| Background:Lung Cancer is one of the most leading causes of cancer – related deaths globally,and meanwhile,non-small cell lung cancer(NSCLC),which accounts for approximately > 80% of all the patients diagnosed with lung tumors,remains the leading malignancy – related incidence and mortality in China.Nowadays,surgical resection is still widely accepted as the most preferred therapeutic option for resectable stage I-II NSCLC,and plays a crucial role in the multidisciplinary treatments for locally advanced NSCLC.In recent years,video-assisted thoracoscopic surgery(VATS)has emerged as a novel minimally invasive surgical technique and gained a dramatic progress.Traditional thoracotomy has been increasingly replaced by VATS in the clinical practice across many countries and regions.Anatomical lobectomy with systemic mediastinal lymph node dissection(SMLND)via VATS procedure has been increasingly utilized as a standard surgical treatment for NSCLC.Despite advances in medical equipment,surgical technique and perioperative care,the in-hospital outcomes following radical surgery for resectable stage I-II NSCLC still remains a large area of improvement,and the survival outcomes of a series of high-risk patients are still frustrating.Therefore,it will be extremely critical for thoracic surgeons and their multidisciplinary teams to precisely identify the high-risk patients who may suffer from unfavorable prognosis and further build an individualized treatment plan in advance through establishing simplified,effective and safe risk scoring systems according to an in-depth understanding of putative prognostic risk factors,such as lymph node metastasis with other most common pathologic parameters,smoking status,cardiopulmonary comorbidity,stress response to surgical injury and perioperative major morbidity.In 2007,Gawande et al.carried out a retrospective analysis on the clinical data of patients who had undergone open colectomy from the database of American College of Surgeons’ National Surgical Quality Improvement Program(ACS-NSQIP),and further found that both of two intraoperative hemodynamic indicators,the lowest mean arterial pressure and the lowest heart beat,and intraoperative blood loss held independently predictive roles for postoperative major morbidity and in-hospital mortality after multivariable Logistic regression analyses.On the basis of the above three intraoperative parameters,Gawande et al.created a novel risk scoring system ranged 0-10 points for estimating surgical outcomes,and finally named it the Surgical Apgar Score(SAS).Subsequently,there were a number of researchers who aimed to apply the SAS in minimally invasive surgery further modified the scoring criteria regarding intraoperative blood loss by using the median with interquartile range(IQR)of each study cohort,and then,named it the modified SAS(mSAS).In recent years,the predictive significance of SAS(mSAS)for risk of postoperative complications has been reported in a variety of surgical oncology specialties,and played as an independent prognostic indicator in the surgical populations with gastric and esophageal carcinomas.However,there is no study yet investigated the clinical significance of SAS in surgical resections for NSCLC,and the predictive value of SAS for perioperative and prognostic outcomes of resectable NSCLC still remains unclear.The present study firstly proposed a novel Thoracoscopic Lobectomy Surgical Apgar Score(TL-SAS)through modifying the SAS(mSAS)scoring system according to the real-world practice of minimally invasive surgery for NSCLC and relevant study strategies in the other surgical oncology specialties,and then,further evaluated the feasibility and efficacy of TL-SAS for postoperative risk assessment in patients undergoing VATS lobectomy with SMLND for resectable stage I-II NSCLC.Our findings revealed that TL-SAS could serve as an independent predictor for risk of postoperative complications and unfavorable overall survival(OS)following VATS lobectomy,and meanwhile,play an adjunctive role to determine clinical risk stratification within in-hospital and follow-up periods.Our research team further synthesized the TL-SAS with other clinicopathologic variables with predictive significance,and thus,created the new TL-SAS-based Thoracoscopic Lobectomy Morbidity Score(SAS-TLMS)and TL-SAS-based Thoracoscopic Lobectomy Prognosis Score(SAS-TLPS).Finally,the SAS-TLMS and the SAS-TLPS,when employed to predict postoperative morbidity and OS respectively,were both validated as excellent clinical risk prediction tools with prominent accuracy,feasibility and stability,and further helped to clinical decision making.Chapter Ⅰ Feasibility and efficacy of Surgical Apgar Score for risk assessment of morbidity and prognosis following VATS lobectomy for resectable lung cancerObjectives:To investigate the clinical significance of TL-SAS scoring system in VATS lobectomy for resectable stage I-II NSCLC.To estimate the feasibility and efficacy of TL-SAS for predicting the occurrence of postoperative complications,length of stay(LOS)and OS outcomes following VATS lobectomy.Materials and Methods:1.Study design: The present study is a retrospective analysis based on the cohort of pateints who had undergone VATS lobectomy with SMLND for resectable stage I-II NSCLC at one research team in Department of Thoracic Surgery,Sichuan University West China Hospital from June 2015 to January 2017.2.Patient characteristics: The clinicopathologic characteristics and outcome endpoints were in compliance with the STS-ESTS joint standardization of variable definition and terminology guidelines.Moreover,according to the Clavien-Dindo surgical complication classification system,overall morbidity was further categorized into minor morbidity(Grade I-II)and major morbidity(Grade III-IV).The terminal follow-up date was updated to September 2020.3.TL-SAS scoring criteria: After applying the median(100 mL)with IQR(70-150 mL)of intraoperative blood loss to modify the point assignment within the original Gawande’s SAS,the newly established TL-SAS is listed as follows:3.1.Intraoperative blood loss: > 150 mL with 0 point,101-150 mL with 1 point,71-100 mL with 2 points,≤ 70 mL with 3 points;3.2.Intraoperative lowest MAP: < 40 mm Hg with 0 point,40-54 mm Hg with 1 point,55-69 mm Hg with 2 points,≥ 70 mm Hg with 3 points;3.3.Intraoperative lowest heart beat: > 85 bpm with 0 point,76-85 bpm with 1 point,66 – 75 bpm with 2 points,56 – 65 bpm with 3 points,≤ 55 bpm with 4 points;3.4.TL-SAS accounts for total points of the above three evaluating parameters.4.Grouping criteria: Receiver operating characteristic(ROC)curve analysis was conducted to determine the Youden index of each TL-SAS with regard to risk prediction of overall morbidity.Moreover,a simple bioinformatic analysis through X-Tile software determined the optimal cut-off value of TL-SAS with regard to prognostic prediction for postoperative OS.A common threshold value of TL-SAS was determined according to the maximal Youden index and X-tile bioinformatic analysis.Patients with TL-SAS ≥ this threshold value belong to the low-risk group,and patients with TL-SAS < this threshold value belong to the high-risk group.5.Statistical analysis: The present study was in compliance with the statistical and data reporting guidelines from the European Association for Cardio-Thoracic Surgery(EACTS).5.1.Dichotomous variables were analyzed by Pearson chi-squared test,Yates correction for continuity,or Fisher’s exact test.Continuous variables were analyzed by Mann-Whitney U test.Survival data were analyzed by Kaplan-Meier survival curve using Log-rank test.5.2.Conventional and time-dependent ROC analyses were utilized to evaluate the predictive value of TL-SAS for occurrence of postoperative complications and OS following VATS lobectomy,respectively.And then,the corresponding area under curve(AUC)was obtained.5.3.The predictive significance of each estimated covariate for risk of postoperative complications was determined by odds ratio(OR)with its 95% confidence interval(CI)derived from binary Logistic regression models after their goodness-of-fit got confirmed by Hosmer-Lemeshow test.The prognostic significance of each estimated covariate for postoperative OS was determined by hazards ratio(HR)with its 95% CI derived from Cox proportional hazard(Cox PH)regression models after validating by-2 log likelihood value and Omnibus likelihood ratio test.Finally,the Harrell’s concordance index(i.e.C-Statistic)was employed to determine predictive roles of both multivariable binary Logistic regression models and multivariable Cox PH regression models.5.4.Nomograms with the aim to visually express both multivariable binary Logistic regression models and multivariable Cox PH regression models were provided,and then,their Calibration curves were applied to verify the accuracy of Nomogram-predicted surgical outcomes by comparing with real-world surgical outcomes.5.5.An analytical cohort of which all patient characteristics were well-matched or not significantly different between TL-SAS groups was extracted according to propensity score matching(PSM)analysis.The correlations between TL-SAS and surgical outcomes were further validated in the PSM analytical cohort.Results:1.The present study included a total of 437 eligible patients who had undergone VATS lobectomy with SMLND for resectable stage I-II NSCLC at our research team from June 2015 to January 2017.The rates of overall morbidity,minor morbidity and major morbidity of the present cohort was 28.1%,25.6% and 8.9%,respectively.No patient dead within the in-hospital period.Until the terminal follow-up date,the median OS time lasted 50 months and the OS rate was 82.4%.2.The TL-SAS ranged 2-10 points in this study,the overall morbidity rate of patients with TL-SAS of 2-5 was significantly higher than that of patients with TL-SAS of 6-10(P < 0.001).Meanwhile,the LOS(P = 0.011)and the length of chest tube drainage(P = 0.007)significantly differed across all the TL-SASs.There was a strong linkage between TL-SAS and postoperative OS,an increasing TL-SAS was found to be significantly associated with a longer mean OS and a higher OS rate(Log-Rank P < 0.001).3.Conventional ROC analysis indicated that TL-SAS held a statistically significant discriminatory capacity for occurrence of overall morbidity(AUC: 0.58;95% CI: 0.52 – 0.64;P = 0.010),with an AUC higher than those regarding intraoperative blood loss,intraoperative lowest MAP and intraoperative lowest heart beat for predicting the occurrence of postoperative complications.Moreover,the predictive power of TL-SAS for both risks of minor morbidity(AUC: 0.58;95% CI: 0.52 – 0.65;P = 0.008)and major morbidity(AUC: 0.62;95% CI: 0.53 – 0.71;P = 0.015)still remained statistically significant.4.Time-dependent ROC analysis indicated that the AUCs regarding TL-SAS for the prediction of OS among the follow-up period,which fluctuated between 0.74 and 0.99,always remained statistically significant and higher than those regarding intraoperative blood loss,intraoperative lowest MAP and intraoperative lowest heart beat for predicting OS among the follow-up period.5.Youden index and X-Tile bioinformatic analysis both demonstrated that there would be the most significant difference in overall morbidity rate and OS between groups when setting up TL-SAS = 6 as the grouping criterion,revealing the most effective clinical risk stratification.Patients in TL-SAS < 6 group had significantly higher rates of overall morbidity(39.3% vs.24.3%;P = 0.002),minor morbidity(35.7% vs.22.2%;P = 0.005)and major morbidity(14.3% vs.7.1%;P = 0.021)than those of patients in TL-SAS ≥ 6 group.Both the LOS(P = 0.001)and the length of chest tube drainage(P < 0.001)in TL-SAS < 6 group were significantly prolonged when compared with those in TL-SAS ≥ 6 group,but no significant difference was thus observed in air leak duration between TL-SAS groups(P = 0.092).Moreover,when compared with patients in TL-SAS ≥ 6 group,patients in TL-SAS < 6 group had a significantly shorter mean OS time,lower OS rate and increased cumulative hazards for death during the follow-up period(Log-Rank P < 0.001).6.Multivariable binary Logistic regression analysis and multivariable Cox PH regression analysis commonly demonstrated that TL-SAS < 6 could not only be an independent risk factor for overall morbidity(OR: 1.90;95% CI: 1.14 – 3.16;P =0.013),but also act as an independent prognostic factor for postoperative OS(HR: 3.66;95% CI: 2.22 – 6.04;P < 0.001).Furthermore,the nomograms plotted on TL-SAS-involved binary Logistic and Cox PH regression models presented statistical significance for predicting overall morbidity and OS,respectively.7.Finally,PSM process extracted totally 76 pairs of patients with well-matched clinicopathologic characteristics between TL-SAS groups.Derivations from the PSM analytical cohort were exactly the same as those from the entire cohort.Conclusions:TL-SAS cannot only serve as an independent risk factor for postoperative complications but also perform as an independent prognostic indicator for postoperative OS in patients undergoing VATS lobectomy with SMLND for resectable stage I-II NSCLC.TL-SAS can be regarded as a simplified,feasible and objective scoring system with respect to risk stratification for overall morbidity and OS following VATS lobectomy.Chapter Ⅱ Feasibility and efficacy of newly established risk assessment models based on TL-SAS in patients undergoing VATS lobectomy for resectable lung cancerObjectives:According to the EACTS statistical guidelines,a risk assessment model will be generally considered to be clinically useful when its AUC for outcome prediction ≥ 0.70,and meanwhile,will be considered to be excellent when its AUC for outcome prediction ≥ 0.80.Therefore,according to the Chapter I,we realized that the clinical risk evaluation according to TL-SAS still remained a large area of improvement.The present study aimed to synthesize the morbidity predictors and OS prognostic parameters identified from multivariable regression models,establish novel TL-SAS-based risk assessment models in patients undergoing VATS lobectomy for resectable NSCLC,and improve their accuracy and reliability for the prediction of postoperative morbidity and prognosis in the real – world practice.Materials and Methods:1.According to the analytical stratigies on grouping criteria in the Chapter I,we identified intraoperative fluid transfusion = 1200 mL as the optimal cut-off value with regard to risk stratification of overall morbidity,and further incorporated it into the newly established TL-SAS-based thoracoscopic lobectomy morbidity score(SAS-TLMS).Similarly,intraoperative fluid transfusion = 1000 mL was found to be the optimal cut-off value with regard to risk stratification of postoperative OS,and further incorporated into the newly established TL-SAS-based thoracoscopic lobectomy prognosis score(SAS-TLPS).2.The scoring criteria for all dichotomous variables included in the new multivariable regression models were determined according to their β values and Wald weight values:2.1.Point assignment in SAS-TLMS: intraoperative fluid transfusion ≥ 1200 mL with 3 points,< 1200 mL with 0 point;TL-SAS < 6 with 1 point,≥ 6 with 0 point;present diabetes with 1 point,absent diabetes with 0 point;present chronic obstructive pulmonary disease(COPD)with 1 point,absent COPD with 0 point;SAS-TLMS accounts for total points of the above four evaluating parameters,with a range of 0-6 points.2.2.Point assignment in SAS-TLPS: TL-SAS < 6 with 4 points,≥ 6 with 0 point;lymph node metastasis N1 stage with 3 points,N0 stage with 0 point;current & former smoking status with 2 points,no smoking status with 0 point;intraoperative fluid transfusion ≥ 1000 mL with 1 point,< 1000 mL with 0 point;SAS-TLPS accounts for total points of the above four evaluating parameters,with a range of 0-10 points.3.Morbidity risk factor analysis including SAS-TLMS and prognostic biomarker analysis including SAS-TLPS were in compliance with the Chapter I.Results:1.The overall morbidity rate was significantly increased along with each point increase in SAS-TLMS,showing a step-wise fashion(P < 0.001).Meanwhile,the LOS(P < 0.001),length of chest tube drainage(P < 0.001)and air leak duration(P < 0.001)were all significantly prolonged along with each point increase in SASTLMS,showing a step-wise fashion.2.There was a strong linkage between SAS-TLPS and postoperative OS,an increasing SAS-TLPS was found to be significantly associated with a shorter mean OS and a lower OS rate(Log-Rank P < 0.001).3.Conventional ROC analysis indicated that SAS-TLMS was the only discriminatory indicator with clinical significance for predicting the occurrence of overall morbidity(AUC: 0.70;95% CI: 0.64 – 0.75;P < 0.001).Moreover,SAS-TLMS held a statistically significant predictive power for risk of minor morbidity(AUC: 0.67;95% CI: 0.61 – 0.73;P < 0.001),and could be clinically useful for predicting risk of major morbidity(AUC: 0.73;95% CI: 0.65 – 0.81;P < 0.001).4.Time-dependent ROC analysis indicated that the AUCs regarding SAS-TLPS for the prediction of OS during the follow-up period,which ranged between 0.81 and 0.93,always remained stable clinical significance(P < 0.001),especially for the prediction of OS during the > 20 months follow-up period(AUC: 0.81-0.90).5.According to the Youden index,there would be the most significant difference in rates of postoperative complications between groups when setting up SAS-TLMS = 2 as the grouping criterion,revealing the most effective morbidity risk stratification.Patients in SAS-TLMS ≥ 2 group had significantly higher rates of overall morbidity(42.6% vs.17.3%;P < 0.001),minor morbidity(38.3% vs.16.1%;P < 0.001)and major morbidity(16.0% vs.3.6%;P < 0.001)than those of patients in SAS-TLMS < 2 group.Furthermore,the incidences of prolonged air leak(P = 0.001),pneumonia(P < 0.001),atelectasis(P = 0.033)and chylothorax(P = 0.001)were significantly different between SAS-TLMS groups.The LOS(P < 0.001),length of chest tube drainage(P < 0.001)and air leak duration(P < 0.001)in SAS-TLMS ≥ 2 group were all significantly prolonged when compared with those in SAS-TLMS < 2 group.6.The X-Tile bioinformatic analysis demonstrated that there would be the most significant difference in postoperative OS between groups when setting up SASTLPS = 6 as the grouping criterion,revealing the most effective prognostic risk stratification.When compared with patients in SAS-TLPS < 6 group,patients in SAS-TLPS ≥ 6 group had a significantly shorter mean OS time,lower OS rate and increased cumulative hazards for death during the follow-up period(Log-Rank P < 0.001).7.Multivariable binary Logistic regression analysis demonstrated that each point increase in SAS-TLMS(OR: 1.43;95% CI: 1.25 – 1.65;P < 0.001)and SASTLMS ≥ 2(OR: 3.27;95% CI: 2.05 – 5.22;P < 0.001)were both strongly significant risk factors for overall morbidity.Furthermore,the nomogram plotted on SAS-TLMS-involved binary Logistic regression model presented statistical significance for predicting risk of postoperative complications.8.Multivariable Cox PH regression analysis demonstrated that both each point increase in SAS-TLPS(HR: 1.42;95% CI: 1.28 – 1.58;P < 0.001)and TL-SAS ≥ 6(HR: 4.86;95% CI: 2.70 – 8.78;P < 0.001)were only independent prognostic markers for postoperative OS with strong clinical significance.Furthermore,the nomogram plotted on SAS-TLPS-involved Cox PH regression model presented statistical significance for predicting postoperative OS.9.Finally,PSM process extracted 97 pairs of patients with well-matched clinicopathologic characteristics between SAS-TLMS groups(PSM analytical cohort A)and 66 pairs of patients with well-matched clinicopathologic characteristics between SAS-TLPS groups(PSM analytical cohort B).Derivations from the above PSM analytical cohorts were exactly the same as those from the entire cohort.Conclusions:SAS-TLMS and SAS-TLPS can be considered as highly accurate,strongly reliable and clinically useful risk assessment models for postoperative complications and OS in patients undergoing VATS lobectomy for resectable stage I-II NSCLC.Both SAS-TLMS and SAS-TLPS possess considerable usefulness to guide clinical decision making. |
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