Salvage surgery for initially unresectable advanced-stage non-small cell lung cancer after chemotherapy with immune-checkpoint inhibitor: a narrative review

Introduction

Background

Immune checkpoint inhibitors (ICIs) are newly developed class of chemotherapy agents that have provided excellent oncological outcomes, particularly for patients with advanced lung cancer (1). Recently, preoperative induction chemotherapy with ICIs (nivolumab or pembrolizumab) was approved for operable advanced non-small cell lung cancer stages II and III to achieve favorable oncological outcomes (2,3). In contrast, the treatment strategy for initially unresectable advanced non-small cell lung cancer generally involves chemotherapy or chemoradiotherapy with one of the ICI agents depending on the patient’s genetic background and biomarkers such as programmed death-1 expression on tumor cells (4-6). Following these radical treatments, an excellent anti-tumor effect has occasionally been observed in select patients, as detected by imaging scans such as computed tomography or positron emission tomography. When the tumor shrinks and downstages or regrows in a localized tumor lesion after reduction, surgical resection of the loco-regional tumor is considered, a procedure generally called “salvage surgery”. However, “salvage surgery” has not been approved via a prospective clinical trial or practical study due to its rarity, nor has it been officially recommended by recent guidelines (6,7). Nevertheless, according to recent publications, this type of “salvage surgery” can be performed safely and is feasible, provided that patient selection is properly performed (4). These results will demonstrate the importance of salvage surgery for treating unresectable advanced lung cancer after chemotherapy with ICIs.

Rationale and knowledge gap

Recently developed chemotherapy, including ICIs, has dramatically improved surgical treatment strategy in many fields including gastrointestinal, gynecological, hepato-biliary-pancreatic, urological, and general thoracic surgery (8). As a result, “salvage lung resection” after ICI treatment for loco-reginal recurrence or regrew tumor among initially unresectable lung cancer patients was occasionally indicated and reported (9-13). However, due to their rarity, pre/peri-operative surgical outcomes as well as long-term survival are unknown. Furthermore, oncological outcomes (extend of viable cells) and feasibility are not clarified either (14).

Objective

This study aims to analyze the preoperative clinical characteristics, perioperative surgical outcomes including the pathological response rate to chemotherapy, and long-term survival of patients who underwent salvage lung resection after receiving immunotherapy for initially unresectable advanced lung cancer. We present this article in accordance with the Narrative Review reporting checklist (available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-40/rc).

Methods

We searched the MEDLINE database of PubMed for English publications regarding human clinical studies on salvage lung cancer surgery conducted from January 2019 to June 2025. On August 1, 2025, we conducted the search using the following terms: “salvage lung cancer surgery and/or immune checkpoint inhibitor” or “salvage lung cancer surgery and/or immunotherapy”, associated with radical lung resection for residual or regrowth tumor after treatment with ICIs. We defined “salvage surgery” as surgery for patients with initially unresectable advanced-stage lung cancer who underwent lung resection for residual downstaged tumor lesion or regrown cancer lesion after chemotherapy or chemoradiotherapy with ICIs such as pembrolizumab, durvalumab, nivolumab, and atezolizumab.

Based on past publications, a definition of salvage surgery including this study criteria were as followed: (I) surgery for cases in which systemic therapy achieved overall disease control, but local progression occurred; (II) surgery for tumors that were initially unresectable but became resectable after treatment (9). Although articles describing salvage surgery after ICIs were rare, we restricted our research to articles that provided detailed information about therapy, perioperative results, postoperative outcomes, and survival. We excluded articles about biopsies, incomplete resections, and non-pulmonary resections. Regarding types of journals, we included single-case reports, and excluded review articles. The search strategy is summarized in Table 1.

H.H. primarily selected these publications, and the final selection was made by all authors after reaching a consensus. Regarding the tumor-node-metastasis (TNM) classification, since we could not distinguish between the eighth and ninth editions in all the selected articles, we used the edition in which the articles were published. This narrative review is a single-arm cohort study: however, we do not have a comparative group.

Discussion

Results

Patient selection

We searched PubMed for 101 articles and selected 46 patients who underwent salvage lung cancer surgery after ICI. We included articles with detailed clinical information (19 publications, including 14 single-case presentations and five multi-case series articles). Figure 1 shows the article selection flowchart and Table 1 presents the summary of the search strategy. Table 2 shows patient clinical characteristics, and Table S1 shows each patient’s information in detail (15-33).

Figure 1 Flow chart of article selection.

Perioperative management

The most of the patient age was around 60 years old (range, 44–82 years old), and male patients was 30 cases out of 46 patients. The histology was adenocarcinoma (18 cases), squamous cell carcinoma (22 cases), large cell carcinoma (2 cases), adenosquamous cell carcinoma (1 case), and other (3 cases). The pretreatment clinical stage was III (27 cases) and IV (19 cases). ICIs included pembrolizumab (21 cases), durvalumab (19 cases), nivolumab (5 cases), and atezolizumab (one case). The surgical procedures were wedge resection (2 cases), segmentectomy (4 cases), lobectomy (32 cases), and pneumonectomy (8 cases). The additional surgical technique of pulmonary artery and/or bronchial plasty was performed in 8 out of 46 patients, and the surgical approach was video-assisted thoracoscopic surgery (7 cases), robot-assisted thoracoscopic surgery (3 cases), thoracotomy (30 cases), or undetected (6 cases). Most of the operation time and bleeding amounts were approximately 200 min (range, 65–525 min) and 100 mL (range, 3–4,000 mL), respectively. The postoperative complications (all grades) occurred in 13 out of 46 patients, and 30-day mortality occurred in 1 out of 46 patients. Immune-related adverse events (irAE) (all grade) occurred in 12 out of 46 patients. Especially, grade III or over grade III irAEs were liver function and interstitial lung disease (1 case), and immunosuppression (1 case), respectively. Additionally, grade III or over grade III complications included air leakage (3 cases), bronchopleural fistula (1 case), and, anastomotic failure (1 case).

Pathological response

The number of pathological complete response (pCR) and the major pathological response (MPR) were nine and 2 out of 25 patients, respectively, among the 25 patients for whom detailed pathological responses were described. The postoperative pathological stage was ypStage 0/I/II/III/IV/NA: 9/17/8/7/3/2. The rates of [programmed death ligand 1 tumor proportion score (PD-L1 TPS)] was ranged from 0 to 100%.

Long-term survival

Documented postoperative survival time was ranged from 1 to 43 months (Table S1).

Reported postoperative follow-ups period is likely to be short and recurrence or death data are very limited. Then, we should care for long term postoperative survival in such salvage series.

Overall, squamous cell carcinoma histology and the surgical procedure of lobectomy were dominant. Regarding the surgical approach, minimally invasive surgery was performed in relatively small numbers of cases and was considered feasible when the tumor and metastatic lymph nodes were peripherally located. As for perioperative outcomes, the incidence of irAEs and postoperative morbidity was approximately 30%, while the mortality rate was relatively low.

This information may be useful for preoperative informed consent. Finally, postoperative survival information was limited because this study included more case presentations with a short observation period. Therefore, we should follow longer postoperative survival and cancer recurrence from now on.

Comment

According to past publications regarding salvage surgery after chemoradiation therapy or target therapy (e.g., tyrosine kinase inhibitors or ICIs), the surgical outcomes of each different therapy were similar and acceptable (9-12,34). Nevertheless, the additional therapeutic effect of chemotherapy with ICIs has dramatically improved, and the number advanced lung cancer patients who responded well to ICI therapy has increased (35,36). Occasionally, downstaged patients may be a candidate for “salvage surgery”, which can remove residual tumor lesions. However, the significance of “salvage surgery” has not been officially evidenced in guidelines (5,6). Nevertheless, clinical studies on salvage surgery after ICI have been increased, and its utility being acknowledged and confirmed. Such kind of surgical procedure was rarely performed and precise short and long-term outcomes were not documented thus far. Therefore, a novelty of the study was a feasibility of salvage surgery after ICI including irAE, and we propose such kinds of surgery when an indication and timing are carefully considered among multidisciplinary team.

Since the introduction of immunotherapy, we have realized that the role of salvage surgery may be changing. A recent clinical study demonstrated that the short-term surgical outcomes of salvage surgery following chemoradiation therapy and immunotherapy were comparable and feasible (37). The study also found that immunotherapy was slightly more effective than non-immunotherapy in terms of oncological outcomes. However, long-term outcomes for immunotherapy patients have not yet been obtained due to the short postoperative observation period. Overall, salvage surgery has been considered to play a more valuable role than conventional chemoradiation therapy since the introduction of immunotherapy. We should closely monitor the long-term survival of future salvage surgery patients.

Relating with strong anti-tumor effect, a procedure of salvage surgery has a considerable difference compared with conventional pulmonary resection. Especially, after preoperative treatment with ICI, severe adhesion and thickening vessel sheath is generally observed in sounding tissues and lymph node which cancer cells metastasized or invaded. Therefore, an exposure for pulmonary artery, vein and bronchus is generally tough procedure and highly technical skills and experience is demanding. In this study, a rate of pulmonary artery/bronchus plasty was 17.4% (8/46), which was feasible and acceptable condition. Apart from those procedures, Dickhoff et al. reported that accidental intraoperative pulmonary injury was encountered in 2 cases out of 10 salvage surgery (27). Furthermore, Goto et al. demonstrated that 7 out of 14 salvage cases was demanded for carinal resection or sleeve resection (30). Overall, this kind of salvage surgery was considered as tough procedure, however, loco-regional control was considerably obtained after surgery, therefore, we should take in mind the challenging procedure and an impact after surgery in patient performed by pretreatment of immunotherapy. Furthermore, irAE is specific problems after ICIs compared with general chemoradiotherapy case. Then, not only surgical procedure, but also postoperative management should be cautious for especially for such kinds of salvage surgery.

Timing of PD-L1 assessment was another important information before immunotherapy. In the journals we analyzed, most of the articles were not documented the assessment timing of PD-L1 tumor proportion score. Probably, preoperative assessment had been performed since most cases were treated by immunotherapy before salvage surgery. However, Goto et al. (30) showed the timing of PD-L1 assessment in their 14 patients; preoperative (6 cases), postoperative (3 cases), pre and postoperative (1 case) and unknown (4 cases). Overall, preoperative assessment of PD-L1 TPS is desirable, however, in case when enough specimen is not obtained before pretreatment, postoperative assessment may be reasonable if possible.

In addition to issues regarding salvage surgical procedure and timing, the indication for salvage surgery is considered another important point. In this study, we included two types of salvage surgery previously described: (I) surgery for cases in which systemic therapy achieved overall disease control, but local progression occurred; (II) surgery for tumors that were initially unresectable but became resectable after treatment. Correctly, (I) and (II) were different indications for salvage surgery and we combined (I) and (II) into one group, which may result in a heterogeneous cohort. Therefore, it might be advisable to discuss them separately; however, we did not distinguish between them due to no description in the case series. Then, if we could analyse each salvage surgery separately, we could discuss the following points: in group (I), the long-term outcomes after surgical intervention would be of greatest interest, whereas in group (II), the key point would be identifying which cases become resectable. The clinical relevance of the data varies depending on the patient group. More numbers of salvage surgery based on different indication may clarify a difference in surgical outcomes and provide a desirable therapeutic strategy in future.

Nemeth et al. conducted a national cancer database study in the United States, comparing 164 salvage lung cancer surgeries after ICI with 446 surgeries after chemoradiation therapy (37). The pCR rate was 22.6% (n=37) for ICI vs. 26.3% (n=117) for chemoradiation. The 30-day mortality rate was 0.6% (n=1) vs. 3.8% (n=17), and the three-year overall survival (OS) rate was 73.4% vs. 69.8%, respectively. For survival analysis, patients who obtained a pCR had significantly better outcomes than those who did not in both the ICI and chemoradiation groups. Regarding the surgical procedure, lobectomy was not significant inferior to pneumonectomy in terms of 90-day mortality: however, it resulted in lower perioperative morbidity and mortality.

Dunne et al. analyzed the outcomes of 120 lung resections in patients with non-small cell lung cancer stage I–IV who had previously received nonoperative treatment, including immunotherapy using a prospectively maintained database (38). The overall morbidity and 30-day mortality rates were 42% (50/120) and 2.5% (3/120), respectively. Three-year and five-year OS were 73% and 61%, respectively, which were similar to our results. Patients receiving immunotherapy had significantly longer survival times compared with the overall cohort. The authors concluded that, although patient inclusion was not standardized and biased selection was inevitable, overall surgical outcomes were considered safe and feasible. Mohamed et al. reported results of single-center retrospective study of 19 salvage lung cancer surgeries after ICI. The study obtained a pCR rate of 36.8% (7/19), and found that postoperative quality of life was maintained one year after operation (39). Gaboran et al. performed a systematic review of salvage pulmonary resection after ICI or tyrosine kinase inhibitor therapy for initially unresectable non-small cell lung cancer obtaining a pCR rate of 27%, a 30-day mortality of 1.3%, and one-year disease-free and OS rates of 68% and 88%, respectively, which were consistent with our results (4). The authors concluded that prospective and registry-based studies are necessary to define selection criteria and long-term benefits, as patients undergoing salvage surgery exhibited heterogenous characteristics.

Takenaka et al. presented the outcomes of salvage surgery following ICI and tyrosine kinase inhibitor (TKI) (40). The pCR rate was 25% (2/8), with squamous cell carcinoma accounting for 50% (4/8). The median OS was 18.7 months (range, 9.7–55.8 months) among all cohorts. Additionally, a variety of fibrosis was observed in TKI group. In contrast, necrosis of the tumor center of tumor was detected in the ICI group. This difference may be based on the anticancer mode and mechanism. Schiavon et al. reported that the pCR rate was 48% (15/31) and the 2- and 3-year survival was 88% among three multi-institutional cohorts after ICI treatment. These results are considered reasonable (41). Regarding the pathological response to salvage surgery in a limited case analysis, ICI was considered to have a significant impact similar to that of TKI.

Another important issue was the difference in outcomes for patients receiving salvage surgery for advanced lung cancer after ICI treatment compared to those receiving TKI treatment. Mangiameli et al. conducted a single-centre study investigating salvage surgery for initially stage III–IV non-small cell lung cancer following ICI or TKI treatment (42). The pCR rate and median OS time in the ICI group (n=9) and the target therapy group receiving TKI (n=8) or alectinib (n=1) were 33.3% (3/9) vs. 22.2% (2/9) (P=0.59) and 23.1 vs. 26.3 months (P=0.75), respectively; these differences were not significant. However, the interval between initial treatment and salvage surgery after TKI therapy appeared to be longer than that after ICI therapy (38 vs. 29 months, P=0.47), with comparable perioperative outcomes between the two groups. Ohtaka et al. conducted a Japanese multi-centre study [2010–2015] analyzing 36 patients who underwent salvage surgery after TKI therapy. They found that 3-year OS and relapse-free survival (RFS) were 75.1% and 22.2%, respectively. This was considered comparable to salvage surgery after ICI (34). Furthermore, Gaborean et al. conducted a review in which they included fourteen observational series (n=312 patients). Major complications (Clavien-Dindo ≥ III) and 30-day mortality were 11% and 1.3% respectively, and the 1-year disease-free rate and OS rates were 68% and 88%, respectively (4). Given these comparable outcomes between the ICI and TKI groups, salvage surgery after ICI could be considered to have a similar indication to that after TKI. However, as the timing, indication, selected procedure and postoperative treatment of salvage surgery are not definitive, it should be discussed in a multidisciplinary team including surgeons, thoracic oncologists and radiologists, taking into account each patient's background.

Recently, neoadjuvant chemotherapy with ICIs has been approved as one of the first induction therapeutic options for initially operable advanced lung cancer patients in the CheckMate-816 (2) and Keynote-671 (3) trial. The pCR rate was 24% vs. 18.1%, and the 3-year OS rate was 78% vs. 71%, respectively. These results seem similar, though there is a difference in outcomes depending on whether adjuvant chemotherapy is performed. For general thoracic surgeons, deciding whether non-small cell lung cancer is resectable or unresectable is very important since the therapeutic strategy depends on the decision. Therefore, prior to proceeding with treatment for advanced lung cancer, the multidisciplinary team should discuss the treatment strategy, which may include upfront surgery or induction chemotherapy followed by surgery, salvage surgery followed by definitive chemotherapy or chemoradiotherapy with or without ICI, based on the patient’s cancer biomarkers, such as PD-L1, epidermal growth factor receptor, and anaplastic lymphoma kinase. This process will provide a promising desirable precision medicine, regardless of how chemotherapy advances in the future. In the era of neoadjuvant chemoimmunotherapy, surgery for those potential cases was clinically significant and offered hope of cure for advanced lung cancer patients.

The LungMate-013 study just reported its initial results at the recent European Society for Medical Oncology Congress (ESMO) conference. The study investigated the effect of serplulimab plus platinum-doublet chemotherapy on unresectable IIIB–IIIC NSCLC. There were 23 patients who received surgery and 27 patients who received radiotherapy after the induction therapy. The survival results demonstrated the superior effect of salvage surgery vs. radiotherapy. We hope next clinical trial comparing salvage surgery or radiotherapy will be promising in near future.

Strengths and limitations

Salvage lung cancer surgery for initially unresectable clinical stage III–IV patients who were downstaged after chemotherapy with ICIs could not be proven superior by a prospective randomized study trial due to its rarity. Furthermore, only a few patients were observed at a single institution, so the overall total response rate and surgical outcomes could not be analyzed in detail. Therefore, this narrative review presented potential evidence based on current clinical practice. However, there are several limitations. First, most of the included studies were single case presentations, and publication and selection bias existed. Second, the search terms used and the postoperative observation period were as short as three years. Third, each surgical indication, timing, procedure, and postoperative treatment varied depending on the decision of each institute. Nevertheless, we gathered the maximum number of articles published worldwide at the current time and demonstrated a robust analysis showing that salvage lung cancer surgery after ICI treatment is feasible when patient selection is properly performed and the surgical procedure is performed by an experienced surgical team following cautious perioperative management.

Conclusions

Salvage lung cancer surgery for residual or regrowth tumor lesions after immunotherapy for initially unresectable advanced lung cancer is a feasible and acceptable procedure when patient selection is properly performed. A large, multi-institutional cohort study is expected to clarify the importance of this type of surgery in the future.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-40/rc

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-40/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-40/coif). H.H. serves as an unpaid editorial board member of Current Challenges in Thoracic Surgery from March 2025 to February 2027. T.M. serves as an unpaid editorial board member of Current Challenges in Thoracic Surgery from November 2023 to December 2025. The authors have no other 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.

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/.

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