Oleg Kshivets, MD, PhD Siauliai Public Hospital, Siauliai, Lithuania

5-YEAR SURVIVAL OF ESOPHAGEAL/CARDIOESOPHAGEAL CANCER PATIENTS AFTER RADICAL SURGERY SIGNIFICANTLY DEPENDED ON PHASE TRANSITION “EARLY-INVASIVE CANCER”, LYMPH NODE METASTASES AND CELL RATIO FACTORS

Oleg Kshivets Surgery Department, Siauliai Public Hospital, Lithuania   OBJECTIVE: We examined factors associated with low/high-risk of generalization of

esophageal/cardioesophageal cancer (ECEC) (T1-4N0M1A) after complete (R0) esophagogastrectomies (EG).    METHODS: We analyzed data of 407 consecutive ECEC patients (ECECP) (age=55.6±8.6 years; tumor size=6.7±3.3 cm) radically operated and monitored in 1975-2010 (m=305, f=102;EG Garlock=271, EG Lewis=136, combined EG with resection of pancreas, liver, diaphragm, colon transversum, lung, trachea, pericardium, splenectomy=125; adenocarcinoma=212, squamous=185, mix=10; T1=62, T2=96, T3=140, T4=109; N0=167, N1=56, M1A=184, G1=116, G2=96, G3=195; early ECEC=43, invasive=364). 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 1612.6±2070.5 days and cumulative 5-year survival (5YS) reached 40%, 10 years – 32.7%, 20 years – 23.5%. 101ECECP lived more than 5 years without ECEC. 215ECECP died because of ECEC. Cox modeling displayed (Chi2=46.0, df=5, P=0.000) that 5YS of ECECP significantly depended on: phase transition (PT) early-invasive ECEC in terms of synergetics, PT N0--N1-M1A, cell ratio factors (CRF) (ratio between cancer cells – CC and blood cells subpopulations) (P=0.001-0.029). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive ECEC (rank=1), PT N0--N1-M1A (rank=2), healthy cells/CC, monocytes/CC, segmented neutrophils/CC, eosinophils/CC, stab neutrophils/CC, leucocytes/CC, lymphocytes/CC, thrombocytes/CC, erythrocytes/CC. Correct prediction of 5YS was 100% by neural networks computing.

    CONCLUSIONS:5YS of ECECP after radical procedures significantly depended on: 1) PT “early-invasive ECEC”; 2) PT N0--N1-M1A; 3) CRF.

Males……………………………………………………………305

Females………….…………………………………………….102

Age=55.6±8.6 years Tumor Size=6.7±3.3 cm Esophagogastrectomies Ivor-

Lewis……………......136 Esophagogastrectomies Garlock………………..

…..271 Combined procedures with resection of

pancreas, liver, diaphragm, VCS, colon transversum, lung, trachea, pericardium, splenectomy …………….….125

T1……..62 N0..…..167 G1..………116 T2……..96 N1……...56 G2…..……..96 T3……140 M1A….184 G3.….……195 T4……109 Early Cancer……………………………………….…….43 Invasive Cancer.............................................364 Adenocarcinoma…………………………………….212 Squamous Cell Carcinoma……..……………….185 Mix Carcinoma..…………………….......................10

5-Year Survivors…………..………….101 (24.8%)

Losses……………………………………215 (52.8%)

General Life Span=1612.6±2070.5 days For 5-Year Survivors=4404.4±2543.9 days For Losses=649.8±388.2 days

Cumulative 5-Year Survival……………....40.0%

Cumulative 10-Year Survival…..............32.7%

Survival FunctionGeneral Esophageal and Cardioesophageal Cancer Patients Survival after

Complete Esophagogastrectomies, n=407Cumulative 5-Year Survival=40%; 10-Year survival=32.7%

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Cumulative Proportion Surviving (Kaplan-Meier)Cumulative 5-Year Survival of Early Cancer Patients=100%

Cumulative 5-Year Survival of Invasive Cancer Patients=33.2%P=0.000 by Log-Rank Test

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Invasive Cancer Patients=364 Early Cancer Patients=43

Cumulative Proportion Surviving (Kaplan-Meier)Cumulative 5-Year Survival of Cancer Patients with N0=60.3%

Cumulative 5-Year Survival of Cancer Patients with N1-M1A=25.1%P=0.000 by Log-Rank Test

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Cancer Patients with N0=167 Cancer Patients with N1-M1A=240

Factors Wald df P

Phase Transition Early-Invasive LC 5.864 1 0.015 Phase Transition N0—N1-2 11.871 1

0.001 Leucocytes/Cancer Cells 5.844 1 0.016 Segmented Neutrophils/Cancer Cells 4.794 1 0.029 Monocytes/Cancer Cells 4.998 1 0.025

Discriminant Function Analysis Summary Wilks' Lambda: 0.703 approx. F (8,307)=16.179 p< 0.0000; Correct Classification Rate=78.5% Wilks'-Lambda P Phase Transition Early-Invasive Lung Cancer 0.714 0.029 Phase Transition N0—N1-2 0.744 0.000 Erythrocytes/Cancer Cells 0.718 0.012 Leucocytes/Cancer Cells 0.719 0.010 Segmented Neutrophils/Cancer Cells 0.719 0.010 Lymphocytes/Cancer Cells 0.716 0.018 Monocytes/Cancer Cells 0.714 0.029 Healthy Cells/Cancer Cells 0.720 0.008

5-Year Survivors LossesBaseline Errors=0.000 Total 215 101Area under ROC Curve=1.0 Correct 215

101Correct Classification Rate=100% Wrong 0 0

Factor Rank Sensitivity Phase Transition Early-Invasive Cancer 1 49239

Phase Transition N0---N12 2 15916 Healthy Cells/Cancer Cells 3 6775 Monocytes/Cancer Cells 4 5656 Segmented Neutrophils/Cancer Cells 5 4612 Eosinophils/Cancer Cells 6 4176 Stab Neutrophils/Cancer Cells 7 3601 Leucocytes/Cancer Cells 8 3469 Lymphocyte/Cancer Cells 9 3136 Thrombocytes/Cancer Cells 10 2925 Erythrocytes/Cancer Cells 11 2885

Factor Useful for 5-Year Survival

Phase Transition Early-Invasive Cancer Yes

Phase Transition N0---N1M1A Yes Leucocyte/Cancer Cells Yes Monocyte/Cancer Cells Yes Healthy Cells/Cancer Cells Yes

Number of Samples=3333 Significant Factors Rank Kend.Tau-A P Healthy Cells/Cancer Cells 1 0.230 0.000 Erythrocytes/Cancer Cells 2 0.226 0.000 Leucocytes/Cancer Cells 3 0.215 0.000 Lymphocytes/Cancer Cells 4 0.205 0.000 Thrombocytes/Cancer Cells 5 0.202 0.000 Segmented Neutrophils/Cancer Cells 6 0.190 0.000 Eosinophils/Cancer Cells 7 0.175 0.000 Phase Transition N0—N1M1A 8 -0.1720.000 Monocytes/Cancer Cells 9 0.158 0.000 Phase Transition Early-Invasive Cancer 10 -0.1250.001 Stab Neutrophils/Cancer Cells 11 0.083 0.048

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Glucose02.557.510Lymphocytes/Cancer Cells

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P=0.000z=a+bx+cx (̂1.5)+dx 2̂+ex (̂2.5)+fx 3̂+gy (̂0.5)lny+hy (̂0.5)+ie (̂-y)

r 2̂=0.22525238 DF Adj r 2̂=0.20246569 FitStdErr=0.41643509 Fstat=11.157259a=-324.15986 b=995.38663 c=-1201.3125 d=607.59325 e=-144.67162

f=13.358387 g=-1.246218 h=5.1686977 i=3.3595194

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Glucose00.511.522.5Monocytes/Cancer Cells

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P=0.000z=a+blnx+c(lnx) 2̂+d(lnx) 3̂+e(lnx) 4̂+f(lnx) 5̂+glny+h(lny) 2̂+i(lny) 3̂+j(lny) 4̂+k(lny) 5̂

r 2̂=0.16790831 DF Adj r 2̂=0.13779973 FitStdErr=0.4329842 Fstat=6.1546145a=-384.21482 b=1274.4403 c=-1669.3899 d=1080.7312 e=-345.52251 f=43.62225

g=0.5669461 h=-0.099389185 i=-0.2903548 j=-0.10570297 k=-0.011258385

5-year survival and life span of esophageal and cardioesophageal cancer patients after complete esophagogastrectomies significantly depended on:

1) phase transition early—invasive cancer; 2) phase tranzition N0---N1M1A; 3) cell ratio factors: ratio of cancer cell

population to blood cell subpopulations in integral patient organism.