5-YEAR SURVIVAL OF UPPER THIRD ESOPHAGEAL CANCER PATIENTS WAS SIGNIFICANTLY SUPERIOR IN COMPARISON WITH MIDDLE AND LOWER THIRD ESOPHAGEAL CANCER PATIENTS.

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5-YEAR SURVIVAL OF UPPER THIRD ESOPHAGEAL CANCER PATIENTS WAS SIGNIFICANTLY SUPERIOR IN COMPARISON WITH MIDDLE AND LOWER THIRD ESOPHAGEAL CANCER PATIENTS AFTER RADICAL SURGERY AND STRONGLY DEPENDED ON PHASE TRANSITION EARLY-INVASIVE CANCER, LYMPH NODE METASTASES, CELL RATIO FACTORS AND ADJUVANT CHEMOIMMUNORADIOTHERAPY Oleg Kshivets , MD, PhD Surgery Department, Kaluga Cancer Center, Kaluga, Russia

ABSTRACT 5-Year Survival of Upper Third Esophageal Cancer Patients was Significantly Superior in Comparison with Middle and Lower Third Esophageal Cancer Patients after Radical Surgery and Strongly Depended on Phase Transition Early-Invasive Cancer, Lymph Node Metastases, Cell Ratio Factors and Adjuvant Chemoimmunoradiotherapy Kshivets Oleg Surgery Department, Kaluga Cancer Center, Russia OBJECTIVE: This study aimed to determine localization influence of tumor for 5-year survival (5YS) of esophageal (EC) cancer patients (ECP) after complete en block (R0) esophagogastrectomies (EG) through left/right thoracoabdominal incision. METHODS: We analyzed data of 428 consecutive patients (age=55.7±8.8 years; tumor size=6.6±3.3 cm) radically operated and monitored in 1975-2014 (m=320, f=108; EG Garlock=273, EG Lewis=155, combined EG with resection of pancreas, liver, diaphragm, colon transversum, lung, trachea, pericardium, splenectomy=133; adenocarcinoma=230, squamous=188, mix=10; T1=66, T2=103, T3=148, T4=111; N0=184, N1=58, N2=186, G1=118, G2=105, G3=205; early cancer=47, invasive cancer=381; upper third=59, middle & lower third=369, only surgery=341, adjuvant chemoimmunoradiotherapy-AT=87: 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 1675.2±2157.1 days and cumulative 5-year survival (5YS) reached 41.8%, 10 years – 35%, 20 years – 25.1%. 112 patients lived more than 5 years without progression. 216 patients died because of generalization. 5YS of upper third ECP (55.7%) was significantly superior in comparison with middle & lower third ECP (38.7%) after surgery (P=0.00175 by log-rank test). Cox modeling displayed that 5YS significantly depended on: phase transition (PT) early-invasive cancer in terms of synergetics, PT N0--N12, tumor localization, T1-4, G1-3, histology, blood cell subpopulations, age, etc. (P=0.000-0.039). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive cancer (rank=1), localization (2), healthy cells/cancer cells (CC) (3), lymphocytes/CC (4), PT N0--N12 (5), thrombocytes/CC (6), leucocytes/CC (7), erythrocytes/CC (8), AT (9). Correct prediction of 5YS was 100% by neural networks computing. CONCLUSIONS: 5YS of upper third ECP was significantly superior in comparison with middle & lower third ECP after radical procedures and strongly depended on PT early-invasive cancer, lymph node metastases, cell ratio factors and AT.

Data: Males………………………………………………….320 Females………..………………………………….......108 Age=55.7±8.8 years Tumor Size=6.6±3.3 cm Only Surgery.………………………………………...341 Adjuvant Chemoimmunoradiotherapy (5FU+thymalin/taktivin, 5-6 cycles+RT 45-50Gy)….87

Radical Procedures:: Left Thoracoabdominal Esophagogastrectomies (Garlock)……………………..………………………273 Right Thoracoabdominal Esophagogastrectomies (Ivor Lewis)………………….……………………….155 Combined Esophagogastrectomies with Resection of Diaphragm, Pericardium, Lung, Liver, Pancreas, VCS, Aorta, Splenectomy…………………………...133 2-Field Lymphadenectomy….………………………302 3-Field Lymphadenectomy….………………………126 Upper Third…………………………………………..59 Middle Third………………………………………….50 Lower Third…………………………………………271 Total Esophagus………………………………………48

Staging: T1…….66 N0..….184 G1…………118 T2……103 N1…….58 G2…………105 T4……111 M1….….0 Adenocarcinoma…………………………….230 Squamos Cell Carcinoma…………………..188 Mix Carcinoma..……………………………...10 Early Cancer……………………………….…47 Invasive Cancer……………………………..381

Survival Rate: Alive………………………………………....185 (43.2%) 5-Year Survivors…………..………………..112 (26.2%) 10-Year Survivors…………………………...63 (14.7%) Losses……………………………………….216 (50.5%) General Life Span=1675.2±2157.1 days For 5-Year Survivors=4490.8±2592.2 days For 10-Year Survivors=6013±2542.9 days For Losses=635.2±323.6 days Cumulative 5-Year Survival………………..41.8% Cumulative 10-Year Survival………………35% Cumulative 20-Year Survival………………25.1%

General Esophageal Cancer Patients Survival after Complete Esophagogastrectomies (Kaplan-Meier) (n=428):

Results of Univariate Analysis of localization (upper/3 vs Results of Univariate Analysis of localization (upper/3 vs. middle/3 & lower/3) in Prediction of Esophageal Cancer Patients Survival (n=428):

Results of Univariate Analysis of Phase Transition Early—Invasive Cancer in Prediction of Esophageal Cancer Patients Survival (n=428)

Results of Univariate Analysis of Phase Transition N0—N1-2 in Prediction of Esophageal Cancer Patients Survival (n=428):

Results of Univariate Analysis of Adjuvant chemoimmunoradioTherapy in Prediction of Esophageal Cancer Patients Survival (n=428):

Cox Proportional Hazards Results Chi-square P value Results of Cox Regression Modeling in Prediction of Esophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=428): Cox Proportional Hazards Results Chi-square P value Localization: Upper/3 vs. Others/3 4.27775 0.038614 N0---N12 9.55416 0.001995 T1-4 43.87534 0.000000 Age 9.25605 0.002347 G1-3 27.90780 Histology 6.87734 0.008730 Prothrombin Index 12.07929 0.000510 Adjuvant Chemoimmunoradiotherapy 17.65735 0.000026 Phase Transition Early---Invasive Cancer 5.95464 0.014679 Residual Nitrogen 15.07960 0.000103 Protein 8.73003 0.003130 Leucocytes 8.88698 0.002872 Eosinophils 9.38542 0.002187 StickP Neutrophils 9.42220 0.002144 Segmented Neutrophils 8.93026 0.002805 Lymphocytes 8.30869 0.003946 Monocytes 6.14115 0.013207

Corect Classification Rate=100% Error=0.000 Area under ROC Curve=1.000 Results of Neural Networks Computing in Prediction of Esophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=328): Factor Rank Sensitivity Phase Transition Early---Invasive Cancer 1 38130 Localization 2 11348 Healthy Cells/Cancer Cells 3 7478 Lymphocytes/Cancer Cells 4 6958 Phase Transition N0---N12 5 4853 Thrombocytes/Cancer Cells 6 3260 Leucocytes/Cancer Cells 7 3196 Erythrocytes/Cancer Cells 8 3075 Adjuvant Chemoimmunoradiotherapy 9 Corect Classification Rate=100% Error=0.000 Area under ROC Curve=1.000

Results of Bootstrap Simulation in Prediction of Esophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=328): Significant Factors (Number of Samples=3333) Rank Kendal Tau-A P T1-4 1 -0.245 0.000 Tumor Size 2 -0.239 Healthy Cells/Cancer Cells 3 0.231 Erythrocytes/Cancer Cells 4 0.224 Leucocytes/Cancer Cells 5 0.218 Lymphocytes/Cancer Cells 6 0.212 Thrombocytes/Cancer Cells 7 0.199 Segmented Neutrophils/Cancer Cells 8 0.193 Phase Transition N0---N12 9 -0.177 Eosinophils/Cancer Cells 10 0.171 Residual Nitrogen 11 -0.164 Monocytes/Cancer Cells 12 0.163 Coagulation Time 13 -0.162 Blood Chlorides 14 0.142 Phase Transition Early---Invasive Cancer 15 -0.133 G1-3 16 -0.115 0.01 Histology 17 -0.102 0.05 Stick Neutrophils/Cancer Cells 18 0.101 Tumor Growth 19 -0.093 Localization (Upper/3 vs. Others) 20 0.079

Results of Kohonen Self-Organizing Neural Networks Computing in Prediction of Esophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=328):

Esophageal Cancer Dynamics:

Prognostic SEPATH-Model of Esophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=328):

Address: oleg Kshivets M. D. , Ph. D 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