Poster Nr.306

ESOPHAGEAL CANCER: THE ROLE OF CHEMOIMMUNORADIOTHERAPY AFTER SURGERYOleg Kshivets, Klaipeda University Hospital, Lithuania,

62nd SSO Annual Cancer Symposium, March 4-8, 2009, Phoenix, AZ, the USA

Genetic algorithm selection and bootstrap simulation also confirmed significant dependence between 5YS of ECP after radical procedures and all recognized variables. Moreover, bootstrap simulation proved the paramount value of cell ratio factors.

Correct prediction of LCP survival after complete pneumonectomies and lobectomies (R0) was 84% by logistic regression, 85.8% by discriminant analysis and 100% by neural networks computing (error=0.0017; urea under ROC curve=1.0).

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).

Multivariate Cox modeling displayed that 5YS of ECP after complete E significantly depended on: AT (P=0.032), phase 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).

METHODS: We analyzed data of 131 consecutive esophageal cancer (EC) patients (ECP) (age=56.7±7.9 years; tumor size=5.3±2.6 cm) radically operated and monitored in 1975-2008 (males=102, females=29; esophagectomy (E) Ivor- Lewis=93, E Garlock=38; combined E with resection of diaphragm, pericardium, lung, liver, etc=43; lymphadenectomy 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.

Survival FunctionCumulative 5-Year Survival of Esophageal Cancer Patients=52.8%, 10-Year Survival=40.8%, n=131

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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

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Early EC, n=21 Invasive EC=110

Cumulative Proportion Surviving (Kaplan-Meier)5-Year Survival of ECP with N0=71.5%, n=59;

5-Year Survival of ECP with N1-M1A=36.4%, n=72;P=0.00003 by Log-Rank Test

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ECP with N0-M1A, n=72

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;

P=0.003 by Long-Rank TestComplete Censored

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ECP After Adjuvant CHIRT, n=33 ECP After Surgery Along, n=98

These results testify by mathematical (Holling-Tanner) and imitating modeling of system “EC—patient homeostasis” in terms of synergetics. Presence of the two phase transitions is evidently shown on Kohonen self-organizing neural networks maps.

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 phase character, i.e. the transition of one state of patient’s homeostasis into another state occurs in spurts (chain reaction or Hopf bifurcation).

All of these differences and discrepancies were further investigated by structural equation modeling (SEPATH) as well as Monte Carlo simulation. It was revealed that the seven clusters significantly predicted 5YS and life span of ECP after esophagectomies: 1) phase transition “early EC—invasive EC” (P=0.001); 2) phase transition “N0—N1-M1A” (P=0.000); 3) cell ratio factors (P=0.001); 4) EC characteristics (P=0.000); 5) biochemical homeostasis (P=0.000); 6) hemostasis system (P=0.043) and 7) combined procedures and adjuvant chemoimmunoradiotherapy (P=0.030). At that both phase transitions strictly depend on blood cell circuit and cell ratio factors.

CONCLUSIONS: Optimal treatment strategies for esophageal cancer patients

are: 1) availability of very experienced surgeons because of

complexity radical procedures; 2) aggressive en block surgery and adequate lymph node

dissection (abdominal, thoracic, cervical) for completeness; 3) high-precise prediction of survival after surgery; 4) adjuvant chemoimmunoradiotherapy significantly

improved 5-year survival of esophageal cancer patients after complete esophagectomies.