OPTIMIZATION OF TREATMENT FOR PATIENTS WITH LOCAL GASTRIC CANCER RELAPSE AFTER

COMPLETE STOMACH STUMP EXTIRPATIONS

Oleg Kshivets, MD, PhD Department of Surgery, Siauliai Public Hospital & Cancer Center, Siauliai, Lithuania2007 Gastrointestinal Cancers Symposium, January 19-21, 2007, Orlando, FL, the USA

Abstract• OBJECTIVE: The survival of patients with local relapse of gastric cancer (RGC) after subtotal

gastrectomies takes several months. Repeated radical operations are extremely complex and remain the prerogative of several best surgeons of the world. We examined the clinicomorphologic factors associated with the low- and high-risk of generalization of RGC (T1-4N0-2M0) after complete stomach stump extirpations (SSE). Relapses were diagnosed during 1-4 years after complete subtotal gastrectomies. METHODS: We analyzed data of 77 consecutive RGC patients (RGCP) (age=54.1±1.1 years; tumor size=9.0±0.4 cm) radically operated and monitored in 1975-2006 (males=54, females=23; combined SSE with resection of 1-5 adjacent organs: esophagus, pancreas, liver, diaphragm, colon transversum, splenectomies =63; T1=4, T2=10, T3=39, T4=24; N0=25, N1=4, N2=48; G1=12, G2=8, G3=58; adjuvant chemoimmunotherapy 5FU+taktivin/thymalin-AT=16). Variables selected for 5-year survival (5YS) study were input levels of 45 blood parameters, sex, age, TNMPG, cell type, tumor size, AT. Survival curves were estimated by the Kaplan-Meier method. Differences in curves between groups of RGCP were evaluated using a log-rank test. Multivariate Cox modeling, multi-factor clustering, discriminant analysis, structural equation modeling, Monte Carlo, bootstrap simulation and neural networks computing were used to determine any significant dependence.   RESULTS: For total of 77 RGCP overall LS was 964.3±154.6 days and cumulative 5YS reached 18.3%. 23 RGCP are alive, 8 RGCP lived more than 5 years and 4 – 10 years without RGC progressing. 53 RGCP died because of RGC LC during first 5 years after surgery. Cox modeling displayed that 5YS of RGCP after SSE significantly depended on: N0-2, T1-4, combined procedures, AT, histology, G1-3, blood monocytes, neutrophils, lymphocytes, eosinophils, ratio of lymphocytes to RGC cells, lymphoid infiltration of RGC, age, hemorrhage time, blood chlorides, RGC growth (P=0.049-0.000). Neural networks computing, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS of CECP and combined procedures (rank=1), G1-3 (2), gender (3), AT (4), RGC growth (5), age (6), N0-2 (7), weight (8), histology (9), blood monocytes (10), lymphocytes (11), neutrophils (12).   CONCLUSIONS: Correct prediction of RGCP survival after SSE was 100% by discriminant analysis and neural networks computing (area under ROC curve=1.0; error=0.0011). AT significantly improved RGCP 5YS after SSE (P=0.046 by log-rank test).

Factors1) Antropometric Factors……………….…….…..42) Blood Analysis…………………………..……..263) Hemostasis Factors……………………..……....34) Cell Ratio Factors………………………….…...9 6) Gastric Cancer Relapse Characteristics..…...127) Biochemic Factors……………………………...78) Treatment Characteristics……………………..39) Survival Data………...…………………………4 In All………………………...…………………..68

Main Problem of Analysis of Alive Supersystems including Combinatorial Optimization (e.g. Cancer Patient Homeostasis, Search of Optimal Treatment Plan ): Phenomenon of «Combinatorial Explosion»

Number of Clinicomorphological Factors:……...…..68Number of Possible Combination for Random Search:……………..………………….n!=68!=2.48e+96 Operation Time of IBM Blue Gene/L Supercomputer (135.5TFLOPS) …………………………5.8e+74 YearsThe Age of Our Universe……….....1.3e+10 Years

Basis:NP RP P n! n*n*2(e+n) or n log n n AI CSA+S+B SMAI - Artificial IntelligenceCSA - Complex System AnalysisS - Statistics B - Biometrics

SM - Simulation Modeling

Data

Males………………………………………………54Females………..…………………………………..23Age=54.1±1.1 yearsTumor Size=9.0±0.4 cmOnly Surgery...……………………………………61Adjuvant Chemoimmunotherapy (5FU+thymalin/taktivin, 5-6 cycles)……………..16

Radical Procedures

Stomach Stump Extirpations………………..……...77Combined Stomach Stump Extirpations with Resection of Liver, Pancreas, Esophagus, Diaphragm, Liver, Mesocolon, Colon Transversum, Jejunum, Splenectomy.………………………………….……...63Lymphadenectomy D2………………………………21Lymphadenectomy D3………………………………56In All….…………………………...………………….77

Schemas of Procedures

Schemas of Procedures

Schemas of Combined Procedures

Schemas of D3 Lymphadenectomy

Staging

T1….…....4 N0..…..25 G1………….12T2……...10 N1……..4 G2…………...8T3……...39 N2…….48 G3…………57T4……...24Adenocarcinoma……....…...……………...………77

SurvivalAlive………..……………….……………….23 (29.9%)5-Year Survivors…………..………………...8 (10.4%) 10-Year Survivors…………………………...4 (5.2%)Losses from Cancer………………………...53 (68.8%)General Life Span=964.3±1356.4 days (SE=154.6)Life Span of 5-Year Survivors=4457.5±1868.4 daysLife Span of Losses=563.0±62.3 daysCumulative 5-Year survival………………...18.3%Cumulative 10-Year survival……………….15.9%

General Survival of Patients with Local Gastric Cancer Relapce after Complete Stomach Stump Extirpations (Kaplan-Meier) (n=77)

Survival FunctionComplete Censored

General Survival of Patients with Local Gasric Cancer Relapse, n=77

Survival TimeYears

Cum

ulat

ive

Prop

ortio

n Su

rviv

ing

0.00.10.20.30.40.50.60.70.80.91.0

0 5 10 15 20 25

Results of Univariate Analysis in Prediction of Patients Survival with Local Gastric Cancer Relapse (n=77, P=0.046 by log-rank test)

Cumulative Proportion Surviving (Kaplan-Meier)Complete Censored

Survival of Patients with Gastric Cancer Relapse P=0.046 by log-rank test

Years

Cum

ulat

ive

Prop

ortio

n Su

rviv

ing

0.00.10.20.30.40.50.60.70.80.91.0

0 5 10 15 20 25

only surgery, n=61 adjuvant chemoimmunotherapy, n=16

Results of Cox Regression Modeling in Prediction of Patients Survival with Gastric Cancer Relapse after Complete Stomach Stump Extirpations (n=77)

Factors Wald df P Exp(B) 95%CI for Exp(B)Lower Upper

Eosinophils% 13.425 1 0.000 0.023 0.003 0.174Stick.Neutrophils% 10.189 1 0.001 0.054 0.009 0.325Seg.Neutrophils% 11.582 1 0.001 0.044 0.007 0.266Lymphocytes% 11.260 1 0.001 0.044 0.007 0.272Monocytes% 8.361 1 0.004 0.076 0.013 0.435Heamorrhage Time 20.967 1 0.000 1.087 1.049 1.126Chlorides 8.347 1 0.004 0.885 0.814 0.961Eosinophils abs 15.447 1 0.000 2.1e+13 4.8e+6 9.5e+19Seg.Neutrophils abs 20.363 1 0.000 44.674 8.578 232.668Monocytes abs 16.292 1 0.000 0.001 0.000 0.000

Results of Cox Regression Modeling in Prediction of Patients Survival with Gastric Cancer Relapse after Complete Stomach Stump Extirpations (n=77)

Factors Wald df P Exp(B) 95%CI for Exp(B)Lower Upper

T1-4 37.175 3 0.000T(1) 32.868 1 0.000 0.000 0.000 0.000T(2) 3.892 1 0.049 0.098 0.010 0.985T(3) 7.797 1 0.005 0.150 0.040 0.568N0-2 31.930 3 0.000N(1) 0.962 1 0.327 0.191 0.007 5.208N(2) 4.593 1 0.032 0.033 0.001 0.747N(3) 7.323 1 0.007 0.012 0.000 0.294G1-3 9.381 2 0.009G(1) 9.311 1 0.002 0.074 0.014 0.395G(2) 0.144 1 0.705 0.769 0.198 2.987

Results of Cox Regression Modeling in Prediction of Patients Survival with Gastric Cancer Relapse after Complete Stomach Stump Extirpations (n=77)

Factors Wald df P Exp(B) 95%CI for Exp(B)Lower Upper

Histology 39.326 2 0.000Histology(1) 5.688 1 0.017 0.028 0.001 0.529Histology(2) 0.167 1 0.682 1.809 0.106 30.974Comb.Procedures 20.648 6 0.002Comb.Procedures(1) 18.522 1 0.000 0.000 0.000 0.000Comb.Procedures(2) 2.986 1 0.084 0.311 0.083 1.170Comb.Procedures(3) 2.017 1 0.156 0.114 0.006 2.281Comb.Procedures(4) 0.736 1 0.391 0.192 0.004 8.365Comb.Procedures(5) 1.671 1 0.196 0.322 0.058 1.796Comb.Procedures(6) 3.503 1 0.061 3.154 0.947 10.500

Results of Cox Regression Modeling in Prediction of Patients Survival with Gastric Cancer Relapse after Complete Stomach Stump Extirpations (n=77)

Factors Wald df P Exp(B) 95%CI for Exp(B)Lower Upper

Growth 38.281 2 0.000Growth(1) 11.422 1 0.001 18.725 3.424 102.406Growth(2) 5.208 1 0.022 0.160 0.033 0.772Monocytes tot 13.888 1 0.000 1031.7 26.830 4.0e+4Eosinophils tot 5.486 1 0.019 0.056 0.005 0.625Seg.Neutrophils tot 22.896 1 0.000 0.414 0.288 0.594Lymphocytes/CC 6.774 1 0.009 65.078 2.804 1510.278Age 3.869 1 0.049 1.047 1.000 1.095Adjuvant CHIT 12.403 1 0.000 0.106 0.030 0.369

Results of Discriminant Analysis in Prediction of Patients Survival with Local Gastric Cancer Relapse after Complete Stomach Stump Extirpations (n=61)

Discriminant Function Analysis Summary

Wilks' Lambda: 0.579 approx. F (12,48)=2.910 p< 0.0042 Wilks' Partial F-remove P-level

Lambda Lambda (1,48) G1-3 .675 .858 7.941 .007Comb.Oper. .671 .863 7.615 .008Adjuvant CHIT .658 .879 6.589 .013Prothrombin Index .615 .879 6.589 .088Seg. Neutrophils .607 .954 2.298 .136

Results of Logistic Regression Analysis in Prediction of Patients Survival with Local Gastric Cancer Relapse after

Complete Stomach Stump Extirpations (n=61)

Est. S.E. Wald P Odds 95.0% C.I.for Odds Ratio Ratio Lower Upper

Const.B 12.47 8.33 2.24 .140 2.6e+5 0.01 4.7e+12PI -.07 .06 1.30 .259 .94 .83 1.05Seg.Neut.abs .08 .04 3.20 .078 2.20 .90 5.50Age -.18 .11 2.32 .134 .84 .66 1.06G1-3 -3.32 1.37 5.86 .019 .04 .00 .57Ad.CHIT 6.50 3.10 4.50 .038 675.5 1.40 3.1+5Comb.Op. -.66 .32 4.20 .045 .52 .27 .99

Chi2=30.342; df=6; P=0.00003; Odds ratio=156.0

SEPATH-Modeling in Prediction of Patients Survival with Local Gastric Cancer Relapse after Complete Stomach Stump Extirpations (n=61)

Neural Networks in Prediction of Patients Survival with Local Gastric Cancer Relapse after Complete Stomach Stump Extirpations (n=61)

Baseline Errors=0.0011 Area under ROC curve=1.00 Correct Classification Rate=100%

Losses 5-year survivors Total 53 8

Correct 53 8 Wrong 0 0

Genetic Algorithm SelectionUseful for S% M% ESS Haemor.Time St.abs Sabs Age Histology G1-3 Survival Yes Yes Yes Yes Yes Yes Yes Yes YesUseful for Ad.CHIT Comb.Oper. Stot Monocytes/CC Growth Tumor SizeSurvival Yes Yes Yes Yes Yes Yes

Results of Neural Networks Computing in Prediction of Patients Survival with Gastric Cancer Relapse after Complete Stomach Stump Extirpations (n=61)

Error=0.0011; Area under ROC Curve=1.00; Correct Classification Rate=100%

Factor Rank Error RatioComb.Operat. 1 0.348 305.8G1-3 2 0.316 278.0Sex 3 0.224 196.8Ad.CHIT 4 0.181 159.2Growth 5 0.146 128.5Age 6 0.121 106.7N0-2 7 0.075 66.1Weight 8 0.072 63.7Histology 9 0.018 16.2Monocytes% 10 0.014 12.1Lymphocytes% 11 0.006 5.2Seg.Neutr.tot 12 0.005 4.7

Factor Rank Error RatioHaem.Time 13 0.005 4.5Coag.Time 14 0.005 4.3Seg.Neutr.abs 15 0.004 3.6ESS 16 0.004 3.1T1-4 17 0.003 3.0Eosinophils% 18 0.003 2.2Tumor Size 19 0.003 2.2Seg.Neutr.% 20 0.002 1.9St.Neutr.abs 21 0.002 1.7Bilirubin 22 0.002 1.5Clucose 23 0.001 1.2Lymph.abs 24 0.001 1.2

Results of Bootstrap Simulation in Prediction of Patients Survival with Local Gastric Cancer Relapse after Complete Stomach Stump Extirpations (n=61)

Number of Samples=3333Significant Factors Rank Kendall’s Tau-A P<Combined Operation 1 -0.109 0.000G1-3 2 -0.109 0.000Haemorrhage Time 3 -0.107 0.000ESS 4 0.098 0.000PI 5 -0.087 0.000Chlorides 6 0.086 0.000Age 7 -0.073 0.000Seg.Neutrophils abs 8 0.072 0.000Seg.Neutrophils tot 9 0.066 0.000Tumor Size 10 0.064 0.000Erythrocytes/CC 11 -0.063 0.000

Results of Bootstrap Simulation in Prediction of Patients Survival with Local Gastric Cancer Relapse after Complete Stomach

Stump Extirpations (n=61)Number of Samples=3333

Significant Factors Rank Kendall’s Tau-A P<Leucocytes 12 0.063 0.000CI 13 -0.060 0.000Seg.Neutrophils % 14 0.054 0.000Leucocytes tot 15 0.051 0.000Healthy Cells/CC 16 -0.050 0.000Residual Nitrogen 17 0.043 0.000Erythrocytes 18 -0.042 0.000Sex 19 0.041 0.000Adjuvant CHIT 20 0.040 0.001Seg.Neutrophils/CC 21 0.040 0.001Lymphocytes abs 22 0.036 0.002

Prediction of Patients Survival with Local Gastric Cancer Relapse after Complete Stomach Stump Extirpatins (n=61)

Classification of Cases by Logistic Regression, n=61(5-Year Survivors--Losses) Odds Ratio=33.5

Observed Pred.Losses Pred.Survivors CorrectLosses 52 1 98.1%5-Year Survivors 2 6 75.0%Total 54 7 95.1%

Classification of Cases by Discriminant Analysis, n=61Observed Pred.Losses Pred.Survivors CorrectLosses 52 1 98.1%5-Year Survivors 2 6 75.0%Total 54 7 95.1%

Classification of Cases by Neural Networks, n=61Observed Pred.Losses Pred.Survivors CorrectLosses 53 0 100%5-Year Survivors 0 8 100%Total 53 8 100%

Ratio Lymphocytes to Cancer Cells Populations in Prediction of Patients Survival with Local Gastric Cancer Relapse after Complete Stomach Stump

Extirpations (n=61)

Conclusions:Optimal treatment strategies for patients with local gastric cancer relapse are:1) dynamic monitoring of gastric cancer patients after gastrectomies for early detection of local cancer relapce; 2) availability of very experienced surgeons because of baffling complexity repeated radical procedures;3) aggressive en block surgery for completeness; 4) precise prediction; 5) adjuvant chemioimmunotherapy for patients with unfavorable prognosis.

Oleg Kshivets, M.D., Ph.D. Consultant Thoracic/Abdominal/General Surgeon & Surgical Oncologist Department of Surgery, Siauliai Public Hospital & Cancer CenterAddress: Tilzes:42-16, LT78206 Siauliai, Lithuania

Tel. (37041)416614 e-mail: kshivets@yahoo.com http//:myprofile.cos.com/Kshivets