1. Lo Screening del Tumore Polmonare: Siamo Pronti? Mario Silva Section of Radiology, Department of Surgical Sciences University of Parma, IT bioMILD Lung Cancer screening Trial Department of Thoracic Surgery, Istituto Nazionale Tumori, Milano, IT

2. Objectives Lung cancer screening chronology since 1970 s : American and European evidence Controversies Optimization – Ideal target

3. JNCI 2000; 92:1308-16 global mortality: + 10% 10 20 30 screening control Mayo Lung Project chest x-ray 4 monthly vs. control 9211 smokers, 1971-1983 0 years

4. lung cancer detection total: 2.7% vs. 0.6% stage I: 2.3% vs. 0.4% ELCAP Project - Cornell NY spiral CT vs. CxR 1000 smokers, median 67 yrs, 45 PY Cancer 2000; 89:474-82 x 6

5. NEJM 2006; 355:1763-71 I-ELCAP conclusion: CT can prevent 80% LC deaths

6. Randomized Clinical Trials on LDCT Screening Detection rates at Baseline & 1 st Repeat 90,866 enrolled subjects, 44,629 LDCT arm Thorac Surg Clin 2013; 23:129-40 Lung Cancers CT lesions BaselineStage I1st repeat LSS316 (17) 30 (1.8)48%8 (.6) NELSON1,570 (21) 70 (.9)64%54 (.7) DANTE226 (18) 47 (3.7)66%13 (1) ITALUNG426 (30) 20 (1.5)48%- NLST6561 (25) 270 (1)63%168 (.6) DLCST179 (9) 17 (.8)53%11 (.6) MILD335 (14) 17 (.7)57%18 (.8) LUSI540 (27) 22 (1.1)-- Overall 10,153 (23) 493 (1.1)62%272 (.7)

7. Randomized Clinical Trials on LDCT Screening Detection rates at Baseline & 1 st Repeat 90,866 enrolled subjects, 44,629 LDCT arm Thorac Surg Clin 2013; 23:129-40 Lung Cancers CT lesions BaselineStage I1st repeat LSS316 (17) 30 (1.8)48%8 (.6) NELSON1,570 (21) 70 (.9)64%54 (.7) DANTE226 (18) 47 (3.7)66%13 (1) ITALUNG426 (30) 20 (1.5)48%- NLST6561 (25) 270 (1)63%168 (.6) DLCST179 (9) 17 (.8)53%11 (.6) MILD335 (14) 17 (.7)57%18 (.8) LUSI540 (27) 22 (1.1)-- Overall 10,153 (23) 493 (1.1) 62% 272 (.7)

8. RCT trials on LDCT screening surgical procedures for benign disease Thorac Surg Clin 2013; 23:129-40 Subjects (n)Cancers (n) Benign (n)Benign (%) NELSON7,55767 2427 DANTE1,27655 1724 ITALUNG1,40616 16 NLST26,309509 16424 DLCST2,04741 816 MILD2,37647 48 LUSI2,02922 929 All published 76,9621,229355 22

9. Randomized screening trial 53,454 persons 3 rounds of annual LDCT vs CxR 20% reduction of LC mortality 7% reduction all cause mortality 24.2% positive subjects 96.4% of these false positive Need to screen 320 subjects to prevent 1 lung cancer death NLST: landmark trial N Engl J Med 2011;365:395-409

10. NLST: landmark trial N Engl J Med 2011;365:395-409 NLST overall survival years from randomization Randomized screening trial 53,454 persons 3 rounds of annual LDCT vs CxR 20% reduction of LC mortality 7% reduction all cause mortality 24.2% positive subjects 96.4% of these false positive Need to screen 320 subjects to prevent 1 lung cancer death

11. NLST: overdiagnosis JAMA 2014;174:269-74

12. Dante trial: 3-year results 2472 males:1276 CT arm, 1196 control arm median follow-up 33 months LCs detected 60 (4.7%)vs 34 (2.8%) p=.016 LC deaths: 20 vs 20 Other deaths: 26 vs 25

13. Thorax 2012; 67:296-301 DLCST trial: 5-year results

14. EUROPEAN RCTs: 2015 no mortality reduction

15. + spiral CT 4,000 smokers ≥ 50 yrs smoking cessation breathing & blood analysis R R CT every year2 years 2005 - 2011 > 100,000 biologic samples MILD trial: design

16. 2005 - 2011 follow-up 17,523 person / year EJCP 2012; 21:308–315 MILD trial: 5-year results

17. 2005 - 2011 Lung cancer incidence LDCT 1 LDCT 2 Control EJCP 2012; 21:308–315 MILD trial: 5-year results

18. 2005 - 2011 All causes mortality LDCT 1 LDCT 2 Control MILD trial: 5-year results EJCP 2012; 21:308–315

19. N Engl J Med 2013; 369:920-31 NLST trial: incidence rounds PPV LDCT 2.4 % at T1 5.2 % at T2

20. Ann Intern Med. 2013;158:246-252 Lancet Oncol 2014; 15: 1332–41 ELCAP trial: optimizing LDCT

21. NELSON: optimizing LDCT Lancet Oncol 2014; 15: 1332–41

22. NELSON: optimizing LDCT Lancet Oncol 2014; 15: 1332–41

23. Eur Radiol 2013; 23:1836–1845 NELSON trial: optimizing LDCT

24. Nodule Characterization J Thorac Imaging 2012;27:230 Eur Radiol. 2015 Mar;25(3):792-9 AJR 2015; 204:281–286

25. Nodule Characterization J Thorac Imaging 2015;30:139–156

26. Nodule Characterization - Radiomics J Thorac Imaging 2015;30:139–156

27. Patient perspective – Positive screen J Thor Oncol in Press JAMA Intern Med. 175(9):1530-7 Perceived risk for lung cancer 20% (IQR 10–50%), Actual risk estimated (Mayo model) 7.1% (IQR 4.6– 10.3%) Surveillance recommended was 2 to 3 years: -7% of patients willed for about 5 years -32% for the rest of their lives 35% reported quitting smoking

29. Incidence round optimization … CT nodule risk modelling now has a more complex role: to determine the frequency and duration of screening over 25 years. Field JK, Lancet Oncology in Press Lancet Oncology in Press

30. Incidence round optimization Negative low-dose CT prevalence screen had a lower incidence of lung cancer and lung cancer- specific mortality…increasing the interval between screens in participants with a negative low- dose CT prevalence screen might be warranted.

31. Incidence round optimization European Radiology in Press Stage shift from diagnostic delay? INTERVAL CANCER?

32. Tumor Stage & Interval cancer

33. Interval cancer 61 subjects with interval cancers (36% retrospectively detectable) 22 % of missed carcinomas originally presented as bulla wall thickening on CT. 22 % of missed carcinomas originally presented as endobronchial lesions on CT. All malignant endobronchial lesions presented as interval carcinomas. In the NELSON trial subsolid nodules were not a source of missed carcinomas.

34. LDCT screening: nailing the targets higher individual risk: 5 – 10 fold avoid useless radiation (CT + PET) targeted resection & chemotherapy less surgery for indolent disease primary prevention is a priority

35. J Thor Oncol 11:1352-6, 2009 LDCT screening: metabolic profile

36. 76 ground-glass nodules (GGNs) detected in 56 patients at baseline CT followed for 5 years by CT: only one (1.3%) progressed (stage Ia ADC) 3 developed LC in other sites JTO 7:1541, 2012 LDCT screening: metabolic profile

37. LDCT arms: 5/8 LD-SCLC Control arm: 2/2 ED-SCLC Median 82 pack-years No survivor @ 3 years JTO 11;2:187, 2016

38. Smoking cessation FORMERQUITTERCURRENT Follow-Up years8.48.9 Person / Years7,8097,20217,846 Deaths5059151 LC deaths111745 Mortality / 100,000 PY 640819846 J Thor Oncol in Press

39. p-value Log-Rank test: 0.0572 CURRENT FORMER / QUITTER Smoking cessation Log-Rank test P = 0.0572 J Thor Oncol in Press

40. Smoking cessation Eur Respir J 2015; 46: 1519–1520 N Engl J Med 2014;370:60-8 Lancet 2013;381:133-41 Ruano-Ravina A. -Overdiagnosis -Radiation exposure -Cost-effectiveness LDCT screen 86.000$/QALY VS Smoking cessation policy 5.000$/QALY …even those who stop at 50 years of age avoid more than half the excess risk…

41. Traslation to community setting: MediCare N Engl J Med (2015) 372;22:2083 Eligibility: - Medicare benefit for at-risk patients 55-77 years of age - Smoking history: distinct visit for formal shared decision making using dedicated evidence-based decision aids - Multidisciplinary care: primary care, radiology, pulmonology, surgery, and oncology

42. individual susceptibility (SNPs) COPD & risk of cancer breath analysis (e-nose, exhalate) pre-diagnostic profile (PET-SUV) blood analysis (DNA, microRNA) 2005 - 2011 LDCT screening: biologic profile

43. 1 - 2 years before CT detection PNAS 2011; 108:3713-18

45. Complementary Diagnostic Performance of LDCT and MSC to Reduce False Positives 1 Increased specificity of identifying subjects without lung cancer Subjects without lung cancer TOTAL MSC High + Interm Low LDCT Administered594116478 No nodule24849199 Nodule diameter ≤ 5 mm 23145186 Nodule diameter > 5 - ≤ 10 mm 941876 Nodule diameter > 10 mm 21417 594 subjects in LDCT arm without lung cancer 594 subjects in LDCT arm without lung cancer 58% had a nodule detected by LDCT This was reduced to 11% by MSC 58% had a nodule detected by LDCT This was reduced to 11% by MSC 19.4% had a ≥ 5mm nodule that required clinical action This was reduced to 3.7% by MSC 19.4% had a ≥ 5mm nodule that required clinical action This was reduced to 3.7% by MSC 1 Sozzi, Boeri et al JCO, in press

46. Three-year survival from date of blood sample collection according to miRNA signature classifier (MSC) among all subjects (n=939) 97% 77% 100%

47. Within stage I, the 5-years survival was 100% in Low to Intermediate risk MSC and 77% in High risk MSC. The difference was not statistically significant, possibly due to the small number of events (4 deaths only) The overall survival of patients with Low to Intermediate risk MSC was significantly higher than those with High risk MSC Milan LDCT Trials (pilot + MILD) 3411 smokers, 24,000 p/y, 111 lung cancers

49. LDCT screening: summary good prospects for screening results of European RCTs are crucial optimize individual selection improve diagnostic algorithm validate biomarkers

50. Lo Screening del Tumore Polmonare: Siamo Pronti? Mario Silva mario.silva@unipr.it Acknowledgement: Ugo Pastorino Chief of Department of Thoracic Surgery, INT, Milano, IT PI @ bioMILD Lung Cancer screening Trial