A bicenter study on adjuvant surgery following treatment with tyrosine kinase inhibitors in patients with advanced lung adenocarcinoma

A bicenter study on adjuvant surgery following treatment with tyrosine kinase inhibitors in... Abstract OBJECTIVES A small number of patients with advanced pulmonary adenocarcinomas treated with tyrosine kinase inhibitors (TKIs) was subsequently considered eligible for surgery. Our goal was to report the clinical characteristics, pathological features and prognosis of these patients with the aim of exploring the feasibility of this strategy of care. METHODS We retrospectively reviewed the medical files of 19 patients in whom systemic treatment, including TKIs, resulted in a possible stabilization of the disease such that they were considered eligible for surgery (adjuvant surgery). RESULTS Lobectomy, pneumonectomy or segmentectomy was performed in 68.4%, 26.3% and 5.3% of cases, respectively. Limited fibrotic tissues were detected intraoperatively in 8 patients who received TKIs as the sole systemic treatment. The postoperative course in the hospital was uneventful in 13 (68.4%) cases; 3 (15.8%) patients suffered major complications. The post-pneumonectomy early morbidity rate was 60%. A pathological analysis of the tumours showed that the median rate of fibrosis was 32.5% (0–100); of viable neoplastic tissue, 25.0% (0–90); and of necrosis, 12.5% (0–80%). Four tumours (21.1%) exhibited no viable tumour cells. The fibrosis ratio was higher in patients older than 60 years (P = 0.01) and in those treated with erlotinib (P = 0.03). The 3- and 5-year overall survival and disease-free survival rates were 79.5%/39.8% and 44.4%/29.6%, respectively. Pneumonectomy and <50% fibrosis or >30% viable tumour cells in the pathological specimens were factors significantly associated with lower disease-free survival. CONCLUSIONS In a subset of highly selected patients, adjuvant lung surgery following treatment with TKI showed a large spectrum of histological changes in the pathological specimens and encouraging preliminary survival results. Pending further research, it may prove a relatively reliable and safe therapeutic choice, except when an extensive resection like a pneumonectomy is planned. Tyrosine kinase inhibitors, Adjuvant surgery, Adenocarcinoma INTRODUCTION In the last 2 decades, tyrosine kinase inhibitors (TKIs) have proven highly effective in selected patients [1], often resulting in an amazing although unsustainable response, with high relapse rates [2]. In increasingly common cases, patients who had received prior definitive non-surgical treatment for advanced non-small-cell lung cancer (NSCLC) were later considered eligible for surgical resection with a curative intent (adjuvant surgery). Analyses on the outcome of such treatment recorded relatively good survival and morbidity rates, but the authors highlighted the small number of included patients and the lack of strong evidence resulting from their studies [3, 4]. We report herein clinical and pathological features in addition to the prognosis of patients who underwent surgical resection after treatment with TKI with the final aim of analysing the feasibility of such a procedure. MATERIALS AND METHODS Our study was submitted to and approved by the institutional review board of the French Society of Thoracic and Cardio-Vascular Surgery (CERC-SFCTCV-2018-1-26-12-38-40-Folu). From November 2009 to February 2017, we retrospectively reviewed clinical pathological records of all patients admitted to 2 different thoracic surgery units who underwent pulmonary resection with curative intent after treatment with TKI for a baseline advanced-stage adenocarcinoma. The baseline clinical workup included a physical examination, computed tomography (CT) scans, bronchoscopy and 18-fludeoxyglucose-positron emission tomography scans. In some cases, the pretreatment histological diagnosis required CT-guided needle or endoscopic ultrasound (EBUS) biopsy or mediastinoscopy. As a general rule, the eligibility for surgery of patients who received TKIs for previous inoperable NSCLC was limited to a few favourable cases (in our centres, around 2% of all advanced adenocarcinomas treated with TKIs). In those patients, surgical resection following treatment with TKI (adjuvant surgery) allowed local control of a possibly stabilized disease. With respect to preoperative mediastinal nodal evaluation, the multidisciplinary team chose a treatment similar to that used in patients with stage IIIa-NSCLC receiving neoadjuvant chemotherapy. Surgical eligibility was not restricted to patients with a complete response but included cases with a good or partial response as long as radical surgical remained feasible. After systemic treatment and before surgery, restaging with CT and/or positron emission tomography/CT scans was performed in all cases, whereas neither mediastinoscopy nor EBUS was routinely performed for preoperative evaluation of mediastinal lymph nodes. Final histopathological assessment was carried out by thoracic pathologists and included the ypathological tumour, node and metastasis (ypTNM) classification, the histological subtype and possible pathological changes following neoadjuvant treatment expressing tumour composition in terms of rates of necrosis, fibrosis and viable tumour cells. Viability was defined as the presence of tumour cells exhibiting distinct nuclear chromatin, an intact nuclear or cytoplasmic membrane and the absence of signs of necrosis (i.e. karyorrhexis, karyolysis and pyknosis) or fibrosis. Follow-up was performed by interviews with physicians and analysis of city registers. Later risk factors were studied and survival analyses were carried out. RESULTS Nineteen patients were identified; their characteristics are detailed in Table 1. After receiving a systemic treatment including TKIs, the patients underwent a lobectomy, pneumonectomy or segmentectomy in 68.4%, 26.3% and 5.3% of cases, respectively (Table 2). Prior to lung resection, 2 patients had a surgical extrapulmonary metastasectomy (1 adrenalectomy, 1 bone resection). At the macroscopic level, a few fibrotic tissues were observed intraoperatively around the area of the tumour area, even in the 8 patients who had received TKIs as the sole treatment prior to surgery. The postoperative hospital course was uneventful in 13 (68.4%) cases whereas 3 (15.8%) patients had major complications. The 5 patients who had a pneumonectomy had a 60% complication rate (31.6% in non-pneumonectomy patients, P = 0.11) postoperatively. The postoperative pathological findings indicated 15 (78.9%) adenocarcinomas, whereas 4 (21.1%) cases showed no viable tumour tissue—just fibrosis and/or necrosis. Within the whole series of surgical specimens, analysis of the 3 pathological patterns included in tumour composition revealed that the median rate of fibrosis was 32.5% (0–100); that of viable neoplastic tissue, 25.0% (0–90); and that of necrosis, 12.5% (0–80%). With respect to the T parameter, when we compared the clinical baseline with the pTNM, we recorded a downstaging in 10 (52.6%) patients and an upstaging in 3 (15.8%) patients when comparing pre-TKI-cT with pT. Table 1: Patients’ characteristics and pathological features Characteristics n (%), mean ± SD Gender  Men 7 (36.8)  Women 12 (63.2) Age (years) 60.4 ± 12.7 Body mass index (kg/m2) 24.2 ± 4.7 Smoking 1 (5.2)  Current smoker  Former smoker 9 (47.4)  Non-smoker 9 (47.4) COPD 1 (4.5) Preoperative FEV1, % predicted value 87.4 ± 14.7 Performance status  PS0 4 (22.7)  PS1 13 (63.6)  PS2 3 (13.7) Pretreatment molecular analysis of tumour biopsy  EGFR mutation 13 (68.4)  ALK rearrangement 2 (10.5)  ROS1 fusion 1 (5.3)  No detected abnormality 3 (15.8) Type of TKI 9 (47.4)  Erlotinib  Gefitinib 7 (36.8)  Crizotinib 3 (15.8) T parameter Baseline clinical yPathological  T0 0 (0.0) 4 (21.0)  T1a,b 5 (26.3) 4 (21.0)  T2a,b 6 (31.6) 9 (47.4)  T3 7 (36.8) 1 (5.3)  T4 1 (5.3) 1 (5.3 N parameter  N0 4 (21.0) 10 (52.6)  N1 3 (15.8) 3 (15.8)  N2,3 12 (63.2) 6 (31.6) M parameter  M0 8 (42.1) 17 (89.5)  M1 11 (57.9) 2 (10.5) Stage  0 0 (0.0) 4 (21.0)  Ia,b 0 (0.0) 4 (21.0)  IIa,b 0 (0.0) 3 (15.8)  IIIa 5 (26.3) 6 (31.6)  IIIb 3 (15.8) 0 (0.0)  IV 11 (57.9) 2 (10.6) Characteristics n (%), mean ± SD Gender  Men 7 (36.8)  Women 12 (63.2) Age (years) 60.4 ± 12.7 Body mass index (kg/m2) 24.2 ± 4.7 Smoking 1 (5.2)  Current smoker  Former smoker 9 (47.4)  Non-smoker 9 (47.4) COPD 1 (4.5) Preoperative FEV1, % predicted value 87.4 ± 14.7 Performance status  PS0 4 (22.7)  PS1 13 (63.6)  PS2 3 (13.7) Pretreatment molecular analysis of tumour biopsy  EGFR mutation 13 (68.4)  ALK rearrangement 2 (10.5)  ROS1 fusion 1 (5.3)  No detected abnormality 3 (15.8) Type of TKI 9 (47.4)  Erlotinib  Gefitinib 7 (36.8)  Crizotinib 3 (15.8) T parameter Baseline clinical yPathological  T0 0 (0.0) 4 (21.0)  T1a,b 5 (26.3) 4 (21.0)  T2a,b 6 (31.6) 9 (47.4)  T3 7 (36.8) 1 (5.3)  T4 1 (5.3) 1 (5.3 N parameter  N0 4 (21.0) 10 (52.6)  N1 3 (15.8) 3 (15.8)  N2,3 12 (63.2) 6 (31.6) M parameter  M0 8 (42.1) 17 (89.5)  M1 11 (57.9) 2 (10.5) Stage  0 0 (0.0) 4 (21.0)  Ia,b 0 (0.0) 4 (21.0)  IIa,b 0 (0.0) 3 (15.8)  IIIa 5 (26.3) 6 (31.6)  IIIb 3 (15.8) 0 (0.0)  IV 11 (57.9) 2 (10.6) ALK: anaplastic lymphoma kinase; COPD: chronic obstructive pulmonary disease; EGFR: endothelial growth factor receptor; FEV1: forced expiratory volume in 1 s; ROS1: c-ROS oncogene 1; SD: standard deviation; TKI: tyrosine kinase inhibitor. Table 1: Patients’ characteristics and pathological features Characteristics n (%), mean ± SD Gender  Men 7 (36.8)  Women 12 (63.2) Age (years) 60.4 ± 12.7 Body mass index (kg/m2) 24.2 ± 4.7 Smoking 1 (5.2)  Current smoker  Former smoker 9 (47.4)  Non-smoker 9 (47.4) COPD 1 (4.5) Preoperative FEV1, % predicted value 87.4 ± 14.7 Performance status  PS0 4 (22.7)  PS1 13 (63.6)  PS2 3 (13.7) Pretreatment molecular analysis of tumour biopsy  EGFR mutation 13 (68.4)  ALK rearrangement 2 (10.5)  ROS1 fusion 1 (5.3)  No detected abnormality 3 (15.8) Type of TKI 9 (47.4)  Erlotinib  Gefitinib 7 (36.8)  Crizotinib 3 (15.8) T parameter Baseline clinical yPathological  T0 0 (0.0) 4 (21.0)  T1a,b 5 (26.3) 4 (21.0)  T2a,b 6 (31.6) 9 (47.4)  T3 7 (36.8) 1 (5.3)  T4 1 (5.3) 1 (5.3 N parameter  N0 4 (21.0) 10 (52.6)  N1 3 (15.8) 3 (15.8)  N2,3 12 (63.2) 6 (31.6) M parameter  M0 8 (42.1) 17 (89.5)  M1 11 (57.9) 2 (10.5) Stage  0 0 (0.0) 4 (21.0)  Ia,b 0 (0.0) 4 (21.0)  IIa,b 0 (0.0) 3 (15.8)  IIIa 5 (26.3) 6 (31.6)  IIIb 3 (15.8) 0 (0.0)  IV 11 (57.9) 2 (10.6) Characteristics n (%), mean ± SD Gender  Men 7 (36.8)  Women 12 (63.2) Age (years) 60.4 ± 12.7 Body mass index (kg/m2) 24.2 ± 4.7 Smoking 1 (5.2)  Current smoker  Former smoker 9 (47.4)  Non-smoker 9 (47.4) COPD 1 (4.5) Preoperative FEV1, % predicted value 87.4 ± 14.7 Performance status  PS0 4 (22.7)  PS1 13 (63.6)  PS2 3 (13.7) Pretreatment molecular analysis of tumour biopsy  EGFR mutation 13 (68.4)  ALK rearrangement 2 (10.5)  ROS1 fusion 1 (5.3)  No detected abnormality 3 (15.8) Type of TKI 9 (47.4)  Erlotinib  Gefitinib 7 (36.8)  Crizotinib 3 (15.8) T parameter Baseline clinical yPathological  T0 0 (0.0) 4 (21.0)  T1a,b 5 (26.3) 4 (21.0)  T2a,b 6 (31.6) 9 (47.4)  T3 7 (36.8) 1 (5.3)  T4 1 (5.3) 1 (5.3 N parameter  N0 4 (21.0) 10 (52.6)  N1 3 (15.8) 3 (15.8)  N2,3 12 (63.2) 6 (31.6) M parameter  M0 8 (42.1) 17 (89.5)  M1 11 (57.9) 2 (10.5) Stage  0 0 (0.0) 4 (21.0)  Ia,b 0 (0.0) 4 (21.0)  IIa,b 0 (0.0) 3 (15.8)  IIIa 5 (26.3) 6 (31.6)  IIIb 3 (15.8) 0 (0.0)  IV 11 (57.9) 2 (10.6) ALK: anaplastic lymphoma kinase; COPD: chronic obstructive pulmonary disease; EGFR: endothelial growth factor receptor; FEV1: forced expiratory volume in 1 s; ROS1: c-ROS oncogene 1; SD: standard deviation; TKI: tyrosine kinase inhibitor. Table 2: Tyrosine kinase inhibitor treatment-related clinical course of each patient Age (years)/ gender Tumour biopsy molecular analysis Treatment with TKI in therapeutic scheme Type of TKI Initial clinical response to treatment with TKI Consecutive treatment to TKIs Lung resection type In-hospital course Follow-up 77/female EGFR m exon 19 del 1st Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 73/male EGFR m exon 19 del 1st Line Erlotinib Progression Chemotherapy Lobectomy Prolonged air-leak No relapse alive 68/male EGFR wt 3rd Line Erlotinib Stable Surgery Lobectomy No adverse event Relapse dead 49/female EGFR m p.L858R 1st Line Erlotinib Progression Chemotherapy Pneumonectomy Atrial fibrillation Relapse alive 66/male EGFR m exon 19 del 1st Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 52/female EGFR m p.L858R 2nd Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 70/male EGFR wt 3rd Line Erlotinib Good Surgery Segmentectomy No adverse event No relapse alive 60/male EGFR wt 3rd Line Erlotinib Progression Chemotherapy Lobectomy Pneumoniae No relapse alive 47/female EGFR m exon 19 del 1st Line Gefitinib Good Surgery Lobectomy No adverse event No relapse dead 54/female EGFR m exon 19 del 1st Line Gefitinib Good Surgery Pneumonectomy Haemothorax Reoperation Relapse alive 64/male ALK r 1st Line Crizotinib Good Surgery Lobectomy No adverse event Relapse alive 26/female EGFR m p.G719S, L861Q 2nd Line Gefitinib Partial Surgery Lobectomy No adverse event Relapse dead 50/female EGFR m exon 19 del 1st Line Gefitinib Partial Surgery Pneumonectomy No adverse event Relapse dead 80/female EGFR m exon 19 del 1st Line Gefitinib Partial Chemotherapy Lobectomy No adverse event No relapse alive 56/female EGFR m exon 19 del 2nd Line Gefitinib Partial Surgery Lobectomy Prolonged air-leak Relapse alive 61/male EGFR m p.L858R 1st Line Gefitinib Partial Surgery Pneumonectomy Haemothorax Reoperation Relapse alive 70/female ALK r 1st Line Crizotinib Partial Surgery Lobectomy No adverse event No relapse alive 57/female EGFR m exon 19 del 2nd Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 67/female ROS-1 r 2nd Line Crizotinib Partial Surgery Pneumonectomy No adverse event No relapse alive Age (years)/ gender Tumour biopsy molecular analysis Treatment with TKI in therapeutic scheme Type of TKI Initial clinical response to treatment with TKI Consecutive treatment to TKIs Lung resection type In-hospital course Follow-up 77/female EGFR m exon 19 del 1st Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 73/male EGFR m exon 19 del 1st Line Erlotinib Progression Chemotherapy Lobectomy Prolonged air-leak No relapse alive 68/male EGFR wt 3rd Line Erlotinib Stable Surgery Lobectomy No adverse event Relapse dead 49/female EGFR m p.L858R 1st Line Erlotinib Progression Chemotherapy Pneumonectomy Atrial fibrillation Relapse alive 66/male EGFR m exon 19 del 1st Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 52/female EGFR m p.L858R 2nd Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 70/male EGFR wt 3rd Line Erlotinib Good Surgery Segmentectomy No adverse event No relapse alive 60/male EGFR wt 3rd Line Erlotinib Progression Chemotherapy Lobectomy Pneumoniae No relapse alive 47/female EGFR m exon 19 del 1st Line Gefitinib Good Surgery Lobectomy No adverse event No relapse dead 54/female EGFR m exon 19 del 1st Line Gefitinib Good Surgery Pneumonectomy Haemothorax Reoperation Relapse alive 64/male ALK r 1st Line Crizotinib Good Surgery Lobectomy No adverse event Relapse alive 26/female EGFR m p.G719S, L861Q 2nd Line Gefitinib Partial Surgery Lobectomy No adverse event Relapse dead 50/female EGFR m exon 19 del 1st Line Gefitinib Partial Surgery Pneumonectomy No adverse event Relapse dead 80/female EGFR m exon 19 del 1st Line Gefitinib Partial Chemotherapy Lobectomy No adverse event No relapse alive 56/female EGFR m exon 19 del 2nd Line Gefitinib Partial Surgery Lobectomy Prolonged air-leak Relapse alive 61/male EGFR m p.L858R 1st Line Gefitinib Partial Surgery Pneumonectomy Haemothorax Reoperation Relapse alive 70/female ALK r 1st Line Crizotinib Partial Surgery Lobectomy No adverse event No relapse alive 57/female EGFR m exon 19 del 2nd Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 67/female ROS-1 r 2nd Line Crizotinib Partial Surgery Pneumonectomy No adverse event No relapse alive ADC: adenocarcinoma; ALK: anaplastic lymphoma kinase; EGFR: endothelial growth factor receptor; m: mutation; r: rearrangement; ROS1: c-ROS oncogene 1; TKI: tyrosine kinase inhibitor; wt: wild-type. Table 2: Tyrosine kinase inhibitor treatment-related clinical course of each patient Age (years)/ gender Tumour biopsy molecular analysis Treatment with TKI in therapeutic scheme Type of TKI Initial clinical response to treatment with TKI Consecutive treatment to TKIs Lung resection type In-hospital course Follow-up 77/female EGFR m exon 19 del 1st Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 73/male EGFR m exon 19 del 1st Line Erlotinib Progression Chemotherapy Lobectomy Prolonged air-leak No relapse alive 68/male EGFR wt 3rd Line Erlotinib Stable Surgery Lobectomy No adverse event Relapse dead 49/female EGFR m p.L858R 1st Line Erlotinib Progression Chemotherapy Pneumonectomy Atrial fibrillation Relapse alive 66/male EGFR m exon 19 del 1st Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 52/female EGFR m p.L858R 2nd Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 70/male EGFR wt 3rd Line Erlotinib Good Surgery Segmentectomy No adverse event No relapse alive 60/male EGFR wt 3rd Line Erlotinib Progression Chemotherapy Lobectomy Pneumoniae No relapse alive 47/female EGFR m exon 19 del 1st Line Gefitinib Good Surgery Lobectomy No adverse event No relapse dead 54/female EGFR m exon 19 del 1st Line Gefitinib Good Surgery Pneumonectomy Haemothorax Reoperation Relapse alive 64/male ALK r 1st Line Crizotinib Good Surgery Lobectomy No adverse event Relapse alive 26/female EGFR m p.G719S, L861Q 2nd Line Gefitinib Partial Surgery Lobectomy No adverse event Relapse dead 50/female EGFR m exon 19 del 1st Line Gefitinib Partial Surgery Pneumonectomy No adverse event Relapse dead 80/female EGFR m exon 19 del 1st Line Gefitinib Partial Chemotherapy Lobectomy No adverse event No relapse alive 56/female EGFR m exon 19 del 2nd Line Gefitinib Partial Surgery Lobectomy Prolonged air-leak Relapse alive 61/male EGFR m p.L858R 1st Line Gefitinib Partial Surgery Pneumonectomy Haemothorax Reoperation Relapse alive 70/female ALK r 1st Line Crizotinib Partial Surgery Lobectomy No adverse event No relapse alive 57/female EGFR m exon 19 del 2nd Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 67/female ROS-1 r 2nd Line Crizotinib Partial Surgery Pneumonectomy No adverse event No relapse alive Age (years)/ gender Tumour biopsy molecular analysis Treatment with TKI in therapeutic scheme Type of TKI Initial clinical response to treatment with TKI Consecutive treatment to TKIs Lung resection type In-hospital course Follow-up 77/female EGFR m exon 19 del 1st Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 73/male EGFR m exon 19 del 1st Line Erlotinib Progression Chemotherapy Lobectomy Prolonged air-leak No relapse alive 68/male EGFR wt 3rd Line Erlotinib Stable Surgery Lobectomy No adverse event Relapse dead 49/female EGFR m p.L858R 1st Line Erlotinib Progression Chemotherapy Pneumonectomy Atrial fibrillation Relapse alive 66/male EGFR m exon 19 del 1st Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 52/female EGFR m p.L858R 2nd Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 70/male EGFR wt 3rd Line Erlotinib Good Surgery Segmentectomy No adverse event No relapse alive 60/male EGFR wt 3rd Line Erlotinib Progression Chemotherapy Lobectomy Pneumoniae No relapse alive 47/female EGFR m exon 19 del 1st Line Gefitinib Good Surgery Lobectomy No adverse event No relapse dead 54/female EGFR m exon 19 del 1st Line Gefitinib Good Surgery Pneumonectomy Haemothorax Reoperation Relapse alive 64/male ALK r 1st Line Crizotinib Good Surgery Lobectomy No adverse event Relapse alive 26/female EGFR m p.G719S, L861Q 2nd Line Gefitinib Partial Surgery Lobectomy No adverse event Relapse dead 50/female EGFR m exon 19 del 1st Line Gefitinib Partial Surgery Pneumonectomy No adverse event Relapse dead 80/female EGFR m exon 19 del 1st Line Gefitinib Partial Chemotherapy Lobectomy No adverse event No relapse alive 56/female EGFR m exon 19 del 2nd Line Gefitinib Partial Surgery Lobectomy Prolonged air-leak Relapse alive 61/male EGFR m p.L858R 1st Line Gefitinib Partial Surgery Pneumonectomy Haemothorax Reoperation Relapse alive 70/female ALK r 1st Line Crizotinib Partial Surgery Lobectomy No adverse event No relapse alive 57/female EGFR m exon 19 del 2nd Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 67/female ROS-1 r 2nd Line Crizotinib Partial Surgery Pneumonectomy No adverse event No relapse alive ADC: adenocarcinoma; ALK: anaplastic lymphoma kinase; EGFR: endothelial growth factor receptor; m: mutation; r: rearrangement; ROS1: c-ROS oncogene 1; TKI: tyrosine kinase inhibitor; wt: wild-type. We observed a pathological downstaging in half of the 12 cN2 patients, with 3 (63.2%) cases of mediastinal complete clearance (clinical versus pathological number of N2, 3+ patients significantly higher = 0.02). Univariate analysis of factors potentially associated with the pathological response to treatment with TKI showed a fibrosis ratio significantly higher in patients older than 60 years (P = 0.01) and in those who received erlotinib versus other TKIs (P = 0.03). Other factors such as body mass index, duration of treatment with TKI and the cT parameter turned out to be substantially unrelated to tumour composition. Mean and median follow-up times reached 28.3 ± 22.7 and 23.8 (7.4–80.6) months, respectively (Table 2). On Kaplan–Meier analysis, the mean overall survival (OS) estimate was 56.5 [95% confidence interval (CI) 40.4–72.7] months and the 1-, 3- or 5-year OS rates were 90.9% ± 0.8%, 79.5% ± 13.5% and 39.8% ± 19.4%, respectively (Supplementary Material, Fig. S1A). All 4 patients without viable tumour cells in pathological specimens remained alive during the study period. No preoperative feature was significantly related to OS. The mean disease-free survival (DFS) estimate was 30.0 months (95% CI 15.7–44.3) whereas the 1-, 3- and 5-year DFS rates were 79.0% ± 1.6%, 44.4% ± 14.7% and 29.6% ± 18.6%, respectively (Supplementary Material, Fig. S1B). The ratio of fibrosis <50% (P = 0.05) or viable tumour cells >30% (P = 0.05) determined from a pathological analysis of the resected specimen and pneumonectomy (P = 0.03) was closely associated with a lower DFS in a log rank test, although none of these factors independently influenced DFS on multivariate analysis. DISCUSSION Our study evaluated the feasibility of adjuvant surgery by analysing short- and long-term findings in a highly selected subset of patients with advanced adenocarcinoma. Although at first they were deemed inoperable, they underwent anatomical pulmonary resection after systemic treatment that included TKI. Despite a significantly high morbidity rate, especially in the pneumonectomy group, we performed a relatively safe operation, because the post-TKI operative area was not particularly demanding, especially in patients who received only TKIs preoperatively—no chemotherapy. We must emphasize, however, that these statements may reflect personal views rather than objective data. In addition to the perioperative safety of this strategy of care, we did not record any negative impacts of TKI on pulmonary function (considering a good preoperative forced expiratory volume in 1 s, mean = 87.4% of predicted value). Because assessing pulmonary functional changes before and after treatment with TKI was not the goal of our study, our analysis can be considered just a simple observation in support of the feasibility of such surgery. To our knowledge, no study supports any impact of TKIs on respiratory function without occurrence of an alteration of the forced expiratory volume in 1 s or other clinical parameters potentially influencing surgical eligibility. Concerning the prognosis, our preliminary analysis showed that patients treated in this setting had relatively rewarding oncological results. A study analysing 9 patients treated surgically after gefitinib-induction therapy reported a poorer prognosis, with a 32-month survival median and a 3-year survival rate reaching approximately 50% [5]. The authors connected these suboptimal oncological results to a remarkable early recurrence rate and an overestimation of the actual radiological response to TKI, as previously suggested [6]. Our analysis failed to determine what affects long-term prognosis. Nevertheless we succeeded in assessing tumour composition after treatment with TKIs for a relatively homogeneous cohort of adenocarcinomas. Indeed, we could detect a wide spectrum of histological changes and significant rates of fibrosis and necrosis. Moreover, our analysis found a correlation between pathological response and patients’ age or type of TKI therapy. However, we probably need to analyse our findings further by taking into account more suitable methods for analysis of post-TKI responses [7, 8]. These data could represent the ‘proof of principle’ for further studies. In fact, we can assume that, following standard chemotherapy, patients who have a pathological response have a better prognosis [9]. Given these results, it seems reasonable to consider the ‘surgical option’ in radiological responders, because resection represents the only way to assess for a pathological response to TKIs and other systemic treatments. The real benefit of adjuvant surgery for OS can indeed be questioned because patients with a complete pathological response (4 of 19 cases) may not require local treatment. On the contrary, we recorded cases whose N parameter was upstaged in the comparison between pre- and postoperative staging. In such cases, one can question the positive prognostic impact of surgical resection because of the controversial results that emerged from previous studies on neoadjuvant chemotherapy and nodal involvement [10]. The topic related to eligibility for adjuvant surgery remains controversial, above all when an extensive resection is required. Although pneumonectomy was not assessed as a negative prognostic factor on multivariate analysis, we may discourage pneumonectomy in such a setting because of the remarkable rates of both recurrence and postoperative morbidity. As previously performed in earlier stages of the disease, randomized studies that include advanced adenocarcinomas should be performed to analyse the impact of this complex and evolving therapeutic option on prognosis [11]. Limitations As a retrospective analysis of a small, slightly heterogeneous group of highly selected patients with NSCLC who received surgery after TKIs, our study has several limitations. Moreover, the follow-up period was too short and there was no control arm including patients with a good response to TKI therapy and no consecutive surgery. Readers should be careful in evaluating the clinical impact of our findings (still limited and preliminary). Indeed, it would be wise to avoid drawing any conclusion about prognosis and consider our findings as a preliminary study on the feasibility and results of surgery after treatment with TKI. Although pathological changes were recorded even for patients undergoing preoperative exclusive treatment with TKI, a study exclusively devoted to the peculiar impact of TKIs on tumour tissue would be of paramount importance in definitively clarifying this aspect, because confounding variables could influence our results. CONCLUSIONS In a subset of highly selected patients, adjuvant lung surgery following treatment with TKI identified a large spectrum of histological changes evident in the pathological specimens and encouraging preliminary survival results. Pending further research, it may prove a relatively reliable and safe therapeutic choice, except when an extensive resection like pneumonectomy is planned. SUPPLEMENTARY MATERIAL Supplementary material is available at ICVTS online. ACKNOWLEDGMENTS The authors thank Daniela Masi (Reggio Emilia AUSL-IRCSS) and Graham Donlon (CHU sud Réunion, Saint Pierre) for English revision and editing. Conflict of interest: none declared. REFERENCES 1 Maemondo M , Inoue A , Kobayashi K , Sugawara S , Oizumi S , Isobe H. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR . N Engl J Med 2010 ; 362 : 2380 – 8 . Google Scholar CrossRef Search ADS PubMed 2 Liao BC , Lin CC , Lee JH , Yang JC. 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Interactive CardioVascular and Thoracic Surgery Oxford University Press

A bicenter study on adjuvant surgery following treatment with tyrosine kinase inhibitors in patients with advanced lung adenocarcinoma

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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1569-9293
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1569-9285
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10.1093/icvts/ivy120
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Abstract

Abstract OBJECTIVES A small number of patients with advanced pulmonary adenocarcinomas treated with tyrosine kinase inhibitors (TKIs) was subsequently considered eligible for surgery. Our goal was to report the clinical characteristics, pathological features and prognosis of these patients with the aim of exploring the feasibility of this strategy of care. METHODS We retrospectively reviewed the medical files of 19 patients in whom systemic treatment, including TKIs, resulted in a possible stabilization of the disease such that they were considered eligible for surgery (adjuvant surgery). RESULTS Lobectomy, pneumonectomy or segmentectomy was performed in 68.4%, 26.3% and 5.3% of cases, respectively. Limited fibrotic tissues were detected intraoperatively in 8 patients who received TKIs as the sole systemic treatment. The postoperative course in the hospital was uneventful in 13 (68.4%) cases; 3 (15.8%) patients suffered major complications. The post-pneumonectomy early morbidity rate was 60%. A pathological analysis of the tumours showed that the median rate of fibrosis was 32.5% (0–100); of viable neoplastic tissue, 25.0% (0–90); and of necrosis, 12.5% (0–80%). Four tumours (21.1%) exhibited no viable tumour cells. The fibrosis ratio was higher in patients older than 60 years (P = 0.01) and in those treated with erlotinib (P = 0.03). The 3- and 5-year overall survival and disease-free survival rates were 79.5%/39.8% and 44.4%/29.6%, respectively. Pneumonectomy and <50% fibrosis or >30% viable tumour cells in the pathological specimens were factors significantly associated with lower disease-free survival. CONCLUSIONS In a subset of highly selected patients, adjuvant lung surgery following treatment with TKI showed a large spectrum of histological changes in the pathological specimens and encouraging preliminary survival results. Pending further research, it may prove a relatively reliable and safe therapeutic choice, except when an extensive resection like a pneumonectomy is planned. Tyrosine kinase inhibitors, Adjuvant surgery, Adenocarcinoma INTRODUCTION In the last 2 decades, tyrosine kinase inhibitors (TKIs) have proven highly effective in selected patients [1], often resulting in an amazing although unsustainable response, with high relapse rates [2]. In increasingly common cases, patients who had received prior definitive non-surgical treatment for advanced non-small-cell lung cancer (NSCLC) were later considered eligible for surgical resection with a curative intent (adjuvant surgery). Analyses on the outcome of such treatment recorded relatively good survival and morbidity rates, but the authors highlighted the small number of included patients and the lack of strong evidence resulting from their studies [3, 4]. We report herein clinical and pathological features in addition to the prognosis of patients who underwent surgical resection after treatment with TKI with the final aim of analysing the feasibility of such a procedure. MATERIALS AND METHODS Our study was submitted to and approved by the institutional review board of the French Society of Thoracic and Cardio-Vascular Surgery (CERC-SFCTCV-2018-1-26-12-38-40-Folu). From November 2009 to February 2017, we retrospectively reviewed clinical pathological records of all patients admitted to 2 different thoracic surgery units who underwent pulmonary resection with curative intent after treatment with TKI for a baseline advanced-stage adenocarcinoma. The baseline clinical workup included a physical examination, computed tomography (CT) scans, bronchoscopy and 18-fludeoxyglucose-positron emission tomography scans. In some cases, the pretreatment histological diagnosis required CT-guided needle or endoscopic ultrasound (EBUS) biopsy or mediastinoscopy. As a general rule, the eligibility for surgery of patients who received TKIs for previous inoperable NSCLC was limited to a few favourable cases (in our centres, around 2% of all advanced adenocarcinomas treated with TKIs). In those patients, surgical resection following treatment with TKI (adjuvant surgery) allowed local control of a possibly stabilized disease. With respect to preoperative mediastinal nodal evaluation, the multidisciplinary team chose a treatment similar to that used in patients with stage IIIa-NSCLC receiving neoadjuvant chemotherapy. Surgical eligibility was not restricted to patients with a complete response but included cases with a good or partial response as long as radical surgical remained feasible. After systemic treatment and before surgery, restaging with CT and/or positron emission tomography/CT scans was performed in all cases, whereas neither mediastinoscopy nor EBUS was routinely performed for preoperative evaluation of mediastinal lymph nodes. Final histopathological assessment was carried out by thoracic pathologists and included the ypathological tumour, node and metastasis (ypTNM) classification, the histological subtype and possible pathological changes following neoadjuvant treatment expressing tumour composition in terms of rates of necrosis, fibrosis and viable tumour cells. Viability was defined as the presence of tumour cells exhibiting distinct nuclear chromatin, an intact nuclear or cytoplasmic membrane and the absence of signs of necrosis (i.e. karyorrhexis, karyolysis and pyknosis) or fibrosis. Follow-up was performed by interviews with physicians and analysis of city registers. Later risk factors were studied and survival analyses were carried out. RESULTS Nineteen patients were identified; their characteristics are detailed in Table 1. After receiving a systemic treatment including TKIs, the patients underwent a lobectomy, pneumonectomy or segmentectomy in 68.4%, 26.3% and 5.3% of cases, respectively (Table 2). Prior to lung resection, 2 patients had a surgical extrapulmonary metastasectomy (1 adrenalectomy, 1 bone resection). At the macroscopic level, a few fibrotic tissues were observed intraoperatively around the area of the tumour area, even in the 8 patients who had received TKIs as the sole treatment prior to surgery. The postoperative hospital course was uneventful in 13 (68.4%) cases whereas 3 (15.8%) patients had major complications. The 5 patients who had a pneumonectomy had a 60% complication rate (31.6% in non-pneumonectomy patients, P = 0.11) postoperatively. The postoperative pathological findings indicated 15 (78.9%) adenocarcinomas, whereas 4 (21.1%) cases showed no viable tumour tissue—just fibrosis and/or necrosis. Within the whole series of surgical specimens, analysis of the 3 pathological patterns included in tumour composition revealed that the median rate of fibrosis was 32.5% (0–100); that of viable neoplastic tissue, 25.0% (0–90); and that of necrosis, 12.5% (0–80%). With respect to the T parameter, when we compared the clinical baseline with the pTNM, we recorded a downstaging in 10 (52.6%) patients and an upstaging in 3 (15.8%) patients when comparing pre-TKI-cT with pT. Table 1: Patients’ characteristics and pathological features Characteristics n (%), mean ± SD Gender  Men 7 (36.8)  Women 12 (63.2) Age (years) 60.4 ± 12.7 Body mass index (kg/m2) 24.2 ± 4.7 Smoking 1 (5.2)  Current smoker  Former smoker 9 (47.4)  Non-smoker 9 (47.4) COPD 1 (4.5) Preoperative FEV1, % predicted value 87.4 ± 14.7 Performance status  PS0 4 (22.7)  PS1 13 (63.6)  PS2 3 (13.7) Pretreatment molecular analysis of tumour biopsy  EGFR mutation 13 (68.4)  ALK rearrangement 2 (10.5)  ROS1 fusion 1 (5.3)  No detected abnormality 3 (15.8) Type of TKI 9 (47.4)  Erlotinib  Gefitinib 7 (36.8)  Crizotinib 3 (15.8) T parameter Baseline clinical yPathological  T0 0 (0.0) 4 (21.0)  T1a,b 5 (26.3) 4 (21.0)  T2a,b 6 (31.6) 9 (47.4)  T3 7 (36.8) 1 (5.3)  T4 1 (5.3) 1 (5.3 N parameter  N0 4 (21.0) 10 (52.6)  N1 3 (15.8) 3 (15.8)  N2,3 12 (63.2) 6 (31.6) M parameter  M0 8 (42.1) 17 (89.5)  M1 11 (57.9) 2 (10.5) Stage  0 0 (0.0) 4 (21.0)  Ia,b 0 (0.0) 4 (21.0)  IIa,b 0 (0.0) 3 (15.8)  IIIa 5 (26.3) 6 (31.6)  IIIb 3 (15.8) 0 (0.0)  IV 11 (57.9) 2 (10.6) Characteristics n (%), mean ± SD Gender  Men 7 (36.8)  Women 12 (63.2) Age (years) 60.4 ± 12.7 Body mass index (kg/m2) 24.2 ± 4.7 Smoking 1 (5.2)  Current smoker  Former smoker 9 (47.4)  Non-smoker 9 (47.4) COPD 1 (4.5) Preoperative FEV1, % predicted value 87.4 ± 14.7 Performance status  PS0 4 (22.7)  PS1 13 (63.6)  PS2 3 (13.7) Pretreatment molecular analysis of tumour biopsy  EGFR mutation 13 (68.4)  ALK rearrangement 2 (10.5)  ROS1 fusion 1 (5.3)  No detected abnormality 3 (15.8) Type of TKI 9 (47.4)  Erlotinib  Gefitinib 7 (36.8)  Crizotinib 3 (15.8) T parameter Baseline clinical yPathological  T0 0 (0.0) 4 (21.0)  T1a,b 5 (26.3) 4 (21.0)  T2a,b 6 (31.6) 9 (47.4)  T3 7 (36.8) 1 (5.3)  T4 1 (5.3) 1 (5.3 N parameter  N0 4 (21.0) 10 (52.6)  N1 3 (15.8) 3 (15.8)  N2,3 12 (63.2) 6 (31.6) M parameter  M0 8 (42.1) 17 (89.5)  M1 11 (57.9) 2 (10.5) Stage  0 0 (0.0) 4 (21.0)  Ia,b 0 (0.0) 4 (21.0)  IIa,b 0 (0.0) 3 (15.8)  IIIa 5 (26.3) 6 (31.6)  IIIb 3 (15.8) 0 (0.0)  IV 11 (57.9) 2 (10.6) ALK: anaplastic lymphoma kinase; COPD: chronic obstructive pulmonary disease; EGFR: endothelial growth factor receptor; FEV1: forced expiratory volume in 1 s; ROS1: c-ROS oncogene 1; SD: standard deviation; TKI: tyrosine kinase inhibitor. Table 1: Patients’ characteristics and pathological features Characteristics n (%), mean ± SD Gender  Men 7 (36.8)  Women 12 (63.2) Age (years) 60.4 ± 12.7 Body mass index (kg/m2) 24.2 ± 4.7 Smoking 1 (5.2)  Current smoker  Former smoker 9 (47.4)  Non-smoker 9 (47.4) COPD 1 (4.5) Preoperative FEV1, % predicted value 87.4 ± 14.7 Performance status  PS0 4 (22.7)  PS1 13 (63.6)  PS2 3 (13.7) Pretreatment molecular analysis of tumour biopsy  EGFR mutation 13 (68.4)  ALK rearrangement 2 (10.5)  ROS1 fusion 1 (5.3)  No detected abnormality 3 (15.8) Type of TKI 9 (47.4)  Erlotinib  Gefitinib 7 (36.8)  Crizotinib 3 (15.8) T parameter Baseline clinical yPathological  T0 0 (0.0) 4 (21.0)  T1a,b 5 (26.3) 4 (21.0)  T2a,b 6 (31.6) 9 (47.4)  T3 7 (36.8) 1 (5.3)  T4 1 (5.3) 1 (5.3 N parameter  N0 4 (21.0) 10 (52.6)  N1 3 (15.8) 3 (15.8)  N2,3 12 (63.2) 6 (31.6) M parameter  M0 8 (42.1) 17 (89.5)  M1 11 (57.9) 2 (10.5) Stage  0 0 (0.0) 4 (21.0)  Ia,b 0 (0.0) 4 (21.0)  IIa,b 0 (0.0) 3 (15.8)  IIIa 5 (26.3) 6 (31.6)  IIIb 3 (15.8) 0 (0.0)  IV 11 (57.9) 2 (10.6) Characteristics n (%), mean ± SD Gender  Men 7 (36.8)  Women 12 (63.2) Age (years) 60.4 ± 12.7 Body mass index (kg/m2) 24.2 ± 4.7 Smoking 1 (5.2)  Current smoker  Former smoker 9 (47.4)  Non-smoker 9 (47.4) COPD 1 (4.5) Preoperative FEV1, % predicted value 87.4 ± 14.7 Performance status  PS0 4 (22.7)  PS1 13 (63.6)  PS2 3 (13.7) Pretreatment molecular analysis of tumour biopsy  EGFR mutation 13 (68.4)  ALK rearrangement 2 (10.5)  ROS1 fusion 1 (5.3)  No detected abnormality 3 (15.8) Type of TKI 9 (47.4)  Erlotinib  Gefitinib 7 (36.8)  Crizotinib 3 (15.8) T parameter Baseline clinical yPathological  T0 0 (0.0) 4 (21.0)  T1a,b 5 (26.3) 4 (21.0)  T2a,b 6 (31.6) 9 (47.4)  T3 7 (36.8) 1 (5.3)  T4 1 (5.3) 1 (5.3 N parameter  N0 4 (21.0) 10 (52.6)  N1 3 (15.8) 3 (15.8)  N2,3 12 (63.2) 6 (31.6) M parameter  M0 8 (42.1) 17 (89.5)  M1 11 (57.9) 2 (10.5) Stage  0 0 (0.0) 4 (21.0)  Ia,b 0 (0.0) 4 (21.0)  IIa,b 0 (0.0) 3 (15.8)  IIIa 5 (26.3) 6 (31.6)  IIIb 3 (15.8) 0 (0.0)  IV 11 (57.9) 2 (10.6) ALK: anaplastic lymphoma kinase; COPD: chronic obstructive pulmonary disease; EGFR: endothelial growth factor receptor; FEV1: forced expiratory volume in 1 s; ROS1: c-ROS oncogene 1; SD: standard deviation; TKI: tyrosine kinase inhibitor. Table 2: Tyrosine kinase inhibitor treatment-related clinical course of each patient Age (years)/ gender Tumour biopsy molecular analysis Treatment with TKI in therapeutic scheme Type of TKI Initial clinical response to treatment with TKI Consecutive treatment to TKIs Lung resection type In-hospital course Follow-up 77/female EGFR m exon 19 del 1st Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 73/male EGFR m exon 19 del 1st Line Erlotinib Progression Chemotherapy Lobectomy Prolonged air-leak No relapse alive 68/male EGFR wt 3rd Line Erlotinib Stable Surgery Lobectomy No adverse event Relapse dead 49/female EGFR m p.L858R 1st Line Erlotinib Progression Chemotherapy Pneumonectomy Atrial fibrillation Relapse alive 66/male EGFR m exon 19 del 1st Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 52/female EGFR m p.L858R 2nd Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 70/male EGFR wt 3rd Line Erlotinib Good Surgery Segmentectomy No adverse event No relapse alive 60/male EGFR wt 3rd Line Erlotinib Progression Chemotherapy Lobectomy Pneumoniae No relapse alive 47/female EGFR m exon 19 del 1st Line Gefitinib Good Surgery Lobectomy No adverse event No relapse dead 54/female EGFR m exon 19 del 1st Line Gefitinib Good Surgery Pneumonectomy Haemothorax Reoperation Relapse alive 64/male ALK r 1st Line Crizotinib Good Surgery Lobectomy No adverse event Relapse alive 26/female EGFR m p.G719S, L861Q 2nd Line Gefitinib Partial Surgery Lobectomy No adverse event Relapse dead 50/female EGFR m exon 19 del 1st Line Gefitinib Partial Surgery Pneumonectomy No adverse event Relapse dead 80/female EGFR m exon 19 del 1st Line Gefitinib Partial Chemotherapy Lobectomy No adverse event No relapse alive 56/female EGFR m exon 19 del 2nd Line Gefitinib Partial Surgery Lobectomy Prolonged air-leak Relapse alive 61/male EGFR m p.L858R 1st Line Gefitinib Partial Surgery Pneumonectomy Haemothorax Reoperation Relapse alive 70/female ALK r 1st Line Crizotinib Partial Surgery Lobectomy No adverse event No relapse alive 57/female EGFR m exon 19 del 2nd Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 67/female ROS-1 r 2nd Line Crizotinib Partial Surgery Pneumonectomy No adverse event No relapse alive Age (years)/ gender Tumour biopsy molecular analysis Treatment with TKI in therapeutic scheme Type of TKI Initial clinical response to treatment with TKI Consecutive treatment to TKIs Lung resection type In-hospital course Follow-up 77/female EGFR m exon 19 del 1st Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 73/male EGFR m exon 19 del 1st Line Erlotinib Progression Chemotherapy Lobectomy Prolonged air-leak No relapse alive 68/male EGFR wt 3rd Line Erlotinib Stable Surgery Lobectomy No adverse event Relapse dead 49/female EGFR m p.L858R 1st Line Erlotinib Progression Chemotherapy Pneumonectomy Atrial fibrillation Relapse alive 66/male EGFR m exon 19 del 1st Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 52/female EGFR m p.L858R 2nd Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 70/male EGFR wt 3rd Line Erlotinib Good Surgery Segmentectomy No adverse event No relapse alive 60/male EGFR wt 3rd Line Erlotinib Progression Chemotherapy Lobectomy Pneumoniae No relapse alive 47/female EGFR m exon 19 del 1st Line Gefitinib Good Surgery Lobectomy No adverse event No relapse dead 54/female EGFR m exon 19 del 1st Line Gefitinib Good Surgery Pneumonectomy Haemothorax Reoperation Relapse alive 64/male ALK r 1st Line Crizotinib Good Surgery Lobectomy No adverse event Relapse alive 26/female EGFR m p.G719S, L861Q 2nd Line Gefitinib Partial Surgery Lobectomy No adverse event Relapse dead 50/female EGFR m exon 19 del 1st Line Gefitinib Partial Surgery Pneumonectomy No adverse event Relapse dead 80/female EGFR m exon 19 del 1st Line Gefitinib Partial Chemotherapy Lobectomy No adverse event No relapse alive 56/female EGFR m exon 19 del 2nd Line Gefitinib Partial Surgery Lobectomy Prolonged air-leak Relapse alive 61/male EGFR m p.L858R 1st Line Gefitinib Partial Surgery Pneumonectomy Haemothorax Reoperation Relapse alive 70/female ALK r 1st Line Crizotinib Partial Surgery Lobectomy No adverse event No relapse alive 57/female EGFR m exon 19 del 2nd Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 67/female ROS-1 r 2nd Line Crizotinib Partial Surgery Pneumonectomy No adverse event No relapse alive ADC: adenocarcinoma; ALK: anaplastic lymphoma kinase; EGFR: endothelial growth factor receptor; m: mutation; r: rearrangement; ROS1: c-ROS oncogene 1; TKI: tyrosine kinase inhibitor; wt: wild-type. Table 2: Tyrosine kinase inhibitor treatment-related clinical course of each patient Age (years)/ gender Tumour biopsy molecular analysis Treatment with TKI in therapeutic scheme Type of TKI Initial clinical response to treatment with TKI Consecutive treatment to TKIs Lung resection type In-hospital course Follow-up 77/female EGFR m exon 19 del 1st Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 73/male EGFR m exon 19 del 1st Line Erlotinib Progression Chemotherapy Lobectomy Prolonged air-leak No relapse alive 68/male EGFR wt 3rd Line Erlotinib Stable Surgery Lobectomy No adverse event Relapse dead 49/female EGFR m p.L858R 1st Line Erlotinib Progression Chemotherapy Pneumonectomy Atrial fibrillation Relapse alive 66/male EGFR m exon 19 del 1st Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 52/female EGFR m p.L858R 2nd Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 70/male EGFR wt 3rd Line Erlotinib Good Surgery Segmentectomy No adverse event No relapse alive 60/male EGFR wt 3rd Line Erlotinib Progression Chemotherapy Lobectomy Pneumoniae No relapse alive 47/female EGFR m exon 19 del 1st Line Gefitinib Good Surgery Lobectomy No adverse event No relapse dead 54/female EGFR m exon 19 del 1st Line Gefitinib Good Surgery Pneumonectomy Haemothorax Reoperation Relapse alive 64/male ALK r 1st Line Crizotinib Good Surgery Lobectomy No adverse event Relapse alive 26/female EGFR m p.G719S, L861Q 2nd Line Gefitinib Partial Surgery Lobectomy No adverse event Relapse dead 50/female EGFR m exon 19 del 1st Line Gefitinib Partial Surgery Pneumonectomy No adverse event Relapse dead 80/female EGFR m exon 19 del 1st Line Gefitinib Partial Chemotherapy Lobectomy No adverse event No relapse alive 56/female EGFR m exon 19 del 2nd Line Gefitinib Partial Surgery Lobectomy Prolonged air-leak Relapse alive 61/male EGFR m p.L858R 1st Line Gefitinib Partial Surgery Pneumonectomy Haemothorax Reoperation Relapse alive 70/female ALK r 1st Line Crizotinib Partial Surgery Lobectomy No adverse event No relapse alive 57/female EGFR m exon 19 del 2nd Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 67/female ROS-1 r 2nd Line Crizotinib Partial Surgery Pneumonectomy No adverse event No relapse alive Age (years)/ gender Tumour biopsy molecular analysis Treatment with TKI in therapeutic scheme Type of TKI Initial clinical response to treatment with TKI Consecutive treatment to TKIs Lung resection type In-hospital course Follow-up 77/female EGFR m exon 19 del 1st Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 73/male EGFR m exon 19 del 1st Line Erlotinib Progression Chemotherapy Lobectomy Prolonged air-leak No relapse alive 68/male EGFR wt 3rd Line Erlotinib Stable Surgery Lobectomy No adverse event Relapse dead 49/female EGFR m p.L858R 1st Line Erlotinib Progression Chemotherapy Pneumonectomy Atrial fibrillation Relapse alive 66/male EGFR m exon 19 del 1st Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 52/female EGFR m p.L858R 2nd Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 70/male EGFR wt 3rd Line Erlotinib Good Surgery Segmentectomy No adverse event No relapse alive 60/male EGFR wt 3rd Line Erlotinib Progression Chemotherapy Lobectomy Pneumoniae No relapse alive 47/female EGFR m exon 19 del 1st Line Gefitinib Good Surgery Lobectomy No adverse event No relapse dead 54/female EGFR m exon 19 del 1st Line Gefitinib Good Surgery Pneumonectomy Haemothorax Reoperation Relapse alive 64/male ALK r 1st Line Crizotinib Good Surgery Lobectomy No adverse event Relapse alive 26/female EGFR m p.G719S, L861Q 2nd Line Gefitinib Partial Surgery Lobectomy No adverse event Relapse dead 50/female EGFR m exon 19 del 1st Line Gefitinib Partial Surgery Pneumonectomy No adverse event Relapse dead 80/female EGFR m exon 19 del 1st Line Gefitinib Partial Chemotherapy Lobectomy No adverse event No relapse alive 56/female EGFR m exon 19 del 2nd Line Gefitinib Partial Surgery Lobectomy Prolonged air-leak Relapse alive 61/male EGFR m p.L858R 1st Line Gefitinib Partial Surgery Pneumonectomy Haemothorax Reoperation Relapse alive 70/female ALK r 1st Line Crizotinib Partial Surgery Lobectomy No adverse event No relapse alive 57/female EGFR m exon 19 del 2nd Line Erlotinib Good Surgery Lobectomy No adverse event No relapse alive 67/female ROS-1 r 2nd Line Crizotinib Partial Surgery Pneumonectomy No adverse event No relapse alive ADC: adenocarcinoma; ALK: anaplastic lymphoma kinase; EGFR: endothelial growth factor receptor; m: mutation; r: rearrangement; ROS1: c-ROS oncogene 1; TKI: tyrosine kinase inhibitor; wt: wild-type. We observed a pathological downstaging in half of the 12 cN2 patients, with 3 (63.2%) cases of mediastinal complete clearance (clinical versus pathological number of N2, 3+ patients significantly higher = 0.02). Univariate analysis of factors potentially associated with the pathological response to treatment with TKI showed a fibrosis ratio significantly higher in patients older than 60 years (P = 0.01) and in those who received erlotinib versus other TKIs (P = 0.03). Other factors such as body mass index, duration of treatment with TKI and the cT parameter turned out to be substantially unrelated to tumour composition. Mean and median follow-up times reached 28.3 ± 22.7 and 23.8 (7.4–80.6) months, respectively (Table 2). On Kaplan–Meier analysis, the mean overall survival (OS) estimate was 56.5 [95% confidence interval (CI) 40.4–72.7] months and the 1-, 3- or 5-year OS rates were 90.9% ± 0.8%, 79.5% ± 13.5% and 39.8% ± 19.4%, respectively (Supplementary Material, Fig. S1A). All 4 patients without viable tumour cells in pathological specimens remained alive during the study period. No preoperative feature was significantly related to OS. The mean disease-free survival (DFS) estimate was 30.0 months (95% CI 15.7–44.3) whereas the 1-, 3- and 5-year DFS rates were 79.0% ± 1.6%, 44.4% ± 14.7% and 29.6% ± 18.6%, respectively (Supplementary Material, Fig. S1B). The ratio of fibrosis <50% (P = 0.05) or viable tumour cells >30% (P = 0.05) determined from a pathological analysis of the resected specimen and pneumonectomy (P = 0.03) was closely associated with a lower DFS in a log rank test, although none of these factors independently influenced DFS on multivariate analysis. DISCUSSION Our study evaluated the feasibility of adjuvant surgery by analysing short- and long-term findings in a highly selected subset of patients with advanced adenocarcinoma. Although at first they were deemed inoperable, they underwent anatomical pulmonary resection after systemic treatment that included TKI. Despite a significantly high morbidity rate, especially in the pneumonectomy group, we performed a relatively safe operation, because the post-TKI operative area was not particularly demanding, especially in patients who received only TKIs preoperatively—no chemotherapy. We must emphasize, however, that these statements may reflect personal views rather than objective data. In addition to the perioperative safety of this strategy of care, we did not record any negative impacts of TKI on pulmonary function (considering a good preoperative forced expiratory volume in 1 s, mean = 87.4% of predicted value). Because assessing pulmonary functional changes before and after treatment with TKI was not the goal of our study, our analysis can be considered just a simple observation in support of the feasibility of such surgery. To our knowledge, no study supports any impact of TKIs on respiratory function without occurrence of an alteration of the forced expiratory volume in 1 s or other clinical parameters potentially influencing surgical eligibility. Concerning the prognosis, our preliminary analysis showed that patients treated in this setting had relatively rewarding oncological results. A study analysing 9 patients treated surgically after gefitinib-induction therapy reported a poorer prognosis, with a 32-month survival median and a 3-year survival rate reaching approximately 50% [5]. The authors connected these suboptimal oncological results to a remarkable early recurrence rate and an overestimation of the actual radiological response to TKI, as previously suggested [6]. Our analysis failed to determine what affects long-term prognosis. Nevertheless we succeeded in assessing tumour composition after treatment with TKIs for a relatively homogeneous cohort of adenocarcinomas. Indeed, we could detect a wide spectrum of histological changes and significant rates of fibrosis and necrosis. Moreover, our analysis found a correlation between pathological response and patients’ age or type of TKI therapy. However, we probably need to analyse our findings further by taking into account more suitable methods for analysis of post-TKI responses [7, 8]. These data could represent the ‘proof of principle’ for further studies. In fact, we can assume that, following standard chemotherapy, patients who have a pathological response have a better prognosis [9]. Given these results, it seems reasonable to consider the ‘surgical option’ in radiological responders, because resection represents the only way to assess for a pathological response to TKIs and other systemic treatments. The real benefit of adjuvant surgery for OS can indeed be questioned because patients with a complete pathological response (4 of 19 cases) may not require local treatment. On the contrary, we recorded cases whose N parameter was upstaged in the comparison between pre- and postoperative staging. In such cases, one can question the positive prognostic impact of surgical resection because of the controversial results that emerged from previous studies on neoadjuvant chemotherapy and nodal involvement [10]. The topic related to eligibility for adjuvant surgery remains controversial, above all when an extensive resection is required. Although pneumonectomy was not assessed as a negative prognostic factor on multivariate analysis, we may discourage pneumonectomy in such a setting because of the remarkable rates of both recurrence and postoperative morbidity. As previously performed in earlier stages of the disease, randomized studies that include advanced adenocarcinomas should be performed to analyse the impact of this complex and evolving therapeutic option on prognosis [11]. Limitations As a retrospective analysis of a small, slightly heterogeneous group of highly selected patients with NSCLC who received surgery after TKIs, our study has several limitations. Moreover, the follow-up period was too short and there was no control arm including patients with a good response to TKI therapy and no consecutive surgery. Readers should be careful in evaluating the clinical impact of our findings (still limited and preliminary). Indeed, it would be wise to avoid drawing any conclusion about prognosis and consider our findings as a preliminary study on the feasibility and results of surgery after treatment with TKI. Although pathological changes were recorded even for patients undergoing preoperative exclusive treatment with TKI, a study exclusively devoted to the peculiar impact of TKIs on tumour tissue would be of paramount importance in definitively clarifying this aspect, because confounding variables could influence our results. CONCLUSIONS In a subset of highly selected patients, adjuvant lung surgery following treatment with TKI identified a large spectrum of histological changes evident in the pathological specimens and encouraging preliminary survival results. Pending further research, it may prove a relatively reliable and safe therapeutic choice, except when an extensive resection like pneumonectomy is planned. SUPPLEMENTARY MATERIAL Supplementary material is available at ICVTS online. ACKNOWLEDGMENTS The authors thank Daniela Masi (Reggio Emilia AUSL-IRCSS) and Graham Donlon (CHU sud Réunion, Saint Pierre) for English revision and editing. Conflict of interest: none declared. REFERENCES 1 Maemondo M , Inoue A , Kobayashi K , Sugawara S , Oizumi S , Isobe H. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR . N Engl J Med 2010 ; 362 : 2380 – 8 . Google Scholar CrossRef Search ADS PubMed 2 Liao BC , Lin CC , Lee JH , Yang JC. Optimal management of EGFR-mutant non-small cell lung cancer with disease progression on first-line tyrosine kinase inhibitor therapy . Lung Cancer 2017 ; 110 : 7 – 13 . Google Scholar CrossRef Search ADS PubMed 3 Takamochi K , Suzuki K , Sugimura H , Funai K , Mori H , Bashar AH et al. Surgical resection after gefitinib treatment in patients with lung adenocarcinoma harboring epidermal growth factor receptor gene mutation . Lung Cancer 2007 ; 58 : 149 – 55 . Google Scholar CrossRef Search ADS PubMed 4 Schreiner W , Dudek W , Sirbu H. Is salvage surgery for recurrent non-small-cell lung cancer after definitive non-operative therapy associated with reasonable survival? Interact CardioVasc Thorac Surg 2015 ; 21 : 682 – 4 . Google Scholar CrossRef Search ADS PubMed 5 Hishida T , Nagai K , Mitsudomi T , Yokoi K , Kondo H , Horinouchi H et al. Salvage surgery for advanced non-small cell lung cancer after response to gefitinib . J Thorac Cardiovasc Surg 2010 ; 140 : e69 – 71 . Google Scholar CrossRef Search ADS PubMed 6 Kappers I , Klomp HM , Burgers JA , Van Zandwijk N , Haas RLM , van Pel R. Neoadjuvant (induction) erlotinib response in stage IIIA non-small-cell lung cancer . J Clin Oncol 2008 ; 26 : 4205 – 7 . Google Scholar CrossRef Search ADS PubMed 7 Lowery A , Han Z. Assessment of tumor response to tyrosine kinase inhibitors . Front Biosci (Landmark Ed) 2011 ; 16 : 1996 – 2007 . Google Scholar CrossRef Search ADS 8 Yamamoto Y , Kodama K , Maniwa T , Takeda M. Surgical resection of advanced non-small cell lung cancer after a response to EGFR-TKI: presentation of two cases and a literature review . J Cardiothorac Surg 2017 ; 12 : 98. Google Scholar CrossRef Search ADS PubMed 9 Lococo F , Cesario A , Margaritora S , Dall'Armi V , Mattei F , Romano R et al. Long-term results in patients with pathological complete response after induction radiochemotherapy followed by surgery for locally advanced non-small-cell lung cancer . Eur J Cardiothorac Surg 2013 ; 43 : e71 – 81 . Google Scholar CrossRef Search ADS PubMed 10 Meacci E , Cesario A , Cusumano G , Lococo F , D'Angelillo R , Dall'armi V et al. Surgery for patients with persistent pathological N2 IIIA stage in non-small-cell lung cancer after induction radio-chemotherapy: the microscopic seed of doubt . Eur J Cardiothorac Surg 2011 ; 40 : 656 – 63 . Google Scholar PubMed 11 Lara-Guerra H , Waddell TK , Salvarrey MA , Joshua AM , Chung CT , Paul N et al. Phase II study of preoperative gefitinib in clinical stage I non-small-cell lung cancer . J Clin Oncol 2009 ; 27 : 6229 – 36 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Interactive CardioVascular and Thoracic SurgeryOxford University Press

Published: Apr 16, 2018

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