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

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; 1997.111: 1710

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

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 80’s 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

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

Year 0

Year 1

Year 1+3 months Adenocarcinoma

Year 1+3 months

Year 0

Year1

Adenocarcinoma

Initial 3-month Follow-up

+ 30%

Adenocarcinoma

Uncontrolled studies with LDCT

Study yearsScreening

typeScreening tests

performedPostive testresults (%)

Lung cancer(%)

Stage I disease (%)

Henschke 1999BaselineIncidence

10001184

243.10.9

8567

Nawa 2002BaselineIncidence

79565568

260.50.1

86100

Sone 2001BaselineIncidence

54838303

50.40.6

10086

Sobue 2002BaselineIncidence

16117891

120.80.2

7779

Swensen 2003BaselineIncidence

15202916

511.80.7

66

Diederich 2002 Baseline 817 43 1.3 58

Pastorino 2003 BaselineIncidence

1035994

151.11.1

77

Uncontrolled studies with LDCT

Prevalence rates of lung cancer have varied widely (0.44-1.8%) , 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

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 : 15-51 %

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

False negative rate of screening CT

Nodules were missed in 26 % of patients on annual incidence screening CT scans1

CT sensitivity for detecting nodules is reduced when central versus peripheral, when adjacent to the vessels and when small2

Double reading and CAD may reduce false negative rates3

1 Swensen. Am J respir Crit Care Med 2002; 165: 5082 Rusinek. Radiology 1998; 209:2433 Ko. J Thorac Imaging 2004; 19:136

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

Strategy for indeterminate nodule(more than 50 y.o. smoker)

Size

Alternative: FDG-PETor contrast enhanced CT

4 - 8 mm

CT Follow-up*3-6, 6-9, 9-12, 12-24

months

< 4 mm

CT Follow-up*12 months

> 8 mm

Biopsyor resection

+

Biopsy or resection

-

McMahon. Radiology. 2005 ; 237: 395-400

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 (1993-2005)

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

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

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

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

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

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

Good :extend quality years of life (QALY)reduce mortality from the tumor

Harm :complications of the screening testsconsequences of false positive diagnoses

Cancer screening programmes :should do more good than harm

at a financial cost acceptable to society

Survival timeSurvival time

Survival timeSurvival time

Lead-Time BiasLead-Time Bias

TimeTime

TimeTime

Screened groupScreened group

Control group Symptoms DiagnosisControl group Symptoms Diagnosis PatientPatient

confirmed diesconfirmed dies

DiagnosisDiagnosisconfirmedconfirmed

Lead timeLead time

PatientPatient diesdies

TimeTime

Length-Time BiasLength-Time Bias

SymptomsSymptoms

SymptomsSymptoms

SymptomsSymptomsTumorTumor

detectabledetectable

TumorTumordetectabledetectable

TumorTumordetectabledetectable

Onset of Onset of tumortumor

Onset of Onset of tumortumor

Onset of Onset of tumortumorAggressive tumorsAggressive tumors

Indolent tumorsIndolent tumors

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

Non solid nodules: malignant causes

Adenocarcinoma

Bronchioloalveolar cell carcinoma

Ground glass opacity

Mixed (part-solid) nodules

Adenocarcinomas

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 daysMixed (part-solid) nodules: 457 daysNon solid nodules: 813 days

Curative limited resection for small peripheral lung cancer

146 stage IA peripheral tumors

Type IGGO

90-100 %

Type IIGGO

50-89 %

Type IIIGGO

10-49 %

Type IVGGO

< 10 %

Nodal metastasis 0 0 20 % 24 %

3-year disease-free survival

98 % 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

Overdiagnosis: a Substantial Concern in Lung Cancer Screening

Lindell. Radiology: 2007; 242: 555

61 cancers reviewed and 48 assessed for morphologic change

Mean tumor size: 16.4 mm (5.5-52.5 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)

Randomized controlled trials eliminate lead-time and lenght biases

RDZ

Test1e yr

Test2e yr

Test3e yr

Test4e yr

Screened group

Control group

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

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

NLST: RCT Design

time

0 1 2 3 4 5 6 7 8

53,476High-Risk

Subjects

CT Arm

CXR Arm

Randomize

F/U

T0

T1

T2

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

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

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

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; 23:3219Zhong. Am J Respir Crit Care Med. 2005; 172:1308