Esophageal Cancer: Surgery and Precise Prognosis

1. ESOPHAGEAL CANCER:
SURGERY AND PRECISE
PROGNOSIS
Kshivets Oleg, MD, PhD
Surgery Department,
Roshal Hospital,
Roshal, Moscow, Russia

2. 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.

3. 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

4. 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

5. 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

6. 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%

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

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

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

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

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

12. 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

13. 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

14. 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

15. 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

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

17. ESOPHAGEAL
CANCER DYNAMICS:

18. PROGNOSTIC SEPATH-MODEL OF ESOPHAGEAL CANCER PATIENTS SURVIVAL AFTER
COMPLETE ESOPHAGOGASTRECTOMIES (N=384):

19. 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:

20. 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