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NEOADJUVANT AND ADJUVANT TREATMENT STRATEGIES
Management of the subset of patients with locally advanced NSCLC remains difficult given their
heterogenous presentations and lack of clear consensus regarding optimal management. Additionally,
important distinction should be made between those for whom medical therapy is definitive compared to
those considered for surgical resection. Finally, those found to have occult N2 disease following surgery
represent a unique treatment dilemma. Current treatment modalities include chemotherapy, radiation,
surgery, and immunotherapy with the recent introduction of immune checkpoint inhibitors such as PD-
(L)-1 inhibitors. Given the complexity of treatment, a multidisciplinary plan is preferred to optimize care.

Unresectable NSCLC
For unresectable NSCLC as defined by unresectable, node-positive Stage II and Stage III or greater, initial
therapy has previously been chemoradiation alone with the American Society of Clinical Oncology
endorsing the American Society for Radiation Oncology Evidence-Based Clinical Practice Guidelines
[10]
which recommend concurrent chemoradiotherapy . In the past decade, attention has turned to the
use of targeted immune therapy as an alternative or in addition to chemotherapy. To date, targeted
immunotherapy (excluding check-point inhibitor) has not been shown to improve overall survival in phase
[12]
III trials for locally advanced NSCLC including most notably the START trial and INSPIRE trial for
[11]
unresectable NSCLC.
Immune checkpoint inhibitors of PD-(L)1 have shown promising results in management of NSCLC. The
recent PACIFIC randomized control trial demonstrated that Stage IIIA patients unable to undergo surgery
had not only improved progression free survival (23.2 months vs. 14.6 months with placebo; P < 0.001), but
also overall survival as high as 66% at 24 months with chemoradiation therapy followed by immunotherapy
(durvalumab) as compared to chemoradiation alone [13,14] . Currently, the NCCN recommends this treatment
[4]
algorithm as standard of care in unresectable disease .

Resectable NSCLC
For potentially resectable NSCLC, the consensus is less clear. All guidelines agree that surgical treatment
alone for IIIA NSCLC continues to have a poor 5-year survival and unimodality therapy is not
recommended. These findings were demonstrated by two landmark randomized control trials (RCTs),
now over two decades old, which demonstrated that the addition of induction chemotherapy to surgery
improved overall survival and disease-free survival (median survival 26 months vs. 8 months and median
disease-free survival 20 months vs. 5 months for chemotherapy plus surgery compared to surgery alone,
which established the standard of care; P < 0.001) in Stage III NSCLC patients [15,16] .

Historically, the most debated topic has been the role of surgery in the management of this subset of Stage
III lung cancer, IIIA. Initial RCTs such as Intergroup 0139 trial, which enrolled over 400 patients with Stage
IIIA NSCLC due to N2 disease to either chemoradiotherapy or surgery, found surgery was not associated
with an improvement in overall survival [5-year survival rate, 27% vs. 20%; odds ratio (OR) 0.63; 95%CI:
0.36-1.10]. The intergroup 0139 trial did however find a sevenfold increase in the control of the primary
tumors and an improvement in 5-year progression-free survival (PFS, 22% vs. 11%). Of note, in this study,
survival was impacted by the high rate of pneumonectomies but there was a clear survival with benefit with
[17]
surgery for patients requiring lobectomy . At the same time, the EORTC 08941 study found no difference
[18]
in overall survival in those who received surgery or radiation following induction chemotherapy . The
latter study was limited as it only enrolled patients with unresectable disease and the rate of incomplete
resection was greater than 50%. Most recently, the ESPATUE trial found in IIIA (N2 disease) that 5-year
overall survival and progression free survival were equivalent in those who received surgery versus
[19]
definitive chemoradiotherapy following induction therapy . In those patients identified as having N2
disease intraoperatively, current NCCN guidelines suggest that those with negative preoperative nodes with