Preoperative Triple Inhalation Therapy in Patients with Non–Small-Cell Lung Cancer and Emphysema: Impact on Postoperative Complications

Technical Summary: Preoperative Triple Inhalation Therapy in NSCLC Patients with Emphysema

Problem Statement
Chronic obstructive pulmonary disease (COPD) and emphysema frequently coexist with non-small-cell lung cancer (NSCLC) and serve as poor prognostic factors, particularly regarding postoperative complications following lung resection. While triple inhalation therapy combining long-acting muscarinic antagonists (LAMA), long-acting beta-agonists (LABA), and inhaled corticosteroids (ICS) has become a standard treatment for moderate-to-severe COPD to reduce acute exacerbations and improve lung function, its specific efficacy and safety as a preoperative intervention for NSCLC patients with emphysematous changes remain unclear. Previous studies have suggested benefits for dual therapy (LAMA/LABA) or LAMA monotherapy, but the utility of fixed-dose triple therapy in the perioperative setting had not been evaluated.

Methodology
This retrospective study, conducted at the National Hospital Organization, Kure Medical Center and Chugoku Cancer Center, analyzed patients who underwent lung resection for NSCLC with emphysematous changes identified on preoperative computed tomography (CT) between January 2019 and March 2024.

• Cohort: From an initial pool of 476 resection patients, 238 had emphysema. After excluding those with prior inhalation therapy or non-triple preoperative regimens, 218 patients were analyzed.
• Grouping: Patients were divided into a triple therapy group (n=21), receiving preoperative ICS/LAMA/LABA (Breztri Aerosphere® or Trelegy Ellipta®), and a control group (n=197) receiving no inhalation therapy.
• Selection Criteria: The decision to prescribe triple therapy was at the attending physician's discretion, typically for patients with impaired pulmonary function and/or moderate-to-severe emphysema.
• Outcomes: The primary focus was the incidence of postoperative complications, specifically those potentially preventable by inhalation therapy (pneumonia, acute exacerbation of interstitial pneumonia or COPD, and atelectasis requiring intervention). Complications were graded using the Clavien–Dindo classification (Grade II or higher). Pulmonary function tests (PFTs) and Goddard scores (GS) for emphysema severity were also assessed.

Key Results

• Baseline Characteristics: The triple therapy group was significantly older (p=0.041) and presented with significantly worse baseline pulmonary function and more severe emphysema compared to the control group. Specifically, the triple therapy group had lower %FEV1 (62.1% vs. 87.6%, p<0.001), lower %DLCO, higher GOLD grades, and higher Goddard scores (mean 10.1 vs. 6.5, p<0.001).
• Safety: No adverse events related to the LAMA/LABA/ICS therapy were observed in the triple therapy group.
• Overall Complications: There was no statistically significant difference in the overall incidence of postoperative complications (Grade ≥ II) between the groups (19.1% in the triple therapy group vs. 23.9% in the control group; p=0.613).
• Pulmonary Complications: Notably, zero patients in the triple therapy group developed pulmonary complications (defined as pneumonia, acute exacerbation of IP/COPD, or intervention-requiring atelectasis). In contrast, 11 patients (5.6%) in the control group experienced these specific complications. While this difference did not reach statistical significance (p=0.130), the absolute absence of events in the triple therapy group despite their higher-risk profile is a key finding.
• Pulmonary Function Trends: In the limited subset of patients who underwent repeat PFTs (n=7 for most metrics), improvements were observed in %VC, %FEV1, FEV1%, and %DLCO after therapy, though these changes did not reach statistical significance, likely due to the small sample size and pandemic-related testing restrictions.

Key Contributions and Claims
The paper claims to be the first study to evaluate the preoperative use of fixed-dose triple inhalation therapy (LAMA/LABA/ICS) in patients with resectable NSCLC and emphysema. Its primary contributions include:

1. Safety Validation: Demonstrating that preoperative triple therapy does not increase adverse events, including pneumonia, even in an older population with severe emphysema.
2. Potential Efficacy: Suggesting that preoperative triple therapy may reduce the incidence of postoperative pulmonary complications (specifically pneumonia and acute exacerbations) in high-risk patients, even when those patients have worse baseline lung function than untreated controls.
3. Mechanistic Insight: The authors propose that the benefit may stem from the combined bronchodilatory effects of LAMA/LABA and the anti-inflammatory properties of ICS, which could mitigate the physiological stress of surgery comparable to an acute COPD exacerbation.

Significance and Limitations
The authors conclude that preoperative LAMA/LABA/ICS therapy may be a viable strategy to optimize perioperative management for NSCLC patients with emphysema, potentially reducing pulmonary complications without increasing risks. They suggest that patients with airflow obstruction (%FEV1 <60%) and moderate-to-severe emphysema (Goddard score ≥6–7) might be ideal candidates for this approach.

However, the paper maintains a modest tone regarding its claims due to several limitations:

• Retrospective Nature: The study lacks randomization, and therapy assignment was based on physician discretion.
• Sample Size: The triple therapy group was small (n=21), and the number of patients with paired pulmonary function data was further reduced by the COVID-19 pandemic.
• Lack of Direct Comparison: The study did not directly compare triple therapy against dual therapy (LAMA/LABA or ICS/LABA) or placebo.

Consequently, the authors emphasize that while their findings are promising, they warrant validation through larger, prospective studies comparing different inhalation regimens to definitively establish the optimal perioperative strategy.