Perioperative considerations for neoadjuvant immunotherapy in non-small cell lung cancer

The mortality of lung cancer has declined over the past decade at record rates of up to 4.3% per year,(1)and immune checkpoint inhibitors (ICIs) are at least partly responsible for this trend. On the basis of efficacy, ICIs have rapidly increased from investigational agents to standard of care for metastatic non-small cell lung cancer (NSCLC). Not long after demonstrating improved survival compared with standard chemotherapy in patients with stage IV disease, ICIs entered clinical trials for earlier stage lung cancer. For example, the programmed death ligand 1 inhibitor durvalumab has recently been adopted as standard of care for patients with locally advanced (stage IIIB) NSCLC after its addition to chemoradiation was shown to improve survival. These and other promising data in advanced NSCLC data have ushered ICIs into the neoadjuvant setting, and clinical trials for stage IB to IIIA NSCLC have completed or are accruing. On the basis of the early output of these trials (reviewed herein) and the track record of ICIs in advanced NSCLC, it is reasonable to suspect that there will be a place for ICIs in the standard of care for early-stage disease. This is a new frontier in thoracic surgery, and operating on patients who have received immunotherapy is becoming commonplace in many institutions. However, there are challenges with neoadjuvant ICI therapy that are not obvious and that are directly relevant to thoracic surgeons. Aside from operative considerations such as the hilar fibrosis that can result from ICIs, and choosing the optimal approach, there are new concepts such as nodal immune flare and pseudo-progression that must be understood and considered in restaging and surgical decision-making. There are new immune-related adverse events and complications germane to preoperative risk stratification and postoperative management (eg, pneumonitis). In the following Expert Opinion article, thoracic surgical oncologists at the forefront of this field offer a succinct and practical primer on preoperative, intraoperative, and postoperative considerations for neoadjuvant ICI therapy in NSCLC. Included also is an expert summary of published and presented neoadjuvant ICI efficacy data that should rally our discipline to pile on to the lung cancer mortality curve and lead its next record decline.