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ESOPHAGEAL CANCER: THE ROLE OF CHEMOIMMUNORADIOTHERAPY AFTER SURGERY
                                                                                                                                       Oleg Kshivets, Klaipeda University Hospital, Lithuania,
                                                                                                                           62nd   SSO Annual Cancer Symposium, March 4-8, 2009, Phoenix, AZ, the USA
   METHODS: We analyzed data of 131 consecutive esophageal cancer (EC) patients (ECP) (age=56.7±7.9 years; tumor                                Genetic algorithm selection and bootstrap simulation also confirmed significant
size=5.3±2.6 cm) radically operated and monitored in 1975-2008 (males=102, females=29; esophagectomy (E) Ivor-                                dependence between 5YS of ECP after radical procedures and all recognized variables.
Lewis=93, E Garlock=38; combined E with resection of diaphragm, pericardium, lung, liver, etc=43; lymphadenectomy                             Moreover, bootstrap simulation proved the paramount value of cell ratio factors.
D2=64, D3=67; adenocarcinoma=95, squamos=34, mix=2; T1=27, T2=40, T3=30, T4=34; N0=59, N1=23, M1a=49; M1b=0;
G1=49, G2=40, G3=42; stage I=24, stage IIA=26, stage IIB=13, stage III=19, stage IVA=49; only surgery-S=98, adjuvant
chemoimmunoradiotherapy-AT=33: 5-FU + thymalin/taktivin + radiotherapy 45-50Gy). Variables selected for 5-year survival
(5YS) study were input levels of 45 blood parameters, sex, age, TNMG, cell type, tumor size. Survival curves were estimated
by the Kaplan-Meier method. Differences in curves between groups of ECP 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: General cumulative 5YS was 52.8%, 10-year survival – 40.8%. 69 ECP (52.7%) were alive, 45 ECP (34.4%) lived
 more than 5 years (life span: LS=3445.2±1680.5 days) and 19 ECP - 10 years (LS=5024.3±1453.9 days) without any features
 of EC progressing. 55 ECP (43.7%) died because of LC during first 5 years after surgery (LS=621.4±366 days).
   It is necessary to pay attention to the two very important prognostic phenomenons. First, we found 100% 5YS for ECP
 with early cancer (T1N0) versus 40.5% for the others ECP after esophagectomies (P=0.00001 by log-rank test). Early
 esophageal cancer was defined, based on the final histopathologic report of the resection specimen, as tumor limited to
 the mucosa or submucosa and not extending into the muscular wall of the esophagus, up to 2 cm in diameter with N0.
 Patients with stage T1N0 did not receive adjuvant chemoimmunoradiotherapy. Correspondingly, the overall 10-year
 survival for ECP with the early cancer was 81% and was significantly better compared to 28% for others patients.
   Second, we observed good 5YS for ECP with N0 (70%) as compared with ECP with N1-M1A (33.1%) after radical
 procedures (P=0.00002 by log-rank test). Accordingly, the overall 10-year survival for ECP with N0 reached 60% and was
 significantly superior compared to 19% for ECP with lymph node metastases.
   5YS was superior significantly in group AT (72.1%; median=1045 days) compared with group S (46.9%; median=895 days)
 (P=0.003 by log-rank test).                                                                                                                  It is necessary to note very important law: the transition of the early cancer into the invasive cancer as well as the cancer with N0 into the cancer with N1-M1A has the
   Multivariate Cox modeling displayed that 5YS of ECP after complete E significantly depended on: AT (P=0.032), phase                       phase character, i.e. the transition of one state of patient’s homeostasis into another state occurs in spurts (chain reaction or Hopf bifurcation).
 transition of early EC into invasive EC (P=0.045), T (P=0.018), N (P=0.013), stage (p=0.002), combined procedures (P=0.012),
 age (P=0.001), blood cell subpopulations (P=0.000-0.045), cell ratio factors (P=0.000-0.037).
    Neural networks computing, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS of
 ECP and phase transition “early-invasive EC” (rank=1), T (2), N (3), AT (4), G (5), sex (6), histology (7), EC growth (8),
 combined procedures (9), hemorrhage time (10), blood bilirubin (11), eosinophils (12). After learning we found the best
 neural networks which confirmed the huge value of phase transition “early---invasive EC” (rank=1), phase transition N0---
 N1-MA (2), AT (3) and cell ratio factors (ratio between blood cell subpopulations and cancer cells in patient’s organism as a
 whole). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.00016).                                                                                                                                                                                                         These results testify by mathematical (Holling-Tanner) and imitating
                                                                                                                                                                                                                                                                                                                          modeling of system “EC—patient homeostasis” in terms of
                                                 Survival Function
          Cumulative 5-Year Survival of Esophageal Cancer Patients=52.8%, 10-Year Survival=40.8%, n=131
                                                                                                                                                                                                                                                                                                                          synergetics. Presence of the two phase transitions is evidently shown
                                               Complete       Censored                                                                                                                                                                                                                                                    on Kohonen self-organizing neural networks maps.
            1.2

                                   1.1                                                                                                                          Correct prediction of LCP survival after complete pneumonectomies and
                                   1.0
                                                                                                                                                                lobectomies (R0) was 84% by logistic regression, 85.8% by discriminant analysis
 Cumulative Proportion Surviving




                                   0.9

                                   0.8
                                                                                                                                                                and 100% by neural networks computing (error=0.0017; urea under ROC
                                   0.7                                                                                                                          curve=1.0).
                                   0.6

                                   0.5

                                   0.4

                                   0.3
                                         -5         0               5              10               15          20    25
                                                                               Survival Time
                                                                        Years After Esophagectomy

                                                       Cumulative Proportion Surviving (Kaplan-Meier)
                                                    5-Year Survival of Patients with Early EC=100%, n=21;
                                                  5-Year Survival of Patients with Invasive EC=43.2%, n=110;
                                                                P=0.00001 by Log-Rank Test
                                                                      Complete        Censored

                                   1.0

                                   0.9
 Cumulative Proportion Surviving




                                   0.8
                                                                                                    Early EC, n=21
                                   0.7                                                              Invasive EC=110

                                   0.6                                                                                                                                                                                                                                                                                      All of these differences and discrepancies were further investigated
                                   0.5
                                                                                                                                                                                                                                                                                                                          by structural equation modeling (SEPATH) as well as Monte Carlo
                                                                                                                                                                                                                                                                                                                          simulation. It was revealed that the seven clusters significantly
                                   0.4
                                                                                                                                                                                                                                                                                                                          predicted 5YS and life span of ECP after esophagectomies: 1) phase
                                   0.3                                                                                                                                                                                                                                                                                    transition “early EC—invasive EC” (P=0.001); 2) phase transition
                                   0.2                                                                                                                                                                                                                                                                                    “N0—N1-M1A” (P=0.000); 3) cell ratio factors (P=0.001); 4) EC
                                              0             5                10              15                20     25
                                                                        Years After Esophagectomy
                                                                                                                                                                                                                                                                                                                          characteristics (P=0.000); 5) biochemical homeostasis (P=0.000); 6)
                                                         Cumulative Proportion Surviving (Kaplan-Meier)                                                                                                                                                                                                                   hemostasis system (P=0.043) and 7) combined procedures and
                                                          5-Year Survival of ECP with N0=71.5%, n=59;
                                                        5-Year Survival of ECP with N1-M1A=36.4%, n=72;
                                                                                                                                                                                                                                                                                                                          adjuvant chemoimmunoradiotherapy (P=0.030). At that both phase
                                                                 P=0.00003 by Log-Rank Test                                                                                                                                                                                                                               transitions strictly depend on blood cell circuit and cell ratio factors.
                                                                      Complete       Censored

                                   1.0

                                   0.9
                                                                                   ECP with N0, n=59
 Cumulative Proportion Surviving




                                                                                   ECP with N0-M1A, n=72
                                   0.8

                                   0.7

                                   0.6

                                   0.5

                                   0.4

                                   0.3
                                                                                                                                                                                                                                 CONCLUSIONS:
                                   0.2

                                   0.1
                                                                                                                                                                                                            Optimal treatment strategies for esophageal cancer patients
                                              0             5                10              15                20     25
                                                                        Years After Esophagectomy                                                                                                         are:
                                                       Cumulative Proportion Surviving (Kaplan-Meier)
                                                  5-Year Survival of ECP After Adjuvant CHIRT=72.1%, n=33;
                                                   5-Year Survival of ECP After Surgery along=46.9%, n=98;
                                                                                                                                                                                                            1) availability of very experienced surgeons because of
                                                                  P=0.003 by Long-Rank Test
                                                                       Complete      Censored                                                                                                             complexity radical procedures;
                                   1.0

                                                                                  ECP After Adjuvant CHIRT, n=33
                                                                                                                                                                                                            2) aggressive en block surgery and adequate lymph node
                                   0.9
                                                                                  ECP After Surgery Along, n=98
                                                                                                                                                                                                          dissection (abdominal, thoracic, cervical) for completeness;
 Cumulative Proportion Surviving




                                   0.8

                                   0.7                                                                                                                                                                      3) high-precise prediction of survival after surgery;
                                   0.6
                                                                                                                                                                                                            4) adjuvant chemoimmunoradiotherapy significantly
                                   0.5

                                   0.4
                                                                                                                                                                                                          improved 5-year survival of esophageal cancer patients after
                                   0.3
                                                                                                                                                                                                          complete esophagectomies.
                                                                                                                                                                                                                                                                                                                                                      Poster Nr.306
                                   0.2
                                              0             5                10              15                20     25
                                                                        Years After Esophagectomy

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Kshivets O. Esophageal Cancer Surgery

  • 1. ESOPHAGEAL CANCER: THE ROLE OF CHEMOIMMUNORADIOTHERAPY AFTER SURGERY Oleg Kshivets, Klaipeda University Hospital, Lithuania, 62nd SSO Annual Cancer Symposium, March 4-8, 2009, Phoenix, AZ, the USA METHODS: We analyzed data of 131 consecutive esophageal cancer (EC) patients (ECP) (age=56.7±7.9 years; tumor Genetic algorithm selection and bootstrap simulation also confirmed significant size=5.3±2.6 cm) radically operated and monitored in 1975-2008 (males=102, females=29; esophagectomy (E) Ivor- dependence between 5YS of ECP after radical procedures and all recognized variables. Lewis=93, E Garlock=38; combined E with resection of diaphragm, pericardium, lung, liver, etc=43; lymphadenectomy Moreover, bootstrap simulation proved the paramount value of cell ratio factors. D2=64, D3=67; adenocarcinoma=95, squamos=34, mix=2; T1=27, T2=40, T3=30, T4=34; N0=59, N1=23, M1a=49; M1b=0; G1=49, G2=40, G3=42; stage I=24, stage IIA=26, stage IIB=13, stage III=19, stage IVA=49; only surgery-S=98, adjuvant chemoimmunoradiotherapy-AT=33: 5-FU + thymalin/taktivin + radiotherapy 45-50Gy). Variables selected for 5-year survival (5YS) study were input levels of 45 blood parameters, sex, age, TNMG, cell type, tumor size. Survival curves were estimated by the Kaplan-Meier method. Differences in curves between groups of ECP 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: General cumulative 5YS was 52.8%, 10-year survival – 40.8%. 69 ECP (52.7%) were alive, 45 ECP (34.4%) lived more than 5 years (life span: LS=3445.2±1680.5 days) and 19 ECP - 10 years (LS=5024.3±1453.9 days) without any features of EC progressing. 55 ECP (43.7%) died because of LC during first 5 years after surgery (LS=621.4±366 days). It is necessary to pay attention to the two very important prognostic phenomenons. First, we found 100% 5YS for ECP with early cancer (T1N0) versus 40.5% for the others ECP after esophagectomies (P=0.00001 by log-rank test). Early esophageal cancer was defined, based on the final histopathologic report of the resection specimen, as tumor limited to the mucosa or submucosa and not extending into the muscular wall of the esophagus, up to 2 cm in diameter with N0. Patients with stage T1N0 did not receive adjuvant chemoimmunoradiotherapy. Correspondingly, the overall 10-year survival for ECP with the early cancer was 81% and was significantly better compared to 28% for others patients. Second, we observed good 5YS for ECP with N0 (70%) as compared with ECP with N1-M1A (33.1%) after radical procedures (P=0.00002 by log-rank test). Accordingly, the overall 10-year survival for ECP with N0 reached 60% and was significantly superior compared to 19% for ECP with lymph node metastases. 5YS was superior significantly in group AT (72.1%; median=1045 days) compared with group S (46.9%; median=895 days) (P=0.003 by log-rank test). It is necessary to note very important law: the transition of the early cancer into the invasive cancer as well as the cancer with N0 into the cancer with N1-M1A has the Multivariate Cox modeling displayed that 5YS of ECP after complete E significantly depended on: AT (P=0.032), phase phase character, i.e. the transition of one state of patient’s homeostasis into another state occurs in spurts (chain reaction or Hopf bifurcation). transition of early EC into invasive EC (P=0.045), T (P=0.018), N (P=0.013), stage (p=0.002), combined procedures (P=0.012), age (P=0.001), blood cell subpopulations (P=0.000-0.045), cell ratio factors (P=0.000-0.037). Neural networks computing, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS of ECP and phase transition “early-invasive EC” (rank=1), T (2), N (3), AT (4), G (5), sex (6), histology (7), EC growth (8), combined procedures (9), hemorrhage time (10), blood bilirubin (11), eosinophils (12). After learning we found the best neural networks which confirmed the huge value of phase transition “early---invasive EC” (rank=1), phase transition N0--- N1-MA (2), AT (3) and cell ratio factors (ratio between blood cell subpopulations and cancer cells in patient’s organism as a whole). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.00016). These results testify by mathematical (Holling-Tanner) and imitating modeling of system “EC—patient homeostasis” in terms of Survival Function Cumulative 5-Year Survival of Esophageal Cancer Patients=52.8%, 10-Year Survival=40.8%, n=131 synergetics. Presence of the two phase transitions is evidently shown Complete Censored on Kohonen self-organizing neural networks maps. 1.2 1.1 Correct prediction of LCP survival after complete pneumonectomies and 1.0 lobectomies (R0) was 84% by logistic regression, 85.8% by discriminant analysis Cumulative Proportion Surviving 0.9 0.8 and 100% by neural networks computing (error=0.0017; urea under ROC 0.7 curve=1.0). 0.6 0.5 0.4 0.3 -5 0 5 10 15 20 25 Survival Time Years After Esophagectomy Cumulative Proportion Surviving (Kaplan-Meier) 5-Year Survival of Patients with Early EC=100%, n=21; 5-Year Survival of Patients with Invasive EC=43.2%, n=110; P=0.00001 by Log-Rank Test Complete Censored 1.0 0.9 Cumulative Proportion Surviving 0.8 Early EC, n=21 0.7 Invasive EC=110 0.6 All of these differences and discrepancies were further investigated 0.5 by structural equation modeling (SEPATH) as well as Monte Carlo simulation. It was revealed that the seven clusters significantly 0.4 predicted 5YS and life span of ECP after esophagectomies: 1) phase 0.3 transition “early EC—invasive EC” (P=0.001); 2) phase transition 0.2 “N0—N1-M1A” (P=0.000); 3) cell ratio factors (P=0.001); 4) EC 0 5 10 15 20 25 Years After Esophagectomy characteristics (P=0.000); 5) biochemical homeostasis (P=0.000); 6) Cumulative Proportion Surviving (Kaplan-Meier) hemostasis system (P=0.043) and 7) combined procedures and 5-Year Survival of ECP with N0=71.5%, n=59; 5-Year Survival of ECP with N1-M1A=36.4%, n=72; adjuvant chemoimmunoradiotherapy (P=0.030). At that both phase P=0.00003 by Log-Rank Test transitions strictly depend on blood cell circuit and cell ratio factors. Complete Censored 1.0 0.9 ECP with N0, n=59 Cumulative Proportion Surviving ECP with N0-M1A, n=72 0.8 0.7 0.6 0.5 0.4 0.3 CONCLUSIONS: 0.2 0.1 Optimal treatment strategies for esophageal cancer patients 0 5 10 15 20 25 Years After Esophagectomy are: Cumulative Proportion Surviving (Kaplan-Meier) 5-Year Survival of ECP After Adjuvant CHIRT=72.1%, n=33; 5-Year Survival of ECP After Surgery along=46.9%, n=98; 1) availability of very experienced surgeons because of P=0.003 by Long-Rank Test Complete Censored complexity radical procedures; 1.0 ECP After Adjuvant CHIRT, n=33 2) aggressive en block surgery and adequate lymph node 0.9 ECP After Surgery Along, n=98 dissection (abdominal, thoracic, cervical) for completeness; Cumulative Proportion Surviving 0.8 0.7 3) high-precise prediction of survival after surgery; 0.6 4) adjuvant chemoimmunoradiotherapy significantly 0.5 0.4 improved 5-year survival of esophageal cancer patients after 0.3 complete esophagectomies. Poster Nr.306 0.2 0 5 10 15 20 25 Years After Esophagectomy