검색
검색 팝업 닫기

Advanced search

Article

Split Viewer

J Chest Surg 2024; 57(4): 351-359

Published online July 5, 2024 https://doi.org/10.5090/jcs.23.165

Copyright © Journal of Chest Surgery.

Risk Factor Analysis of Morbidity and 90-Day Mortality of Curative Resection in Patients with Stage IIIA–N2 Non-Small Cell Lung Cancer after Induction Concurrent Chemoradiation Therapy

Ga Hee Jeong , M.D., Junghee Lee , M.D., Ph.D., Yeong Jeong Jeon , M.D., Ph.D., Seong Yong Park , M.D., Ph.D., Hong Kwan Kim , M.D., Ph.D., Yong Soo Choi , M.D., Ph.D., Jhingook Kim , M.D., Ph.D., Young Mog Shim , M.D., Ph.D., Jong Ho Cho , M.D., Ph.D.

Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence to:Jong Ho Cho
Tel 82-2-3410-1696
Fax 82-2-3410-6986
E-mail mic95@naver.com
ORCID
https://orcid.org/0000-0003-3362-4621

Received: November 27, 2023; Revised: January 14, 2024; Accepted: January 26, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background: Major pulmonary resection after neoadjuvant concurrent chemoradiation therapy (nCCRT) is associated with a substantial risk of postoperative complications. This study investigated postoperative complications and associated risk factors to facilitate the selection of suitable surgical candidates following nCCRT in stage IIIA–N2 non-small cell lung cancer (NSCLC).
Methods: We conducted a retrospective analysis of patients diagnosed with clinical stage IIIA–N2 NSCLC who underwent surgical resection following nCCRT between 1997 and 2013. Perioperative characteristics and clinical factors associated with morbidity and mortality were analyzed using univariable and multivariable logistic regression.
Results: A total of 574 patients underwent major lung resection after induction CCRT. Thirty-day and 90-day postoperative mortality occurred in 8 patients (1.4%) and 41 patients (7.1%), respectively. Acute respiratory distress syndrome (n=6, 4.5%) was the primary cause of in-hospital mortality. Morbidity occurred in 199 patients (34.7%). Multivariable analysis identified significant predictors of morbidity, including patient age exceeding 70 years (odds ratio [OR], 1.8; p=0.04), low body mass index (OR, 2.6; p=0.02), and pneumonectomy (OR, 1.8; p=0.03). Patient age over 70 years (OR, 1.8; p=0.02) and pneumonectomy (OR, 3.26; p<0.01) were independent predictors of mortality in the multivariable analysis.
Conclusion: In conclusion, the surgical outcomes following nCCRT are less favorable for individuals aged over 70 years or those undergoing pneumonectomy. Special attention is warranted for these patients due to their heightened risks of respiratory complications. In high-risk patients, such as elderly patients with decreased lung function, alternative treatment options like definitive CCRT should be considered instead of surgical resection.

Keywords: Neoadjuvant concurrent chemoradiation therapy, Non-small cell lung carcinoma, Mortality, Risk factor

Lung cancer remains the leading cause of death from malignancies worldwide [1]. Locally advanced non-small cell lung cancer (NSCLC) is a heterogeneous entity, and the optimal intervention for stage IIIA–N2 NSCLC remains a subject of debate. However, neoadjuvant therapy before surgery, including chemotherapy and chemoradiotherapy, has been increasingly used to improve locoregional control and eradicate lymph node metastasis in the mediastinum [2]. Clinical trials have explored effective approaches for combining radiation therapy and chemotherapy to improve treatment results. At Samsung Medical Center, we employ a tri-modality approach, involving preoperative concurrent chemoradiation therapy (CCRT) followed by surgical resection, aimed at curing stage IIIA NSCLC with mediastinal lymph node metastases. Tri-modality therapy has been prospectively performed in medically fit patients with stage IIIA–N2 NSCLC at Samsung Medical Center, and it has subsequently shown acceptable oncologic treatment outcomes [3-6]. However, patients who undergo major pulmonary resection after induction therapy confront a considerably heightened risk of postoperative complications, which constitute the predominant source of operative morbidity and mortality. Furthermore, detailed reports on perioperative outcomes following lung resection in the neoadjuvant context are scarce, particularly those involving large-scale analyses.

In the present study, we retrospectively analyzed perioperative outcomes, including surgical morbidity and mortality, after neoadjuvant CCRT in patients with stage IIIA NSCLC. We present the clinical results and an analysis of risk factors associated with morbidity and mortality following tri-modality therapy.

Patients’ demographics

We conducted a comprehensive review of cases that underwent pulmonary resection following induction therapy from August 1997 to December 2013. The inclusion criteria were as follows: (1) a confirmed diagnosis of NSCLC, (2) clinical stage IIIA disease, as determined by the presence of mediastinal lymph node metastasis, (3) an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, (4) no significant medical conditions that could interfere with intensive treatment, and (5) exclusion of patients with a prior history of other solid malignancies. Additionally, patients with a second primary or recurrent NSCLC were excluded from the study. The study protocol received approval from the Institutional Review Board (IRB) of Samsung Medical Center (IRB approval no., 2023-11-087-001). The requirement for informed consent from individual patients was omitted because of the retrospective design of this study.

Pretreatment staging work-up and treatment regimen

The preoperative work-up included pulmonary function tests, computed tomography (CT) scans of the chest and upper abdomen, 18F-fluorodeoxyglucose positron emission tomography (PET)/CT, and brain magnetic resonance imaging. Nodal staging involved fiberoptic bronchoscopy, mediastinoscopy, or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). For cases with nodes in challenging locations, video-assisted thoracoscopic surgery (VATS) or the Chamberlain procedure was employed for staging. Patients who did not have histological confirmation of nodal involvement were diagnosed with N2 disease based on radiological evidence.

Neoadjuvant CCRT consisted of chemotherapy and concurrent thoracic radiotherapy. From May 1997 to 2008, radiation therapy was administered at a total dose of 45 Gy over 5 weeks (1.8 Gy/fraction/day). Starting from 2009 and onwards, the radiation dose was 44 Gy over 4.5 weeks (2.0 Gy/fraction/day). The chemotherapy regimen included weekly paclitaxel or docetaxel plus carboplatin or cisplatin for 5 weeks.

After the completion of chemoradiotherapy, tumor response was assessed using CT or PET scans, following the Response Evaluation Criteria in Solid Tumors guidelines (version 1.0). A multidisciplinary committee determined patient eligibility for surgical resection and evaluated tumor response. Routine restaging with re-mediastinoscopy or EBUS was not conducted.

Surgery

Surgery was scheduled for 4–6 weeks after the completion of neoadjuvant CCRT. The choice between lobectomy, bilobectomy, or pneumonectomy was based on the size and extent of the primary tumor to ensure its complete removal. After excising the main tumor, all patients underwent comprehensive mediastinal lymph node dissection according to the American Joint Committee on Cancer (AJCC) lymph node map, which includes nodal stations 2R, 4R, 7, 8, and 9 for right-sided tumors, and 4L, 5, 6, 7, 8, and 9 for left-sided tumors. R0 resection and R1/R2 resection were defined in line with the AJCC/Union for International Cancer Control definition. Postoperative radiation therapy and/or chemotherapy were considered if histologically positive N2 lymph nodes were present or if a positive resection margin was detected during surgery.

Perioperative management

Patients who underwent major pulmonary resection, except for those receiving a pneumonectomy, were routinely extubated in the operating room. Those who underwent a pneumonectomy were transferred to the intensive care unit (ICU) and extubated thereafter. Postoperatively, all patients spent at least one day in the ICU. Upon discharge from the ICU, patients were transferred to and managed in the thoracic surgical ward. Throughout the postoperative period, all patients participated in active chest physiotherapy, which included deep breathing exercises and incentive spirometry.

Postoperative complications

Postoperative complications were defined as those occurring within 30 days after surgery or before hospital discharge. To analyze any complications, we used the Clavien-Dindo classification: grade I: any deviation from the typical postoperative recovery that does not necessitate medication or medical procedures, including surgery, endoscopy, or radiology; grade II: needing medication for treatment, but not the same drugs used for grade I complications; grade III: requiring surgical, endoscopic, or radiological intervention; grade IIIa: intervention without the need for general anesthesia; grade IIIb: intervention that requires general anesthesia; grade IV: a complication that poses a life-threatening situation necessitating ICU management; and grade V: death. The identification of pneumonia was considered when patients presented with lung infiltration and purulent sputum, along with a significant presence of microorganisms in the sputum culture. Acute respiratory distress syndrome (ARDS) was characterized by the sudden onset of arterial hypoxemia resistant to oxygen therapy (with a partial pressure of oxygen/fraction of inspired oxygen [PaO2/FiO2] ratio of ≤200), diffuse infiltrates on chest radiographs, and no evidence of heart failure. Acute lung injury was defined similarly to ARDS, except with a PaO2/FiO2 ratio >200 and ≤300.

Data collection and analysis

Descriptive statistics were used to examine patient demographic characteristics and outcomes. Continuous data that followed a normal distribution were expressed as the mean±standard deviation, and categorical data were presented as frequencies and percentages. To compare continuous variables, we used the Student t-test or the Wilcoxon rank-sum test, depending on whether the data were normally distributed. The chi-square test or Fisher exact test was used to compare categorical variables, as deemed appropriate. We analyzed risk factors for morbidity and perioperative mortality using both univariate and multivariate logistic regression. Variables that achieved a p-value of less than 0.1 in the univariate analysis were subsequently included in the multivariate analysis. All statistical tests were 2-tailed, with the significance threshold set at 0.05. The analyses were performed using JMP ver. 10.1 software (SAS Institute Inc., Cary, NC, USA).

Patient demographics

From 1997 to 2013, 574 patients underwent major pulmonary resection at Samsung Medical Center after neoadjuvant CCRT due to stage IIIA–N2 NSCLC. Patients’ demographic characteristics are summarized in Table 1. The median age was 60 years (range, 23–76 years), and majority of patients were men (77.4%). The median body mass index (BMI) was 23.5 kg/m2 (range, 15.4–46.0 kg/m2). The ECOG performance status was 0 in 566 patients (98.6%) and 1 in 8 patients (1.4%). There were 399 smokers (59.1%) and 235 never-smokers (40.9%).

Table 1. Patients’ demographics

CharacteristicValue
Age (yr)60 (23–76)
Male444 (77.4)
Body mass index (kg/m2)23.5 (15.4–46.0)
ECOG performance status
0566 (98.6)
18 (1.4)
20
30
40
Chronic obstructive pulmonary disease18 (3.1)
Smoking status
Ever smoker339 (59.1)
Never smoker235(40.9)
Cerebrovascular accident15 (2.6)
Coronary artery disease3 (0.5)
Hypertension163 (28.4)
Diabetes67 (11.7)
FEV1 %93.0±18.6
FEV1/FVC%71.1±9.8
DLCO% (N=282)a)89.9±20.3

Values are presented as median (interquartile range), number (%), or mean±standard deviation.

ECOG, Eastern Cooperative Oncology Group; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; DLCO, diffusing capacity of the lungs for carbon monoxide.

a)292 (50.9%) did not undergo a preoperative DLCO test.



Pretreatment staging work-up and treatment regimen

All patients enrolled in this study underwent neoadjuvant CCRT prior to surgery. Perioperative characteristics are summarized in Table 2. Of the patients, 322 (56.1%) had adenocarcinoma, followed by 210 with squamous cell carcinoma (36.6%), 12 with large cell carcinoma (2.3%), and 29 with NSCLC not otherwise specified (5.1%). The clinical T stage distribution was T1 in 128 patients (22.3%), T2 in 386 patients (67.2%), and T3 in 60 patients (10.4%). Histologic confirmation of N2 stage was obtained in 505 patients (88%). Among these, 341 underwent mediastinoscopy, 146 had EBUS-TBNA, 19 underwent VATS, and 10 were assessed using the Chamberlain approach. The median radiation therapy dose was 45 Gy (interquartile range, 44–45 Gy). The clinical response to CCRT was categorized as a complete radiographic response in 5 patients (0.8%), a partial response in 559 patients (97.4%), and stable disease in 10 patients (1.7%). The median interval between the completion of CCRT and surgery was 33 days (range, 5–79 days).

Table 2. Perioperative characteristics

CharacteristicValue
Tumor histologic type
Adenocarcinoma322 (56.1)
Squamous cell carcinoma210 (36.6)
Large cell carcinoma12 (2.3)
NSCLC, NOS29 (5.1)
Time interval between CCRT and operation (day)33 (5–79)
Histologic confirmation of N2505 (88.0)
Mediastinoscopy341
EBUS-TBNA146
VATS19
Chamberlain10
Clinical T staging
cT1128 (22.3)
cT2386 (67.2)
cT360 (10.4)
Type of resection
Wedge resection3 (0.5)
Segmentectomy1 (0.2)
Lobectomy440 (76.7)
Bilobectomy57 (9.9)
Pneumonectomy73 (12.7)
Surgical approach
Thoracotomy555 (96.7)
VATS19 (3.3)
Completeness of resection
R0 resection543 (95)
R1/R2 resection31 (5.4)

Values are presented as number (%) or median (interquartile range).

NSCLC, non-small-cell lung cancer; NOS, not otherwise specified; CCRT, concurrent chemoradiotherapy; EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration; VATS, video-assisted thoracoscopic surgery.



Surgical treatment and pathologic findings

Among these patients, 440 underwent a lobectomy, 57 had a bilobectomy, 73 underwent a pneumonectomy, and 4 received a limited resection (3 wedge resections and 1 segmentectomy). Fig. 1 illustrates the distribution of these procedures. The surgical approach involved thoracotomy in 555 patients (96.7%) and VATS in 19 patients (3.3%). Complete resection was achieved in 543 patients (95%), while the resection was incomplete in 31 patients (5.4%). Within the cohort, 57% of patients (n=327) underwent adjuvant treatment, which included radiation therapy alone in 30.3% (n=174), chemotherapy alone in 13.1% (n=75), and CCRT in 13.6% (n=78).

Figure 1.The extent of surgery after neoadjuvant chemoradiotherapy.

In terms of resection completeness, complete resection was achieved in 543 patients (95%), while R1 resection was observed in 31 patients. The average number of lymph nodes dissected was 17, with a range from 0 to 52. Notably, a pathologic complete response was exhibited by 72 patients (13%). Compared to the nodal status before treatment, mediastinal nodal downstaging was observed in 304 patients (53%), whereas 268 patients (47%) continued to exhibit persistent N2 disease.

Postoperative outcomes

Perioperative outcomes, including the length of hospital stay, morbidity, and mortality, are summarized in Table 3. The median hospital stay was 8 days. Early postoperative mortality (within 30 days) occurred in 1.4% of patients (n=8), while late postoperative mortality (within 90 days) occurred in 7.1% (n=41). The rates of morbidity and mortality were associated with the extent of the surgical resection (Table 3). Postoperative complications according to the Clavien-Dindo classification are detailed in Table 4. The overall morbidity rate was 34.7% (199 patients). The most common complications included arrhythmia (20.2%), prolonged air leak (6.1%), and pneumonia (5.6%). Bronchopleural fistulas occurred in 11 patients (1.9%), and postoperative empyema was seen in 13 patients (2.3%).

Table 3. Perioperative outcomes

OutcomesTotalThe extent of surgical resectionp-value

Limited resectionLobectomyBilobectomyPneumonectomy
30-Day mortality8 (1.4)03 (0.7)1 (1.8)4 (5.5)0.014
60-Day mortality25 (4.4)015 (3.4)2 (3.5)8 (11.0)0.031
90-Day mortality41 (7.1)023 (5.2)5 (8.8)13 (17.8)0.006
Length of stay (day)8 (7–11)7 (4.5–15.5)8 (7–11)9 (8–15)10 (8–12.5)<0.001
Morbidity199 (34.7)0137 (31.1)26 (45.6)36 (49.3)0.002

Values are presented as number (%) or median (interquartile range).


Table 4. Postoperative complications

MorbidityTotalThe Clavien-Dindo classification of surgical complicationsa)

IIIIIIaIIIbIVV
Arrhythmia116 (20.2)116
Pneumonia32 (5.6)711914
Acute lung injury12 (2.1)534
Acute respiratory distress syndrome18 (3.1)18
Atelectasisb)10 (1.7)10
Bronchopleural fistula11 (1.9)1172
Empyema13 (2.3)211
Prolonged air leak35 (6.1)52712
Chylothorax8 (1.4)341
Vocal cord paralysis20 (3.5)812
Postop bleedingc)2 (0.3)2
Delirium12(2.1)12
Acute kidney injury3 (0.5)3
Pulmonary thromboembolism3 (0.5)12
Deep vein thrombosis1 (0.2)1
Pleural effusion4 (0.7)13
Hemoptysis2 (0.3)2
Hemorrhagic gastritis1 (0.2)1
Ileus1 (0.2)1
Total199 (34.7)

Values are presented as number (%) or number.

a)Clavien-Dindo classification: grade I: any deviation from the typical postoperative recovery that does not necessitate medication or medical procedures, including surgery, endoscopy, or radiology; grade II: needing medication for treatment, but not the same drugs used for grade I complications; grade III: requiring surgical, endoscopic, or radiological intervention; grade IIIa: intervention without the need for general anesthesia; grade IIIb: intervention that requires general anesthesia; grade IV: a complication that poses a life-threatening situation necessitating intensive care unit management; and grade V: death. b)Atelectasis requiring therapeutic bronchoscopy. c)Postoperative bleeding requiring re-operation.



In the univariate analysis using the predictors listed in Tables 1 and 2, several factors were identified as independent risk factors for postoperative morbidity. These factors included male sex, patient age over 70 years, non-adenocarcinoma histology, a history of smoking, a BMI below 18.5 kg/m2, and undergoing a pneumonectomy (Table 5). The multivariable analysis further confirmed that being over 70 years of age (odds ratio [OR], 1.82; p=0.040), having a BMI below 18.5 kg/m2 (OR, 2.62; p=0.022), and undergoing a pneumonectomy (OR, 1.8; p=0.026) were significant predictors of morbidity (Table 5).

Table 5. Univariate and multivariate risk factor analyses for morbidity

VariableNo. of patients (%)UnivariateMultivariate logistic regression analysis


p-valueOdds ratio (95% CI)p-value
Sex<0.0010.056
Male171 (38.5)1.70 (0.98–2.98)
Female28 (21.5)1
Age (yr)0.0370.040
≥7027 (47.4)1.82 (1.03–3.20)
<70172 (33.3)1
Cell type0.0030.140
Non-ADC104 (41.3)1.33 (0.91–1.94)
ADC95 (29.5)1
Smoking0.0060.382
Ever smoker133 (39.2)1.21 (0.79–1.84)
Never smoker66 (28.1)1
Body mass index (kg/m2)0.0260.022
<18.514 (56.0)2.63 (1.15–6.15)
≥18.5185 (33.7)1
Extent of surgery0.0020.026
Pneumonectomy36 (49.3)1.8 (1.07–3.00)
Non-pneumonectomy163 (32.5)1

Statistically significant results are marked in bold.

CI, confidence interval; ADC, adenocarcinoma.



Similarly, in the univariate analysis (Table 6), significant risk factors for postoperative mortality included male gender, patient age over 70 years, a history of smoking, an interval of more than 5 weeks between the completion of CCRT and surgery, and undergoing a pneumonectomy. The subsequent multivariate analysis revealed that being over the age of 70 (OR, 1.82; p=0.022) and undergoing a pneumonectomy (OR, 3.256; p=0.003) were independently associated with an increased risk of mortality within 90 days following surgery (Table 6).

Table 6. Univariate and multivariate risk factor analyses for perioperative mortality(within 90 days)

VariableNo. of patients (%)UnivariateMultivariate logistic regression analysis



p-valueOdds ratio (95% CI)p-value
Sex<0.001
Male41 (9.23)-
Female0-
Age (yr)0.0370.019
≥709 (15.8)1.82 (1.21–6.43)
<7032 (6.2)1
Smoking0.0060.100
Ever smoker30 (8.9)1.81 (0.90–3.91)
Never smoker11 (4.7)1
Time interval (wk)a)0.0060.085
≥523 (10.6)1.80 (0.92–3.56)
<518 (5.2)1
Extent of surgery0.0020.003
Pneumonectomy13 (17.8)3.25 (1.50–6.78)
Non-pneumonectomy28 (5.6)1

Statistically significant results are marked in bold.

CI, confidence interval; ADC, adenocarcinoma.

a)Time interval refers to the time period between the end of neoadjuvant chemoradiation therapy and surgery.


The impact of induction therapy on postoperative morbidity and mortality for patients with stage IIIa–N2 NSCLC undergoing major pulmonary resection has been a subject of debate. Some studies have suggested that induction therapy may increase the risk of morbidity and mortality following surgery [7,8]. It is logical to expect that neoadjuvant chemoradiation therapy could affect the likelihood of postoperative complications and death. Consequently, it is crucial to carefully select patients for surgery who are likely to achieve complete resection with minimal morbidity and mortality following induction chemoradiation therapy. Typically, the most significant risk factors for perioperative morbidity and mortality include age, pulmonary reserve, cardiovascular disease, respiratory infection, arrhythmia, renal failure, and diabetes [9-11]. However, there is scant literature on the risk factors associated with morbidity and mortality in surgical treatment for patients with stage IIIa–N2 NSCLC after induction therapy.

Herein, we have reported the morbidity and mortality rates of patients who underwent major pulmonary resection following induction therapy for stage IIIA–N2 NSCLC. Our study evaluated various predictors of postoperative morbidity and mortality in a uniform cohort of patients who had significant pulmonary resections after induction therapy. Notably, being over the age of 70 years was also identified as a risk factor for increased morbidity and mortality. Chronological age is widely recognized as a significant risk factor for elderly patients undergoing surgical procedures. The authors of this study believe that individuals aged 70 years or older have reduced cardiopulmonary reserve, which places them in the category of the elderly population undergoing lung resection. According to Birim et al. [12], advancing age was a significant prognostic factor for long-term outcomes, along with other indices such as the Charlson comorbidity index. It is suggested that patients aged 70 years or older be considered elderly in medical evaluations, as this age threshold typically marks the beginning of numerous age-related adverse changes [13]. The adoption of the Comprehensive Geriatric Assessment (CGA) for evaluating elderly cancer patients [14,15] aims to identify those who are robust and more likely to benefit from standard cancer treatment, as opposed to those who are vulnerable and require personalized surgery or chemotherapy regimens, or those who are frail and are suitable for supportive care only [16]. However, there is an ongoing debate about the actual impact of the CGA on treatment decision-making in clinical settings, due to its time-consuming, burdensome, and non-standardized nature [17].

Another risk factor identified for adverse outcomes following trimodal therapy is pneumonectomy. Among pulmonary resections, pneumonectomy is associated with the highest rates of morbidity and mortality of all elective thoracic surgical procedures. Furthermore, the mortality rate after pneumonectomy without neoadjuvant therapy has been reported to range from 1.6% to 13.4% [18,19]. Some authors have suggested that pneumonectomy should be considered a distinct disease entity due to its significant impact on cardiorespiratory physiology and consequent reduction in overall survival [20]. Therefore, pneumonectomy with neoadjuvant therapy is regarded as a major procedure with high mortality rates and should be only performed by experienced surgeons [21]. In the Intergroup Study (INT) 0139, 429 patients with stage IIIA–N2 disease were randomized after receiving 2 cycles of cisplatin/etoposide and concomitant radiotherapy (45 Gy), followed by either surgical resection or 2 additional cycles of chemotherapy [22]. A 30-day mortality rate of 25.9% was observed in patients who underwent pneumonectomy in the INT 0139 trial. Our data indicate that the 30-day and 90-day mortality rates for pneumonectomy after neoadjuvant therapy were 5.5% and 17.8%, respectively. Clearly, the operative mortality is significantly high. Consequently, we advocate for every effort to be made to avoid pneumonectomy, such as opting for sleeve lobectomy whenever feasible.

The role of nutrition in predicting the outcome of operations for lung cancer is also of growing interest. We identified the underweight BMI category as a potential risk factor for postoperative morbidity. The detrimental impact of malnutrition has been recently emphasized, especially for pneumonectomy [23]. Furthermore, research by Thomas et al. [24] has shown that underweight patients are significantly more likely to suffer from pulmonary, surgical, and infectious complications. In this study, prolonged air leaks and bronchial stump dehiscence were significantly more frequent in underweight patients than in patients with a normal BMI, but obesity was not associated with an increased incidence of postoperative complications.

Regarding morbidity, studies have reported postoperative complication rates of approximately 30%, irrespective of whether patients received induction therapy [11,25,26]. Arrhythmia is the most frequently reported complication in these studies. Our morbidity rate was 34.7%, aligning with the rates found in prior research.

The primary focus after surgery is to prevent morbidity and mortality. Careful patient selection, informed by comprehensive preoperative assessments, can reduce the risk of postoperative complications. In thoracic oncology, it is important to create personalized treatment plans based on detailed risk analysis to prevent postoperative issues. However, despite meticulous patient selection, postoperative complications can still occur. Experienced thoracic surgeons and intensive care specialists should manage these complications. Over the past 2 decades, our group has developed a multidisciplinary approach for patients with stage IIIA–N2 NSCLC, addressing preoperative and postoperative management, including complications. This approach is based on our experience with nearly 600 patients who underwent surgery following induction therapy. Consequently, our group continues to endorse trimodal therapy as the most effective treatment for stage IIIA–N2 NSCLC, except when preoperative radiologic findings indicate that complete tumor resection is unlikely.

This study had several limitations. First, it utilized a retrospective design. Additionally, the research included a diverse patient cohort, with variability in histologic subtypes and the prevalence of bulky N2 disease. This diversity could have affected the outcomes of surgical interventions following induction therapy. Moreover, the study covered a period of nearly 16 years, potentially leading to inconsistencies in outcomes due to changes in chemotherapy and radiotherapy practices over this time. Specifically, the extended duration of the study may have introduced unmeasured bias into our results.

In conclusion, the surgical outcomes following neoadjuvant CCRT are less favorable for individuals over the age of 70 years or for those undergoing pneumonectomy. These patients require special attention due to an increased risk of respiratory complications. For high-risk patients, particularly older individuals with diminished lung function, alternative treatment options such as definitive CCRT may be preferable to surgical resection.

Author contributions

Conceptualization: JHC. Data curation: JL, GHJ. Formal analysis: JHC. Funding acquisition: JHC. Methodology: YJJ, SYP. Project administration: JHC. JL, YJJ, SYP. Visualization: JK, GHJ. Writing–original draft: GHJ, JHC. Writing–review & editing: YSC, YMS, JHC, GHJ. Final approval of the manuscript: all authors.

Conflict of interest

Seong Yong Park is an associate editor, Junghee Lee is an editorial board member, and Hong Kwan Kim was an associate editor of the journal during the submission of this article. They were not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflict of interest relevant to this article was reported.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11-30. https://doi.org/10.3322/caac.21166.
    Pubmed CrossRef
  2. Rosell R, Gomez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 1994;330:153-8. https://doi.org/10.1056/NEJM199401203300301.
    Pubmed CrossRef
  3. Ahn YC, Park K, Kim DY, et al. Preoperative concurrent chemoradiotherapy for stage IIIA non-small cell lung cancer. Acta Oncol 2001;40:588-92. https://doi.org/10.1080/028418601750444123.
    Pubmed CrossRef
  4. Kang MK, Ahn YC, Lim DH, et al. Preoperative concurrent radiochemotherapy and surgery for stage IIIA non-small cell lung cancer. J Korean Med Sci 2006;21:229-35. https://doi.org/10.3346/jkms.2006.21.2.229.
    Pubmed KoreaMed CrossRef
  5. Kim KJ, Ahn YC, Lim DH, et al. Analyses on prognostic factors following tri-modality therapy for stage IIIa non-small cell lung cancer. Lung Cancer 2007;55:329-36. https://doi.org/10.1016/j.lungcan.2006.10.024.
    Pubmed CrossRef
  6. Lee H, Ahn YC, Pyo H, et al. Pretreatment clinical mediastinal nodal bulk and extent do not influence survival in N2-positive stage IIIA non-small cell lung cancer patients treated with trimodality therapy. Ann Surg Oncol 2014;21:2083-90. https://doi.org/10.1245/s10434-014-3540-x.
    Pubmed CrossRef
  7. Doddoli C, Thomas P, Thirion X, Seree Y, Giudicelli R, Fuentes P. Postoperative complications in relation with induction therapy for lung cancer. Eur J Cardiothorac Surg 2001;20:385-90. https://doi.org/10.1016/s1010-7940(01)00764-3.
    Pubmed CrossRef
  8. Roberts JR, Eustis C, Devore R, Carbone D, Choy H, Johnson D. Induction chemotherapy increases perioperative complications in patients undergoing resection for non-small cell lung cancer. Ann Thorac Surg 2001;72:885-8. https://doi.org/10.1016/s0003-4975(01)02836-3.
    Pubmed CrossRef
  9. Patel RL, Townsend ER, Fountain SW. Elective pneumonectomy: factors associated with morbidity and operative mortality. Ann Thorac Surg 1992;54:84-8. https://doi.org/10.1016/0003-4975(92)91145-y.
    Pubmed CrossRef
  10. Wada H, Nakamura T, Nakamoto K, Maeda M, Watanabe Y. Thirty-day operative mortality for thoracotomy in lung cancer. J Thorac Cardiovasc Surg 1998;115:70-3. https://doi.org/10.1016/s0022-5223(98)70444-1.
    Pubmed CrossRef
  11. Duque JL, Ramos G, Castrodeza J, et al. Early complications in surgical treatment of lung cancer: a prospective, multicenter study. Grupo Cooperativo de Carcinoma Broncogenico de la Sociedad Espanola de Neumología y Cirugia Toracica. Ann Thorac Surg 1997;63:944-50. https://doi.org/10.1016/s0003-4975(97)00051-9.
    Pubmed CrossRef
  12. Birim O, Kappetein AP, Bogers AJ. Charlson comorbidity index as a predictor of long-term outcome after surgery for nonsmall cell lung cancer. Eur J Cardiothorac Surg 2005;28:759-62. https://doi.org/10.1016/j.ejcts.2005.06.046.
    Pubmed CrossRef
  13. Balducci L. ESH-SIOG International Conference on Haematological Malignancies in the Elderly. Expert Rev Hematol 2010;3:675-7. https://doi.org/10.1586/ehm.10.72.
    Pubmed CrossRef
  14. Extermann M, Hurria A. Comprehensive geriatric assessment for older patients with cancer. J Clin Oncol 2007;25:1824-31. https://doi.org/10.1200/JCO.2007.10.6559.
    Pubmed CrossRef
  15. Extermann M. Integrating a geriatric evaluation in the clinical setting. Semin Radiat Oncol 2012;22:272-6. https://doi.org/10.1016/j.semradonc.2012.05.003.
    Pubmed CrossRef
  16. Wedding U, Kodding D, Pientka L, Steinmetz HT, Schmitz S. Physicians' judgement and comprehensive geriatric assessment (CGA) select different patients as fit for chemotherapy. Crit Rev Oncol Hematol 2007;64:1-9. https://doi.org/10.1016/j.critrevonc.2007.05.001.
    Pubmed CrossRef
  17. Puts MT, Hardt J, Monette J, Girre V, Springall E, Alibhai SM. Use of geriatric assessment for older adults in the oncology setting: a systematic review. J Natl Cancer Inst 2012;104:1133-63. https://doi.org/10.1093/jnci/djs285.
    Pubmed KoreaMed CrossRef
  18. Licker M, Spiliopoulos A, Frey JG, et al. Risk factors for early mortality and major complications following pneumonectomy for non-small cell carcinoma of the lung. Chest 2002;121:1890-7. https://doi.org/10.1378/chest.121.6.1890.
    Pubmed CrossRef
  19. Van Raemdonck DE, Schneider A, Ginsberg RJ. Surgical treatment for higher stage non-small cell lung cancer. Ann Thorac Surg 1992;54:999-1013. https://doi.org/10.1016/0003-4975(92)90677-v.
    Pubmed CrossRef
  20. Mansour Z, Kochetkova EA, Santelmo N, et al. Risk factors for early mortality and morbidity after pneumonectomy: a reappraisal. Ann Thorac Surg 2009;88:1737-43. https://doi.org/10.1016/j.athoracsur.2009.07.016.
    Pubmed CrossRef
  21. Romano PS, Mark DH. Patient and hospital characteristics related to in-hospital mortality after lung cancer resection. Chest 1992;101:1332-7. https://doi.org/10.1378/chest.101.5.1332.
    Pubmed CrossRef
  22. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379-86. https://doi.org/10.1016/S0140-6736(09)60737-6.
    Pubmed CrossRef
  23. Bagan P, Berna P, De Dominicis F, et al. Nutritional status and postoperative outcome after pneumonectomy for lung cancer. Ann Thorac Surg 2013;95:392-6. https://doi.org/10.1016/j.athoracsur.2012.06.023.
    Pubmed CrossRef
  24. Thomas PA, Berbis J, Falcoz PE, et al. National perioperative outcomes of pulmonary lobectomy for cancer: the influence of nutritional status. Eur J Cardiothorac Surg 2014;45:652-9. https://doi.org/10.1093/ejcts/ezt452.
    Pubmed CrossRef
  25. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995;13:1880-92. https://doi.org/10.1200/JCO.1995.13.8.1880.
    Pubmed CrossRef
  26. Deslauriers J, Ginsberg RJ, Piantadosi S, Fournier B. Prospective assessment of 30-day operative morbidity for surgical resections in lung cancer. Chest 1994;106(6 Suppl):329S-330S. https://doi.org/10.1378/chest.106.6_supplement.329s.
    Pubmed CrossRef

Article

Clinical Research

J Chest Surg 2024; 57(4): 351-359

Published online July 5, 2024 https://doi.org/10.5090/jcs.23.165

Copyright © Journal of Chest Surgery.

Risk Factor Analysis of Morbidity and 90-Day Mortality of Curative Resection in Patients with Stage IIIA–N2 Non-Small Cell Lung Cancer after Induction Concurrent Chemoradiation Therapy

Ga Hee Jeong , M.D., Junghee Lee , M.D., Ph.D., Yeong Jeong Jeon , M.D., Ph.D., Seong Yong Park , M.D., Ph.D., Hong Kwan Kim , M.D., Ph.D., Yong Soo Choi , M.D., Ph.D., Jhingook Kim , M.D., Ph.D., Young Mog Shim , M.D., Ph.D., Jong Ho Cho , M.D., Ph.D.

Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence to:Jong Ho Cho
Tel 82-2-3410-1696
Fax 82-2-3410-6986
E-mail mic95@naver.com
ORCID
https://orcid.org/0000-0003-3362-4621

Received: November 27, 2023; Revised: January 14, 2024; Accepted: January 26, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background: Major pulmonary resection after neoadjuvant concurrent chemoradiation therapy (nCCRT) is associated with a substantial risk of postoperative complications. This study investigated postoperative complications and associated risk factors to facilitate the selection of suitable surgical candidates following nCCRT in stage IIIA–N2 non-small cell lung cancer (NSCLC).
Methods: We conducted a retrospective analysis of patients diagnosed with clinical stage IIIA–N2 NSCLC who underwent surgical resection following nCCRT between 1997 and 2013. Perioperative characteristics and clinical factors associated with morbidity and mortality were analyzed using univariable and multivariable logistic regression.
Results: A total of 574 patients underwent major lung resection after induction CCRT. Thirty-day and 90-day postoperative mortality occurred in 8 patients (1.4%) and 41 patients (7.1%), respectively. Acute respiratory distress syndrome (n=6, 4.5%) was the primary cause of in-hospital mortality. Morbidity occurred in 199 patients (34.7%). Multivariable analysis identified significant predictors of morbidity, including patient age exceeding 70 years (odds ratio [OR], 1.8; p=0.04), low body mass index (OR, 2.6; p=0.02), and pneumonectomy (OR, 1.8; p=0.03). Patient age over 70 years (OR, 1.8; p=0.02) and pneumonectomy (OR, 3.26; p<0.01) were independent predictors of mortality in the multivariable analysis.
Conclusion: In conclusion, the surgical outcomes following nCCRT are less favorable for individuals aged over 70 years or those undergoing pneumonectomy. Special attention is warranted for these patients due to their heightened risks of respiratory complications. In high-risk patients, such as elderly patients with decreased lung function, alternative treatment options like definitive CCRT should be considered instead of surgical resection.

Keywords: Neoadjuvant concurrent chemoradiation therapy, Non-small cell lung carcinoma, Mortality, Risk factor

Introduction

Lung cancer remains the leading cause of death from malignancies worldwide [1]. Locally advanced non-small cell lung cancer (NSCLC) is a heterogeneous entity, and the optimal intervention for stage IIIA–N2 NSCLC remains a subject of debate. However, neoadjuvant therapy before surgery, including chemotherapy and chemoradiotherapy, has been increasingly used to improve locoregional control and eradicate lymph node metastasis in the mediastinum [2]. Clinical trials have explored effective approaches for combining radiation therapy and chemotherapy to improve treatment results. At Samsung Medical Center, we employ a tri-modality approach, involving preoperative concurrent chemoradiation therapy (CCRT) followed by surgical resection, aimed at curing stage IIIA NSCLC with mediastinal lymph node metastases. Tri-modality therapy has been prospectively performed in medically fit patients with stage IIIA–N2 NSCLC at Samsung Medical Center, and it has subsequently shown acceptable oncologic treatment outcomes [3-6]. However, patients who undergo major pulmonary resection after induction therapy confront a considerably heightened risk of postoperative complications, which constitute the predominant source of operative morbidity and mortality. Furthermore, detailed reports on perioperative outcomes following lung resection in the neoadjuvant context are scarce, particularly those involving large-scale analyses.

In the present study, we retrospectively analyzed perioperative outcomes, including surgical morbidity and mortality, after neoadjuvant CCRT in patients with stage IIIA NSCLC. We present the clinical results and an analysis of risk factors associated with morbidity and mortality following tri-modality therapy.

Methods

Patients’ demographics

We conducted a comprehensive review of cases that underwent pulmonary resection following induction therapy from August 1997 to December 2013. The inclusion criteria were as follows: (1) a confirmed diagnosis of NSCLC, (2) clinical stage IIIA disease, as determined by the presence of mediastinal lymph node metastasis, (3) an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, (4) no significant medical conditions that could interfere with intensive treatment, and (5) exclusion of patients with a prior history of other solid malignancies. Additionally, patients with a second primary or recurrent NSCLC were excluded from the study. The study protocol received approval from the Institutional Review Board (IRB) of Samsung Medical Center (IRB approval no., 2023-11-087-001). The requirement for informed consent from individual patients was omitted because of the retrospective design of this study.

Pretreatment staging work-up and treatment regimen

The preoperative work-up included pulmonary function tests, computed tomography (CT) scans of the chest and upper abdomen, 18F-fluorodeoxyglucose positron emission tomography (PET)/CT, and brain magnetic resonance imaging. Nodal staging involved fiberoptic bronchoscopy, mediastinoscopy, or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). For cases with nodes in challenging locations, video-assisted thoracoscopic surgery (VATS) or the Chamberlain procedure was employed for staging. Patients who did not have histological confirmation of nodal involvement were diagnosed with N2 disease based on radiological evidence.

Neoadjuvant CCRT consisted of chemotherapy and concurrent thoracic radiotherapy. From May 1997 to 2008, radiation therapy was administered at a total dose of 45 Gy over 5 weeks (1.8 Gy/fraction/day). Starting from 2009 and onwards, the radiation dose was 44 Gy over 4.5 weeks (2.0 Gy/fraction/day). The chemotherapy regimen included weekly paclitaxel or docetaxel plus carboplatin or cisplatin for 5 weeks.

After the completion of chemoradiotherapy, tumor response was assessed using CT or PET scans, following the Response Evaluation Criteria in Solid Tumors guidelines (version 1.0). A multidisciplinary committee determined patient eligibility for surgical resection and evaluated tumor response. Routine restaging with re-mediastinoscopy or EBUS was not conducted.

Surgery

Surgery was scheduled for 4–6 weeks after the completion of neoadjuvant CCRT. The choice between lobectomy, bilobectomy, or pneumonectomy was based on the size and extent of the primary tumor to ensure its complete removal. After excising the main tumor, all patients underwent comprehensive mediastinal lymph node dissection according to the American Joint Committee on Cancer (AJCC) lymph node map, which includes nodal stations 2R, 4R, 7, 8, and 9 for right-sided tumors, and 4L, 5, 6, 7, 8, and 9 for left-sided tumors. R0 resection and R1/R2 resection were defined in line with the AJCC/Union for International Cancer Control definition. Postoperative radiation therapy and/or chemotherapy were considered if histologically positive N2 lymph nodes were present or if a positive resection margin was detected during surgery.

Perioperative management

Patients who underwent major pulmonary resection, except for those receiving a pneumonectomy, were routinely extubated in the operating room. Those who underwent a pneumonectomy were transferred to the intensive care unit (ICU) and extubated thereafter. Postoperatively, all patients spent at least one day in the ICU. Upon discharge from the ICU, patients were transferred to and managed in the thoracic surgical ward. Throughout the postoperative period, all patients participated in active chest physiotherapy, which included deep breathing exercises and incentive spirometry.

Postoperative complications

Postoperative complications were defined as those occurring within 30 days after surgery or before hospital discharge. To analyze any complications, we used the Clavien-Dindo classification: grade I: any deviation from the typical postoperative recovery that does not necessitate medication or medical procedures, including surgery, endoscopy, or radiology; grade II: needing medication for treatment, but not the same drugs used for grade I complications; grade III: requiring surgical, endoscopic, or radiological intervention; grade IIIa: intervention without the need for general anesthesia; grade IIIb: intervention that requires general anesthesia; grade IV: a complication that poses a life-threatening situation necessitating ICU management; and grade V: death. The identification of pneumonia was considered when patients presented with lung infiltration and purulent sputum, along with a significant presence of microorganisms in the sputum culture. Acute respiratory distress syndrome (ARDS) was characterized by the sudden onset of arterial hypoxemia resistant to oxygen therapy (with a partial pressure of oxygen/fraction of inspired oxygen [PaO2/FiO2] ratio of ≤200), diffuse infiltrates on chest radiographs, and no evidence of heart failure. Acute lung injury was defined similarly to ARDS, except with a PaO2/FiO2 ratio >200 and ≤300.

Data collection and analysis

Descriptive statistics were used to examine patient demographic characteristics and outcomes. Continuous data that followed a normal distribution were expressed as the mean±standard deviation, and categorical data were presented as frequencies and percentages. To compare continuous variables, we used the Student t-test or the Wilcoxon rank-sum test, depending on whether the data were normally distributed. The chi-square test or Fisher exact test was used to compare categorical variables, as deemed appropriate. We analyzed risk factors for morbidity and perioperative mortality using both univariate and multivariate logistic regression. Variables that achieved a p-value of less than 0.1 in the univariate analysis were subsequently included in the multivariate analysis. All statistical tests were 2-tailed, with the significance threshold set at 0.05. The analyses were performed using JMP ver. 10.1 software (SAS Institute Inc., Cary, NC, USA).

Results

Patient demographics

From 1997 to 2013, 574 patients underwent major pulmonary resection at Samsung Medical Center after neoadjuvant CCRT due to stage IIIA–N2 NSCLC. Patients’ demographic characteristics are summarized in Table 1. The median age was 60 years (range, 23–76 years), and majority of patients were men (77.4%). The median body mass index (BMI) was 23.5 kg/m2 (range, 15.4–46.0 kg/m2). The ECOG performance status was 0 in 566 patients (98.6%) and 1 in 8 patients (1.4%). There were 399 smokers (59.1%) and 235 never-smokers (40.9%).

Table 1 . Patients’ demographics.

CharacteristicValue
Age (yr)60 (23–76)
Male444 (77.4)
Body mass index (kg/m2)23.5 (15.4–46.0)
ECOG performance status
0566 (98.6)
18 (1.4)
20
30
40
Chronic obstructive pulmonary disease18 (3.1)
Smoking status
Ever smoker339 (59.1)
Never smoker235(40.9)
Cerebrovascular accident15 (2.6)
Coronary artery disease3 (0.5)
Hypertension163 (28.4)
Diabetes67 (11.7)
FEV1 %93.0±18.6
FEV1/FVC%71.1±9.8
DLCO% (N=282)a)89.9±20.3

Values are presented as median (interquartile range), number (%), or mean±standard deviation..

ECOG, Eastern Cooperative Oncology Group; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; DLCO, diffusing capacity of the lungs for carbon monoxide..

a)292 (50.9%) did not undergo a preoperative DLCO test..



Pretreatment staging work-up and treatment regimen

All patients enrolled in this study underwent neoadjuvant CCRT prior to surgery. Perioperative characteristics are summarized in Table 2. Of the patients, 322 (56.1%) had adenocarcinoma, followed by 210 with squamous cell carcinoma (36.6%), 12 with large cell carcinoma (2.3%), and 29 with NSCLC not otherwise specified (5.1%). The clinical T stage distribution was T1 in 128 patients (22.3%), T2 in 386 patients (67.2%), and T3 in 60 patients (10.4%). Histologic confirmation of N2 stage was obtained in 505 patients (88%). Among these, 341 underwent mediastinoscopy, 146 had EBUS-TBNA, 19 underwent VATS, and 10 were assessed using the Chamberlain approach. The median radiation therapy dose was 45 Gy (interquartile range, 44–45 Gy). The clinical response to CCRT was categorized as a complete radiographic response in 5 patients (0.8%), a partial response in 559 patients (97.4%), and stable disease in 10 patients (1.7%). The median interval between the completion of CCRT and surgery was 33 days (range, 5–79 days).

Table 2 . Perioperative characteristics.

CharacteristicValue
Tumor histologic type
Adenocarcinoma322 (56.1)
Squamous cell carcinoma210 (36.6)
Large cell carcinoma12 (2.3)
NSCLC, NOS29 (5.1)
Time interval between CCRT and operation (day)33 (5–79)
Histologic confirmation of N2505 (88.0)
Mediastinoscopy341
EBUS-TBNA146
VATS19
Chamberlain10
Clinical T staging
cT1128 (22.3)
cT2386 (67.2)
cT360 (10.4)
Type of resection
Wedge resection3 (0.5)
Segmentectomy1 (0.2)
Lobectomy440 (76.7)
Bilobectomy57 (9.9)
Pneumonectomy73 (12.7)
Surgical approach
Thoracotomy555 (96.7)
VATS19 (3.3)
Completeness of resection
R0 resection543 (95)
R1/R2 resection31 (5.4)

Values are presented as number (%) or median (interquartile range)..

NSCLC, non-small-cell lung cancer; NOS, not otherwise specified; CCRT, concurrent chemoradiotherapy; EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration; VATS, video-assisted thoracoscopic surgery..



Surgical treatment and pathologic findings

Among these patients, 440 underwent a lobectomy, 57 had a bilobectomy, 73 underwent a pneumonectomy, and 4 received a limited resection (3 wedge resections and 1 segmentectomy). Fig. 1 illustrates the distribution of these procedures. The surgical approach involved thoracotomy in 555 patients (96.7%) and VATS in 19 patients (3.3%). Complete resection was achieved in 543 patients (95%), while the resection was incomplete in 31 patients (5.4%). Within the cohort, 57% of patients (n=327) underwent adjuvant treatment, which included radiation therapy alone in 30.3% (n=174), chemotherapy alone in 13.1% (n=75), and CCRT in 13.6% (n=78).

Figure 1. The extent of surgery after neoadjuvant chemoradiotherapy.

In terms of resection completeness, complete resection was achieved in 543 patients (95%), while R1 resection was observed in 31 patients. The average number of lymph nodes dissected was 17, with a range from 0 to 52. Notably, a pathologic complete response was exhibited by 72 patients (13%). Compared to the nodal status before treatment, mediastinal nodal downstaging was observed in 304 patients (53%), whereas 268 patients (47%) continued to exhibit persistent N2 disease.

Postoperative outcomes

Perioperative outcomes, including the length of hospital stay, morbidity, and mortality, are summarized in Table 3. The median hospital stay was 8 days. Early postoperative mortality (within 30 days) occurred in 1.4% of patients (n=8), while late postoperative mortality (within 90 days) occurred in 7.1% (n=41). The rates of morbidity and mortality were associated with the extent of the surgical resection (Table 3). Postoperative complications according to the Clavien-Dindo classification are detailed in Table 4. The overall morbidity rate was 34.7% (199 patients). The most common complications included arrhythmia (20.2%), prolonged air leak (6.1%), and pneumonia (5.6%). Bronchopleural fistulas occurred in 11 patients (1.9%), and postoperative empyema was seen in 13 patients (2.3%).

Table 3 . Perioperative outcomes.

OutcomesTotalThe extent of surgical resectionp-value

Limited resectionLobectomyBilobectomyPneumonectomy
30-Day mortality8 (1.4)03 (0.7)1 (1.8)4 (5.5)0.014
60-Day mortality25 (4.4)015 (3.4)2 (3.5)8 (11.0)0.031
90-Day mortality41 (7.1)023 (5.2)5 (8.8)13 (17.8)0.006
Length of stay (day)8 (7–11)7 (4.5–15.5)8 (7–11)9 (8–15)10 (8–12.5)<0.001
Morbidity199 (34.7)0137 (31.1)26 (45.6)36 (49.3)0.002

Values are presented as number (%) or median (interquartile range)..


Table 4 . Postoperative complications.

MorbidityTotalThe Clavien-Dindo classification of surgical complicationsa)

IIIIIIaIIIbIVV
Arrhythmia116 (20.2)116
Pneumonia32 (5.6)711914
Acute lung injury12 (2.1)534
Acute respiratory distress syndrome18 (3.1)18
Atelectasisb)10 (1.7)10
Bronchopleural fistula11 (1.9)1172
Empyema13 (2.3)211
Prolonged air leak35 (6.1)52712
Chylothorax8 (1.4)341
Vocal cord paralysis20 (3.5)812
Postop bleedingc)2 (0.3)2
Delirium12(2.1)12
Acute kidney injury3 (0.5)3
Pulmonary thromboembolism3 (0.5)12
Deep vein thrombosis1 (0.2)1
Pleural effusion4 (0.7)13
Hemoptysis2 (0.3)2
Hemorrhagic gastritis1 (0.2)1
Ileus1 (0.2)1
Total199 (34.7)

Values are presented as number (%) or number..

a)Clavien-Dindo classification: grade I: any deviation from the typical postoperative recovery that does not necessitate medication or medical procedures, including surgery, endoscopy, or radiology; grade II: needing medication for treatment, but not the same drugs used for grade I complications; grade III: requiring surgical, endoscopic, or radiological intervention; grade IIIa: intervention without the need for general anesthesia; grade IIIb: intervention that requires general anesthesia; grade IV: a complication that poses a life-threatening situation necessitating intensive care unit management; and grade V: death. b)Atelectasis requiring therapeutic bronchoscopy. c)Postoperative bleeding requiring re-operation..



In the univariate analysis using the predictors listed in Tables 1 and 2, several factors were identified as independent risk factors for postoperative morbidity. These factors included male sex, patient age over 70 years, non-adenocarcinoma histology, a history of smoking, a BMI below 18.5 kg/m2, and undergoing a pneumonectomy (Table 5). The multivariable analysis further confirmed that being over 70 years of age (odds ratio [OR], 1.82; p=0.040), having a BMI below 18.5 kg/m2 (OR, 2.62; p=0.022), and undergoing a pneumonectomy (OR, 1.8; p=0.026) were significant predictors of morbidity (Table 5).

Table 5 . Univariate and multivariate risk factor analyses for morbidity.

VariableNo. of patients (%)UnivariateMultivariate logistic regression analysis


p-valueOdds ratio (95% CI)p-value
Sex<0.0010.056
Male171 (38.5)1.70 (0.98–2.98)
Female28 (21.5)1
Age (yr)0.0370.040
≥7027 (47.4)1.82 (1.03–3.20)
<70172 (33.3)1
Cell type0.0030.140
Non-ADC104 (41.3)1.33 (0.91–1.94)
ADC95 (29.5)1
Smoking0.0060.382
Ever smoker133 (39.2)1.21 (0.79–1.84)
Never smoker66 (28.1)1
Body mass index (kg/m2)0.0260.022
<18.514 (56.0)2.63 (1.15–6.15)
≥18.5185 (33.7)1
Extent of surgery0.0020.026
Pneumonectomy36 (49.3)1.8 (1.07–3.00)
Non-pneumonectomy163 (32.5)1

Statistically significant results are marked in bold..

CI, confidence interval; ADC, adenocarcinoma..



Similarly, in the univariate analysis (Table 6), significant risk factors for postoperative mortality included male gender, patient age over 70 years, a history of smoking, an interval of more than 5 weeks between the completion of CCRT and surgery, and undergoing a pneumonectomy. The subsequent multivariate analysis revealed that being over the age of 70 (OR, 1.82; p=0.022) and undergoing a pneumonectomy (OR, 3.256; p=0.003) were independently associated with an increased risk of mortality within 90 days following surgery (Table 6).

Table 6 . Univariate and multivariate risk factor analyses for perioperative mortality(within 90 days).

VariableNo. of patients (%)UnivariateMultivariate logistic regression analysis



p-valueOdds ratio (95% CI)p-value
Sex<0.001
Male41 (9.23)-
Female0-
Age (yr)0.0370.019
≥709 (15.8)1.82 (1.21–6.43)
<7032 (6.2)1
Smoking0.0060.100
Ever smoker30 (8.9)1.81 (0.90–3.91)
Never smoker11 (4.7)1
Time interval (wk)a)0.0060.085
≥523 (10.6)1.80 (0.92–3.56)
<518 (5.2)1
Extent of surgery0.0020.003
Pneumonectomy13 (17.8)3.25 (1.50–6.78)
Non-pneumonectomy28 (5.6)1

Statistically significant results are marked in bold..

CI, confidence interval; ADC, adenocarcinoma..

a)Time interval refers to the time period between the end of neoadjuvant chemoradiation therapy and surgery..


Discussion

The impact of induction therapy on postoperative morbidity and mortality for patients with stage IIIa–N2 NSCLC undergoing major pulmonary resection has been a subject of debate. Some studies have suggested that induction therapy may increase the risk of morbidity and mortality following surgery [7,8]. It is logical to expect that neoadjuvant chemoradiation therapy could affect the likelihood of postoperative complications and death. Consequently, it is crucial to carefully select patients for surgery who are likely to achieve complete resection with minimal morbidity and mortality following induction chemoradiation therapy. Typically, the most significant risk factors for perioperative morbidity and mortality include age, pulmonary reserve, cardiovascular disease, respiratory infection, arrhythmia, renal failure, and diabetes [9-11]. However, there is scant literature on the risk factors associated with morbidity and mortality in surgical treatment for patients with stage IIIa–N2 NSCLC after induction therapy.

Herein, we have reported the morbidity and mortality rates of patients who underwent major pulmonary resection following induction therapy for stage IIIA–N2 NSCLC. Our study evaluated various predictors of postoperative morbidity and mortality in a uniform cohort of patients who had significant pulmonary resections after induction therapy. Notably, being over the age of 70 years was also identified as a risk factor for increased morbidity and mortality. Chronological age is widely recognized as a significant risk factor for elderly patients undergoing surgical procedures. The authors of this study believe that individuals aged 70 years or older have reduced cardiopulmonary reserve, which places them in the category of the elderly population undergoing lung resection. According to Birim et al. [12], advancing age was a significant prognostic factor for long-term outcomes, along with other indices such as the Charlson comorbidity index. It is suggested that patients aged 70 years or older be considered elderly in medical evaluations, as this age threshold typically marks the beginning of numerous age-related adverse changes [13]. The adoption of the Comprehensive Geriatric Assessment (CGA) for evaluating elderly cancer patients [14,15] aims to identify those who are robust and more likely to benefit from standard cancer treatment, as opposed to those who are vulnerable and require personalized surgery or chemotherapy regimens, or those who are frail and are suitable for supportive care only [16]. However, there is an ongoing debate about the actual impact of the CGA on treatment decision-making in clinical settings, due to its time-consuming, burdensome, and non-standardized nature [17].

Another risk factor identified for adverse outcomes following trimodal therapy is pneumonectomy. Among pulmonary resections, pneumonectomy is associated with the highest rates of morbidity and mortality of all elective thoracic surgical procedures. Furthermore, the mortality rate after pneumonectomy without neoadjuvant therapy has been reported to range from 1.6% to 13.4% [18,19]. Some authors have suggested that pneumonectomy should be considered a distinct disease entity due to its significant impact on cardiorespiratory physiology and consequent reduction in overall survival [20]. Therefore, pneumonectomy with neoadjuvant therapy is regarded as a major procedure with high mortality rates and should be only performed by experienced surgeons [21]. In the Intergroup Study (INT) 0139, 429 patients with stage IIIA–N2 disease were randomized after receiving 2 cycles of cisplatin/etoposide and concomitant radiotherapy (45 Gy), followed by either surgical resection or 2 additional cycles of chemotherapy [22]. A 30-day mortality rate of 25.9% was observed in patients who underwent pneumonectomy in the INT 0139 trial. Our data indicate that the 30-day and 90-day mortality rates for pneumonectomy after neoadjuvant therapy were 5.5% and 17.8%, respectively. Clearly, the operative mortality is significantly high. Consequently, we advocate for every effort to be made to avoid pneumonectomy, such as opting for sleeve lobectomy whenever feasible.

The role of nutrition in predicting the outcome of operations for lung cancer is also of growing interest. We identified the underweight BMI category as a potential risk factor for postoperative morbidity. The detrimental impact of malnutrition has been recently emphasized, especially for pneumonectomy [23]. Furthermore, research by Thomas et al. [24] has shown that underweight patients are significantly more likely to suffer from pulmonary, surgical, and infectious complications. In this study, prolonged air leaks and bronchial stump dehiscence were significantly more frequent in underweight patients than in patients with a normal BMI, but obesity was not associated with an increased incidence of postoperative complications.

Regarding morbidity, studies have reported postoperative complication rates of approximately 30%, irrespective of whether patients received induction therapy [11,25,26]. Arrhythmia is the most frequently reported complication in these studies. Our morbidity rate was 34.7%, aligning with the rates found in prior research.

The primary focus after surgery is to prevent morbidity and mortality. Careful patient selection, informed by comprehensive preoperative assessments, can reduce the risk of postoperative complications. In thoracic oncology, it is important to create personalized treatment plans based on detailed risk analysis to prevent postoperative issues. However, despite meticulous patient selection, postoperative complications can still occur. Experienced thoracic surgeons and intensive care specialists should manage these complications. Over the past 2 decades, our group has developed a multidisciplinary approach for patients with stage IIIA–N2 NSCLC, addressing preoperative and postoperative management, including complications. This approach is based on our experience with nearly 600 patients who underwent surgery following induction therapy. Consequently, our group continues to endorse trimodal therapy as the most effective treatment for stage IIIA–N2 NSCLC, except when preoperative radiologic findings indicate that complete tumor resection is unlikely.

This study had several limitations. First, it utilized a retrospective design. Additionally, the research included a diverse patient cohort, with variability in histologic subtypes and the prevalence of bulky N2 disease. This diversity could have affected the outcomes of surgical interventions following induction therapy. Moreover, the study covered a period of nearly 16 years, potentially leading to inconsistencies in outcomes due to changes in chemotherapy and radiotherapy practices over this time. Specifically, the extended duration of the study may have introduced unmeasured bias into our results.

In conclusion, the surgical outcomes following neoadjuvant CCRT are less favorable for individuals over the age of 70 years or for those undergoing pneumonectomy. These patients require special attention due to an increased risk of respiratory complications. For high-risk patients, particularly older individuals with diminished lung function, alternative treatment options such as definitive CCRT may be preferable to surgical resection.

Article information

Author contributions

Conceptualization: JHC. Data curation: JL, GHJ. Formal analysis: JHC. Funding acquisition: JHC. Methodology: YJJ, SYP. Project administration: JHC. JL, YJJ, SYP. Visualization: JK, GHJ. Writing–original draft: GHJ, JHC. Writing–review & editing: YSC, YMS, JHC, GHJ. Final approval of the manuscript: all authors.

Conflict of interest

Seong Yong Park is an associate editor, Junghee Lee is an editorial board member, and Hong Kwan Kim was an associate editor of the journal during the submission of this article. They were not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflict of interest relevant to this article was reported.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Fig 1.

Figure 1.The extent of surgery after neoadjuvant chemoradiotherapy.
Journal of Chest Surgery 2024; 57: 351-359https://doi.org/10.5090/jcs.23.165

Table 1 . Patients’ demographics.

CharacteristicValue
Age (yr)60 (23–76)
Male444 (77.4)
Body mass index (kg/m2)23.5 (15.4–46.0)
ECOG performance status
0566 (98.6)
18 (1.4)
20
30
40
Chronic obstructive pulmonary disease18 (3.1)
Smoking status
Ever smoker339 (59.1)
Never smoker235(40.9)
Cerebrovascular accident15 (2.6)
Coronary artery disease3 (0.5)
Hypertension163 (28.4)
Diabetes67 (11.7)
FEV1 %93.0±18.6
FEV1/FVC%71.1±9.8
DLCO% (N=282)a)89.9±20.3

Values are presented as median (interquartile range), number (%), or mean±standard deviation..

ECOG, Eastern Cooperative Oncology Group; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; DLCO, diffusing capacity of the lungs for carbon monoxide..

a)292 (50.9%) did not undergo a preoperative DLCO test..


Table 2 . Perioperative characteristics.

CharacteristicValue
Tumor histologic type
Adenocarcinoma322 (56.1)
Squamous cell carcinoma210 (36.6)
Large cell carcinoma12 (2.3)
NSCLC, NOS29 (5.1)
Time interval between CCRT and operation (day)33 (5–79)
Histologic confirmation of N2505 (88.0)
Mediastinoscopy341
EBUS-TBNA146
VATS19
Chamberlain10
Clinical T staging
cT1128 (22.3)
cT2386 (67.2)
cT360 (10.4)
Type of resection
Wedge resection3 (0.5)
Segmentectomy1 (0.2)
Lobectomy440 (76.7)
Bilobectomy57 (9.9)
Pneumonectomy73 (12.7)
Surgical approach
Thoracotomy555 (96.7)
VATS19 (3.3)
Completeness of resection
R0 resection543 (95)
R1/R2 resection31 (5.4)

Values are presented as number (%) or median (interquartile range)..

NSCLC, non-small-cell lung cancer; NOS, not otherwise specified; CCRT, concurrent chemoradiotherapy; EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration; VATS, video-assisted thoracoscopic surgery..


Table 3 . Perioperative outcomes.

OutcomesTotalThe extent of surgical resectionp-value

Limited resectionLobectomyBilobectomyPneumonectomy
30-Day mortality8 (1.4)03 (0.7)1 (1.8)4 (5.5)0.014
60-Day mortality25 (4.4)015 (3.4)2 (3.5)8 (11.0)0.031
90-Day mortality41 (7.1)023 (5.2)5 (8.8)13 (17.8)0.006
Length of stay (day)8 (7–11)7 (4.5–15.5)8 (7–11)9 (8–15)10 (8–12.5)<0.001
Morbidity199 (34.7)0137 (31.1)26 (45.6)36 (49.3)0.002

Values are presented as number (%) or median (interquartile range)..


Table 4 . Postoperative complications.

MorbidityTotalThe Clavien-Dindo classification of surgical complicationsa)

IIIIIIaIIIbIVV
Arrhythmia116 (20.2)116
Pneumonia32 (5.6)711914
Acute lung injury12 (2.1)534
Acute respiratory distress syndrome18 (3.1)18
Atelectasisb)10 (1.7)10
Bronchopleural fistula11 (1.9)1172
Empyema13 (2.3)211
Prolonged air leak35 (6.1)52712
Chylothorax8 (1.4)341
Vocal cord paralysis20 (3.5)812
Postop bleedingc)2 (0.3)2
Delirium12(2.1)12
Acute kidney injury3 (0.5)3
Pulmonary thromboembolism3 (0.5)12
Deep vein thrombosis1 (0.2)1
Pleural effusion4 (0.7)13
Hemoptysis2 (0.3)2
Hemorrhagic gastritis1 (0.2)1
Ileus1 (0.2)1
Total199 (34.7)

Values are presented as number (%) or number..

a)Clavien-Dindo classification: grade I: any deviation from the typical postoperative recovery that does not necessitate medication or medical procedures, including surgery, endoscopy, or radiology; grade II: needing medication for treatment, but not the same drugs used for grade I complications; grade III: requiring surgical, endoscopic, or radiological intervention; grade IIIa: intervention without the need for general anesthesia; grade IIIb: intervention that requires general anesthesia; grade IV: a complication that poses a life-threatening situation necessitating intensive care unit management; and grade V: death. b)Atelectasis requiring therapeutic bronchoscopy. c)Postoperative bleeding requiring re-operation..


Table 5 . Univariate and multivariate risk factor analyses for morbidity.

VariableNo. of patients (%)UnivariateMultivariate logistic regression analysis


p-valueOdds ratio (95% CI)p-value
Sex<0.0010.056
Male171 (38.5)1.70 (0.98–2.98)
Female28 (21.5)1
Age (yr)0.0370.040
≥7027 (47.4)1.82 (1.03–3.20)
<70172 (33.3)1
Cell type0.0030.140
Non-ADC104 (41.3)1.33 (0.91–1.94)
ADC95 (29.5)1
Smoking0.0060.382
Ever smoker133 (39.2)1.21 (0.79–1.84)
Never smoker66 (28.1)1
Body mass index (kg/m2)0.0260.022
<18.514 (56.0)2.63 (1.15–6.15)
≥18.5185 (33.7)1
Extent of surgery0.0020.026
Pneumonectomy36 (49.3)1.8 (1.07–3.00)
Non-pneumonectomy163 (32.5)1

Statistically significant results are marked in bold..

CI, confidence interval; ADC, adenocarcinoma..


Table 6 . Univariate and multivariate risk factor analyses for perioperative mortality(within 90 days).

VariableNo. of patients (%)UnivariateMultivariate logistic regression analysis



p-valueOdds ratio (95% CI)p-value
Sex<0.001
Male41 (9.23)-
Female0-
Age (yr)0.0370.019
≥709 (15.8)1.82 (1.21–6.43)
<7032 (6.2)1
Smoking0.0060.100
Ever smoker30 (8.9)1.81 (0.90–3.91)
Never smoker11 (4.7)1
Time interval (wk)a)0.0060.085
≥523 (10.6)1.80 (0.92–3.56)
<518 (5.2)1
Extent of surgery0.0020.003
Pneumonectomy13 (17.8)3.25 (1.50–6.78)
Non-pneumonectomy28 (5.6)1

Statistically significant results are marked in bold..

CI, confidence interval; ADC, adenocarcinoma..

a)Time interval refers to the time period between the end of neoadjuvant chemoradiation therapy and surgery..


References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11-30. https://doi.org/10.3322/caac.21166.
    Pubmed CrossRef
  2. Rosell R, Gomez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 1994;330:153-8. https://doi.org/10.1056/NEJM199401203300301.
    Pubmed CrossRef
  3. Ahn YC, Park K, Kim DY, et al. Preoperative concurrent chemoradiotherapy for stage IIIA non-small cell lung cancer. Acta Oncol 2001;40:588-92. https://doi.org/10.1080/028418601750444123.
    Pubmed CrossRef
  4. Kang MK, Ahn YC, Lim DH, et al. Preoperative concurrent radiochemotherapy and surgery for stage IIIA non-small cell lung cancer. J Korean Med Sci 2006;21:229-35. https://doi.org/10.3346/jkms.2006.21.2.229.
    Pubmed KoreaMed CrossRef
  5. Kim KJ, Ahn YC, Lim DH, et al. Analyses on prognostic factors following tri-modality therapy for stage IIIa non-small cell lung cancer. Lung Cancer 2007;55:329-36. https://doi.org/10.1016/j.lungcan.2006.10.024.
    Pubmed CrossRef
  6. Lee H, Ahn YC, Pyo H, et al. Pretreatment clinical mediastinal nodal bulk and extent do not influence survival in N2-positive stage IIIA non-small cell lung cancer patients treated with trimodality therapy. Ann Surg Oncol 2014;21:2083-90. https://doi.org/10.1245/s10434-014-3540-x.
    Pubmed CrossRef
  7. Doddoli C, Thomas P, Thirion X, Seree Y, Giudicelli R, Fuentes P. Postoperative complications in relation with induction therapy for lung cancer. Eur J Cardiothorac Surg 2001;20:385-90. https://doi.org/10.1016/s1010-7940(01)00764-3.
    Pubmed CrossRef
  8. Roberts JR, Eustis C, Devore R, Carbone D, Choy H, Johnson D. Induction chemotherapy increases perioperative complications in patients undergoing resection for non-small cell lung cancer. Ann Thorac Surg 2001;72:885-8. https://doi.org/10.1016/s0003-4975(01)02836-3.
    Pubmed CrossRef
  9. Patel RL, Townsend ER, Fountain SW. Elective pneumonectomy: factors associated with morbidity and operative mortality. Ann Thorac Surg 1992;54:84-8. https://doi.org/10.1016/0003-4975(92)91145-y.
    Pubmed CrossRef
  10. Wada H, Nakamura T, Nakamoto K, Maeda M, Watanabe Y. Thirty-day operative mortality for thoracotomy in lung cancer. J Thorac Cardiovasc Surg 1998;115:70-3. https://doi.org/10.1016/s0022-5223(98)70444-1.
    Pubmed CrossRef
  11. Duque JL, Ramos G, Castrodeza J, et al. Early complications in surgical treatment of lung cancer: a prospective, multicenter study. Grupo Cooperativo de Carcinoma Broncogenico de la Sociedad Espanola de Neumología y Cirugia Toracica. Ann Thorac Surg 1997;63:944-50. https://doi.org/10.1016/s0003-4975(97)00051-9.
    Pubmed CrossRef
  12. Birim O, Kappetein AP, Bogers AJ. Charlson comorbidity index as a predictor of long-term outcome after surgery for nonsmall cell lung cancer. Eur J Cardiothorac Surg 2005;28:759-62. https://doi.org/10.1016/j.ejcts.2005.06.046.
    Pubmed CrossRef
  13. Balducci L. ESH-SIOG International Conference on Haematological Malignancies in the Elderly. Expert Rev Hematol 2010;3:675-7. https://doi.org/10.1586/ehm.10.72.
    Pubmed CrossRef
  14. Extermann M, Hurria A. Comprehensive geriatric assessment for older patients with cancer. J Clin Oncol 2007;25:1824-31. https://doi.org/10.1200/JCO.2007.10.6559.
    Pubmed CrossRef
  15. Extermann M. Integrating a geriatric evaluation in the clinical setting. Semin Radiat Oncol 2012;22:272-6. https://doi.org/10.1016/j.semradonc.2012.05.003.
    Pubmed CrossRef
  16. Wedding U, Kodding D, Pientka L, Steinmetz HT, Schmitz S. Physicians' judgement and comprehensive geriatric assessment (CGA) select different patients as fit for chemotherapy. Crit Rev Oncol Hematol 2007;64:1-9. https://doi.org/10.1016/j.critrevonc.2007.05.001.
    Pubmed CrossRef
  17. Puts MT, Hardt J, Monette J, Girre V, Springall E, Alibhai SM. Use of geriatric assessment for older adults in the oncology setting: a systematic review. J Natl Cancer Inst 2012;104:1133-63. https://doi.org/10.1093/jnci/djs285.
    Pubmed KoreaMed CrossRef
  18. Licker M, Spiliopoulos A, Frey JG, et al. Risk factors for early mortality and major complications following pneumonectomy for non-small cell carcinoma of the lung. Chest 2002;121:1890-7. https://doi.org/10.1378/chest.121.6.1890.
    Pubmed CrossRef
  19. Van Raemdonck DE, Schneider A, Ginsberg RJ. Surgical treatment for higher stage non-small cell lung cancer. Ann Thorac Surg 1992;54:999-1013. https://doi.org/10.1016/0003-4975(92)90677-v.
    Pubmed CrossRef
  20. Mansour Z, Kochetkova EA, Santelmo N, et al. Risk factors for early mortality and morbidity after pneumonectomy: a reappraisal. Ann Thorac Surg 2009;88:1737-43. https://doi.org/10.1016/j.athoracsur.2009.07.016.
    Pubmed CrossRef
  21. Romano PS, Mark DH. Patient and hospital characteristics related to in-hospital mortality after lung cancer resection. Chest 1992;101:1332-7. https://doi.org/10.1378/chest.101.5.1332.
    Pubmed CrossRef
  22. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379-86. https://doi.org/10.1016/S0140-6736(09)60737-6.
    Pubmed CrossRef
  23. Bagan P, Berna P, De Dominicis F, et al. Nutritional status and postoperative outcome after pneumonectomy for lung cancer. Ann Thorac Surg 2013;95:392-6. https://doi.org/10.1016/j.athoracsur.2012.06.023.
    Pubmed CrossRef
  24. Thomas PA, Berbis J, Falcoz PE, et al. National perioperative outcomes of pulmonary lobectomy for cancer: the influence of nutritional status. Eur J Cardiothorac Surg 2014;45:652-9. https://doi.org/10.1093/ejcts/ezt452.
    Pubmed CrossRef
  25. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995;13:1880-92. https://doi.org/10.1200/JCO.1995.13.8.1880.
    Pubmed CrossRef
  26. Deslauriers J, Ginsberg RJ, Piantadosi S, Fournier B. Prospective assessment of 30-day operative morbidity for surgical resections in lung cancer. Chest 1994;106(6 Suppl):329S-330S. https://doi.org/10.1378/chest.106.6_supplement.329s.
    Pubmed CrossRef

Stats or Metrics

Share this article on :

  • line