Thoracic Oncology Preprint Ch07

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  • Conquering Thoracic Cancers Worldwide

    InternatIonal assocIatIon for the study of lung cancer

    Conquering Thoracic Cancers Worldwide

    Chapter preprintScreening for Lung CancerJames r. Jett, Md nanda horeweg, Md harry J. de Koning, Md, Phd

    Full textbook available for purchase May 2014

  • This Preprint Chapter is from the forthcoming text, The IASLC Multidisciplinary

    Approach to Thoracic Oncology, scheduled to be published May/June 2014.

    Preprint chapters may be further updated in the final publication.

    International Association for the Study of Lung

    Cancer Aurora, Colorado, USA

    Harvey I. Pass, MD, Executive Editor

    David Ball, MD, FRANZCR, Editor

    Giorgio V. Scagliotti, MD, Editor

    An IASLC publication published by IASLC Press

    Original cover and preprint layout design by Biographics

    IASLC Press Office:

    IASLC, 13100 East Colfax Ave., Unit 10, Aurora, Colorado 80011, USA

    ISBN: 978-1-940488-02-8

    Copyright 2013-2014 International Association for the Study of Lung Cancer

    All rights reserved

    Without limiting the rights under copyright reserved above, no part of this

    publication may be reproduced, stored in or introduced into a retrieval system,

    or transmitted in any form, or by any means without prior written permission.

    While the information in this book is believed to be true and accurate as of

    the publication date, neither the IASLC nor the editors nor the publisher can

    accept any legal responsibility for any errors or omissions that may be made.

    The publisher makes no warranty, express or implied, with response to the

    material contained therein.

    Preprint sponsored by Boehringer Ingelheim

    Boehringer Ingelheim is not responsible for and had no influence on the

    contents of the Chapter.

  • James R. Jett, MD; Nanda Horeweg, MD; Harry J. de Koning, MD, PhD



    Lung cancer is the most common cancer in the world. Accord-

    ing to data from GLOBOCAN, an estimated 1.6 million cases of

    lung cancer were diagnosed in 2008 and 1.38 million lung can-

    cer-related deaths.1 In the European Union, 250,000 lung cancer-

    related deaths were recorded in 2007 and 257,000 deaths from

    lung cancer were projected in 2011.2 The American Cancer Soci-

    ety estimates that in the United States, 228,000 new cases of lung

    cancer and 160,000 lung cancer-related deaths occurred in 2013.3

    The association between smoking and lung cancer was

    described more than 50 years ago.4 Worldwide, smoking accounts

    for 80% of lung cancers in men and for 50% in women.

    The fatality rate (ratio of mortality to incidence) for lung

    cancer is high, estimated to be 0.86 in the GLOBOCAN report.1

    The 5-year survival rate varies by country but is generally 5-15%.

    A substantial problem is that most patients have advanced and

    incurable disease at the time of diagnosis. In the United States,

    56% of patients have distant metastasis and 22% have regional

    spread of disease; 15% of lung cancers are localized at the time of

    initial diagnosis.3 The reason for this low percentage of early-stage

    disease is that it is asymptomatic; most early-stage lung cancers

    are currently detected by chance imaging procedures performed

    for other reasons.5

    Until recently, there has been no role for lung cancer screen-

    ing. Screening trials in which chest radiography and sputum

    cytology were evaluated did not demonstrate a decrease in lung

    cancer-related mortality.6-8 In the 1990s, single-arm screening

    trials with low-dose (radiation) computed tomography (LDCT)

    of the chest demonstrated an increase in sensitivity for detect-

    ing lung cancer compared with chest radiography.9-11 Authors of

    the initial trials reported that 60-80% of detected lung cancers

    were stage I and resulted in increased 5-year survival compared

    with current clinical practice.12-15 These studies led to a number

    of randomized screening trials to compare LDCT to either chest

    radiography or observation alone.

    Three European randomized control trials included an LDCT

    screening arm and a control arm.16-18 However, these trials were

    underpowered to detect a clinically plausible benefit in terms of

    lung cancer-related mortality.19 The largest of the current ran-

    domized LDCT screening trials are the National Lung Screening

    Trial (NLST) and the Dutch-Belgian Randomised Lung Cancer

    Screening (NELSON) Trial .20,21 The final results of the NLST have

    been reported, and the NELSON trial is still in progress. In the

    NLST, LDCT screening was associated with a 20% reduction in

    mortality compared with chest radiography.20 The cost-efficacy

    analysis of NLST is still pending.

    In this chapter, we review the risks and benefits of screening

    for lung cancer with LDCT, with an emphasis on the data from

    the two largest prospective randomized controlled trials.


    NLSTObservational studies showed that LDCT screening detects

    more lung cancer and more early-stage cancers than chest radi-

    ography,10-15 which led the US National Cancer Institute to fund

    the NLST.22,23 The NLST was a randomized multicenter study in

    which LDCT was compared with chest radiography to deter-

    mine whether screening with LDCT would reduce lung cancer-

    related mortality among high-risk persons. Chest radiography

    was chosen as the screening method for the control arm because

    radiographic screening was already being compared with usual

    care in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer

    screening trial.24 Eligible participants were 55-74 years old and

    were current or former smokers with a cigarette smoking history

    of at least 30 pack-years. Participants were randomly assigned

    to annual screening with LDCT or chest radiography for 3 years.

  • 4 Chapter 7: Screening for Lung Cancer

    With 25,000 participants in each arm, it was estimated that the

    study would have a 90% power to detect a 21% decrease in mortal-

    ity in the LDCT arm compared with the chest radiography arm.

    The primary endpoint was a comparison of lung cancer-related

    mortality between the two arms. A secondary analysis was done

    to compare the rate of death from any cause and the incidence

    of lung cancer in the two arms. Additional details on the study

    design have been published.22 Thirty-three US centers enrolled

    53,456 persons between September 2002 and April 2004. The

    NLST screening centers maintained close contact with partici-

    pants and collected medical records. Serial specimens of blood,

    urine, and sputum were collected at 15 screening centers from a

    total of 10,208 participants.23

    NELSON TrialThe NELSON trial was initiated in 2003, 1 year after the start of the

    NLST.21,22 The trial was designed as a randomized controlled trial

    to compare LDCT screening with no screening.21 A population-

    based recruitment strategy was chosen to minimize self-selection

    bias; instead of recruitment through the media, potential partici-

    pants were identified through population registries and received

    a questionnaire by mail. The information obtained by the ques-

    tionnaire was used to decide whom to invite for the trial.21,25-28

    Eligible participants were 50-75 years old, were current or former

    smokers who had quit less than 10 years ago, and had a smok-

    ing history of at least 15 cigarettes per day for 25 years or at least

    10 cigarettes per day for 30 years. Exclusion criteria have been

    published previously.21

    The primary endpoint of the NELSON trial is lung cancer-

    specific mortality, a secondary endpoint is all-cause mortality.21,29

    It was estimated that with a total sample size of 17,300 partici-

    pants, a reduction in lung cancer-specific mortality of at least 25%

    could be demonstrated with a power of 80%, assuming 95% com-

    pliance in the screening group, 5% contamination in the control

    group, and 10 years of follow-up after randomization.21 Details

    on the equipment, execution of screening examinations, and the

    protocol for management of nodules have been published.30-32

    A total of 15,822 eligible individuals were included in the

    NELSON trial and randomly assigned to screening with low-dose

    CT scanning at baseline (first round), 1 year later (second round),

    3 years later (third round), and 5 years later (7,915 individuals),

    or to no screening (7,907 individuals). All data on the diagnosis,

    treatment, and follow-up of lung cancer until the death of the

    individual were prospectively collected, and with use of a link-

    age with the national cancer registries of the Netherlands and

    Belgium, all participants with lung cancer not diagnosed through

    screening will be identified.29,33 The collected data will be blinded

    for study group and offered for cause of death evaluation to an

    independent endpoint committee.29 These data will be used to

    determine whether LDCT screening has reduced lung cancer

    mortality by at least 25% at 10 years after randomization.21,29


    NLSTFor LDCT, all noncalcified nodules with long-axis diameters of 4

    mm or greater in the axial plane were