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Extended resection for potentially operable patients with stage III non–small cell lung cancer after induction treatment

      Abstract

      Objective

      Surgical treatment of locally advanced non–small cell lung cancer including single or multilevel N2 remains a matter of debate. Several trials demonstrate that selected patients benefit from surgery if R0 resection is achieved. We aimed to assess resectability and outcome of patients with locally advanced clinical T3/T4 (American Joint Committee on Cancer 8th edition) tumors after induction treatment followed by surgery in a pooled analysis of 3 prospective multicenter trials.

      Methods

      A total of 197 patients with T3/T4 non–small cell lung cancer of 368 patients with stage III non–small cell lung cancer enrolled in the Swiss Group for Clinical Cancer Research 16/96, 16/00, 16/01 trials were treated with induction chemotherapy or chemoradiation therapy followed by surgery, including extended resections. Univariable and multivariable analyses were applied for analysis of outcome parameters.

      Results

      Patients’ median age was 60 years, and 67% were male. A total of 38 of 197 patients were not resected for technical (81%) or medical (19%) reasons. A total of 159 resections including 36 extended resections were performed with an 80% R0 and 13.2% pathological complete response rate. The 30- and 90-day mortality were 3% and 7%, respectively, without a difference for extended resections. Morbidity was 32% with the majority (70%) of minor grading complications. The 3-, 5-, and 10-year overall survivals for extended resections were 61% (95% confidence interval, 43-75), 44% (95% confidence interval, 27-59), and 29.5% (95% confidence interval, 13-48), respectively. R0 resection was associated with improved overall survival (hazard ratio, 0.41; P < .001), but pretreatment N2 extension (177/197) showed no impact on overall survival.

      Conclusions

      Surgery after induction treatment for advanced T3/T4 stage including single and multiple pretreatment N2 disease resulted in 80% R0 resection rate and 7% 90-day mortality. Favorable overall survival for extended and not extended resection was demonstrated to be independent of pretreatment N status.

      Graphical abstract

      Key Words

      Abbreviations and Acronyms:

      CT (computed tomography), EFS (event-free survival), HR (hazard ratio), IQR (interquartile range), MPR (major pathologic response), MRI (magnetic resonance imaging), NCCN (National Comprehensive Cancer Network), NSCLC (non–small cell lung cancer), OS (overall survival), OR (odds ratio), pCR (pathological complete response), PET (positron emission tomography), SAKK (Swiss Group for Clinical Cancer Research)
      Figure thumbnail fx2
      Extended and not extended resections yield similar outcomes in clinical stage T3/T4 NSCLC (95% CI).
      Extended resections for advanced T3/T4 NSCLC after induction treatment can be associated with a high R0 rate, low morbidity and mortality, and promising OS regardless of N2 status.
      Patients with T3/T4 NSCLC with multilevel N2 before induction are considered inoperable according to current guidelines. Patients undergoing surgery after induction therapy demonstrate low mortality and promising long-term survival influenced by R0 rate and age. Critical discussion is needed for determination of potentially operable patients before induction treatment in light of new therapies.
      The role of surgery for patients with T3/4 locally advanced non–small cell lung cancer (NSCLC) including single or multilevel N2 remains a matter of debate. Resectable stage III is poorly defined and not uniformly standardized. Nevertheless, several trials have demonstrated that selected patients benefit from surgery
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      after induction therapy. Until recently, prognosis and treatment concepts of patients with lung cancer were mainly based on local disease extent and lymph node involvement. However, patients with stage III disease often receive induction therapy before resection with an unpredictable response that is based mainly on the biology of the tumor and less on the TNM stage. This results in a difference between clinical and pathological stage. One of the intentions of induction therapy is that patients become resectable and that R0 resection can be achieved.
      In 3 prospective phase III and phase II trials
      • Betticher D.C.
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      • Totsch M.
      • Hansen E.
      • Joss C.
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      • et al.
      Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial.
      • Stupp R.
      • Mayer M.
      • Kann R.
      • Weder W.
      • Zouhair A.
      • Betticher D.C.
      • et al.
      Neoadjuvant chemotherapy and radiotherapy followed by surgery in selected patients with stage IIIB non-small-cell lung cancer: a multicentre phase II trial.
      • Pless M.
      • Stupp R.
      • Ris H.B.
      • Stahel R.A.
      • Weder W.
      • Thierstein S.
      • et al.
      Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.
      of the Swiss Group for Clinical Cancer Research (SAKK), different induction protocols followed by surgery were investigated. They represent an important source of information about pretreatment clinical stage because precise mediastinal staging including tissue conformation before study inclusion was mandatory in all trials. Additionally, patients with extensive stage III disease, currently considered unresectable according to current guidelines,
      • Postmus P.E.
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      • Vansteenkiste J.
      • et al.
      Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      • Kris M.G.
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      • Kennedy E.B.
      • Azzoli C.G.
      • Ellis P.M.
      • et al.
      Adjuvant systemic therapy and adjuvant radiation therapy for stage I to IIIA completely resected non-small-cell lung cancers: American Society of Clinical Oncology/Cancer Care Ontario Clinical Practice Guideline Update.
      were included even with multilevel and bulky N2 and in combination with locally advanced (T3/T4) tumors.
      To overcome the existing evidence gaps relating to the optimal selection criteria for locally advanced T3/T4 tumors including N2 involvement into induction treatment followed by surgery, we aimed to assess the resectability, outcome of surgery, and long-term survival in this challenging patient's group.
      The present pooled analysis of 3 prospective multicenter clinical trials (SAKK16/96,
      • Betticher D.C.
      • Hsu Schmitz S.F.
      • Totsch M.
      • Hansen E.
      • Joss C.
      • von Briel C.
      • et al.
      Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial.
      16/00,
      • Pless M.
      • Stupp R.
      • Ris H.B.
      • Stahel R.A.
      • Weder W.
      • Thierstein S.
      • et al.
      Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.
      16/01
      • Stupp R.
      • Mayer M.
      • Kann R.
      • Weder W.
      • Zouhair A.
      • Betticher D.C.
      • et al.
      Neoadjuvant chemotherapy and radiotherapy followed by surgery in selected patients with stage IIIB non-small-cell lung cancer: a multicentre phase II trial.
      ) summarizes the short- and long term results of extended and not extended resections after induction treatment with chemotherapy or chemoradiotherapy.

      Materials and Methods

      This analysis included individual patient data of 197 patients with locally advanced (T3/T4) NSCLC of 368 patients with operable stage III (IIIA/N2 and IIIB) NSCLC enrolled in a phase III SAKK 16/00 and 2 phase II SAKK 16/96 and SAKK 16/01 trials
      • Betticher D.C.
      • Hsu Schmitz S.F.
      • Totsch M.
      • Hansen E.
      • Joss C.
      • von Briel C.
      • et al.
      Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial.
      • Stupp R.
      • Mayer M.
      • Kann R.
      • Weder W.
      • Zouhair A.
      • Betticher D.C.
      • et al.
      Neoadjuvant chemotherapy and radiotherapy followed by surgery in selected patients with stage IIIB non-small-cell lung cancer: a multicentre phase II trial.
      • Pless M.
      • Stupp R.
      • Ris H.B.
      • Stahel R.A.
      • Weder W.
      • Thierstein S.
      • et al.
      Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.
      between 1997 and 2012 summarized in the flow chart (Figure E1).
      Briefly, patients enrolled in these trials were treated with induction chemotherapy alone (3 cycles of cisplatin, docetaxel) or chemo-radiation therapy (3 cycles of cisplatin, and docetaxel ± radiation [44 Gy in 22 fractions in 3 weeks]) followed by resection (Figure 1). All resected patients completed chemotherapy before surgery. Surgery was performed 21 to 28 days after completion of radiotherapy for patients in the chemoradiotherapy group and 21 days after the last chemotherapy cycle for patients in the chemotherapy group. The median time between completion of induction therapy and surgery (interquartile range [IQR]) was defined as the time span between day 22 of the last cycle and the date of surgery. These trials were approved by the local ethics committee at each participating center (SAKK 16/96: ClinicalTrials.gov, number NCT00003231, SWS-SAKK-16/96; EU-97034; SAKK 16/00: ClinicalTrials.gov, number NCT00030771, SWS-SAKK-16/00, EU-20138; SAKK 16/01: ClinicalTrials.gov, number NCT00030810, SWS-SAKK-16/01; EU-20137).
      Figure thumbnail gr1
      Figure 1Graphical Abstract providing an overview of the methods, results, and implication of the analysis. Surgery for advanced T3/T4 stage including single and multiple pretreatment N2 disease resulted in a high R0 resection rate and low 90-day mortality. Kaplan–Meier curve in Graphical Abstract depicting OS in a cohort of extended resections (blue line; n = 36) versus not extended resections (red line, n = 123) and demonstrated favorable OS independent of pretreatment lymph node involvement (95% CI). NSCLC, Non–small cell lung cancer; SAKK, Swiss Group for Clinical Cancer Research; CT, computed tomography; MRI, magnetic resonance imaging; EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration; EUS-FNA, endoscopic ultrasound-guided fine needle aspiration; VATS, video-assisted thoraoscopic surgery; LAD, lymphadenectomy.
      Ethic agreement including corresponding specific IRB/ERB approval numbers (exemplary for SAKK 16/00; ClinicalTrials.gov, number NCT00030771, SWS-SAKK-16/00, EU-20138: 2001/038, 35/01, 35/01, 11,026, 51/2001, 01/005, 02/032, 1411, 9/2009, 47/01, 019/10, STZ 25/01, KSW 16/06, 05/01was given by each institution of participating center as described previously
      • Betticher D.C.
      • Hsu Schmitz S.F.
      • Totsch M.
      • Hansen E.
      • Joss C.
      • von Briel C.
      • et al.
      Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial.
      • Stupp R.
      • Mayer M.
      • Kann R.
      • Weder W.
      • Zouhair A.
      • Betticher D.C.
      • et al.
      Neoadjuvant chemotherapy and radiotherapy followed by surgery in selected patients with stage IIIB non-small-cell lung cancer: a multicentre phase II trial.
      • Pless M.
      • Stupp R.
      • Ris H.B.
      • Stahel R.A.
      • Weder W.
      • Thierstein S.
      • et al.
      Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.
      ). Written informed consent was obtained from all patients.
      The multicenter phase II trial (SAKK 16/96) investigated the efficacy and toxicity of induction docetaxel-cisplatin in locally advanced NSCLC and examined prognostic factors for patients not benefiting from surgery.
      • Betticher D.C.
      • Hsu Schmitz S.F.
      • Totsch M.
      • Hansen E.
      • Joss C.
      • von Briel C.
      • et al.
      Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial.
      This trial enrolled 90 patients with previously untreated, potentially operable stage IIIA NSCLC received 3 cycles of docetaxel 85 mg/m2 on day 1 plus cisplatin 40 mg/m2 on days 1 and 2, with subsequent surgical resection.
      • Betticher D.C.
      • Hsu Schmitz S.F.
      • Totsch M.
      • Hansen E.
      • Joss C.
      • von Briel C.
      • et al.
      Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial.
      Resectability was assessed by a multidisciplinary tumor board before initiation of treatment. Histologic diagnosis and assessment of mediastinal lymph nodes were performed with mediastinoscopy, using American Thoracic Society mapping criteria in all patients.
      • De Leyn P.
      • Lardinois D.
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      • Rami-Porta R.
      • Passlick B.
      • Zielinksi M.
      • et al.
      ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer.
      A phase III randomized trial (SAKK 16/00) investigated whether the addition of induction radiotherapy improves outcomes in 232 patients with pathologically proven stage IIIA/N2 NSCLC randomly assigned to treatment groups.
      • Pless M.
      • Stupp R.
      • Ris H.B.
      • Stahel R.A.
      • Weder W.
      • Thierstein S.
      • et al.
      Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.
      Patients in the chemoradiotherapy group received 3 cycles of induction chemotherapy (docetaxel 85 mg/m2 and cisplatin 100 mg/m2, given every 3 weeks) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received induction chemotherapy alone.
      • Pless M.
      • Stupp R.
      • Ris H.B.
      • Stahel R.A.
      • Weder W.
      • Thierstein S.
      • et al.
      Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.
      N2 involvement was verified by mediastinoscopy, endobronchial ultrasound, endoscopic ultrasound, or bronchoscopy with transbronchial fine-needle aspiration.
      Patients with histological or cytological confirmed NSCLC but N2 lymph nodes not accessible to biopsy (eg, American Thoracic Society
      • Roth J.A.
      • Fossella F.
      • Komaki R.
      • Ryan M.B.
      • Putnam Jr, J.B.
      • Lee J.S.
      • et al.
      A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer.
      ,
      • Depierre A.
      • Milleron B.
      • Moro-Sibilot D.
      • Chevret S.
      • Quoix E.
      • Lebeau B.
      • et al.
      Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer.
      ) were included as long as the N2 node with a diameter more than 1 cm was positron-emission tomography (PET)/computed tomography (CT) positive, and the N3 nodes had diameters of less than 1 cm and were PET/CT negative.
      • Pless M.
      • Stupp R.
      • Ris H.B.
      • Stahel R.A.
      • Weder W.
      • Thierstein S.
      • et al.
      Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.
      A multicenter phase II trial (SAKK 16/01) assessed the efficacy and toxicity of induction chemotherapy and radiotherapy followed by surgery in 46 patients with technically operable stage IIIB NSCLC, sequentially treated with 3 cycles of induction chemotherapy (docetaxel 85 mg/m2 and cisplatin 100 mg/m2, every 3 weeks), immediately followed by accelerated concomitant boost radiotherapy (44 Gy in 22 fractions) and surgery.
      • Stupp R.
      • Mayer M.
      • Kann R.
      • Weder W.
      • Zouhair A.
      • Betticher D.C.
      • et al.
      Neoadjuvant chemotherapy and radiotherapy followed by surgery in selected patients with stage IIIB non-small-cell lung cancer: a multicentre phase II trial.
      Staging included CT scan of the chest and upper abdomen, bronchoscopy, brain CT, or magnetic resonance imaging (MRI), and exclusion of bone metastases by a bone scan. Over the course, increased availability of PET/CT complemented staging and replaced bone scans in many patients. Mediastinoscopy was required for centrally located tumors and in all patients without PET/CT scans. Patients with PET-positive (according to local assessment) mediastinal lymph nodes underwent mediastinoscopy or fine-needle biopsy for histological confirmation.
      • Stupp R.
      • Mayer M.
      • Kann R.
      • Weder W.
      • Zouhair A.
      • Betticher D.C.
      • et al.
      Neoadjuvant chemotherapy and radiotherapy followed by surgery in selected patients with stage IIIB non-small-cell lung cancer: a multicentre phase II trial.
      Restaging after induction therapy was performed by imaging in all patients enrolled in the 3 trials. Subsequent inclusion of patients to surgical therapy was done by the local surgeons’ judgment within a multidisciplinary team. In trial 16/96, a tumor staging at the end of chemotherapy was performed including chest x-ray, chest CT scan, or MRI. In trial 16/00, a tumor staging at the end of chemo- and radiotherapy was performed with PET-CT if available, or with CT scan and scintigraphy. MRI of central nervous system was not required at restaging but at baseline. In trial 16/01, a tumor staging at end of chemotherapy included CT scan, x-ray, MRI, bronchoscopy, scintigraphy, and PET assessment at the end of chemotherapy and at the end of radiotherapy. Pretreatment N3-positive disease was considered resectable, when resection could be performed through standard thoracotomy without additional sternotomy.
      • Stupp R.
      • Mayer M.
      • Kann R.
      • Weder W.
      • Zouhair A.
      • Betticher D.C.
      • et al.
      Neoadjuvant chemotherapy and radiotherapy followed by surgery in selected patients with stage IIIB non-small-cell lung cancer: a multicentre phase II trial.
      In the present pooled analysis, mediastinal lymph node staging before induction of 352 patients who completed the full analysis of each respective trial (see Figure E1) was performed by mediastinoscopy, endobronchial ultrasound, endoscopic ultrasound, bronchoscopy with transbronchial fine-needle aspiration, or video-assisted thoracoscopic surgery with biopsy of lymph nodes (Figure 1) according to American Thoracic Society stations.
      • De Leyn P.
      • Lardinois D.
      • Van Schil P.E.
      • Rami-Porta R.
      • Passlick B.
      • Zielinksi M.
      • et al.
      ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer.
      ,
      • Martini N.
      Mediastinal lymph node dissection for lung cancer. The Memorial experience.
      After quality control of all case report forms and histological reports, 35 of 41 missing pathological reports were requested from the centers and underwent a second review. Mediastinal (N2) lymph node involvement was divided in single N2, double N2, and multiple N2 stations (including N3 lymph nodes). The median number and IQR for lymph nodes were reported. To apply the latest 8th TNM staging edition,
      • Goldstraw P.
      • Chansky K.
      • Crowley J.
      • Rami-Porta R.
      • Asamura H.
      • Eberhardt W.E.E.
      • et al.
      The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer.
      tumor stages, in particular T3 and T4 staging and N staging of patients, were transferred to the corresponding stages as described previously.
      • Früh M.
      • Betticher D.C.
      • Stupp R.
      • Xyrafas A.
      • Peters S.
      • Ris H.B.
      • et al.
      Multimodal treatment in operable stage III NSCLC: a pooled analysis on long-term results of three SAKK trials (SAKK 16/96, 16/00, and 16/01).
      Surgical resection comprised anatomic lung resections such as lobectomy, bilobectomy, or pneumonectomy with systematic mediastinal lymphadenectomy, and in some cases sleeve resection. Extended resections were defined as anatomic lung resection including additional procedures such as resection of chest wall (n = 16), intrapericardial dissection (n = 14), partial resection of pericardium (n = 7) or right atrium (n = 1), partial resection of the left atrium (n = 1), resection of vertebra (n = 1), partial resection of the esophagus (n = 1), superior vena cava (n = 1), carina (n = 11), or release of C8 nerve roots and partial resection of brachial plexus (n = 1) with prevertebral fascia (n = 1) during chest wall resection. All patients were resected via open thoracotomy as elective surgery. No salvage operations were conducted.
      The 30- and 90-day mortality, perioperative morbidity, and long-term outcomes are reported. Postoperative complications were reclassified from case report forms according to the criteria of Clavien-Dindo classification.
      • Dindo D.
      • Demartines N.
      • Clavien P.A.
      Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.
      Subgroup analyses were performed to assess the role of pretreatment N2 lymph node extend and other factors on overall survival (OS) and event-free survival (EFS).
      Outcome analyses including age, rate of complete (R0) resection versus non-R0 (including R1 or R2), pathological complete response (pCR) to therapy, radiotherapy, pattern of recurrence (local vs distant), and long-term results at 3, 5, and 10 years were conducted in all patients included in the 3 trials. pCR was defined as 95% or greater of necrosis and fibrosis (eg, <5% viable tumor cells) in the 16/96 trial and as no tumor cells in the other trials.
      EFS was defined as the time from randomization/registration until relapse/progression, second tumor (only for SAKK 16/00), or death due to any cause and OS were defined as a death from any cause and considered as an event.

      Statistical Analysis

      Patients’ characteristics were descriptively summarized by median and range for continuous variables and frequency distribution table for categorical variables. Comparison of binary end points was carried out using the Fisher exact test or chi-square test. Kaplan–Meier method was used to analyze the time-to-event. Survival curves and rates were compared using the log rank test the Kaplan–Meier estimator at a specific time, respectively. The present study is a retrospective, pooled analysis of 3 trials that were initially designed to test different hypotheses. Therefore, no “a priori calculation” of power has been done for the pooled results of the survival in patients with extended resections versus not extended resections. Instead, we reported 95% confidence intervals (CIs) for the odds ratios (ORs) and hazard ratios (HRs) (Tables 3 and E1). The prognostic impact of certain variables on categorical outcomes was investigated using multivariable logistic regression analysis. Factors associated with time to event outcomes were investigated using the Cox regression. Clustering was not considered for centers or surgeons because much of the information was not available for analysis. All data were collected and analyzed at the SAKK Coordinating Center in Bern, Switzerland. All statistical analyses were carried out using SAS version 9.4 (SAS Institute Inc) and R v3.5.1.

      Results

      Demographics

      Table 1 depicts the demographic and clinical variables of 197 of 352 patients being included in the current analysis. The median age was 59.8 (28-76) years, and 67% of patients were male. All patients initially included in these 3 SAKK protocols were potentially resectable. A total of 38 of 197 patients were not considered after induction therapy for resection for technical (31/38, 81%) or medical (7/38, 19%) reasons, leading to a resectability rate of 81%.
      Table 1Patient demographic and clinical characteristics
      CharacteristicsOverall (N = 197)Extended (n = 36)Not extended (n = 123)
      n (%)n (%)n (%)
      Age y, median (range)59.8 (28.0-76.0)57.0 (37.0-73.0)59.8 (30.0-76.0)
      Gender
       Female53 (26.9%)13 (36.1%)33 (26.8%)
       Male144 (73.1%)23 (63.9%)90 (73.2%)
      T stage (8th edition)
      Only subcategories of T3 and T4 are shown.
       T3154 (78.2%)24 (66.7%)103 (83.7%)
       T443 (21.8%)12 (33.3%)20 (16.3%)
      Performance status (ECOG PS)
       0123 (62.4%)21 (58.3%)86 (69.9%)
       173 (37.1%)15 (41.7%)36 (29.3%)
       21 (0.5%)0 (0.0%)1 (0.8%)
      ASA score
       137 (18.8%)8 (22.2%)28 (22.8%)
       254 (27.4%)16 (44.4%)37 (30.1%)
       337 (18.8%)6 (16.7%)29 (23.6%)
       41 (0.5%)0 (0.0%)1 (0.8%)
       Missing68 (34.5%)6 (16.7%)28 (22.8%)
      Trial treatment
       Bimodal (CTX + S)97 (49.2%)14 (38.9%)63 (51.2%)
       Trimodal (CTX + RT + S)100 (50.8%)22 (61.1%)60 (48.8%)
      Histology
       Squamous82 (41.6%)17 (47.2%)55 (44.7%)
       Adenocarcinoma63 (32.0%)10 (27.8%)40 (32.5%)
       Large cell carcinoma13 (6.6%)3 (8.3%)6 (4.9%)
       Poorly differentiated NSCLC38 (19.3%)5 (13.9%)22 (17.9%)
       Not otherwise specified1 (0.5%)1 (2.8%)0 (0.0%)
      Mediastinal staging
       Yes193 (98%)36 (100%)121 (98.4%)
       Missing4 (2.0%)0 (0.0%)2 (1.6%)
      Clinical lymph node involvement
      After mediastinal staging with mediastinoscopy, endobronchial ultrasound/transbronchial fine-needle aspiration, endoscopic ultrasound, CT, or PET/CT.
       N015 (7.6%)6 (16.7%)4 (3.3%)
       N12 (1.0%)1 (2.8%)1 (0.8%)
       Single N2107 (54.3%)19 (52.8%)72 (58.5%)
       Double N249 (24.9%)9 (25.0%)31 (25.2%)
       Multiple N221 (10.7%)1 (2.8%)13 (10.6%)
       Missing3 (1.5%)0 (0.0%)2 (1.6%)
      TNM stage (8th edition)
       IIB1 (0.5%)0 (0.0%)1 (0.8%)
       IIIA16 (8.1%)4 (11.1%)6 (4.9%)
       IIIB173 (87.8%)31 (86.1%)111 (90.2%)
       IIIC7 (3.6%)1 (2.8%)5 (4.1%)
      ECOG PS, Eastern Cooperative Oncology Group Performance Status; ASA, American Society of Anesthesiologists; CT, computed tomography; CTX, chemotherapy; S, surgery; RT, radiotherapy; NSCLC, non–small cell lung cancer.
      Only subcategories of T3 and T4 are shown.
      After mediastinal staging with mediastinoscopy, endobronchial ultrasound/transbronchial fine-needle aspiration, endoscopic ultrasound, CT, or PET/CT.
      A total of 31 of 38 patients were excluded from surgery for technical reasons due to progressive disease after restaging based on imaging (24/31) or intraoperative findings (7/31). A total of 7 of 38 patients were excluded from surgery for medical reasons due to patients’ refusal (3/7), death (2/7) during induction therapy, stroke (1/7), and toxicity (1/7) of induction treatment.
      Invasive mediastinal staging was performed in 161 of 197 patients (mediastinoscopy: n = 105, endobronchial ultrasound/transbronchial fine-needle aspiration: n = 55, and video-assisted thoracoscopic surgery: n = 1) and noninvasive in 32 of 197 (PET/CT: n = 31 and CT: n = 1). All except 3 patients have completed chemotherapy with 1 to 4 days delay as planned, and median time between completion of induction therapy and surgery was 42 days (IQR, 9-57). Of 159 resected patients within T3/T4 stages, 145 (91.2%) had positive N2 lymph nodes, 2 had N1 (1.3%), and 10 had N0 (6.3%) lymph nodes (2 missing) before induction treatment. The median number for lymph nodes sampled before initiation of induction therapy was 11 (IQR, 5-11). Mediastinal (N2) lymph node involvement (91 single N2, 40 double N2, and 14 multiple N2) before induction treatment showed no influence on the extension of the surgical resection (extended vs not extended: 19 single-N2 vs 72, 9 double-N2 vs 31, and 1 multiple-N2 vs 13, P = .439). The comparison bimodal versus trimodal treatment with regard to lymph node sterilization showed 32.5% in chemotherapy versus 50.0% in chemoradiotherapy group (P = .036), and the rate of persistent N2 was 35.1% in bimodal versus 30.5% in trimodal (P = .613) group, respectively.
      The following 159 anatomic lung resections (with 36 extended resections) and systematic lymphadenectomy (Figure 1 and Video 1) resulted in 80% [95% confidence interval, 72.8-85.8] (127/159) R0 rate and 83% [95% CI, 67.2-93.6] (30/36) R0 in the group with extended resections) with response pCR of 13.2% [95% CI, 8.4-19.5] (21/159) (Table 2).
      Table 2Summary of R0 resections and pathological complete response in resected patients with locally advanced T3/T4 III stage non–small cell lung cancer
      R0 and pathological complete responseOverall (n = 159)Extended (n = 36)Not extended (n = 123)
      R0 resection
       n (%)127 (79.9%)30 (83.3%)97 (78.9%)
       95% CI (Clopper-Pearson)[72.8-85.8][67.2-93.6][70.6-85.7]
      Pathological complete response
       n (%)21 (13.2%)3 (8.3%)18 (14.6%)
       95% CI (Clopper-Pearson)[8.4-19.5][1.8-22.5][8.9-22.1]
      CI, Confidence interval.

      Perioperative Outcomes

      Overall, postoperative 30-day mortality was 3% (5/159 [95% CI, 1.0-7.2]) with no significant differences for extended resections (3/36, 8.3% [95% CI, 1.8-22.5]) versus (2/123, 1.6% [95% CI, 0.2-5.8]) not extended resections (P = .077) and 90-day mortality was 7% (11/159 [95% CI, 3.5-12.0]) (Figure 1) with 5 of 36 (13.9% [95% CI, 4.7-29.5]) in the group of extended compared with 6 of 123 (5.9% [95% CI, 1.8-10.3]) (Table E2) in not extended resections (P = .126). A significant difference in 30-day mortality (5/66, 7.6% [95% CI, 2.5-16.8] pneumonectomies and 0/93 [95% CI, 0-3.9] lobectomies or bilobectomies; P = .011) but not 90-day mortality rates (7/66, 10.6% [95% CI, 4.4-20.6] pneumonectomies and 4/93, 4.3% [95% CI, 1.2-10.7] lobectomies or bilobectomies; P = .203) was observed between patients who underwent pneumonectomy compared with lobectomy or bilobectomy.
      Morbidity was reported in 51 of 159 [95% CI, 24.9-39.9] (32.1%) with 36 of 51 [95% CI, 56.2-82.5] (70.6%) being complications of minor grade II according to Clavien-Dindo classification with 3 of 51 (5.9%) grade IIIA, 9 of 51 (17.6%) grade IIIB, and 3 of 51 (5.9%) grade IV, and was statistically not significant after extended (16/36; 44.4%]) versus not extended (35/123 [8.4%]) resections (OR, 2.01 [95% CI, 0.93-4.32], P = .071). Pulmonary infections in 13 of 51 (8.2%) and atrial fibrillation in 10 of 51 (6.3%) were the most frequent postoperative complications, and 11 of 159 patients (6.9%) underwent reoperation (6/66 [9.1%] after pneumonectomy and 5/93 [5.4%] after lobectomy) due to postoperative complications. Bronchial stump insufficiency (3/36 [8.3%]) and acute respiratory distress syndrome (3/36 [8.3%]) were observed more frequently after extended versus not extended resections (2/123 [1.6%]) of bronchial stump insufficiency and (1/23 [0.8%]) acute respiratory distress syndrome ([OR, 5.5 [95% CI, 0.19-0.03], P = .077 and OR, 0.09 [95% CI, 0.01-0.91], P = .037, respectively).
      Among patients undergoing pneumonectomy, postoperative complications occurred in the same frequency of 20 of 66 (30.3%) [95% CI, 1.086-0.724] versus 31 of 93 (33.3%) after lobectomy or bilobectomy (OR, 0.94 [95% CI, 0.71-1.24], P = .687). Postoperative complications occurred in 14 of 49 patients (28.6%) with not extended pneumonectomy versus 6 of 17 patients (35.3%) with extended pneumonectomy (P = .603). A total of 10 of 19 patients (52.6%) with extended lobectomies had postoperative complications versus 21 of 74 patients (28.4%) with not extended resections (OR, 0.45 [95% CI, 0.20-0.99], P = .045).

      Recurrence and Survival

      The date for this analysis was February 24, 2020. Median follow-up from registration was 11.2 years [95% CI, 9.0-12.9]. A total of 127 resected patients within T3 or T4 achieved R0 resection, and 63 patients were free from recurrence. The number of patients with relapse with occurrence of both local recurrence and distant metastases was 5 in patients with extended and 12 in patients with not extended resections. Distant metastases in 50 patients constituted the most frequent localization of the recurrence. Median OS (from registration) of all 197 patients was 3.7 years [95% CI, 2.3-5.9]. The median OS and EFS of 4.1 years [95% CI, 3.0-6.7] in resected patients (n = 159) were significantly longer than 0.7 years [95% CI, 0.6-0.8] (P < .001) in the group of not resected patients (n = 38): 11.1% [95% CI, 3.5-23.5] at 3 years, 8.3% [95% CI, 2.1-19.9] at 5 years, and 5.5% [95% CI, 1.0-16.2] at 10 years (Figure E2, A and B). The median OS and EFS after extended versus not extended resections were not significantly different between the 2 groups (4.3 years [95% CI, 1.3-10] vs 3.8 years [95% CI, 2.2-6.5] P = .966 and 3 years [95% CI, 1.2-6.4] vs 1.1 years [95% CI, 0.7-2.7]; P = .406, respectively).
      At median follow-up, Kaplan–Meier (Figure 2, A and B) estimates of 3-year OS after extended resections versus not extended resections were 61.1% ([95% CI, 43.3-74.8]) versus 54.2% ([95% CI, 45.0%-62.6%]) (P = .472), and EFS was 47.7% ([95% CI, 30.4-63.1]) versus 40% ([95% CI, 31.3-48.5]) (P = .430), independent of completeness of resection. The 5-year OS was 43.7% ([95% CI, 27.2-59.2]) versus 45.7% ([95% CI, 36.7-54.3]) (P = .834) (Figure 1), and EFS was 33.8% ([95% CI, 8.2-50.2]) versus 32.9% ([95% CI, 24.6-41.4]) (P = .922). The 10-year OS was 29.5% ([95% CI, 13.1-48.1]) versus 26.8% ([95% CI, 18.4-35.8]) (P = .789), and EFS was 18.1% ([95% CI, 5.7-36.1]) versus 18.5% ([95% CI, 10.8-27.7]) (P = .971). The median OS and EFS after lobectomy with 4.4 years [95% CI, 3.2-9.8] were longer than 2.5 years [95% CI, 1.3-5.2] (P = .02) after pneumonectomy (Figure 2, C and D). The most common course of death after lobectomy and pneumonectomy was tumor progression (Table E3). The comparison of median OS and EFS after bimodal versus trimodal treatment at 10 years was 36.7% in the chemotherapy group versus 30.3% in the chemoradiotherapy group and 26.4% versus 13.8%, respectively (Table E4). Pretreatment N2 involvement (single-, double-, or multiple-N2 in 145/159) in resected patients included in this analysis showed OS of 4.9 years [95% CI, 2.8-9.2] in single-N2 versus 1.9 years [95% CI, 1.2-4.8] in double-N2, 4.5 years [95% CI, 2.0-NR] in multiple-N2 and EFS of 1.3 years [95% CI, 1.0-3.0] in single-N2 versus 0.9 years in double-N2 [95% CI, 0.6-1.8], and 1.9 years [95% CI, 0.7-8.9] in multiple-N2, without a significant impact on median OS (P = .247 and .613, Figure 3, A and B). Furthermore, pathologic type (adenocarcinoma vs squamous carcinoma) was not significantly associated with OS (HR, 1.20 [95% CI, 0.77-1.87], P = .431) in a univariable analysis.
      Figure thumbnail gr2ab
      Figure 2Kaplan–Meier curves depicting OS and EFS in a cohort of extended resections (blue line; n = 36) versus not extended resections (red line, n = 123) for patients with locally advanced clinical T3/T4 and stage III NSCLC. The difference was not statistically significant in OS (A) and EFS (B) between both surgical groups (P = .966, P = .406, respectively) as well as OS (C) and EFS (D) between lobectomy (n = 93, red line) and pneumonectomy (n = 66, blue line). Median OS after lobectomy was significantly longer than after pneumonectomy (4 years [95% CI, 3.2-9.8]) versus 2.5 years [95% CI, 1.3-5.2]) (P = .02) and EFS showed a similar tendency (2.3 years ([95% CI, 1.0-3.2] vs (0.9 years [95% CI, 0.6-3.5]) (P = .131) for lobectomy compared with pneumonectomy, which was not statistically significant. Cyan crossed line at the 5- and 10-year time-points.
      Figure thumbnail gr2cd
      Figure 2Kaplan–Meier curves depicting OS and EFS in a cohort of extended resections (blue line; n = 36) versus not extended resections (red line, n = 123) for patients with locally advanced clinical T3/T4 and stage III NSCLC. The difference was not statistically significant in OS (A) and EFS (B) between both surgical groups (P = .966, P = .406, respectively) as well as OS (C) and EFS (D) between lobectomy (n = 93, red line) and pneumonectomy (n = 66, blue line). Median OS after lobectomy was significantly longer than after pneumonectomy (4 years [95% CI, 3.2-9.8]) versus 2.5 years [95% CI, 1.3-5.2]) (P = .02) and EFS showed a similar tendency (2.3 years ([95% CI, 1.0-3.2] vs (0.9 years [95% CI, 0.6-3.5]) (P = .131) for lobectomy compared with pneumonectomy, which was not statistically significant. Cyan crossed line at the 5- and 10-year time-points.
      Figure thumbnail gr3
      Figure 3Kaplan–Meier curves depicting OS and EFS in resected patients with locally advanced clinical T3/T4; III stage NSCLC with pretreatment N2 lymph node involvement (n = 145) dividing in single (blue line, n = 91), double (red line, n = 40), and multiple (n = 14, green line) lymph nodes. The difference was not statistically significant in OS (A) and EFS (B) between the groups (P = .247, P = .613, respectively). Cyan crossed line at the 5- and 10-year time-points. In detail, the 3-year OS was 59.2% for single-N2 ([95% CI, 48.4-68.5]) versus 45.0% for double-N2 ([95% CI, 29.3-59.5]) and 77.9% for multiple N2 ([95% CI, 45.9-92.3], P = .061), and EFS was 39.4% for single-N2 [95% CI, 29.4-49.3] versus 32.5% for double-N2 [95% CI, 18.8-47.0] and 49.0% for multiple-N2 ([95% CI, 21.6%, 71.7%]; P = .301) similarly as the following demonstrated no statistically significant differences between groups in 5-year survival (48.9% [95% CI, 8.2-58.8], 34.8% [95% CI, 20.6-49.4], 46.8% [95% CI, 19.6-70.2] (P = .457) and EFS (95% CI, 31.5% [22.3-41.2], 25.3% [95% CI, [12.5-40.4], 32.7% [95% CI, [10.5-57.4] (P = .623) as well in 10-year survival (37.7% [95% CI, 27.2-48.1], 26.1% [95% CI, 12.4-42.2], 35.1% [95% CI, 10.3-61.7], P = .586) and EFS (20.0% [95% CI, 11.2-30.5], 20.3% [95% CI, 8.2-36.2], and 21.8% [95% CI, 4.2-48.2]; P = .917).
      The median, 3-, 5-, and 10- year OS and EFS were significantly longer for patients with R0 versus non-R0 (R1 and R2) resections (Figure 4, A and B) with a median OS of 5.9 years [95% CI, 3.7-8.9] versus 1.3 years [95% CI, 0.7-3] (P < .001) and EFS of 2.5 years [95% CI, 1-4] versus 0.6 years [95% CI, 0.4-1] P = .009) (Figure 4, A and B). Long-term survival (from registration) of the 38 patients who did not undergo surgery was 11.1% (3.5%, 23.5%) at 3 years, 8.3% (2.1%, 19.9%) at 5 years, and 5.5% (1.0%, 16.2%) at 10 years. Among the 21 patients with pCR, median OS was 6.9 years [95% CI, 3.9-15.1], and median EFS was 4.6 years [95% CI, 1.6-15.3]. Multi-station N2 (double N2 and multiple N2) was found in 54 patients, and 12 of 54 were found to have pCR (Table E5).
      Figure thumbnail gr4
      Figure 4Kaplan–Meier curves depicting OS and EFS in an entire cohort of completed (R0) resected patients (red line; n = 127) versus non–R0 resected patients (blue line, n = 32) for patients with locally advanced clinical T3/T4 and stage III NSCLC. The difference was statistically significant in OS (A) and EFS (B) between both surgical groups (P < .001, P = .009, respectively). Cyan crossed line at 5- and 10-year time points. The 3-year OS for advanced T3/T4 stages after complete R0 resection versus R1/R2 resection was 62.9% [95% CI, 53.9-70.6] versus 27.5% [95% CI, 13.4-43.6]; P < .001 and EFS was 46.7% [95% CI, 37.8-55.1] versus 20% [95% CI, 7.8-36.2] (P = .005), at 5 years 52.4% [95% CI, 43.3-60.7] versus 17.2% [95% CI, 6.4-32.3], P < .001 and EFS of 36.6% [95% CI, 28.2-45.1] versus 20.0% [95% CI,7.8-36.2]; P = .073 and 10-year survival with 32.6% [95% CI, 23.6-42] versus 5.7% [95% CI, 0.5-21.6] (P = .006) and not significantly different EFS of 20.6% [95% CI, 2.7-29.8] versus 10.0% [95% CI, 1.0-31.2]; (P = .311) at the 10-year time point.

      Multivariable Analysis

      On univariable analysis including all patients, age and surgical R0 margin were identified as statistically significant factors influencing OS (HR, 1.030 [95% CI, 1.007-1.053], P = .009 and HR, 0.380 [95% CI, 0.246-0.587], P < .001), as well as R0 and pCR as factors influencing EFS ([HR, 0.557 [95% CI, 0.356-0.872], P = .011 and .531 [95% CI, 0.291-0.968], P = .039) (Table E1).
      Multivariable analysis regarding mortality, morbidity, and OS were performed assessing the following factors: age, pCR, R0 resection margin, radiotherapy, and type of pulmonary resection (extended vs not extended). There were no significant differences in morbidity for patients who underwent trimodal versus bimodal treatment (OR, 1.99 [95% CI, 0.96-4.11], P = .063). Extended resections had impact on 90- day mortality ([OR, 4.050 [95% CI, 1.083-15.141], P = .038). Complete R0-resection margin was associated with improved OS ([HR, 0.417 [95% CI, 0.262-0.664], P < .001) and EFS ([HR, 0.602 [95% CI, 0.375-0.965], P = .035, Table 3).
      Table 3Multivariable analysis with independent prognostic factors for postoperative morbidity and mortality at 30 and 90 days and factors influencing overall survival and event-free survival for patients with locally advanced T3/T4 (8th edition) III stage non–small cell lung cancer
      OutcomePrognostic factorOR [95% CI]P value
      MorbidityAge1.02 [0.98-1.06].408
      R0 (Yes vs No)0.81 [0.33-1.99].644
      pCR (Yes vs No)1.10 [0.40-3.02].853
      Radiotherapy (Yes vs No)1.99 [0.96-4.11].063
      Pulmonary resection (Extended vs Not Extended)1.97 [0.90-4.32].090
      30-d MortalityAge1.01 [0.90-1.13].836
      R0 (Yes vs No)1.18 [0.11-12.65].892
      Radiotherapy (Yes vs No)0.49 [0.07-3.34].465
      Pulmonary resection (Extended vs Not Extended)6.11 [0.95-39.14].056
      90-d MortalityAge1.04 [0.96-1.13].335
      R0 (Yes vs No)0.44 [0.10-1.84].260
      pCR (Yes vs No)2.15 [0.40-11.66].376
      Radiotherapy (Yes vs No)0.55 [0.14-2.22].405
      Pulmonary resection (Extended vs Not Extended)4.05 [1.08-15.14].038
      HR [95% CI]
      OSAge1.03 [1.00-1.05].017
      R0 (Yes vs No)0.42 [0.26-0.66]<.001
      pCR (Yes vs No)0.61 [0.33-1.14].120
      Radiotherapy (Yes vs No)1.23 [0.82-1.82].317
      Pulmonary resection (Extended vs Not Extended)1.08 [0.69-1.70].738
      EFSAge1.01 [0.99-1.03].419
      R0 (Yes vs No)0.61 [0.38-0.98].042
      pCR (Yes vs No)0.55 [0.30-1.01].053
      Radiotherapy (Yes vs No)1.11 [0.76-1.61].603
      Pulmonary resection (Extended vs Not Extended)0.83 [0.53-1.29].403
      For 30-day mortality, pCR was excluded due to no death without pCR. OR, Odds ratio; CI, confidence interval; pCR, pathological complete response; HR, hazard ratio; OS, overall survival; EFS, event-free survival.

      Discussion

      Current guidelines,
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      except the new National Comprehensive Cancer Network (NCCN)
      guidelines, propose to select patients for surgery in stage III when the disease is assessed to be resectable before induction therapy and only if a single nonbulky station of mediastinal lymph nodes is involved. Over the past years, 3 SAKK studies have explored resectability and outcome in patients with locally advanced stage III disease before induction chemo- and chemoradiation and today, many of them would be considered as unresectable according to these guidelines. Patients with locally advanced tumors and multilevel and even bulky N2 were a main focus of these protocols to assess efficacy of induction therapy followed by resection.
      In the present analysis of 197 patients with T3/T4 tumors including multi-station N2 disease, we were able to demonstrate that a R0 resection could be achieved in 80% after chemo- or chemoradiation therapy with a low surgical mortality of 0% at 30 days for lobectomies and 5% for pneumonectomies. But most important, OS was approximately 45% at 5 years and 28% at 10 years. These results support the new NCCN guidelines (version 4.2021)
      where potentially resectable stage III can be selected for induction therapy and resectability is assessed thereafter. Furthermore, we observed that response to chemo- or chemoradiation therapy is relatively independent from the initial tumor burden assessed by clinical TNM staging by CT, PET/CT (in recent years), and invasive mediastinal staging. For most patients, N2 was proven by tissue, which we also believe is standard of care. However, patients underwent mediastinal staging by imaging methods in 16% of the cases, which is not ideal, but 95% were truly positive in the Swiss population. Compared with the North American population, infectious diseases such as histoplasmosis, cryptococcosis, coccidioidomycosis, or blastomycosis that affect PET avidity of mediastinal lymph nodes do not occur in Switzerland, except for rare sarcoidal-like lesions.
      Induction treatment of patients with T3/T4 and proven single or multilevel N2 can result in partial or complete pathological response and a high rate of R0 resections. However, best treatment for patients with upfront unresectable stage III (potentially resectable) disease, who might become resectable after induction therapy, is a matter of debate in multidisciplinary tumor boards and some patients might be directed too often to definitive chemo-radiation. No doubt, it is not defined what potentially resectable disease at pretreatment evaluation means in cases of local invasion and mediastinal lymph nodes. Resectability depends largely on the experience of the surgical team. Institutional, national, and international differences make an agreement on general recommendations difficult. Clinically proven stage IIIA-N2 (with nonbulky, single-level N2 [<3 cm] involvement) disease before induction treatment included in the multimodality treatment is considered as resectable after consideration of response (downstaging) after induction therapy, whereas patients with clinically multiple, bulky N2 or N3
      are considered primarily unresectable according to current guidelines. In addition, the heterogeneity of stage III disease further complicates the decision-making, and response to induction therapy cannot be anticipated by pretreatment staging.
      The definition of “upfront unresectable disease” differs among institutions and nations. Most likely, it is uniformly accepted that bulky, multilevel N2 with or without tumor extend beyond the mediastinal nodes is unresectable and might not become resectable even after induction therapy. Everything below this tumor extend might become resectable after an effective induction therapy, and this will be decided after restaging and discussion during the interdisciplinary tumor boards (involving oncologists, thoracic surgeons, radiation oncologists, and radiologists) and treated by multidisciplinary teams.
      In the view of more effective options for induction treatment (immunotherapy in combination with chemotherapy or targeted treatment), more “potentially resectable” patients could profit in the future from such concepts. They might become resectable through downstaging, and clear pathological margins (R0) can be achieved resulting in good long-term survival. In our institution, we prefer a bimodal therapy regime with induction chemotherapy only or chemo-immunotherapy rather than chemoradiotherapy, except for specific clinical situations such as Pancoast or superior sulcus tumor or patients included in clinical trials.
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      In addition, imaging techniques, patient selection, surgical techniques, and perioperative management have evolved during the years, enabling us to include these selected patients for safe surgery. The rate of R0 resections varies importantly between studies
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      ,
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      • et al.
      Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with resectable stage IIIA(N2) and selected IIIB Non-Small-Cell Lung Cancer after Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE).
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      Resection following concurrent chemotherapy and high-dose radiation for stage IIIA non-small cell lung cancer.
      More effective induction treatments using immunotherapy or targeted therapy will further enhance the pathologic response. This has been shown for immunotherapy in the SAKK 16/14 trial with 18.2% pCR and 61.8% major pathologic response (MPR).
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      SAKK 16/14: anti-PD-L1 antibody durvalumab in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small cell lung cancer (NSCLC)—a multicenter single-arm phase II trial.
      Other studies using induction immunotherapy as part of multimodal treatment for NSCLC report a pCR of 15% to 63%
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      and an MPR of 19% to 82.9%.
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      ,
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      Induction cisplatin docetaxel followed by surgery and erlotinib in non-small cell lung cancer.
      A new treatment concept, using induction therapy with a tyrosine kinase inhibitor with or without chemotherapy in epidermal growth factor receptor–mutated NSCLC is currently evaluated in a large randomized multicenter study for stage II-III (phase III NeoADAURA, NCT04351555). Response to treatment has been shown with pCR 12.1% and MPR of 24.2% in preliminary studies.
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      In these more effective induction treatment regimens, locally advanced tumor stages should be studied,
      as well as resectability assessed after treatment as recommended in the new NCCN guidelines. It is often criticized that surgeons select only the best patients for their treatment. However, this criticism is not justified because patient selection, from both a medical and technical operability standpoint, is a key element for good practice.
      Low surgical mortality and morbidity are of paramount importance for surgical oncologic treatment. We, as others,
      • van Meerbeeck J.P.
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      • Smit E.F.
      • Schramel F.
      • et al.
      Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer.
      ,
      • Pisters K.M.
      • Vallières E.
      • Crowley J.J.
      • Franklin W.A.
      • Bunn Jr, P.A.
      • Ginsberg R.J.
      • et al.
      Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial.
      ,
      • Eberhardt W.E.
      • Pöttgen C.
      • Gauler T.C.
      • Veit S.
      • Heinreich V.
      • Welter S.
      • et al.
      Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with resectable stage IIIA(N2) and selected IIIB Non-Small-Cell Lung Cancer after Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE).
      showed that this is feasible especially for lobectomies, but for pneumonectomies as well. Morbidity was also relatively low taking into account that extensive resections through thoracotomies were performed. Major complications were mainly due to acute respiratory distress syndrome or other pulmonary complications.
      • Albain K.S.
      • Swann R.S.
      • Rusch V.W.
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      • Shepherd F.A.
      • Smith C.
      • et al.
      Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial.
      In the present article, the 30- and 90-day mortality of 3% and 7% were low and comparable or better compared with other studies with a 30-day mortality of 4%,
      • van Meerbeeck J.P.
      • Kramer G.W.
      • Van Schil P.E.
      • Legrand C.
      • Smit E.F.
      • Schramel F.
      • et al.
      Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer.
      7.2%,
      • Pisters K.M.
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      • Crowley J.J.
      • Franklin W.A.
      • Bunn Jr, P.A.
      • Ginsberg R.J.
      • et al.
      Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial.
      or 7.1%.
      • Eberhardt W.E.
      • Pöttgen C.
      • Gauler T.C.
      • Veit S.
      • Heinreich V.
      • Welter S.
      • et al.
      Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with resectable stage IIIA(N2) and selected IIIB Non-Small-Cell Lung Cancer after Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE).
      The surgical mortality rates are difficult to compare with nonsurgical mortality rates such as in the PACIFIC trail.
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • Vicente D.
      • Murakami S.
      • Hui R.
      • et al.
      Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
      However, death due to adverse events occurred in 4.4% of patients in the durvalumab group and in 6.4% of patients in the chemoradiation group.
      • Antonia S.J.
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      Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
      In addition, the reported surgical morbidity in the presented article is 32.1%. Approximately two-thirds (70.6%) of complications are of minor grade II according to Clavien-Dindo classification. They are difficult to be compared with nonsurgical morbidity such as side effects of immunotherapy after chemoradiotherapy in the PACIFIC trial. However, grade 3 or 4 adverse events of any cause were reported in the PACIFIC trial in 30.5% of patients in the durvalumab group and in 26.1% of patients in the chemoradiation alone group.
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • Vicente D.
      • Murakami S.
      • Hui R.
      • et al.
      Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
      Furthermore, discontinuation of the trial due to adverse events occurred in 15.4% of the patients in the durvalumab group and in 9.8% of those in the placebo group.
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • Vicente D.
      • Murakami S.
      • Hui R.
      • et al.
      Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
      In the presented analysis, 30% morbidity after pneumonectomy was comparable to 33% after lobectomy. Another debate is whether a pneumonectomy should still be used in selected cases as an oncologic treatment. In our study, OS but not EFS after lobectomy was significantly longer than after pneumonectomy (4.4 vs 2.5 years, P = .02). Nevertheless, taking into account that patients who received a pneumonectomy most likely have had a more extensive local disease at the time of resection means that pneumonectomy, as long as physiologically tolerable, might still be an option in selected patients, especially if margin-free (R0) resection can be achieved.
      This is also in accordance with the recently updated NCCN guidelines.
      In our study, OS and EFS rates were similar after extended (4.3 years) versus not extended resections (3.8 years) and showed advances of the applied induction treatment compared with the recently published systematic analysis by Steuer and colleagues.
      • Steuer C.E.
      • Behera M.
      • Ernani V.
      • Higgins K.A.
      • Saba N.F.
      • Shin D.M.
      • et al.
      Comparison of concurrent use of thoracic radiation with either carboplatin-paclitaxel or cisplatin-etoposide for patients with stage III non-small-cell lung cancer: a systematic review.
      The most significant factor for OS and EFS was R0 resections. The 5-year OS of 52.4% and 10-year OS of 32.6% seems relatively high especially in consideration of advanced T3/T4 NSCLC stages including pretreatment N2 involvement. Furthermore, we have identified age as a continuous variable (HR, 1.03 [95% CI, 1.00-1.05], P = .017) as a prognostic factor influencing OS. However, when analyzed as a categorical variable (≥70 vs <70 years), age was not significantly associated with OS and EFS (HR, 1.176 [95% CI, 0.644-2.146], P = .598 and HR, 0.796 [95% CI, 0.428-1.482], P = .473, respectively). Zhang and colleagues
      • Zhang Y.H.
      • Lu Y.
      • Lu H.
      • Zhou Y.M.
      Development of a survival prognostic model for non-small cell lung cancer.
      recently identified age (HR, 1.25 [95% CI, 1.02-1.54]) as an independent prognosticator of 1-year survival. Moreover, it was shown that age less than 65 years was associated with a longer OS in univariate (HR, 1.42 [95% CI, 1.18-1.73]) and multivariate (HR, 1.23 [95% CI, 1.00-1.52]) analyses.
      The therapeutic options for locally advanced, unresectable stage III NSCLC changed in the last years as a result of the PACIFIC trial.
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • Vicente D.
      • Murakami S.
      • Hui R.
      • et al.
      Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
      ,
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • Vicente D.
      • Murakami S.
      • Hui R.
      • et al.
      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
      However, the weakness of the PACIFIC trial is the lack of definition of unresectable disease and that no information about lymph node status and tumor stage is given. This makes a comparison with other trials such as the present analysis impossible.

      Study Limitations

      This is a retrospective analysis of 3 trials initially designed to test different hypotheses. Additionally, the patient population is younger than the average lung cancer patient population. The fact that the data on comorbidities are missing in SAKK 16/96 represents a potential bias of the results. Furthermore, we have excluded 38 patients from resection for good reasons: They were medically not operable or a complete resection (R0 resection) was not achievable assessed intraoperatively or during restaging after induction therapy. Taking into account that many patients would not have been operable upfront, the rate of resectability of 81% is not a surprise. Nevertheless, we believe that this pooled analysis of 3 SAKK trials provides a valuable resource to assess the potential of extended resections for advanced stages T3/T4 NSCLC including N2 disease after induction treatment.
      Recent immunotherapy trials using induction chemo-immunotherapy followed by surgery and immunotherapy as a maintenance administration for locally advanced stage III NSCLC report their preliminary or final results that are promising to become the new standard of care. Ultimately, they will provide good long-term benefit by optimal local control of the tumor and systemic immunotherapy-mediated cell death to avoid distant relapse. By recognition of the current study results, decisions at multidisciplinary tumor boards may be influenced for the selection of potentially operable patients with stage III disease for induction therapy.

      Conclusions

      Surgery for T3/T4 tumors, even in the presence of N2 disease, is highly effective after induction chemo- or chemoradiation therapy resulting in an 80% R0 rate with low perioperative morbidity and mortality. OS is similar for extended and not extended resections with a survival of approximately 45% at 5 years and 28% at 10 years. Even pretreatment N2 lymph node involvement leads to favorable OS (∼44% at 5 years and 33% at 10 years).
      This report illustrates that resectable stage III disease needs to be defined after, not before, induction therapy because the response to treatment and downstaging cannot be predicted from the clinical stage. A complete and radical resection is only appropriate for potentially operable patients with good response and successful downstaging after induction therapy, and finally if R0 resection can be achieved. In addition, we propose to further study this question by including these patients with locally advanced lung cancer in upcoming studies using more effective induction therapies before surgery, such as immunotherapy in combination with chemotherapy or targeted treatment.

      Conflict of Interest Statement

      K.F.: AstraZeneca: Contract partner since 03.09.2021. W.W.: AstraZeneca: Advisory Board and Speaker, Covidien (Medtronic): Teaching Grant and Speaker. M.P.: Personal financial interests: AbbVie, Advisory Board; Astra Zeneca, Advisory Board, Travel Grant; Boehringer Ingelheim, Advisory Board, Travel Grant; BMS, Advisory Board, Travel Grant; Eisei, Advisory Board; MSD, Advisory Board; Novartis, Advisory Board; Pfizer, Advisory Board; Roche, Advisory Board; Takeda, Advisory Board; Merck, Advisory Board; Vifor, Travel Grant; Janssen, Speaker's Fee M.F.: Advisory role for BMS, MSD, Astra Zeneca, Boehringer Ingelheim, Roche, Takeda; Grants to institution: BMS, Astra Zeneca. S.P. Consultation/Advisory role: AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, Foundation Medicine, Illumina, Imedex, IQVIA, Incyte, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Phosplatin Therapeutics, PER, Pfizer, PRIME, Regeneron, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda. Talk in a company's organized public event: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ecancer, Eli Lilly, Illumina, Imedex, Medscape, Merck Sharp and Dohme, Novartis, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, Takeda. Receipt of grants/research supports: (Sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics, Roche/Genentech. R.A.S.: Financial Interests: Amgen, Invited Speaker, Personal; AstraZeneca, Advisory Board, Personal; AstraZeneca, Invited Speaker, Personal; Blueprint, Invited Speaker, Personal; BMS, Advisory Board, Personal; Boehringer Ingelheim, Invited Speaker, Personal; Eli Lilly, Invited Speaker, Personal; GSK, Invited Speaker, Personal; Janssen, Advisory Board, Personal; MSD, Advisory Board, Personal; MSD, Invited Speaker, Personal; Novartis, Invited Speaker, Personal; Pfizer, Advisory Board, Personal; Regeneron, Advisory Board, Personal; Roche, Advisory Board, Personal; Roche, Invited Speaker, Personal; Sandoz, Advisory Board, Personal; Seattle Genetics, Advisory Board, Personal; Takeda, Advisory Board, Personal; Takeda, Other, Personal, DMC; Genentech/Roche, Other, Personal, DMC; Lung Cancer, Other, Personal, Editor in Chief; CTR, Other, Personal, Editor; Roche, Research Grant, Financial interest, Institutional, ETOP study; AstraZeneca, Research Grant, Financial interest, Institutional, ETOP study; BMS, Research Grant, Financial interest, Institutional, ETOP study; MSD, Research Grant, Financial interest, Institutional, ETOP study; Pfizer, Research Grant, Financial interest, Institutional, ETOP study; Novartis, Research Grant, Financial interest, Institutional, IBCSG study; Ipsen, Research Grant, Financial interest, Institutional, IBCSG study; Pierre Fabre, Research Grant, Financial interest, Institutional, IBCSG study; MSD, Research Grant, Financial interest, Institutional, IBCSG study; Pfizer, Research Grant, Financial interest, Institutional, IBCSG study; Roche, Research Grant, Financial interest, Institutional, IBCSG study. Nonfinancial Interests: IBCSG, Member of Board of Directors, President Foundation Council; ETOP, Member of Board of Directors, President Foundation Council. S.I.R.: Grants, nonfinancial support and other from AstraZeneca, other from Pfizer, nonfinancial support and other from Takeda, grants, nonfinancial support and other from Roche, nonfinancial support and other from MSD Oncology, other from Novartis, grants, nonfinancial support and other from Boehringer-Ingelheim, nonfinancial support and other from Bristol-Myers-Squibb, other from Eli Lilly, other from Eisai, grants and other from Merck Serono, grants from AbbVie, other from Amgen, other from PharmaMar, other from Janssen, outside the submitted work; and Member of the Drug Commission of the Federal Office of Public Health Switzerland. Board Member SAKK; grants, nonfinancial support and other from AstraZeneca, other from Pfizer, nonfinancial support and other from Takeda, grants, nonfinancial support and other from Roche, nonfinancial support and other from MSD Oncology, other from Novartis, grants, nonfinancial support and other from Boehringer-Ingelheim, nonfinancial support and other from Bristol-Myers-Squibb, other from Eli Lilly, other from Eisai, grants and other from Merck Serono, grants from AbbVie, other from Amgen, other from PharmaMar, outside the submitted work; and Member of the Drug Commission of the Federal Office of Public Health Switzerland. Board Member Swiss Group for Clinical Cancer Research. I.O.: Roche, Institutional Grant for Fellowship and Speakers Bureau; AstraZeneca, Advisory Board and Speakers Bureau; Medtronic, Institutional Grant; MSD, Advisory Board. All other authors reported no conflicts of interest.
      The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

      Supplementary Data

      • Video 1

        Extended right upper lobe lobectomy in patient with stage IIIA NSCLC. TNM stage initially cT2 cN2 cM0 and definitive TNM stage ypT1 ypN0 cM0 after induction chemoradiotherapy. Video available at: https://www.jtcvs.org/article/S0022-5223(22)00403-2/fulltext.

      Appendix E1

      Figure thumbnail fx5
      Figure E1Flow chart summarizing the included and excluded patients, as well as performed resections. Excluded were 6 patients after quality control. Included were 197 patients with clinical T3/T4 stage of advanced NSCLC, of whom 159 were resected. SAKK, Swiss Group for Clinical Cancer Research; NSCLC, non–small cell lung cancer.
      Figure thumbnail fx6
      Figure E2Kaplan–Meier curves depicting OS and EFS in a cohort of resected (blue line; n = 159) versus not resected (red line, n = 38) for patients with locally advanced clinical T3/T4; III stage NSCLC. The difference was statistically significant in OS (A) between both surgical groups (4.1 years [95% CI, 3.0-6.7]) versus 0.7 years [95% CI, 0.6.3-0.8]), P < .001) and EFS (B) (1.3 years ([95% CI, 1.0-2.8] vs (0.2 years [95% CI, 0.2-0.2]), P < .001).
      Table E1Univariable analysis of factors influencing outcomes
      OutcomeOR/HR, 95% CIP value
      30-d mortalityAge (y)1.00 [0.90-1.12].912
      R0 resection (Yes vs No)1.00 [0.10-9.34].994
      Radiotherapy treatment (Yes vs No)0.61 [0.10-3.79].602
      Pulmonary resection (Extended vs Not extended)5.50 [0.88-34.29].068
      90-d mortalityAge, y1.04 [0.96-1.12].296
      R0 resection (Yes vs No)0.40 [0.11-1.49].175
      Pathological complete response (Yes vs No)1.50 [0.30-7.51].616
      Radiotherapy treatment (Yes vs No)0.51 [0.14-1.82].303
      Pulmonary resection (Extended vs Not extended)3.14 [0.90-10.99].073
      MorbidityAge, y1.01 [0.97-1.05].557
      R0 resection (Yes vs No)1.04 [0.45-2.41].911
      Pathological complete response (Yes vs No)1.06 [0.40-2.83].895
      Radiotherapy treatment (Yes vs No)1.95 [0.98-3.86].054
      Pulmonary resection (Extended vs Not extended)2.01 [0.93-4.32].073
      Overall survivalAge, y1.03 [1.00-1.05].009
      R0 resection (Yes vs No)0.38 [0.24-0.58]<.001
      Pathological complete response (Yes vs No)0.58 [0.32-1.07].082
      Radiotherapy treatment (Yes vs No)0.98 [0.67-1.42].914
      Pulmonary resection (Extended vs Not extended)1.01 [0.64-1.57].966
      Progression-free survivalAge, y1.01 [0.99-1.03].282
      R0 resection (Yes vs No)0.55 [0.35-0.87].011
      Pathological complete response (Yes vs No)0.53 [0.29-0.96].039
      Radiotherapy treatment (Yes vs No)0.99 [0.69-1.43].993
      Pulmonary resection (Extended vs Not extended)0.83 [0.53-1.28].407
      OR, Odds ratio; HR, hazard ratio; CI, confidence interval.
      Table E2Perioperative outcomes: Extended versus not extended resections and pneumonectomy versus lobectomy/bilobectomy
      Pulmonary resectionOverall (n = 159)Overall mortality (n = 16 deaths, 10%)
      30-d Mortality (n = 5 deaths, 3.1%)90-d Mortality (n = 11 deaths, 6.9%)
      Extended3635
      Not extended12326
      Pneumonectomy6657
      Simple4213
       Sleeve200
       Carinal pneumonectomy511
      Complex
       Extended1633
       Extended with sleeve100
      Lobectomy/bilobectomy9304
      Simple5702
       Sleeve1700
      Complex
       Extended1202
       Extended with sleeve700
      n: Number of patients who underwent pulmonary resections and number of deaths.
      Table E3Final causes of deaths after pneumonectomy versus lobectomy/bilobectomy
      Final causes of deathsPneumonectomy (N = 66)Lobectomy/bilobectomy (N = 93)
      n (%)n (%)
      Tumor progression35 (53.0)38 (40.9)
      Cardiac arrest0 (0.0)2 (2.2)
      Pancytopenia0 (0.0)1 (1.1)
      Acute upper gastrointestinal bleeding1 (1.5)0 (0.0)
      Other14 (21.2)15 (16.1)
      Missing16 (24.2)37 (39.8)
      Table E4Median overall survival and event-free survival at 3, 5, and 10 years after bimodal versus trimodal treatment
      YearsBimodal (CT + S)

      % [95% CI]
      Trimodal (CT + RT + S)

      % [95% CI]
      OS
       353.0% [41.2%, 63.4%]62.2% [50.8%, 71.7%]
       544.5% [33.1%, 55.4%]46.3% [35.3%, 56.7%]
       1036.7% [25.1%, 48.4%]30.3% [20.3%, 41.0%]
      EFS
       337.9% [27.0-48.6]46.1% [35.0-56.4]
       536.1% [25.4-47.0]31.9% [22.0-42.2]
       1026.4% [15.6-38.4]13.8% [6.1-24.6]
      OS, Overall survival; CT, computed tomography; RT, radiotherapy; CI, confidence interval; EFS, event-free survival.
      Table E5Pathological complete response in single, double, or multistage N2 disease before induction therapy
      Positive lymph nodes before inductionpCR
      No (N = 138)Yes (N = 21)
      n (%)n (%)
      N08 (5.8)2 (9.5)
      N12 (1.4)0 (0.0)
      Single N284 (60.9)7 (33.3)
      Double N231 (22.5)9 (42.9)
      Multiple N211 (8.0)3 (14.3)
      Missing2 (1.4)0 (0.0)
      pCR, Pathological complete response.

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