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ARTIFICIAL INTELLIGENCE, SYSTEM ANALYSIS AND SIMULATION MODELING IN PRECISE PREDICTION OF 5-YEAR SURVIVAL OF ESOPHAGEAL CANCER PATIENTS AFTER COMPLETE ESOPHAGOGASTRECTOMIES Oleg Kshivets, MD, PhD Surgery Department, Kaluga Cancer Clinical Center, Russia

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ARTIFICIAL INTELLIGENCE, SYSTEM ANALYSIS AND SIMULATION MODELING IN PRECISE PREDICTION OF 5-YEAR SURVIVAL OF ESOPHAGEAL CANCER PATIENTS AFTER COMPLETE ESOPHAGOGASTRECTOMIES

Oleg Kshivets, MD, PhD

Surgery Department, Kaluga Cancer Clinical Center, Russia

ABSTRACTArtificial Intelligence, System Analysis and Simulation Modeling in Precise Prediction of 5-Year Survival of Esophageal Cancer Patients after Complete EsophagogastrectomiesOleg Kshivets OBJECTIVE: We examined factors in terms of precise prediction of 5-year survival (5YS) of esophageal cancer (EC) patients (ECP) (T1-4N0-2M0) after complete (R0) esophagogastrectomies (EG).    METHODS: We analyzed data of 491 consecutive ECP (age=56.2±8.8 years; tumor size=6.3±3.4 cm) radically operated and monitored in 1975-2015 (m=359, f=132; EG Garlock=280, EG Lewis=211, combined EG with resection of pancreas, liver, diaphragm, aorta, VCS, colon transversum, lung, trachea, pericardium, splenectomy=147; adenocarcinoma=279, squamous=202, mix=10; T1=90, T2=112, T3=166, T4=123; N0=227, N1=69, N2=195; G1=136, G2=123, G3=232; early EC=71, invasive=420; only surgery=377, adjuvant chemoimmunoradiotherapy-AT=114: 5-FU+thymalin/taktivin+radiotherapy 45-50Gy). Multivariate Cox modeling, clustering, SEPATH, Monte Carlo, bootstrap and neural networks computing were used to determine any significant dependence.    RESULTS: Overall life span was 1776.1±2223.2 days and cumulative 5-year survival (5YS) reached 47.1%, 10 years – 40.3%, 20 years – 30%. 147 ECP lived more than 5 years, 79 – 10 years. 223 ECP died because of EC. Cox modeling displayed (Chi2=293.38, df=18, P=0.000) that 5YS of ECP significantly depended on: phase transition (PT) N0—N12 in terms of synergetics, cell ratio factors (CRF) (ratio between cancer cells and blood cells subpopulations), T, G, age, AT, localization, blood cells, prothrombin index, coagulation time, residual nitrogen (P=0.000-0.014). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT N0--N12 (rank=1), T, AT, G, prothrombin index, glucose, blood cells, localization, PT early-invasive EC, CRF. Correct prediction of 5YS was 100% by neural networks computing.    CONCLUSIONS: 5YS of ECP after radical procedures significantly depended on: 1) PT “early-invasive cancer”; 2) PT N0--N12; 3) CRF; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) adjuvant chemotherapy; 8) tumor characteristics and localization.

DATA: Males…………………………………………….359 Females………..…………………………….......132

Age=56.2±8.8 years Tumor Size=6.3±3.4 cm Only Surgery.…………………………………...377 Adjuvant Chemoimmunoradiotherapy (5FU+thymalin/taktivin, 5-6 cycles+ Radiotherapy 45-50Gy)………………………...........................114

RADICAL PROCEDURES: Esophagogastrectomies Lewis (R0)……………211 Esophagogastrectomies Garlock (R0)………....280 Combined Esophagogastrectomies with Resection of Pancreas, Liver, Trachea, Lung, Aorta, Vena Cava Superior, Colon Transversum, Diaphragm,

Pericardium, Splenectomy (R0)…………….....147 2-Field Lymphadenectomy…………………….364 3-Field Lymphadenectomy.……………………127

STAGING: T1……..90 N0..….227 G1…………136 T2……112 N1….....69 G2…………123 T3……166 N2…...195 G3…………232 T4……123 M0…..491 Adenocarcinoma……………………………279 Squamos Cell Carcinoma…………………..202 Mix………………….....…………………........10 Early Cancer……………………………...…..71 Invasive Cancer…………………………..….420

SURVIVAL RATE: Alive………………………………………...238 (48.5%) 5-Year Survivors…………..……………….147 (29.9%) 10-Year Survivors…………………………...79 (16.1%) Losses……………………………………….223 (45.4%) General Life Span=1776.1±2223.2 days For 5-Year Survivors=4382.8±2559.8 days For 10-Year Survivors=6047.8±2454.2 days For Losses=630.2±320.5 days Cumulative 5-Year Survival…………………….47.1% Cumulative 10-Year Survival…………………...40.3% Cumulative 20-Year Survival…………………...30%

GENERAL ESOPHAGEAL CANCER PATIENTS SURVIVAL AFTER COMPLETE ESOPHAGOGASTRECTOMIES (KAPLAN-MEIER) (N=491):

RESULTS OF UNIVARIATE ANALYSIS OF PHASE TRANSITION EARLY—INVASIVE CANCER IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL (N=491):

RESULTS OF UNIVARIATE ANALYSIS OF PHASE TRANSITION N0—N1-2 IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL (N=491):

RESULTS OF UNIVARIATE ANALYSIS OF ADJUVANT CHEMOIMMUNORADIOTHERAPY IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL (N=491):

RESULTS OF UNIVARIATE ANALYSIS OF LOCALIZATION (UPPER/3 VS. MIDDLE/3 & LOWER/3) IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL (N=491):

RESULTS OF COX REGRESSION MODELING IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL AFTER COMPLETE ESOPHAGOGASTRECTOMIES (N=491):

Cox Regression: Chi2 = 293,38; df = 18; P = 0,0000

Factors: Beta Standard - Error

t-value Wald - Statist.

P Risk ratio

Segmented Neutrophils (%) 0,06904 0,019857 3,47683 12,08835 0,000508 1,07148

Hemorrhage Time 0,00161 0,000407 3,95875 15,67167 0,000076 1,00161

Residual Nitrogen 0,05555 0,012072 4,60139 21,17282 0,000004 1,05712

Prothrombin Index 0,02379 0,006833 3,48133 12,11967 0,000500 1,02407

Segmented Neutrophils (abs) -0,29839 0,108834 -2,74169 7,51684 0,006116 0,74201

Lymphocytes (abs) 0,87499 0,279575 3,12972 9,79513 0,001751 2,39885

Phase Transition N0---N1-2 0,60876 0,158391 3,84337 14,77148 0,000122 1,83814

Age 0,01975 0,007759 2,54520 6,47805 0,010926 1,01995

G1-3 0,25393 0,083591 3,03780 9,22823 0,002385 1,28909

Adjuvant Chemoimmunoradiotherapy -1,01275 0,207721 -4,87554 23,77090 0,000001 0,36322

Phase Transition Early—Invasive Cancer 0,30738 0,564374 0,54464 0,29664 0,586003 1,35986

Eosinophils (tot) 0,49432 0,149800 3,29984 10,88897 0,000968 1,63938

Leucocytes/Cancer Cells -3,01478 1,102960 -2,73335 7,47123 0,006273 0,04906

Stick Neutrophils/Cancer Cells 3,71584 1,141413 3,25548 10,59811 0,001133 41,09317

Segmented Neutrophils/Cancer Cells 2,84619 1,116486 2,54924 6,49861 0,010800 17,22201

Lymphocytes/Cancer Cells 2,62863 1,141840 2,30210 5,29967 0,021336 13,85481

Monocytes/Cancer Cells 4,59519 1,225403 3,74994 14,06208 0,000177 99,00706

Localization: Upper/3 vs. Others/3 -0,38786 0,195170 -1,98728 3,94929 0,046900 0,67851

RESULTS OF DISCRIMINANT FUNCTION ANALYSIS IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL AFTER COMPLETE ESOPHAGOGASTRECTOMIES (N=370):

Discriminant Function Analysis Summary: Wilks' Lambda: ,50259 approx. F (13,356)=27,102 p<0,0000

Factors: Wilks' Lambda

Partial Lambda

F-remove (1,356)

p-value Toler. 1-Toler. (R-Sqr.)

Phase Transition N0---N1-2 0,527146 0,953418 17,39330 0,000038 0,800697 0,199303

T1-4 0,526761 0,954115 17,12054 0,000044 0,614592 0,385408

Prothrombin Index 0,514526 0,976803 8,45443 0,003870 0,925757 0,074243

Residuel Nitrogen 0,538135 0,933949 25,17715 0,000001 0,821853 0,178147

Phase Transition Early---Invasive Cancer 0,527284 0,953169 17,49095 0,000036 0,605391 0,394609

Adjuvant Chemoimmunoradiotherapy 0,527790 0,952255 17,84942 0,000030 0,864724 0,135276

Combined Procedures 0,511148 0,983257 6,06192 0,014286 0,826192 0,173808

Hemorrhage Time 0,516423 0,973214 9,79824 0,001891 0,910109 0,089891

Monocytes (%) 0,511187 0,983183 6,08916 0,014071 0,333019 0,666981

Lymphocytes (%) 0,509637 0,986174 4,99107 0,026099 0,043299 0,956701

Segmented Neutrophils (%) 0,512693 0,980295 7,15602 0,007816 0,041717 0,958283

Hemoglobin 0,514185 0,977450 8,21295 0,004406 0,904335 0,095665

Stick Neutrophils (%) 0,506503 0,992274 2,77170 0,096824 0,398101 0,601899

RESULTS OF NEURAL NETWORKS COMPUTING IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL AFTER COMPLETE ESOPHAGOGASTRECTOMIES (N=370):

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

Factors: Rank Sensitivity

Phase Transition N0---N12 1 311

T1-4Adjuvant ChemoimmunoradiotherapyG1-3Prothrombin IndexGlucoseErythrocytesLocalizationPhase Transition Early---Invasive Cancer

2 3456789

294 22421719015214510864

MonocytesEosinophils/Cancer CellsStick Neutrophils/Cancer Cells

10 1112

23 129

Thrombocytes/Cancer Cells 13 6

Erythrocytes/Cancer Cells 14 4

Segmented Neutrophils/Cancer Cells 15 3.8

Healthy Cells/Cancer Cells 16 3.6

Leucocytes/Cancer Cells 17 1.5

Monocytes/Cancer Cells 18 1.2

Lymphocytes/Cancer Cells 19 1.1

RESULTS OF BOOTSTRAP SIMULATION IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL AFTER ESOPHAGOGASTRECTOMIES (N=370):

Significant Factors (Number of Samples=3333)

Rank Kendal Tau-A P

Tumor Size 1 -0.272 0.000

Healthy Cells/Cancer Cells 2 0.270 0.000

T1-4 3 -0.269 0.000

Erythrocytes/Cancer Cells 4 0.261 0.000

Leucocytes/Cancer Cells 5 0.248 0.000

Thrombocytes/Cancer Cells 6 0.247 0.000

Lymphocytes/Cancer Cells 7 0.241 0.000

Segmented Neutrophils/Cancer Cells 8 0.229 0.000

Residual Nitrogen 9 -0.222 0.000

Monocytes/Cancer Cells 10 0.207 0.000

Hemorrhage Time 11 -0.201 0.000

Phase Transition Early---Invasive Cancer 12 -0.179 0.000

Stick Neutrophils/Cancer Cells 13 0.159 0.000

Chlorides 14 0.157 0.000

Eosinophils/Cancer Cells 15 0.144 0.000

Tumor Growth 16 -0.121 0.001

G1-3 17 -0.118 0.001

Erythrocytes 18 0.086 0.05

Glucose 19 0.085 0.05

Prothrombin Index 20 -0.081 0.05

Localization 21 0.079 0.05

Weight 22 0.076 0.05

RESULTS OF KOHONEN SELF-ORGANIZING NEURAL NETWORKS COMPUTING IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL AFTER COMPLETE ESOPHAGOGASTRECTOMIES (N=370):

ESOPHAGEAL CANCER DYNAMICS:

PROGNOSTIC SEPATH-MODEL OF ESOPHAGEAL CANCER PATIENTS SURVIVAL AFTER COMPLETE

ESOPHAGOGASTRECTOMIES (N=370):

5-YEAR SURVIVAL OF ESOPHAGEAL CANCER PATIENTS AFTER RADICAL PROCEDURES SIGNIFICANTLY DEPENDED ON: 1) PHASE TRANSITION “EARLY-INVASIVE CANCER”; 2) PHASE TRANSITION N0--N12; 3) CELL RATIO FACTORS; 4) BLOOD CELL CIRCUIT; 5) BIOCHEMICAL FACTORS; 6) HEMOSTASIS SYSTEM; 7) ADJUVANT CHEMOTHERAPY; 8) TUMOR CHARACTERISTICS AND

LOCALIZATION.

Conclusion:

ADDRESS:

OLEG KSHIVETS, M.D.,PH.D.

CONSULTANT THORACIC, ABDOMINAL, GENERAL SURGEON & SURGICAL ONCOLOGIST

e-mail: [email protected] skype: okshivets http: //www.ctsnet.org/home/okshivets