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Oleg Kshivets , MD, PhD
Surgery Department, Kaluga Cancer Clinical Center, Russia
PRECISE PREDICTION OF 5-YEAR
SURVIVAL OF LUNG CANCER PATIENTS
AFTER RADICAL SURGERY
ABSTRACT
Precise Prediction of 5-Year Survival of Lung Cancer Patients after Radical Surgery
Oleg 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………………………………………………….575
 Females………..………………………………….........90
 Age=57.5±8.3 years
 Tumor Size=4.4±2.4 cm
 Only Surgery.………………………………………...524
 Adjuvant Chemoimmunoradiotherapy
 (CAV/gemzar+ cisplatin+thymalin/taktivin, 5-6 cycles+
Radiotherapy 45-50Gy)……………………………...141
Radical Procedures::
 Pneumonectomies (R0)……..………………………...242
 Lobectomies (R0)………….………………………….423
 Combined Pneumonectomies/Lobectomies with
Resection of Trachea, Carina, Atrium, Aorta, Vena
 Cava Superior, Vena Azygos, Diaphragm, Pericardium,
Esophagus, Liver, Ribs (R0)………………………....180
 N1 Lymph Node Dissection………………………..…132
 Mediastinal Lymph Node Dissection……………..….533
Staging:
 T1……237 N0..….419 G1…………163
 T2……248 N1…...130 G2…………199
 T3……125 N2…...116 G3…………303
 T4……..55 M0…..665
 Adenocarcinoma…………………………….243
 Squamos Cell Carcinoma…………………...377
 Large Cell Carcinoma.……………………….45
 Early Cancer…………………………………132
 Invasive 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 days
 For 5-Year Survivors=3041.4±1472.5 days
 For 10-Year Survivors=5053.8±1477.2 days
 For Losses=559.6±373.5 days
 Cumulative 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 CL
95%
Upper CL
Hazard
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=0.000
Area 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

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Kshivets iaslc denver2015

  • 1. Oleg Kshivets , MD, PhD Surgery Department, Kaluga Cancer Clinical Center, Russia PRECISE PREDICTION OF 5-YEAR SURVIVAL OF LUNG CANCER PATIENTS AFTER RADICAL SURGERY
  • 2. ABSTRACT Precise Prediction of 5-Year Survival of Lung Cancer Patients after Radical Surgery Oleg 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.
  • 3. Data:  Males………………………………………………….575  Females………..………………………………….........90  Age=57.5±8.3 years  Tumor Size=4.4±2.4 cm  Only Surgery.………………………………………...524  Adjuvant Chemoimmunoradiotherapy  (CAV/gemzar+ cisplatin+thymalin/taktivin, 5-6 cycles+ Radiotherapy 45-50Gy)……………………………...141
  • 4. Radical Procedures::  Pneumonectomies (R0)……..………………………...242  Lobectomies (R0)………….………………………….423  Combined Pneumonectomies/Lobectomies with Resection of Trachea, Carina, Atrium, Aorta, Vena  Cava Superior, Vena Azygos, Diaphragm, Pericardium, Esophagus, Liver, Ribs (R0)………………………....180  N1 Lymph Node Dissection………………………..…132  Mediastinal Lymph Node Dissection……………..….533
  • 5. Staging:  T1……237 N0..….419 G1…………163  T2……248 N1…...130 G2…………199  T3……125 N2…...116 G3…………303  T4……..55 M0…..665  Adenocarcinoma…………………………….243  Squamos Cell Carcinoma…………………...377  Large Cell Carcinoma.……………………….45  Early Cancer…………………………………132  Invasive Cancer……………………………...533
  • 6. 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 days  For 5-Year Survivors=3041.4±1472.5 days  For 10-Year Survivors=5053.8±1477.2 days  For Losses=559.6±373.5 days  Cumulative 5-Year Survival………………..69.6%  Cumulative 10-Year Survival………………61.2%  Cumulative 20-Year Survival………………43.1%
  • 7. General Lung Cancer Patients Survival after Complete Lobectomies/Pneumonectomies (Kaplan-Meier) (n=665):
  • 8. Results of Univariate Analysis of Phase Transition Early—Invasive Cancer in Prediction of Lung Cancer Patients Survival (n=665)
  • 9. Results of Univariate Analysis of Phase Transition N0—N1-2 in Prediction of Lung Cancer Patients Survival (n=665):
  • 10. Results of Univariate Analysis of Adjuvant chemoimmunoradioTherapy in Prediction of Lung Cancer Patients Survival with N1-2 (n=246):
  • 11. 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 CL 95% Upper CL Hazard 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
  • 12. 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=0.000 Area under ROC Curve=1.000
  • 13. 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
  • 14. Results of Kohonen Self-Organizing Neural Networks Computing in Prediction of Lung Cancer Patients Survival after Complete Lobectomies/Pneumonectomies (n=609):
  • 16. Prognostic SEPATH-Model of Lung Cancer Patients Survival after Complete Lobectomies/Pneumonectomies (n=609):
  • 17. 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