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Giulia Veronesi Division of Thoracic Surgery European Institute of Oncology

NUOVE PROSPETTIVE NELLA PREVENZIONE E CURA DEI TUMORI POLMONARI. Giulia Veronesi Division of Thoracic Surgery European Institute of Oncology CERIGNOLA 7 MAGGIO 2011. 1) PREVENTION 2) ROBOTIC SURGERY 3) TARGET THERAPY. TOBACCO USE REMAINS THE LEADing preventable cause of death in the

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Giulia Veronesi Division of Thoracic Surgery European Institute of Oncology

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  1. NUOVE PROSPETTIVE NELLA PREVENZIONE E CURA DEI TUMORI POLMONARI Giulia VeronesiDivision of Thoracic Surgery European Institute of Oncology CERIGNOLA 7 MAGGIO 2011

  2. 1) PREVENTION 2) ROBOTIC SURGERY 3) TARGET THERAPY

  3. TOBACCO USE REMAINS THE LEADing preventable cause of death in the world 5.4 premature Deaths in 2000 US Dept of Health and Human Services. Women and Smoking: A Report of the Surgeon General. Public Health Service, Office of the Surgeon General. 2001 Ezzati M. Estimates of global mortality attributable to smoking in 2000. Lancet. 2003

  4. MORTALITA’ PER CANCRO UOMINI DONNE

  5. The World HealthOrganization • In 2030 • Tobacco-attributable deaths: • 3 millions western countries • 7 milions in developing countries

  6. LUNG CANCER FIRST CAUSE OF CANCER DEATH Richard Doll

  7. Anti smoking campaign LIMITS 1) High lung cancer risk in former smokers 2) Women and young people 3) Smoking in deveoping countries Early detection

  8. COSMOS ContinousObservationofSMokingSubjects diametro < 1 cm SOPRAVVIVENZA A 5 ANNI 80-90%

  9. LD-CT • Scientific world divided in twogroups • Pro RCT > Mortalityissue • Contra RCT > Ethicalissue -mortalityanalysiswithhistoricalcontrols -proofofprinciple “early detection is the cornerstoneofanyeffective treatment”

  10. LCST (LungCancer Screening Trial) 2002-2010 53.000 subjects 55 years, 30 packs-year R 3 annual LD TC 3 annual Chest x ray FUP x 5 years 20% lung cancer specific mortality reduction 6.9% reduction of overall mortality Nodules > 4mm Furtherexamsearly treatment

  11. CRITERIA FOR IMPLEMENTATION OF CT SCREENING • False positive cases • Best target population • Overdiagnosis • Best screen interval • Cost effectiveness analysis • Radiation exposure NO NEED OF RCT

  12. The COSMOS trial(Continuous Observation of Smoking Subjects)Annual low-dose CT for lung cancer 194 patients with lung cancers ( + 17 second primary) - 65% stage I - 78% initial stage (N0M0) (including multifocal disease) • 5203 participants Enrollment 2004-2005 • Gender 3439 men (66%) – 1764 women (34%) • Age Median 57 years (range 50-84 years) • Smoking status Current smokers (80%) • Former smokers (20%) • Pack-year Median 44 pack-years (range 20-260)

  13. COSMOSTRIAL

  14. STAGE Cosmosstudy SEER Screencancers stage I-II: 78% Non screencancers stage I-II: 17%

  15. SURGERY Pneumonectomy 2% versus 10% in the routine Postop morbidity 23.7%, 90 days mortality 0.5%

  16. SURVIVAL OF SCREENING-DETECTED* LUNG CANCER * including 6 interval cancers 35 DEATHS after a median follow-up of 64 months Overall survival (95% CI) 1-year 91% (86-95%) 2-year 85% (80-91%) 3-year 82% (76-88%) 4-year 79% (72-88%) 5-year 72% (63-82%) (60% LCST) Lung cancer mortality 1.3/1000-year Years Patients at risk 194 149 119 87 56 16

  17. OVERALL MORTALITY 116 deaths 37 Other primary cancer34 Cardiovascular31 Lung Cancer 9 Other cause5 Unknown cause 5-year survival = 97% (NSLT Trial 96%)

  18. CRITERIA FOR IMPLEMENTATION OF CT SCREENING • False positive • Best target population • Overdiagnosis • Costeffectivenessanalysis • Best screeninterval • Radiationexposure

  19. DIAGNOSTIC PERFORMANCE OF COSMOS PROTOCOL FP Invasive procedure forbenigndisease = 34/5203 in 5 years = 1.3 per thousandeveryyear NELSON trial NEJM 2009

  20. BENIGN NODULES False positive False positive cases 15% ofall positive cases lessthanthoseobserved in the routine clincialpractice (22%)

  21. DIAGNOSTIC PERFORMANCE OF COSMOS PROTOCOL Sensitivity of protocol: 168/194 = 87.0% Specificity of protocol: 4976/5001 = 99.5% PPV: 168/202 = 83.2% NPV: 4976/5001 = 99.5%

  22. CRITERIA FOR IMPLEMENTATION OF CT SCREENING • False positive • Best target population • Best screeninterval • Overdiagnosis • Costeffectivenessanalysis • Radiationexposure

  23. LUNG CANCER RISK SCORE A risk model based on clinical and radiological variables extrapolated by the data of the Cosmos study identifies subgroups of subjects at different risk of cancer Results • quantify the risk of an asymptomatic smoker to be identified with lung cancer by LD-CT screening • optimize the timing of low dose CT • target chemopreventive trials Low risk group (40% of cosmos population) can safely perform CT screening every 2-3 years Submitted

  24. CRITERIA FOR IMPLEMENTATION OF CT SCREENING • False positive • Best target population • Best screeninterval • Overdiagnosis • Costeffectivenessanalysis • Radiationexposure

  25. ASSESSMENT OF DOUBLING TIME IN CT SCREENING FOR LUNG CANCER DISTRIBUTION OF VOLUME DOUBLING-TIME Classification according to VDT • Fast-growing: <400 days • Slow growing: 400 - 600 days • Indolent : >600 days Results Indolent and slow growing lung cancer represent 12% and 9% of screened detected cases The other 79% screen detected lung cancers are fast growing Prognosis in patients with indolent and slow growing tumors is excellent (100% stage I) A sublobar resection can be appropriate surgical approach for slow growing tumors to avoid overtreatment VDT 95 days

  26. Median follow-up 24 months

  27. Analised 100 Metafasis no 28% Metafasis yes 72% Normal 30% Aneuployd 70% Oncogene 2010 GENOMIC ANALYSIS IN EARLY STAGE LUNG CANCER • The majority of screening detected tumors presented aneuploidy and advanced genomic abnormalities despite very initial stage • Genomic scanning was able to detect regions of chromosomal alterations in early lung cancer patients. • Three common regions of copy number variations were identified: two large scale events (5p amplification and 8p deletion) and one focal 1Mb amplification at 8p11. • INDO-INDOL1 involved in the tryptophan catabolism and immune tolerance against tumors One region contains the Gene INDO involved in immuno

  28. CRITERIA FOR IMPLEMENTATION OF CT SCREENING • False positive • Best target population • Best screeninterval • Overdiagnosis • Costeffectivenessanalysis • Radiationexposure

  29. COSTS/RADIATIONS • It has been estimated that annual low-dose screening CT from age 50 to 75 incurs a lifetime lung cancer risk of 0.23% in men and 0.85% women • Costs analysis report range 10-50.000 dollars per year life- saved (lower than raccomandation values and not different from breast screening) Chirikos CHEST 2008 Berrington de González J Med Screen 2008

  30. OTHER QUESTIONS • Best Treatment For Small Screen Detected Cancers • Long Term Outcome Of Screening And Optimal Duration Of Screening • Role Of Serum Markers In Screening • Prevention Of Cardiovascular Disease

  31. Screening-detected lung cancers: is systematic nodal dissection always essential? Journal of Thoracic Oncology 2011 We analysed a consecutive series of clinical N0 screening detected lung malignancy to identify predictive criteria of nodal involvement. Preoperative PET scan c-Stage T1N0M0 lung cancer < 3 cm Ø Anatomical resection + lymphadenectomy no prior treatment In either very small (less than 1 cm) or PET negative tumors, hilar and mediastinal lymph node dissection is nonessential with very limited risk of nodal involvement (0-2.3%)

  32. ROBOTIC SURGERY AND SUBLOBAR RESECTIONS Posterolateral Thoracotomy LateralMuscleSparing Thoracotomy Minimally invasive RoboticApproach

  33. S39 Lungcancer detection rate % per year S39 RATE OF STAGE IA Mean 0.8% /year Mean 66%

  34. MICRO RNAs • Short non-coding fragments of RNAs • Function as modulators of gene expression • Involved in the regulation of cellular differentiation, proliferation, and apoptosis • Expression often deregulated in human cancers in a tissue- and cancer-specific manner • Present in human plasma in a remarkably stable form (they are protected from endogenous RNAse activity) We investigated the role of circulating miRNAs as a non-invasive diagnostic tool for the detection of lung cancer

  35. CONCLUSIONS • High detection of stage I tumors with limited rate of • recalls • Mainly non invasive diagnostic protocol • High resectability rate with low p.o. morbidity and • mortality • Good overall survival (72% at 5-years) • Mortality reduction demontrated in the largest • randomised trial • These data support CT screening of lung cancer

  36. Future STUDIES • Increase effectiveness of screening by application of COSMOS risk models reducing radiation exposure and costs • Validate serological markers and develop genomic analysis • Control concomitant causes of death such as cardiovascular disease (i.e. calcium scoreanalisys) • Implement smoking cessation clinics • Reduce invasiveness of treatment by implementing limited resections in slow growing and subcentimetrictumors (roll), robotics and non surgical treatments (stereotactic radiotherapy) • Develop chemoprevention and WOP trials

  37. ROBOTIC SURGERY

  38. VATS LOBECTOMY Introduction of the minimally invasive approach marks one of the great advances in surgery and the advantages of VATS lobectomy are well accepted Shortcomings: - limited visual information - limited freedom of movement - poor ergonomics Significant learning curve to develop and maintain advanced skills The majority of advanced thoracoscopic cases are performed by a small number of surgeons

  39. ROBOTIC SYSTEM Advantages: natural movements of the surgeon’s hands are traslated into precise instrument movements inside the patient with tremor filtration. Three dimensional view offers a visual magnification even better than that available in open surgery Robotic system has made advanced thoracoscopic surgery accessible to surgeons who do not have advanced videoendoscopic training

  40. ROBOT vs. CONVENTIONAL VIDEOSURGERY INSTRUMENTS: ADVANTAGES AND DISADVANTAGES As every evolving technology, robotic has many limitations, but its advantages were already proven and seem to overcome the disadvantages

  41. ROBOTIC LOBECTOMIES: CASE SERIES

  42. ROBOTIC LOBECTOMIES: TECHNIQUE Number of arms: 3 versus 4 Insufflation C02 Timing of utility incision Site of utility incision and other ports

  43. IEO SURGICAL TECHNIQUE Lateral position Robot at the head posteriorly Four incisions including a small utility incision Camera arm: VII space mid axillary line No rib spreading Individual ligation of hilar elements

  44. PATIENTS AND ROBOT POSITIONING

  45. RIGH UPPER LOBECTOMY Isolation of RUL pulmonary VEIN Isolation of RUL pulmonary artery

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