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Screening for Lung Cancer using Low Dose CT: State of the Art and Controversies Philippe GRENIER University Pierre et Marie Curie (UPMC), Pitié-Salpêtrière.

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Presentation on theme: "Screening for Lung Cancer using Low Dose CT: State of the Art and Controversies Philippe GRENIER University Pierre et Marie Curie (UPMC), Pitié-Salpêtrière."— Presentation transcript:

1 Screening for Lung Cancer using Low Dose CT: State of the Art and Controversies Philippe GRENIER University Pierre et Marie Curie (UPMC), Pitié-Salpêtrière Hospital, Paris, FRANCE

2 Rationale for lung cancer screening Lung cancer remains the leading cause of cancer- related death among men and women in the world The 5-year survival rate of 10-15% has been roughly unchanged for the past two decades despite treatment advances Strauss. Surg Oncol Clin N Am 1999; 8: 747 At diagnosis, most lung cancers are already at advanced stage Mountain. Chest; : 1710

3 Rationale for lung cancer screening Early stage lung cancer patients have a much higher 5-year survival rate (between 60 and 80%) Pisters. J Clin Oncol 2005; 23:3270 Changing smoking habits could reduce lung cancer incidence and deaths The risk for lung cancer does not decrease for many years after smoking cessation Cessation programs have long-term cessation rates of only 20% to 35% at one year

4 Lung Cancer Screening with Chest Radiography with or without Sputum Cytologic Examination Some lower-quality evidence (case-control studies) has shown benefit Higher-quality evidence (randomized controled trials) conducted in the 80s has not (the screened groups had the same number of death from lung cancer as the control group) Humphrey. Ann Intern Med 2004; 140:740


6 Early Lung Cancer Action Project (ELCAP) 1000 asymptomatic volunteers (> 60 yo) smoking : 45 py (median). Subjects received both low dose computer tomography (LDCT) and chest radiography (CR) Non-calcified nodules were detected on 23% of LDCT and 7% of CR Lung cancer was detected in 2.7% LDCT screens (85% were stage I disease) and in 0.7% CR screens Henschke. Lancet 1999; 354:99 Uncontrolled observational trial

7 Year 0 Year 1 Year 1+3 months Adenocarcinoma

8 Year 1+3 months Year 0 Year1 Adenocarcinoma

9 Initial3-month Follow-up + 30% Adenocarcinoma

10 Uncontrolled studies with LDCT Study years Screening type Screening tests performed Postive test results (%) Lung cancer (%) Stage I disease (%) Henschke 1999 Baseline Incidence Nawa 2002 Baseline Incidence Sone 2001 Baseline Incidence Sobue 2002 Baseline Incidence Swensen 2003 Baseline Incidence Diederich 2002 Baseline Pastorino 2003 Baseline Incidence

11 Uncontrolled studies with LDCT Prevalence rates of lung cancer have varied widely ( %), due to different risk profiles based on age and smoking disease status, Stage I or II cancers have been 75% to 100% High level of non-calcified benign nodules detected (15- 51%) with the risks of invasive procedures and futile thoracotomies

12 False positive rate of screening CT Definition :number of patients who required further evaluation after CT but did not have cancer Rate of positive tests in prevalence screening : % Rate of positive tests in incidence screening : 3-12 % Most are resolved with follow-up CT 5 % - 14 % of those undergoing follow CT were referred to biopsy and most (63 % - 90 %) then received a diagnosis of cancer

13 False negative rate of screening CT Nodules were missed in 26 % of patients on annual incidence screening CT scans 1 CT sensitivity for detecting nodules is reduced when central versus peripheral, when adjacent to the vessels and when small 2 Double reading and CAD may reduce false negative rates 3 1 Swensen. Am J respir Crit Care Med 2002; 165: Rusinek. Radiology 1998; 209:243 3 Ko. J Thorac Imaging 2004; 19:136

14 Computer Aided Diagnosis: Detection and Nodule growth assessment on follow-up CT

15 Strategy for indeterminate nodule ( more than 50 y.o. smoker) Size Alternative: FDG-PET or contrast enhanced CT mm CT Follow-up* 3-6, 6-9, 9-12, months < 4 mm CT Follow-up* 12 months > 8 mm Biopsy or resection + Biopsy or resection - McMahon. Radiology ; 237:

16 Survival of patients with stage I lung cancer detected on CT screening 31,567 asymptomatic persons at risk for lung cancer were screened using LDCT ( ) 412/484 (85%) had clinical stage I lung cancer and estimated 10-year survival rate was 88% Among 302/412 who underwent surgical resection within 1 month after diagnosis, the 10-year survival rate was 92% The 8 participants with clinical stage I who did not receive treatment died within 5 years after diagnosis Henschke. N Engl J Med. 2006; 355:1763

17 Are Increasing 5-Year Survival Rates Evidence of Success Against Cancer? Welch. JAMA; 2000; 283:2975 There is little correlation between the change in 5-year survival for a specific tumor and the change in tumor- related mortality The change in 5-year survival is positively correlated with the change in the tumor incidence rate

18 Uncontrolled studies with LDCT Lung cancer can be diagnosed at a significantly earlier stage with CT screening. However whether this will translate to a mortality benefit is unclear

19 CT Screening for Lung Cancer: Five-year Prospective Experience 1520 individuals with high risk for lung cancer 68 lung cancers diagnosed (31 initial, 34 subsequent,3 interval) 28 subsequent cases of non-small cell cancers were detected, of which 17 (61%) were stage I tumors No difference in the observed incidence lung cancer mortality rate to a historic benchmark 2.8 vs 2.0 per 1000 person-years Swensen. Radiology: 2005; 235: 259

20 CT Screening and Lung Cancer Outcomes Bach. JAMA: 2007; 297: 953 Longitudinal analysis of 3246 individuals current or former smokers screened for lung cancer in academic centers with a follow-up of 3.9 years Comparison of predicted with observed number of new lung cancer cases, lung cancer resections, advanced lung cancer cases, and deaths from lung cancer

21 CT Screening and Lung Cancer Outcomes 144 individuals diagnosed with lung cancer compared with 44.5 expected cases (RR, 3.2; P<.001) 109 had a lung resection compared with 10.9 expected cases (RR, 10; P<.001) No evidence of decline in the number of diagnoses of advanced lung cancers (42 vs 33.4 expected cases) or deaths from lung cancer (38 observed and 38.8 expected; RR, 1; P=.9) Bach. JAMA: 2007; 297: 953

22 Good : extend quality years of life (QALY) reduce mortality from the tumor Harm : complications of the screening tests consequences of false positive diagnoses Cancer screening programmes : should do more good than harm at a financial cost acceptable to society

23 Survival time Lead-Time Bias Time Time Screened group Control group Symptoms Diagnosis Patient confirmed dies confirmed dies Diagnosisconfirmed Lead time Patient dies dies

24 Time Length-Time Bias Symptoms Symptoms Symptoms Tumordetectable Tumordetectable Tumordetectable Onset of tumor tumor tumor Aggressive tumors Indolent tumors

25 Overdiagnosis and consequent overtreatment Overdiagnosis bias is the result of slow-growing relatively indolent lung cancers that a patient dies with and not from The high rate of adenocarcinomas raises the possibility of overdiagnosis Slow-growing adenocarcinomas (bronchioloalveolar carcinomas or non-invasive adenocarcinomas) that are not lethal may be identified with CT screening Lindell. Radiology: 2007; 242: 555

26 Non solid nodules: malignant causes Adenocarcinoma Bronchioloalveolar cell carcinoma Ground glass opacity

27 Mixed (part-solid) nodules Adenocarcinomas

28 Solid and non-solid nodules: growth rate Doubling time of nodules from a 3-year screening program for lung cancer* *Hasegawa. Br J Radiol 2000; 73: 1252 Solid nodules: 189 days Mixed (part-solid) nodules: 457 days Non solid nodules: 813 days

29 Curative limited resection for small peripheral lung cancer 146 stage IA peripheral tumors Type I GGO % Type II GGO % Type III GGO % Type IV GGO < 10 % Nodal metastasis0020 %24 % 3-year disease-free survival 98 % 86 %78 % Patients with tumor that have GGO ratio > 50 % are regarded to be possible candidates for limited pulmonary resection Nakata. J Thorac Cardiovasc Surg 2005; 129: 1226

30 Overdiagnosis: a Substantial Concern in Lung Cancer Screening Lindell. Radiology: 2007; 242: cancers reviewed and 48 assessed for morphologic change Mean tumor size: 16.4 mm ( mm) 74% prevalence, 37% incidence detected lung cancers were adenocarcinomas Mean volume doubling time (VDT) was 518 days 13/48 (27%) cancers had a VDT longer than 400 days (11/13 were in women)

31 y later Without screening With screening 10-y survival == 10% 10-y survival = = 82% Welch. Arch Intern Med; 2007; 167: 2289

32 Randomized controlled trials eliminate lead-time and lenght biases RDZ Test 1 e yr Test 2 e yr Test 3 e yr Test 4 e yr Screened group Control group

33 Randomized controlled trials They are very difficult to set up Contamination is a major problem They take a very long time to produce definitive results (enough time to allow for lead time and length biases) In the interval technology changes and the results may not be relevant when trial finally reports

34 Lung Cancer Study: a randomized controlled trial (LDCT vs CR) 3,318 tobacco-exposed subjects Compliance at baseline was 96% in the LDCT arm and 93% in the CR arm At year one screening compliance was 86% in the LDCT arm and 80% in the CR arm Gohagan. Chest 2004; 126: 114

35 NLST: RCT Design t ime ,476 High-Risk Subjects CT Arm CXR Arm Randomize F/U T0T0 T1T1 T2T2

36 The NELSON Trial 15,428 subjects LDCT screened arm is beeing compared to a control arm without screening Van Iersel. Int J Cancer 2007; 120:868

37 Conclusion Screening for lung cancer with LDCT may increase the rate of lung cancer diagnosis and treatment, but may not meaningfully reduce the risk of advanced lung cancer or death from lung cancer Until more conclusive data are available, asymptomatic individuals should not be screened outside of clinical research studies

38 Conclusion Randomized controlled trials are the only way to reliably determine whether screening does more good than harm Although expensive and time-consuming, rigorous trials of cancer screening are far more cost-effective than widespread adoption of costly screening interventions that cause more harm than good Welch. Arch Intern Med; 2007; 167: 2289

39 Genetic abnormalities and biomarkers of premalignancy or early malignancy Detection of biomarkers will have profound implications for more precise selection and stratification of population at risk for lung cancer Field. J Thorac Oncol. 2006; 1:497 Genomic and proteomic methods may offer a much easier mass screening as the first step of a screening strategy Meyerson. J Clin Oncol. 2005; 23:3219 Zhong. Am J Respir Crit Care Med. 2005; 172:1308

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