Major Pulmonary Resection After Neoadjuvant Therapy in Potentially Resectable Stage IIIA/B Non-Small Cell Lung Carcinoma: R0 or No R0

Objective The aim of this study was to identify predictors of postoperative outcome and survival of locally advanced non-small cell lung carcinoma (NSCLC) resections after neoadjuvant chemotherapy or chemoradiation. Methods Medical records of all patients with clinical stage III potentially resectable NSCLC initially treated by neoadjuvant chemotherapy or chemoradiation followed by major pulmonary resections between 1999 to 2019 were retrieved from the databases of four Israeli Medical Centers. Results: The 124 suitable patients included, 86 males (69.4%) and 38 females (30.6%), mean age of 64.2 years (range 37-82) and mean hospital stay of 12.6 days (range 5-123). Complete resection was achieved in 92.7% of the patients, while complete pathologic response was achieved in 35.5%. Overall readmission rate was 16.1%. The overall 5-year survival rate was 47.9%. One patient (0.8%) had local recurrence. Postoperative complications were reported in 49.2% of the patients, mainly atrial brillation (15.9%) and pneumonia (13.7%), empyema (10.3%), and early bronchopleural stula (7.3%). Early in-hospital mortality rate was 6.5% and the six-month mortality rate was 5.6%. Pre-neoadjuvant bulky mediastinal disease (lymph nodes >20 mm) (p=0.034), persistent postoperative N2 disease (p=0.016), R1 resection (p=0.027) and postoperative stage IIIA (p=0.001), emerged as negative predictive factors for survival. Conclusions: Our ndings demonstrate that neoadjuvant chemotherapy or chemoradiation in locally advanced potentially resectable NSCLC followed by major pulmonary resection is a benecial approach in selected cases.


Introduction
Stage III non-small cell lung carcinoma (NSCLC) is a very heterogeneous disease that depends upon the tumor size (T1-4), tumor local extension and extension of nodal involvement. N2 disease is heterogeneous by itself, as it may include several options depending on site, number of stations, and nature of nodes: bulky or separate. Stage IIIA disease is usually approached by preoperative induction therapy followed by surgical resection. Postoperative anti-EGFR osimertinib has shown to improve disease-free survival in patients with EGFR-mutated tumors [1]. On the other hand, IIIB disease may be approached by chemoradiation followed by immunotherapy (PACIFIC trial) [2]. Selected cases of IIIB disease may be treated by induction therapy followed by a curative surgery only. Post-operative immunotherapy in these cases has not yet been de ned. The goals of induction therapy are downstaging and downsizing the primary disease, in order to improve resectability, and eradicate systemic micrometastatic disease. Patients whose disease is downstaged may be good candidates for surgery.
Surgery, however, is still associated with an increased incidence of postoperative morbidity and mortality, with pneumonectomy being associated with high complication rates [3,4].
Skilled surgeons, modern surgical techniques and perioperative care in highly specialized thoracic intensive care units are key words for improving the postoperative outcome. We have analyzed our results in treating stage IIIA/B potentially resectable NSCLC, and investigated the factors that have affected the patient's outcome.

Patients
We retrospectively reviewed the data of 124 patients, with a con rmed diagnosis of stage IIIA/B NSCLC. All the patients were oncologically treated and followed in one of four Israeli centers: Tel Aviv Medical Center, Tel Aviv, Shamir Medical Center, Zeri n, Kaplan Medical Center, Rehovot, and Wolfson Medical Center, Holon, from May 1999 and through December 2019. Follow up data were available for 121 patients.
There were 86 (69.4%) males and 38 females (30.6%) with mean age of 64.2 years (range, 37-82). Onehundred and ten patients (88.7%) were smokers. The retrieved baseline data were comprised of patient demographics, comorbidities, induction therapy, primary tumor size, location, and histology, side and type of surgery, stages at diagnosis (clinical) and postoperative stages (pathologic), postoperative outcome, including complications, morbidity, mortality, length of hospital stay, readmission, and local recurrence rates. Patient demographics, comorbidities, histological type of tumor, type and kind of surgery, induction treatment, and other characteristics were summarized in Table 1.

Methods
The initial treatment plan, medical treatment results and options for surgery or immunotherapy were discussed and approved by a multidisciplinary team at a tumor board meetings in each case.
In all the patirnts, an induction chemotherapy by platinum-based chemotherapy regimen was administered, together with a second agent such as paclitaxel, etoposide, vinorelbine or pemetrexed, depending on tumor histology, (checkpoint inhibitors were not registered for induction therapy, and were not available).
Radiation therapy (RT) was given concurrently (60 Gy/30 courses, 5 days weekly) in 85 patients [68.5%], starting from cycle one or 2 or 3, depending on availability of RT service. The radiation dose of 60Gy is used in our centers as for induction as for de nitive therapy. Thirty-nine patients (31.5%) got only chemotherapy. Time elapsed between the end of the induction therapy to the date of surgery was 4-6 weeks.
All the patients underwent resection by permanent thoracic-oncology surgical team.

Preoperative workup and tumor classi cation
The diagnostic workup/staging included a complete medical history and a physical examination, chest radiography, bronchoscopy, contrast-enhanced computed tomography (CT) of the chest, electrocardiography, and complete blood counts, chemistry pro les, and coagulation tests. All patients underwent pre-treatment (neo-adjuvant therapy) and post-treatment (preoperative) restaging by positronemission tomography-CT (PET-CT) or contrast-enhanced CT of the chest, as well as contrast-enhanced CT of the brain.
Congestive heart failure was de ned as a reduced ejection fraction of less than 45%. Cardiac comorbidity was de ned as the presence of coronary artery disease, or any previous cardiac surgery or catheterization, current cardiac failure, or arrhythmia. Chronic renal failure (CRF) was de ned as an elevated creatinine level of >1.5 mg/dl. Chronic obstructive pulmonary disease (COPD) was de ned as a forced expiratory volume in 1 second/forced vital capacity ratio less than 70%.
Tumors were classi ed and staged preoperatively and postoperatively according to the 1997 International System for Staging Lung Cancer [5]. Most of the patients had either squamous cell carcinoma or adenocarcinoma (37.9% and 41.1%, respectively). Pretreatment mediastinal staging was performed by cervical mediastinoscopy (27 patients, 21.8%), or endobronchial ultrasound (EBUS) (16 patients, 12.9%, when enlarged (>1.0 cm) mediastinal lymph nodes were seen on CT, or when high uorodeoxyglucose (FDG) uptake was seen in mediastinal lymph nodes on PET-CT (performed in 92 patients (74.2%). Chest wall involvement was classi ed as invasion of the diaphragm, chest wall muscles, or ribs. Involvement of mediastinal structures was classi ed as invasion of mediastinal pleura (or pericardium), the great vessels (aorta), esophageal wall, vertebral bodies, trachea, carina, or recurrent laryngeal nerve. Fifteen patients had been diagnosed preoperatively as having superior sulcus (Pancoast) tumors (SST) (12.1%).
Single-station N2 disease was classi ed according to PET-CT results when only one mediastinal station lymph node was positive (generally, R4, 7 or L5), and as multi-station N2 disease when at least one mediastinal and one or more hilar and mediastinal station lymph nodes were positive on PET-CT; or >10 mm on the CT of the chest in pre-PET-CT era. The data on the clinical staging of the 124 patients before admission to induction therapy are summarized in Table 2. Hilar/mediastinal lymph nodes were dissected or sampled within anatomical landmarks during surgery; at least three mediastinal/hilar nodal stations were routinely revised. The data on the pathologic staging of the 124 patients without radiologic disease progression by pre-surgical staging are summarized in Table 3.

Surgical technique
All of the study patients underwent standard anesthesia with a double-lumen endotracheal tube; perioperative low thoracic epidural analgesia, and surgery by means of a similar technique consisting of a standard serratus muscle-sparing posterolateral thoracotomy in the fth or sixth intercostal space [6] with lung surgery performed according to the European Society of Thoracic Surgeons Guidelines [7]. Mechanical staples were used for the closing of pulmonary veins and arteries, and bronchi. The bronchial stumps were reinforced with viable intercostal, serratus or latissimus muscle aps in selected cases (5 patients, 4.0%). Additional thoracic structures, and/or the mediastinal pleura including the pericardium were resected in cases of local invasion. The pericardium reconstruction was done by bovine pericardium (Gore-tex soft tissue patch, Delaware Corp, Newark) in cases of intrapericardial resections. One 36 French chest tube was placed in the empty chest cavity, and it was generally removed within 24 hours after the surgery in cases of pneumonectomy. One curved and one straight 36 French chest tubes were used in cases of bilobectomy or lobectomy.
Patients were generally extubated in the recovery room and initially monitored in the high-dependency unit for 24-48 hours and transferred to the thoracic surgery department intensive care ward thereafter. Early hospital mortality was de ned as death occurring during the postoperative hospitalization period.
Late mortality was de ned as death occurring within six months from surgery. The data relating to all types of postoperative complications are summarized in Table 4.
The patients were followed postoperatively for cancer recurrence and survival every three months for the rst year and every six months thereafter (mean follow up duration was 43.6 months); the nal data on survival were recorded on January 1, 2020.
Patients preoperative, surgical and postoperative characteristics were compared between the groups, continuous variables with normal distribution were summarized with means & standard deviation and compared using independent t-test, for variables that deviate from normal distribution were summarized with medians and IQR (interquartile range) and compared using Mann Whitney test. Categorical variables were summarized with counts and percentages and compared using chi square test. The primary endpoint was death.
The cumulative rates of death were compared using the Kaplan-Meier curves and the cox regression model was applied to evaluate the adjusted effect of surgery and patient characteristics on patient survival (Figures 1-4). The p value < 0.05 was considered to de ne statistical signi cance (Table 5). Analyses were carried out using IBM Corp. Released 2020 IBM SPSS Statistics for Windows, Version 27.0.
The mean hospital stay for the operated patients was 12.6 days (range, 5-123). Postoperative complications were sustained by 61 patients (49.2%), including seven patients with intraoperative hemorrhage (5.6%). Atrial brillation and pneumonia were the most common postoperative complications: 19 (15.9%) and 17 (13.7%) patients, respectively. Lobar atelectasis con rmed by chest radiography and treated by immediate bronchoscopy was recorded for 11 patients (8.9%). A prolonged air leak de ned as an air leak documented one week after lobectomy or bilobectomy was recorded for six patients (4.8%). Empyema occurred in 13 patients (10.5%), with early broncho-pleural stulas (BPF), during the rst 3 postoperative months, occurred in nine patients (7.3%), and a late BPF (between 3-6 months postoperatively) in two patients (1.6%). BPF was treated by an Amplatzer device implantation Early (in-hospital) mortality was recorded for eight patients (6.5%), ve after pneumonectomy (three rightsided and two left-sided), one after bilobectomy (RML/RLL), and two after lobectomy (RUL). The causes of death were ARDS in three patients, pneumonia in two, complicated BPF with empyema in two, and empyema without BPF in one. Late (six months) mortality was recorded for seven patients (5.6%), four after pneumonectomy (three right-sided and one left-sided), one after bilobectomy (RML/RLL), and two after lobectomy (RUL/LUL). The causes of death were empyema without BPF in one patient, complicated BPF with empyema in two, metastatic disease in three, and pneumonia in one.

Discussion
Management of patients with locally advanced NSCLC remains one of the major challenges of thoracic oncology [8]. The treatment strategy is in uenced by disease stage, the patient's functional status, and the decisions reached by the interdisciplinary discussions at the institutional tumor board meetings. Resectable patients bene t from surgery when a radical resection is achieved without major morbidity and mortality. Patients with locally advanced NSCLC undergoing surgery without preoperative oncologic treatment, chemotherapy, or chemoradiation, however, are at a greater risk to develop distant metastases or locally recurrent disease. There is a statistically con rmed survival bene t of neoadjuvant chemotherapy followed by surgery compared with surgery alone [9][10][11][12][13], but the main concern with regard to surgery is the increased risk of postoperative morbidity and mortality [3,4,14,15].
Pneumonectomy remains associated with high and possibly unacceptable rates of perioperative morbidity and mortality, especially after induction therapy [16][17][18][19]. The recommendation of the American College of Chest Physicians (ACCP) is to avoid performing pneumonectomy after neoadjuvant chemoradiotherapy [20]. For example, Thomas et al. [16] found that independent predictors of mortality on multivariate analysis in patients that received induction therapy followed by pneumonectomy were age more than 65 years, male sex, ASA score of three or greater, and right laterality of the procedure. Contrarily, Mansour et al. [21] and Refai et al. [22] did not nd any signi cant differences in terms of early or late morbidity and mortality when comparing patients undergoing pneumonectomy after induction chemoradiotherapy with those who had no form of induction treatment. We had also concluded in our study that pneumonectomy could safely be performed after neoadjuvant chemoradiation or chemotherapy with low early and late mortality rates [23].
Detterbeck FC et al. [24] reported the 5-year survival rates was 19%/24%for clinical/pathological stage IIIA NSCLC (TNM 7), respectively, and 7%/9% for clinical/pathologic stage IIIB NSCLC (TNM 7), respectively. Andre F et al. [25] reported the 5-years survival rates was 35% versus 5%, if the ipsilateral single mediastinal station lymph node versus multiple mediastinal station lymph node involvement was detected. The PACIFIC was the rst randomized study which demonstrated a bene t in progression-free survival after simultaneous chemoradiotherapy with immunotherapy by durvalumab (PDL-1 inhibitor), with signi cantly prolonged overall survival compared to placebo (p = 0.0025) in patients with unresectable stage III NSCLC (2), but limitations of this study were in the exact staging and re-staging methods and high local recurrence rate [26].
Five-year survival rates after neoadjuvant chemotherapy or chemoradiation have been reported to range from 21-41% [11][12][13]27]. Van Meerbeck et al. [27] reported that only complete resection has a positive impact on survival, and that the results of an incomplete resection are compatible with the results of patients treated solely with radiotherapy (a 5-year survival of 15.7%). Koshy et al. [11] and Kim et al. [28] reported a 40% and 61% 5-year survival rate, respectively, in patients achieving a pathologic complete nodal response.
Martin et al. [29] concluded that pulmonary resection after neoadjuvant chemotherapy is associated with acceptable morbidity and mortality, with right pneumonectomy (p < 0.002), blood loss (p < 0.001), and forced expiratory volume in one second (p < 0.001) being predictive risk factors for postoperative complications. Weder et al. [30] demonstrated that pneumonectomy after chemotherapy or chemoradiotherapy can be performed with low perioperative mortality (3%) and acceptable major morbidity (13%) rates, and Kim et al.
[28] demonstrated a 3% rate of early 30-day mortality and an 8% rate of 90-day mortality for patients that underwent pulmonary resection after neoadjuvant chemoradiation.
Mc Elnay et al. [31] posed the key question of whether surgery should be considered as part of multimodality treatment for patients with resectable lung cancer and ipsilateral mediastinal nodal disease. Those authors concluded that there were no signi cant differences in overall survival in patients randomized to surgery as part of bimodality (chemotherapy + surgery) or trimodality (chemoradiation + surgery) treatment. Other studies that reviewed randomized evidence of radiochemotherapy versus surgery within multimodality treatment in stage III NSCLC found no signi cantly different overall survival in patients with locally advanced NSCLC after induction treatment and surgery compared with those receiving de nitive radiochemotherapy [32,33]. Arguments in favor of surgery in patients with resectable disease were referring to large residual necrotic tumors, which are di cult to control with radiotherapy and which may lead to the formation of a lung abscess, or to multiple nodules in the same lobe. The combination of preoperative concurrent chemotherapy and radiotherapy followed by surgery should be considered also where local control is especially important for quality of life, such as with invasion of the brachial plexus in superior sulcus tumors (the Pancoast tumors) or central tumors without mediastinal nodal disease.
Looking back upon more than 20 years of performing major pulmonary resections after neoadjuvant chemoradiation or chemotherapy, we must admit that not all of our results were good and that some were inarguably bad. We statistically found that positive surgical margins, persistent mediastinal disease & pathologic IIIA stage, pre-neoadjuvant bulky mediastinal disease & central extension of the tumors to the proximal airways negatively in uenced on our patients' postoperative outcome and survival. At the same time, we found that our results are compatible with those of other authors [34]. Our study has several potential limitations. This is a retrospective nonrandomized study, which is subject to selection bias; others are a need for more scrupulous preoperative mediastinal staging after neoadjuvant chemoradiation or chemotherapy and a need for lung sparing surgeries instead to pneumonectomies.
It is our impression that by selection of good surgical candidates, by achieving complete pathologic response, negative surgical margins & R0 radical resections, we can continue to perform major pulmonary resections that may be considered an acceptable treatment option in selected patients with stage III potentially resectable NSCLC after neoadjuvant chemoradiation or chemotherapy.

Conclusions
Based upon the results of our 20 years' experience operating post-neoadjuvant major pulmonary resections, we recommend to avoid operate patients with bulky mediastinal disease; and to avoid pneumonectomies' in patients with tumors involving central airways before neoadjuvant chemotherapy or chemoradiation, but we strongly recommend operate the selected patients that are free of those contraindications, including the performance of pneumonectomies'. Finally, we recommend performing more aggressive surgical staging before induction therapy, and restaging to reduce the incidence of postoperative N2 disease. We suppose that development of lung-sparing resection techniques will avoid part of pneumonectomies in the future, strongly dedicated to achieve R0 resections.

Declarations Compliance with Ethical Standards
The Institutional Review Board of Shamir Medical Center (formerly Assaf Harofeh), a referral Center of thoracic surgery until 2019, approved this retrospective study and waived informed Consent.

Funding
This research received no speci c grant from any funding agency, commercial or others.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding Author on reasonable request.

Con ict of Interest
The authors declare that they have no competing interests.    Survival for patients underwent PET-CT before induction therapy Survival for patients with bulky mediastinal disease (lymph nodes >20mm) before induction therapy