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

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

JNCI 2000; 92: global mortality: + 10% screening control Mayo Lung Project chest x-ray 4 monthly vs. control 9211 smokers, years

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: x 6

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

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: 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)

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: 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)

RCT trials on LDCT screening surgical procedures for benign disease Thorac Surg Clin 2013; 23: Subjects (n)Cancers (n) Benign (n)Benign (%) NELSON7, DANTE1, ITALUNG1, NLST26, DLCST2, MILD2, LUSI2, All published 76,9621,

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:

NLST: landmark trial N Engl J Med 2011;365: 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

NLST: overdiagnosis JAMA 2014;174:269-74

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

Thorax 2012; 67: DLCST trial: 5-year results

EUROPEAN RCTs: 2015 no mortality reduction

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

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

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

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

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

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

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

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

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

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

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

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

Patient perspective – Positive screen J Thor Oncol in Press JAMA Intern Med. 175(9): 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

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

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.

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

Tumor Stage & Interval cancer

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.

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

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

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

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

Smoking cessation FORMERQUITTERCURRENT Follow-Up years Person / Years7,8097,20217,846 Deaths LC deaths Mortality / 100,000 PY J Thor Oncol in Press

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

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

Traslation to community setting: MediCare N Engl J Med (2015) 372;22:2083 Eligibility: - Medicare benefit for at-risk patients 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

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

1 - 2 years before CT detection PNAS 2011; 108:

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 Administered No nodule Nodule diameter ≤ 5 mm Nodule diameter > 5 - ≤ 10 mm Nodule diameter > 10 mm 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

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

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

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

Lo Screening del Tumore Polmonare: Siamo Pronti? Mario Silva Acknowledgement: Ugo Pastorino Chief of Department of Thoracic Surgery, INT, Milano, IT bioMILD Lung Cancer screening Trial