Thanks to the implementation of neoadjuvant immunotherapy, new horizons have opened up with respect to the limits of surgical tumor resection in patients with lung cancer. However, technical problems need to be addressed, and there is great variability regarding the feasibility of the procedures and the results that can be achieved.
Respectability has a technical aspect (i.e., high probability of achieving R0 resection) as well as an oncological aspect (i.e., low probability of occult disease). A pan-European expert panel has defined resectable stage III non-small-cell lung cancer (NSCLC) based on 104 real-world cases, providing a nuanced approach depending on factors such as the extent of disease within the T and N categories (1). A T3 situation, for instance, can be present because of tumor size, the presence of satellite nodules, or invasion. According to this categorization, there is no point in offering surgery to patients with N2-multistation or N2-bulky lymph node involvement. Within the T3 category, chest wall invasion appears resectable, while invasion of the brachial plexus does not. With regard to T4, patients with esophageal and spinal cord invasion were classified as unresectable, whereas cases with an invasion of the heart or vertebrae need to be discussed. Here, the decision depends on the expertise of the team and the amount of disease.
In the pre-immunotherapy era, neoadjuvant treatment in stage III was restricted to disease with single-station, non-invasive and non-bulky nodal involvement. Immunotherapy has changed this scenario by improving locoregional control, which is very meaningful as local recurrences after surgery or radiotherapy are often difficult to treat. Another reason for the importance of locoregional control is that overall survival can be improved in patients who have failed to achieve complete pathological remission. Resection rates are indeed very high after neoadjuvant chemoimmunotherapy, ranging between 83.2 % and 94.7 % in the CheckMate 816 and AEGEAN trials, respectively (2). These percentages exceeded those achieved with standard chemotherapy, and the number of lobectomies was greater.
Technical Issues
Of course, resectability has limits, and the quality of the tissue after neoadjuvant treatment is unpredictable. Ideally, pathologists should be ready to perform multiple frozen section analyses at the time of surgery. This is important because the surrounding structures can be affected by the inflammation produced by the immunotherapeutic treatment. Therefore, the surrounding tissues need to be reviewed, and the analysis of frozen sections ensures that surgery is conducted in the right places and to the correct extent. Given the issue of treatment-related inflammatory changes, the actual extent of surgery can deviate from the procedure that had been planned initially in a given patient. This needs to be taken into account, as patients are required to be fit enough for more expansive resections.
Pneumonectomy is a very good tool, which is demonstrated by an analysis showing higher rates of R0 resection in countries where pneumonectomies are routinely performed compared to those where this type of surgery is avoided (3). Here, R1 disease rates are comparatively higher, which is of course a problem from the oncological point of view. The only way to avoid pneumonectomy is to have pathologists analyze frozen sections, as this allows for a more accurate delineation of the tumor. Sometimes the immune response is so massive that the situation cannot be dealt with unless by pneumonectomy. However, clinical experience shows that pneumonectomy is very well tolerated nowadays, and we should not be afraid of it. Thoracic surgeons are performing much more technically demanding procedures today than in the past. Sleeve resections involving vascular and bronchial reconstruction are increasingly becoming routine.
Reevaluation in Stage III
A challenging part of lung cancer surgery is the issue of lymph nodes. R0 resection cannot be provided if the highest and lowest lymph nodes in the resection area are not negative, which means that we have to review all stations. Non-bulky lymph nodes are resectable by definition; these are nodes with a diameter < 3 cm that are easily measurable and defined and free of major mediastinal structures. After neoadjuvant chemoimmunotherapy, lymph node reactions are possible that lead to fibrosis and impede resection. This might give rise to the necessity to remove more tissue to ensure R0 resection.
Taken together, immunotherapy has definitely changed the surgical scenario. Dickhoff et al. emphasized the need to reevaluate resectability in stage III NSCLC in light of the availability of neoadjuvant chemoimmunotherapy, proposing multidisciplinary assessments at certain time points (Figure 1) (4). Initially, patients fit for surgery need to be told from those who are not fit for surgery. In those who are fit and show resectability or borderline resectability, induction treatment (i.e., chemotherapy, chemoradiotherapy, chemoimmunotherapy) followed by resection is the path to go unless the response is insufficient. However, the authors suggest chemoradiotherapy followed by reevaluation even in those who appear unresectable but fit for surgery, as deep responses might allow for radical resection in some cases.

 © Dickhoff C et al
Figure 1. Proposed multidisciplinary evaluation and reevaluation of resectability in stage III NSCLC (taken from Dickhoff C et al).
Conclusion
Generally speaking, the resectability of NSCLC in the immunotherapy era is unpredictable. To a great extent, it depends on the team’s experience, which implies great variability. The favorable outcomes observed after neoadjuvant immunotherapy in clinical trials have definitely changed our view on resectability. In patients fit for surgery in whom reevaluation indicates resectability even in pre-treatment stage IIIB, very high resection rates can be achieved. There is always the possibility of fewer expanded resections depending on the extent of inflammation.
Pneumonectomy is very well tolerated and should be conducted whenever appropriate. Thoracic surgeons should be prepared for performing sleeve resections, and special attention should be paid to the reaction of lymph nodes. There is still a grey zone in some patients with T4 N0 disease who might be amenable to surgery, although this needs to be discussed at the multidisciplinary level.
This article is based on the talk by Dr. Nuria M. Novoa from the ILCS 2024. Explore more on the topic by watching her full presentation below.
References
- Brandao M et al: Definition of resectable stage III non-small cell lung cancer (NSCLC): A clinical case review by a pan-European expert panel. J Thorac Oncol 2023; 18(11): S292-S293
- Sorin M et al: Neoadjuvant chemoimmunotherapy for NSCLC: A systematic review and meta-analysis. JAMA 2024; 10(5): 621-633
- Bryan DS and Donnington JS: Current management of stage IIIA (N2) non-small-cell lung cancer: Role of perioperative immunotherapy, and tyrosine kinase inhibitors. Thorac Surg Clin 2023; 33(2): 189-196
- Dickhoff C et al: Unresectable stage III NSCLC can be reevaluated for resectability after initial treatment. J Thorac Oncol 2023; 18(9): 1124-1128