Introduction
Recently, there has been increasing evidence for the use of neo-adjuvant chemoimmunotherapy
in patients with resectable lung cancer. We aimed to analyze the pneumonectomy rates
in the recently published phase 3 trials (including CM 816, KN 671, AEGEAN, and NEO-TORCH)[1]
[2]
[3]
[4] in patients with resectable NSCLC and compare them with historical data. In this
paper, we highlight the changing total surgical and pneumonectomy rates in the era
of chemo-immunotherapy in resectable nonsmall cell lung cancer (NSCLC) patients.
Materials and Methods
We aimed to analyze the pneumonectomy rates in the recently published phase 3 trials
in patients with resectable NSCLC and compare them with historical data. Pneumonectomy
rates were collected from published or presented trials including CM 816, KN 671,
AEGEAN, and NEO-TORCH. These trials enrolled patients with stage II and stage III
disease except for CM 816 which also included stage IB patients. All four trials have
used different immunotherapies.
Results and Discussion
These trials report that neoadjuvant chemoimmunotherapy resulted in longer event-free
survival (EFS) than chemotherapy in resectable NSCLC. The benefit of EFS was pronounced
especially in the Stage IIIA group according to the CM-816 trial.[1] Historically, Felip et al have reported a total surgical resection rate of 91% with
pneumonectomy rates of 23.2% in the preoperative chemotherapy arm of a landmark phase
III study of neoadjuvant versus adjuvant chemotherapy in early-stage NSCLC.[5] Of note, this study included clinical stage IA, IB, II, or T3N1 disease. Similarly,
Scagliotti et al reported a total surgical resection rate of 85.3% and pneumonectomy
rates of 15.45% in the chemotherapy plus surgery arm of a phase III study of surgery
alone or surgery plus preoperative chemotherapy.[6] In this study, stages IB to IIIA NSCLC were included. While challenges in surgical
operability for lung cancer are easier to understand with patient comorbidities like
advanced heart failure or extremely poor pulmonary function prohibiting an operation;
surgical resectability of lung cancer is more ambiguous usually based on the particular
surgeon the patient is seeing. In general, surgeons shy away from surgical resection
in patients with bulky or multi-station N2 disease as an R0 resection is paramount.
As all of the neoadjuvant chemoimmunotherapy studies enrolled stage IIIA patients
who were evaluated to be amenable to surgery, direct comparisons to surveillance,
epidemiology, and end results (SEER) data[7] cannot be performed. Analysis from the SEER database[7] shows that surgery was not recommended in 65% and was actually performed in only
25% of 22,558 stage IIIA NSCLC cases (10% did not undergo surgery due to patient preference,
stage migration, or co-morbidities). This practice rests on the INT-0139 trial which
showed no survival benefit from the addition of surgery to chemoradiation.[8]
When surgeons are faced with performing a pneumonectomy, an R0 resection is not the
only consideration. There are acute changes in the postoperative setting which can
be challenging, and there are long-term cardiovascular and respiratory changes that
affect survival when compared with lobectomy.[9] While the overall pneumonectomy rates were lower in the four neoadjuvant chemo-immunotherapy
studies (11.2% in the chemo-immunotherapy arm and 12.8% in the chemotherapy arm) compared
with historical data, these numbers are not negligible ([Fig. 1]). It is important to be reminded that the control arm of all four neoadjuvant chemo-immunotherapy
trials was chemotherapy and not chemoradiation. This suggests that there may be a
fair number of cases that would be left with reduced lung function when compelling
data from the PACIFIC trial[10] has matured with an estimated 42.9% of patients randomly assigned to durvalumab
remaining alive at 5 years versus 33.4% of patients randomly assigned to placebo remain
alive and free of disease progression, establishing a new benchmark for the standard
of care in this setting. However, the PACIFIC trial only included patients who were
inoperable or not amenable to surgical resection. Adding to this, if patients are
deemed to be unresectable after chemo-immunotherapy, they will be subjected to radiation
therapy. Thus, a trial comparing overall survival and quality-of-life between definitive
chemoradiation and neoadjuvant chemoimmunotherapy is warranted especially for those
patients where pneumonectomy could be required for an R0 resection. Furthermore, Stage
3A is heterogeneous (T4N0, T3-T4N1, T1-T2N1, T1-T2N2). Reporting surgical/survival
data by nodal status would also clarify the evolving role of surgery in the advent
of immunotherapy in the nonmetastatic setting.
Fig. 1 Flow diagram showing total surgical rates and pneumonectomy rates in the chemotherapy
plus immunotherapy arm versus chemotherapy plus placebo arm.
