We retrospectively reviewed the data of 124 patients, with a confirmed 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, Zerifin, 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). One-hundred 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.
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 definitive 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 classification
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 profiles, and coagulation tests. All patients underwent pre-treatment (neo-adjuvant therapy) and post-treatment (preoperative) restaging by positron-emission tomography-CT (PET-CT) or contrast-enhanced CT of the chest, as well as contrast-enhanced CT of the brain.
Congestive heart failure was defined as a reduced ejection fraction of less than 45%. Cardiac comorbidity was defined as the presence of coronary artery disease, or any previous cardiac surgery or catheterization, current cardiac failure, or arrhythmia. Chronic renal failure (CRF) was defined as an elevated creatinine level of >1.5 mg/dl. Chronic obstructive pulmonary disease (COPD) was defined as a forced expiratory volume in 1 second/forced vital capacity ratio less than 70%.
Tumors were classified and staged preoperatively and postoperatively according to the 1997 International System for Staging Lung Cancer . 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 fluorodeoxyglucose (FDG) uptake was seen in mediastinal lymph nodes on PET-CT (performed in 92 patients (74.2%). Chest wall involvement was classified as invasion of the diaphragm, chest wall muscles, or ribs. Involvement of mediastinal structures was classified 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 classified 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.
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 fifth or sixth intercostal space  with lung surgery performed according to the European Society of Thoracic Surgeons Guidelines . 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 flaps 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 defined as death occurring during the postoperative hospitalization period. Late mortality was defined 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 first year and every six months thereafter (mean follow up duration was 43.6 months); the final data on survival were recorded on January 1, 2020.
Due to the heterogeneity of stage III NSCLC, we evaluated different parameters of locally advanced potentially resectable disease separately and together in order to analyze the factors that potentially influence on postoperative outcome or survival. They included:
- postoperative complications: atelectasis, mechanical ventilation, atrial fibrillation, acute renal failure, empyema, tracheostomy, pneumonia, early and late bronchopleural fistula, acute respiratory distress syndrome (ARDS), air leak, intraoperative hemorrhage and recurrent laryngeal nerve palsy (Table 5);
- comorbidities: coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), peripheral vascular disease (PVD), chronic renal failure (CRF), hypothyroidism, obesity, non-insulin dependent diabetes mellitus (NIDDM), hypertension (HTN), pulmonary edema (PE), cerebrovascular accident (CVA) and smoking (Table 5);
- sex, side of surgery, kind of surgery (pneumonectomy, lobectomy, bilobectomy), extent of surgery (extrapleural, intrapericardial & completion resections), location of the tumors (endobronchial, Pancoast tumors, subcarinal & paraesophageal tumors) (Table 5);
- histologic type of the tumors, preoperative treatment (chemotherapy & chemoradiation), pre-neoadjuvant PET-CT, surgical margins (R0 & R1), pre-neoadjuvant mediastinal staging (N2 negative or N2 single & N2 multiple lymph nodes), pre-neoadjuvant size of mediastinal lymph nodes (<20 mm and >20 mm), pretreatment staging (IIIA & IIIB), pathologic staging (IA-IV & complete pathologic response), persistent N2 disease, visceral & parietal pleural invasion, vascular invasion and local recurrence (Table 5).
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 define statistical significance (Table 5). Analyses were carried out using IBM Corp. Released 2020 IBM SPSS Statistics for Windows, Version 27.0. Armonk, NY: IBM Corp.