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Brief Report: Contralateral Lobectomy for Second Primary NSCLC: Perioperative and Long-Term Outcomes

Introduction Anatomical resection—often by lobectomy—is the standard of care for patients with early stage NSCLC. With increased diagnosis, survival, and prevalence of persons with early stage NSCLC, the incidence of second primary NSCLC, and consequently, the need for contralateral lobectomy for a metachronous cancer, is increasing. Perioperative outcomes after contralateral lobectomy are unknown. Methods Among patients who underwent contralateral lobectomy for second primary NSCLC during 1995 to 2020, we evaluated 90-day mortality and major morbidity (Clavien-Dindo grades 3–5) rates and their association with clinicopathologic variables, including the year of contralateral lobectomy and duration between lobectomies. Results A total of 98 patients underwent contralateral lobectomy for second primary NSCLC; 51 during an early time period (1995–2009) and 47 from a late time period (2010–2020). There were five mortalities and 23 patients with major morbidities after contralateral lobectomy; both rates decreased in 2010 to 2020 compared with 1995 to 2009 (mortality 10%–0%, major morbidity 35%–11%). Major morbidity was associated with an interval of less than 1 year between lobectomies, a diffusing capacity of the lung for carbon monoxide <80%, and right lower lobe resections. Mortality was associated with squamous cell carcinoma. Patients who underwent contralateral lobectomy for stage I NSCLC had 74% (95% confidence interval: 64%–85%) 3-year overall survival and 15% (95% confidence interval: 6.5%–24%) 3-year lung cancer cumulative incidence of death. Conclusions Contralateral lobectomy for second primary early stage NSCLC was associated with poor outcomes before 2010. Since 2010, perioperative and long-term outcomes of contralateral lobectomy have been comparable with reported outcomes after unilateral lobectomy.

Conclusions: Contralateral lobectomy for second primary early stage NSCLC was associated with poor outcomes before 2010. Since 2010, perioperative and long-term outcomes of contralateral lobectomy have been comparable with reported outcomes after unilateral lobectomy.

Introduction
Lung cancer mortality decreased from 55.8 to 33.4 per 100,000 during 2000 to 2019, predominantly due to a decrease in NSCLC mortality. Decreased NSCLC mortality is associated with stage shift in diagnosis; from 2006 to 2016, the proportion of stage I and II NSCLC diagnosis increased from 26.5% to 31.2%, and that of stage III and IV diagnosis decreased from 70.8% to 66.1%. 1 In addition to early stage diagnosis, 5-year relative survival among patients with localized disease increased from 52% to 59% from 2004 to 2013. 2 Consequently, the prevalence of NSCLC increased from 175.3 to 198.3 per 100,000 from 2010 to 2016. 3 With increased detection, survival, and prevalence of early stage NSCLC, there has been an expected increase in second primary NSCLC from surveillance and survivorship programs. We and others have reported an 11.6% to 13.5% incidence of second primary lung cancer among NSCLC survivors. [4][5][6] Anatomical resection-often by lobectomy-is the standard of care for early stage NSCLC. With an expected increase in second primary NSCLC amenable to resection, there is paucity of data on outcomes after second lobectomy.

Materials and Methods
After approval by the Institutional Review Board at Memorial Sloan Kettering Cancer Center, we conducted a retrospective investigation by review of a prospectively maintained database of all patients who underwent contralateral lobectomy for second primary NSCLC at the Memorial Sloan Kettering Cancer Center from January 1, 1995, to December 31, 2020. Diagnosis of second primary NSCLC rather than pulmonary metastases was confirmed by following an algorithmic approach (Supplementary Fig. 1).

Outcomes
The objective of this investigation was to determine the incidence of perioperative (90-d) mortality and morbidity according to the Clavien-Dindo classification, 7 after contralateral lobectomy for second primary NSCLC. Grades 3, 4, and 5 were considered major morbidities.

Statistical Analysis
The Wilcoxon ranked sum test, Pearson's chi-square test, and Fisher's exact test were used to compare clinical variables between early and late time periods and determine their associations with mortality and major morbidity. The Kaplan-Meier method was used to estimate overall survival (OS). The cumulative incidence rate was estimated for lung cancer-specific death, treating other causes of death as a competing event. Landmark survival analyses on morbidity grade were performed with the landmark time at day 90 after contralateral lobectomy using the log-rank test and Gray's test.

Variables Associated With Major Morbidity
When stratified by time between lobectomies, patients who underwent initial and contralateral lobectomies within one year had the highest incidence of mortality (9%); the incidence was 3% among patients with a time interval of 1 to 5 years and 4% among patients who underwent contralateral lobectomy more than five years after the initial lobectomy (Fig. 1C).
When stratified by anatomical location of the resected lobe, patients who underwent right lower lobe (RLL) resection during either lobectomy had the highest incidence of mortality (24%) after contralateral lobectomy (Fig. 1D).
When stratified by histology, patients who had squamous cell carcinoma (SCC) on initial lobectomy had the highest incidence of mortality (20%) after contralateral lobectomy; the incidence was 3% among patients
No association was observed between outcomes and FEV1 or percentage changes in DLCO or FEV1 from initial to contralateral lobectomy ( Supplementary  Fig. 2E-H) or receiving chemotherapy during initial lobectomy and experiencing major morbidity after contralateral lobectomy (Supplementary Fig. 2I).

Changes in Variables Between Time Periods
Among patients who had contralateral lobectomy within one year of initial lobectomy, all mortalities occurred in the early time period (Fig. 1E). Among patients who underwent RLL resection, all mortalities also occurred in the early time period (Fig. 1F). The proportion of patients with SCC on contralateral lobectomy decreased from early to late time period (25%-2%, p < 0.001; Supplementary Fig. 3A). Median DLCO increased from early to late time period. DLCO before contralateral lobectomy had a positive correlation with year across the study period (p ¼ 0.0048), whereas DLCO before initial lobectomy had no correlation with year (p ¼ 0.27; Supplementary Fig. 3B-E).

Characteristics of Patients Who Had Major Morbidities
Among the 18 patients who had grade 3 or 4 morbidities after contralateral lobectomy, DLCO value before contralateral lobectomy was available for 16 patients. Of 16 patients, 15 (94%) had DLCO less than 80% (Supplementary Fig. 4A).
Among the five mortalities, DLCO value before contralateral lobectomy was available for three patients. Three of three patients (100%) had DLCO less than 80%. Three of five patients (60%) underwent both lobectomies within 1 year. Four of the 10 resected lobes (40%) from initial and contralateral lobectomies were RLLs ( Supplementary Fig. 4B), and five of the 10 resected tumors (50%) had SCC histology ( Supplementary  Fig. 4C and D).

Discussion
At a time when there is an increase in the incidence of second primary lung cancer requiring contralateral lobectomy, there is an often held view among thoracic surgeons (unsupported by data) that a second lobectomy is equivalent to pneumonectomy with respect to perioperative outcomes. An investigation by Hattori et al. 8 reported high rates of in-hospital mortality (24%) and major morbidity (19%) in a cohort of 21 patients who underwent staged bilateral lobectomies for lung cancers from 1996 to 2012. Other studies that reported sequential resections included either lobar and sublobar or sublobar and sublobar resections or ipsilateral second lobectomies (Supplementary Table 5) 9,10 ; comparison across these studies is not feasible due to lack of uniform classification used to report outcomes. In our study, we excluded ipsilateral second lobectomies because they are feasible only for the right lung and would almost certainly involve a right middle lobectomy, which is anatomically very small; nevertheless, we report the 90day mortality of ipsilateral lobectomies separately (Supplementary Table 6).
short intervals between lobectomies, RLL resections, and low values of DLCO before contralateral lobectomy; higher incidence of mortality is associated with high incidence of SCC. Our report should be interpreted within the limitations of a retrospective study with selected patients from a single institution. Nevertheless, patient selection and resections in this large series performed by multiple surgeons (>15) in 25 years reflect clinical practice.
In conclusion, although contralateral lobectomy for second primary NSCLC was associated with high rates of perioperative mortality and morbidity before 2010, perioperative outcomes are currently comparable with those of unilateral lobectomy. After contralateral lobectomy for pathologic stage I NSCLC, 3-year OS and LC-CID in patients are comparable with those in patients who underwent single lobectomy for early stage NSCLC.