Oleg Kshivets , MD, PhDSurgery Department, Kaluga Cancer Clinical Center, Russia

PRECISE PREDICTION OF 5-YEAR SURVIVAL OF LUNG CANCER PATIENTS AFTER RADICAL SURGERY

ABSTRACTPrecise Prediction of 5-Year Survival of Lung Cancer Patients after Radical SurgeryOleg Kshivets OBJECTIVE: This study aimed to determine homeostasis and tumor factors for 5-year survival (5YS) of non-small cell lung cancer (LC) patients (LCP) (T1-4N0-2M0) after complete en block (R0) lobectomies/pneumonectomies (LP).     METHODS: We analyzed data of 665 consecutive LCP (age=57.5±8.3 years; tumor size=4.4±2.4 cm) radically operated and monitored in 1985-2015 (m=575, f=90; lobectomies=423, pneumonectomies=242, combined LP with resection of trachea, carina, atrium, aorta, VCS, vena azygos, pericardium, liver, diaphragm, ribs, esophagus=180; only surgery-S=524, adjuvant chemoimmunoradiotherapy-AT=141: CAV/gemzar + cisplatin + thymalin/taktivin + radiotherapy 45-50Gy; T1=237, T2=248, T3=125, T4=55; N0=419, N1=130, N2=116, M0=665; G1=163, G2=199, G3=303; squamous=377, adenocarcinoma=243, large cell=45; early LC=132, invasive LC=533. Multivariate Cox modeling, clustering, SEPATH, Monte Carlo, bootstrap and neural networks computing were used to determine any significant dependence.    RESULTS: Overall life span (LS) was 2114.8±1685 days and cumulative 5YS reached 69.6%, 10 years – 61.2%, 20 years – 43.1%. 416 LCP lived more than 5 years without cancer (LS=3041.4±1472.5 days). 193 LCP died because of LC (LS=559.6±373.5 days). AT significantly improved 5YS (65.1% vs. 34.3%) (P=0.00001 by log-rank test) only for LCP with N1-2. Cox modeling displayed (Chi2=290.78, df=13, P=0.000) that 5YS of LCP significantly depended on: phase transition (PT)“early-invasive LC”, PT N0-N12, histology, G, blood cell subpopulations, cell ratio factors (ratio between blood cells subpopulations and cancer cells-CC), prothrombin index, heparin tolerance, recalcification time, glucose, AT (P=0.000-0.035). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT N0-N12 (rank=1), PT “early-invasive LC” (rank=2), lymphocytes (3), segmented neutrophils (4), tumor size (5), AT (6), T1-4 (7), ESS (8), prothrombin index (9), glucose (10), thrombocytes/CC (11), healthy cells/CC (12), lymphocytes/CC (13), erythrocytes/CC (14). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).    CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: tumor characteristics, blood cell circuit, cell ratio factors, hemostasis system and AT.

Data:Males………………………………………………….575Females………..………………………………….........90

Age=57.5±8.3 yearsTumor Size=4.4±2.4 cmOnly Surgery.………………………………………...524Adjuvant Chemoimmunoradiotherapy (CAV/gemzar+ cisplatin+thymalin/taktivin, 5-6 cycles+

Radiotherapy 45-50Gy)……………………………...141

Radical Procedures::Pneumonectomies (R0)……..………………………...242Lobectomies (R0)………….………………………….423Combined Pneumonectomies/Lobectomies with

Resection of Trachea, Carina, Atrium, Aorta, Vena Cava Superior, Vena Azygos, Diaphragm, Pericardium,

Esophagus, Liver, Ribs (R0)………………………....180N1 Lymph Node Dissection………………………..…132Mediastinal Lymph Node Dissection……………..….533

Staging:T1……237 N0..….419 G1…………163T2……248 N1…...130 G2…………199T3……125 N2…...116 G3…………303T4……..55 M0…..665Adenocarcinoma…………………………….243 Squamos Cell Carcinoma…………………...377 Large Cell Carcinoma.……………………….45Early Cancer…………………………………132Invasive Cancer……………………………...533

Survival Rate:Alive………………………………………....434 (65.3%)5-Year Survivors…………..………………...416 (62.6%) 10-Year Survivors…………………………...108 (16.2%)Losses………………………………………..193 (29%)General Life Span=2114.8±1685 daysFor 5-Year Survivors=3041.4±1472.5 daysFor 10-Year Survivors=5053.8±1477.2 daysFor Losses=559.6±373.5 daysCumulative 5-Year Survival………………..69.6%Cumulative 10-Year Survival………………61.2%Cumulative 20-Year Survival………………43.1%

General Lung Cancer Patients Survival after Complete Lobectomies/Pneumonectomies (Kaplan-Meier) (n=665):

Results of Univariate Analysis of Phase Transition Early—Invasive Cancer in Prediction of Lung Cancer Patients Survival (n=665)

Results of Univariate Analysis of Phase Transition N0—N1-2 in Prediction of Lung Cancer Patients Survival (n=665):

Results of Univariate Analysis of Adjuvant chemoimmunoradioTherapy in Prediction of Lung Cancer Patients Survival with N1-2 (n=246):

Results of Cox Regression Modeling in Prediction of Lung Cancer Patients Survival after Complete Lobectomies/Pneumonectomies (n=665):

Cox Proportional Hazard Results: Chi² = 290.777 df = 13 p = 0.0000; n=665

Factors: Parameter Estimate

Standard Error Chi² P 95%

Lower CL95%

Upper CLHazard Ratio

95% Hazard Ratio Lower CL

95% Hazard Ratio Upper CL

Histology 0.28729 0.088150 10.62140 0.001118 0.11451 0.460058 1.332806 1.121329 1.584165

G1-3 0.33416 0.090194 13.72639 0.000211 0.15738 0.510939 1.396769 1.170445 1.666855

Phase Transition Early-Invasive Cancer -1.30081 0.393540 10.92567 0.000948 -2.07213 -0.529483 0.272312 0.125917 0.588909

Adjuvant Chemoimmunoradiotherapy -1.00123 0.201243 24.75293 0.000001 -1.39566 -0.606803 0.367426 0.247669 0.545091

Phase Transition N0---N12 1.07094 0.148805 51.79528 0.000000 0.77928 1.362588 2.918108 2.179908 3.906291

Glucose -0.28464 0.081338 12.24633 0.000466 -0.44406 -0.125221 0.752285 0.641427 0.882302

Prothrombin Index 0.03035 0.006847 19.65302 0.000009 0.01693 0.043773 1.030819 1.017078 1.044746

Recalcification Time -0.00599 0.001786 11.24486 0.000798 -0.00949 -0.002488 0.994030 0.990557 0.997515

Heparin Tolerance 0.00366 0.000669 29.84859 0.000000 0.00234 0.004967 1.003662 1.002347 1.004979

Eosinophils/Cancer Cells -1.01650 0.430309 5.58024 0.018164 -1.85989 -0.173108 0.361860 0.155690 0.841046

Lymphocytes/Cancer Cells -0.17837 0.067674 6.94706 0.008396 -0.31101 -0.045732 0.836633 0.732707 0.955298

Erythrocytes tot -0.03776 0.017929 4.43498 0.035210 -0.07290 -0.002617 0.962947 0.929696 0.997386

Thrombocytes tot 0.00049 0.000192 6.45838 0.011043 0.00011 0.000863 1.000487 1.000111 1.000863

Results of Neural Networks Computing in Prediction of Lung Cancer Patients Survival after Complete Lobectomies/Pneumonectomies (n=609):

Factor Rank Sensitivity

Phase Transition N0---N12 1 4552

Phase Transition Early---Invasive Cancer 2 2430

Lymphocytes 3 2182

Segmented Neutrophils 4 2109

Tumor Size 5 1551

Adjuvant Chemoimmunoradiotherapy 6 1483

T1-4 7 1478

ESS 8 1209

Prothrombin Index 9 1107

Glucose 10 999

Thrombocytes/Cancer Cells 11 906

Healthy Cells/Cancer Cells 12 624

Lymphocytes/Cancer Cells 13 509

Erythrocytes/Cancer Cells 14 404

Corect Classification Rate=100%Error=0.000Area under ROC Curve=1.000

Results of Bootstrap Simulation in Prediction of Lung Cancer Patients Survival after Complete Lobectomies/Pneumonectomies (n=609): Significant Factors (Number of Samples=3333) Rank Kendal Tau-A P Phase Transition N0---N12 1 -0.215 0.000 Lymphocytes/Cancer Cells 2 -0.206 0.000 Healthy Cells/Cancer Cells 3 -0.203 0.000 Erythrocytes/Cancer Cells 4 -0.202 0.000 Thrombocytes/Cancer Cells 5 -0.176 0.000 Leucocytes/Cancer Cells 6 -0.168 0.000 Prothrombin Index 7 0.162 0.000 Tumor Size 8 -0.144 0.000 Eosinophils/Cancer Cells 9 -0.140 0.000 Phase Transition Early---Invasive Cancer 10 -0.131 0.000 T1-4 11 0.126 0.000 Monocytes/Cancer Cells 12 -0.125 0.000 Segmented Neutrophils/Cancer Cells 13 -0.115 0.000 Segmented Neutrophils 14 0.107 0.000 Weight 15 -0.104 0.000 Lymphocytes 16 -0.102 0.000 Erythrocytes 17 -0.098 0.001 ESS 18 0.084 0.01 G1-3 19 -0.082 0.01 Heparin Tolerance 20 0.077 0.01 Glucose 21 -0.071 0.01 Surgery alone 22 -0.066 0.01 Eosinophils 23 -0.062 0.05

Results of Kohonen Self-Organizing Neural Networks Computing in Prediction of Lung Cancer Patients Survival after Complete Lobectomies/Pneumonectomies (n=609):

Lung Cancer Dynamics:

Prognostic SEPATH-Model of Lung Cancer Patients Survival after

Complete Lobectomies/Pneumonectomies (n=609):

Address:

Oleg Kshivets, M.D.,Ph.D.

Consultant Thoracic, Abdominal, General Surgeon & Surgical Oncologist

e-mail: okshivets@yahoo.com skype: okshivets http: //www.ctsnet.org/home/okshivets