Survival Outcomes in Patients with Esophageal Cancer after Complete Esophagogastrectomies

1. Survival Outcomes in Patients with
Esophageal Cancer after Complete
Esophagogastrectomies
Kshivets Oleg, MD, PhD
Surgery Department, Roshal Hospital,
Roshal, Moscow, Russia

2. • Survival Outcomes in Patients with Esophageal Cancer after
• Complete Esophagogastrectomies
• Kshivets Oleg Surgery Department, Roshal Hospital
• Roshal, Moscow, Russia
• OBJECTIVE: Survival outcomes of radical surgery in esophageal cancer (EC) patients (ECP)
• (T1-4N0-2M0) were analyzed.
• METHODS: We analyzed data of 543 consecutive ECP (age=56.4±8.8 years; tumor
• size=6±3.5 cm) radically operated (R0) and monitored in 1975-2018 (m=405, f=138;
• esophagogastrectomies (EG) Garlock=280, EG Lewis=263, combined EG with resection of pancreas, liver, diaphragm, aorta, VCS,
colon transversum, lung, trachea, pericardium, splenectomy=151; adenocarcinoma=308, squamous=225, mix=10; T1=126, T2=114,
T3=178, T4=125; N0=275, N1=69, N2=199; G1=157, G2=139, G3=247; early EC=107, invasive=436; only surgery=420, adjuvant
chemoimmunoradiotherapy-AT=123: 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 1892.4±2241 days and cumulative 5-year survival (5YS) reached 51.9%, 10 years – 45.7%, 20
years – 33.5%. 183 ECP lived more than 5 years (LS=4311±2419.7 days), 98 ECP – more than 10 years (LS=5903.4±2299.4 days). 224
ECP died because of EC (LS=629.2±320.1 days). AT significantly improved 5YS (68.2% vs. 48.5%) (P=0.00033 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, histology, age, AT, localization, blood cells, prothrombin
index, coagulation time, residual nitrogen, blood group, Rh, glucose, protein (P=0.000-0.008). Neural networks, genetic algorithm
selection and bootstrap simulation revealed relationships between 5YS and healthy cells/CC (rank=1), PT early-invasive EC (rank=2),
PT N0—N12 (rank=3), erythrocytes/CC (4), thrombocytes/CC (5), stick neutrophils/CC (6), lymphocytes/CC (7), segmented
neutrophils/CC (8), eosinophils/CC (9), leucocytes/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: Survival outcomes 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 unfavorable prognosis.

3. Data:
• Males………………………………………………………………….405
• Females………..……………………………..................................138
• Age=56.4±8.8 years
• Tumor Size=6±3.5 cm
• Only Surgery.………………………………..................................420
• Adjuvant Chemoimmunoradiotherapy (5FU+thymalin/taktivin,
• 5-6 cycles + Radiotherapy 45-50Gy)…………………………….123

4. Radical Procedures:
• Esophagogastrectomies Lewis (R0)……………….……..…....…263
• 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…….…………………………………....374
• 3-Field Lymphadenectomy.……………………………….…...……169

5. Staging:
• T1……..126 N0..……275 G1…………157
• T2……..114 N1…........69 G2…………139
• T3……..178 N2…......199 G3…………247
• T4……..125 M0……...543
• Adenocarcinoma………………………………………………..……..308
• Squamous Cell Carcinoma…………………………………………..225
• Mix………………….....…………………………………………..............10
• Early Cancer……………………………...……………………………..107
• Invasive Cancer…………………………..………………………..…...436

6. Survival Rate:
• Alive……………………………………..............................................284 (52.3%)
• 5-Year Survivors………………………………………………............183 (33.7%)
• 10-Year Survivors………………………............................................98 (18%)
• Losses……………………..…………………………………………….224 (41.3%)
• General Life Span=1892.4±2241 days
• For 5-Year Survivors=4311±2419.7 days
• For 10-Year Survivors=5903.4±2299.4 days
• For Losses=629.2±320.1 days
• Cumulative 5-Year Survival……………………………………………...….51.9%
• Cumulative 10-Year Survival………………………………………………..45.7%
• Cumulative 20-Year Survival………………………………………………...33.5%

7. General Esophageal Cancer Patients Survival after Complete
Esophagogastrectomies (Kaplan-Meier) (n=543):
Survival Function
General Esophageal Cancer Patients Survival, n=543
5-Year Survival=51.9%; 10-Year Survival=45.7%; 20-Year Survival=33.5%
Complete Censored
-5 0 5 10 15 20 25 30 35 40
Years after Esophagogastrectomies
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
CumulativeProportionSurviving

8. Results of Univariate Analysis of Phase Transition Early—
Invasive Cancer in Prediction of Esophageal Cancer Patients
Survival (n=543):
Cumulative Proportion Surviving (Kaplan-Meier)
5-Year Survival of Early ECP=100; 5-Year Survival of Invasive ECP=38.5%,
P=0.00000 by Log-Rank Test
Complete Censored
0 5 10 15 20 25 30 35 40
Years after Esophagogastrectomies
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
CumulativeProportionSurviving
Invasive ECP, n=436
Early ECP, n=107

9. Results of Univariate Analysis of Phase Transition N0—N1-2
in Prediction of Esophageal Cancer Patients Survival (n=543):
Cumulative Proportion Surviving (Kaplan-Meier)
5-Year Survival of ECP with N0=73.9%; 5-Year Survival of ECP with N1-2=27.5%
P=0.00000 by Log-Rank Test
Complete Censored
0 5 10 15 20 25 30 35 40
Years after Esophagogastrectomies
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
CumulativeProportionSurviving
ECP with N1-2, n=268
ECP with N0, n=275

10. Results of Univariate Analysis of Adjuvant
ChemoimmunoradioTherapy in Prediction of Esophageal
Cancer Patients Survival (n=543):
Cumulative Proportion Surviving (Kaplan-Meier)
5-Year Survival of ECP after Adjuvant Treatment=68.2%;
5-Year Survival of ECP after Surgery alone=48.5%;
P=0.00033 by Log-Rank Test
Complete Censored
0 5 10 15 20 25 30 35 40
Years after Esophagogastrectomies
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
CumulativeProportionSurviving
Adjuvant Chemoimmunoradiotherapy, n=123
Only Surgery, n=420

11. Results of Univariate Analysis of localization (upper/3 vs.
middle/3 & lower/3) in Prediction of Esophageal Cancer
Patients Survival (n=543):
Cumulative Proportion Surviving (Kaplan-Meier)
5-Year Survival of ECP of Upper/3=64.7%; 5-Year Survival of Others ECP=49.2%;
P=0.00323 by Log Rank Test
Complete Censored
0 5 10 15 20 25 30 35 40
Years after Esophagogastrectomies
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
CumulativeProportionSurviving
Uper/3 ECP, n=80
Others ECP, n=463

12. Results of Cox Regression Modeling in Prediction of
Esophageal Cancer Patients Survival after Complete
Esophagogastrectomies (n=543):
Cox Proportional Hazards Results;
ECP=543;
Factors:
Parameter
Estimate
Standard
Error
Chi-square P value
95%
Lower CL
95%
Upper CL
Hazard
Ratio
95%
Hazard
Ratio
Lower CL
95%
Hazard
Ratio
Upper CL
Blood Group 0.23476 0.073446 10.21678 0.001392 0.09081 0.378711 1.264605 1.095060 1.460401
Rh-Factor -0.54240 0.179819 9.09838 0.002558 -0.89483 -0.189958 0.581353 0.408675 0.826993
Hemorrhage Blood 0.00144 0.000421 11.77796 0.000599 0.00062 0.002268 1.001445 1.000619 1.002271
Glucose -0.23830 0.083967 8.05437 0.004539 -0.40287 -0.073728 0.787965 0.668396 0.928924
Residual Nitrogen 0.05252 0.011743 20.00367 0.000008 0.02951 0.075537 1.053925 1.029945 1.078463
Protein 0.02684 0.008990 8.91663 0.002826 0.00922 0.044464 1.027208 1.009267 1.045467
Prothrombin Index 0.02029 0.006681 9.22243 0.002391 0.00719 0.033384 1.020497 1.007221 1.033948
T1-4 0.40732 0.095442 18.21334 0.000020 0.22026 0.594382 1.502783 1.246396 1.811911
N0---N12 0.70052 0.165865 17.83760 0.000024 0.37543 1.025613 2.014807 1.455623 2.788804
Age 0.03072 0.007906 15.10444 0.000102 0.01523 0.046219 1.031201 1.015346 1.047304
Histology -0.34704 0.131313 6.98449 0.008222 -0.60440 -0.089668 0.706780 0.546400 0.914235
G1-3 0.39807 0.089616 19.73142 0.000009 0.22243 0.573719 1.488955 1.249109 1.774855
Adjuvant Chemoimmunoradiotherapy -0.94293 0.202241 21.73792 0.000003 -1.33931 -0.546541 0.389487 0.262026 0.578949
Leucocytes tot -1.37250 0.359513 14.57453 0.000135 -2.07713 -0.667865 0.253473 0.125289 0.512802
Eosinophils tot 1.43485 0.369265 15.09867 0.000102 0.71111 2.158599 4.199029 2.036244 8.659002
Stick Neutrophils tot 1.39116 0.360961 14.85367 0.000116 0.68369 2.098628 4.019503 1.981172 8.154972
Segmented Neutrophils tot 1.39745 0.359085 15.14529 0.000100 0.69366 2.101242 4.044866 2.001016 8.176317
Lymphocytes tot 1.33711 0.361121 13.70979 0.000213 0.62933 2.044896 3.808030 1.876350 7.728351
Monocytes tot 1.32704 0.372737 12.67540 0.000370 0.59649 2.057588 3.769859 1.815728 7.827070
Segmented Neutrophils/Cancer Cells -0.14398 0.045351 10.07984 0.001499 -0.23287 -0.055097 0.865903 0.792258 0.946393
Llocalization: Upper/3 vs. Others -0.52502 0.193950 7.32779 0.006790 -0.90516 -0.144886 0.591543 0.404479 0.865121

13. Results of Discriminant Function Analysis in Prediction of
Esophageal Cancer Patients Survival after Complete
Esophagogastrectomies (n=407):
Discriminant Function Analysis Summary:
No. of vars in model=32; n=407
Wilks' Lambda: .39522 approx. F (32,374)=17.885 p<0.0000
Wilks'
Lambda
Partial
Lambda
F-remove
(1,374)
p-value Toler.
1-Toler.
(R-Sqr.)
Hemoglobin 0.405250 0.975248 9.492130.0022160.359799 0.640201
Erythrocytes 0.407808 0.969131 11.912960.0006210.024344 0.975657
Leucocytes 0.413786 0.955129 17.570300.0000350.000405 0.999595
Stick Neutrophils (%) 0.401817 0.983580 6.243450.0128940.081515 0.918486
Segmented Neutrophils (%) 0.412991 0.956969 16.817370.0000510.010315 0.989685
Lymphocytes (%) 0.404156 0.977887 8.457150.0038530.010516 0.989484
Hemorrhage Blood 0.404068 0.978100 8.373820.0040300.843012 0.156988
Residual Nitrogen 0.438737 0.900811 41.181470.0000000.742369 0.257631
Prothrombin Index 0.399773 0.988609 4.309160.0385900.836103 0.163898
Segmented Neutrophils (abs) 0.417926 0.945668 21.487700.0000050.000587 0.999413
Lymphocytes (abs) 0.407544 0.969759 11.662840.0007080.002901 0.997099
T1-4 0.436492 0.905444 39.056850.0000000.541731 0.458269
N0--N12 0.424456 0.931120 27.666640.0000000.704162 0.295838
Weight 0.407512 0.969834 11.633060.0007190.011910 0.988090
G1-3 0.407735 0.969303 11.844210.0006440.835999 0.164001
Tumor Growth 0.407466 0.969943 11.589550.0007350.653263 0.346737
Adjuvant Chemoimmunoradiotherapy 0.400524 0.986755 5.020140.0256410.911147 0.088853
Combined Procedures 0.405038 0.975759 9.291320.0024660.720317 0.279683
Erythrocytes (tot) 0.405575 0.974467 9.799760.0018830.008919 0.991081
Leucocytes (tot) 0.409886 0.964218 13.879260.0002250.000036 0.999964
Eosinophils (tot) 0.405589 0.974434 9.812550.0018700.010102 0.989898
Stick Neutrophils (tot) 0.400922 0.985776 5.396570.0207120.003166 0.996834
Segmented Neutrophils (tot) 0.411970 0.959341 15.850910.0000820.000068 0.999933
Lymphocytes (tot) 0.408867 0.966622 12.914500.0003700.000381 0.999619
Monocytes (tot) 0.407706 0.969373 11.816570.0006530.005423 0.994577
Leucocytes/Cancer Cells 0.401196 0.985102 5.656050.0178970.000009 0.999991
Eosinophils/Cancer Cells 0.401077 0.985396 5.542900.0190720.009880 0.990120
Stick Neutrophils/Cancer Cells 0.401480 0.984406 5.924400.0154000.008813 0.991187

14. Results of Neural Networks Computing in Prediction of
Esophageal Cancer Patients Survival after Complete
esophagogastrectomies (n=407):
Correct Classification Rate=100%
Error=0.000
Area under ROC Curve=1.000
Factors: Rank Sensitivity
Healthy Cells/Cancer Cells
Phase Transition Early---Invasive Cancer
Phase Transition N0---N12
Erythrocytes/Cancer Cells
Thrombocytes/Cancer Cells
Stick Neutrophils/Cancer Cells
Lymphocytes/Cancer Cells
Segmented Neutrophils/Cancer Cells
Eosinophils/Cancer Cells
Leucocytes/Cancer Cells
Monocytes/Cancer Cells
1
2
3
4
5
6
7
8
9
10
11
28794
20554
16562
8666
7464
7425
5836
5771
4024
3734
3230

15. Results of Bootstrap Simulation in Prediction of esophageal
Cancer Patients Survival after esophagogastrectomies (n=407):
Significant Factors
(Number of Samples=3333)
Rank Kendal
Tau-A
P
Tumor Size 1 -0.316 0.000
Healthy Cells/Cancer Cells 2 0.315 0.000
T1-4 3 -0.307 0.000
Erythrocytes/Cancer Cells 4 0.307 0.000
Leucocytes/Cancer Cells 5 0.298 0.000
Thrombocytes/Cancer Cells 6 0.293 0.000
Lymphocytes/Cancer Cells 7 0.289 0.000
Segmented Neutrophils/Cancer Cells 8 0.280 0.000
Residual Nitrogen 9 -0.277 0.000
Phase Transition N0---N12 10 -0.248 0.000
Monocytes/Cancer Cells 11 0.240 0.000
Hemorrhage Time 12 -0.233 0.000
Phase Transition Early---Invasive Cancer 13 -0.225 0.000
Procedure Type 14 -0.192 0.000
Eosinophils/Cancer Cells 15 0.163 0.000
Chlorides 16 0.163 0.000
G1-3 17 -0.140 0.000
Tumor Growth 18 -0.117 0.001
Stick Neutrophils/Cancer Cells 19 0.105 0.01
Erythrocytes 20 0.103 0.01
Weight 21 0.100 0.01
Combined Procedure 22 0.098 0.01
Localization 23 0.070 0.05

16. Results of Kohonen Self-Organizing Neural Networks
Computing in Prediction of esophageal Cancer Patients
Survival after Complete esophagogastrectomies (n=407):

17. Esophageal Cancer
Dynamics:

18. Prognostic Equation Models of Esophageal Cancer Patients
Survival after Complete Esophagogastrectomies (n=407):

19. Prognostic SEPATH-Model of Esophageal Cancer Patients
Survival after Complete Esophagogastrectomies (n=407):

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