Short-term results of salvage surgery after immune and target therapies in non-small cell lung cancer

Introduction

In the recent years, the presence of molecular target therapies and immune checkpoint inhibitors (ICIs) have changed the approach and the outcome of patients with advanced non-small cell lung cancer (NSCLC) with specific oncogenic drivers (1-3). Although these therapies targeting epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1, receptor tyrosine kinase, B-Raf proto-oncogene etc., are mainly indicated in advanced or recurrent disease, some ongoing studies are evaluating their effectiveness in neo-adjuvant settings (4,5).

In some cases, these therapies may lead to an unpredictable clinical response, reducing primary tumour dimension, nodal involvement and distant metastases. In this scenario, the therapeutic program may be re-evaluated, considering the possibility of salvage surgery (6,7). Similarly, other studies reported the improvement in survival, considering local consolidative therapy (surgery and or radiotherapy) also in oligometastastic patients (less than 5 metastases) (8,9).

The rationale of salvage surgery after target therapy consists of two principal issues related to this kind of treatment: the acquired resistance to target therapy and the inability of the target therapy to eradicate micro-metastatic residual tumor cells (10,11).

Nowadays, despite the progressive integration of these treatments into daily clinical practice and the extension of their use in early stages, many questions are still unanswered, starting from the number of effective doses/cycles for neo-adjuvant purpose to the definition of the correct duration of the induction therapy. Moreover, information from surgical reports and pathological analysis, may improve the knowledge about the acquired resistance, possible intra-operative matters and the real efficacy of this therapeutic options.

Therefore, the aim of this study was to describe the clinical, surgical and pathological characteristics of patients who underwent salvage surgery after target therapy or immunotherapy, for initially non-resectable NSCLC. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-387/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional ethics board of Fondazione Policlinico Universitario A. Gemelli IRCCS (number of protocol 0012949/22 on 13 April 2022) and individual consent for this study was waived due to the retrospective nature.

This is a retrospective, multicentric study. Data of patients who underwent salvage surgery after target therapy or immunotherapy from three different centres from January 1, 2015 to December 31, 2022 were retrospectively collected and analyzed. Patients included in the study were selected using the following criteria:

• Inclusion criteria:
  • Not directly operable NSCLC (adenocarcinoma or squamous cell carcinoma) including stage IIIa with bulky nodal involvement or multi-station inoperable disease;
  • Pathologically proven mutation susceptible of target therapy;
  • Evaluation of programmed death-ligand 1 (PD-L1) expression rate for immunotherapy consideration;
  • Pre-treatment multidisciplinary discussion;
  • Surgery performed with radical intent.
• Exclusion criteria:
• Absence of chemo and/or radiotherapy treatment before target therapy;
• Surgery performed with re-biopsy intent;
• Disease progression during therapy:
• ­ Stable disease and stage during therapy;
• ­ Partial response to therapy without radiological downstaging or response;
• Directly operable patients: stage I–IIb or stage IIIa with single N2 station involvement;
• Stage IV with pericardial or pleural effusion.

EGFR mutation test was used to evaluate EGFR mutation, including T790M, detected in the context of a comprehensive cancer genome profiling by next-generation sequencing (NGS). Similarly, ALK rearrangement was examined by immunohistochemistry screening, followed by fluorescent in-situ hybridization confirmation (12).

Even though different tests and panels were used in the different centers, the results were clinically validated with a large, real-world cohort of NSCLC-patients.

Pre-treatment evaluation included physical examination, blood testing, total body computed tomography (CT) scans and 18-fludeoxyglucose-positron emission tomography (PET) scans. Tissue biopsy was obtained using bronchoscopy, endobronchial ultrasound (EBUS) bronchoscopy or CT-guided fine-needle biopsy, as already described (13,14).

Indication of surgery was re-considered after post-therapy follow-up exams. Clinical response was based on CT scans or CT-PET, using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (15). If patients presented a clinical downstaging or a volume reduction of the tumor (T) or node (N) component, in particular resolution of N3 disease and of the distant metastasis, a new multidisciplinary discussion was scheduled, evaluating the possibility of salvage surgery. Salvage surgery was defined as lung resection for patients with responses to therapy and demonstrated down-staging.

Before surgical treatment, patients were also evaluated by pneumologists, cardiologists and anesthesiologists to assess the fitness for surgical resection.

Surgery was performed via thoracotomy or minimally invasive approach (thoracoscopic or robotic) in accordance with the stage of the disease, the possible outcomes of previous therapy and the surgeon’s personal skills. When feasible, a minimally invasive approach was always proposed, and surgery was always performed with the aim of performing a complete resection and a radical lymphadenectomy.

For patients with pre-treatment stage IV tumor, lung surgical resection was proposed in cases of observed clinical response in the metastatic site, and if the site was considered susceptible of local control by means of surgical resection or radiotherapy.

Pathological analysis was based on the Pataer criteria (16), defining major pathological response (MPR) in presence of <10% of viable tumors cell in the primary tumor and <70% viable tumor cells in the lymph nodes.

Pathological complete response (pCR) was defined as the absence of residual viable tumor cells in all specimens.

Follow-up was performed every 6 months via total body CT scan, irrespective of some variations in patients’ characteristics or single center protocols.

The primary endpoints evaluated were:

• Rate of pCR;
• Surgical feasibility (in terms of complete resection, lymphadenectomy and kind of resection).

Statistical analysis

Descriptive statistics were used to summarize pertinent study information. The SPSS (version 21.0; SPSS, Inc., Chicago, IL, USA) a licensed statistical program was used for all analyses.

Results

The final analysis was conducted on 30 patients that met the inclusion criteria. The clinical and pre-operative characteristics are reported in Table 1.

About the clinical stage, 22 patients presented stage III disease, while 8 presented stage IV with distant metastases involving brain or adrenal grand, treated with surgery and/or radiotherapy. Target therapy was administrated in 8 cases. Alectinib was administrated all the 4 cases with ALK rearrangement. In the 4 patients with EGFR mutation, 2 were treated with gefitinib, 1 with osimertinib and 1 with afatinib.

The other 22 patients underwent immunotherapy, alone or after chemotherapy (PD-L1 >50% in 19 cases and <1% in 3 cases), according to recent trials results (17,18). Nivolumab was administered in one case only, while pembrolizumab and durvalumab were administered in 15 and 6 cases respectively.

In the 22 patients without distant metastases, initial contraindication to surgery was due to bulky/multi-stations N2 involvement in 8 cases, advanced T stage with concomitant N1/N2 involvement in 8 cases and N3 involvement in 6 patients.

During treatments, 22 (73.4%) patients presented a clinical downstaging, but considering the RECIST criteria, all patients except one with stage IIIA disease, presented a partial or complete response to therapy. In detail, 10 patients that were judged inoperable due to tumor invasion of neighboring structures, presented a clinical response with non-negligible tumor shrinkage that permitted the surgical indication.

Surgical and peri-operative outcomes are summarized in Table 2.

Surgery consisted mostly of lobectomy/bilobectomy (25 patients), and was considered feasible in all cases except for 2, which presented a local involvement that did not allow an anatomical resection, resulting in a wedge resection without lymphadenectomy with macroscopically residual of disease at lymph nodes level. In all the remaining cases, lymphadenectomy was performed, with at least 3 mediastinal stations and 6 nodes removed. In the series, no arterioplasty was performed, while bronchoplasty was necessary in 2 cases (with knife bronchial resection and manual suture).

No peri-operative mortality was reported, while complications occurred in 6 (20%) cases and the mean length of stay of the whole cohort was 5.9±2.8 days. The 30- and 60-day mortality rates were zero.

Pathological examination confirmed the downstaging in 26 patients (Figures 1,2), with 11 (36.6) patients presenting pCR (Table 3). pCR occurred in 37% of adenocarcinoma and 33% of squamous cell carcinomas. pCR was observed in 10 out of the 22 patients treated with immunotherapy (Figures 3,4), 1 patient treated with alectinib and in none of the 4 patients treated with tyrosine kinase inhibitor (TKI).

Figure 1 Partial pathological response after alectinib therapy. (A) At low power, nests of neoplastic cells of adenocarcinoma surround a thick-walled vessel (red arrows). A heavy stromal infiltrate, mainly composed of lymphocytes and histiocytes, is present (H&E, original magnification 40×). (B) At high power, adenocarcinoma nests on a cellular background. On the left, optically clear, cholesterol clefts (yellow arrow) are present within the cytoplasm of a multinucleated giant cell (H&E, original magnification 200×). H&E, hematoxylin and eosin.

Figure 2 Pathological response after alectinib therapy. (A) At low power, regressive changes consisting of necrosis (on the right), bordered by numerous multinucleated giant cells with cholesterol clefts (yellow arrows) (H&E, original magnification 40×). (B) At high power, giant cells with cholesterol clefts (yellow arrows), lympho-histiocytic (xanthomatous) infiltrate, and necrosis (H&E, original magnification 100×). H&E, hematoxylin and eosin.

Figure 3 Complete pathologic response after immunotherapy—case 1. At low power, an almost completely necrotic mass on the right, bordered by a thick, fibrous capsule (white arrows) (H&E, original magnification 20×). H&E, hematoxylin and eosin.

Figure 4 Complete pathologic response after immunotherapy—case 2. At high power, the mass is necrotic and centered by a necrotic vessel (green arrows). Few inflammatory cells are present (H&E, original magnification 100×). H&E, hematoxylin and eosin.

Conversely, as previously mentioned, macroscopic residual disease was found in 2 patients, while in other 2 cases, the presence of microscopic residual disease was in doubt, due to the consideration of the extracapsular nodal invasion and the tumor margin next to the resection line.

Adjuvant therapy (platinum-based therapy) was administered in 20 patients, while 4 patients received a sort of maintenance therapy of the original adopted drug.

During a median follow up of 12 months (range, 2–83 months), 5 patients experienced a recurrence and 4 died due to cancer related causes. Recurrence resulted locally in 3 cases (intrathoracic lymph nodes, pleura and lung), while both local and distant recurrence were observed in 2 cases (brain + lung and lung + pleura + bones).

The recurrence detected in 5 patients occurred after surgery in months 2, 5, 9, 10 and 21 respectively. Out of these 5 patients, 2 cases presented persistent N2 involvement, 2 cases had ypT3–T4 disease, while the last case had ypT2N0.

Discussion

In this study, we reported the surgical outcome of patients who underwent salvage surgery after target therapy or immunotherapy in originally inoperable NSCLC, thereby investigating the feasibility and the risk of a surgical approach in these cases.

We found a non-negligible complication rate of about the 20%. However, none of these complications was life threatening and they all required only medical management. Moreover, we did not report any fatal case of 30- and 60-day mortality.

Our results are in line with previous studies concerning the surgical outcomes after salvage surgery (19-22), in reporting rare peri-operative deaths. However, we also reported a complication rate of about 20–40%, even if grade III complications according to the Clavien-Dindo classification are quite uncommon.

The peri-operative outcome in patients who are candidates for salvage surgery after target therapy or immunotherapy should be considered the first step to propose this treatment in a selected class of patients who presented an important response to therapy. Some information will be available from different prospective studies evaluating these drugs in a neoadjuvant setting (3,23,24), although salvage surgery may present some differences compared to scheduled surgery after neoadjuvant therapy. In case of scheduled surgery, the nodal involvement is usually limited to 1–2 mediastinal stations with a non-bulky involvement and potential technical operability, evaluated before the induction treatment (4,25). Conversely, in case of salvage surgery, pre-treatment nodal involvement may have been more extensive and surgery may have been contraindicated due to local invasion or high risk of complication and incomplete resection.

Kobayashi et al. (21) reported a significant difference, comparing extent of resection in patients that underwent salvage surgery vs the induction group, with a pneumonectomy rate of the 30%. In their study, salvage surgery was indicated after chemoradiation. while in the studies of Ohtaki et al. (20) and Higuchi et al. (19), the pneumonectomy rates were 5.6% and 0% respectively after TKI and immunotherapy, and an extended resection was present in about the 15–30% of cases. In our study, pneumonectomy was performed in 10% of the whole cohort, and in particular in all cases after immunotherapy. Despite the relatively small cohort of patients, these data are not negligible, and should be considered. Indeed, pneumonectomy is a kind of intervention with high complication risks and with implications on quality of life terms, performed in patients with locally advanced or metastatic tumor. For this reason, the indication of this resection for these patients should be carefully evaluated. Another issue was about the surgery feasibility in patients treated with immunotherapy, that presented fibrosis of the peri-vascular and nodal tissue, thereby indicating an increased risk of extended resection. For this reason, future studies should also investigate if the kind of pre-operative treatment influences intraoperative outcomes, not only in terms of morbidity and mortality, but also in terms of pneumonectomy rate, incomplete resection and nodal dissection.

This could help in clarifying if salvage surgery in these patients is really safe or almost comparable to induction therapy and so recommended for specific patients. Moreover, in the future, longer follow-up periods will also clarify if surgery in these cases represent a real survival benefit compared to maintenance therapy.

In this cohort of patients, pCR was present in 11 (36%) patients, showing an excellent response to therapy. This result could reflect potential improvement in terms of survival, even if longer follow-up times and larger studies are needed to confirm this possibility. In this study, the mean follow up was quite short, so considerations on survival should be carefully taken.

The prognostic role of pathological and in particular, pCR after induction therapy is a matter of debate. However, it could be used as a surrogate for survival, even if some issues concerning this still need to be clarified (26). For example, the tissue assessment and the vital cancer cells detection may be hard to be determined, due to the presence of fibrosis, scar and induction therapy effects. As a result, the actual definition of “complete pathological response” may be difficult to be assessed. Furthermore, in some cases, lymphadenectomy was limited due to technical difficulties, making the pathological evaluation incomplete. Concerning the other kind of response, an interesting analysis is the one from Betticher and colleagues (27), who evaluated the degree of pathologic response in terms of overall survival. In survival analysis, patients with >60% pathologic response had median overall survival of 61 months compared to 22 months in those with <60% response (P=0.03).

In the considerations from William and colleagues (28), studying patients after a follow up period, only pathologic stage and pathologic response (≤10% viable tumor) were associated with overall survival in multivariate analysis [hazard ratio (HR) =2.39, P=0.05 if >10% viable tumor].

Nonetheless, we are living a period of numerous and rapid innovations in terms of new drugs and protocols to be tested, and assessing the results based on overall or disease-free survival may be a waste time. It is indeed understandable that different ongoing phase 3 trials on induction therapy for NSCLC included pathological response as a co-primary or independent primary endpoint (24,26,29). Compared to the past, pathological response as a surrogate endpoint seemed to be quite reliable, by-passing the limits of long follow-ups and waiting time to assess results of prospective trials such as the ANITA, which results were published 12 years after the enrollment of the first patient (30).

To support this concept, different studies reported excellent survival outcomes in patients who presented pCR after induction therapy.

Martinez-Meehan et al. (31), in a large study with 759 patients who presented pCR after induction therapy, reported a 5-year overall survival rate of 60.9%, 66.1% and 58.6% in pre-induction stages I, II and III respectively, without statistically significant differences among stages. Moreover, the authors also reported a significant worse survival in patients with less than 10 harvested lymph nodes and in patients who underwent pneumonectomy.

These results are similar to those of Lococo et al. (13), reporting a 5-year overall and disease-free survival of 56% and 45% respectively, in patients with pCR. More in detail, the authors reported a significant worse outcome in pneumonectomy patients, with a median survival of 37.0±27.9 vs. 86.0±15.6 months in lobectomy. Guerrera and colleagues (32), in a multicentric study, analyzing survival and oncological outcome after salvage surgery in patients treated with ICIs and targeted therapy (TT), they observed that pCR was an independent prognostic predictor of improved survival (P=0.025) and they could conclude that patients selected for salvage surgery after ICI or TT had reasonable post-operative and long-term outcomes. Similar outcomes were reported recently by Schiavon et al. (33) who demonstrated, after salvage surgery, a trend toward a correlation between pCR and reduction of mortality and relapse.

Based on these reports, pathological response could be potentially considered as a good surrogate marker after induction therapy, after salvage surgery, target therapy or immunotherapy. Hence, it would be essential to know and predict pathological response rates after these treatments.

In our study, we noticed pCR in 36% of the cases, which is in line with reports of Higuchi et al. (19) (30% after immunotherapy) and Lococo et al. (12) (50% after alectinib), but quite higher than the 8% reported by Ohtaki et al. after TKI treatment (20).

To the state of the art, only few studies with a limited number of patients have considered this parameter after salvage surgery, so the identification of the real response rates after these treatments is far from being defined. Moreover, as reported by Lococo (12), the time between the beginning of therapy and the indication of surgery may be extremely long, and this may influence the pathological response. Another possibility taken into account is that, this rate may effectively vary among different therapies or histology. In this study, in the immunotherapy group, all the patients except achieved pCR, while in the TKI group they all obtained all downstaging, but not pCRs.

Despite the small cohort size, it is reasonable to suppose that the type of response and response rate may vary according to the different therapies. Therefore, it may be valid for some groups of patients and not for others. Indeed, future studies with a larger cohort including ongoing trials, will clarify this issue and guide physicians to the most effective treatment strategy.

Another crucial point to be considered for such treatments is patient selection. Certainly, the identification of patients who may benefit from this treatment with a good performance status, have a higher chance to achieve a complete resection without pneumonectomy and also, predict pathological response. Indeed, long-term analysis is fundamental to identify patients with a significant survival improvement and to assess if all patients may benefit from salvage surgery or only those who present a complete or MPR.

This study presents some limitations, due to its retrospective nature, small sample size (30 patients) and the heterogeneity of the patients involved (different stages before treatment and different treatment applied before surgery). Another limitation is the multi-centric nature of the study with possible variations in terms of administered therapies and schedules. The immunotherapy drug varied, according to the different protocol in study in each center all these factors concours to make our cohort very heterogeneous, so that results on efficacy and survival are not still far from being generalizable.

Finally, very short follow-up periods serve as major limitations, due to the inclusion of recently treated patients with reduced observation times. Therefore, to make our results more reliable, we avoided performing statistical analysis on survival rates to reduce bias regarding the heterogeneity of the patients and the relatively small number of cases. Also, it is interesting to note that three patients with follow-ups longer than 3 years were alive and free from disease after 41, 49 and 83 months after surgery, and presented a pathological stage of ypT0N0, ypT1N0 and ypT3N0 respectively.

On the other hand, this is one of the largest studies reporting the peri-operative results of patients that underwent salvage surgery after immunotherapy or target therapies, with the aim to uncover the possible advantages and limits of this approach. Moreover, these patients were all managed by a multidisciplinary team, working together to identify the best treatment strategy in this clinical scenario. On the base of these encouraging results, a larger study, with a more homogenous cohort is going to be planned, to better assess the predictive factors of the pathological response (i.e., duration of therapy) so to submit to surgery patients who really could benefit from it.

Conclusions

Salvage surgery after target therapy or immunotherapy seems to be a feasible approach in selected patients who present clinical response after therapy with acceptable results in terms of peri-operative morbidity.

Although the pCR rate of about 36% is encouraging, survival outcomes need to be evaluated with longer follow-up times.

Acknowledgments

Language revision has been performed by Akshaya Balamurugan, MD, Thoracic Surgery, Università Cattolica del Sacro Cuore, Rome, Italy.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-387/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-387/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-387/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-387/coif). The 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 and its subsequent amendments. The study was approved by institutional ethics board of Fondazione Policlinico Universitario A. Gemelli IRCCS (number of protocol 0012949/22 on 13 April 2022) and individual consent for this study was waived due to the retrospective nature.

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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