantly lower FEV1 actual
when compared to patients with stage II NSCLC (p ¼0.001).
Table 1
Pre-operative patient demographics.
Patients with stage IIIA had a significantly higher diffusing capa-
city of the lungs for carbon monoxide (DLCO) than patients with
stage I and II (p ¼0.002). Lobectomy was the most used procedure
in all three groups; 93% in patients with stage I NSCLC, 73% and
76% in patients with stage II and IIIA, respectively (po 0.001; Ta-
ble 1). Video-assisted thoracoscopic surgery (VATS) was used in
69% of lobectomies in patients with stage I NSCLC, 37% in stage II
and 45% of lobectomies in patients with IIIA NSCLC (p o0.001;
Table 1).
Of all clinical stage IIIA NSCLC patients, 106 (89%) patients re-
ceived adjuvant therapy (i.e. treatment with surgery as their initial
intervention followed by chemotherapy and/or radiation therapy
in any sequence) and 13 (11%) patients received neoadjuvant
therapy, (i.e. treatment with chemotherapy and/or radiation
therapy in any sequence followed by surgery. Preoperative patient
characteristics of these 2 groups are shown in Table 2
supplement).
3.2. Clinical outcomes and post-op complications
More stage IIIA patients had prolonged ventilation ( 424 h; 3%)
than stage I (o 1%) and stage II (0%; p ¼0.032; Table 2). No dif-
ference was found in reintubation rate, prolonged (4 5 days) air
leak, reoperation rate, pneumonia, urinary tract infections and the
occurrence of any cardiac events post-operatively (p 40.05; Ta-
ble 2). No difference was found in hospital readmission and 30-day
survival rates between the groups (p4 0.05). Median hospital
length of stay was 2 days for patients with stage I and 3 days for
stage II and IIIA patients (p o0.001; Table 2). No difference was
found in clinical outcomes and post-op complications between
patients receiving adjuvant and neoadjuvant therapy (Table 3
supplement).
3.3. Post treatment survival
Patients were monitored for 5 years or until death. Overall survival
rate for stage IIIA patients at 1-, 3- and 5-years was 85%, 58% and 48%
(Fig. 1). When divided by surgery type, overall survival was 85%, 58%
and 50% at 1-, 3- and 5-years, respectively for patients undergoing
lobectomy and 86%, 58% and 43% at 1-, 3- and 5-years, respectively for
patients undergoing pneumonectomy (p¼ 0.58; Fig. 2).
4. Discussion
The main goal of our study was to assess the impact of locally
advanced lung cancer on post-operative outcomes based on STS

Stage I Stage II Stage IIIA p-Value Table 2

(n ¼240) (n¼ 71) (n¼119) Post-operative outcomes and 30-day complications.

Demographics Stage I Stage II Stage IIIA p-Value

Mean age (yr) 66 7 11 65 7 10 657 11 0.66 (n¼ 240) (n¼ 71) (n ¼119)
Female gender (%) 160 (67%) 45 (63%) 70 (59%) 0.51
BMI 287 7 27 7 7 277 6 0.35 Prolonged ventilation 1 ( o 1%) 0 3 (3%) 0.099
FEV1 predicted (%) 857 22 81 7 25 877 22 0.23 Reintubation 1 ( o 1%) 2 (3%) 4 (3%) 0.079
DLCO predicted (%) 677 18 66 7 20 757 22 0.002* ADRS 0 0 0
Air leak 45 days 12 (5%) 7 (10%) 11 (9%) 0.19
Cardiac Event 12 (5%) 5 (7%) 11 (9%) 0.30
Primary procedure UTI 7 (3%) 2 (3%) 3 (2.5%) 0.97
Lobectomy (%) 223 (93%) 52 (73%) 91 (76%) o 0.001* Reoperation 14 (6%) 2 (3%) 7 (6%) 0.58
VATS (%) 154 (69%) 19 (37%) 59 (65%) o 0.001* 30-day readmission 16 (7%) 6 (8%) 5 (4%) 0.47
Pneumonectomy (%) 12 (5%) 19 (27%) 25 (21%) o 0.001* 30-day mortality 1 (0.4%) 0 0 0.67
Segmentectomy (%) 5 (2%) 0 5 (4%) 0.065 Hospital LOS (days) 2 (2, 4) 3 (2, 4) 3 (2, 4) o 0.001*

Values are n (%) or median (interquartile range). ADRS – acute respiratory distress Values are n (%) or median (interquartile range). ADRS – acute respiratory distress
syndrome; LOS – length of stay. FEV1 and DLCO predicted are the % predicted syndrome; Cardiac event – ventricular arrhythmias, atrial arrhythmias, other car-
values which take into account height, weight and gender. diac event; LOS-length of stay.
* *
Statistically significant associations (p o 0.05). Statistically significant associations (po 0.05).
24 E.B. Lushaj et al. / Cancer Treatment Communications 5 (2016) 22–25
Fig. 1. Kaplan–Meier analysis for overall survival for patients with stage IIIA NSCLC.
Fig. 2. Kaplan–Meier survival of patients with stage IIIA NSCLC undergoing lo-
bectomy or pneumonectomy. Pneum – pneumonectomies.
criteria. We sought to demonstrate that by STS standards, surgery
in the setting of locally advance disease does not confer a sub-
stantial increase in morbidity or mortality compared to earlier
stages of disease. A comparison to surgery alone is inaccurate as
we can all agree that multimodality therapy is better than single
modality. This is important for patients who have received
neoadjuvant therapy and imperative if we are trying to move pa-
tients quickly to adjuvant therapy. We also want to start the dis-
cussion as to whether the best sequence of multimodality therapy
is known.
We found low complication rates and high survival rates in
patients with clinical stage IIIA NSCLC, treated surgically, regard-
less of sequencing of multimodality treatment. There was a
slightly higher rate of prolonged ventilation in the stage IIIA group.
Hospital length of stay was similar to stage II group. There was no
difference in 30-day mortality or other significant post-operative
complications.
There has been constant controversy with regards to the opti-
mal treatment of stage IIIA NSCLC. This controversy stems from
conflicting results in a few existing studies and a lack of definitive
randomized trials examining the role of surgery in stage IIIA
NSCLC. Van Meerbeeck and colleagues [11] reported no difference
in long-term survival between patients treated with definitive
chemoradiation and those treated with tri-modality therapy. This
was attributed to early postoperative deaths as long-term survival
was equivalent between treatments. This study had a very high
number of patients undergoing pneumonectomy (47%), who were
found to have significantly increased early and late mortality
compared to lobectomy patients. In another randomized trial from
2008 [5], patients were treated with chemoradiation alone or
neoadjuvant chemoradiation followed by surgery. Initial analysis
demonstrated increased disease free survival in the surgery group,
although overall survival was no different between the two
treatment arms. When patients were stratified into groups based
on either lobectomy or pneumonectomy, there was a significant
increase in survival in lobectomy patients over chemoradiotherapy
alone. This was not observed in the pneumonectomy group. Koshy
and colleagues [12] in a national cancer database review demon-
strated improved survival in patients undergoing surgery as
compared to chemoradiation alone. Despite these three studies,
and other single institution series that suggest a survival benefit in
patients treated with lobectomy in addition to chemoradiation,
current recommendations for the treatment of IIIA NSCLC do not
suggest that tri-modality therapy is superior to definitive che-
moradiation [13].
Practitioners remain slow to incorporate surgery into the
treatment of most patients with IIIA. In a survey of thoracic sur-
geons from 2012, participants were given various scenarios re-
garding the treatment of IIIA patients [9]. In this study, there was
poor consensus between practicing thoracic surgeons on how to
proceed with treatment in IIIA disease, and up to 18% of re-
sponders did not believe surgery should be offered to patients who
had N2 disease and required lobectomy. Another study examining
the changes in surgical resection rates in Medicare lung cancer
patients found further results suggesting that adoption of surgery
in IIIA remains poor [14] with only approximately 20% of patients
with IIIA undergoing surgical resection, down from over 30% in the
early 1990s. Finally, in a retrospective study Cerfolio and collea-
gues [8] found that of patients beginning neoadjuvant therapy,
only 28% actually go on for complete surgical resection and that
patients who underwent resection had significantly improved
survival. It seems that much of the reluctance to adopt surgery in
the treatment of IIIA patients has to do with the worry of increased
complications and early mortality compared to chemoradiation.
However, as prior studies have demonstrated, much of this mor-
bidity lies within patients treated with pneumonectomy (STS na-
tional data shows 5.9% 30-day mortality post-pneumonectomy).
Pneumonectomies were performed in 21% of our patients with
stage IIIA NSCLC (38% of them had neoadjuvant and 18% had sur-
gery plus adjuvant therapy). 30 day mortality in both groups was
zero. We make every effort to limit resection to lobectomy or bi-
lobectomy and utilize techniques such as sleeve resections. It is
our opinion that sleeve resection to spare parenchyma is far more
challenging in the setting of neoadjuvant radiation. If pneumo-
nectomy is indicated oncologically and the patients’ lung and right
heart function supports it, we do not hesitate to perform
pneumonectomy.
In our study, 23% of our IIIA study population received radia-
tion; in 48% of them radiation was given preoperatetively and in
52% it was given adjuvantly. All our IIIA patients are seen in clinic
by radiation oncologists. We are excited to see the results of the
Lung Art trial comparing post-operative conformal radiotherapy to
no post-operative radiotherapy in patients with completely re-
sected non-small cell lung cancer and mediastinal N2 involvement
[15]. Currently we are considering PORT in all patients with IIIA
disease who have elected for surgery first.
The main limitations of this study include its retrospective
nonrandomized design, analysis of limited number of patients
from a single institution, data collection restricted to the variables
which were available in electronic medical records. In addition,
details about the regimens of chemotherapy or radiation, or
 E.B. Lushaj et al. / Cancer Treatment Communications 5 (2016) 22–25
completeness of therapy that may expose differences in the im-
plementation of induction therapy among participating centers
were unavailable.
Based on our data, we believe that pulmonary resection is safe
for patients with stage IIIA NSCLC and concerns regarding theo-
retical increased peri-operative morbidity should not stop practi-
tioners from adopting trimodality therapy as the standard of care.
Disclosure statement
This work was funded by the University of Wisconsin, De-
partment of Surgery. None of the authors have a financial re-
lationship with a commercial entity that has an interest in the
subject of the presented manuscript or other conflict of interest to
disclose.
Appendix A. Supplementary material
Supplementary data associated with this article can be found in
the online version at http://dx.doi.org/10.1016/j.ctrc.2015.12.002.
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