american thoracic society documents · 1 day ago · american thoracic society documents an...

AMERICAN THORACIC SOCIETYDOCUMENTS

An Official American Thoracic Society Research Statement: AResearch Framework for Pulmonary Nodule Evaluationand ManagementChristopher G. Slatore, Nanda Horeweg, James R. Jett, David E. Midthun, Charles A. Powell, Renda Soylemez Wiener,Juan P. Wisnivesky, and Michael K. Gould; on behalf of the ATS Ad Hoc Committee on Setting a Research Frameworkfor Pulmonary Nodule Evaluation

THIS OFFICIAL RESEARCH STATEMENT OF THE AMERICAN THORACIC SOCIETY (ATS) WAS APPROVED BY THE ATS BOARD OF DIRECTORS, APRIL 2015

Background: Pulmonary nodules are frequently detected duringdiagnostic chest imaging and as a result of lung cancer screening.Current guidelines for their evaluation are largely based on low-quality evidence, and patients and clinicians could benefit frommoreresearch in this area.

Methods: In this research statement from the American ThoracicSociety, a multidisciplinary group of clinicians, researchers, andpatient advocates reviewed available evidence for pulmonary noduleevaluation, characterized six focus areas to direct future researchefforts, and identified fundamental gaps in knowledge and strategiesto address them.We did not use formalmechanisms to prioritize oneresearch area over another or to achieve consensus.

Results:Therewaswidespread agreement that novel tests (includingnovel imaging tests and biopsy techniques, biomarkers, and

prognostic models) may improve diagnostic accuracy foridentifying cancerous nodules. Before they are used inclinical practice, however, better evidence is needed toshow that they improve more distal outcomes of importanceto patients. In addition, the pace of research and the qualityof clinical care would be improved by the development ofregistries that link demographic and nodule characteristics withpatient-level outcomes.Methods to share data from registries are alsonecessary.

Conclusions: This statement may help researchers todevelop impactful and innovative research projects andenable funders to better judge research proposals. We hopethat it will accelerate the pace and increase the efficiency ofdiscovery to improve the quality of care for patients withpulmonary nodules.

ContentsOverviewIntroductionMethodsResults

Framing Research Questions forNovel Diagnostic Procedures

Nodule RegistriesData SharingDiagnostic Imaging and InvasiveProcedures

BiomarkersPrediction and Prognostic ModelsEmerging TreatmentsLogistics and ImplementationPatient-centered Outcomes

DiscussionLimitationsConclusions

Overview

Pulmonary nodules are frequently detectedduring diagnostic chest imaging and asa result of lung cancer screening. Currentguidelines for their evaluation are largelybased on low-quality evidence, and patientsand clinicians could benefit from moreresearch in this area.

In this research statement fromthe American Thoracic Society,

C.G.S. is supported by a VA HSR&D Career Development Award (CDP 11-227) as well as resources and the use of facilities at the VA Portland Health CareSystem, Portland, Oregon.

ORCID ID: 0000-0003-0958-8122 (C.G.S.).

The Department of Veterans Affairs did not have a role in the conduct of the study, in the collection, management, analysis, interpretation of data, or in thepreparation of the manuscript. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department ofVeterans Affairs or the U.S. Government.

Correspondence and requests for reprints should be addressed to Christopher G. Slatore, M.D., M.S., 3710 SWU.S. Veterans Hospital Road, R&D 66, Portland,OR 97239. E-mail: [email protected]

Am J Respir Crit Care Med Vol 192, Iss 4, pp 500–514, Aug 15, 2015

Copyright © 2015 by the American Thoracic Society

DOI: 10.1164/rccm.201506-1082ST

Internet address: www.atsjournals.org

500 American Journal of Respiratory and Critical Care Medicine Volume 192 Number 4 | August 15 2015

http://orcid.org/0000-0003-0958-8122

mailto:[email protected]

http://10.1164/rccm.201506-1082ST

http://www.atsjournals.org

a multidisciplinary group of clinicians,researchers, and patient advocates reviewedavailable evidence for pulmonary noduleevaluation, characterized areas to directfuture research efforts, and identifiedfundamental gaps in knowledge andstrategies to address them.

We developed the following keyrecommendations:

d The efficacy and effectiveness of newdiagnostic strategies (including novelimaging tests and biopsy techniques,biomarkers, and prognostic models)should be evaluated using establishedphases of test development, fromidentification of a novel strategy orcharacteristic to establishment of clinicalutility.

d Registries that link demographic andnodule characteristics with patient-leveloutcomes should be developed.

d Pulmonary nodule evaluation strategies areguided by subsequent treatment optionsfor early-stage lung cancer, and thesetreatments should be rigorously studied.

d Potential interventions and qualitymetrics to improve nodule evaluationprocesses should be studied beforerequiring their implementation.

d Tests and interventions should beevaluated for their impact on patient-centered outcomes.This statement may help researchers

develop impactful and innovative proposalsand enable funders to better judge novelresearch proposals. We hope that it willquicken the pace and increase the efficiencyof discovery to improve the quality of carefor patients with pulmonary nodules.

Introduction

Hundreds of thousands of patients arediagnosed every year with incidentalpulmonary nodules (1–3), fueled by the ever-increasing number of individuals whoundergo imaging studies (4–7). The numberof patients with pulmonary nodules willincrease, because multiple organizations,including the American Thoracic Society(ATS), recommend annual low-dosecomputed tomography (CT) screening foradults at high risk of developing lung cancer(8–13). These recommendations are basedon the results of the National LungScreening Trial, which showed thatscreening decreased lung cancer mortality(14). But this benefit came with a substantial

drawback, as almost 40% of subjects hada positive screening test result during thethree rounds of screening, mostly as a resultof pulmonary nodule identification.

The majority of pulmonary nodules arebenign, but the most worrisome cause ofa pulmonary nodule is bronchogeniccarcinoma. Because of the lethality of lungcancer, the difficulty of sampling smalllesions for biopsy, and the relatively slowrate of growth even if the nodule is lungcancer, it is recommended that mostpatients with nodules undergo furtherevaluation (15–17). Patients essentially havethree options to consider after a noduleis identified: (1) active surveillance; (2)additional diagnostic procedures, includingpositron emission tomography (PET),biopsy (percutaneous or bronchoscopic),and surgical removal; or (3) no furthermonitoring or workup (17, 18). Optimizingbenefit and reducing risk for patientsundergoing nodule evaluation requires thepatient and clinician to balance a desire forthe certainty of a diagnosis against thetolerance for the unknown, while assessingthe likelihood of malignancy, the yield andrisk of invasive procedures, and thepotential risk of delayed diagnosis andtreatment of cancer. Patients withpulmonary nodules want to know howlikely the nodule is to be cancer, what arethe safest and most reliable methods ofdiagnosis, which nodules can be seriallyobserved and which need more invasiveevaluation, and what are the best ways todiscuss these concerns with their clinicians(19, 20). For the most part, answers to thesefundamental questions are based onlimited, indirect, or low-quality evidence.

We convened a workshop to establisha framework for lung nodule evaluationresearch and to facilitate the pace, impact,and efficiency of discovery. Outliningimportant research questions and potentialstrategies for evaluation bymultidisciplinarygroups can better and more effectivelyaddress the needs of patients (21).

Methods

We assembled an internationalmultidisciplinary (medical oncology, nursing,pulmonary, radiology, thoracic surgery, andpublic health) group of researchers, clinicians,and patient advocate stakeholders withexpertise in pulmonary nodules at the May2013 ATS International Conference. We

obtained representation from the followingATS committees and assemblies: DocumentsDevelopment and ImplementationCommittee, Patient and Family EducationCommittee, Behavioral Science and HealthServices Research Assembly, ClinicalProblems Assembly, Nursing Assembly,Thoracic Oncology Assembly, and the PatientAdvisory Roundtable (COPD Foundation andFree to Breathe). Conflicts of interest weredisclosed and managed according to thepolicies and procedures of the ATS.

The chairs (C.G.S. and M.K.G.)identified several topics for discussion thatwere vetted before the workshop. Participantswere selected as moderators for breakoutsessions, and each provided input about theplanned agenda. We selected six focus areas:(1) diagnostic imaging and invasiveprocedures, (2) biomarkers, (3) prognosticmodels, (4) emerging treatments, (5)logistics and implementation, and (6)patient-centered outcomes.

The workshop consisted ofpresentations by experts in related fields,including screening for colorectal cancer,comparative effectiveness research, and lungcancer biomarker research. After thesepresentations, each participant engaged inbreakout sessions in two of the focus areas,depending on interest. We did not useformal checklists or consensus methods,because we did not intend to prioritize onearea or specific topic over another (21).

If available, participants considered thefindings of systematic reviews whenevaluating these topics but did not conductnew or updated reviews. Participantsdiscussed key questions related to five topics:(1) identify the information/knowledge gaps,(2) identify why the topic is important, (3)identify relevant stakeholders, (4) reviewappropriate methods and approaches toaddress the gaps, and (5) identify potentialsources of research funding.

Participants also suggested potentialderivatives. For example, we identified tools ormethods that would enhance or facilitateresearch efforts. Participants also identifiedpotential products that could be developedafter evaluating many of the key questions.Each item includes: (1) a description, (2) howit would improve care or advance the field,(3) what resources would be required fordevelopment, (4) what resources would berequired for validation and evaluation, and(5) how would it be implemented.

After the workshop, a writingcommittee drafted a report based on an

AMERICAN THORACIC SOCIETY DOCUMENTS

American Thoracic Society Documents 501

outline developed by the project co-chairs.The draft was circulated to the members ofthe writing group with revisions at each stepand consensus achieved through discussion.The final document was approved by theATS Board of Directors as an Official ATSPolicy Statement.

The primary audience for this reportincludes clinicians, scientists, and patientswho are affected by pulmonary nodules orlung cancer and undergo lung cancerscreening. Institutions and organizationsthat solicit and fund research projects inthese areas may also use this report to guidetheir efforts and decisions, particularly thosethat focus on patient-centered outcomes.Finally, healthcare systems and purchasersmay find this report helpful when evaluatingthe evidence base for implementation ofperformance measures for the care ofpatients with pulmonary nodules.

Results

We identified several key questions andderivatives (Tables 1 and 2) for each focusarea as well as several themes thatoverlapped multiple areas. These cross-cutting themes are discussed first, followedby a section for each focus area.

Framing Research Questions forNovel Diagnostic ProceduresThere is a fair amount of evidence that noveldiagnostic imaging and invasive procedures,biomarkers, and predictive models canimprove diagnostic accuracy and predict therisk of future events, such as developing lungcancer. Unfortunately, the evaluation ofmost of these tests and algorithms has beenlimited to uncontrolled studies of diagnosticaccuracy performed in specialized centers.There are limited data regarding whetherthey influence outcomes that are moreimportant to patients, clinicians, and/orhealthcare systems. We agreed that noveldiagnostic procedures should be proven toprovide incremental value above and beyondcurrently available information before theyare widely adopted into clinical care.

Many novel diagnostic tests andprocedures have promise for improving carefor patients with pulmonary nodules. Theseinclude imaging methodologies, such ascomputer-aided detection (X-ray [22] andCT scan [23–25]), computer-aided diagnosis(CAD) (26–29), volume and mass analysis(30, 31), gated PET imaging (32, 33), PET

imaging using novel radioactive tracers (32,33), novel algorithms to reconstruct CTimages allowing lower radiation dose(32–34) (e.g., model-based iterativereconstruction), and procedures such asnavigational bronchoscopy and radialultrasound (17). There is also great potentialfor novel biomarkers to distinguish benignfrom malignant nodules and aggressiveversus relatively indolent cancers (35, 36).Biomarkers can be classified in multipleways based on anatomic site of sampling(e.g., serum, sputum, urine, and exhaledbreath markers), target of detection (e.g.,DNA methylation, gene expression, andELISA), or type (e.g., DNA, microRNA, andautoantibody). In addition, several modelsusing patient and nodule characteristics forpredicting cancer risk in patients with solidnodules have been developed (37–41), butmore studies are needed to determinewhether these models provide incrementalvalue above and beyond clinical judgmentand intuition (42).

It is critical to develop novel diagnostictests and strategies to improve diagnosticaccuracy for patients with pulmonarynodules. But at least over the short term, itmight be more impactful to demonstrate thatexisting diagnostic technologies improvepatient-centered outcomes. Use of definedphases of research should guide how thesetests are evaluated (43–46) (Figure 1). Few tono prospective trials of diagnosis or theimpact of potential novel tests or strategieson clinical outcomes have been performed.

It is important to consider which testsshow the most promise to impact clinicalpractice when choosing candidates forprospective studies. Currently, most patientswith nodules undergo follow-up CT scans(16). Given the relatively low risk of serialimaging, the negative predictive value ofa novel test will likely need to be very high tosubstantially reduce the number of patientswho require follow-up imaging or the totalnumber of scans these patients receive.Conversely, a novel test would need to havevery high positive predictive value torecommend surgical resection wheninformation from currently available imagingstudies suggests the nodule is benign or canbe safely monitored. Accordingly, studiesthat report the likelihood of how thebiomarker would change decision-making(e.g., the net reclassification index [47]) maybe useful to guide decisions for which testsshould be studied past Phase 2 (Figure 1). Inaddition, explicit information of the risks of

the novel test (including invasiveness andcosts to patients and systems), feasibility, anddata regarding the potential use of the test(see Reference 48 as an example) wouldstrengthen research proposals.

Although developed for biomarkers, useof the prospective-specimen-collection andretrospective-blinded-evaluation (PRoBE)design may improve the rigor of intermediatephases of novel test development and couldstrengthen research proposals for otherdiagnostic tests and strategies (45). The cruxof the PRoBE design requires a prioriconsideration of how the novel test willchange diagnostic accuracy above currentmethods while also stipulating datacollection processes. Furthermore, whileawaiting trials for evidence regarding theimpact of diagnostic imaging andprocedures on health outcomes, it may behelpful to use evidence-based gradingsystems to more formally evaluate theirclinical utility (49, 50).

Nodule RegistriesThe pace of discovery would be substantiallyimproved through the creation of noduleregistries. Current research is stymied by thelack of reliable methods to identify patientswith nodules in routine practice. Notably, theATS and American College of ChestPhysicians recommend the use of a registry tosupport lung cancer screening efforts, and useof a registry is required by the Centers forMedicare and Medicaid Services (51, 52).Registries should be based on protocolizedradiology reports, with detailed informationregarding imaging and nodule characteristicsand recommendations (53). As an example,the Lung Imaging Reporting and DataSystem (Lung-RADS), developed by theAmerican College of Radiology to supportlung cancer screening, is a reporting tool (54,55) that could serve as one element ofa registry. Ideally, data regarding risks forlung cancer and nodule development, suchas age, smoking characteristics, occupationalexposures (e.g., asbestos), family history, andgeographic information (e.g., residence inendemic fungal areas and radon exposure)would be linked with the electronic medicalrecord. Natural language processing isincreasingly used to identify nodulecharacteristics and may be useful to identifyother data from the electronic medicalrecord that are not routinely collected inindividual data fields (56).

Registries should incorporate dataregarding oncologic outcomes, procedures



Tab

le1.

Sum

maryof

Key

Que

stions

Gap

sIm

portan

ceStake

holders

Metho

ds/Approac

hes

Fund

ing

Diagn

ostic

imag

ingan

dinva

sive

proce

dures

Que

stion1:

How

canweva

lidatecu

rren

tpracticegu

idelines

fortheev

alua

tionof

lung

nodules

?Effec

tiven

essof

andad

herenc

eto

thecu

rren

tpracticegu

idelines

,as

sociated

patient

outcom

es,

andreso

urce

useen

gend

ered

bythegu

idelines

areun

know

n,es

pec

ially

forsu

bso

lidno

dules

Determinetheproper

balan

ceof

ben

efit

andha

rmat

thepatient

andsy

stem

leve

lDeterminetheco

steffectiven

essof

evalua

tionstrategies

Determineclinicianad

herenc

ebas

edon

guidelines

Determinewhe

nto

inco

rporateinto

clinical

practice

Patients

Clinicians

(P,R,TS

)Indus

try

Pay

ers

Guidelinedev

elop

ers

Com

parativeeffectiven

essrese

arch

metho

dolog

ies

Cos

t-effectiven

essmetho

ds

Ran

dom

ized

andpragm

atic

trials

ofev

alua

tionstrategies

AHRQ

ACRIN

Foun

dations

NIH

(NHLB

I/NCI)

VA

Que

stion2:

How

andwhe

nsh

ould

adva

nces

inim

age-bas

eddetec

tionan

dch

arac

teriz

ationof

lung

nodules

(e.g.,co

mputer-aided

detec

tionmetho

ds)

andno

nsurgica

lbiopsy

tech

nique

sbec

omeinco

rporated

into

clinical

practice?

Iden

tifica

tionan

dreportin

gof

lung

nodules

isun

predictable

Ability

tomea

sure

and

charac

teriz

eno

dules

isinco

nsistent

Surve

illan

cepractices

vary

Nodefi

nitio

nof

thead

ded

value

ofane

wtech

nology

Use

ofne

wmod

alities

bas

edon

test

charac

teris

tics,

with

outun

derstan

ding

ofris

ksan

dben

efits,may

be

asso

ciated

with

adve

rseou

tcom

es(unn

eces

sary

testing,

anxiety,

and

inap

propria

teus

e)Inap

propria

tely

slow

uptake

ofne

wmod

alities

canlead

tomisse

dop

portunitie

sto

interven

ein

patients

with

early

canc

erEffica

cyof

stan

dardized

review

and

reportin

gof

imag

ingfind

ings

dem

onstratedin

similarcircum

stan

ces

(e.g.,mam

mog

raphy

)

Patients

Clinicians

(P,R)

Hea

lthca

resy

stem

sIndus

try

Com

parativeeffectiven

essrese

arch

metho

dolog

ies,

includ

ingev

alua

tion

oftest

charac

teris

ticsin

usua

lcare

settings

andris

ks/ben

efits

ofus

eCos

t-effectiven

essmetho

ds

Ran

dom

ized

andpragm

atic

trials

ofne

wtech

nologies

Qua

si-exp

erim

entala

pproac

hes

ACR

AHRQ

Indus

try

NIH

(NHLB

I/NCI)

Biomarke

rsQue

stion1:

Can

weop

timizebiomarke

rac

quisitio

nfrom

smalls

pec

imen

s?Amou

ntof

histolog

ical

and

molec

ular

inform

ationrequired

from

smalls

pec

imen

sis

increa

sing

Optim

alproce

dures

toprovide

sufficien

tsp

ecim

ensare

unkn

own

Qua

lityof

proce

dures

inclinical

settings

isun

know

n

Acq

uisitio

nof

adeq

uate

tissu

efor

asse

ssmen

tof

poten

tialb

iomarke

rsPrio

ritizationof

testingas

number

oftargeted

therap

eutic

sincrea

seMoreac

curate

predictio

nof

ratesof

grow

than

dris

kof

maligna

ncy

Patients

Clinicians

(MO,P,TS

)Hea

lthca

resy

stem

sIndus

try

Pay

ers

Policymak

ers

Ben

chrese

arch

todetermine

feas

ibility

Com

parativeeffectiven

ess

metho

dolog

ies,

includ

ingev

alua

tion

ofpropos

edproce

dures

Obse

rvationa

lstudies

Tran

slationa

lres

earchto

determine

effica

cyof

biomarke

rac

quisitio

nin

aus

ualc

arese

tting

Ran

dom

ized

andpragm

atic

trials

ofne

wtech

nologies

AHRQ

Coo

perative

onco

logy

grou

ps

(e.g.,

SWOG)

DOD

Foun

dations

Indus

try

NIH

(NCI)

VA (Con

tinue

d)



Tab

le1.

(Con

tinue

d)

Gap

sIm

portan

ceStake

holders

Metho

ds/Approac

hes

Fund

ing

Que

stion2:

Can

riskbiomarke

rsdistin

guishbetwee

nben

ignan

dmaligna

ntpulmon

aryno

dules

aswella

sag

gres

sive

andno

nagg

ress

ivetumors?

Patho

gene

sisof

canc

erdev

elop

men

t,grow

th,an

dsp

read

ispoo

rlyun

derstoo

dCurrent

clinical

predictio

nmod

els

may

notb

esu

fficien

tlyac

curate

toinflue

ncepractice

Current

diagn

ostic

testing

proce

sses

dono

tad

equa

tely

differen

tiate

patientswho

shou

ldrece

ivedifferen

tintens

ityof

follo

wup

Iden

tifica

tionof

biomarke

rsca

nalso

iden

tifyke

ymec

hanism

sof

canc

erdev

elop

men

tan

dsp

read

Use

ofbiomarke

rsmay

improve

discrim

inationbetwee

nben

ignan

dmaligna

ntno

dules

Ben

efitof

new

tech

nologies

shou

ldou

tweigh

harm

san

dco

stsbothat

patient

andpop

ulationleve

l

Patients

Clinicians

(P,RO,TS

)Hea

lthca

resy

stem

sIndus

try

Policymak

ers

Pay

ers

Ben

chdev

elop

men

tof

biomarke

rsValidationstud

ies

Com

parativeeffectiven

essrese

arch

metho

dolog

ies

Ran

dom

ized

andpragm

atic

trials,

includ

ingex

aminationof

obse

rvationsu

rveillanc

evs

.biopsy

,gu

ided

bybiomarke

rris

kas

sess

men

t

ATS

DOD

EDRN

Foun

dations

Indus

try

NIH

(NCI)

VA

Progn

ostic

mod

els

Que

stion1:

Wha

tclinical,laboratory,

andradiologicch

arac

teris

ticsca

nbeus

edto

improve

lung

canc

erris

kpredictio

nan

dim

prove

subse

que

ntou

tcom

es?

Mod

elsfores

timatingthe

probab

ility

ofmaligna

ncyin

patientswith

solid

solitary

pulmon

aryno

dules

have

bee

ndev

elop

edan

dva

lidated

atpop

ulationleve

lbut

notin

routinepracticese

ttings

Acc

urac

yof

thes

emod

elsfor

estim

atingris

kof

lung

canc

erforpatientswith

subso

lidan

d/

ormultip

leno

dules

isun

know

n

Wides

pread

adop

tionof

lung

canc

ersc

reen

ingwillincrea

sethenu

mber

ofsm

okersiden

tified

with

subso

lidan

d/or

multip

leno

dules

Acc

urateas

sess

men

tof

theris

kof

lung

canc

erha

sim

portant

implications

for

thene

edof

addition

al,an

dpoten

tially

inva

sive

,follo

w-upproce

dures

Patients

Clinicians

(P,R,TS

)Hea

lthca

resy

stem

sPay

ers

Policymak

ers

Med

ical

societies

Com

parativeeffectiven

essrese

arch

metho

dolog

ies,

includ

ingev

alua

tion

ofris

kfactors,

radiologicfeatures

,an

dno

velb

iomarke

rsValidationac

ross

multip

lese

ttings

and

pop

ulations

Foun

dations

NIH

(NCI)

VA

Que

stion2:

Which

small,slow

-growingno

dules

canbeob

served

with

seria

limag

ingvs

.requirin

gbiopsy

orrese

ction?

Riskof

inva

sion

and/orm

etas

tasis

forslow

-growing,

potentially

maligna

ntlung

nodu

lesis

not

wellc

haracterized

Which

subs

etof

slow

-growing

1-to

3-cm

nodu

lesca

nbe

followed

with

seria

limag

ingvs.

need

forbiop

syan

d/or

trea

tmen

tis

unclea

r

Scree

ning

willca

useov

erdiagn

osis

ofslow

lygrow

ingca

ncersthat

wou

ldno

tothe

rwisesp

read

ormetas

tasize

Predictiv

emod

elsof

theris

kof

spread

andmetas

tasismay

behe

lpfulin

guidingclinical

man

agem

ent

Patients

Clinicians

Hea

lthca

resy

stem

sPay

ers

Policymak

ers

Med

ical

societies

Obse

rvationa

lstudiesev

alua

tingthe

asso

ciationof

riskfactors,

radiologicfeatures

,an

dno

vel

biomarke

rswith

riskof

aggres

sive

,inva

sive

canc

erValidationac

ross

multip

lese

ttings

and

pop

ulations

DOD

Foun

dations

NIH

(NCI)

VA

Emerging

trea

tmen

tsQue

stion1:

Wha

tis

theeffectiven

essof

SBRTan

dothe

rab

lativ

etherap

iesforpatientswith

stag

eIA

NSCLC

?Des

pite

increa

sesin

theus

eof

SBRTforstag

eIA

NSCLC

,its

effectiven

essco

mpared

with

surgical

rese

ctionforop

erab

lepatientsha

sno

tbee

nes

tablishe

d

Man

ypatientswith

nodules

areno

tca

ndidates

foran

atom

icsu

rgical

rese

ction

Emerging

therap

iesforea

rly-stage

NSCLC

willinflue

nceup

stream

diagn

ostic

testingan

ddec

ision-

mak

ing,

includ

ingthene

cess

ityof

defi

nitiv

etis

suediagn

osis

Patients

Clinicians

(P,RO,TS

)Hea

lthca

resy

stem

sIndus

try

Pay

ers

Policymak

ers

Com

parativeeffectiven

essrese

arch

,includ

ingrese

ctionvs

.SBRT

Trials

(SBRTon

goingtrials

have

enco

untereddiffi

cultrecruitm

ent)

Cos

t-effectiven

essmetho

ds

Multicen

terph

aseIItrials

toevalua

teab

lativeproc

edures

such

asRFA

,cryo

ablatio

n,an

dmicrowaveab

latio

nRan

dom

ized

pha

seIItrialtoco

mpare

RFA

toSBRTforstag

eIA

NSCLC

with

tumors<

3cm

Coo

perative

onco

logy

grou

ps

NIH

(NCI)

VA (Con

tinue

d)



Tab

le1.

(Con

tinue

d)

Gap

sIm

portan

ceStake

holders

Metho

ds/Approac

hes

Fund

ing

Que

stion2:

Wha

tinterven

tions

ortherap

iesmay

stop

orslow

thegrow

thrate

oflung

canc

erthat

isiden

tified

assm

alln

odules

?Lo

w-qua

lityev

iden

cesu

gges

tsso

metherap

iesmay

preve

ntthedev

elop

men

tof

canc

erin

high

-riskpatients

Eviden

cefortheeffectiven

essof

trea

tingpatientswith

nodules

with

thes

epoten

tialthe

rapiesis

lack

ing

Che

mop

reve

ntionha

sstrong

poten

tialto

improve

mortalityan

dreduc

emorbidity

Any

poten

tialtreatmen

tne

edsto

beve

rysa

fean

dwelltolerated

bec

ause

man

ypatientswith

nodules

dono

tha

velung

canc

er

Patients

Clinicians

(P,RO,TS

)Hea

lthca

resy

stem

sIndus

try

Pay

ers

Policymak

ers

Com

parativeeffectiven

essrese

arch

,includ

ingan

alys

isof

administrative

data

Multic

enterpha

seIItrials

Ran

dom

ized

trials

Coo

perative

onco

logy

grou

ps

Indus

try

NIH

(NCI)

VA

Implemen

tatio

nQue

stion1:

How

shou

ldno

duleev

alua

tionproce

sses

andtoolsbeim

plemen

tedto

optim

izeris

ksan

dben

efits?

Which

noduleev

alua

tion

strategies

canbeim

plemen

ted

inroutine-ca

rese

ttings

that

max

imizepatient-cen

tered

outcom

esis

unclea

r

Limite

dev

iden

cesu

gges

tssy

stem

ic,

stan

dardized

,an

dmultid

isciplinary

approac

hesto

noduleev

alua

tionare

asso

ciated

with

betterou

tcom

esUnc

lear

which

proce

sses

andstrategies

offerthemos

tben

efitto

patientswith

leas

tris

kan

dap

propria

tereso

urce

use

Patients

Clinicians

(N,MO,P,

R,RO,TS

)Hea

lthca

resy

stem

sPay

ers

Policymak

ers

Med

ical

societies

Com

parativeeffectiven

ess

metho

dolog

ies

Ran

dom

ized

andpragm

atic

trials

Foun

dations

Hea

lthca

resy

stem

sNIH

(NCI)

VA

Que

stion2:

Which

,ifan

y,perform

ance

mea

suresan

dqua

litymetric

ssh

ould

beinco

rporated

into

routinepractice?

Which

,ifan

y,perform

ance

mea

sureswillmos

tpos

itive

lyim

pac

tpracticeis

unclea

r

Current

guidelines

arebas

edon

low-qua

lityev

iden

ce,a

ndinap

propria

teus

eof

perform

ance

mea

suresmay

nega

tivelyim

pac

tou

tcom

esQua

lityas

sess

men

tis

esse

ntialfor

dev

elop

inghigh

-qua

lityca

rean

dminim

izingha

rms

Patients

Clinicians

(N,MO,P,

R,RO,TS

)Hea

lthca

resy

stem

sPay

ers

Policymak

ers

Med

ical

societies

Com

parativeeffectiven

ess

metho

dolog

ies

Ran

dom

ized

andpragm

atic

trials

Foun

dations

Hea

lthca

resy

stem

sNIH

(NCI)

VA

Patient-cen

teredou

tcom

esQue

stion1:

Wha

taretheun

met

need

san

dcritica

lcon

cernsof

patients,

families

,clinicians

,an

dothe

rstak

eholderssu

rrou

ndingpulmon

aryno

duleev

alua

tion?

Clinicians

,rese

arch

ers,

andothe

rstak

eholdersmay

not

understan

dpatients’

conc

erns

Relev

antstak

eholdersha

veno

tdiscu

ssed

competingprio

rities

andun

met

need

sof

differen

tpartie

s

Patient

need

ssh

ould

driv

eag

endafor

furthe

rrese

arch

andim

prove

men

tsin

patient

care

Allstak

eholderssh

ould

have

avo

ice

Patients

Clinicians

(N,MO,P,

R,RO,TS

)Hea

lthca

resy

stem

sPay

ers

Policymak

ers

Tech

nique

sto

build

cons

ensu

s,give

alls

take

holdersavo

ice,

and

prio

ritizetopics(e.g.,mod

ified

Delphi

approac

h,no

minal

grou

ptech

nique

,an

alytic

hierarch

yproce

ss)

Patient-cen

teredou

tcom

esrese

arch

,includ

ingmixed

qua

litativean

dqua

ntita

tivemetho

dsto

elicitpatient

view

s

AHRQ

DOD

Foun

dations

NIH

(NCI)

PCORI

VA (Con

tinue

d)



Tab

le1.

(Con

tinue

d)

Gap

sIm

portan

ceStake

holders

Metho

ds/Approac

hes

Fund

ing

Que

stion2:

How

canpatient–clinicianco

mmun

icationproce

sses

andtoolsinflue

ncepatient-cen

teredou

tcom

eswhe

napoten

tially

maligna

ntno

duleha

sbee

niden

tified

?Mos

tpatientsdono

tun

derstan

dtheirperso

nalriskof

lung

canc

erPatient–clinicianco

mmun

ication

issu

bop

timal

intheco

ntex

tof

lung

noduleev

alua

tion

Mos

tpatientsan

dclinicians

do

notop

timally

enga

gein

shared

dec

ision-mak

ing,

includ

ingin

settingof

noduleev

alua

tion

Poo

rco

mmun

icationproce

sses

may

lead

todistres

san

dan

xiety

Ove

restim

atinglung

canc

erris

kmay

lead

toinap

propria

tech

oice

s(e.g.,rese

ction

oflow-riskno

dule,

long

erthan

nece

ssaryfollo

w-up)

Und

eres

timatinglung

canc

erris

kmay

be

asso

ciated

with

harm

fulb

ehav

iors

(con

tinue

dsm

oking)

andno

nadhe

renc

ewith

noduleev

alua

tion

Sub

optim

aldec

ision-mak

ingproce

sses

inwhich

patient

view

sareno

tfully

inco

rporated

may

beas

sociated

with

patient

distres

san

dno

nadhe

renc

ewith

subse

que

ntsc

reen

ingor

nodule

evalua

tion

Patients

Clinicians

(N,MO,P,

R,RO,TS

)Hea

lthca

resy

stem

sPay

ers

Policymak

ers

Patient-cen

teredou

tcom

esrese

arch

,includ

ingob

servationa

l,mixed

qua

litativean

dqua

ntita

tivemetho

ds

toev

alua

tetheas

sociationof

risk

commun

icationwith

patient-cen

teredou

tcom

esRan

dom

ized

andpragm

atic

trials

ofco

mmun

icationan

d/or

dec

ision-mak

ingtools

AHRQ

DOD

Foun

dations

NIH

(NCI)

PCORI

VA

Definitionofabbreviatio

ns:

ACR=Americ

anCollegeofRadiology;

ACRIN

=Americ

anCollegeofRadiologyIm

agingNetw

ork;AHRQ=AgencyforHealth

Care

ResearchandQuality;

ATS=Americ

anThoracic

Society;DOD=DepartmentofDefense;EDRN=Early

Detectio

nResearchNetw

ork;MO=medicaloncology;

N=nursing;NCI=

Natio

nalCancerInstitu

te;

NIH

=Natio

nalInstitu

tesofHealth

;NSCLC=non–smallcelllungcancer;P=pulm

onary;PCORI=

Patent-CenteredOutcomesResearchInstitu

te;R=radiology;

RFA=radiofrequency

ablatio

n;RO=radiatio

noncology;

SBRT=stereotactic

bodyradiotherapy;

TS=thoracic

surgery;VA=DepartmentofVeteransAffairs.



Tab

le2.

Sum

maryof

Derivatives

Des

cription

How/W

hy?

Dev

elopmen

tRes

ource

sValidation/Eva

luation

How/W

here?

Cross

-cuttin

gderivatives

Nod

uleregistrie

s:EMR-bas

edradiology

reports

with

links

topatient-lev

elad

ministrative

dataforiden

tifica

tionan

ddes

criptio

nof

lung

nodules

onch

estim

aging

Dev

elop

men

tof

clinically

useful

EMR-bas

edregistrie

s,po

tentially

aide

dby

natural

lang

uage

proc

essing

,will

facilitateon

goingrese

arch

and

quality

improv

emen

tinitiatives

ATS

(BSHSR,C

linical

Problems,

nursing,

TOA)

Multic

enterad

optio

nan

dtrac

king

ofsu

bse

que

ntman

agem

ent

Mak

eav

ailable

onATS

(and

othe

r)web

siteson

ceva

lidated

Iden

tifying

patientswith

nodules

andas

sociated

clinical

and

radiologica

lcha

racteristic

sis

curren

tlyve

ryex

pen

sive

orim

practical

Other

profess

iona

lsoc

ietie

sCom

pareto

prio

rman

agem

ent

Coo

peratewith

providersof

reportin

gsy

stem

sor

EMR

toinco

rporate

Cou

ldreduc

eva

riability

inpractice

Con

sens

usstatem

enton

reportin

gelem

ents,

inco

rporationinto

reportin

gsy

stem

s/EMR

Partner

with

othe

rstak

eholders

such

astheAmerican

College

ofRad

iology

,ACCP,Soc

iety

ofTh

orac

icSurge

ons,

American

Soc

iety

forRad

iatio

nOnc

olog

y,American

College

ofPhy

sician

s

Cou

ldinform

clinicians

abou

tap

propria

teman

agem

ent

Con

sortiumsto

poo

lclinical

dataan

dsp

ecim

ensfor

biomarke

rdev

elop

men

tan

dva

lidationin

screen

ing

centers

Cou

ldprovidediverse

,unb

iase

dap

proac

hto

valid

ate

biomarke

rsan

dstrategies

toim

plemen

tbiomarke

rs

ATS

(TOA,RCMB,Clinical

Problems)

Patient

testing

Poten

tialp

artnersinclud

eATS

,DOD/VA,foun

dations

,IASLC

,NCIan

dCRN,NIH-N

HLB

I

Cou

ldgu

ideus

eof

biomarke

rs,

refine

diagn

ostic

approac

hto

lung

nodules

Grants:

NCI

Labtesting

Hea

lthca

resy

stem

sCliniciantesting

Pay

ers

Policymak

ers

Dev

elop

men

tof

afram

ework

andco

nsen

susman

ualo

nad

ded

valueof

new

tech

nologies

forthe

evalua

tionof

pulmon

ary

nodules

Cou

ldprov

ideminim

alrequ

iremen

tsor

gold

stan

dardsfortheleve

lof

eviden

ceof

thestud

yitself,

mathe

matical

evalua

tionof

adde

dva

lue,

balanc

eof

gainin

diag

nostic

accu

racy

vs.

additio

nale

ffortsan

dco

stsof

thene

wtech

nology

.Cou

ldim

prov

etran

slationof

rese

arch

outcom

esto

clinical

prac

tice

andto

educ

ateclinicians

Con

sens

usstatem

ent

dev

elop

edbyworking

grou

pco

nnec

tedto

asso

ciation

(rese

arch

ers,

clinicians

,patients,

system

s,pay

ers,

gran

tfund

ers)

Multic

enterad

optio

nan

dtrac

king

ofsu

bse

que

ntman

agem

ent

Con

nect

toATS

/ACCPto

form

working

grou

pof

interested

experts

Pragm

atic

trials

Rev

iew

ofliteraturean

dco

nsen

susmee

tings

Com

parativeeffectiven

ess

rese

arch

metho

dolog

ies

Diagn

ostic

imag

ingan

dinva

sive

proce

dures

Eviden

ce-based

,easily

elec

tronically

accessed

(web

,mob

ileap

plications)u

ser

(clinicianan

dpa

tient)-friend

lylung

canc

erriskstratificatio

ntoolsforpu

lmon

aryno

dules.

Cou

ldinclud

eun

biased

inform

ationon

lung

canc

errisk

stratificatio

n,co

mmercially

availablediag

nostic

tests,

and

listings

ofclinical

expe

rtise

basedon

availabilityof

tech

nologies

andno

duleclinics

Cou

ldim

prove

riskes

timation

byclinicians

.Cou

ldprovide

tailo

redinform

ationfor

patients.

Cou

ldim

prove

inform

ationdisse

mination,

region

alization,

dec

ision-

mak

ing,

andreso

urce

use

ATS

(BSHSR,C

linical

Problems,

nursing,

TOA)

Patient

testing

Con

ferenc

e

Other

profess

iona

lsoc

ietie

sLa

btesting

Pee

r-review

edjourna

l

Hea

lthca

resy

stem

sCliniciantesting

Res

earchstud

y

Pay

ers

Feed

bac

kse

ctionon

web

site

ATS

web

site

Policymak

ers

Web

site

dev

elop

er,co

nten

tdev

elop

men

t,co

nnec

tionto

anas

sociation(e.g.,ATS

,ACCP,

patient

advo

cacy

grou

p)

(Con

tinue

d)



Tab

le2.

(Con

tinue

d)

Des

cription

How/W

hy?

Dev

elopmen

tRes

ource

sValidation/Eva

luation

How/W

here?

Biomarke

rsInco

rporationof

dataelem

ents

rega

rdingsm

alls

pec

imen

acquisitio

nan

dproce

ssing

into

avo

luntaryregistry

that

acquiresqua

lityan

dperform

ance

datafrom

interven

tiona

lpulmon

ary

proce

dures

Cou

ldprovideed

ucationto

interven

tiona

lpulmon

ary

program

s.Cou

lden

hanc

estan

dardizationof

protoco

lsan

dinno

vatio

nto

improve

perform

ance

ATS

/ACCP

Patient

testing

Con

ferenc

eGrants

Labtesting

Pee

r-review

edjourna

lHea

lthca

resy

stem

sCliniciantesting

Res

earchstud

yPay

ers

Policymak

ers

Implemen

tatio

nDev

elop

men

tof

eviden

ce-bas

edperform

ance

mea

suresan

dqua

litymetric

s

Cou

ldim

prove

qua

lityan

dad

herenc

eto

guidelines

.Cou

ldfacilitatereportin

gof

nodulean

dpatient

charac

teris

tics

Hea

lthca

resy

stem

sStake

holder

cons

ensu

sOutput

from

stak

eholder

conferen

cePatient

stak

eholder

grou

ps

Pay

ers

Policymak

ers

Profess

iona

lsoc

ietie

s

Patient-cen

teredou

tcom

esMulti-stak

eholder

cons

ensu

sgrou

pwho

sepurpos

eis

tous

eform

almetho

dsto

elicit

unmet

patient

need

s,prio

ritizearese

arch

agen

da,

iden

tifyco

ncerns

,an

doffer

poten

tials

olutions

Use

sform

almetho

dsto

obtain

cons

ensu

sfrom

multip

lestak

eholders.

Setsarese

arch

agen

dabas

edon

need

siden

tified

asmos

tim

portant

topatients,

with

input

from

multip

lestak

eholders

ATS

(BSHSR,C

linical

Problems,

nursing,

TOA,PAR)

Elicitfeed

bac

kfrom

othe

rsno

tinvo

lved

ingrou

pbut

pulled

from

samestak

eholder

grou

psto

ensu

reface

valid

ity

Con

ferenc

e

Hea

lthca

resy

stem

sPoten

tialfun

dingfrom

NCI,

PCORI,profess

iona

lsoc

ietie

s,an

dhe

althca

resy

stem

sOther

profess

iona

lsoc

ietie

sPatients

Patient

advo

cacy

orga

niza

tions

Pay

ers

Policymak

ers

Instrumen

tsthat

mea

sure

dec

isionqua

litysp

ecificto

issu

essu

rrou

ndinglung

canc

ersc

reen

ingan

dno

dule

evalua

tion

Con

text-spec

ificinstrumen

tsbetterab

leto

mea

sure

dec

isionqua

litythan

gene

ricinstrumen

ts.Cou

ldhe

lpmea

sure

effect

ofdec

ision

supporttools

ATS

(BSHSR,C

linical

Problems,

nursing,

TOA)

Patient

testing

Con

ferenc

e

Grants

Pee

r-review

edjourna

l

Hea

lthca

resy

stem

sRes

earchstud

y

Pay

ers

Policymak

ers

Individua

llytailo

redpatient-an

dclinician-ac

cess

ible

commun

icationaids,

includ

ingdec

isionsu

pport

toolsan

ded

ucationa

lmaterials

that

address

key

patient

que

stions

and

improve

satis

factionwith

dec

ision-mak

ing

Cou

ldim

prove

patient–clinician

commun

icationproce

sses

.Cou

ldallow

patientsto

weigh

optio

nsbas

edon

theirow

npreferenc

esan

dva

lues

.Cou

ldfacilitatesh

ared

dec

ision-

mak

ing

ATS

(BSHSR,C

linical

Problems,

SOTO

,PAR)

Patient

testing

Con

ferenc

e

Grants

Cliniciantesting

ATS

web

site

Hea

lthca

resy

stem

sLa

btesting/role

play/simulated

clinic

visits

Pay

ers

Actua

lrec

orded

clinic

visits

Policymak

ers

Definitionofabbreviatio

ns:

ACCP=Americ

anCollegeofChest

Physicians;

ATS=Americ

anThoracic

Society;BSHSR=BehavioralScienceandHealth

ServicesResearch;CRN=Cancer

ResearchNetw

ork;DOD=DepartmentofDefense;EMR=electronic

medicalrecord;IASLC=Internatio

nalAssociatio

nfortheStudyofLungCancer;NCI=

Natio

nalCancerInstitu

te;

NIH

=Natio

nalInstitu

tesofHealth

;PAR=Public

Adviso

ryRoundtable;PCORI=

Patent-CenteredOutcomesResearchInstitu

te;RCMB=Resp

iratory

CellandMolecularBiology;

SOTO=Sectio

nonThoracic

Oncology;

TOA=Thoracic

OncologyAssembly;VA=VeteransAffairs.



(including complications), smokingcessation efforts, adherence to managementguidelines, and resource use. TheSurveillance, Epidemiology, and End Results(SEER)–Medicare Program (57) collectssimilar information and should guide thecollection of patient-level variables.Healthcare systems may want to emulatethe registry used by the Department ofVeterans Affairs to support its pilot lungcancer screening program (58). Some datamay be challenging to collect by individualsystems because patients frequently receivecare at multiple institutions, so processeswill need to be developed to link noduledata via healthcare information exchange.

Registries should ideally be a corecomponent of system-level interventions tofacilitate patient care. They are unlikely to gaintraction if solely used for research purposes.They should optimize current practices andinformation technology systems to be feasible,user friendly, and cost effective. Registries couldbe used to track patients to improve adherenceto follow-up plans and longitudinally followchanges in nodule characteristics. Given thatmost institutions lack systematic methods toidentify or follow patients with nodules,registries could guide quality-improvementefforts. They could also be used as recruitmenttools for trials and in comparative effectivenessresearch (59). Finally, registries themselvesshould be evaluated for their impact onpatient-centered outcomes, healthcare systemresource use, and costs.

Data SharingRegistries are necessary but not sufficient toimprove research efforts. Methods to sharethe data in registries are also required. Forexample, nodule consortiums could facilitatevalidation of prognostic models and increasethe ability to test their clinical effectiveness.In addition, consortiums to pool clinical datawith specimens should be developed. Theability to compare different diagnostic testsand implementation strategies will also begreatly facilitated by consortiums.

In particular, biomarker studies areoften limited by lack of generalizability andinability to validate the marker in othersettings. Registries should collect dataregarding small sample acquisition andprocessing and have the ability to be linkedwith specimen banks. Several existinggroups and consortiums could serve asmodels for collaboration, including COPDOutcomes-based Network for ClinicalEffectiveness and Research Translation(CONCERT), the Early Detection ResearchNetwork of the National Cancer Institute,and the American College of ChestPhysicians Quality Improvement Registry(AQuIRE) (60) (61–63).

Diagnostic Imaging and InvasiveProceduresPractice guidelines for the evaluation of lungnodules must be studied. Currentrecommendations regarding follow-upimaging and procedures after nodule

detection (15–17) are based on indirectevidence regarding the risk of malignancy,the expected growth rate of malignantnodules, the capability to detect growth,and the risks of radiation, rather thanevidence from randomized trials or large,well-designed observational studies.Guidelines for the management of subsolidnodules are grounded in even weakerevidence than those for solid nodules andshould also be studied (15). It may also behelpful for guideline developers to usea living guideline model to more rapidlyand efficiently disseminate importantdevelopments in the field (64).

BiomarkersGiven expected changes in treatmentoptions, it will be important to obtainadequate samples from small specimens.Although most developmental work to datehas used specimens from patients withadvanced lung cancer, more research isrequired to understand the accuracy andprognostic value of biomarkers in local andregional stage disease. Optimizing the abilityto test for multiple markers in small sampleswill also help to evaluate pathogenesis ofcancer development, growth, and spread.Focusing biomarker studies on mechanisticfactors will facilitate development oftargeted therapies that can decrease or stopmalignant nodule growth and metastasis.

Prediction and Prognostic ModelsIt is important to determine what factorsaccurately estimate the probability of lungcancer among patients with nodules andwhether their use leads to improvedoutcomes. Several models for predictingcancer risk in patients with solid nodules havebeen developed, but they require additionalvalidation (37–41). Only one model hasexplicitly included identification of multiplenodules as a predictor (39). No model hasbeen developed for subsolid nodules,a common finding among subjectsundergoing lung cancer screening. It isalso important to assess the value ofincorporating into future models readilyavailable CT scan findings, such as thepresence of emphysema. Another key issue isrelated to the concern for overdiagnosis ofscreening-detected nodules. Models thataccurately predict nodule growth, invasion,and metastasis or other determinants ofprognosis would be valuable to clinicians andpatients and may help reduce overtreatmentof slow-growing cancers. Finally, it will be

Phases of study designs for new diagnostic strategies

Preclinical Promising directions identified

Clinical assay detects established disease

Biomarker detects disease early before it becomes

Extent and characteristics of disease detected by the

Impact of screening on reducing the burden of diseaseon the population is quantified

test and the false referral rate are identified

clinical, and a “screen positive” rule is defined

PHASE 1

PHASE 2

PHASE 3

PHASE 4

PHASE 5

Exploratory

Clinical Assay

Retrospective

Prospective

Cancer Control

Screening

Longitudinal

and Validation

Figure 1. Proposed phases of study designs for new diagnostic strategies for improving ability topredict which pulmonary nodules are benign and which are cancerous (adapted by permission fromReference 44).



useful to follow the Transparent Reportingof a multivariable prediction model forIndividual Prognosis Or Diagnosis(TRIPOD) reporting guidelines (65, 66).

Emerging TreatmentsTreatment options for early-stage lung cancerdirectly impact the evaluation of pulmonarynodules (17, 18) and thus should be rigorouslyevaluated. For instance, stereotactic bodyradiotherapy (SBRT) has rapidly disseminatedas a treatment for patients with stage I non-small cell lung cancer at high risk forperioperative morbidity and mortality. Avariety of other ablative therapies, such asradiofrequency ablation (RFA), cryoablation,and microwave ablation, have been used forinoperable patients (67). However, there areno randomized trials comparing ablativetherapies to surgery (67), and recent studies ofSBRT versus sublobar resection wereterminated early due to poor accrual (68).Because of the risks and challenges of biopsyin marginal surgical candidates, many patientswith nodules undergo ablative therapywithout a diagnosis of lung cancer (69). It willbe important to compare the efficacy andeffectiveness of emerging therapies to surgeryto guide decision-making about the risks andbenefits of different evaluation strategies andtreating patients with pulmonary nodules thatmay not be cancerous. Guidelines (17) anddecision models (70) should be evaluated forwhich patients SBRT constitutes acceptabletreatment when a tissue diagnosis is notestablished.

It is also important to study theeffectiveness of novel therapies on cancerprevention and tumor growth amongpatients with nodules. Trials of novelprevention agents and comparativeeffectiveness studies of potential existingtherapies (e.g., oral or inhaled iloprost)should be conducted (71). Nodule growthon surveillance imaging may be animportant intermediate outcome in thesetrials if they are underpowered to detectdifferences in lung cancer mortality (72).

Logistics and ImplementationProcesses for nodule evaluation should beoptimally implemented into routine caresettings, because many patients do not receiveguideline-adherent follow up (73, 74).Evidence supporting specific system-levelinterventions for nodule evaluation is limited,but these have been shown to be helpful inother settings (75–77). Possible interventionscould include: creation of multidisciplinary

teams, standardized reporting of results,development of care pathways, anddevelopment of registries to track patientswith nodules. It is important to study thefacilitators and barriers, effects on healthoutcomes, unintended consequences, andcost effectiveness of these interventions.

Performance measures and qualitymetrics will undoubtedly be developed.Indeed, the dissemination of lung cancerscreening into practice has been accompaniedby calls to institute these measures (51, 78).However, there is little high-quality evidenceon which to base specific measures or toestablish quality thresholds. A multi-stakeholder group should identify potentialmetrics, categorize the evidence base fortheir use, and suggest steps for adoption andimplementation. Possible quality indicatorsinclude accuracy of image acquisition andprocessing, timeliness of reporting, the use ofa tracking system, the percentage of benigndiagnoses among surgically resected nodules,the percentage of nondiagnosticbronchoscopic and CT-guided nodulebiopsies, timely diagnosis and treatment ofmalignant nodules, and complication ratesfrom biopsies and resections. The ATS haspreviously recommended that measures besubjected to rigorous review and testingbefore widespread implementation (79). Inaddition, it will be important to study theimplementation process itself to moreeffectively and efficiently establish theinterventions in real-world settings.

Patient-centered OutcomesPatient centeredness is defined by theInstitute of Medicine as care “that isrespectful of and responsive to individualpatient preferences, needs, and values, andensuring that patient values guide allclinical decisions” (80). To conductinnovative patient-centered research, thefield should incorporate feedback fromdiverse stakeholders to understand theunmet needs of patients, their families, andtheir clinicians. Some patients sufferpsychological harm when a pulmonarynodule is discovered during screening(81–85) or incidentally (19, 20, 86, 87). Weidentified communication processes as themost likely factors that that could bemodified to improve patient-centeredoutcomes. Tools and systems designed toimprove communication processes shouldbe evaluated regarding their effect onoutcomes important to patients. To ensurethese tools are helpful and ultimately used

in practice, they should be developed withsystematic input from stakeholders.

As a next step to this statement, itwould be optimal to form an organized,multi-stakeholder group, similar to theCONCERT effort (88). Like CONCERT,this effort should use formal consensusprocesses to elicit concerns and unmetneeds from multiple stakeholders. Thepurpose of the group would be to prioritizeresearch and assess the evolving needs ofthe patient and research community.

Discussion

Our workshop identified many researchquestions regarding the evaluation ofpulmonary nodules. Given the large numbersof patients affected, which is likely to increasewith the implementation of lung cancerscreening, it is critical to conduct research toanswer the most pressing questions.

We developed the following keyrecommendations:

d The efficacy and effectiveness of newdiagnostic strategies (including novelimaging tests and biopsy techniques,biomarkers, and prognostic models)should be evaluated using establishedphases of test development, fromidentification of a novel strategy orcharacteristic to establishment of clinicalutility.

d Registries that link demographic andnodule characteristics with patient-leveloutcomes should be developed.

d Pulmonary nodule evaluation strategies areguided by subsequent treatment optionsfor early-stage lung cancer, and thesetreatments should be rigorously studied.

d Potential interventions and qualitymetrics to improve nodule evaluationprocesses should be studied beforerequiring their implementation.

d Tests and interventions should beevaluated for their impact on patient-centered outcomes.

There were substantial overlaps in thekey research gaps we identified. Forinstance, participants recognized the need tovalidate novel prediction models, imagingtests, invasive procedures, and biomarkers.We also agreed that these interventions needto be rigorously evaluated in randomizedand/or pragmatic trials for their effectson patient, clinician, and healthcaresystem outcomes before widespread



implementation. The ATS may want toconsider how to frame these issues morebroadly, because processes related to theevaluation of diagnostic tests and prognosticmarkers are relevant to many problems inpulmonary, critical care, and sleepmedicine.This framework would provide actionablecriteria for discovery and validation and toassess impact on patient outcomes.

Pulmonary nodules are just one ofmany incidental findings commonlyidentified when patients undergo imagingprocedures. A recent PresidentialCommission for the Study of BioethicalIssues related to incidental and secondaryfindings recommended that professionalorganizations develop guidelines and bestmanagement practices; that research effortsshould be funded to evaluate the frequencyof incidental findings along with their costs,benefits, and harms; and that all affectedpatients have access to informationregarding individualized risks and benefitsto make informed decisions (89).Researchers may want to use ourframework along with this statement toguide future proposals.

Workshop participants identified thelack of nodule registries as a key barrier toresearch and quality improvement efforts.The American College of Radiology createdthe Breast Imaging Reporting and DataSystem (BI-RADS) to address a similarbarrier (90) and could serve as a guide fornodule registries. This system was developedwith input from multiple stakeholders,initially to support the needs of clinicians tobetter understand and use the informationcontained in radiology reports. We agreedthat nodule registries need to be carefullydesigned and implemented and shown to beuseful if they are to be widely adopted.

LimitationsWe did not use formal methods to achieveconsensus and therefore did not attempt to setpriorities. We did not include representativesfrom health systems, purchasers, or groupsthat fund research, so inclusion of thesestakeholders in future discussions may behelpful. The international participants did notseem to have disparate views, but this reportlikely does not fully represent the views ofstakeholders from other countries. Finally, we

included stakeholders from organizations thatrepresent patients who are often identifiedwith a nodule and influenced by lung cancerscreening efforts, but there are no readilyidentifiable organizations that advocatespecifically on behalf of patients withpulmonary nodules. We hope that oneoutcome of this statement is to facilitate thecreation of multidisciplinary stakeholdergroups that more fully incorporate patientviews.

ConclusionsThis statement establishes a researchframework to address fundamentalquestions about the care of patients withpulmonary nodules. We engaged clinicaland patient stakeholders to addressquestions of importance. This statementmay help researchers develop impactful andinnovative proposals and enable funders tobetter judge novel research proposals. Wehope that it will quicken the pace andincrease the efficiency of discovery toimprove the quality of care for patients withpulmonary nodules. n

Members of the Writing Committee are asfollows:

CHRISTOPHER G. SLATORE, M.D., M.S. (Chair)MICHAEL K. GOULD, M.D., M.S. (Co-Chair)NANDA HOREWEG, M.D., PH.D.JAMES R. JETT, M.D.DAVID E. MIDTHUN, M.D.CHARLES A. POWELL, M.D.RENDA SOYLEMEZ WIENER, M.D., M.P.H.JUAN P. WISNIVESKY, M.D., DR.P.H.

Author Disclosures: C.G.S. receivedresearch support from the U.S. Departmentof Veterans Affairs, the American LungAssociation, and the Radiation OncologyInstitute; he was a speaker for the NationalLung Cancer Partnership and on an advisorycommittee pertaining to Centers for Medicare& Medicaid Services lung cancer screeningdecisions. J.R.J. received research supportfrom Oncimmune Inc. D.E.M. receivedresearch support from IntegratedDiagnostics. C.A.P. was a consultant forPfizer. J.P.W. was a consultant and on an

advisory committee for EHE International.M.K.G. received research support fromArchimedes and is an author for UpToDate.N.H. and R.S.W. reported no relevantcommercial interests.

Workshop Attendees:

DOUG A. ARENBERG, M.D.DAVID H. AU, M.D., M.S.PETER B. BACH, M.D., M.A.P.P.CHRISTINE D. BERG, M.D.ROBERT L. KEITH, M.D.BILL CLARK, B.S.HARRY J. DE KONING, M.D., PH.D.FRANK C. DETTERBECK, M.D.STEVE M. DUBINETT, M.D.BARBARA M. FISCHER, M.D., PH.D.MICHAEL K. GOULD, M.D., M.S.EDWARD A. HIRSCHOWITZ, M.D.KATHY HOPKINS, M.S., R.N.NANDA HOREWEG, M.D.JAMES R. JETT, M.D.

JERRY A. KRISHNAN, M.D., PH.D.ANN N. LEUNG, M.D.PIERRE P. MASSION, M.D.PETER J. MAZZONE, M.D., M.P.H.DAVID E. MIDTHUN, M.D.GEORGIA L. NARSAVAGE, PH.D., A.P.R.N.DAVID E. OST, M.D., M.P.H.CHARLES A. POWELL, M.D.DAWN PROVENZALE, M.D., M.S.CHRISTOPHER G. SLATORE, M.D., M.S.ANIL VACHANI, M.D.REGINA VIDAVER, PH.D.RENDA SOYLEMEZ WIENER, M.D., M.P.H.AVRUM SPIRA, M.D., M.SC.JUAN P. WISNIVESKY, M.D., DR.P.H.

Acknowledgment: The authors thank Jerry A.Krishnan, M.D., Ph.D.; Dawn Provenzale, M.D.,M.S.; and Avrum Spira, M.D., M.Sc., for theirinsight and willingness to provide advice duringthe workshop.

References

1. Ost D, Fein AM, Feinsilver SH. Clinical practice: the solitary pulmonarynodule. N Engl J Med 2003;348:2535–2542.

2. The Dartmouth Institute for Health Policy and Clinical Practice.Dartmouth atlas of health care. Raleigh, NC: Lulu; 2008.

3. Holden WE, Lewinsohn DM, Osborne ML, Griffin C, Spencer A,Duncan C, Deffebach ME. Use of a clinical pathway tomanage unsuspected radiographic findings. Chest 2004;125:1753–1760.

4. Rao VM, Levin DC. The overuse of diagnostic imaging and the ChoosingWisely Initiative. Ann Intern Med 2012;157:574–576.



http://www.atsjournals.org/doi/suppl/10.1164/rccm.201506-1082ST/suppl_file/disclosures.pdf

5. Rao VM, Levin DC, Parker L, Frangos AJ, Sunshine JH. Trends inutilization rates of the various imaging modalities in emergencydepartments: nationwide Medicare data from 2000 to 2008. J Am CollRadiol 2011;8:706–709.

6. Meer AB, Basu PA, Baker LC, Atlas SW. Exposure to ionizing radiationand estimate of secondary cancers in the era of high-speed CTscanning: projections from the Medicare population. J Am Coll Radiol2012;9:245–250.

7. Smith-Bindman R, Miglioretti DL, Johnson E, Lee C, Feigelson HS, FlynnM, Greenlee RT, Kruger RL, Hornbrook MC, Roblin D, et al. Use ofdiagnostic imaging studies and associated radiation exposure forpatients enrolled in large integrated health care systems, 1996-2010.JAMA 2012;307:2400–2409.

8. Bach PB, Mirkin JN, Oliver TK, Azzoli CG, Berry DA, Brawley OW, ByersT, Colditz GA, Gould MK, Jett JR, et al. Benefits and harms of CTscreening for lung cancer: a systematic review. JAMA 2012;307:2418–2429.

9. Jaklitsch MT, Jacobson FL, Austin JH, Field JK, Jett JR, Keshavjee S,MacMahon H, Mulshine JL, Munden RF, Salgia R, et al. The AmericanAssociation for Thoracic Surgery guidelines for lung cancer screeningusing low-dose computed tomography scans for lung cancer survivorsand other high-risk groups. J Thorac Cardiovasc Surg 2012;144:33–38.

10. National Comprehensive Cancer Network. NCCN guidelines on lungcancer screening. 2012 [accessed 2012 Jun 27]. Available from:http://www.nccn.org/professionals/physician_gls/pdf/lung_screening.pdf

11. Samet JM, Crowell R, San Jose Estepar R, Rand CS, Rizzo AA, Yung R;American Lung Association. Providing guidance on lung cancerscreening to patients and physicians. 2012 [accessed 2012 Jun 27].Available from: http://www.lung.org/lung-disease/lung-cancer/lung-cancer-screening-guidelines/lung-cancer-screening.pdf

12. Wender R, Fontham ET, Barrera E Jr, Colditz GA, Church TR, EttingerDS, Etzioni R, Flowers CR, Gazelle GS, Kelsey DK, et al. AmericanCancer Society lung cancer screening guidelines. CA Cancer J Clin2013;63:107–117.

13. Moyer VA. Screening for lung cancer: US Preventive Services TaskForce recommendation statement. Ann Intern Med 2014;160:330–338.

14. Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM,Gareen IF, Gatsonis C, Marcus PM, Sicks JD; National LungScreening Trial Research Team. Reduced lung-cancer mortality withlow-dose computed tomographic screening. N Engl J Med 2011;365:395–409.

15. Naidich DP, Bankier AA, MacMahon H, Schaefer-Prokop CM, PistolesiM, Goo JM, Macchiarini P, Crapo JD, Herold CJ, Austin JH, et al.Recommendations for the management of subsolid pulmonarynodules detected at CT: a statement from the Fleischner Society.Radiology 2013;266:304–317.

16. MacMahon H, Austin JH, Gamsu G, Herold CJ, Jett JR, Naidich DP, PatzEF Jr, Swensen SJ; Fleischner Society. Guidelines for management ofsmall pulmonary nodules detected on CT scans: a statement from theFleischner Society. Radiology 2005;237:395–400.

17. Gould MK, Donington J, Lynch WR, Mazzone PJ, Midthun DE, NaidichDP, Wiener RS. Evaluation of individuals with pulmonary nodules:when is it lung cancer? Diagnosis and management of lung cancer,3rd ed: American College of Chest Physicians evidence-basedclinical practice guidelines. Chest 2013;143:e93S–e120S.

18. Ost DE, Gould MK. Decision making in patients with pulmonarynodules. Am J Respir Crit Care Med 2012;185:363–372.

19. Slatore CG, Press N, Au DH, Curtis JR, Wiener RS, Ganzini L. What theheck is a “nodule”? A qualitative study of veterans with pulmonarynodules. Ann Am Thorac Soc 2013;10:330–335.

20. Slatore CG, Golden SE, Ganzini L, Wiener RS, Au DH. Distress andpatient-centered communication among veterans with incidental (notscreen-detected) pulmonary nodules: a cohort study. Ann AmThorac Soc 2015;12:184–192.

21. Viergever RF, Olifson S, Ghaffar A, Terry RF. A checklist for healthresearch priority setting: nine common themes of good practice.Health Res Policy Syst 2010;8:36.

22. Schalekamp S, van Ginneken B, Koedam E, Snoeren MM, Tiehuis AM,Wittenberg R, Karssemeijer N, Schaefer-Prokop CM. Computer-aided detection improves detection of pulmonary nodules in chest

radiographs beyond the support by bone-suppressed images.Radiology 2014;272:252–261.

23. Bogoni L, Ko JP, Alpert J, Anand V, Fantauzzi J, Florin CH, Koo CW,Mason D, Rom W, Shiau M, et al. Impact of a computer-aideddetection (CAD) system integrated into a picture archiving andcommunication system (PACS) on reader sensitivity and efficiencyfor the detection of lung nodules in thoracic CT exams. J DigitImaging 2012;25:771–781.

24. Zhao Y, de Bock GH, Vliegenthart R, van Klaveren RJ, Wang Y, BogoniL, de Jong PA, Mali WP, van Ooijen PM, Oudkerk M. Performance ofcomputer-aided detection of pulmonary nodules in low-dose CT:comparison with double reading by nodule volume. Eur Radiol 2012;22:2076–2084.

25. Szucs-Farkas Z, Patak MA, Yuksel-Hatz S, Ruder T, Vock P.Improved detection of pulmonary nodules on energy-subtractedchest radiographs with a commercial computer-aided diagnosissoftware: comparison with human observers. Eur Radiol 2010;20:1289–1296.

26. Fraioli F, Serra G, Passariello R. CAD (computed-aided detection) andCADx (computer aided diagnosis) systems in identifying andcharacterising lung nodules on chest CT: overview of research,developments and new prospects. Radiol Med (Torino) 2010;115:385–402.

27. Chen H, Xu Y, Ma Y, Ma B. Neural network ensemble-based computer-aided diagnosis for differentiation of lung nodules on CT images:clinical evaluation. Acad Radiol 2010;17:595–602.

28. Lee MC, Boroczky L, Sungur-Stasik K, Cann AD, Borczuk AC,Kawut SM, Powell CA. Computer-aided diagnosis ofpulmonary nodules using a two-step approach for featureselection and classifier ensemble construction. Artif Intell Med2010;50:43–53.

29. Kusano S, Nakagawa T, Aoki T, Nawa T, Nakashima K, Goto Y, KorogiY. Efficacy of computer-aided diagnosis in lung cancer screeningwith low-dose spiral computed tomography: receiver operatingcharacteristic analysis of radiologists’ performance. Jpn J Radiol2010;28:649–655.

30. Scholten ET, de Hoop B, Jacobs C, van Amelsvoort-van de Vorst S,van Klaveren RJ, Oudkerk M, Vliegenthart R, de Koning HJ, van derAalst CM, Mali WT, et al. Semi-automatic quantification of subsolidpulmonary nodules: comparison with manual measurements. PlosOne 2013;8:e80249.

31. Cascio D, Magro R, Fauci F, Iacomi M, Raso G. Automatic detection oflung nodules in CT datasets based on stable 3D mass-springmodels. Comput Biol Med 2012;42:1098–1109.

32. Kubota K, Murakami K, Inoue T, Saga T, Shiomi S. Additional effects ofFDG-PET to thin-section CT for the differential diagnosis of lungnodules: a Japanese multicenter clinical study. Ann Nucl Med 2011;25:787–795.

33. Ohno Y, Nishio M, Koyama H, Fujisawa Y, Yoshikawa T, Matsumoto S,Sugimura K. Comparison of quantitatively analyzed dynamic area-detector CT using various mathematic methods with FDG PET/CT inmanagement of solitary pulmonary nodules. AJR Am J Roentgenol2013;200:W593-602.

34. Chen B, Barnhart H, Richard S, Robins M, Colsher J, Samei E.Volumetric quantification of lung nodules in CT with iterativereconstruction (ASiR and MBIR). Med Phys 2013;40:111902.

35. Nana-Sinkam SP, Powell CA. Molecular biology of lung cancer.Diagnosis and management of lung cancer, 3rd ed: AmericanCollege of Chest Physicians evidence-based clinical practiceguidelines. Chest 2013;143:e30S–e39S.

36. Hassanein M, Callison JC, Callaway-Lane C, Aldrich MC, Grogan EL,Massion PP. The state of molecular biomarkers for the earlydetection of lung cancer. Cancer Prev Res (Phila) 2012;5:992–1006.

37. Swensen SJ, Silverstein MD, Ilstrup DM, Schleck CD, Edell ES. Theprobability of malignancy in solitary pulmonary nodules. Applicationto small radiologically indeterminate nodules. Arch Intern Med 1997;157:849–855.

38. Gould MK, Ananth L, Barnett PG; Veterans Affairs SNAP CooperativeStudy Group. A clinical model to estimate the pretest probability oflung cancer in patients with solitary pulmonary nodules. Chest 2007;131:383–388.



http://www.nccn.org/professionals/physician_gls/pdf/lung_screening.pdf

http://www.nccn.org/professionals/physician_gls/pdf/lung_screening.pdf

http://www.lung.org/lung-disease/lung-cancer/lung-cancer-screening-guidelines/lung-cancer-screening.pdf

http://www.lung.org/lung-disease/lung-cancer/lung-cancer-screening-guidelines/lung-cancer-screening.pdf

39. McWilliams A, Tammemagi MC, Mayo JR, Roberts H, Liu G, SoghratiK, Yasufuku K, Martel S, Laberge F, Gingras M, et al. Probability ofcancer in pulmonary nodules detected on first screening CT. N EnglJ Med 2013;369:910–919.

40. Herder GJ, van Tinteren H, Golding RP, Kostense PJ, Comans EF,Smit EF, Hoekstra OS. Clinical prediction model to characterizepulmonary nodules: validation and added value of18F-fluorodeoxyglucose positron emission tomography.Chest 2005;128:2490–2496.

41. Schultz EM, Sanders GD, Trotter PR, Patz EF Jr, Silvestri GA, OwensDK, Gould MK. Validation of two models to estimate the probabilityof malignancy in patients with solitary pulmonary nodules. Thorax2008;63:335–341.

42. Balekian AA, Silvestri GA, Simkovich SM, Mestaz PJ, Sanders GD,Daniel J, Porcel J, Gould MK. Accuracy of clinicians and models forestimating the probability that a pulmonary nodule is malignant. AnnAm Thorac Soc 2013;10:629–635.

43. Fryback DG, Thornbury JR. The efficacy of diagnostic imaging. MedDecis Making 1991;11:88–94.

44. Pepe MS, Etzioni R, Feng Z, Potter JD, Thompson ML, Thornquist M,Winget M, Yasui Y. Phases of biomarker development for earlydetection of cancer. J Natl Cancer Inst 2001;93:1054–1061.

45. Pepe MS, Feng Z, Janes H, Bossuyt PM, Potter JD. Pivotal evaluationof the accuracy of a biomarker used for classification or prediction:standards for study design. J Natl Cancer Inst 2008;100:1432–1438.

46. Schully SD, Carrick DM, Mechanic LE, Srivastava S, Anderson GL,Baron JA, Berg CD, Cullen J, Diamandis EP, Doria-Rose VP, et al.Leveraging biospecimen resources for discovery or validation ofmarkers for early cancer detection. J Natl Cancer Inst 2015;107:djv012.

47. Kerr KF, Wang Z, Janes H, McClelland RL, Psaty BM, Pepe MS. Netreclassification indices for evaluating risk prediction instruments:a critical review. Epidemiology 2014;25:114–121.

48. Vachani A, Tanner NT, Aggarwal J, Mathews C, Kearney P, Fang KC,Silvestri G, Diette GB. Factors that influence physician decisionmaking for indeterminate pulmonary nodules. Ann Am Thorac Soc2014;11:1586–1591.

49. Gopalakrishna G, Langendam MW, Scholten RJ, Bossuyt PM, LeeflangMM. Guidelines for guideline developers: a systematic review ofgrading systems for medical tests. Implement Sci 2013;8:78.

50. Gopalakrishna G, Mustafa RA, Davenport C, Scholten RJ, Hyde C,Brozek J, Schunemann HJ, Bossuyt PM, Leeflang MM, LangendamMW. Applying Grading of Recommendations Assessment,Development and Evaluation (GRADE) to diagnostic tests waschallenging but doable. J Clin Epidemiol 2014;67:760–768.

51. Mazzone P, Powell CA, Arenberg D, Bach P, Detterbeck F, Gould M,Jaklitsch MT, Jett J, Naidich D, Vachani A, et al. Componentsnecessary for high-quality lung cancer screening: American Collegeof Chest Physicians and American Thoracic Society PolicyStatement. Chest 2015;147:295–303.

52. Jensen TS, Chin J, Ashby L, Hermansen J, Hutter JD. Decision memofor screening for lung cancer with low dose computed tomography(LDCT) (cag-00439n). 2015 [accessed 2015 Feb 6]. Available from:http://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=274

53. Woloshin S, Schwartz LM, Dann E, Black WC. Using radiology reportsto encourage evidence-based practice in the evaluation of small,incidentally detected pulmonary nodules: a preliminary study. AnnAm Thorac Soc 2014;11:211–214.

54. McKee BJ, Regis SM, McKee AB, Flacke S, Wald C. Performance ofACR lung-rads in a clinical ct lung screening program. J Am CollRadiol 2015;12:273–276.

55. American College of Radiology. Lung CT screening reporting and datasystem (Lung-RADS) [accessed 2015 Jul 22]. Available from: http://www.acr.org/Quality-Safety/Resources/LungRADS

56. Danforth KN, Early MI, Ngan S, Kosco AE, Zheng C, Gould MK.Automated identification of patients with pulmonary nodules in anintegrated health system using administrative health plan data,radiology reports, and natural language processing. J Thorac Oncol2012;7:1257–1262.

57. National Cancer Institute. SEER-medicare: Medicare claims files. 2011[accessed 2011 Dec 28]. Available from: http://healthservices.cancer.gov/seermedicare/medicare/claims.html

58. Kinsinger LS, Atkins D, Provenzale D, Anderson C, Petzel R.Implementation of a new screening recommendation in health care:the Veterans Health Administration’s approach to lung cancerscreening. Ann Intern Med 2014;161:597–598.

59. Carson SS, Goss CH, Patel SR, Anzueto A, Au DH, Elborn S,Gerald JK, Gerald LB, Kahn JM, Malhotra A, et al.;American Thoracic Society Comparative EffectivenessResearch Working Group. An official American Thoracic Societyresearch statement: comparative effectiveness research inpulmonary, critical care, and sleep medicine. Am J Respir Crit CareMed 2013;188:1253–1261.

60. Yarmus LB, Akulian J, Lechtzin N, Yasin F, Kamdar B, Ernst A,Ost DE, Ray C, Greenhill SR, Jimenez CA, et al.; AmericanCollege of Chest Physicians Quality Improvement Registry,Education, and Evaluation (AQuIRE) Participants. Comparison of21-gauge and 22-gauge aspiration needle in endobronchialultrasound-guided transbronchial needle aspiration: results of theAmerican College of Chest Physicians Quality ImprovementRegistry, Education, and Evaluation Registry. Chest 2013;143:1036–1043.

61. Krishnan JA, Lindenauer PK, Au DH, Carson SS, Lee TA, McBurnie MA,Naureckas ET, Vollmer WM, Mularski RA; COPD Outcomes-basedNetwork for Clinical Effectiveness and Research Translation.Stakeholder priorities for comparative effectiveness research inchronic obstructive pulmonary disease: a workshop report. Am JRespir Crit Care Med 2013;187:320–326.

62. Lung Cancer Mutation Consortium [accessed 2015 Jul 22]. Availablefrom: http://www.golcmc.com/

63. Early Detection Research Network [accessed 2015 Jul 22]. Availablefrom: http://edrn.nci.nih.gov/

64. Cooke CR, Gould MK. Advancing clinical practice and policy throughguidelines: the role of the American Thoracic Society. Am J RespirCrit Care Med 2013;187:910–914.

65. Collins GS, Reitsma JB, Altman DG, Moons KGM. TransparentReporting of a multivariable prediction model for Individual Prognosisor Diagnosis (TRIPOD): the TRIPOD statement. Ann Intern Med 2015;162:55–63.

66. Moons KGM, Altman DG, Reitsma JB, Ioannidis JPA, Macaskill P,Steyerberg EW, Vickers AJ, Ransohoff DF, Collins GS. TransparentReporting of a multivariable prediction model for Individual Prognosisor Diagnosis (TRIPOD): explanation and elaboration. Ann Intern Med2015;162:W1–73.

67. Howington JA, Blum MG, Chang AC, Balekian AA, Murthy SC.Treatment of stage I and II non-small cell lung cancer. Diagnosis andmanagement of lung cancer, 3rd ed: American College of ChestPhysicians evidence-based clinical practice guidelines. Chest 2013;143:e278S–313S.

68. Timmerman RD, Herman J, Cho LC. Emergence of stereotactic bodyradiation therapy and its impact on current and future clinicalpractice. J Clin Oncol 2014;32:2847–2854.

69. Rutter CE, Corso CD, Park HS, Mancini BR, Yeboa DN, Lester-Coll NH,Kim AW, Decker RH. Increase in the use of lung stereotactic bodyradiotherapy without a preceding biopsy in the United States. LungCancer 2014;85:390–394.

70. Louie AV, Senan S, Patel P, Ferket BS, Lagerwaard FJ, Rodrigues GB,Salama JK, Kelsey C, Palma DA, Hunink MG. When is a biopsy-proven diagnosis necessary before stereotactic ablativeradiotherapy for lung cancer?: a decision analysis. Chest 2014;146:1021–1028.

71. Keith RL. Lung cancer chemoprevention. Proc Am Thorac Soc 2012;9:52–56.

72. Szabo E, Mao JT, Lam S, Reid ME, Keith RL. Chemoprevention of lungcancer. Diagnosis and management of lung cancer, 3rd ed:American College of Chest Physicians evidence-based clinicalpractice guidelines. Chest 2013;143:e40S–60S.

73. Blagev DP, Lloyd JF, Conner K, Dickerson J, Adams D, Stevens SM,Woller SC, Evans RS, Elliott CG. Follow-up of incidental pulmonarynodules and the radiology report. J Am Coll Radiol 2014;11:378–383.



http://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=274

http://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=274

http://www.acr.org/Quality-Safety/Resources/LungRADS

http://www.acr.org/Quality-Safety/Resources/LungRADS

http://healthservices.cancer.gov/seermedicare/medicare/claims.html

http://healthservices.cancer.gov/seermedicare/medicare/claims.html

http://www.golcmc.com/

http://edrn.nci.nih.gov/

74. Wiener RS, Gould MK, Slatore CG, Fincke BG, Schwartz LM, WoloshinS. Resource use and guideline concordance in evaluation ofpulmonary nodules for cancer: too much and too little care. JAMAIntern Med 2014;174:871–880.

75. Blackwood B, Murray M, Chisakuta A, Cardwell CR, O’Halloran P.Protocolized versus non-protocolized weaning for reducing theduration of invasive mechanical ventilation in critically ill paediatricpatients. Cochrane Database Syst Rev 2013;7:CD009082.

76. Boyle R, Solberg L, Fiore M. Use of electronic health records to supportsmoking cessation. Cochrane Database Syst Rev 2011;12:CD008743.

77. Kruis AL, Smidt N, Assendelft WJ, Gussekloo J, Boland MR, Rutten-van Molken M, Chavannes NH. Integrated disease managementinterventions for patients with chronic obstructive pulmonarydisease. Cochrane Database Syst Rev 2013;10:CD009437.

78. Centers for Medicare and Medicaid Services. Proposed decision memofor screening for lung cancer with low dose computed tomography(LDCT) (CAG-00439N) [accessed 2015 Jul 22]. Available from: http://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=274

79. Kahn JM, Gould MK, Krishnan JA, Wilson KC, Au DH, Cooke CR,Douglas IS, Feemster LC, Mularski RA, Slatore CG, et al.; ATS AdHoc Committee on the Development of Performance Measures fromATS Guidelines. An official American Thoracic Society workshopreport: developing performance measures from clinical practiceguidelines. Ann Am Thorac Soc 2014;11:S186–S195.

80. Committee on Quality of Health Care in America. Crossing the qualitychasm: a new health system for the 21st century. Washington, DC:National Academies Press; 2001.

81. Bach PB, Mirkin JN, Oliver TK, Azzoli CG, Berry DA, Brawley OW, ByersT, Colditz GA, Gould MK, Jett JR, et al. Benefits and harms of CTscreening for lung cancer: a systematic review. JAMA 2012;307:2418–2429.

82. Slatore CG, Sullivan DR, Pappas M, Humphrey LL. Patient-centeredoutcomes among lung cancer screening recipients with computedtomography: a systematic review. J Thorac Oncol 2014;9:927–934.

83. Humphrey LL, Deffebach M, Pappas M, Baumann C, Artis K, MitchellJP, Zakher B, Fu R, Slatore CG. Screening for lung cancer with low-dose computed tomography: a systematic review to update the USPreventive Services Task Force recommendation. Ann Intern Med2013;159:411–420.

84. Gareen IF, Duan F, Greco EM, Snyder BS, Boiselle PM,Park ER, Fryback D, Gatsonis C. Impact of lung cancerscreening results on participant health-related quality of life and stateanxiety in the National Lung Screening Trial. Cancer 2014;120:3401–3409.

85. Rasmussen JF, Siersma V, Pedersen JH, Brodersen J. Psychosocialconsequences in the Danish randomised controlled lung cancerscreening trial (DLCST). Lung Cancer 2015;87:65–72.

86. Wiener RS, Gould MK, Woloshin S, Schwartz LM, Clark JA. ‘The thingis not knowing’: Patients’ perspectives on surveillance of anindeterminate pulmonary nodule. Health Expect 2015;18:355–365.

87. Wiener RS, Gould MK, Woloshin S, Schwartz LM, Clark JA. What doyou mean, a spot?: a qualitative analysis of patients’ reactions todiscussions with their physicians about pulmonary nodules. Chest2013;143:672–677.

88. Mularski RA, McBurnie MA, Lindenauer PK, Lee TA, Vollmer WM, AuDH, Carson SS, Krishnan JA; CONCERT Investigator Consortium.Comparative effectiveness research in chronic obstructivepulmonary disease. J Comp Eff Res 2012;1:71–82.

89. Presidential Commission for the Study of Bioethical Issues. Anticipateand communicate: ethical management of incidental and secondaryfindings in the clinical, research, and direct-to-consumer contexts.Washington, D.C.: Presidential Commission for the Study ofBioethical Issues; 2013.

90. Joe BN, Sickles EA. The evolution of breast imaging: past to present.Radiology 2014;273:S23–S44.



http://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=274

