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PRECISE PREDICTION OF PRECISE PREDICTION OF 5-YEAR SURVIVAL OF ESOPHAGEAL AND 5-YEAR SURVIVAL OF ESOPHAGEAL AND CARDIOESOPHAGEAL CANCER PATIENTS CARDIOESOPHAGEAL CANCER PATIENTS AFTER ESOPHAGOGASTRECTOMIES AFTER ESOPHAGOGASTRECTOMIES Oleg Kshivets , MD, PhD Oleg Kshivets , MD, PhD

Kshivets O. Esophageal & Cardioesophageal Surgery

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Page 1: Kshivets O. Esophageal & Cardioesophageal Surgery

PRECISE PREDICTION OF PRECISE PREDICTION OF 5-YEAR SURVIVAL OF ESOPHAGEAL 5-YEAR SURVIVAL OF ESOPHAGEAL AND CARDIOESOPHAGEAL CANCER AND CARDIOESOPHAGEAL CANCER

PATIENTS AFTER PATIENTS AFTER ESOPHAGOGASTRECTOMIESESOPHAGOGASTRECTOMIES

Oleg Kshivets , MD, PhDOleg Kshivets , MD, PhD

Page 2: Kshivets O. Esophageal & Cardioesophageal Surgery

Abstract: PRECISE PREDICTION OF 5-YEAR SURVIVAL OF ESOPHAGEAL AND CARDIOESOPHAGEAL CANCER PATIENTS AFTER ESOPHAGOGASTRECTOMIES Oleg Kshivets OBJECTIVE: We examined factors in terms of precise prediction of 5-year survival (5YS) of esophageal and cardioesophageal cancer (ECEC) patients (ECECP) (T1-4N0M1A) after complete (R0) esophagogastrectomies (EG).    METHODS: We analyzed data of 407 consecutive ECECP (age=55.6±8.6 years; tumor size=6.7±3.3 cm) radically operated and monitored in 1975-2011 (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%. 101 ECECP lived more than 5 years without cancer. 215 ECECP died because of ECEC. Cox modeling displayed (Chi2=232, df=26, P=0.000) that 5YS of ECECP significantly depended on: phase transition (PT) N0—N1-M1A in terms of synergetics, cell ratio factors (CRF) (ratio between cancer cells and blood cells subpopulations), T, G, tumor growth, tumor size, sex, age, adjuvant chemotherapy, localization, blood cells, prothrombin index, ESS, blood chlorides, residual nitrogen (P=0.000-0.043). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT N0--N1-M1A (rank=1), PT early-invasive ECEC (rank=2), tumor size, prothrombin index, blood cells, ESS, age, CRF, blood chlorides, residual nitrogen, localization, adjuvant chemotherapy. Correct prediction of 5YS was 100% by neural networks computing.    CONCLUSIONS: 5YS of ECECP after radical procedures significantly depended on: 1) PT “early-invasive cancer”; 2) PT N0--N1-M1A; 3) CRF; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) anthropometric data; 8) adjuvant chemotherapy; 9) tumor localization.

Page 3: Kshivets O. Esophageal & Cardioesophageal Surgery

DataData::• Males……………………………………………Males………………………………………………….305…….305• Females………..…………………………………Females………..………………………………….......102.......102

• Age=5Age=555..66±±88..66 years years• Tumor Size=Tumor Size=66..77±±33..33 cm cm• Only Surgery.……………………………………Only Surgery.………………………………………...324…...324• Adjuvant ChemoimmunoAdjuvant Chemoimmunoradio/Chemoimmunotherapyradio/Chemoimmunotherapy

(5FU+thymalin/taktivin, 5-6 cycles(5FU+thymalin/taktivin, 5-6 cycles+RT 45-50Gy+RT 45-50Gy))…..83…..83

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Radical Procedures:Radical Procedures:• Left Thoracoabdominal Esophagogastrectomies Left Thoracoabdominal Esophagogastrectomies

(Garlock)……………………..………………271(Garlock)……………………..………………271• Right Thoracoabdominal Esophagogastrectomies Right Thoracoabdominal Esophagogastrectomies • (Ivor Lewis)………………….………………136(Ivor Lewis)………………….………………136• Combined Esophagogastrectomies with Combined Esophagogastrectomies with • Resection of Diaphragm, Pericardium, Lung, Resection of Diaphragm, Pericardium, Lung,

Liver, Pancreas, etc…………..…………..…125Liver, Pancreas, etc…………..…………..…125• 2-Field Lymphadenectomy….………………3012-Field Lymphadenectomy….………………301• 3-Field Lymphadenectomy….………………1063-Field Lymphadenectomy….………………106

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Left Thoracoabdominal Esophagogastrectomy Left Thoracoabdominal Esophagogastrectomy (Garlock)…………………………………….271(Garlock)…………………………………….271

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Garlock Procedures…………………..…271Garlock Procedures…………………..…271

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Right Thoracoabdominal Esophagogastrectomy Right Thoracoabdominal Esophagogastrectomy (Ivor Lewis)......................................................136(Ivor Lewis)......................................................136

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Ivor Lewis Procedures…………………136Ivor Lewis Procedures…………………136

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One-Stage Esophagogastroplasty One-Stage Esophagogastroplasty Intrapleural Anastomosis……….301 Intrapleural Anastomosis……….301 Neck Anastomosis……………….106Neck Anastomosis……………….106

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Staging:Staging:• T1……62 N0..…167 G1…………116T1……62 N0..…167 G1…………116• T2……96 N1……56 G2…………..96T2……96 N1……56 G2…………..96• T3…..140 M1A..184 G3…………195T3…..140 M1A..184 G3…………195• T4…..109 M1B…..0T4…..109 M1B…..0• Stage I…………..43 Stage IIA………...98Stage I…………..43 Stage IIA………...98• Stage IIB………..28 Stage III…………54Stage IIB………..28 Stage III…………54• Stage IVA……..184 Stage IVB…………0 Stage IVA……..184 Stage IVB…………0 • Adenocarcinoma………..................................212 Adenocarcinoma………..................................212 • Squamos Cell Carcinoma……………………185 Squamos Cell Carcinoma……………………185 • Mix Carcinoma..……………………………….10Mix Carcinoma..……………………………….10• Early Cancer……43 Invasive Cancer…….364Early Cancer……43 Invasive Cancer…….364•

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Survival Rate:Survival Rate:• Alive………………………………………....167 (41%)Alive………………………………………....167 (41%)• 5-Year Survivors…………..……………….101 (24.8%) 5-Year Survivors…………..……………….101 (24.8%) • 10-Year Survivors…………………………...53 (13%)10-Year Survivors…………………………...53 (13%)• Losses………………………………………215 (52.8%)Losses………………………………………215 (52.8%)• General Life Span=1612.6General Life Span=1612.6±2070.5 days±2070.5 days• For 5-Year Survivors=4404.4±2543.9 daysFor 5-Year Survivors=4404.4±2543.9 days• For 10-Year Survivors=6095.9±2468.3 daysFor 10-Year Survivors=6095.9±2468.3 days• For Losses=691.1±389.5 daysFor Losses=691.1±389.5 days• Cumulative 5-Year Survival………………..40%Cumulative 5-Year Survival………………..40%• Cumulative 10-Year Survival………………32.7%Cumulative 10-Year Survival………………32.7%

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General General EEsophagealsophageal/Cardioesophageal/Cardioesophageal Cancer Patients Survival Cancer Patients Survival after Complete Esophagogastrectomies (Kaplan-Meier) (after Complete Esophagogastrectomies (Kaplan-Meier) (n=n=407)407)

Survival FunctionGeneral Esophageal and Cardioesophageal Cancer Patients Survival after

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

Complete Censored

-5 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

1.1

1.2

Cum

ulat

ive

Prop

ortio

n Su

rviv

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Results of Univariate Analysis Results of Univariate Analysis of Phase Transition Early—Invasive of Phase Transition Early—Invasive Cancer iCancer in Prediction of n Prediction of EEsophagealsophageal/Cardioesophageal/Cardioesophageal Cancer Cancer

Patients SurvivalPatients Survival ( (n=n=407)407)

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

Complete Censored

0 5 10 15 20 25 30 35 40

Years after Esophagogastrectomies

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

Cum

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Invasive Cancer Patients=364 Early Cancer Patients=43

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Results of Univariate Analysis Results of Univariate Analysis of Phase Transition N0—N1M1A of Phase Transition N0—N1M1A in in Prediction of Prediction of EEsophagealsophageal/Cardioesophageal/Cardioesophageal Cancer Patients Cancer Patients

SurvivalSurvival ( (n=n=407)407)

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

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

Cum

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

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Results of Univariate Analysis Results of Univariate Analysis of Adjuvant Therapy of Adjuvant Therapy in Prediction of in Prediction of EEsophagealsophageal/Cardioesophageal /Cardioesophageal Cancer Patients Survival Cancer Patients Survival ( (n=n=407)407)

Cumulative Proportion Surviving (Kaplan-Meier)Complete Censored

5-Year Survival after Adjuvant Treatment=60.8%;5-Year Survival after Surgery Along=36.4%;

P=0.00018 by Log-Rank Test

0 5 10 15 20 25 30 35 40

Years after Esophagogastrectomies

0.0

0.1

0.2

0.3

0.4

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0.6

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Adjuvant Treatment, n=83 Only Surgery, n=324

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Results of Univariate Analysis Results of Univariate Analysis of Tumor Localization of Tumor Localization in Prediction in Prediction of of EEsophagealsophageal/Cardioesophageal /Cardioesophageal Cancer Patients Survival Cancer Patients Survival ( (n=n=407)407)

Cumulative Proportion Surviving (Kaplan-Meier)Complete Censored

5-Year Survival of Esophageal Cancer Patients=49.1%;5-Year Survival of Cardioesophageal Cancer Patients=34.4%;

P=0.003 by Log-Rank Test

0 5 10 15 20 25 30 35 40

Years after Esophagogastrectomies

0.0

0.1

0.2

0.3

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Cardioesophageal Cancer Patients, n=272 Esophageal Cancer Patients, n=135

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Results of Cox Regression Modeling in Prediction of Results of Cox Regression Modeling in Prediction of Esophageal/Cardioesophageal Cancer Patients Survival after Complete Esophageal/Cardioesophageal Cancer Patients Survival after Complete

Esophagogastrectomies (n=407Esophagogastrectomies (n=407))

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Results of Neural Networks ComputingResults of Neural Networks Computing in Prediction of in Prediction of Esophageal/Cardioesophageal Cancer Patients Survival after Complete Esophageal/Cardioesophageal Cancer Patients Survival after Complete

Esophagogastrectomies (n=316Esophagogastrectomies (n=316))

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Results of Bootstrap Simulation Results of Bootstrap Simulation in Prediction of Esophageal Cancer in Prediction of Esophageal Cancer Patients Survival after Complete Esophagectomies (n=316Patients Survival after Complete Esophagectomies (n=316))

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Holling-Tenner Models of Esophageal /Cardioesophageal Cancer Holling-Tenner Models of Esophageal /Cardioesophageal Cancer Cell Population and Cytotoxic Cell Population DynamicsCell Population and Cytotoxic Cell Population Dynamics

3 4 5 6 7 8

Glucose02.557.510Lymphocytes/Cancer Cells

00

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

11

5-Ye

ar S

urviv

al

5-Ye

ar S

urviv

al

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

3 4 5 6 7 8

Glucose00.511.522.5Monocytes/Cancer Cells

00

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

11

5-Ye

ar S

urviv

al

5-Ye

ar S

urviv

al

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

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Results of Results of Kohonen Self-Organizing Kohonen Self-Organizing Neural Neural Networks Computing in Prediction ofNetworks Computing in Prediction of

Esophageal/Cardioesophageal CEsophageal/Cardioesophageal Cancer Patients ancer Patients SurvivalSurvival after Complete Esophagogastrectomies after Complete Esophagogastrectomies

(n=316) (n=316)

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Esophageal/Cardioesophageal Cancer DynamicsEsophageal/Cardioesophageal Cancer Dynamics

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Prognostic SEPATH-Model of Esophageal/Cardioesophageal Prognostic SEPATH-Model of Esophageal/Cardioesophageal Cancer Patients Survival after Complete Esophagectomies, n=316Cancer Patients Survival after Complete Esophagectomies, n=316

Page 24: Kshivets O. Esophageal & Cardioesophageal Surgery

Conclusions:Conclusions:• 5-Year Survival of Esophageal and Cardioesophageal 5-Year Survival of Esophageal and Cardioesophageal

Cancer Patients after Radical Procedures Cancer Patients after Radical Procedures Significantly Depended on: Significantly Depended on:

• 1) Phase Transition “Early—Invasive Cancer”; 1) Phase Transition “Early—Invasive Cancer”; • 2) Phase Transition N0—N1M1A; 2) Phase Transition N0—N1M1A; • 3) Cell Ratio Factors (ratio between cancer cells and 3) Cell Ratio Factors (ratio between cancer cells and

blood cells subpopulations); blood cells subpopulations); • 4) Blood Cell Circuit; 4) Blood Cell Circuit; • 5) Biochemical Homeostasis; 5) Biochemical Homeostasis; • 6) Hemostasis System; 6) Hemostasis System; • 7) Anthropometry; 7) Anthropometry; • 8) Adjuvant Treatment; 8) Adjuvant Treatment; • 9) Tumor Localization and Characteristics.9) Tumor Localization and Characteristics.

Page 25: Kshivets O. Esophageal & Cardioesophageal Surgery

Address:Address:Oleg KshivetsOleg Kshivets M.D., Ph.D.,M.D., Ph.D.,

Consultant Thoracic, Consultant Thoracic, Abdominal, General Surgeon Abdominal, General Surgeon & Surgical Oncologist & Surgical Oncologist

• e-mail: [email protected] e-mail: [email protected] • skype: okshivets skype: okshivets • http: //www.ctsnet.org/home/okshivets http: //www.ctsnet.org/home/okshivets