Esophageal Cancer: System Approach

1. Esophageal Cancer:
System Approach
Kshivets Oleg, MD, PhD
Surgery Department, Roshal Hospital, Roshal, Russia

2. Esophageal Cancer: System Approach
Kshivets Oleg Surgery Department, Roshal Hospital, Moscow, Russia
OBJECTIVE: Search of optimal diagnosis and treatment strategies for esophageal cancer (EC) pa­tients (ECP)
(T1-4N0-2M0) realized.
METHODS: We analyzed data of 515 consecutive ECP (age=56.3±8.9 years; tumor size=6.2±3.4 cm)
radically operated (R0) 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 5-year survival (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, blood group, Rh, glucose (P=0.000-0.037). Neural networks, genetic
algorithm selection and bootstrap simulation revealed relationships between 5YS and healthy cells/CC
(rank=1), erythrocytes/CC (2), protein (3), T (4), segmented neutrophils/CC (5), eosinophils/CC (6), stick
neutrophils/CC (7), G (8), CC (9), PT early-invasive EC (10), PT N0—N12 (11), localization (12), thrombocytes/CC
(13), lymphocytes/CC (14), monocytes/CC (15), prothrombin index (16), leucocytes/CC (17). 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. Optimal diagnosis and treatment
strategies for EC are: 1) screening and early detection of EC; 2) availability of experienced thoracoabdominal
surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph
node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for ECP with

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):
ECP=515; Cox Proportional Hazards Results
Factors:
Parameter
Estimate
Standard
Error
Chi-square P value 95% Lower CL 95% Upper CL
Hazard
Ratio
Blood Group 0,20689 0,073286 7,96949 0,004757 0,06325 0,350527 1,229846
Rh-Factor -0,41598 0,178497 5,43097 0,019783 -0,76583 -0,066130 0,659695
Hemorrhage Time 0,00132 0,000426 9,62521 0,001919 0,00049 0,002155 1,001321
Glucose -0,19071 0,084851 5,05136 0,024607 -0,35701 -0,024400 0,826376
Residual Nitrogen 0,05300 0,011885 19,88396 0,000008 0,02970 0,076292 1,054427
Prothrombin Index 0,02341 0,007084 10,92358 0,000949 0,00953 0,037299 1,023690
T1-4 0,28869 0,096365 8,97459 0,002738 0,09982 0,477561 1,334675
N0---N12 0,63361 0,161618 15,36978 0,000088 0,31685 0,950376 1,884404
Age 0,02439 0,007805 9,76377 0,001780 0,00909 0,039685 1,024688
G1-3 0,24259 0,081640 8,82932 0,002964 0,08257 0,402596 1,274540
Adjuvant Chemoimmunoradiotherapy -0,91093 0,201521 20,43288 0,000006 -1,30590 -0,515955 0,402151
Leucocytes (tot) -1,56821 0,380900 16,95066 0,000038 -2,31476 -0,821660 0,208418
Eosinophils (tot) 1,81465 0,431282 17,70363 0,000026 0,96935 2,659945 6,138915
Stick Neutrophils (tot) 1,34835 0,362871 13,80709 0,000203 0,63714 2,059569 3,851080
Segmented Neutrophils (tot) 1,59067 0,383243 17,22707 0,000033 0,83953 2,341815 4,907042
Lymphocytes (tot) 1,58322 0,386595 16,77144 0,000042 0,82551 2,340934 4,870621
Monocytes (tot) 1,30273 0,374977 12,06987 0,000512 0,56779 2,037675 3,679343
Leucocytes/Cancer Cells 1,37589 0,652189 4,45064 0,034888 0,09763 2,654160 3,958610
Eosinophils/Cancer Cells -3,73063 1,566692 5,67018 0,017256 -6,80129 -0,659969 0,023978
Segmented Neutrophils/Cancer Cells -1,54011 0,694547 4,91698 0,026594 -2,90139 -0,178819 0,214359
Lymphocytes/Cancer Cells -1,64546 0,789598 4,34273 0,037167 -3,19305 -0,097877 0,192924
Localization: Upper/3 vs. Others/3 -0,48978 0,194124 6,36565 0,011635 -0,87026 -0,109304 0,612761

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):
Correct Classification Rate=100%
Error=0.000
Area under ROC Curve=1.000
Factors: Rank Sensitivity
Healthy Cells/Cancer Cells
Erythrocytes/Cancer Cells
Protein
T1-4
Segmented Neutrophils/Cancer Cells
Eosinophils/Cancer Cells
Stick Neutrophils/Cancer Cells
G1-3
Tumor Size
Phase Transition Early---Invasive
Phase Transition N0---N12
Localization
Thrombocytes/Cancer Cells
Lymphocytes/Cancer Cells
Monocytes/Cancer Cells
Prothrombin Index
Leucocytes/Cancer Cells
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
84570090
77764200
37976840
3958902
3518292
397879
304065
190705
40263
10246
9281
1107
140
64
10
5
1

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
Prothrombin Index 22 -0.073 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 Equation Models of Esophageal Cancer Patients
Survival after Complete Esophagogastrectomies (n=384):

19. Prognostic SEPATH-Model of Esophageal Cancer Patients
Survival after Complete Esophagogastrectomies (n=384):

20. 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:

21. Optimal Diagnosis and Treatment Strategies for Esophageal
Cancer are:
1) Screening and Early Detection of Esophageal Cancer;
2) Availability of Experienced Thoracoabdominal Surgeons
because of Complexity of Radical Procedures;
3) Aggressive en block Surgery and Adequate Lymph Node
Dissection for Completeness;
4) Precise Prediction;
5) Adjuvant Chemoimmunoradiotherapy for Esophageal
Cancer Patients with Unfavorable Prognosis.
Conclusion:

22. 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