Survival impact of pathologic features after salvage lung resection following definitive chemoradiotherapy or systemic therapy for initially unresectable lung cancer

doi:10.21203/rs.3.rs-3439945/v1

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Survival impact of pathologic features after salvage lung resection following definitive chemoradiotherapy or systemic therapy for initially unresectable lung cancer

https://doi.org/10.21203/rs.3.rs-3439945/v1

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Purpose

Salvage surgery for non-small cell lung cancer (NSCLC) is expected to become increasingly more common; however, the association between pathologic features and the postoperative prognosis remains unclear. This study aimed to clarify the survival impact of pathologic characteristics after salvage lung resection.

Methods

Twenty-three patients who underwent salvage surgery following definitive chemoradiotherapy or systemic therapy for initially unresectable NSCLC from 2010 to 2020 were enrolled in this study. The tumor slides were reviewed to determine the size of the tumor bed and the proportions of viable tumor, necrosis, and stroma according to the recent recommendations from the International Association for the Study of Lung Cancer (IASLC).

Results

Initially, 18 patients (79%) had clinical stage IIIB-IV disease. Six (26%) received chemoradiotherapy and 17 (74%) received systemic therapy alone. A major pathologic response (MPR, ≤10% of viable tumor) was observed in 6 patients, and 4 patients achieved a pathological complete response. The 3-year overall and recurrence-free survival rates (OS and RFS) were 78.6% and 59.2%, respectively. There was no significant difference in OS between patients with and without MPR, and even non-MPR patients achieved a favorable 3-year OS of 70.2%. Meanwhile, patients with high (≥30%) stroma showed significantly better OS than those with low (<30%) stroma (3-year OS: 100% vs. 23.3%, p < 0.001).

Conclusion

The proportion of stroma based on the recent IASLC recommendations was an important feature for predicting long-term survival after salvage lung resection. A low-stroma signature may serve as an indicator for considering proactive postoperative therapies after salvage surgery.

Trial registration number and date of registration

This study was approved by the institutional ethics committee of Keio University School of Medicine on September 16^th, 2020 (registration no. 20200092).

Non-small cell lung cancer

salvage surgery

viable tumor

stroma

prognosis

Salvage surgery is a relatively new entity in the treatment of primary lung cancer. It originally referred to surgical resection as the only remaining treatment option for patients with locoregional residual or recurrent lesions after curative-intent radiotherapy or chemoradiotherapy for locally advanced (stage III) non-small cell lung cancer (NSCLC) (Shepherd et al. 1991; Bauman et al. 2008). Recently, due to the introduction of novel regimens such as molecularly targeted therapy and immune checkpoint inhibitors, some patients, even those with stage IV NSCLC, experience isolated local recurrence or residual disease after systemic therapy under the remission of distant metastases, and selected patients are indicated for salvage surgery (Hishida et al. 2010; Ohtaki et al. 2021; Chaft et al. 2017). Candidates for salvage lung resection will be increased, especially in the initial stage IV population due to further improvements in medical oncology, so that accurate assessment of the prognosis is mandatory after salvage surgery.

Pathological assessment of resected specimens has been a gold standard for predicting survival after surgical resection for NSCLC (Goldstraw et al. 2016), and several studies have attempted to clarify the association between the pathological change caused by neoadjuvant therapy and the prognosis after surgery (Junker et al. 1997, 2001; Hellmann et al. 2014; Pataer et al. 2012; Qu et al. 2019; Machtay et al. 2004). Some previous studies showed that a major pathological response (MPR), defined as 10% or less of residual viable tumor, was a surrogate marker for a favorable prognosis (Junker et al. 1997, 2001; Hellmann et al. 2014; Machtay et al. 2004), and the International Association for the Study of Lung Cancer (IASLC) recently recommended detailed pathological assessment for resected specimens receiving neoadjuvant therapy followed by surgery (Travis et al. 2020). Surgical research on salvage surgery has been gradually increasing; however, no study has yet evaluated the association between pathological features and the prognosis in detail after salvage surgery.

This study aimed to analyze clinical and pathologic characteristics of patients who underwent salvage surgery and to identify pathological indicators for predicting postoperative survival.

Ethical statement

This study was approved by the institutional ethics committee of Keio University School of Medicine on 16th September 2020 (approval no. 20200092) and informed consent from each patient was waived due to the retrospective nature of the study.

Study population

We retrospectively reviewed the medical records of patients who underwent surgical resection for primary lung cancer between January 2010 and December 2020 and identified patients who underwent salvage surgery. In this study, salvage surgery was defined as lung resection for locally residual or regrowing primary tumor after definitive chemoradiotherapy or systemic therapy for initially unresectable lung cancer. Patients who received induction chemotherapy or chemoradiotherapy with an initial plan for subsequent surgery were strictly excluded. As for treatment before surgery, we defined switching medication as the transition to a next treatment line and regarded the use of the same medication as remaining in the same treatment line. Salvage surgery for initial stage IV disease was indicated only when all distant and mediastinal/cervical/contralateral hilar nodal metastatic lesions disappeared during systemic therapy with or without additional local therapy on imaging modalities including computed tomography (CT), fluorodeoxyglucose positron emission tomography (FDG-PET), and brain magnetic resonance imaging (MRI) and the primary tumor with or without ipsilateral hilar nodes was deemed to be completely resectable. Tumors were classified in accordance with the fifth edition of the WHO classification of thoracic tumors and the TNM classification was determined according to the UICC eighth edition. Postoperative complications were classified as grade 2 or more according to Common Terminology Criteria for Adverse Events (National Cancer Institute 2017).

Histopathologic evaluation

The resected specimens were fixed with 10% formalin and embedded in paraffin. The tumors were cut into 5 to 10 mm slices, and serial 4 µm sections were stained with haematoxylin and eosin. During this study period, the tissue fixation and staining protocols of our institution remained unchanged. We routinely evaluated information regarding histologic type, pathological tumor size, pathological TNM status, lymphovascular invasion, and pleural invasion, which was collected from a pathological report for each patient. In addition, in this study, pathologic changes in response to preoperative therapy were evaluated to consider the tumor bed and the components according to the recent recommendations from the IASLC Pathology Committee published in 2020 (Travis et al. 2020). The stained slides were initially scanned and digitally converted into virtual slides using a NanoZoomer-XR C12000 slide scanner (Hamamatsu Photonics, Hamamatsu, Japan). The virtual slides were viewed and evaluated using NDP.view2 version 2.9 (Hamamatsu Photonics, Hamamatsu, Japan). The tumor bed was defined as the area where the original pre-treatment tumor was considered to be located, and consisted of three components: viable tumor, necrosis, and stroma (Travis et al. 2020). We evaluated the percentages of these three components within the tumor bed of all slides containing tumor in 5% increments so that these three components added up to 100% based on a previous recommendation (Fig. 1a, b) (Qu et al. 2019; Travis et al. 2020). Next, we measured the area of each tumor bed with viewer software and the total proportion of each component in each case was determined by using the area ratio of the tumor bed. As shown in the formula below, if the tumor bed was located in three slides with an area of X₁, X₂, and X₃ mm² and the percentages of viable tumor within each tumor were A₁%, A₂%, and A₃%, respectively, the total proportion of each component was calculated by multiplying A₁, A₂, and A₃ by X₁, X₂, and X₃, respectively, and dividing the sum of the multiplications by the total area of the tumor bed (X₁ + X₂ + X₃).

MPR was defined as 10% or less of viable tumor. A pathological complete response (pCR) was defined as no viable tumor in resected specimens and no detectable metastases according to preoperative imaging test.

Statistical analyses

Overall survival (OS) after surgery and initial treatment were defined as the time from the date of salvage surgery and first line treatment initiation until death from any cause, respectively. Recurrence-free survival (RFS) was defined as the time from salvage surgery until tumor recurrence or death from any cause. The patients were divided into two groups based on the percentage of each histologic component within the tumor bed, and OS and RFS were calculated using the Kaplan-Meier method. The differences in OS between groups were evaluated using a log-rank test. The optimal cut-off percentages of histologic components for predicting postoperative survival were estimated using the differences in OS for each cut-off percentage of the histologic components. Univariate analysis was performed with a log-rank test, and multivariable analysis was not performed because of the small number of patients. All statistical tests were two-sided, and a p value of less than 0.05 was considered significant. The statistical analyses were performed using SPSS Statistics software (version 27, IBM SPSS Statistics for Windows, IBM Corp., Armonk, NY, USA). Time-dependent receiver operating characteristic (ROC) analysis was conducted using EZR (Saitama Medical Centre, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (version 4.0.2, The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R commander (version 1.52) designed to add statistical functions frequently used in biostatistics.

Clinicopathologic characteristics

During the study period, 1767 consecutive patients underwent surgical resection for primary lung cancer. Among them, a total of 23 patients (1.3%) underwent salvage surgery. Patient characteristics are shown in Table 1. The median age at salvage surgery was 61 years (IQR [interquartile range], 32-80 years) and 12 patients (52%) were women. Clinical stage IV was the most frequent initial stage and was found in 14 patients (61%), followed by stage IIIB in 4 (18%). One patient with clinical stage IIB had combined small cell carcinoma diagnosed by pre-treatment biopsy and received definitive chemoradiotherapy. In terms of treatment before surgery, 6 (26%) received concurrent or sequential definitive chemoradiotherapy and 17 (74%) received systemic therapy. Among 8 patients who received chemotherapy alone, 5 received carboplatin-based doublets and 3 received cisplatin-based doublets. Eight patients (35%) received epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with or without chemotherapy at the initial treatment, while the preoperative use of any EGFR-TKIs was identified in 11 (48%). One patient received a combination of carboplatin, nab-paclitaxel, and the immune checkpoint inhibitor pembrolizumab. Twelve patients (52%) underwent salvage surgery just after 1^st line therapy. On the other hand, the maximum number of treatment lines before surgery was 4 in one patient. The median time from the initiation of 1^st-line therapy to surgery was 24.6 months (IQR, 8.3-46.2 months). The indication for salvage surgery was residual primary tumor in 13 patients (57%) and regrowth primary tumor in 10 patients (43%).

The type of surgery and pathological characteristics are shown in Table 2. Lobectomy was the most frequently performed procedure (82%). One patient underwent sleeve lobectomy and one required pulmonary arterioplasty. Nine patients (39%) received systemic therapy postoperatively by using chemotherapy or EGFR-TKI. Postoperative complications occurred in 5 patients (22%) and included pneumonia in 2 patients, prolonged air leakage (>5 days) in one, excessive pleural effusion in one, and wound infection in one. There was no 90-day postoperative mortality.

Adenocarcinoma was the most common histologic type (88%). Complete R0 resection was achieved in 20 patients (87%). In a detailed pathological evaluation of resected specimens, the median proportions of viable tumor, necrosis, and stroma within the tumor bed were 50% (IQR, 15-73%), 0% (IQR, 0-5%), and 40% (IQR, 20-83%), respectively. MPR and pathological stage of 0, which is consistent with pCR, were observed in 6 patients (27%) and 4 patients (17%), respectively. Of 4 patients with pathological stage IV disease, 2 had pleural dissemination in resected lung surface and the other 2 had brain metastases that were treated with stereotactic radiotherapy and craniotomy before salvage lung resection.

Postoperative survival

The median follow-up time after salvage surgery was 33 months (IQR, 18-81 months). During follow-up, a total of 11 patients recurred and 4 patients died. Distant lesion was a frequent site of recurrence (7 patients), and 4 patients developed isolated locoregional recurrence. The 3- and 5-year RFS were 59.2% (95% CI: 38.4-80.0%) and 53.3% (95% CI: 31.5-75.1%), respectively (Fig. 2a). Both 3- and 5-year OS after surgery were 78.6% (95% CI: 59.8-97.4%) (Fig. 2b), and a total of 8 patients (35%) survived for more than 5 years after surgery. Both 5- and 10-year OS after initial treatment were 79.5% (95% CI: 61.5-97.5%) (Fig. 2c).

Prognostic factors after salvage surgery

Figures 3A-C show the results of the changes in estimated 3-year OS and p value according to the serial cut-off values of viable tumor, necrosis, and stroma. Regarding viable tumor, nonsequential changes were seen in the differences in 3-year OS and p value for all of the cut-off values (Fig. 3a). With a cut-off value of 10%, which was the criteria for MPR, the 3-year OS tended to be better in patients with MPR compared to those without it (100% vs. 70.2%); however, this difference was not significant (p = 0.187) and even the non-MPR group showed relatively favorable OS. No optimal cut-off value was identified for the proportion of necrosis because of no significant differences between groups at any cut-off value (Fig. 3b). On the other hand, the proportion of stroma showed continuous changes in 3-year OS and p value by serial cut-off values (Fig. 3c). Time-dependent ROC analysis for estimating 3-year OS showed that 30% was the optimal cut-off value of stroma (Fig. 4a), and the high-stroma (≥ 30%) group showed significantly better OS than the low-stroma (< 30%) group (3-year OS: 100% in high stroma vs. 23.3% in low stroma, p<0.001). Although all 6 patients in the MPR group were also included in the high-stroma group and showed excellent 3-year OS of 100%, the survival in the non-MPR group clearly depended on the proportion of stroma. The 3-year OS in patients with non-MPR and high-stroma tumor was 100%, which was better than 23.3% in patients with non-MPR and low-stroma tumor (Fig. 4b). Among 8 patients who survived for more than 5 years after surgery, 7 had high-stroma tumor. Although we analyzed RFS by cut-off values for all three histologic components, no statistically significant differences in RFS were found in any of the cut-off values. Table 3 shows the results of univariate analysis to identify prognostic factors affecting OS by including MPR status, the proportion of stroma, and conventional clinicopathological factors. The high-stroma feature (≥ 30%) in the resected specimen was the only prognostic factor affecting OS.

This study analyzed clinicopathologic features and the survival outcome in patients who underwent salvage lung resection for initially unresectable NSCLC. We particularly focused on the pathologic features and changes in the resected primary tumor in detail and clarified the relationship between the pathologic signature and the prognosis. We observed MPR in 6 patients (27%) and they showed an excellent 3-year OS of 100%. However, the proportion of viable tumor had nonsequential effects on OS and the non-MPR group also showed a favorable 3-year OS of 70.2%. Survival curves of both the MPR and non-MPR groups were not statistically different from each other, and this implied that selected patients even in the non-MPR group could survive for long term. This suggested that MPR did not act as an absolute indicator for predicting OS after salvage surgery. In contrast, the percentage of stroma was directly related to a serially positive effect on OS, and ROC analysis showed that high (\(\ge\)30%) stroma was associated with favorable OS. Even in the non-MPR group, patients who had a high-stroma signature showed excellent 3-year OS of 100%, and the present study urged us to consider the percentage of stroma as a useful prognostic indicator after salvage surgery.

Past studies have investigated the relationship between histologic changes and the prognosis, particularly in patients who underwent induction therapy followed by surgery for initially operable NSCLC (Junker et al. 1997, 2001; Hellmann et al. 2014; Pataer et al. 2012; Qu et al. 2019; Chaft et al. 2013; Mouillet et al. 2012; Liu-Jarin et al. 2003; Yamane et al. 2010). Although most studies were performed before the IASLC recommendations were released in 2020 and histologic evaluation has been basically performed based solely on the percentage of viable tumor (Junker et al. 1997, 2001; Hellmann et al. 2014; Chaft et al. 2013), the sparseness of viable tumor such as pCR or MPR has been reported to an important factor for a favorable prognosis and non-MPR has been recognized as an ominous sign almost without exception (Junker et al. 1997, 2001; Pataer et al. 2012). On the other hand, for salvage surgery, no published studies have examined the details regarding the pathologic characteristics of resected specimens. Our study was the first to conduct a detailed analysis of pathologic specimens after salvage surgery based on the recent IASLC recommendations. The current results were remarkable in that non-pCR or non-MPR was not necessarily associated with a poor prognosis and the sparseness of viable tumor did not seem to serve as an absolute prognostic indicator after salvage surgery. This is believed to be due to the differences in the types of surgery between induction therapy followed by surgery and salvage surgery. In the induction setting, surgery is generally conducted for residual tumor after the patient responds to induction therapy. However, salvage surgery is indicated for resection of not only residual lesion but also regrown lesion. The percentage of viable tumor is essentially increasing when surgery is indicated for a regrown lesion irrespective of the response to non-surgical treatment before surgery. If the regrowth of primary tumor is positively associated with the systemic progression of disease, an abundance of viable tumor can predict a poor prognosis. However, if the initial metastasized lesions are well controlled by non-surgical treatment before salvage surgery but the primary tumor alone shows regrowth, surgery can contribute to long-term survival. Consequently, the percentage of viable tumor may not correctly reflect the systemic effect of non-surgical treatment before salvage surgery. In contrast, some portions of stroma are generated by non-surgical treatment before salvage surgery, and they remain in the tumor bed regardless of whether the primary tumor is residual or regrown. The abundance of stroma in the tumor bed is potentially associated with both the responsiveness to non-surgical therapy before salvage surgery and even the prognosis more strongly than the viable tumor. Indeed, among 8 patients who survived for more than five years after salvage surgery, 5 did not achieve MPR and 3 showed a high percentage of viable cells (range, 60–70%); however, all 8 patients had stroma with a range of 20–100% and 7 showed a high proportion (\(\ge\)30%). There was only a scant necrotic component, and the majority of the tumor bed consisted of viable tumor and stroma components. The three constituent components add up to 100% (Travis et al. 2020); therefore, the percentage of stroma might have an inverse relationship with the viable tumor. Although an extremely high proportion of viable tumor indicated a worse prognosis, the high-stroma feature (\(\ge\)30%) implied that the percentage of viable tumor was \(<\)70% at most, so that there was not much viable tumor under the condition of an abundance of stroma. Taken together, these results suggest that a high proportion of stromal component in a resected specimen can potentially be a useful predictor of long-term survival after salvage lung resection. On the other hand, a low-stroma signature is an unfavorable predictor of survival and may be a potential indicator to consider aggressive adjuvant therapy postoperatively in the future.

In previous series, 3- and 5-year OS rates after salvage surgery have been reported to range widely from 32–75% and from 20–75%, respectively (Bauman et al. 2008; Ohtaki et al. 2021; Yang et al. 2015; Sonobe et al. 2019; Suzuki et al. 2022; Shimizu et al. 2021; Casiraghi et al. 2017; Sawada et al. 2017; Kobayashi et al. 2020). The present study showed that the 3- and 5-year OS rates were both 78.6%, which is encouraging. Our data were for patients who were treated within the past 10 years and enrolled patients received not only conventional chemotherapy but also novel targeted therapy or immunotherapy in the pre- or post-operative period. The study period and many options of systemic therapy might have influenced the favorable survival outcome.

This study has several limitations. First, this study was a single-institution retrospective study, and the number of enrolled patients was small. The current study was exploratory and further studies with a large sample size will be needed to confirm the present results. Second, non-surgical treatment before and after salvage surgery and the histological type varied. The optimal cut-off percentage of viable tumor for predicting survival after induction therapy has been reported to differ between adenocarcinoma and squamous cell carcinoma (Qu et al. 2019). Although we analyzed all patients together as a single cohort regardless of their histology and pre- and post-operative treatment due to the limited number of patients, it would be desirable to also perform subgroup analyses according to the type of treatment and histology using a larger cohort. Nonetheless, the current study was remarkable in that, to the best of our knowledge, this was the first study to demonstrate the importance of the proportion of stroma for predicting survival after salvage lung resection. Another strength of this study was the method used to measure the proportion of stroma. We adopted the recent IASLC recommendations, which can be easily done by a usual histologic assessment and can be easily introduced into clinical practice.

The percentage of stroma in the tumor bed of the resected specimen was an important pathologic signature for predicting OS after salvage surgery for initially unresectable NSCLC. A low-stroma signature in the resected specimen may be an indicator for proactive post-operative adjuvant therapy to improve OS. Future multiple-institution studies with a large number of patients will be needed to confirm the current results.

Acknowledgement

The authors would like to thank Yasunori Sato, Department of Preventive Medicine and Public Health, Keio University School of Medicine for statistical suggestions.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing Interests

Financial interests: Author Naoyuki Oka, Tomoyuki Hishida, Kaoru Kaseda, Yu Okubo, Kyohei Masai, Keisuke Asakura, and Hisao Asamura have received research grants to their institution from Covidien Japan CO., LTD., Johnson & Johnson K.K., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Kyowa Kirin Co., Ltd., and Eli Lilly Japan K.K. All other authors declare that there are no financial interests.

Author contributions

Conceptualization: Naoyuki Oka, Tomoyuki Hishida; Data curation: Naoyuki Oka, Tomoyuki Hishida, Kaoru Kaseda, Yuri Suzuki, Yu Okubo, Kyohei Masai, Keisuke Asakura; Formal analysis: Naoyuki Oka; Investigation: Naoyuki Oka, Tomoyuki Hishida, Yuri Suzuki, Katsura Emoto; Writing- original draft: Naoyuki Oka, Tomoyuki Hishida; Writing- review & editing: Tomoyuki Hishida, Kaoru Kaseda, Yu Okubo, Kyohei Masai, Keisuke Asakura, Hisao Asamura; Methodology: Katsura Emoto; Project administration and Supervision: Hisao Asamura

Data Availability

The data underlying this article will be shared on reasonable request to the corresponding author.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the institutional ethics committee of Keio University School of Medicine on September 16^th, 2020 (approval no. 20200092).

Consent to participate and to publish

Informed consent from each patient was waived due to the retrospective nature of the study.

Bauman JE, Mulligan MS, Martins RG, Kurland BF, Eaton KD, Wood DE (2008) Salvage lung resection after definitive radiation (>59 Gy) for non-small cell lung cancer: surgical and oncologic outcomes. Ann Thorac Surg 86:1632-1638. https://doi.org/10.1016/j.athoracsur.2008.07.042
Casiraghi M, Maisonneuve P, Piperno G, Bellini R, Brambilla D, Petrella F, et al (2017) Salvage surgery after definitive chemoradiotherapy for non-small cell lung cancer. Semin Thorac Cardiovasc Surg 29:233-241. https://doi.org/10.1053/j.semtcvs.2017.02.001
Chaft JE, Hellmann MD, Velez MJ, Travis WD, Rusch VW (2017) Initial experience with lung cancer resection after treatment with T-cell checkpoint inhibitors. Ann Thorac Surg 104:e217-e218. https://doi.org/10.1016/j.athoracsur.2017.03.038
Chaft JE, Rusch V, Ginsberg MS, Paik PK, Finley DJ, Kris MG, et al (2013) Phase II trial of neoadjuvant bevacizumab plus chemotherapy and adjuvant bevacizumab in patients with resectable nonsquamous non-small-cell lung cancers. J Thorac Oncol 8:1084-1090. https://doi.org/10.1097/JTO.0b013e31829923ec
Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, et al (2016) The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 11:39-51. https://doi.org/10.1016/j.jtho.2015.09.009
Hellmann MD, Chaft JE, William WN Jr, Rusch V, Pisters KM, Kalhor N, et al (2014) Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint. Lancet Oncol 15:e42-50. https://doi.org/10.1016/s1470-2045(13)70334-6
Hishida T, Nagai K, Mitsudomi T, Yokoi K, Kondo H, Horinouchi H, et al (2010) Salvage surgery for advanced non-small cell lung cancer after response to gefitinib. J Thorac Cardiovasc Surg 140:e69-71. https://doi.org/10.1016/j.jtcvs.2010.06.035
Junker K, Langner K, Klinke F, Bosse U, Thomas M (2001) Grading of tumor regression in non-small cell lung cancer : morphology and prognosis. Chest 120:1584-1591. https://doi.org/10.1378/chest.120.5.1584
Junker K, Thomas M, Schulmann K, Klinke F, Bosse U, Müller KM (1997) Tumor regression in non-small-cell lung cancer following neoadjuvant therapy. Histological assessment. J Cancer Res Clin Oncol 123:469-477. https://doi.org/10.1007/bf01192200
Kobayashi AK, Horinouchi H, Nakayama Y, Ohe Y, Yotsukura M, Uchida S, et al (2020) Salvage surgery after chemotherapy and/or radiotherapy including SBRT and proton therapy: a consecutive analysis of 38 patients. Lung Cancer 145:105-110. https://doi.org/10.1016/j.lungcan.2020.04.013
Liu-Jarin X, Stoopler MB, Raftopoulos H, Ginsburg M, Gorenstein L, Borczuk AC (2003) Histologic assessment of non-small cell lung carcinoma after neoadjuvant therapy. Mod Pathol 16:1102-1108. https://doi.org/10.1097/01.Mp.0000096041.13859.Ab
Machtay M, Lee JH, Stevenson JP, Shrager JB, Algazy KM, Treat J, et al (2004) Two commonly used neoadjuvant chemotherapy regimens for locally advanced stage III non-small cell lung carcinoma: long-term results and associations with pathologic response. J Thorac Cardiovasc Surg 127:108-113. https://doi.org/10.1016/j.jtcvs.2003.07.027
Mouillet G, Monnet E, Milleron B, Puyraveau M, Quoix E, David P, et al (2012) Pathologic complete response to preoperative chemotherapy predicts cure in early-stage non-small-cell lung cancer: combined analysis of two IFCT randomized trials. J Thorac Oncol 7:841-849. https://doi.org/10.1097/JTO.0b013e31824c7d92
National Cancer Institute (2017) Common Terminology Criteria for Adverse Events (CTCAE); Version 5.0. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm (19 April 2021, date last updated).
Ohtaki Y, Shimizu K, Suzuki H, Suzuki K, Tsuboi M, Mitsudomi T, et al (2021) Salvage surgery for non-small cell lung cancer after tyrosine kinase inhibitor treatment. Lung Cancer 153:108-116. https://doi.org/10.1016/j.lungcan.2020.12.037
Pataer A, Kalhor N, Correa AM, Raso MG, Erasmus JJ, Kim ES, et al (2012) Histopathologic response criteria predict survival of patients with resected lung cancer after neoadjuvant chemotherapy. J Thorac Oncol 7:825-832. https://doi.org/10.1097/JTO.0b013e318247504a
Qu Y, Emoto K, Eguchi T, Aly RG, Zheng H, Chaft JE, et al (2019) Pathologic assessment after neoadjuvant chemotherapy for NSCLC: importance and implications of distinguishing adenocarcinoma from squamous cell carcinoma. J Thorac Oncol 14:482-493. https://doi.org/10.1097/JTO.0b013e318247504a
Sawada S, Suehisa H, Ueno T, Yamashita M (2017) Eight cases of salvage pulmonary resection for residual disease or isolated local recurrence detected after definitive chemoradiotherapy for N2 Stage-IIIA lung cancer. Asian J Surg 40:95-99. https://doi.org/10.1016/j.asjsur.2015.05.006
Shepherd FA, Ginsberg R, Patterson GA, Feld R, Goss PE, Pearson FG, et al (1991) Is there ever a role for salvage operations in limited small-cell lung cancer?. J Thorac Cardiovasc Surg 101:196-200. https://doi.org/10.1016/S0022-5223(19)36752-2
Shimizu K, Ohtaki Y, Suzuki K, Date H, Yamashita M, Iizasa T, et al (2021) Salvage surgery for non-small cell lung cancer after definitive radiotherapy. Ann Thorac Surg 112:862-873. https://doi.org/10.1016/j.athoracsur.2020.10.035
Sonobe M, Yutaka Y, Nakajima D, Hamaji M, Menju T, Ohsumi A, et al (2019) Salvage surgery after chemotherapy or chemoradiotherapy for initially unresectable lung carcinoma. Ann Thorac Surg 108:1664-1670. https://doi.org/10.1016/j.athoracsur.2019.06.087
Suzuki S, Asakura K, Okui M, Sawafuji M, Shigenobu T, Tajima A, et al (2022) Safety and efficacy of salvage surgery for non-small cell lung cancer: a retrospective study of 46 patients from four Keio-affiliated hospitals. Gen Thorac Cardiovasc Surg 70:891-899. https://doi.org/10.1007/s11748-022-01808-4
Travis WD, Dacic S, Wistuba I, Sholl L, Adusumilli P, Bubendorf L, et al (2020) IASLC multidisciplinary recommendations for pathologic assessment of lung cancer resection specimens after neoadjuvant therapy. J Thorac Oncol 15:709-740. https://doi.org/10.1016/j.jtho.2020.01.005
Yamane Y, Ishii G, Goto K, Kojima M, Nakao M, Shimada Y, et al (2010) A novel histopathological evaluation method predicting the outcome of non-small cell lung cancer treated by neoadjuvant therapy: the prognostic importance of the area of residual tumour. J Thorac Oncol 5:49-55. https://doi.org/10.1097/JTO.0b013e3181c0a1f8
Yang CF, Meyerhoff RR, Stephens SJ, Singhapricha T, Toomey CB, Anderson KL, et al (2015) Long-term outcomes of lobectomy for non-small cell lung cancer after definitive radiation treatment. Ann Thorac Surg 99:1914-1920. https://doi.org/10.1016/j.athoracsur.2015.01.064

Table 1

Patient characteristics
Variables	No. of patients (%)
Overall	23
Median age at surgery, years (IQR)	61 (49–69)
Gender
Male	11 (48)
Female	12 (52)
Smoking history
Current or former	12 (52)
Never	11 (48)
Clinical stage at the initial treatment
IIB	1 (4)
IIIA	3 (13)
IIIB	4 (18)
IV	14 (61)
Postoperative recurrence	1 (4)
Initial treatment
Chemoradiotherapy	6 (26)
Concurrent chemoradiotherapy	4 (17)
Sequential chemoradiotherapy	2 (9)
Systemic therapy alone	17 (74)
Chemotherapy	8 (35)
EGFR-TKI	7 (31)
Chemotherapy and EGFR-TKI	1 (4)
Chemotherapy and ICI	1 (4)
Number of treatment lines before surgery
1	12 (52)
2	7 (31)
3	3 (13)
4	1 (4)
Use of any EGFR-TKIs before surgery	11 (48)
Median time from initial treatment to surgery, months (IQR)	24.6 (8.3–46.2)
Indication for salvage surgery
Residual primary tumor	13 (57)
Regrowth primary tumor	10 (43)
IQR, interquartile range; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor; ICI, Immune-checkpoint inhibitor.

Table 2

Surgical parameters and pathological characteristics
Variables	No. of patients (%)
Extent of resection
Lobectomy	19 (82)
Segmentectomy	2 (9)
Wedge resection	2 (9)
Postoperative systemic therapy
Chemotherapy	5 (22)
EGFR-TKI	4 (17)
No	14 (61)
Histologic type
Adenocarcinoma	20 (88)
Squamous cell carcinoma	1 (4)
Large cell neuroendocrine carcinoma	1 (4)
Pleomorphic carcinoma	1 (4)
Viable tumour (%)
Median (IQR)	50 (15–73)
Necrosis (%)
Median (IQR)	0 (0–5)
Stroma (%)
Median (IQR)	40 (20–83)
MPR	6 (27)
pN
N0	15 (66)
N1	4 (17)
N2	4 (17)
Pathological stage
0 (pathological complete response [pCR])	4 (17)
I	4 (17)
II	6 (27)
III	5 (22)
IV	4 (17)
Lymphovascular invasion
Present	14 (61)
Pleural invasion
Present	9 (39)
IQR, interquartile range; MPR, major pathologic response.

Table 3

Univariate analyses for survival in all patients
Variables	3-year OS (%)	p value
Age, years
< 60	68	0.253
≥ 60	89
Gender
Male	66	0.249
Female	90
Smoking history
Current or former	67	0.267
Never	90
Initial clinical stage
II or III	89	0.55
IV	72
Targeted therapy before surgery
Yes	81	0.681
No	76
Indication for salvage surgery
Residual primary tumor	91	0.097
Regrowing primary tumor	58
Extent of pulmonary resection
Lobectomy	85	0.052
Sublobar resection	50
Adjuvant systemic therapy
Yes	73	0.763
No	83
Final pathologic stage
0/I/II	90	0.103
III/IV	64
MPR
Yes	100	0.187
No	70
Proportion of stroma
Low (< 30%)	23	< 0.001
High (≥ 30%)	100
MPR, major pathologic response.

Competing interest reported. Naoyuki Oka, Tomoyuki Hishida, Kaoru Kaseda, Yu Okubo, Kyohei Masai, Keisuke Asakura, and Hisao Asamura have received research grants to their institution from Covidien Japan CO., LTD., Johnson & Johnson K.K., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Kyowa Kirin Co., Ltd., and Eli Lilly Japan K.K. All other authors declare that there are no financial interests.

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Survival impact of pathologic features after salvage lung resection following definitive chemoradiotherapy or systemic therapy for initially unresectable lung cancer

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