Page 100 - Read Online

Page 4 of 10 Dolan et al. Mini-invasive Surg 2020;4:40 I http://dx.doi.org/10.20517/2574-1225.2020.17
[4]
one single positive node found at time of surgery are resectable candidates . However, the decision to stop
and proceed with neoadjuvant therapy upfront continues to be debated amongst clinicians.

The use of targeted immunotherapy as part of multimodality therapy with surgery is less well known.
The most recent systematic review of nine eligible trials (eight with surgically resected locally advanced
NSCLC) utilizing immunotherapy (excluding immune checkpoint inhibitors) totaling 4940 randomized
participants found no statistical survival benefit in overall survival in their pooled meta-analysis (HR =
0.94; 95%CI: 0.83-1.06; P = 0.35), and progression free survival (HR = 0.93; 95%CI: 0.81-1.07; P = 0.19;
high-quality) when compared to conventional therapy except for checkpoint inhibitors such as PD-(L)-1
[20]
inhibitors for which results are promising . Recently, R0 resection has been demonstrated as still being
possible in the majority of cases (95%) after immunotherapy, with two recent pilot studies demonstrating
no delay in surgery following neoadjuvant nivolumab [21-23] . Unfortunately, no RCT results are yet available
that have examined incorporation of immunotherapy with surgically resectable disease, with four studies
(NCT01857271, NCT02201992, NCT02347839, and NCT02595944) created to examine this question with
one trial [Erlotinib Hydrochloride Before Surgery In Treating Patients with Stage III Non-Small Cell Lung
Cancer (EVENT trial) NCT02347839] closed to poor accrual already (https://clinicaltrials.gov/ct2/show/
NCT02347839).

In terms of timing of therapy, current guidelines recommend neoadjuvant therapy followed by possible
[4]
surgery in the appropriate candidate for curative resection if N2 disease is recognized upfront .
Trimodality therapy, consisting of chemotherapy, radiation, and surgery, has been associated with improved
median survival and in certain cases has been shown to demonstrate a survival benefit even with Stage IIIB
[24]
disease (P < 0.001) and N3 (P = 0.010) in non-randomized trial . In this regard, one recent meta-analysis
by McElnay et al. demonstrated improved survival with neoadjuvant chemoradiation compared to
[25]
neoadjuvant chemotherapy alone prior to surgery (HR 0.87 vs. HR 1.1, although neither reached statistical
significance). However, one phase III trial found no survival benefit with induction chemoradiation
[26]
compared to induction chemotherapy alone followed by surgery . To date, there continues to be a lack of
consensus regarding utilization of trimodality therapy.

When examining forms of adjuvant therapy, the role of postoperative adjuvant radiation (PORT) is not
clear. Initial studies demonstrated a modest benefit in Stage IIIA disease with adjuvant radiation treatment
[27]
but had limited reduction in local recurrence or survival benefit in early stage disease . The ANITA
III trial is the only RCT to demonstrate increased survival in N2 disease with the addition of adjuvant
radiation to chemotherapy (median, 47 months if given radiation vs. 24 months in those without radiation
given adjuvant chemotherapy; 23 months vs. 13 months with or without adjuvant radiation in those not
[28]
given adjuvant chemotherapy) .
For those who may be candidates for adjuvant radiation, survival differences occur based on degree
[29]
of resection. In a non-clinical trial, PORT was associated with improved survival in R1 resection .
In contrast, a recent meta-analysis found patients treated with PORT have worse survival after R0
[30]
resection . Only one recent study noted a survival benefit in R0 patients if given sequentially following
[31]
chemoradiation, which has not yet been confirmed by RCT . The NCCN guidelines currently recommend
those found to have occult N2 disease after resection should either receive chemotherapy for R0 resection
or combined chemoradiation for R1 or R2 resection .
[4]

OPEN THORACOTOMY VS. MINIMALLY INVASIVE SURGERY FOR LOCALLY ADVANCED
DISEASE (INCLUDING ROBOTICS)
Thoracotomy has been the standard surgical approach to thoracic surgery, but the past 30 years has seen
the development of VATS. While this modality has been further advanced to include robotics, some