Transcript
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LOCAL ADVANCED LUNG CANCER: OPTIMAL SURGERY STRATEGIES

Oleg Kshivets, MD, PhDKlaipeda University Hospital, Klaipeda, Lithuania

13th World Conference on Lung CancerJuly 31-August 4.2009, San Francisco, CA, the USA

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Abstract:• LOCAL ADVANCED LUNG CANCER: OPTIMAL SURGERY STRATEGIES

• Oleg Kshivets• Klaipeda University Hospital, Klaipeda, Lithuania

• Objective: Survival of patients with local advanced non-small lung cancer (ALC) takes several months. Radical operations are complex and remain the prerogative of world best surgeons. The search of optimal surgery strategies for ALC patients (ALCP) with stage T3-4N0-2M0 was realized. We examined factors associated with generalization of ALC after complete (R0) combined pneumonectomies and lobectomies (PL).

• Methods: We analyzed data of 155 consecutive ALCP (age=58.5±8.2 years; tumor diameter: D=6.7±2.6 cm) radically operated and monitored in 1985-2008 (m=143, f=12; pneumonectomy=88, bi/lobectomy=67, mediastinal lymphadenectomy=155; combined procedures with resection of pericardium=48, atrium=6, aorta=4, v. cava superior=9, carina=19, trachea=11, diaphragm=16, ribs=41, liver=7, esophagus=6; only surgery: S=66, adjuvant chemoimmunoradiotherapy-AT: CAV/gemzar+thymalin/taktivin+radiotherapy=52, postoperative radiotherapy=37; squamous=113, adenocarcinoma=30, large cell=12; T3=114, T4=41; N0=75, N1=35, N2=45; G1=35, G2=42, G3=78; stage IIB=60, IIIA=54, IIIB=41). Variables selected for 5-year survival (5YS) study were input levels of blood, biochemic and hemostatic factors, sex, age, TNMG, D. Survival curves were estimated by Kaplan-Meier method. Differences in curves between groups were evaluated using a log-rank test. Neural networks computing, Cox regression, clustering, discriminant analysis, structural equation modeling, Monte Carlo and bootstrap simulation were used to determine any significant regularity.

• Results: Cumulative 5YS was 58.3%, 10-years survival – 49.7%. 91 ALCP were alive, 70 ALCP lived more than 5 years without any features of ALC progressing (life span: LS=2438.3±1004.2 days). 60 LCP died because of generalization during the first 5 years after radical procedures (LS=462.0±367.8 days). AT significantly improved 5YS compared with S (P=0.003 by log-rank test) and with RT (P=0.002). Cox modeling displayed that 5YS of ALCP after PL significantly depended on: N0-2, T3-4, sex, AT, prothrombin index, fibrinogen-B, heparin tolerance, thrombocytes, cell ratio factors (P=0.000-0.047). Neural networks computing, genetic algorithm selection

• and bootstrap simulation revealed relationships between 5YS and N0-2 (rank=1), AT (2), histology (3), type of operations (4), G (5), RT (6), heparin tolerance (7), S (8), T (9), sex (10), recalcification time (11), fibrinogen-B (12), eosinophils (13), protein (14), Hb (15), lymphocytes (16), prothrombin index (17), ESS (18), thrombotest (19), monocytes (20), thrombocytes/Cancer Cells (21), segmented neutrophils (22), coagulation time (23), eosinophils/Cancer Cells (24), D (25). Correct prediction of 5YS after PL was 100% by neural networks computing (area under ROC curve=1.0; error=0.0021).

• Conclusions: Optimal surgery strategies for ALCP are: 1) availability of experienced surgeons because of complexity of radical procedures; 2) aggressive en block surgery and adequate mediastinal lymphadenectomy for completeness; 3) precise prediction; 4) adjuvant chemoimmunoradiotherapy for ALCP with unfavorable prognosis.

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Data

• Males……………………………………………143• Females………….………………………………12• Age=58.5±8.2 years• Tumor Size=6.7±2.6 cm• Only Surgery.……..………………………........66• Ad. Chemoimmunoradiotherapytherapy…..52• Postoperative Radiotherapy…………………37

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Adjuvant Therapy after Combined Procedures

Adjuvant Chemoimmunoradiotherapy (n=52): 1 cycle of bolus chemotherapy (CAVT) was initiated 10-14 days after resections and consisted of Cyclophosphamid 500 mg/m2 IV on day 1, Doxorubicin 50 mg/m2 IV on day 1, Vincristin 1.4 mg/m2 IV on day 1. Immunotherapy consisted Thymalin or Taktivin 20 mg IM on days 1, 2, 3, 4 and 5. Chest radiotherapy (45-50 Gy) was administered since 7 day after 1 cycle chemoimmunotherapy at a daily dose of 1.8-2 Gy. No prophylactic cranial irradiation was used. From 2 to 3 weeks after completion of radiotherapy 3-4 courses of CAVT were repeated every 21-28 day. Since 1999 chemotherapy by gemzar 1250 mg/m2 IV on day 1, 8, 15 and cisplatin 75 mg/m2 on day 1 was initiated on 14 day after surgery and was repeated every 14 day (5-6 courses).

P/o Radiotherapy (n=37): Radiotherapy (60CO; ROKUS, Russia) with a total tumor dose 45-50 Gy (2-4 weeks after surgery) consisted of single daily fractions of 180-200 cGy 5 days weekly. The treatment volume included the ipsilateral hilus, the supraclavicular fossa and the mediastinum from the incisura jugularis to 5-7 cm below the carina. The lower mediastinum was included in cases of primary tumors in the lower lobes. The resected tumor bed was included in all patients. Parallel-opposed AP-PA fields were used. All fields were checked using the treatment planning program COSPO. Doses were specified at middepth for parallel-opposed technique or at the intersection of central axes for oblique technique. No prophylactic cranial irradiation was used.

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Combined Radical Procedures• Combined Pneumonectomy.……..………..…………88• Combined Bi/Lobectomy…….………….…………….67• Combined Procedures with Resection of

Pericardium……………………………………………...48• Diaphragm…………………………………………….....16• Atrium…………………………………………..................6 • Vena Cava Superior………………………………..........9• Aorta………………………………………………….........4• Carina…………………………………………................19• Trachea…………………………………………………..11• Liver …………………………………………………….....7• Esophagus………………………………………………...6• Ribs……………………………………………................41

• Mediastinal Lymphadenectomy……………..……..155

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Staging

• T3……114 N0..…..75 G1..………35• T4……..41 N1……35 G2…..……42• N2……45 G3.….……78

• Central…………………………………………..83• Peripherical……….........................................72• Right..…………………………………………....86• Left…………………………………………….…69• Adenocarcinoma……………………………....30• Squamous Cell Carcinoma……..…………..113• Large Cell Carcinoma..…………………….....12

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Survival Rate• 5-Year Survivors…………..…….70 (45.2%) • Losses………………………….…60 (38.7%)

• General Life Span= 1384.9±1201.6 days• For 5-Year Survivors= 2438.3±1004.2 days• For Losses= 462.0±367.8 days

• Cumulative 5-Year Survival………….58.3%• Cumulative 10-Year Survival…..........49.7%

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General Local Advanced Lung Cancer Patients Survival after Complete Combined Procedures (Kaplan-Meier) (n=155)

Survival FunctionComplete Censored

General Local Advaced Lung Cancer Patients after Radical Surgery, n=155

-5 0 5 10 15 20

Years After Combined Procedures

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

Cum

ulat

ive

Pro

porti

on S

urvi

ving

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Results of Univariate Analysis in Prediction of Local Advanced Lung Cancer Patients Survival (n=155)

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Results of Cox Regression Modeling in Prediction of Local Advanced Lung Cancer Patients Survival after Complete Combined Procedures (n=155)

Overall Chi2=89.907; df=15; P=0.000;

• Factors Wald df P•• N0-2 17.370 2 0.000• T3-4 8.512 1 0.004• Ad.Chemoimmunoradiotherapy 11.543 1 0.001• Gender8.516 1 0.004• Prothrombin Index 6.577 1 0.010• Fibrinogen-B 8.832 1 0.003• Heparin Tolerance 6.064 1 0.014• Thrombocytes 5.241 1 0.022• Seg.Neutrophils/Cancer Cells 3.875 1 0.047• Lymphocytes/Cancer Cells 5.423 1 0.020

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Results of Discriminant Analysis in Prediction of Local Advanced Lung Cancer Patients Survival after Complete Combined Procedures (n=155)

• Discriminant Function Analysis Summary • Wilks' Lambda: 0.492 approx. F (22,107)=5.024 p< 0.0000; Correct Classification Rate=83.1%• Wilks'-Lambda P • Prothrombin Index 0.560 0.000 • Fibrinogen-B 0.534 0.003• Recalcification Time 0.524 0.009• N0-2 0.517 0.021• Heparin Tolerance 0.517 0.021• Monocytes/Cancer Cells 0.517 0.021• Segmented Neutrophils/Cancer Cells 0.516 0.023• Stab Neutrophilc/Cancer Cells 0.516 0.024• Leucocytes/Cancer Cells 0.516 0.024• Eosinophils/Cancer Cells 0.516 0.025• Lymphocytes/Cancer Cells 0.516 0.025• Monocytes (%) 0.515 0.027• Erythrocytes (tot) 0.513 0.033• Segmented Neutrophils (%) 0.513 0.034• T3-4 0.512 0.037• Lymphocytes (%) 0.512 0.037• Eosinophils (%) 0.512 0.037• Stab Neutrophils (%) 0.512 0.038

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Results of Multi-Factor Clustering of Clinicopathological Data in Prediction of Local Advanced Lung Cancer Patients Survival after

Complete Combined Procedures (n=155)

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Results of Clustering in Prediction of Local Advanced Lung Cancer Patients Survival after

Complete Combined Procedures (n=155) •

Logical Formulas based on Simple Mean• 5-Year Survivors:• 50.00 <= Weight (5.3%) <= 103.00 &• 0.00 <= N (6.7%) <= 2.00 &• 76.00 <= Prothrombin Index (7.1%) <= 115.00 &• 0.99 <= Erythrocytes/Cancer Cells (5.1%) <= 7.54 &• 11.90 <= Erythrocytes (tot) (7.2%) <= 36.80• Objects 70 Error= 0.00 (0) Error2= 0.88 (53)

• Losses:• 44.00 <= Weight (5.3%) <= 90.00 &• 0.00 <= N (6.7%) <= 2.00 &• 84.00 <= Prothrombin Index (7.1%) <= 118.00 &• 0.93 <= Erythrocytes/Cancer Cells (5.1%) <= 7.93 &• 10.50 <= Erythrocytes (tot) (7.2%) <= 28.40• Objects 60 Error1 = 0.00 (0) Error2 = 0.79 (55)

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Neural Networks in Prediction of Local Advanced Lung Cancer Patients Survival after Complete Combined Procedures (n=130)

5-Year Survivors LossesBaseline Errors=0.0021 Total 70 60Area under ROC Curve=1.0 Correct 70 60Correct Classification Rate=100% Wrong 0 0

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Results of Neural Networks Computing in Prediction of Local Advanced Lung Cancer Patients Survival after Complete Combined Procedures (n=130)

Error=0.0021; Area under ROC Curve=1.00; Correct Classification Rate=100%

Factor Rank Error Ratio• N0-2 1 0.284 135.2• Ad.CHIRT 2 0.199 94.7• Histology 3 0.186 88.7• Procedures Type 4 0.177 84.6• G1-3 5 0.149 70.9• P/O RT 6 0.137 65.2• Heparin Tolerance 7 0.128 60.8• Surgery Alone 8 0.121 57.8• T3-4 9 0.114 54.3• Gender 10 0.093 44.4• Recalcification Time 11 0.090 42.7• Fibrinogen-B 12 0.090 42.6

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Results of Neural Networks Computing in Prediction of Local Advanced Lung Cancer Patients Survival after Complete Combined Procedures (n=130)

Error=0.0021; Area under ROC Curve=1.00; Correct Classification Rate=100%

Factor Rank Error Ratio• Eosinophils 13 0.075 35.7• Protein 14 0.024 11.4• Hemoglobin 15 0.022 10.6• Lymphocytes 16 0.019 9.1• Prothrombin Index 17 0.019 8.8• ESS 8 0.014 6.6• Thrombotest 19 0.013 6.1• Monocytes 20 0.011 5.2• Thrombocytes/Cancer Cells 21 0.011 5.2• Segmented Neutrophils 22 0.009 4.5• Coagulation Time 23 0.008 3.9• Eosinophils/Cancer Cells 24 0.008 3.7• Tumor Size 25 0.006 2.7

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Results of Genetic Algorithm Selection in Prediction of Local Advanced Lung Cancer Patients Survival after Complete Combined Procedures (n=130)

Factor Useful for 5-Year Survival• N0-2 Yes• T3-4 Yes• Adjuvant Chemoimmunoradiotherapy Yes• Procedures Type Yes• Erythrocytes/Cancer Cells Yes• Thrombocytes/Cancer Cells Yes• Leucocytes/Cancer Cells Yes• Stab Neutrophils/Cancer Cells Yes• Segmented Neutrophils/Cancer Cells Yes• Healthy Cells/Cancer Cells Yes• Glucose Yes• Prothrombin Index Yes• ESS Yes• Tumor Size Yes• Gender Yes• Heparin Tolerance Yes• Recalcification Time Yes• Erythrocytes Yes

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Results of Kohonen Self-Organizing Neural Networks Computing in Prediction of Local Advanced Lung Cancer Patients Survival after

Complete Combined Procedures (n=130)

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Results of Bootstrap Simulation in Prediction of Local Advanced Lung Cancer Patients Survival after Complete Combined Procedures (n=130)

• Number of Samples=3333• Significant Factors Rank Kendall’s Tau-A P<• Prothrombin Index 1 -0.183 0.01• Erythrocytes (tot) 2 0.170 0.01• Erythrocytes/Cancer Cells 3 0.166 0.01• N0-2 4 -0.163 0.01• Weight 5 0.157 0.01• Monocytes/Cancer Cells 6 0.148 0.05• Healthy Cells/Cancer Cells 7 0.140 0.05• Eosinophils/Cancer Cells 8 0.134 0.05• Erythrocytes (abs) 9 0.133 0.05• Glucose 10 0.133 0.05• ESS 11 -0.120 0.05

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Ratio of Lymphocytes and Erythrocytes to Cancer Cells & Glucose Level in Prediction of Local Advanced Lung Cancer Patients Survival

after Complete Combined Procedures (n=130)

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Prognostic SEPATH-Model of Local Advanced Lung Cancer Patients Survival after Complete Combined Procedures (n=130)

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Lung Cancer Dynamics

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Conclusions (1):

• 5-year survival and life span of local advanced lung cancer patients after complete combined procedures significantly depended on:

• 1) cell ratio factors: ratio of cancer cell population to blood cell subpopulations in integral patient organism;

• 2) cancer characteristics; • 3) blood cell circuit; • 4) biochemical homeostasis;• 5) hemostasis system;• 6) adjuvant chemoimmonoradiotherapy.

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Conclusions (2):

Optimal surgery strategies for local advanced lung cancer patients are:

1) availability of experienced surgeons because of complexity of radical procedures;

2) aggressive en block surgery and adequate mediastinal lymphadenectomy for completeness;

3) precise prediction; 4) adjuvant chemoimmunoradiotherapy for local

advanced lung cancer patients with unfavorable prognosis.

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

Consultant Thoracic, Abdominal, General Surgeon & Surgical Oncologist

• Thoracic Surgery Department • Klaipeda University Hospital• Tilzes: 42-16, LT78206 Siauliai, Lithuania• Tel. 37060878390• e-mail: [email protected] • http//:myprofile.cos.com/Kshivets


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