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Salvage surgery after chemo- or chemoradiotherapy for initially unresectable lung carcinoma
Journal Pre-proof Salvage surgery after chemo- or chemoradiotherapy for initially unresectable lung carcinoma Makoto Sonobe, MD, PhD, Yojiro Yutaka, MD, PhD, Daisuke Nakajima, MD, PhD, Masatsugu Hamaji, MD, PhD, Toshi Menju, MD, PhD, Akihiro Ohsumi, MD, PhD, Toyofumi F. Chen-Yoshikawa, MD, PhD, Toshihiko Sato, MD, PhD, Hiroshi Date, MD, PhD PII:
S0003-4975(19)31207-X
DOI:
https://doi.org/10.1016/j.athoracsur.2019.06.087
Reference:
ATS 32911
To appear in:
The Annals of Thoracic Surgery
Received Date: 8 January 2019 Revised Date:
30 April 2019
Accepted Date: 24 June 2019
Please cite this article as: Sonobe M, Yutaka Y, Nakajima D, Hamaji M, Menju T, Ohsumi A, ChenYoshikawa TF, Sato T, Date H, Salvage surgery after chemo- or chemoradiotherapy for initially unresectable lung carcinoma, The Annals of Thoracic Surgery (2019), doi: https://doi.org/10.1016/ j.athoracsur.2019.06.087. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons
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Salvage surgery after chemo- or chemoradiotherapy for initially unresectable lung carcinoma Running head: Salvage resection for lung cancer
Makoto Sonobe, MD, PhD, Yojiro Yutaka, MD, PhD, Daisuke Nakajima, MD, PhD, Masatsugu Hamaji, MD, PhD, Toshi Menju, MD, PhD, Akihiro Ohsumi, MD, PhD, Toyofumi F Chen-Yoshikawa, MD, PhD, Toshihiko Sato, MD, PhD, Hiroshi Date, MD, PhD
Department of Thoracic Surgery, Kyoto University Hospital, Shogoin-Kawahara-cho 54, Sakyo-ku, Kyoto 606-8507, Japan
Total number of words: 4,482 words
Corresponding author: Makoto Sonobe, Department of Thoracic Surgery, Kyoto University Hospital, Shogoin-Kawara-cho 54, Sakyo-ku, Kyoto 606-8507, Japan. Email: [email protected]
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Abstract Background: Salvage surgery is used for resection of loco-regionally recurrent or re-growing lesions after treatment for unresectable non-small cell lung cancer. It is also used to resect lesions that have regressed following treatment and that had not initially been indicated for resection. Relationships between salvage surgery, safety and prognosis, however, have remained unclear. Methods: Between 2006 and 2017, 29 patients received salvage resection (median age: 60 years, 25 men and 4 women). Safety and prognosis were analyzed. Results: Tumor grade at the time of initial treatment was Stage III or IV in 23 and 6 patients, respectively. Twenty-two patients received chemoradiotherapy (radiation: 40–66 Gy) and seven received chemotherapy. Time from initial treatment to surgery ranged from 2–60 months. Segmentectomy, lobectomy, bi-lobectomy and pneumonectomy were performed in 1, 25, 2, and 1 patient, respectively. Combined resections were needed in 17 patients; this included 10 bronchoplasties, 9 pulmonary arterioplasties, 4 chest wall resections, and 1 great vessel resection. There was no 30-day postoperative mortality. Grade 3 or higher-grade postoperative complications (mostly cardiopulmonary) were observed in 11 patients. Five-year overall survival after initial treatment was 61%; after surgery it was 51%. Five-year relapse-free survival after surgery was 49%. On recurrent-free survival, patients with clinical stage III at the initial treatment, pathological stage 0-II, or a good response to initial treatment showed a favorable prognosis. Conclusions: Although cardiopulmonary complications can accompany salvage surgery, the procedure is generally safe. Survival outcome is encouraging, especially in cases with good response to initial treatment.
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Half of Japanese patients with non-small cell lung cancer (NSCLC) have clinical stage III or IV disease [1]. Most of these cases are classed as unresectable, or have contra-indications for surgical resection. Thoracic radiotherapy or chemoradiotherapy has been the first-line standard treatment modality for unresectable stage III NSCLC, whereas systemic chemotherapy (including specific kinase inhibitors or immune checkpoint inhibitors if indicated) is used to treat stage IV NSCLC [2]. Meta-analyses indicate that these standard treatment modalities lack efficacy, as 5-year survival at stage III is 15.1% [3] and less than 10% at stage IV [4, 5]. After these treatments, many patients develop recurrence that manifests as distant metastases with or without local relapse. In a small proportion of patients, however, the recurrent disease is isolated local relapse; such recurrence is no longer eligible for curative-intent radiation therapy, and complete resection is the only curative-intent treatment modality. This type of surgery is called “salvage surgery” [6]. In addition, there is a group of patients with unexpected application of resection into treatment modality because of shrink of primary and/or metastatic lesions. Patients in this group undergo curative resection as part of a “conversion of treatment” strategy. This type of management strategy resembles induction chemotherapy/chemoradiotherapy followed by planned surgery [7], but differs in that surgical resection is initially not planned. Lung resection along with a conversion of treatment strategy seems compatible to the Group C appeared in the report by Bauman et al [6], in which it refers as empiric conversion from medical treatment to multidisciplinary therapy including surgery. Previous reports on the treatment of initially unresectable NSCLC may include both salvage surgery and conversion of treatment strategies, because it is
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often difficult to strictly distinguish between the two treatment modalities. Salvage surgery has been associated with acceptable safety and prognosis profiles in previous reports [8-17]. Each of these reports, however, studied only a small number of patients, and therefore did not have the statistical power to identify associations between salvage surgery and prognosis. Therefore, we conducted a retrospective study to clarify the safety, survival, and prognostic factors associated with surgery after medical treatment for initially unresectable NSCLC.
Patients and Methods Patients This retrospective study was approved by the institutional ethics committee and patient data was included on an “opt out” basis. Salvage lung resection in this study was defined as; 1) true salvage: resection for locally remaining or re-growing NSCLC 12 weeks or more after chemoradiotherapy which had been initially evaluated as mainly technically unresectable stage III or IV disease and to which resection was the only way to curative treatment, and 2) conversion: resection for NSCLC cases that were converted from ‘initially unresectable’ to ‘potentially resectable’ status due to a favorable response to non-surgical treatment (conversion of treatment strategy). In our hospital, 2,345 patients underwent resection for lung cancer between 2006 and 2017. Of these, 29 patients (1.2%) received salvage lung resection with curative intent and were included in this study. Patients whose NSCLC was evaluated as potentially resectable and who underwent induction chemotherapy or chemoradiotherapy followed by planned resection were excluded. Detailed patient
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characteristics are shown in Table 1. Initial treatment strategy and evaluation of resectability were discussed at the thoracic oncology board in our hospital; the board was composed of medical oncologists, radiologists, pathologists, and thoracic surgeons. Surgery for initial stage IV patients was permitted only when complete remission of all metastatic lesions was confirmed using chest computed tomography, 18-fluorodeoxyglucose positron emission tomography, and brain magnetic resonance imaging study and when the primary lesion was deemed to be curatively resectable.
Surgical procedure and postoperative treatment Because complex surgical procedures were expected to be required for many of these patients, open thoracotomy and reinforcement of bronchial stump/anastomotic site were preferred. Bronchial and/or arterial plasty were performed if complete resection was achieved by lobectomy with these procedures. We made every effort to avoid pneumonectomy. Hilar and mediastinal lymphnode dissection was performed in all patients. Adjuvant chemotherapy was not routinely performed, because there was no evidence of adjuvant treatment after salvage surgery. The postoperative follow-up examination schedule was arranged by each individual surgeon; most of the patients received medical check-ups and chest X-rays at least four times per year, and whole body computed tomography twice per year. 18-fluorodeoxyglucose positron emission tomography was optional. Tumor recurrence was diagnosed with the results of radiological examination. If possible, biopsy and/or resection were performed to confirm recurrence pathologically.
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Analyses The collected data included age, sex, clinical and pathological TNM classification, the day of starting the initial treatment, detailed procedure of preoperative treatment, indication for operation (“true salvage” or “conversion”), operation date, operation procedure and parameters, tumor histology, postoperative complications, date of diagnosis of recurrent tumor, and follow-up information until either death or October 2018. Postoperative complications that developed within 30 days after surgery were characterized according to the Clavien-Dindo classification (CDC) [19]; those not defined by the CDC were classified according to the Common Terminology Criteria for Adverse Events, version 4.0 (CTC-AEv4). Persistent air leakages that required 7 days or more drainage but did not require surgical intervention were counted as Grade 2 (compatible to CTC-AEv4 Grade 2). The therapeutic effects of preoperative treatments on resected specimens were evaluated according to the General Rules for Clinical and Pathological Record of Lung Cancer, 8th edition [20] which accorded with UICC classification. In brief, Ef.0: no effect, Ef.1: one third or more of the tumor cells are viable, Ef.2: less than one third of the tumor cells are viable, Ef.3: no viable tumor cells are detected. Statistics were shown by true salvage group and conversion group. Continuous variables were compared by using the Mann-Whitney U-test. Rates of overall survival (OS) after the start of initial treatment, OS after surgery, and recurrence-free survival (RFS) after surgery were calculated using the Kaplan-Meier method. Prognostic analyses were performed on RFS, because OS was strongly affected by post-recurrence treatment [21]. Monovariate analysis of RFS was performed with a log-rank test, and a P-value less than 0.05 was considered significant. Multivariable analyses were not performed because of smaller number of recurrent
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events. JMP software version 9.03 (SAS Institute, Cary, NC, USA) was used to carry out all statistical calculations.
Results Patients (Table 1) Resection with true salvage indication was performed in 10 patients. They all received irradiation at the primary lesion site and mediastinum with a median dose of 60 Gy (range: 54–66 Gy). Time from the start of initial treatment to the surgery was a median of 47.8 weeks (range: 12.3–260.0 weeks). Another 19 patients underwent resection as they were in the conversion group. Radiation therapy to primary lesion was performed in 14 patients and the median dose of 50 Gy (range: 40–66 Gy) was lower than that in the true salvage group (P = 0.0105). There were no patients treated with specific kinase inhibitor(s) or immunotherapy as a pre-resection treatment. Median time from initial treatment to surgery was 12.9 weeks (range: 9.0–155.6 weeks) and was shorter than that of patients within the salvage indication group (P = 0.0019).
Operation mode (Table 2) In 26 (90%) patients, surgery was performed through open thoracotomy. Of these, median sternotomy plus lateral incision was selected in 10 patients because of visualization and proximal control of the main pulmonary artery. Lobectomy or larger resection was performed in 28 (97%) patients. Selection of segmentectomy in one patient from conversion group was due to small residual lesion and limited pulmonary
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reserve. The median operation time was 315 min (range: 136–1,100 min) and the median blood loss was 330 mL (range: 2–1,830 mL). Pathological effects of preoperative treatment were Ef.1 in 12 patients (true salvage: 5, conversion: 7), Ef.2 in 9 patients (true salvage: 4, conversion: 5), and Ef.3 in 8 patients (true salvage: 1, conversion: 7). In all patients, microscopically complete resection was achieved.
Postoperative complications (Table 3) Postoperative complications within 30 days after surgery were classified as Grade 2 or more and are shown in Table 3. There was no 90-day postoperative mortality. However, 29 complication events developed in 18 patients (62%). Most of them were cardiac or pulmonary events, from which patients completely recovered.
Postoperative survival (Table 4) Three patients whose surgical indication was conversion and whose tumor was pathological stage III disease received postoperative platinum-doublet adjuvant chemotherapy. One patient with pathological stage I tumor received oral tegafur-uracil. The other 25 patients did not receive adjuvant chemotherapy. During the follow-up period, 13 patients developed lung cancer recurrence and 10 of them died. Three patients developed brain metastases as a first recurrent site and other ten patients experienced metastases to multiple organs. One patient died of respiratory failure caused by pneumonia without lung cancer recurrence. The 5-year OS rate after the start of initial treatment was 61% (Figure 1a) and OS after
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resection was 51% (Figure 1b). The 5-year RFS rate after resection was 49% (Figure 1c). Analyses of RFS-related prognostic factors revealed that patients with clinical stage III at the time of initial treatment had a better RFS than those with clinical stage IV in all patients and in true salvage group (Table 4). RFS was better in patients with pathological stage 0, I, or II than in those with pathological stage III or IV in all patients and in conversion group (Table 4). With regard to pathological evaluation after medical treatment, patients with Ef.3 showed a favorable RFS in all patients and in conversion group (Table 4). In detail, RFS of patients with Ef.3 (100% at 5 years) was better than that with Ef.2 (38% at 5 years, P = 0.0091) or that with Ef.1 (not reached at 5 years, P = 0.0011) in all patients group. Time from initial treatment to surgery (Table 4) and surgical indication (Figure 1c, 40% in conventional salvage surgery group vs. 52% in conversion of treatment strategy group, P = 0.5439) were not significantly different in RFS.
Comment Here, we show that salvage surgery for patients with initially unresectable NSCLC that responded favorably to non-surgical treatment could be performed with no 90-day operative mortality and an acceptable complication rate. The survival outcomes were 51% for the 5-year OS rate after surgery and 49% for the 5-year RFS rate and were encouraging. Prognostic factor analysis showed that stage III disease at the start of treatment, and postoperative pathological stage 0 to II, or Ef.3 (no viable malignant cells) were associated with better RFS. Patient selection is critical for the success of salvage surgery. Participation of thoracic surgeons in
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the initial staging and decision of treatment strategy may change the entire treatment regimen to a given patient with advanced NSCLC [12]. In our hospital, a thoracic oncology board that includes thoracic surgeons reviews all patients with locally advanced NSCLC that require multimodal treatment, including surgery. The oncology board also has discreet discussion on the indication of so-called salvage surgery, including on referred cases from other hospital, because this type of surgery is often accompanied by a complicated procedure and challenging tumor dissection. These multidisciplinary evaluation of patients before treatment likely contributes to the completeness, safety and acceptable survival rate in our study. In salvage lung resection, the postoperative mortality rate ranges from 0% to 6.7%, and there is frequent development of postoperative complications [6, 8-18]. In our series, no postoperative deaths were observed. This is likely due to the fact that we utilized bronchoplastic and/or pulmonary arterioplastic procedures to avoid pneumonectomy that associated with higher mortality during surgery after chemoradiotherapy [7]. Cardiopulmonary complications, however, frequently developed; this is probably due to the complexity and length of surgery, as has been reported previously [6, 8-13, 15-18]. Acute respiratory distress syndrome develops frequently and is a major cause of postoperative death [6, 8, 9, 13, 17, 18]. Sonett et al. emphasized the importance of restriction of fluid administration [6]. Development of these complications, however, is also common in surgery after induction chemoradiotherapy [7, 22]. Therefore, drawing on the careful postoperative management experience gained during these surgeries will be helpful for salvage lung resection. In salvage surgery, desmoplastic reactions due to preoperative irradiation and/or chemotherapy can impair wound healing and provide disadvantages to bronchial stump and anastomotic sites.
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Indeed, coverage of the bronchial stump was enhanced in many cases of salvage surgery [6, 8, 10, 12, 13, 16, 17]. We also applied coverage and reinforcement of bronchial stump/anastomosis with a pedicled flap; this precaution could prevent lethal complications such as bronchopleural or bronchovascular fistula. In reports of salvage lung resection, 5-year OS rates ranged widely from 20% to 75% because the indication for resection was variable [6, 8, 10, 12, 13, 15, 16, 18]. The 5-year OS of 51% in our series is comparable and very encouraging. Complete resection [10, 12, 16], resection for recurrence detected by 18
-fluorodeoxyglucose positron emission tomography [6], and pathological stage [12, 16] are reported as
favorable prognostic factors. In our study, patients with pretreatment clinical stage III, postoperative pathological stage 0 to II, and higher histopathological effectiveness of initial treatment were more likely to have improved RFS. These results are similar to those obtained from N2-stage IIIA NSCLC patients with induction chemoradiotherapy followed by planned surgery [22]. Time from initial treatment to surgery did not influence the survival outcome in our study. In true salvage group, shorter time from initial treatment to resection can implicate rapid tumor progression which may indicate worse prognosis. In conversion group, however, it can implicate early application of resection due to good response to initial medical treatment. These opposing tendencies may cancel the influence of time from initial treatment to surgery. Indication of resection (true salvage or conversion) did not influence the survival outcome. We infer from these data that a patient with stage III disease who responds well to definitive medical treatment and has whose disease is down-staged is a good candidate for salvage lung resection regardless of detailed indication. Although prediction of the histopathological efficacy of initial treatment is difficult, biopsy of primary tumor or of a
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lymph node that may contain a metastasis may help inform the decision to refer a patient for salvage surgery. Our study has several limitations. Because the number of patients included was small, we could not perform detailed analyses of potential prognostic factors. Multi-institutional database analysis may be appropriate for further analysis of the impact of salvage lung resection. To date, the definition of salvage lung resection has been ambiguous, although the definition by Bauman et al. [6] is a valuable reference. In other oncology indications, such as colorectal or pancreatic cancer, a conversion of treatment strategy or adjuvant surgery has been proposed [23, 24]. Including resection of local recurrent / residual disease after stereotactic lung irradiation and that after treatment with specific tyrosine kinase inhibitors or the immune checkpoint inhibitor, a more precise definition of salvage resection on NSCLC is required to clarify the efficacy of so-called “salvage lung resection”. Our definition in this study may be helpful. Despite these issues, our results show that salvage surgery could be a selective alternative method for locally advanced NSCLC if indicated. Furthermore, our results related to prognostic factor analyses of salvage surgery provide a framework for further discussion of the factors that may determine the decision to undertake this complex and risky treatment strategy.
13 / 21 References 1) National Cancer Center Japan, ganjoho.jp. Available at https://ganjoho.jp/reg_stat/statistics/brochure/hosp_c_registry.html, Accessed November 12, 2018. 2) Ettinger DS, Wood DE, Aisner DL, et al. Non-Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017;15:504-35. 3) Aupérin A, Le Péchoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:2181-90. 4) Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy and supportive care versus supportive care alone for advanced non-small cell lung cancer. Cochrane Database Syst Rev. 2010. Online-only publications (doi:10.1002/14651858.CD007309.pub2.). 5) Hanna N, Johnson D, Temin S, et al. Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2017;35:3484-3515. 6) Bauman JE, Mulligan MS, Martins RG, Kurland BF, Eaton KD, Wood DE. Salvage lung resection after definitive radiation (>59 Gy) for non-small cell lung cancer: surgical and oncologic outcomes. Ann Thorac Surg. 2008;86:1632-8; discussion 1638-9. 7) Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374:379-86. 8) Sonett JR, Suntharalingam M, Edelman MJ, et al. Pulmonary resection after curative intent radiotherapy (>59 Gy) and concurrent chemotherapy in non-small-cell lung cancer. Ann Thorac Surg. 2004;78:1200-5;
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discussion 1206. 9) Kuzmik GA, Detterbeck FC, Decker RH, et al. Pulmonary resections following prior definitive chemoradiation therapy are associated with acceptable survival. Eur J Cardiothorac Surg. 2013;44:e66-70. 10) Shiraishi T, Hiratsuka M, Yanagisawa J, et al. Pulmonary resection after chemoradiotherapy for advanced non-small cell lung cancer: the impact of presurgical radiation therapy. Surg Today. 2014;44:123-30. 11) Uramoto H, Tanaka F. Salvage thoracic surgery in patients with primary lung cancer. Lung Cancer. 2014;84:151-5. 12) Yang CF, Meyerhoff RR, Stephens SJ, et al. Long-Term Outcomes of Lobectomy for Non-Small Cell Lung Cancer After Definitive Radiation Treatment. Ann Thorac Surg. 2015;99:1914-20. 13) Dickhoff C, Dahele M, Paul MA, et al. Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy for locally advanced non-small cell lung cancer. Lung Cancer. 2016;94:108-13. 14) Shimada Y, Suzuki K, Okada M, et al. Feasibility and efficacy of salvage lung resection after definitive chemoradiation therapy for Stage III non-small-cell lung cancer. Interact Cardiovasc Thorac Surg. 2016;23:895-901. 15) Sawada S, Suehisa H, Ueno T, Yamashita M. 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. 2017;40:95-9. 16) Casiraghi M, Maisonneuve P, Piperno G, et al. Salvage Surgery After Definitive Chemoradiotherapy for
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Non-small Cell Lung Cancer. Semin Thorac Cardiovasc Surg. 2017;29:233-41. 17) Kaba E, Ozyurtkan MO, Ayalp K, Cosgun T, Alomari MR, Toker A. Salvage thoracic surgery in patients with lung cancer: potential indications and benefits. J Cardiothorac Surg. 2018;13 (doi: 10.1186/s13019-018-0693-x). 18) Schreiner W, Dudek W, Lettmaier S, Fietkau R, Sirbu H. Long-Term Survival after Salvage Surgery for Local Failure after Definitive Chemoradiation Therapy for Locally Advanced Non-small Cell Lung Cancer. Thorac Cardiovasc Surg. 2018;66:135-41. 19) Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Annals of surgery 2004;240:205-13. 20) The Japan Lung Cancer Society. Japan Lung General Rule for Clinical and Pathological Record of Lung Cancer, 8th edition. Tokyo: Kanehara, 2017:184-5. 21) Sonobe M, Yamada T, Sato M, et al. Identification of subsets of patients with favorable prognosis after recurrence in completely resected non-small cell lung cancer. Ann Surg Oncol.2014;21:2546-54. 22) Chen F, Okubo K, Sonobe M, et al. Hyperfractionated irradiation with 3 cycles of induction chemotherapy in stage IIIA-N2 lung cancer. World J Surg. 2012;36:2858-64. 23) Satoi S, Yamaue H, Kato K, et al. Role of adjuvant surgery for patients with initially unresectable pancreatic cancer with a long-term favorable response to non-surgical anti-cancer treatments: results of a project study for pancreatic surgery by the Japanese Society of Hepato-Biliary-Pancreatic Surgery. J Hepatobiliary Pancreat Sci. 2013;20:590-600.
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24) Poston G, Adam R, Xu J, et al. The role of cetuximab in converting initially unresectable colorectal cancer liver metastases for resection. Eur J Surg Oncol. 2017;43:2001-11.
17 / 21 Table 1
Characteristics of patients enrolled (n = 29)
Characteristics
Number of patients (%)
Age at the time of surgery (years) Median
(range)
60 (37 - 73)
Gender Male
25 (86%)
Female
4 (14%)
Smoking history Current or former
26 (90%)
Never
3 (10%)
Clinical stage* at the time of initial treatment Stage IIIA
13 (45%)
Stage IIIB
10 (34%)
Stage IV
6 (21%)
Treatment before surgery Concurrent chemoradiotherapy
21 (72%)
Sequential chemotherapy and radiotherapy
2 (7%)
Concurrent chemoradiotherapy and radiation for metastatic lesions
1 (3%)
Concurrent chemotherapy and radiation for metastatic lesions
2 (7%)
Chemotherapy
3 (10%)
Dose of radiation to primary lesion and mediastinum (n = 24) 40 Gy - 59 Gy
12 (50%)
>= 60 Gy
12 (50%)
Time from initial treatment to surgery (week) Median (range)
13.1
(9.0 – 260.0)
Indication for operation True salvage (residual or recurrent lesion)
10 (34%)
Conversion
19 (66%)
(tumor remission to be resectable)
Tumor histology Adenocarcinoma
12 (41%)
Squamous cell carcinoma
11 (38%)
Sarcomatoid carcinoma
2 (7%)
Others (including unspecified non-small cell carcinoma)
4 (14%)
*: Clinical stage was classified according to Union for International Cancer Control, 7th edition
18 / 21 Table 2
Surgical procedures, parameters, and pathological stage according to indication of resection Number of patients (%)
Parameters
Salvage (n = 10)
Conversion (n = 19)
Approach Videothoracoscopy-assisted minithoracotomy
0 (0%)
3 (16%)
Antero-lateral thoracotomy
2 (20%)
2 (11%)
Postero-lateral thoracotomy
6 (60%)
4 (21%)
Postero-lateral thoracotomy plus supine position
0 (0%)
2 (7%)
Median sternotomy
2 (20%)
8 (42%)
Segmentectomy
0 (0%)
1 (5%)
Lobectomy
9 (90%)
16 (84%)
Bi-lobectomy
1 (7%)
1 (5%)
Pneumonectomy
0 (0%)
1 (5%)
Bronchoplasty
4 (40%)
6 (32%)
Pulmonary arterial plasty
3 (30%)
6 (32%)
Chest wall resection (including vertebrae)
0 (0%)
4 (21%)
Resection of subclavian vein
0 (0%)
1 (5%)
Pedicled intercostal muscle
6 (60%)
5 (26%)
Pericardial fat pad
4 (40%)
9 (47%)
Pedicled greater omentum
0 (0%)
3 (16%)
No
0 (0%)
2 (11%)
plus lateral incision
Pulmonary resection
Combined procedure
Coverage of bronchial stump / anastomotic site
Median operation time
276 min. (197 - 526)
315 min. (136 – 1,100)
Median blood loss (range)
265 mL
320 mL
Blood transfusion
(25 – 840)
(2 – 1,830)
1 (10%)
8 (42%)
Stage 0 (no residual tumor)
1 (10%)
7 (37%)
Stage I
5 (50%)
1 (5%)
Stage II
2 (20%)
4 (21%)
Stage III
2 (20%)
6 (32%)
Stage IV (d1)
0 (0%)
1 (5%)
Pathological stage*
Median days to discharge
(range)
21 days
(12 - 34)
17 days
(5 - 46)
*: Pathological stage was classified according to Union for International Cancer Control, 7th edition
19 / 21 Table 3
Postoperative complications and course Number of patients (%)
Parameters
Salvage (n = 10)
90-day operative mortality
Conversion (n = 19)
0
0
Grade 2
0
2
Grade 3
0
1
Grade 2
1
1
Atrial fibrillation
Grade 2
2
3
Congestive heart failure
Grade 4a
0
1
Takotsubo mycocarditis
Grade 4a
0
1
Grade 2
0
1
Grade 3a
1
2
Grade 2
1
2
Postoperative complications (Grade 2 or more according to CDC* or CTC-AEv4**) Neuro-psycologic Delirium Recurrent nerve palsy Cardiac and vascular
Pulmonary Prolonged air leak Pneumonia
Grade 3a Atelectasis
1
Grade 3a
1
2
Grade 4a
1
0
Interstitial lung disease
Grade 4
0
1
Pleural effusion
Grade 3a
0
2
Chylothorax
Grade 3a
0
1
Respiratory failure
Grade 3a
0
1
*CDC: Clavien-Dindo classification of surgical complication, **CTC-AEv4: Common Terminology Criteria for Adverse Events version 4.0
20 / 21 Table 4
Monovariate analyses on recurrence-free survival (RFS) in all patients and by indication of surgery
Variables
All patients (n = 29)
True salvage (n = 10)
Conversion (n = 19)
5-year RFS (%) P-value
5-year RFS (%) P-value
5-year RFS (%) P-value
45%
64%
Initial clinical stage
Stage III
58%
0.0176
0.0047
at the start of treatment
Stage IV
not reached
Time from initial treatment
<= 6 months
56%
to resection
> 6 months
39%
Pathological stage
yp-stage 0
100%
yp-stage I
40%
50%
not reached
yp-stage II
67%
not reached
75%
yp-stage III or IV
not reached
not reached
not reached
Therapeutic effect of
Ef.1
not reached
initial treatment*
Ef.2
38%
33%
40%
Ef.3
100%
not reached
100%
not reached 0.3598
not reached
not reached 0.5478
47% 0.0001
0.0058
100%
not reached
0.0666
60%
0.2402
not reached 0.4808
0.5930
100%
not reached
0.0005
0.0068
*Ef.1: one third or more of the tumor cells are viable, Ef.2: less than one third of the tumor cells are viable, Ef.3: no viable tumor cells are detected.
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Figure legends Figure 1. Solid line, broken line, and chain line indicate all patients (n = 29), true salvage group (n = 10), and conversion group (n = 19), respectively. (a) Kaplan–Meier curves for overall survival after the start of initial treatment. The five-year overall survival rates of all patients, true salvage group, and conversion group were 61%, 85%, and 51%, respectively. (b) Kaplan–Meier curves for overall survival after resection. The five-year overall survival rates of all patients, true salvage group, and conversion group were 51%, 51%, and 51%, respectively. (c) Kaplan–Meier curves for recurrent-free survival after resection. The five-year recurrent-free survival rates of all patients, true salvage group, and conversion group were 49%, 40%, and 52%, respectively.
S0003-4975(19)31207-X
DOI:
https://doi.org/10.1016/j.athoracsur.2019.06.087
Reference:
ATS 32911
To appear in:
The Annals of Thoracic Surgery
Received Date: 8 January 2019 Revised Date:
30 April 2019
Accepted Date: 24 June 2019
Please cite this article as: Sonobe M, Yutaka Y, Nakajima D, Hamaji M, Menju T, Ohsumi A, ChenYoshikawa TF, Sato T, Date H, Salvage surgery after chemo- or chemoradiotherapy for initially unresectable lung carcinoma, The Annals of Thoracic Surgery (2019), doi: https://doi.org/10.1016/ j.athoracsur.2019.06.087. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons
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Salvage surgery after chemo- or chemoradiotherapy for initially unresectable lung carcinoma Running head: Salvage resection for lung cancer
Makoto Sonobe, MD, PhD, Yojiro Yutaka, MD, PhD, Daisuke Nakajima, MD, PhD, Masatsugu Hamaji, MD, PhD, Toshi Menju, MD, PhD, Akihiro Ohsumi, MD, PhD, Toyofumi F Chen-Yoshikawa, MD, PhD, Toshihiko Sato, MD, PhD, Hiroshi Date, MD, PhD
Department of Thoracic Surgery, Kyoto University Hospital, Shogoin-Kawahara-cho 54, Sakyo-ku, Kyoto 606-8507, Japan
Total number of words: 4,482 words
Corresponding author: Makoto Sonobe, Department of Thoracic Surgery, Kyoto University Hospital, Shogoin-Kawara-cho 54, Sakyo-ku, Kyoto 606-8507, Japan. Email: [email protected]
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Abstract Background: Salvage surgery is used for resection of loco-regionally recurrent or re-growing lesions after treatment for unresectable non-small cell lung cancer. It is also used to resect lesions that have regressed following treatment and that had not initially been indicated for resection. Relationships between salvage surgery, safety and prognosis, however, have remained unclear. Methods: Between 2006 and 2017, 29 patients received salvage resection (median age: 60 years, 25 men and 4 women). Safety and prognosis were analyzed. Results: Tumor grade at the time of initial treatment was Stage III or IV in 23 and 6 patients, respectively. Twenty-two patients received chemoradiotherapy (radiation: 40–66 Gy) and seven received chemotherapy. Time from initial treatment to surgery ranged from 2–60 months. Segmentectomy, lobectomy, bi-lobectomy and pneumonectomy were performed in 1, 25, 2, and 1 patient, respectively. Combined resections were needed in 17 patients; this included 10 bronchoplasties, 9 pulmonary arterioplasties, 4 chest wall resections, and 1 great vessel resection. There was no 30-day postoperative mortality. Grade 3 or higher-grade postoperative complications (mostly cardiopulmonary) were observed in 11 patients. Five-year overall survival after initial treatment was 61%; after surgery it was 51%. Five-year relapse-free survival after surgery was 49%. On recurrent-free survival, patients with clinical stage III at the initial treatment, pathological stage 0-II, or a good response to initial treatment showed a favorable prognosis. Conclusions: Although cardiopulmonary complications can accompany salvage surgery, the procedure is generally safe. Survival outcome is encouraging, especially in cases with good response to initial treatment.
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Half of Japanese patients with non-small cell lung cancer (NSCLC) have clinical stage III or IV disease [1]. Most of these cases are classed as unresectable, or have contra-indications for surgical resection. Thoracic radiotherapy or chemoradiotherapy has been the first-line standard treatment modality for unresectable stage III NSCLC, whereas systemic chemotherapy (including specific kinase inhibitors or immune checkpoint inhibitors if indicated) is used to treat stage IV NSCLC [2]. Meta-analyses indicate that these standard treatment modalities lack efficacy, as 5-year survival at stage III is 15.1% [3] and less than 10% at stage IV [4, 5]. After these treatments, many patients develop recurrence that manifests as distant metastases with or without local relapse. In a small proportion of patients, however, the recurrent disease is isolated local relapse; such recurrence is no longer eligible for curative-intent radiation therapy, and complete resection is the only curative-intent treatment modality. This type of surgery is called “salvage surgery” [6]. In addition, there is a group of patients with unexpected application of resection into treatment modality because of shrink of primary and/or metastatic lesions. Patients in this group undergo curative resection as part of a “conversion of treatment” strategy. This type of management strategy resembles induction chemotherapy/chemoradiotherapy followed by planned surgery [7], but differs in that surgical resection is initially not planned. Lung resection along with a conversion of treatment strategy seems compatible to the Group C appeared in the report by Bauman et al [6], in which it refers as empiric conversion from medical treatment to multidisciplinary therapy including surgery. Previous reports on the treatment of initially unresectable NSCLC may include both salvage surgery and conversion of treatment strategies, because it is
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often difficult to strictly distinguish between the two treatment modalities. Salvage surgery has been associated with acceptable safety and prognosis profiles in previous reports [8-17]. Each of these reports, however, studied only a small number of patients, and therefore did not have the statistical power to identify associations between salvage surgery and prognosis. Therefore, we conducted a retrospective study to clarify the safety, survival, and prognostic factors associated with surgery after medical treatment for initially unresectable NSCLC.
Patients and Methods Patients This retrospective study was approved by the institutional ethics committee and patient data was included on an “opt out” basis. Salvage lung resection in this study was defined as; 1) true salvage: resection for locally remaining or re-growing NSCLC 12 weeks or more after chemoradiotherapy which had been initially evaluated as mainly technically unresectable stage III or IV disease and to which resection was the only way to curative treatment, and 2) conversion: resection for NSCLC cases that were converted from ‘initially unresectable’ to ‘potentially resectable’ status due to a favorable response to non-surgical treatment (conversion of treatment strategy). In our hospital, 2,345 patients underwent resection for lung cancer between 2006 and 2017. Of these, 29 patients (1.2%) received salvage lung resection with curative intent and were included in this study. Patients whose NSCLC was evaluated as potentially resectable and who underwent induction chemotherapy or chemoradiotherapy followed by planned resection were excluded. Detailed patient
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characteristics are shown in Table 1. Initial treatment strategy and evaluation of resectability were discussed at the thoracic oncology board in our hospital; the board was composed of medical oncologists, radiologists, pathologists, and thoracic surgeons. Surgery for initial stage IV patients was permitted only when complete remission of all metastatic lesions was confirmed using chest computed tomography, 18-fluorodeoxyglucose positron emission tomography, and brain magnetic resonance imaging study and when the primary lesion was deemed to be curatively resectable.
Surgical procedure and postoperative treatment Because complex surgical procedures were expected to be required for many of these patients, open thoracotomy and reinforcement of bronchial stump/anastomotic site were preferred. Bronchial and/or arterial plasty were performed if complete resection was achieved by lobectomy with these procedures. We made every effort to avoid pneumonectomy. Hilar and mediastinal lymphnode dissection was performed in all patients. Adjuvant chemotherapy was not routinely performed, because there was no evidence of adjuvant treatment after salvage surgery. The postoperative follow-up examination schedule was arranged by each individual surgeon; most of the patients received medical check-ups and chest X-rays at least four times per year, and whole body computed tomography twice per year. 18-fluorodeoxyglucose positron emission tomography was optional. Tumor recurrence was diagnosed with the results of radiological examination. If possible, biopsy and/or resection were performed to confirm recurrence pathologically.
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Analyses The collected data included age, sex, clinical and pathological TNM classification, the day of starting the initial treatment, detailed procedure of preoperative treatment, indication for operation (“true salvage” or “conversion”), operation date, operation procedure and parameters, tumor histology, postoperative complications, date of diagnosis of recurrent tumor, and follow-up information until either death or October 2018. Postoperative complications that developed within 30 days after surgery were characterized according to the Clavien-Dindo classification (CDC) [19]; those not defined by the CDC were classified according to the Common Terminology Criteria for Adverse Events, version 4.0 (CTC-AEv4). Persistent air leakages that required 7 days or more drainage but did not require surgical intervention were counted as Grade 2 (compatible to CTC-AEv4 Grade 2). The therapeutic effects of preoperative treatments on resected specimens were evaluated according to the General Rules for Clinical and Pathological Record of Lung Cancer, 8th edition [20] which accorded with UICC classification. In brief, Ef.0: no effect, Ef.1: one third or more of the tumor cells are viable, Ef.2: less than one third of the tumor cells are viable, Ef.3: no viable tumor cells are detected. Statistics were shown by true salvage group and conversion group. Continuous variables were compared by using the Mann-Whitney U-test. Rates of overall survival (OS) after the start of initial treatment, OS after surgery, and recurrence-free survival (RFS) after surgery were calculated using the Kaplan-Meier method. Prognostic analyses were performed on RFS, because OS was strongly affected by post-recurrence treatment [21]. Monovariate analysis of RFS was performed with a log-rank test, and a P-value less than 0.05 was considered significant. Multivariable analyses were not performed because of smaller number of recurrent
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events. JMP software version 9.03 (SAS Institute, Cary, NC, USA) was used to carry out all statistical calculations.
Results Patients (Table 1) Resection with true salvage indication was performed in 10 patients. They all received irradiation at the primary lesion site and mediastinum with a median dose of 60 Gy (range: 54–66 Gy). Time from the start of initial treatment to the surgery was a median of 47.8 weeks (range: 12.3–260.0 weeks). Another 19 patients underwent resection as they were in the conversion group. Radiation therapy to primary lesion was performed in 14 patients and the median dose of 50 Gy (range: 40–66 Gy) was lower than that in the true salvage group (P = 0.0105). There were no patients treated with specific kinase inhibitor(s) or immunotherapy as a pre-resection treatment. Median time from initial treatment to surgery was 12.9 weeks (range: 9.0–155.6 weeks) and was shorter than that of patients within the salvage indication group (P = 0.0019).
Operation mode (Table 2) In 26 (90%) patients, surgery was performed through open thoracotomy. Of these, median sternotomy plus lateral incision was selected in 10 patients because of visualization and proximal control of the main pulmonary artery. Lobectomy or larger resection was performed in 28 (97%) patients. Selection of segmentectomy in one patient from conversion group was due to small residual lesion and limited pulmonary
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reserve. The median operation time was 315 min (range: 136–1,100 min) and the median blood loss was 330 mL (range: 2–1,830 mL). Pathological effects of preoperative treatment were Ef.1 in 12 patients (true salvage: 5, conversion: 7), Ef.2 in 9 patients (true salvage: 4, conversion: 5), and Ef.3 in 8 patients (true salvage: 1, conversion: 7). In all patients, microscopically complete resection was achieved.
Postoperative complications (Table 3) Postoperative complications within 30 days after surgery were classified as Grade 2 or more and are shown in Table 3. There was no 90-day postoperative mortality. However, 29 complication events developed in 18 patients (62%). Most of them were cardiac or pulmonary events, from which patients completely recovered.
Postoperative survival (Table 4) Three patients whose surgical indication was conversion and whose tumor was pathological stage III disease received postoperative platinum-doublet adjuvant chemotherapy. One patient with pathological stage I tumor received oral tegafur-uracil. The other 25 patients did not receive adjuvant chemotherapy. During the follow-up period, 13 patients developed lung cancer recurrence and 10 of them died. Three patients developed brain metastases as a first recurrent site and other ten patients experienced metastases to multiple organs. One patient died of respiratory failure caused by pneumonia without lung cancer recurrence. The 5-year OS rate after the start of initial treatment was 61% (Figure 1a) and OS after
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resection was 51% (Figure 1b). The 5-year RFS rate after resection was 49% (Figure 1c). Analyses of RFS-related prognostic factors revealed that patients with clinical stage III at the time of initial treatment had a better RFS than those with clinical stage IV in all patients and in true salvage group (Table 4). RFS was better in patients with pathological stage 0, I, or II than in those with pathological stage III or IV in all patients and in conversion group (Table 4). With regard to pathological evaluation after medical treatment, patients with Ef.3 showed a favorable RFS in all patients and in conversion group (Table 4). In detail, RFS of patients with Ef.3 (100% at 5 years) was better than that with Ef.2 (38% at 5 years, P = 0.0091) or that with Ef.1 (not reached at 5 years, P = 0.0011) in all patients group. Time from initial treatment to surgery (Table 4) and surgical indication (Figure 1c, 40% in conventional salvage surgery group vs. 52% in conversion of treatment strategy group, P = 0.5439) were not significantly different in RFS.
Comment Here, we show that salvage surgery for patients with initially unresectable NSCLC that responded favorably to non-surgical treatment could be performed with no 90-day operative mortality and an acceptable complication rate. The survival outcomes were 51% for the 5-year OS rate after surgery and 49% for the 5-year RFS rate and were encouraging. Prognostic factor analysis showed that stage III disease at the start of treatment, and postoperative pathological stage 0 to II, or Ef.3 (no viable malignant cells) were associated with better RFS. Patient selection is critical for the success of salvage surgery. Participation of thoracic surgeons in
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the initial staging and decision of treatment strategy may change the entire treatment regimen to a given patient with advanced NSCLC [12]. In our hospital, a thoracic oncology board that includes thoracic surgeons reviews all patients with locally advanced NSCLC that require multimodal treatment, including surgery. The oncology board also has discreet discussion on the indication of so-called salvage surgery, including on referred cases from other hospital, because this type of surgery is often accompanied by a complicated procedure and challenging tumor dissection. These multidisciplinary evaluation of patients before treatment likely contributes to the completeness, safety and acceptable survival rate in our study. In salvage lung resection, the postoperative mortality rate ranges from 0% to 6.7%, and there is frequent development of postoperative complications [6, 8-18]. In our series, no postoperative deaths were observed. This is likely due to the fact that we utilized bronchoplastic and/or pulmonary arterioplastic procedures to avoid pneumonectomy that associated with higher mortality during surgery after chemoradiotherapy [7]. Cardiopulmonary complications, however, frequently developed; this is probably due to the complexity and length of surgery, as has been reported previously [6, 8-13, 15-18]. Acute respiratory distress syndrome develops frequently and is a major cause of postoperative death [6, 8, 9, 13, 17, 18]. Sonett et al. emphasized the importance of restriction of fluid administration [6]. Development of these complications, however, is also common in surgery after induction chemoradiotherapy [7, 22]. Therefore, drawing on the careful postoperative management experience gained during these surgeries will be helpful for salvage lung resection. In salvage surgery, desmoplastic reactions due to preoperative irradiation and/or chemotherapy can impair wound healing and provide disadvantages to bronchial stump and anastomotic sites.
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Indeed, coverage of the bronchial stump was enhanced in many cases of salvage surgery [6, 8, 10, 12, 13, 16, 17]. We also applied coverage and reinforcement of bronchial stump/anastomosis with a pedicled flap; this precaution could prevent lethal complications such as bronchopleural or bronchovascular fistula. In reports of salvage lung resection, 5-year OS rates ranged widely from 20% to 75% because the indication for resection was variable [6, 8, 10, 12, 13, 15, 16, 18]. The 5-year OS of 51% in our series is comparable and very encouraging. Complete resection [10, 12, 16], resection for recurrence detected by 18
-fluorodeoxyglucose positron emission tomography [6], and pathological stage [12, 16] are reported as
favorable prognostic factors. In our study, patients with pretreatment clinical stage III, postoperative pathological stage 0 to II, and higher histopathological effectiveness of initial treatment were more likely to have improved RFS. These results are similar to those obtained from N2-stage IIIA NSCLC patients with induction chemoradiotherapy followed by planned surgery [22]. Time from initial treatment to surgery did not influence the survival outcome in our study. In true salvage group, shorter time from initial treatment to resection can implicate rapid tumor progression which may indicate worse prognosis. In conversion group, however, it can implicate early application of resection due to good response to initial medical treatment. These opposing tendencies may cancel the influence of time from initial treatment to surgery. Indication of resection (true salvage or conversion) did not influence the survival outcome. We infer from these data that a patient with stage III disease who responds well to definitive medical treatment and has whose disease is down-staged is a good candidate for salvage lung resection regardless of detailed indication. Although prediction of the histopathological efficacy of initial treatment is difficult, biopsy of primary tumor or of a
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lymph node that may contain a metastasis may help inform the decision to refer a patient for salvage surgery. Our study has several limitations. Because the number of patients included was small, we could not perform detailed analyses of potential prognostic factors. Multi-institutional database analysis may be appropriate for further analysis of the impact of salvage lung resection. To date, the definition of salvage lung resection has been ambiguous, although the definition by Bauman et al. [6] is a valuable reference. In other oncology indications, such as colorectal or pancreatic cancer, a conversion of treatment strategy or adjuvant surgery has been proposed [23, 24]. Including resection of local recurrent / residual disease after stereotactic lung irradiation and that after treatment with specific tyrosine kinase inhibitors or the immune checkpoint inhibitor, a more precise definition of salvage resection on NSCLC is required to clarify the efficacy of so-called “salvage lung resection”. Our definition in this study may be helpful. Despite these issues, our results show that salvage surgery could be a selective alternative method for locally advanced NSCLC if indicated. Furthermore, our results related to prognostic factor analyses of salvage surgery provide a framework for further discussion of the factors that may determine the decision to undertake this complex and risky treatment strategy.
13 / 21 References 1) National Cancer Center Japan, ganjoho.jp. Available at https://ganjoho.jp/reg_stat/statistics/brochure/hosp_c_registry.html, Accessed November 12, 2018. 2) Ettinger DS, Wood DE, Aisner DL, et al. Non-Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017;15:504-35. 3) Aupérin A, Le Péchoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:2181-90. 4) Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy and supportive care versus supportive care alone for advanced non-small cell lung cancer. Cochrane Database Syst Rev. 2010. Online-only publications (doi:10.1002/14651858.CD007309.pub2.). 5) Hanna N, Johnson D, Temin S, et al. Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2017;35:3484-3515. 6) Bauman JE, Mulligan MS, Martins RG, Kurland BF, Eaton KD, Wood DE. Salvage lung resection after definitive radiation (>59 Gy) for non-small cell lung cancer: surgical and oncologic outcomes. Ann Thorac Surg. 2008;86:1632-8; discussion 1638-9. 7) Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374:379-86. 8) Sonett JR, Suntharalingam M, Edelman MJ, et al. Pulmonary resection after curative intent radiotherapy (>59 Gy) and concurrent chemotherapy in non-small-cell lung cancer. Ann Thorac Surg. 2004;78:1200-5;
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discussion 1206. 9) Kuzmik GA, Detterbeck FC, Decker RH, et al. Pulmonary resections following prior definitive chemoradiation therapy are associated with acceptable survival. Eur J Cardiothorac Surg. 2013;44:e66-70. 10) Shiraishi T, Hiratsuka M, Yanagisawa J, et al. Pulmonary resection after chemoradiotherapy for advanced non-small cell lung cancer: the impact of presurgical radiation therapy. Surg Today. 2014;44:123-30. 11) Uramoto H, Tanaka F. Salvage thoracic surgery in patients with primary lung cancer. Lung Cancer. 2014;84:151-5. 12) Yang CF, Meyerhoff RR, Stephens SJ, et al. Long-Term Outcomes of Lobectomy for Non-Small Cell Lung Cancer After Definitive Radiation Treatment. Ann Thorac Surg. 2015;99:1914-20. 13) Dickhoff C, Dahele M, Paul MA, et al. Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy for locally advanced non-small cell lung cancer. Lung Cancer. 2016;94:108-13. 14) Shimada Y, Suzuki K, Okada M, et al. Feasibility and efficacy of salvage lung resection after definitive chemoradiation therapy for Stage III non-small-cell lung cancer. Interact Cardiovasc Thorac Surg. 2016;23:895-901. 15) Sawada S, Suehisa H, Ueno T, Yamashita M. 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. 2017;40:95-9. 16) Casiraghi M, Maisonneuve P, Piperno G, et al. Salvage Surgery After Definitive Chemoradiotherapy for
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Non-small Cell Lung Cancer. Semin Thorac Cardiovasc Surg. 2017;29:233-41. 17) Kaba E, Ozyurtkan MO, Ayalp K, Cosgun T, Alomari MR, Toker A. Salvage thoracic surgery in patients with lung cancer: potential indications and benefits. J Cardiothorac Surg. 2018;13 (doi: 10.1186/s13019-018-0693-x). 18) Schreiner W, Dudek W, Lettmaier S, Fietkau R, Sirbu H. Long-Term Survival after Salvage Surgery for Local Failure after Definitive Chemoradiation Therapy for Locally Advanced Non-small Cell Lung Cancer. Thorac Cardiovasc Surg. 2018;66:135-41. 19) Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Annals of surgery 2004;240:205-13. 20) The Japan Lung Cancer Society. Japan Lung General Rule for Clinical and Pathological Record of Lung Cancer, 8th edition. Tokyo: Kanehara, 2017:184-5. 21) Sonobe M, Yamada T, Sato M, et al. Identification of subsets of patients with favorable prognosis after recurrence in completely resected non-small cell lung cancer. Ann Surg Oncol.2014;21:2546-54. 22) Chen F, Okubo K, Sonobe M, et al. Hyperfractionated irradiation with 3 cycles of induction chemotherapy in stage IIIA-N2 lung cancer. World J Surg. 2012;36:2858-64. 23) Satoi S, Yamaue H, Kato K, et al. Role of adjuvant surgery for patients with initially unresectable pancreatic cancer with a long-term favorable response to non-surgical anti-cancer treatments: results of a project study for pancreatic surgery by the Japanese Society of Hepato-Biliary-Pancreatic Surgery. J Hepatobiliary Pancreat Sci. 2013;20:590-600.
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24) Poston G, Adam R, Xu J, et al. The role of cetuximab in converting initially unresectable colorectal cancer liver metastases for resection. Eur J Surg Oncol. 2017;43:2001-11.
17 / 21 Table 1
Characteristics of patients enrolled (n = 29)
Characteristics
Number of patients (%)
Age at the time of surgery (years) Median
(range)
60 (37 - 73)
Gender Male
25 (86%)
Female
4 (14%)
Smoking history Current or former
26 (90%)
Never
3 (10%)
Clinical stage* at the time of initial treatment Stage IIIA
13 (45%)
Stage IIIB
10 (34%)
Stage IV
6 (21%)
Treatment before surgery Concurrent chemoradiotherapy
21 (72%)
Sequential chemotherapy and radiotherapy
2 (7%)
Concurrent chemoradiotherapy and radiation for metastatic lesions
1 (3%)
Concurrent chemotherapy and radiation for metastatic lesions
2 (7%)
Chemotherapy
3 (10%)
Dose of radiation to primary lesion and mediastinum (n = 24) 40 Gy - 59 Gy
12 (50%)
>= 60 Gy
12 (50%)
Time from initial treatment to surgery (week) Median (range)
13.1
(9.0 – 260.0)
Indication for operation True salvage (residual or recurrent lesion)
10 (34%)
Conversion
19 (66%)
(tumor remission to be resectable)
Tumor histology Adenocarcinoma
12 (41%)
Squamous cell carcinoma
11 (38%)
Sarcomatoid carcinoma
2 (7%)
Others (including unspecified non-small cell carcinoma)
4 (14%)
*: Clinical stage was classified according to Union for International Cancer Control, 7th edition
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Surgical procedures, parameters, and pathological stage according to indication of resection Number of patients (%)
Parameters
Salvage (n = 10)
Conversion (n = 19)
Approach Videothoracoscopy-assisted minithoracotomy
0 (0%)
3 (16%)
Antero-lateral thoracotomy
2 (20%)
2 (11%)
Postero-lateral thoracotomy
6 (60%)
4 (21%)
Postero-lateral thoracotomy plus supine position
0 (0%)
2 (7%)
Median sternotomy
2 (20%)
8 (42%)
Segmentectomy
0 (0%)
1 (5%)
Lobectomy
9 (90%)
16 (84%)
Bi-lobectomy
1 (7%)
1 (5%)
Pneumonectomy
0 (0%)
1 (5%)
Bronchoplasty
4 (40%)
6 (32%)
Pulmonary arterial plasty
3 (30%)
6 (32%)
Chest wall resection (including vertebrae)
0 (0%)
4 (21%)
Resection of subclavian vein
0 (0%)
1 (5%)
Pedicled intercostal muscle
6 (60%)
5 (26%)
Pericardial fat pad
4 (40%)
9 (47%)
Pedicled greater omentum
0 (0%)
3 (16%)
No
0 (0%)
2 (11%)
plus lateral incision
Pulmonary resection
Combined procedure
Coverage of bronchial stump / anastomotic site
Median operation time
276 min. (197 - 526)
315 min. (136 – 1,100)
Median blood loss (range)
265 mL
320 mL
Blood transfusion
(25 – 840)
(2 – 1,830)
1 (10%)
8 (42%)
Stage 0 (no residual tumor)
1 (10%)
7 (37%)
Stage I
5 (50%)
1 (5%)
Stage II
2 (20%)
4 (21%)
Stage III
2 (20%)
6 (32%)
Stage IV (d1)
0 (0%)
1 (5%)
Pathological stage*
Median days to discharge
(range)
21 days
(12 - 34)
17 days
(5 - 46)
*: Pathological stage was classified according to Union for International Cancer Control, 7th edition
19 / 21 Table 3
Postoperative complications and course Number of patients (%)
Parameters
Salvage (n = 10)
90-day operative mortality
Conversion (n = 19)
0
0
Grade 2
0
2
Grade 3
0
1
Grade 2
1
1
Atrial fibrillation
Grade 2
2
3
Congestive heart failure
Grade 4a
0
1
Takotsubo mycocarditis
Grade 4a
0
1
Grade 2
0
1
Grade 3a
1
2
Grade 2
1
2
Postoperative complications (Grade 2 or more according to CDC* or CTC-AEv4**) Neuro-psycologic Delirium Recurrent nerve palsy Cardiac and vascular
Pulmonary Prolonged air leak Pneumonia
Grade 3a Atelectasis
1
Grade 3a
1
2
Grade 4a
1
0
Interstitial lung disease
Grade 4
0
1
Pleural effusion
Grade 3a
0
2
Chylothorax
Grade 3a
0
1
Respiratory failure
Grade 3a
0
1
*CDC: Clavien-Dindo classification of surgical complication, **CTC-AEv4: Common Terminology Criteria for Adverse Events version 4.0
20 / 21 Table 4
Monovariate analyses on recurrence-free survival (RFS) in all patients and by indication of surgery
Variables
All patients (n = 29)
True salvage (n = 10)
Conversion (n = 19)
5-year RFS (%) P-value
5-year RFS (%) P-value
5-year RFS (%) P-value
45%
64%
Initial clinical stage
Stage III
58%
0.0176
0.0047
at the start of treatment
Stage IV
not reached
Time from initial treatment
<= 6 months
56%
to resection
> 6 months
39%
Pathological stage
yp-stage 0
100%
yp-stage I
40%
50%
not reached
yp-stage II
67%
not reached
75%
yp-stage III or IV
not reached
not reached
not reached
Therapeutic effect of
Ef.1
not reached
initial treatment*
Ef.2
38%
33%
40%
Ef.3
100%
not reached
100%
not reached 0.3598
not reached
not reached 0.5478
47% 0.0001
0.0058
100%
not reached
0.0666
60%
0.2402
not reached 0.4808
0.5930
100%
not reached
0.0005
0.0068
*Ef.1: one third or more of the tumor cells are viable, Ef.2: less than one third of the tumor cells are viable, Ef.3: no viable tumor cells are detected.
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Figure legends Figure 1. Solid line, broken line, and chain line indicate all patients (n = 29), true salvage group (n = 10), and conversion group (n = 19), respectively. (a) Kaplan–Meier curves for overall survival after the start of initial treatment. The five-year overall survival rates of all patients, true salvage group, and conversion group were 61%, 85%, and 51%, respectively. (b) Kaplan–Meier curves for overall survival after resection. The five-year overall survival rates of all patients, true salvage group, and conversion group were 51%, 51%, and 51%, respectively. (c) Kaplan–Meier curves for recurrent-free survival after resection. The five-year recurrent-free survival rates of all patients, true salvage group, and conversion group were 49%, 40%, and 52%, respectively.