Is Neoadjuvant Chemoimmunotherapy Safe in Surgically High-Risk Lung Cancer Patients? A Single-Centre IPTW Analysis

Background: Neoadjuvant chemoimmunotherapy is now a standard approach for resectable stage II–III non-small cell lung cancer (NSCLC), demonstrating improved pathological response and survival. However, its safety in physiologically high-risk surgical patients is unclear, as these groups are underrepresented in trials. This study compares 30-day and 90-day mortality and oncological outcomes of neoadjuvant chemoimmunotherapy followed by surgery versus upfront surgery within a high-risk multidisciplinary team (MDT) cohort. Methods: A retrospective single-centre study was performed, including consecutive high-risk MDT patients undergoing resection for stage II -III NSCLC between January 2022 and December 2025. High-risk status was defined by established physiological, cardiopulmonary, and comorbidity criteria. Patients were stratified into neoadjuvant chemoimmunotherapy followed by surgery (Chemo-IO; n = 33) or upfront surgery (n = 57). The primary outcome was 30-day mortality. Secondary outcomes included 90-day mortality, R0 resection rate, and length of hospital stay. Inverse probability of treatment weighting (IPTW) based on propensity scores was used to balance baseline differences between groups. Results: Ninety patients were included. Patients receiving neoadjuvant therapy had a greater comorbidity burden (Charlson Comorbidity Index 3.2 ± 1.5 vs. 1.4 ± 1.7, p < 0.001) and more advanced disease (stage III: 57.6% vs. 29.8%, p = 0.014). Thirty-day mortality was 0% in the Chemo-IO group and 1.8% following upfront surgery. After IPTW adjustment, neoadjuvant therapy was not associated with increased perioperative mortality. Ninety-day mortality was similar between groups (3.0% vs. 3.5%; IPTW OR 0.91, 95% CI 0.05–15.39, p = 0.948). R0 resection rates were numerically higher following Chemo-IO (87.9% vs. 78.9%; IPTW OR 3.42, 95% CI 0.71–16.59, p = 0.127). Median hospital stay was identical in both cohorts (6 days), with no significant difference after weighting (p = 0.722). Conclusions: Neoadjuvant chemoimmunotherapy appears safe and feasible in carefully selected high-risk patients with resectable stage II–III NSCLC. Despite greater comorbidity burden and more advanced disease, short-term perioperative outcomes were not compromised, while a trend towards improved R0 resection rates was observed. These findings support the consideration of multimodal treatment strategies within high-risk MDT pathways.