ESOPHAGEAL CANCER: SURGERY AND PRECISE PROGNOSIS Kshivets Oleg, MD, PhD

Surgery Department, Roshal Hospital, Roshal, Moscow, Russia

ABSTRACT ESOPHAGEAL CANCER: SURGERY AND PRECISE PROGNOSIS

BACKGROUND: We examined factors in terms of precise prognosis of 5-year survival (5YS) of esophageal cancer (EC) patients (ECP) (T1-4N0-2M0) after complete (R0) esophagogastrectomies (EG). METHODS: We analyzed data of 515 consecutive ECP (age=56.3±8.9 years; tumor size=6.2±3.4 cm) radically operated and monitored in 1975-2017 (m=380, f=135; esophagogastrectomies (EG) Garlock=280, EG Lewis=235, combined EG with resection of pancreas, liver, diaphragm, aorta, VCS, colon transversum, lung, trachea, pericardium, splenectomy=151; adenocarcinoma=292, squamous=213, mix=10; T1=101, T2=114, T3=175, T4=125; N0=248, N1=69, N2=198; G1=148, G2=125, G3=242; early EC=82, invasive=433; only surgery=394, adjuvant chemoimmunoradiotherapy-AT=121: 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 (LS) was 1814.5±2225.6 days and cumulative 5YS reached 48.8%, 10 years – 42.3%, 20 years – 31.7%. 160 ECP lived more than 5 years (LS=4384.1±2474.1 days), 89 ECP – more than 10 years (LS=5913.1±2360.3 days). 224 ECP died because of EC (LS=629.2±320.1 days). AT significantly improved 5YS (67.6% vs. 44.6%) (P=0.00008 by log-rank test). Cox modeling displayed that 5YS of ECP significantly depended on: phase transition (PT) N0—N12 in terms of synergetics, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), T, G, age, AT, localization, blood cells, prothrombin index, coagulation time, residual nitrogen , RH (P=0.000-0.026). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and healthy cells/CC (rank=1), PT early-invasive EC (rank=2), thrombocytes/CC (3), PT N0—N12 (4), erythrocytes/CC (5), stick neutrophils/CC (6), segmented neutrophils/CC (7), lymphocytes/CC (8), leucocytes/CC (9), eosinophils/CC (10), monocytes/CC (11) . Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0 ). CONCLUSIONS: 5YS of ECP after radical procedures significantly depended on: 1) PT “early-invasive cancer”; 2) PT N0--N12; 3) Cell Ratio Factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) EC characteristics; 9) tumor localization; 10) anthropometric data.

DATA:

Males…………………………………………………………………….380 Females………..…………………………….....................................135 Age=56.3±8.9 years Tumor Size=6.2±3.4 cm Only Surgery.…………………………………..................................394 Adjuvant Chemoimmunoradiotherapy (5FU+thymalin/taktivin, 5-6 cycles+ Radiotherapy 45-50Gy)....121

RADICAL PROCEDURES: Esophagogastrectomies Lewis (R0)……………………………...…235 Esophagogastrectomies Garlock (R0)………................................280 Combined Esophagogastrectomies with Resection of Pancreas,

Liver, Trachea, Lung, Aorta, Vena Cava Superior, Colon Transversum, Diaphragm, Pericardium, Splenectomy (R0)…….151

2-Field Lymphadenectomy…………………………………………....364 3-Field Lymphadenectomy.……………………………………...……151

STAGING: T1……..101 N0..……248 G1…………148 T2……..114 N1…........69 G2…………125 T3……..175 N2…......198 G3…………242 T4……..125 M0……...515 Adenocarcinoma………………………………..292 Squamos Cell Carcinoma……………………..213 Mix………………….....…………………...............10 Early Cancer……………………………...………..82 Invasive Cancer…………………………..……...433

SURVIVAL RATE: Alive………………………………………............................260 (50.5%) 5-Year Survivors…………..…………………………..........160 (31.1%) 10-Year Survivors…………………………...........................89 (17.3%) Losses………………………..……………………………….224 (43.5%) General Life Span=1814.5±2225.6 days For 5-Year Survivors=4384.1±2474.1 days For 10-Year Survivors=5913.1±2360.3 days For Losses=629.2±320.1 days Cumulative 5-Year Survival…………………….48.8% Cumulative 10-Year Survival…………………...42.3% Cumulative 20-Year Survival…………………...31.7%

GENERAL ESOPHAGEAL CANCER PATIENTS SURVIVAL AFTER COMPLETE ESOPHAGOGASTRECTOMIES (KAPLAN-MEIER) (N=515):

RESULTS OF UNIVARIATE ANALYSIS OF PHASE TRANSITION EARLY—INVASIVE CANCER IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL (N=515):

RESULTS OF UNIVARIATE ANALYSIS OF PHASE TRANSITION N0—N1-2 IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL (N=515):

RESULTS OF UNIVARIATE ANALYSIS OF ADJUVANT CHEMOIMMUNORADIOTHERAPY IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL (N=515):

RESULTS OF UNIVARIATE ANALYSIS OF LOCALIZATION (UPPER/3 VS. MIDDLE/3 & LOWER/3) IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL (N=515):

RESULTS OF COX REGRESSION MODELING IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL AFTER COMPLETE ESOPHAGOGASTRECTOMIES (N=515):

Cox Regression: Factors Parameter Estimate

Standard Error

Chi-square

P value 95% Lower CL 95% Upper CL Hazard Ratio

Rh-factor -0.45229 0.176756 6.54776 0.010502 -0.79873 -0.105858 0.636168 Hemorrhage Time 0.00126 0.000433 8.40139 0.003749 0.00041 0.002105 1.001257 Glucose -0.18331 0.084425 4.71444 0.029910 -0.34878 -0.017840 0.832511 Residual Nitrogen 0.05237 0.011983 19.10326 0.000012 0.02889 0.075860 1.053770 Protein 0.02949 0.009120 10.45502 0.001223 0.01161 0.047361 1.029926 Prothrombin Index 0.02483 0.007028 12.48251 0.000411 0.01106 0.038606 1.025142 T1-4 0.38912 0.098018 15.76015 0.000072 0.19701 0.581233 1.475684 Phase Transition N0---N1-2 0.64369 0.165528 15.12176 0.000101 0.31926 0.968115 1.903483 Age 0.03037 0.008013 14.36858 0.000150 0.01467 0.046077 1.030839 Histology -0.29687 0.131185 5.12126 0.023634 -0.55399 -0.039757 0.743137 G1-3 0.40780 0.091366 19.92147 0.000008 0.22872 0.586871 1.503502 Adjuvant Chemoimmunoradiotherapy -0.85863 0.200235 18.38792 0.000018 -1.25108 -0.466177 0.423742 Leucocytes (tot) -1.47405 0.367150 16.11886 0.000059 -2.19365 -0.754444 0.228997 Eosinophils (tot) 1.84217 0.421596 19.09271 0.000012 1.01586 2.668487 6.310240 Stick Neutrophils (tot) 1.26769 0.347754 13.28861 0.000267 0.58610 1.949274 3.552630 Segmented Neutrophils (tot) 1.49871 0.369391 16.46123 0.000050 0.77472 2.222700 4.475901 Leucocytes/Cancer Cells 1.43528 0.626593 5.24687 0.021986 0.20718 2.663375 4.200804 Eosinophils/Cancer Cells -4.02473 1.558966 6.66499 0.009832 -7.08024 -0.969211 0.017868 Segmented Neutrophils/Cancer Cells -1.59111 0.666185 5.70439 0.016923 -2.89680 -0.285408 0.203700 Lymphocytes/Cancer Cells -1.68907 0.762446 4.90766 0.026738 -3.18343 -0.194699 0.184692 Lymphocytes (tot) 1.47963 0.374498 15.61013 0.000078 0.74563 2.213633 4.391320 Monocytes (tot) 1.17235 0.358303 10.70567 0.001068 0.47009 1.874612 3.229575 Localization: Upper/3 vs. Others/3 -0.53733 0.196847 7.45108 0.006340 -0.92314 -0.151514 0.584309

RESULTS OF DISCRIMINANT FUNCTION ANALYSIS IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL AFTER COMPLETE ESOPHAGOGASTRECTOMIES (N=384):

Discriminant Function Analysis Summary Wilks' Lambda: .45402 approx. F (18,365)=24.385 p<0.0000 Factors Wilks' -

Lambda Partial - Lambda

F-remove - (1,365)

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

Rh-factor 0.465749 0.974809 9.43249 0.002292 0.906600 0.093400 HB 0.468602 0.968873 11.72619 0.000686 0.850765 0.149235 Hemorrhage Time 0.461163 0.984502 5.74568 0.017031 0.892014 0.107986 Residual Nitrogen 0.491681 0.923395 30.28066 0.000000 0.794226 0.205774 Stick Neutrophils (abs) 0.462830 0.980957 7.08579 0.008113 0.021425 0.978575 Segmented Neutrophils (abs) 0.462213 0.982266 6.58971 0.010655 0.119903 0.880097 T1-4 0.480596 0.944693 21.36875 0.000005 0.549885 0.450115 Phase Transition N0---N1-2 0.488041 0.930283 27.35391 0.000000 0.709487 0.290513 G1-3 0.465201 0.975956 8.99241 0.002897 0.867697 0.132303 Tumor Growth 0.469517 0.966985 12.46197 0.000468 0.646569 0.353431 Adjuvant Chemoimmunoradiotherapy 0.480222 0.945429 21.06826 0.000006 0.806219 0.193781 Combined Procedure 0.466634 0.972958 10.14446 0.001572 0.785403 0.214598 Phase Transition Early---Invasive Cancer 0.476821 0.952172 18.33426 0.000024 0.533466 0.466534 Leucocytes (tot) 0.464663 0.977086 8.55995 0.003651 0.000260 0.999740 Eosinophils (tot) 0.461626 0.983514 6.11822 0.013834 0.059994 0.940006 Segmented Neutrophils (tot) 0.465465 0.975402 9.20488 0.002587 0.000461 0.999539 Lymphocytes (tot) 0.464409 0.977622 8.35510 0.004076 0.003106 0.996894 Monocytes (tot) 0.464288 0.977876 8.25781 0.004295 0.029356 0.970644

RESULTS OF NEURAL NETWORKS COMPUTING IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL AFTER COMPLETE ESOPHAGOGASTRECTOMIES (N=384):

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

Factors: Rank Sensitivity

Healthy Cells/Cancer Cells

Phase Transition Early---Invasive Thrombocytes/Cancer Cells Phase Transition N0---N12 Erythrocytes/Cancer Cells Stick Neutrophils/Cancer Cells Segmented Neutrophils/Cancer Cells Lymphocytes/Cancer Cells Leucocytes/Cancer Cells Eosinophils/Cancer Cells

Monocytes/Cancer Cells

1 2 3 4 5 6 7 8 9 10 11

17383 13238 9124 8767 4909 4418 4043 3705 2808 2330 1792

RESULTS OF BOOTSTRAP SIMULATION IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL AFTER ESOPHAGOGASTRECTOMIES (N=384):

Significant Factors (Number of Samples=3333)

Rank Kendal Tau-A P

Tumor Size 1 -0.290 0.000 Healthy Cells/Cancer Cells 2 0.288 0.000 T1-4 3 -0.280 0.000 Erythrocytes/Cancer Cells 4 0.278 0.000 Leucocytes/Cancer Cells 5 0.268 0.000 Thrombocytes/Cancer Cells 6 0.265 0.000 Lymphocytes/Cancer Cells 7 0.259 0.000 Segmented Neutrophils/Cancer Cells 8 0.249 0.000 Residual Nitrogen 9 -0.243 0.000 Phase Transition N0---N12 10 -0.228 0.000 Monocytes/Cancer Cells 11 0.223 0.000 Hemorrhage Time 12 -0.223 0.000 Phase Transition Early---Invasive Cancer 13 -0.189 0.000 Eosinophils/Cancer Cells 14 0.163 0.000 Chlorides 15 0.162 0.000 Stick Neutrophils/Cancer Cells 16 0.152 0.000 Tumor Growth 17 -0.131 0.000 G1-3 18 -0.128 0.000 Glucose 19 0.087 0.05 Erythrocytes 20 0.080 0.05 Weight 21 0.080 0.05 Localization 22 0.075 0.05 Prothrombin Index 22 -0.073 0.05

RESULTS OF KOHONEN SELF-ORGANIZING NEURAL NETWORKS COMPUTING IN PREDICTION OF ESOPHAGEAL CANCER PATIENTS SURVIVAL AFTER COMPLETE ESOPHAGOGASTRECTOMIES (N=384):

ESOPHAGEAL CANCER DYNAMICS:

PROGNOSTIC SEPATH-MODEL OF ESOPHAGEAL CANCER PATIENTS SURVIVAL AFTER

COMPLETE ESOPHAGOGASTRECTOMIES (N=384):

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 CHEMOIMMUNORADIOTHERAPY; 8) CANCER CHARACTERISTICS ; 9) TUMOR LOCALIZATION; 10) ANTHROPOMETRIC DATA.

Conclusion:

ADDRESS: OLEG KSHIVETS, M.D.,PH.D. CONSULTANT THORACIC, ABDOMINAL, GENERAL SURGEON & SURGICAL ONCOLOGIST

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