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Lung Cancer: System Approach
Oleg Kshivets, MD, PhD Surgery Department, Roshal Hospital, Roshal, Moscow, Russia
OBJECTIVE: Search of optimal diagnosis and treatment strategies for non-small cell lung cancer (LC) pa­tients (LCP) (T1-4N0-
2M0) was realized.
METHODS: We analyzed data of 708 consecutive LCP (age=57.5±8.3 years; tumor size=4.3±2.4 cm) radically operated (R0) and
monitored in 1985-2017 (m=613, f=95;lobectomies=461, pneumonectomies=247, mediastinal lymph node dissection=708; combined
procedures with resection of trachea, carina, atrium, aorta, VCS, vena azygos, pericardium, liver, diaphragm, ribs, esophagus=192;
only surgery-S=563, adjuvant chemoimmunoradiotherapy-AT=145: CAV/gemzar + cisplatin + thymalin/taktivin + radiotherapy 45-
50Gy; T1=269, T2=251, T3=131, T4=57; N0=460, N1=130, N2=118, M0=708; G1=178, G2=216, G3=314; squamous=394,
adenocarcinoma=266, large cell=48; early LC=164, invasive LC=544. 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 2196.3±1764.1 days and cumulative 5-year survival (5YS) reached 71.1%, 10 years – 63%, 20
years – 43.4%. 451LCP lived more than 5 years (LS=3125.7±1560.3 days), 128LCP – more than 10 years (LS=5123.1±1547.9
days).195 LCP died because of LC (LS=560±372.1 days). AT significantly improved 5YS (58.3% vs. 34.1%) (P=0.001 by log-rank test)
only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC
in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3,
histology, glucose, RH, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time, weight (P=0.000-0.030).
Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive
LC (rank=1), PT N0—N12(rank=2),healthy cells/CC (3), lymphocytes/CC (4), thrombocytes/CC (5), eosinophils/CC (6),
erythrocytes/CC (7), segmented neutrophils/CC (8), glucose (9), monocytes/CC (10), stick neutrophils/CC (11), leucocytes/CC (12).
Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3)
cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9)
anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability
of experienced thoracoabdominal surgeons because of complexity of radical procedures; 3) aggressive en block surgery and
adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with
unfavorable prognosis.
Cox Regression: n=708 Parameter
Estimate
Standard
Error
Chi-square P value 95%
Lower CL
95%
Upper CL
Hazard Ratio
Weight -0.03847 0.009494 16.41380 0.000051 -0.05707 -0.019857 0.962265
Rh-factor 0.46842 0.210741 4.94059 0.026233 0.05538 0.881470 1.597475
Histology 0.28926 0.085602 11.41872 0.000727 0.12149 0.457039 1.335442
G1-3 0.34479 0.088371 15.22237 0.000096 0.17158 0.517989 1.411688
Glucose -0.30720 0.081717 14.13231 0.000170 -0.46736 -0.147036 0.735504
Prothrombin Index 0.02908 0.006817 18.19131 0.000020 0.01572 0.042439 1.029504
Recalcification Time -0.00522 0.001705 9.39082 0.002181 -0.00857 -0.001883 0.994789
Heparin Tolerance 0.00366 0.000672 29.69991 0.000000 0.00234 0.004979 1.003669
Phase Transition Early—Invasive Cancer -1.74787 0.398789 19.21033 0.000012 -2.52949 -0.966263 0.174144
Adjuvant Chemoimmunoradiotherapy -1.10726 0.204380 29.35098 0.000000 -1.50784 -0.706684 0.330463
Thrombocytes/Cancer Cells -0.00401 0.001847 4.71895 0.029832 -0.00763 -0.000392 0.995997
Eosinophils/Cancer Cells -0.88030 0.403518 4.75925 0.029141 -1.67118 -0.089422 0.414657
Lymphocytes/Cancer Cells -0.25257 0.074446 11.51021 0.000692 -0.39848 -0.106660 0.776800
Healthy Cells/Cancer Cells 0.08529 0.030272 7.93770 0.004842 0.02596 0.144619 1.089030
Thrombocytes (tot) 0.00149 0.000383 15.25088 0.000094 0.00074 0.002244 1.001495
Phase Transition N0---N12 1.16358 0.148822 61.13067 0.000000 0.87190 1.455267 3.201377
Neural Networks: n=646;
Baseline Error=0.000;
Area under ROC Curve=1.000;
Correct Classification Rate=100%
Rank Sensitivity
Phase Transition Early---Invasive Cancer 1 31912
Phase Transition N0---N12 2 23902
Healthy Cells/Cancer Cells 3 2324
Lymphocytes/Cancer Cells 4 10104
Thrombocytes/Cancer Cells 5 9822
Eosinophils/Cancer Cells 6 9448
Erythrocytes/Cancer Cells 7 8308
Segmented Neutrophils/Cancer Cells 8 8289
Glucose 9 7268
Monocytes/Cancer Cells 10 5583
Stick Neutrophils/Cancer Cells 11 5285
Leucocytes/Cancer Cells 12 3871
Bootstrap Simulation Rank Kendall’Tau-
A
P<
Healthy Cells/Cancer Cells 1 -0.229 0.000
Erythrocytes/Cancer Cells 2 -0.225 0.000
Lymphocytes/Cancer Cells 3 -0.220 0.000
Thrombocytes/Cancer Cells 4 -0.202 0.000
PT N0---N12 5 0.200 0.000
Leucocytes/Cancer Cells 6 -0.189 0.000
Tumor Size 7 0.158 0.000
Prothrombin Index 8 0.154 0.000
Eosinophils/Cancer Cells 9 -0.148 0.000
PT Early---Invasive Cancer 10 -0.146 0.000
Monocytes/Cancer Cells 11 -0.140 0.000
Segmented Neutrophils/Cancer Cells 12 -0.138 0.000
T1-4 13 0.137 0.000
Weight 14 -0.098 0.000
Segmented Neutrophils (%) 15 0.098 0.001
Erythrocytes (tot) 16 -0.092 0.000
G1-3 17 0.085 0.001
ESS 18 0.085 0.001
Lymphocytes (tot) 19 -0.082 0.01
Lymphocytes (%) 20 -0.078 0.01
Only Surgery 21 -0.073 0.01
Glucose 22 -0.072 0.01
Heparin Tolerance 23 0.067 0.05
Eosinophils (%) 24 -0.057 0.05
Procedures Type 25 -0.055 0.05