Characteristics and outcomes of salvage surgery after immune checkpoint inhibitor therapy for initially unresectable non-small cell lung cancer

Introduction

The emergence of immune checkpoint inhibitors (ICIs) has improved the long-term survival outcome of patients with unresectable non-small cell lung cancer (NSCLC) (1,2). To the best of our knowledge, data on patients undergoing salvage surgery after ICI therapy were mainly based on sample sizes <10 patients and focused on short- or medium-term outcomes (3,4). We previously reported data from a single center, focusing on important differences in data from salvage surgery after definitive chemoradiotherapy without ICIs (5-7). This study aimed to further investigate the characteristics and outcomes of salvage surgery after ICI therapy based on data from a multicenter database. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-891/rc).

Methods

This study was approved by the Kyoto University Hospital Institutional Review Board (reference No. R2504) and individual consent for this retrospective analysis was waived. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). A retrospective chart review was performed using the multicenter database to identify all consecutive patients who underwent salvage surgery after multimodality treatments, including ICIs, for initially unresectable NSCLC between January 2016 and 2022. Included in this study were patients undergoing resection of primary or metastatic lesions (including postoperative recurrences) that were residual or recurrent after treatment with ICIs. Patients undergoing surgical biopsy only for lesions after ICIs were excluded. Pathological staging was based on the Union for International Cancer Control 8^th edition. Progression-free survival (PFS) was defined as the interval from the date of surgery until the date of progression, death from any cause, or the date of the last clinic visit. Overall survival (OS) was defined as the interval from the date of surgery until the date of death from any cause or the date of the last clinic visit.

Statistical analysis

The Kaplan-Meier method was used to generate survival curves, which were compared using the log-rank test in subgroup analyses, with P values <0.05 considered significant. All analyses were performed using JMP^® 14 software (SAS Institute Inc., Cary, NC, USA).

Immunohistochemical staining

Exploratory immunohistochemistry was used to detect the expression of CD39 (ab223842, Abcam, Waltham, USA, dilution 1:1,000) and T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3; ab241332, Abcam, dilution 1:1,000), as potential markers of exhausted T cells, on tumor cells in selected patients whose biopsy specimens prior to ICI treatment and resected specimens at salvage surgery are both available. Incubation and washing procedures were carried out at room temperature. Following deparaffinization and antigen retrieval, the activity of endogenous peroxidase was inhibited by 0.3% H₂O₂ in methyl alcohol for 30 minutes. The glass slides were rinsed in phosphate-buffered saline (PBS) six times, for 5 minutes each, and then mounted using 1% normal saline in PBS for 30 minutes. Following this, the primary antibody was applied and left overnight at 4 ℃. The samples were then incubated with a biotinylated secondary antibody, diluted 1:300 in PBS, for 40 minutes, followed by six washes in PBS, each for 5 minutes. The avidin-biotin-peroxidase complex (ABC-Elite, Vector Laboratories, Burlingame, CA, USA) at a 1:100 dilution in body surface area (BSA) was then applied for 50 minutes. After another round of washing in PBS (6 times, 5 minutes each), a color reaction was performed using 3,3'-diaminobenzidine (DAB), and the nuclei were counterstained with hematoxylin.

Results

A total of 15 patients were identified. The characteristics of these patients are summarized in Table 1, and the details are shown in Tables S1,S2 and Figure S1 (Swimmer’s plot). The available images of preoperative computed tomography were shown in Figure S2.

Histopathological findings

Viable tumor cells were confirmed in all resected specimens, except for one of the two resected fluorine-18-deoxyglucose-avid lesions showing no viable cells in the patient undergoing pleural metastasectomy. As exploratory immunohistochemistry, the cluster of differentiation 39 (CD39) and TIM-3 were evaluated in three patients (Patient A, Patient B, and Patient C in Tables S1,S2), whose specimens from initial biopsy and salvage surgery were both available. In all three patients, the positivity rates of CD39 and TIM-3 were higher at salvage surgery than before ICI therapy, as shown in Figures S3-S5.

Long-term outcomes

The median follow-up period was 24.5 (range, 12.3–60.5) months. The 3-year PFS and OS rates were 57.9% and 68.2% in the entire cohort, respectively. The median PFS was 47.9 months, and the median OS was not reached (Figure 1A,1B). Recurrences were noted in three patients with metastatic lesions and one with primary lesions, with the details shown in Tables S1,S2.

Figure 1 Survival curves for all patients. (A) Progression-free survival curve for all patients; (B) overall survival curve for all patients.

Subgroup analysis

The 3-year PFS was 0% and 87.5% for those with metastatic and primary lesions, respectively (Figure 2A, P=0.12). The 3-year OS was 83.3% and 53.3% for those with primary and metastatic lesions, respectively (Figure 2B, P=0.53).

Figure 2 Survival curves comparing patients with primary lesion and those with metastatic lesions. (A) Progression-free survival curves comparing patients with primary lesions and those with metastatic lesions; (B) overall survival curves comparing patients with primary lesions and those with metastatic lesions.

The 3-year PFS was 51.4% and 75.0% for those with programmed cell death 1 (PD-1) blockade and programmed death-ligand 1 (PD-L1) blockade, respectively (Figure 3A, P=0.94). The 3-year OS was 70.0% and 66.7% for those with primary and metastatic lesions, respectively (Figure 3B, P=0.61).

Figure 3 Survival curves comparing patients with PD-1 blockade and those with PD-L1 blockade as immunotherapy. (A) Progression-free survival curves comparing patients with PD-1 blockade and those with PD-L1 blockade as immunotherapy; (B) overall survival curves comparing patients with PD-1 blockade and those with PD-L1 blockade as immunotherapy. PD-1, programmed cell death 1; PD-L1, programmed death-ligand 1.

The 3-year PFS was 60.0% and 43.8% for those with pre-ICI stage 3 and pre-ICI stage 4, respectively (Figure 4A, P=0.49). The 3-year OS was 50.0% and 85.7% for those with primary and metastatic lesions, respectively (Figure 4B, P=0.31).

Figure 4 Survival curves comparing patients with stage 3 disease and those with stage 4 disease prior to immunotherapy. (A) Progression-free survival curves comparing patients with stage 3 disease prior to immunotherapy and those with stage 4 disease prior to immunotherapy; (B) overall survival curves comparing patients with stage 3 disease prior to immunotherapy and those with stage 4 disease prior to immunotherapy.

Discussion

To the best of our knowledge, this study, including 15 patients undergoing salvage surgery after ICI therapy for unresectable NSCLC, has the largest sample size, demonstrating that most patients initially responded well to ICI therapy and developed immune-related adverse events. Salvage surgery was performed with low perioperative morbidity and acceptable long-term survival outcomes, and there were several interesting differences between patients with primary lesions and those with metastatic lesions.

This study highlights several differences between salvage surgery after ICI therapy and salvage surgery after definitive chemotherapy or chemoradiotherapy (7,8). Specifically, previous studies on salvage surgery after definitive chemotherapy or chemoradiotherapy report a 3-year PFS of approximately 50%, with most patients initially staged as III. In contrast, the present study achieved a 3-year PFS of 57.9%, with most patients initially staged as IV. Furthermore, unlike previous studies, approximately 50% of patients in the present study underwent salvage surgery for metastatic lesions.

Patients with metastatic lesions showed a worse PFS than those with primary lesions, whereas, OS curves appeared similar between patients with primary and metastatic lesions. Most patients undergoing salvage resection of metastatic lesions developed postoperative recurrences that various treatments managed. Therefore, patients undergoing salvage surgery for metastatic lesions require closer postoperative follow-up.

The exploratory immunohistochemical analysis in this study may confirm the value of pathological assessment using immunohistochemical analysis of resected specimens after ICI therapy. CD39 and TIM-3, which are markers of exhausted T cells, were evaluated in three patients, who were considered to develop resistance to ICIs, consistent with the exploratory immunohistochemical findings.

This study had several limitations, including a retrospective study with a small sample size and selection bias for patients undergoing salvage surgery after ICI therapy. The indications for salvage surgery varied and were unclear in some cases. Treatments prior to salvage surgery also varied. Inclusion of both primary and metastatic lesions, for which salvage surgery was performed, may be controversial and made the study group heterogeneous. We were not able to identify a control group for our study patients. Despite these limitations, this study revealed distinct features of patients undergoing salvage surgery after ICI treatment for initially unresectable NSCLC based on a real-world database, which may be difficult to obtain from clinical trials.

Conclusions

Salvage surgery after ICI treatment for initially unresectable NSCLC may be associated with low perioperative morbidity and acceptable long-term outcomes in selected patients. Salvage resection of primary lesions may be associated with a more favorable PFS than resection of metastatic lesions.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-891/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-891/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-891/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-891/coif). M.H. serves as an unpaid editorial board member of Journal of Thoracic Disease from October 2022 to January 2025. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Kyoto University Hospital Institutional Review Board (reference No. R2504) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med 2018;379:2342-50. [Crossref] [PubMed]
2. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med 2018;379:2040-51. [Crossref] [PubMed]
3. Bott MJ, Cools-Lartigue J, Tan KS, et al. Safety and Feasibility of Lung Resection After Immunotherapy for Metastatic or Unresectable Tumors. Ann Thorac Surg 2018;106:178-83. [Crossref] [PubMed]
4. Etienne H, Fournel L, Mordant P, et al. Anatomic lung resection after immune checkpoint inhibitors for initially unresectable advanced-staged non-small cell lung cancer: a retrospective cohort analysis. J Thorac Dis 2023;15:270-80. [Crossref] [PubMed]
5. Hamaji M, Ozasa H, Yoshizawa A, et al. Salvage thoracoscopic resection after nivolumab for stage IV. Asian Cardiovasc Thorac Ann 2020;28:216-8. [Crossref] [PubMed]
6. Nagata S, Hamaji M, Ozasa H, et al. Salvage Surgery After Immune Checkpoint Inhibitors for Advanced Non-Small Cell Lung Cancer: Potential Association Between Immune-Related Adverse Events and Longer Survival. Clin Lung Cancer 2022;23:e321-4. [Crossref] [PubMed]
7. Sonobe M, Yutaka Y, Nakajima D, et al. Salvage Surgery After Chemotherapy or Chemoradiotherapy for Initially Unresectable Lung Carcinoma. Ann Thorac Surg 2019;108:1664-70. [Crossref] [PubMed]
8. Shimizu K, Ohtaki Y, Suzuki K, et al. Salvage Surgery for Non-Small Cell Lung Cancer After Definitive Radiotherapy. Ann Thorac Surg 2021;112:862-73. [Crossref] [PubMed]