systematic review of health state utility values in
TRANSCRIPT
REVIEW Open Access
Systematic review of health state utilityvalues in metastatic non-small cell lungcancer with a focus on previously treatedpatientsNoman Paracha1*, Ahmed Abdulla1,3 and Katherine S. MacGilchrist2
Abstract
Background: Health state utility values (HSUVs) are an important input to economic evaluations and the choice ofHSUV can affect the estimate of relative cost-effectiveness between interventions. This systematic review identifiedutility scores for patients with metastatic non-small cell lung cancer (mNSCLC), as well as disutilities or utilitydecrements relevant to the experience of patients with mNSCLC, by treatment line and health state.
Methods: The MEDLINE®, Embase and Cochrane Library databases were systematically searched (September 2016)for publications describing HSUVs in mNSCLC in any treatment line. The EQ-5D website, the School of Health andRelated Research Health Utilities Database (ScHARRHUD) and major pharmacoeconomic and clinical conferences in2015–2016 were also queried. Studies in adults with previously treated mNSCLC were selected for further analysis.The information extracted included study design, description of treatment and health state, respondent details,instrument and tariff, HSUV or (dis) utility decrement estimates, quality of study, and appropriateness for use ineconomic evaluations.
Results: Of 1883 references identified, 36 publications of 34 studies were included: 19 reported EQ-5D scores; eightreported HSUVs from valuations of vignettes made by members of the public using standard gamble (SG) or timetrade-off (TTO); two reported SG or TTO directly elicited from patients; two reported EQ-5D visual analogue scalescores only; one reported Assessment of Quality of Life instrument scores; one reported HSUVs for caregivers topatients with mNSCLC using the 12-item Short-Form Health Survey; and one estimated HSUVs based on expertopinion. The range of HSUVs identified for comparable health states showed how differences in study type, tariff,health state and the measures used can drive variation in HSUV estimates.
Conclusions: This systematic review provides a set of published HSUVs that are relevant to the experience of adultpatients previously treated for mNSCLC. Our review begins to address the challenge of identifying reliable estimatesof utility values in mNSCLC that are suitable for use in economic evaluations, and also highlights how varyingestimates result from differences in methodology.
Keywords: Health state utility values (HSUVs), Health-related quality of life (HRQoL), Metastatic non-small cell lungcancer (mNSCLC), Multi-attribute utility instruments (MAUIs), Standard gamble (SG), Time trade-off (TTO), Systematicliterature review
* Correspondence: [email protected]. Hoffmann-La Roche AG, Basel, SwitzerlandFull list of author information is available at the end of the article
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 https://doi.org/10.1186/s12955-018-0994-8
BackgroundNon-small cell lung cancer (NSCLC) is the most com-mon form of lung cancer, occurring in 85–90% of lungcancer cases [1], and includes adenocarcinoma (40% ofall lung cancers), squamous cell carcinoma (25–30%)and large cell carcinoma (10–15%) [2]. NSCLC is stagedaccording to the American Joint Committee on Cancer/Union for International Cancer Control system [3], andmeasurement of lesions follows the Response EvaluationCriteria in Solid Tumors (RECIST) [4]. Approximately40% of patients will have metastatic NSCLC (mNSCLC)at diagnosis [5], which includes cancers found in the lungand in the lymph nodes in the middle of the chest (definedas stage IIIA and IIIB; no distant metastasis), and cancersthat have spread to both lungs or to another part of thebody (defined as stage IV; distant metastasis) [6, 7].Treatment is recommended according to the stage of
mNSCLC, but treatment options are limited in the laterstages of disease [7, 8]. Five-year survival rates are con-siderably lower in later than in earlier stages of NSCLC(stage IA, 45%; stage IIIA, 14%; stage IIIB, 5%; stage IV,1%) [9]. Moreover, symptoms such as coughing andwheezing, chest pain, hoarseness and weight loss can se-verely reduce functional independence in patients withmNSCLC [10, 11]. Patient-reported health-related qual-ity of life (HRQoL) provides an overall evaluation ofhealth, well-being and daily functioning, and is impairedin patients with mNSCLC owing both to the disease andto treatment sequelae. Maintenance or improvement ofHRQoL is an important treatment goal [12].HRQoL can be expressed as a health state utility value
(HSUV) ranging from 0 (death) to 1 (full health). If thehealth state is considered to be worse than death, healthstates can be valued at less than 0. Utility values are keydrivers in cost-effectiveness analyses because estimatesof quality-adjusted life-years (QALYs) are obtained bymultiplying HSUVs for each health state by the timespent in that health state. Estimates of cost per QALYare highly sensitive to the choice of HSUV. It is there-fore important to identify specifically those HSUVs thathave been derived using methods acceptable to healthtechnology assessment (HTA) authorities [13].HSUVs can be derived using a range of instruments
and techniques [14, 15]. In brief, instruments include:generic preference-based measures such as the EQ-5D-3 L[16] or EQ-5D-5 L [17], Health Utilities Index (HUI) [18],6-dimension Short-Form Health Survey (SF-6D) [19], As-sessment of Quality of Life instrument (AQoL) [20], 15-di-mensional HRQoL measure [21], Quality of Well-Beingscale [22], and multi-attribute utility instrument; as well asdirectly elicited standard gamble (SG), time trade-off(TTO) and visual analogue scale (VAS, e.g. EuroQoL VAS[EQ-VAS]). Mapping algorithms may also be used to con-vert values obtained from a condition-specific questionnaire
to a generic preference-based measure; or to convert datafrom the 12- or 36-item Short-Form Health Survey (SF-12or SF-36) to SF-6D [23]. Techniques may vary in terms ofwhose health is being measured (a patient’s or a caregiver’s),who responds to the questionnaire or, if using vignettes,who considers the health-state description (the patient re-garding their own health, a patient with a different disease,the patient’s closest caregiver, another caregiver, a physicianor another healthcare provider). For preference-based mea-sures, variation can stem from who values the health state(e.g. UK general population sample) and which choice-based method is used in this valuation (SG or TTO).HTA bodies including the UK National Institute for
Health and Care Excellence (NICE) [24, 25], the ScottishMedicines Consortium (SMC) [26], the Canadian Agencyfor Drugs and Technologies in Health (CADTH) [27], theFrench Haute Autorité de Santé (HAS) [28] and the Aus-tralian Pharmaceutical Benefits Advisory Committee(PBAC) [29] have stated preferences for HSUV method-ology. Across these agencies, there is a preference forHSUVs estimated using generic preference-based mea-sures. NICE has a strong preference for EQ-5D, as thisreduces variability induced when different instruments areused between different disease areas. Agencies alsostrongly prefer patients to be the respondents, as patientscan best describe their own health state. Finally, valuationestimated using a country-specific general-population tar-iff via a choice-based elicitation technique such as SG orTTO is preferred, as this represents societal preferences.This systematic review had three main aims: first, to
identify HSUVs for adults with previously treatedmNSCLC, by treatment line and health state, and toevaluate the relevance of each health state to patients,for example, line of treatment, adverse events (AEs),response status and prognostic factors; second, to iden-tify relevant disutilities or utility decrements associatedwith adverse events (irrespective of line of treatment orhealth state). Finally, the suitability of the HSUVs ac-cording to HTA reference case was explored and thequality of the HSUVs assessed.
MethodsStudy design and search strategyA systematic review of HSUVs in mNSCLC was under-taken to identify HSUV studies in any treatment line.Studies, published either as full papers or as conferenceabstracts, in patients previously treated for mNSCLCwere selected for further analysis. The following data-bases were searched: Embase (1974 to 7 September2016); MEDLINE® (1966 to 7 September 2016); MED-LINE In-Process and e-publications ahead of print (data-base inception to 7 September 2016); and the CochraneLibrary (including the Cochrane Database of SystematicReviews, the Database of Abstracts of Reviews of Effects,
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 2 of 30
the Cochrane Central Register of Controlled Trials, theNational Health Service Economic Evaluation Databaseand the HTA database; 1968 to 7 September 2016).Search strings are summarized in Additional file 1:
Table S1, and were constructed not only to find utilitiesin mNSCLC (using a wide range of NSCLC and mNSCLCterms combined with the HSUV filter adapted from Arberet al. 2015 [30]) but also to identify all relevant disutilitiesor utility decrements associated with AEs/comorbidities.To ensure that estimates would be available from previ-ously treated mNSCLC populations for all AEs or comor-bidity health states relevant to the experience of suchpatients, the strings were designed to search for disutilitiesor decrements from a broader group of populations, asfollows: from lung cancer; for progressive disease disutil-ities from advanced/metastatic cancer; for disutilities asso-ciated with the most common sites of metastasis from the
lung (bone, respiratory system, nervous system, adrenalgland and liver) from advanced cancer; for disutilities as-sociated with AEs or toxicities of cancer therapy; and dis-utilities associated with specific grade 3–4 AEs known tooccur with cancer treatments from advanced cancer popu-lations (pneumonia, pneumonitis, increased aspartate ami-notransferase, febrile neutropenia, neutropenia, infection,sepsis, fatigue, lethargy, nausea, vomiting, ulcers, stoma-titis, gastrointestinal disturbance, diarrhoea, visual disturb-ance, hearing loss, hair loss, psychological/self-esteemchanges, rash, anaemia, bleeding and hypertension).From the identified disutilities/decrements for eachAE/co-morbidity health state, those from the mostrelevant population available could be selected follow-ing an order of decreasing population specificity fromfirst-line mNSCLC to NSCLC, lung cancer and ad-vanced/metastatic cancer (Fig. 1).
(Nafees [69])
(Tabberer [52])
(Doyle [65])
(Nafees [68])
(Handorf [70])
Grade III/IV neutropenia, febrile neutropenia, fatigue, nausea and vomiting, diarrhoea, hair loss, rash
Neutropenia, febrile neutropenia, nausea, diarrhoea, rash, stomatitis and neuropathy
Severe symptoms for cough, dyspnoea, pain
Grade III/IV neutropenia, febrile neutropenia, fatigue, nausea and vomiting, diarrhoea, hair loss, rash, bleeding, hypertension
Neutropenia, pneumothorax, haemorrhage, thrombocytopenia, thrombosis
• Stage IV 2L: UK
• Stage IV LNS: UK
• Stage IV LNS: UK
• Stage IV 1L: UK + multinational
• Stage IV 1L: USA
Advanced/mNSCLC
Early stage NSCLC (Grutters [44])• LNS/early stage
Advanced/mLC (NSCLC + SCLC)
(Yokoyama [55])• Stage IIIB/IV LC with BM: Japan
Not reported(Westwood [71])• Lilly and Roche NSCLC
NICE submissions
Cancer(Lloyd [59])• Cancer unclear stage:
UK
LC + BC(Grunberg [58])• LC + BC: USA
Advanced cancer
(Matza [67])
Grade III+ dyspnoea
Average disutility for SREs (pathologic fracture, radiation or surgery to bone lesion, spinal cordcompression or hypercalcaemia)
Anaemia (single disutility), i.v. treatmentmode, oral treatment mode
Anaemia (by Hb level)
Chemotherapy-related limited nausea, limited vomiting, limited nausea and vomiting, continuous nausea and vomiting
Specific SRE disutilities for spinal cord compression with/without paralysis, fracture of leg, fracture of rib, fracture of arm, radiation treatments, surgery to stabilize bone
• Stage IV cancer with BM: UK, Canada
Fig. 1 Studies reporting adverse event health state (dis) utilities by patient population and country. Abbreviations: 1L first line, 2L second line, BCbreast cancer, BM bone metastasis, Hb haemoglobin, i.v. intravenous, LC lung cancer, LNS line of treatment not specified, mLC metastatic lungcancer, mNSCLC metastatic non-small cell lung cancer, NICE National Institute for Health and Care Excellence, NSCLC non-small cell lung cancer,SCLC small cell lung cancer, SRE skeletal-related event
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 3 of 30
Using the term “NSCLC” or “non-small cell lung can-cer”, manual searching of the EQ-5D website, of theSchool of Health and Related Research Health UtilitiesDatabase (ScHARRHUD) and of major pharmacoeco-nomic and clinical conferences in 2015–2016 was con-ducted on 3 and 5 December 2016. Conferences included:the International Society for Pharmacoeconomics andOutcomes Research (ISPOR) International Meetings andEuropean Congresses; the HTA International AnnualMeetings (HTAi); the Society for Medical Decision Mak-ing (SMDM) North American Meetings and EuropeanConferences; the American Society of Clinical Oncology(ASCO) Meetings; and the European Society for MedicalOncology (ESMO) Congresses. Bibliographic referencelists of relevant systematic reviews from 2010 onwardswere searched and of relevant cost-utility analyses, andHTA reports from various bodies identified in a paralleleconomic systematic review, including: NICE; SMC; AllWales Medicines Strategy Group (AWMSG); PBAC;CADTH; Institut National d’Excellence en Santé et enServices Sociaux; pan-Canadian Oncology Drug Review(pCODR); and HAS.The PICOS (patient, intervention, comparator, outcome,
study) statements for study inclusion and exclusioncriteria are summarized in Table 1. Although, second- andlater-line data were of primary interest, studies thatreported utilities for patients with mNSCLC who wereeither treatment-naïve or in receipt of maintenancefirst-line treatment were included for reference at the firstscreening but data were not extracted. These studies arelisted in Additional file 2: Table S2.Mapping from condition-specific to preference-based
studies was not sought because it was anticipated thatsufficient published utility and EQ-5D data would beavailable to populate the health states of an economicmodel, and because results based on mapping algo-rithms sit lower in the acceptance hierarchy used bysome HTA authorities (Additional file 3: Figure S1). Wehave acknowledged NICE’s stated preference for EQ-5D-3 L data over EQ-5D-5 L (Additional file 3: FigureS1) and provide detailed information of the instru-ment used for generating data for each identifiedstudy in Table 2 [31].
Study selectionThe screening process complied with the 2009 PreferredReporting Items for Systematic Reviews and Meta-Ana-lyses (PRISMA) guidelines [32]. Publications werede-duplicated using EndNote (Clarivate Analytics, Phila-delphia, PA, USA) and using Rayyan (Qatar ComputingResearch Institute, Doha, Qatar) [33], an internet-basedreference management system endorsed as suitable forsystematic review screening by the European Network forHTA [34]. Abstracts and titles of papers were screened by
one reviewer, and a 50% sample check conducted by asecond reviewer; exclusion criteria are summarized inTable 1. The full texts of papers potentially meeting theselection criteria were screened by one reviewer, and a50% sample check was conducted by a second reviewer.Discrepancies were discussed between reviewers, and anyunresolved disputes were referred to a third reviewer.
Data extractionData were collected using a piloted data-extractionsheet. Extraction was conducted by one reviewer, andpriority data elements were quality checked by a secondreviewer. The information extracted included studydesign, whether the selection criteria yielded a popula-tion that matched the target population (i.e. previouslytreated adult patients with mNSCLC), health state de-scription, instrument type, instrument scale, HSUV or(dis) utility or decrement estimates and measure of vari-ability (median with interquartile range or mean withstandard error, standard deviation or 95% confidenceinterval), derivation methods and if the data presentedwere appropriate for use in HTA submissions to NICE,SMC, CADTH, HAS and PBAC.
Quality and relevance assessmentThe appropriateness of utilities reported for use in eco-nomic evaluations was determined by whether data metthe requirements of the HTA body reference case; andthe quality of utility estimates (based on sample size, re-sponse to the questionnaire, loss to follow-up, handlingof missing data, and reporting of point and variance esti-mates, as discussed in NICE Decision Support UnitTechnical Support Document 11 and its related publica-tion [25, 35]; Additional file 4: Table S3). Any recom-mendation for, or rationale against, the use of specificutilities in a cost–utility analysis model in previouslytreated patients with mNSCLC was also taken into consid-eration in line with preliminary guidance from the ISPORHealth State Utility Good Practices Task Force [36].
ResultsSearch yieldsElectronic database searches identified 1883 citations(1521 from MEDLINE/Embase, 144 from MEDLINE In-Process/e-publications and 218 from the Cochrane Li-brary databases). After de-duplication (51 citations: 30via Endnote and 21 via Rayyan) and title/abstract screen-ing (1557 exclusions), 275 full-text papers werereviewed. Of these, 250 were excluded (21 of which weretagged as reporting first-line treatment; Additional file 2:Table S2), yielding 25 citations that were included fromelectronic sources. Manual searching identified 11 cita-tions. In total, 36 articles were included, reporting 34studies (Table 2). Two articles [37, 38] were linked to
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 4 of 30
other publications [39, 40], and were retained becausethey provided additional information. The study selec-tion is summarized in a PRISMA flow chart in Fig. 2.
Description of studies identifiedAmong the 36 articles (34 studies) identified, 19 reportedEQ-5D scores [37–55] (three studies further specified theinstrument as EQ-5D-3 L [39, 41, 56] and two asEQ-5D-5 L [44, 57]; Table 2), two reported SG or TTOdirectly elicited from patients [58, 59], two reportedEQ-VAS scores only [57, 60], and one reported AQoL
scores [61] (Table 2). Moreover, one study reported SF-12scores for caregivers to patients with mNSCLC [62], eightreported HSUVs from valuations of vignettes made bymembers of the public using SG or TTO [59, 63–69] (oneof which reported both general public-elicited SG andpatient-elicited TTO) [59], and one reported disutility esti-mates based on expert opinion for pneumothorax,thrombocytopenia and thrombosis, adverse event healthstates for which disutilities were not available from otherHSUV derivation methods [70]. A further two articles re-ported HSUVs but were unclear about how these were
Table 1 Inclusion criteria
Characteristic Inclusion criteria Exclusion criteria
Population Adult patients (aged ≥16 years)Locally advanced NSCLC or mNSCLC, second/subsequent lineLocally advanced or metastatic NSCLC, line unspecified
Population not of interest, e.g.• in vitro data• animal data• mixed adult/child population or child population• mixed disease populations without mNSCLC datareported separately
• not disease of interest• 1 L mNSCLC data (treatment-naïve or maintenancefirst-line treatment) were excluded but taggeda
Interventions/comparators
Not relevant for QoL SR selection. Intervention-specificutility data were noted as such during data extraction
N/A
Outcomes For mNSCLC patients:• individual (patient or caregiver) derived mean or medianhealth state utilities from indirect generic HRQoL measure(EQ-5D (-3 L and -5 L), SF-6D, HUI2, HUI3, AQoL, QWB, 15D,MAUI) or direct valuation by TTO, SG or EQ-VAS
• SF-36 or SF-12• general public valuations of vignettes using TTO or SGFor NSCLC or wider population:• disutilities or decrements for AEsb or progressive disease
No outcome of interest:• expert or healthcare provider (doctor, nurse) valuationsof utilities
• utilities not relating to a specific health state
Study design RCTs, non-RCTs, observational data Study design not of interest:• case reports, n = 1 before-and-after studies• PK/PD study only• (Non-systematic) reviews• SRs/NMAsc
Date limits Unlimited –
Child citation Citation linked to another paper but with unique data Child citation or sub-study with no unique data, determinedat first or second pass
Duplicate citation Duplicate/copy
Publication type Publication type not of interest e.g. editorials, commentaries,letters, notes, press articles, unless relevant data has beenpublished in a letter, for example, that does not appearelsewhere in the literatureConfidential reports where unable to use report, or HayesInc. reports requiring purchase
Language English or FrenchAny foreign language paper with an English abstractwere included if sufficient information is present in theEnglish abstract to ensure the eligibility criteria are met
Full text in language other than English or French with noEnglish abstract or no abstract; or insufficient information inEnglish language abstract of foreign language full paper toassess eligibility
aTo enable listing in the reportbDisutilities may be included for AEs, inconvenience of treatment or progressive health states from diseases outside NSCLC (preferably from lung cancer or fromadvanced/metastatic cancer) where no such data are available from patients with NSCLCcSRs were kept in until the second pass, where the full paper’s included studies were examined, after which the SR itself was excludedAbbreviations: 1 L first line, 3 L 3-level, 5 L 5-level, 15D 15-dimensional health-related quality of life measure, AE adverse event, AQoL Assessment of Quality of Lifeinstrument, EQ-VAS EuroQoL visual analogue scale, HRQoL health-related quality of life, HUI2/3 Health Utilities Index Mark 2/3, MAUI multi-attribute utilityinstrument, mNSCLC metastatic non-small cell lung cancer, N/A not available, NMA network meta-analysis, NSCLC non-small cell lung cancer, PD pharmacodynamic,PK pharmacokinetic, QoL quality of life, QWB Quality of Well-Being scale, RCT randomized controlled trial, SF-6D 6-dimension Short-Form Health Survey, SF-12/3612/36-item Short-Form Health Survey, SG standard gamble, SR systematic review, TTO time trade-off, VAS visual analogue scale
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 5 of 30
Table
2Iden
tifiedutility
stud
iesby
lineof
treatm
ent
Autho
r,year,cou
ntry
Line
oftreatm
ent
Health
state
Instrumen
tTreatm
ent
Firstlinea
Hando
rf2012
USA
[70]
1L
StageIV
aden
ocarcino
maSD
is,PD,SDis+AEs
(neutrop
enia,
pneumotho
rax,haem
orrhage,thrombo
cytope
nia,thrombo
sis)
Expe
rtop
inionestim
ates,bpu
blishe
dsources
NTS
Nafees2016
Multin
ational
andUK[68]
1L
Metastatic
NSC
LCcommon
gradeIII/IV
toxicities(neutrop
enia,
febrile
neutrope
nia,fatig
ue,nauseaandvomiting
,diarrhe
a,hair
loss,rash),b
leed
ing,
hype
rten
sion
TTO(gen
eralpu
blic)
NTS
≥Firstlinec
Che
valier2013
France
and
nine
othe
rcoun
tries[38]
1L,2L,3/4LandBSC
Advanced/metastatic
NSC
LC1L,2L,3/4LPF
andPD
EQ-5D
NTS
Cho
uaid
2013
Multin
ational[39]
1L55.1%
2L24.7%
3/4L17.9%
BSC2.3%
Advanced/metastatic
NSC
LC1L,2L,3/4L,BSCandmixed
linePF
andPD
EQ-5D,EQ-VAS
NTS
Iyer
2013
France,G
ermany[46]
1L52%
2LL
48%
Advanced/metastatic
NSC
LCEQ
-5D
NTS
Second
line
Blackhall2014Multin
ational[41]
2Lafterprog
ressionon
platinum
-based
1L
therapy
Locally
advanced
/metastatic
ALK+NSC
LCBL
andtreatm
ent-
specificutilities(not
PSS)
EQ-5DEQ
-VAS
CRZ
PEM
DOC
Huang
2016
Worldwide[45]
2Lafterplatinum
-based
therapy
AdvancedPD
-L1+
NSC
LCNTS
PF,PD
NTS
timeto
death
EQ-5D
PEMB
DOC
Lang
ley2013
UK,Australia[48]
2Ld
Treatm
ent-specificstageIV
NSC
LCwith
BMat
BLandafter
certaintim
epo
intson
treatm
ent
EQ-5D
OSC
WBRT+OSC
Nafees2008
UK[69]
2L
Metastatic
NSC
LCPD
,RES,SDis,com
mon
gradeIII/IV
toxicities
(neutrop
enia,feb
rilene
utrope
nia,fatig
ue,nauseaandvomiting
,diarrhea,hairloss,rash)
SG(gen
eralpu
blic)
NTS
Novello
2015
Multin
ational[49]
2L
StageIII/IV
recurren
tNSC
LC(SQandNSQ
)treatm
ent-specificat
BLandcertaintim
epo
intson
treatm
ent(≤
30weeks)
EQ-5D,EQ-VAS
NIN
+DOC
PLA+DOC
Reck
2015
Multin
ational[50]
2L
AdvancedSQ
NSC
LCtreatm
ent-specificat
BLrepo
rted
.Collected
also
forup
to1year
butvalues
NRin
abstract
EQ-5D,EQ-VAS
NIVO
DOC
Rude
ll2016
USA
,Canada,Hon
gKo
ng,Italy,Japan,Rep
ublic
ofKo
rea,Spain,Taiwan
[57]
2L
AdvancedEG
FR+NSC
LC,treatmen
t-specificat
BLand36
weeks
onOSI
EQ-VAS
OSI
Schu
ette
2012
Germany,
Austria[51]
2L
StageIII/IV
NSC
LCtreatm
ent-specificat
BL,6
weeks
(secon
dcycle)
andsixthcycle
EQ-5D
EQ-VAS
PEM
Vargas
2009
Mexico[72]
2Lafterprevious
CHEM
ONSC
LC,stage
NR(assum
edadvanced
),treatm
ent-specificno
tPSS
GlobalQ
oLinde
xERL
Taxane
s
≥Second
line
Che
n2010
UK/multin
ational[64]
2L,3LandBSC
StageIIIb/IV
EGFR+NSC
LCtreatm
ent-specific
(not
PSS)
SG(gen
eralpu
blic)
DOC
PEM
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 6 of 30
Table
2Iden
tifiedutility
stud
iesby
lineof
treatm
ent(Con
tinued)
Autho
r,year,cou
ntry
Line
oftreatm
ent
Health
state
Instrumen
tTreatm
ent
On/afterDOC2L
On/afterPEM
2L
OnERL3LBSC
ERL
BSC
Griebsch
2014
Multin
ational[37]
2LLe
andtreatm
ent-
naïve
StageIIIbwith
pleuraleffu
sion
orstageIV
NSC
LCaden
ocarcino
matreatm
ent-specificandNTS
effect
ofprog
ression
EQ-5D,EQ-VAS
AFA
BSC
CIS/PEM
Hirsh2013
Multin
ational[40]
2LLf
StageIIIb/IV
NSC
LCBL
andtreatm
ent-specificon
oralAFA
50mgq.d.
+BSCor
PLA+BSC
EQ-5D
AFA
+BSC
PLA+BSC
Stew
art2015
Canada[56]
Targeted
therapy84%
3LL25%
RCT22%
Metastatic
EGFR+NSC
LC,allpatientsno
tPSS
PR/SDisEG
FRTKI
RESCHEM
ORESGEF
RESERL
RESOSI
PDEG
FRTKI
EQ-5D-3
LGEF
ERL
OSI
Schw
artzbe
rg2015
USA
,Canada[60]
2LL
Squamou
sandno
n-squamou
sstageIIIb/IV
NSC
LCtreatm
ent-specificweeks
6–30
Treatm
ent-specificPR,SDisandPD
weeks
6–30
EQ-VAS
NIVO
Treatm
entlineno
tspecified
Bradbu
ry2008
Canada[42]
Unclear
AdvancedNSC
LCTreatm
ent-specific(not
PSS)
EQ-5D
ERL
BSC
Chang
2016
SouthKo
rea[63]
NR
AdvancedNSC
LCfro
m>360days
before
deathto
<30
days
before
death(not
PSS)
TTO(gen
eralpu
blic)
NTS
Dansk
2016
UK[43]
NR
Synthe
sizedadvanced
NSC
LCPF,PDused
inNICEHTA
sTrial-b
ased
PF,PD
Non
-trialb
ased
PF,PD
EQ-5D
NTS
Doyle2008
UK[65]
NR
Metastatic
NSC
LCSD
is,RES,severesymptom
s(cou
gh,d
yspn
oea,pain)
SG(gen
eralpu
blic)
NTS
Grunb
erg2009
USA
[58]
NR
Mixed
cancer
popu
latio
nchem
othe
rapy-related
nausea,
vomiting
,and
nausea
andvomiting
,ofd
ifferen
tseverities
SG(patient)
CHEM
O
Grutters2010
Nethe
rland
s[44]
NR
NSC
LCwith
grade3+
dyspno
eaEQ
-5D
NTS
Jang
2010
Canada[47]
NR
StageIV
NSC
LCandlocally
advanced
NSC
LCEQ
-5D
NTS
Linn
et2015
Den
mark[62]
Unclear
Metastatic
NSC
LCsecond
andthird
CHEM
Ocycles
onoralVINO
Patient
andcaregiverutilitiesrepo
rted
SF-12
VINO
Lloyd2005
UK[66]
NR
StageIV
NSC
LCRES,SD
isi.v.treatmen
t,SD
isoraltreatm
ent,
PD,end
oflife
SG(gen
eralpu
blic)
NTS
Lloyd2008
[59]
Previous
CHEM
OAnaem
iaby
haem
oglobinlevel
Gen
eralpu
blicSG
,patient
TTO
NTS
Manser2006
Australia[61]
NR
StageIV
NSC
LCAQoL
NTS
Matza
2014
UKandCanada[67]
NR
StageIV
cancer
with
BMsanddifferent
type
sof
SRE
(spinalcordcompression
with
/with
outparalysis,fracture
TTO(gen
eralpu
blic)
NTS
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 7 of 30
Table
2Iden
tifiedutility
stud
iesby
lineof
treatm
ent(Con
tinued)
Autho
r,year,cou
ntry
Line
oftreatm
ent
Health
state
Instrumen
tTreatm
ent
ofleg,
fractureof
rib,fractureof
arm),radiationtreatm
ent
(2weeks,5
appo
intm
ents/w
eek),radiatio
ntreatm
ent
(2appo
intm
ents),surgeryto
stabilize
bone
Tabb
erer
2006
UK[52]
NR
AdvancedNSC
LCRES,SD
is,SDisoraltreatm
ent,SD
isi.v.
treatm
ent,PD
,nearde
ath,AEs
(neutrop
enia,feb
rile
neutrope
nia,nausea,d
iarrho
ea,rash,stom
atitis,ne
urop
athy)
EQ-5D(gen
eralpu
blic)
NTS
Trippo
li2001
Italy[53]
NR
Metastatic
NSC
LCEQ
-5D,EQ-VAS
NTS
Westw
ood2014
[71]
NRforothe
rdisutilities
AdvancedNSC
LCDisutility
foranaemiaandfori.v./o
raltreatmen
tmod
eSG
NRforothe
rdisutilities
NTS
ERL
i.v.tx
Yang
2014
Taiwan
[54]
NR
NSC
LCop
erable(I–IIIA)andNSC
LCinop
erable(IIIB/IV
)EQ
-5D
NTS
Yokoyama2013
Japan[55]
NR
StageIIIB/IV
mixed
NSC
LC/SCLC
with
bone
metastasis
andSRE(patho
logicfracture,radiationor
surgeryto
bone
lesion
,spinalcordcompression
orhype
rcalcaem
ia)
EQ-5D
NTS
a Studies
wereretained
,despite
repo
rtingfirst-line
treatm
enton
ly,b
ecau
sethey
repo
rted
prog
ressivediseaseutility
estim
ates
similarto
thoseseen
inasecond
-line
popu
latio
n,or
repo
rted
AEdisutility
estim
ates
from
popu
latio
nsbroa
derthan
mNSC
LCbAlth
ough
theutilitie
swereba
sedon
expe
rtop
inion,
thesewereretained
,asthey
prov
idedisutility
estim
ates
forthead
verseeven
tspn
eumotho
rax,thrombo
cytope
niaan
dthrombo
sis,no
tavailableelsewhe
rec Studies
repo
rted
data
onfirst-line
treatm
entan
dsubseq
uent
treatm
entlin
esdPrevious
treatm
entwith
system
icCHEM
Oor
EGFR
inhibitors
allowed
e Lux-Lun
g1triald
atawerein
patie
ntsprog
ressed
on1–
2lin
esof
treatm
ent,on
eof
which
was
platinum
based(cou
ldinclud
ead
juvant
settingtreatm
entlin
e),and
hadPD
afterat
least12
wks
ofER
Lor
GEF.Lux-Lun
g3triald
atawerein
treatm
ent-na
ïvepa
tients,so
not2L.
f Progressedon
1–2lin
esof
treatm
ent,on
eof
which
was
platinum
based,
andha
dPD
afterat
least12
wks
ofER
Lor
GEF
Abb
reviations:1
Lfirst
line,
2Lsecond
line,
2LL
second
andsubseq
uent
line,3LLthird
andsubseq
uent
line,
3/4Lthird
andfourth
line,
AEad
verseeven
t,AFA
afatinib,A
QoL
Assessm
entof
Qua
lityof
Life
instrumen
t,BL
baselin
e,BM
bone
metastasis,BSCbe
stsupp
ortiv
ecare,C
HEM
Ochem
othe
rapy
,CIScisplatin
,CRZ
crizotinib,D
OCdo
cetaxel,EG
FRep
idermal
grow
thfactor
receptor,EQ-VASEu
roQol
visual
analog
uescale,
ERLerlotin
ib,
GEF
gefitinib,G
EMge
mcitabine
,i.v.intraveno
us,N
INninted
anib,N
IVOnivo
lumab
,NRno
trepo
rted
,NSC
LCno
n-sm
allcelllun
gcancer,N
SQno
n-squa
mou
s,NTS
nottreatm
ent-specific,OSC
optim
alstan
dard
care,O
SIosim
ertin
ib,P
Dprog
ressivedisease,
PEM
pemetrexed,
PEMBpe
mbrolizum
ab,P
Fprog
ression-free,P
LAplaceb
o,PR
partialrespo
nse,
PSSprog
ression-status-spe
cific,q
.d.o
nceda
ily,Q
oLqu
ality
oflife,
RCTrand
omized
controlledtrial,RESrespon
se,SCLCsm
allcelllun
gcancer,SDisstab
ledisease,
SF-1212
-item
Short–Fo
rmHealth
Survey,SGstan
dard
gamble,
SREskeletal-related
even
t,TKItyrosinekina
seinhibitor,TTOtim
etrad
e-off,
VASvisual
analog
uescale,
VINOvino
relbine,
WBR
Twho
le-brain
radiothe
rapy
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 8 of 30
derived; one reported disutilities used in previous NICEsubmissions, for anaemia and for oral and intravenoustreatment modes [71], and one reported a “global qualityof life index” for second-line NSCLC [72].Among the dataset, two studies were retained despite
reporting first-line treatment only, because they reportedAE disutility estimates from populations broaderthan mNSCLC [68, 70]; three further studies that re-ported first-line data also reported on subsequenttreatment lines [38, 39, 46]. Eleven studies focusedexclusively on HSUVs associated with second-linetreatment [41, 45, 48–51, 57, 59, 69, 71, 72], and fivereported HSUVs in second-line and subsequent treatment[37, 40, 56, 60, 73]. Line of treatment was unspecified in15 studies [42–44, 47, 52–55, 58, 61–63, 65–67].
Relevant HSUVs by line of treatmentUtilities were reported for a range of health state types:treatment-specific or not, RECIST response-based ornot, time-on-treatment, time-till-death, or a combin-ation of these. Details of HSUV estimates by treatmentline are given in Table 3. Among patients receivingsecond-line or subsequent treatment for advanced
NSCLC or mNSCLC, mean HSUV estimates based onEQ-5D for stable/progression-free disease and for pa-tients at baseline or pre-treatment were in the range0.66–0.76 [38, 39, 41, 45, 49, 50]; in the same group,mean values for patients with progressive disease weregenerally lower (0.55–0.69) [38, 39, 45]. Among patientson treatment at this stage of disease and treatment line,the range of mean HSUVs based on EQ-5D was broad(0.53–0.82) [40, 41, 46, 51, 56], the highest value beingassociated with treatment with tyrosine kinase inhibitors[41, 56]. A similar range of HSUV values was seenamong patients being treated for advanced NSCLC ormNSCLC when the treatment line was unspecified (0.53–0.77) [42, 47, 52, 53]. Only three papers specified usingEQ-5D-3 L [39, 41, 56] and only two EQ-5D-5 L [44, 57].Disutilities for progression from a stable state were
− 0.056 or − 0.065 by EQ-5D, both from Griebsch et al.[37], or − 0.1798 by general population-derived SG [69].Overall, HSUVs varied not only by treatment line and dis-ease state, but also by the treatment received under thesame health state (potentially reflecting differences insafety profiles) and by the instrument/tariff used to derivethe HSUV.
Duplicate papers removed: 51Via Endnote: 30Via Rayyan: 21
Citations excluded: 1557Excluded design: 657
Excluded population: 414No outcome of interest: 255No relevant camparator: 129
Secondary source: 51Duplicates: 51
Child: 0
Citations excluded: 250Duplicate: 21
Sub-study/child citation: 12No relevant outcome: 93
Population: 40Design: 50
Language: 4Publication type: 2
First-line: 21Mapping algorithm or validation: 5
Full paper unavailable: 1Mapped utility: 1
Total number of papers identified: 1883Embase and MEDLINE: 1521
MEDLINE In-Process and e-publications: 144Cochrane: 218
Title/abstract screening: 1832
Included from manual search: 11
Full-text articles assessed for eligibility: 275
Included in systematic review: 36(34 unique studies)
Fig. 2 PRISMA flow chart for study selection. Abbreviation: PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 9 of 30
Relevant disutilities and decrementsEleven studies identified in this systematic review re-ported disutilities or decrements for AE health states[44, 52, 55, 58, 59, 65, 67–71]. Only two studies reporteddisutilities specifically associated with second-line treat-ment [69, 71], and another two studies did not specifythe treatment line [44, 65]; disutility and decrement dataare summarized in Table 4. Utility-incorporating decre-ments were identified for the following AEs in thecontext of second-line “stable disease” or second-line“responding”: diarrhoea, fatigue, febrile neutropenia, hairloss and nausea/vomiting. Disutilities associated withsecond-line treatment were reported for the followingevents [69]: “moving from stable to progressive state”(− 0.18), neutropenia (− 0.09), febrile neutropenia (− 0.09),fatigue (− 0.07), nausea/vomiting (− 0.05), diarrhoea(− 0.05), hair loss (− 0.04) and rash (− 0.03).Further recommended sources of AE health state (dis)
utilities were as follows (Fig. 1): in 2 L from generalpopulation SG in Nafees et al. 2008 [69]; in metastaticNSCLC (line unspecified) from general population SG inDoyle et al. 2008 [65]; in 1 L from patients withoutNSCLC using directly elicited TTO in Nafees et al. 2016[68]; in 2 L in NSCLC as reported in Westwood et al.2014 [71]; in cancer with bone metastases forskeletal-related events from general population TTO inMatza et al. 2014 [67]; stage IV NSCLC in 1 L fromexpert opinion estimates in Handorf et al. 2012(expert-opinion-derived utilities from this study wereincluded, as they are the only source of estimates forpneumothorax, thrombocytopenia and thrombosis dis-utilities) [70]; and anaemia from general population SGor from patient-derived TTO in Lloyd et al. 2008 [59].
Description of HTA-relevant HSUVs and disutilitiesOf the 36 publications, 13 provided HSUVs that meetthe NICE reference case or are considered acceptable tothe HTA agencies of interest [37–40, 42, 45, 46, 49, 53,56, 58, 64, 69], based on the measurement technique forgeneration of HSUVs, as outlined in Additional file 3:Figure S1. The main characteristics of these studies arepresented in Table 3. These 13 publications reporteddata from multinational studies [37–40, 45, 49, 64], andfrom Canada [42, 56], France/Germany [46], USA [58],Italy [53] and the UK [69]. In these studies, HRQoL wasmeasured using EQ-5D [37–40, 42, 45, 46, 49, 53, 56],EQ-VAS [37, 39, 40, 49] and SG [58, 64, 69]. The HTAsuitability of disutilities and decrements for AE healthstates in previously treated patients are reported in Table 4.
DiscussionEconomic evaluation, particularly cost–utility analysis,provides important information for guiding decision-making in health care, and its use in HTA is increasing
globally. Such evaluation includes examination of thetime spent in different disease states and uses an HSUVfor each disease state to calculate QALYs; HSUVs there-fore play a key role in economic evaluation. As summa-rized in Additional file 3: Figure S1, NICE, SMC,CADTH, HAS and PBAC prefer utilities to be estimatedusing a generic preference-based instrument, with healthstates described by patients through use of a question-naire, and with the health state valued using acountry-specific tariff that reflects societal preferences.As the aim of this systematic review was to evaluate theexperience of adults with previously treated mNSCLC,the synthesis of health state utility estimates was outsideits scope. However, the findings presented here may pro-vide a basis for generation of an accurate estimate of themean HSUV for use in economic evaluations [74, 75].This systematic review identified HSUVs relevant to
the experience of previously treated adult patients withmNSCLC. Search strings were designed to allow (dis)utilities from a broader population (including lung can-cer, advanced/metastatic cancer and specific metastasescommon in patients with lung cancer). In the absence ofsecond-line mNSCLC (dis) utilities, alternatives were se-lected with decreasing population specificity and rele-vance from first-line mNSCLC, NSCLC, lung cancer oradvanced/metastatic cancer, as outlined in Fig. 1. Order-ing the HSUVs by line of treatment reflects the practiceof switching treatment at progression. However, for thenewer immunotherapies, patients may remain on treat-ment post-progression, and their HRQoL may remain atpre-progression levels. Thus, HSUVs estimated for progres-sion status-specific health states from patients receivingchemotherapy may not be suitable to apply to the equiva-lent health states when patients receive immunotherapy.In total, the 36 identified articles reported 591 HSUVs
relevant to the experience of previously treated adult pa-tients with mNSCLC, and 11 of these studies reported atotal of 195 disutilities or decrements for AE healthstates that are relevant to the experience of patients withmNSCLC. The range of HSUVs identified for compar-able health states, such as progression-free/stable diseaseamong patients treated second-line for advanced/meta-static NSCLC [39, 45], highlights how differences instudy type, tariff, health state and the measures used candrive variation in HSUV estimates. For instance, disutil-ities for progression from a stable state were − 0.056 or− 0.065 using EQ-5D, [37] or − 0.1798 by general-popu-lation-derived SG. [69] To overcome such variations,where possible, HSUV studies should seek to use instru-ments, respondents and valuation populations that aremost acceptable to HTA bodies. However, there are in-stances where variation in methods can be justified. Forexample, disutility values derived from vignettes and ageneral public sample were used by Nafees et al. [69],
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 10 of 30
Table
3Health
stateutility
values
bytreatm
entline,he
alth
stateandinstrumen
t
Stud
yHealth
state
Utility
valuea
Instrumen
tTariff
Respon
dent
details
HTA
suitability
1stline
Nafees2016
[68]
Metastatic
NSC
LCb
PDvs
BLstate
0.095
TTO
N/A
Patients(but
notNSC
LCpatients)fro
mthege
neral
publicin
UK,Australia,France,
China,S.Korea,Taiwan
No
RESno
side
effectsvs
BL0.773
SDisno
side
effectsvs
BL0.460
Che
valier2013
c[38]
Advanced/metastatic
NSC
LC1LPF
0.69
(0.26)
EQ-5D
Fren
ch(TTO
)StageI–StageIII/IV
PFandPD
MeetsHASrequ
iremen
ts
1LPD
0.61
(0.24)
Cho
uaid
2013
[39]
Advanced/metastatic
NSC
LC1LPF
0.71
(0.24)
(95%
CI,
0.67–0.76)
EQ-5D-3
LUK
Attim
eof
advanced
diagno
sis,meanage
64.8years
Ade
nocarcinom
a:65.2%
Large-cellcarcinom
a:6.8%
SQcellcarcinom
a:17.1%
Other:9.9%
Clinicalstageat
timeof
survey:
IIIb:
17.9%
IV:82.1%
MeetsNICErequ
iremen
ts
69.31(18.33)(95%
CI,
65.9–72.8)
EQ-5DVA
SN/A
No
1LPD
0.67
(0.2)(95%
CI
0.59–0.75)
EQ-5D-3
LUK
MeetsNICErequ
iremen
ts
58.67(17.4)
(95%
CI
51.3–66.0)
EQ-5DVA
SN/A
No
Iyer
2013
[46]
Advanced/metastatic
NSC
LCFrance,G
ermany1L
0.63
(0.31)
EQ-5D
UK1
Patientswith
:Ade
nocarcinom
a:56.3%
Large-cellcarcinom
a:11.8%
SQcellcarcinom
a:29.3%
Other:2.5%
StageIIIb:
15.4%
Stage:IV
84.6%
MeetsNICErequ
iremen
t
60.8(19.9)
EQ-5DVA
SN/A
No
≥1stline
Iyer
2013
[46]
Advanced/metastatic
NSC
LCFrance,G
ermany1L/2L
0.58
(0.35)
EQ-5D
UK
Patientswith
:Ade
nocarcinom
a:56.3%
Large-cellcarcinom
a:11.8%
SQcellcarcinom
a:29.3%
Other:2.5%
StageIIIb:
15.4%
Stage:IV
84.6%
MeetsNICEandSM
Crequ
iremen
tsFrance,1
L/2L
0.57
(0.41)
Germany,1L/2L
0.59
(0.31)
France,G
ermany1L/2L
58.0(19.9)
EQ-5DVA
SNo
France,1
L/2L
57.1(21.1)
Germany,1L/2L
58.6(19.1)
2ndline
Blackhall2014[41]
Advanced/metastatic
ALK+NSC
LC
2LBL
CRZ
0.73
(0.24)
EQ-5D-3
LNR
Multin
ationalp
atients,locally
advanced
/metastatic
ALK+
NSC
LC,2
L
Unclear
astariffNR
2LBL
chem
othe
rapy
(PEM
orDOC)
0.70
(0.26)
2LBL
PEM
0.73
(0.24)
2LBL
DOC
0.67
(0.29)
2Lon
CRZ
0.82
(SE,0.01)
(95%
CI,0.79–0.85)
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 11 of 30
Table
3Health
stateutility
values
bytreatm
entline,he
alth
stateandinstrumen
t(Con
tinued)
Stud
yHealth
state
Utility
valuea
Instrumen
tTariff
Respon
dent
details
HTA
suitability
2Lon
Che
mothe
rapy
0.73
(SE,0.02)
(95%
CI,0.70–0.77)
2Lon
PEM
0.74
(SE,0.02)
(95%
CI,0.70–0.79)
2Lon
DOC
0.66
(SE,0.04)
(95%
CI,0.58–0.74)
Che
valier2013
c[38]
Advanced/metastatic
NSC
LC2LPF
0.70
(0.22)
EQ-5D
Fren
ch(TTO
)StageI–StageIII/IV
PFandPD
MeetsHASrequ
iremen
ts
2LPD
0.55
(0.35)
Cho
uaid
2013
[39]
Advanced/metastatic
NSC
LC2LPF
0.74
(0.18)
(95%
CI,0.68–0.80)
EQ-5D-3
LUK
Attim
eof
advanced
diagno
sis,meanage
64.8years
Ade
nocarcinom
a:65.2%
Large-cellcarcinom
a:6.8%
SQcellcarcinom
a:17.1%
Other:9.9%
Clinicalstageat
timeof
survey:
IIIb:
17.9%
IV:82.1%
MeetsNICErequ
iremen
ts
65.0(19.6)
(95%
CI,59.2–70.8)
EQ-5DVA
SN/A
No
2LPD
0.59
(0.34)
(95%
CI,0.42–0.77)
EQ-5D-3
LUK
MeetsNICErequ
iremen
ts
53.5(23.3)
(95%
CI,41.5–65.4)
EQ-5DVA
SN/A
No
Huang
2016
c[45]
AdvancedPD
-L1+
NSC
LC2LPF
0.76
(95%
CI,0.75–
0.77)
EQ-5D
NR
Multin
ationalp
atientswith
advanced
NSC
LCandPD
-L1+
tumou
rsin
2Lon
PEMBor
DOC,after
platinum
-based
chem
othe
rapy
Unclear
astariffNR
2LPD
0.69
(95%
CI,0.66–
0.71)
AdvancedPD
-L1+
NSC
LC,
2L,>
360days
from
death
0.81
(0.79,0.83)
Patientswith
advanced
NSC
LCandPD
-L1+
tumou
rsin
2Lon
PEMBor
DOC,after
platinum
-based
chem
othe
rapy
AdvancedPD
-L1+
NSC
LC,
2L,180–360days
from
death
0.73
(0.71,0.75)
AdvancedPD
-L1+
NSC
LC,
2L,90–180
days
from
death
0.69
(0.66,0.72)
AdvancedPD
-L1+
NSC
LC,
2L,30–90days
from
death
0.60
(0.56,0.64)
AdvancedPD
-L1+
NSC
LC,
2L,<
30days
from
death
0.40
(0.31,0.48)
Iyer
2013
[46]
Advanced/metastatic
NSC
LCOntreatm
ent:2Lon
ly0.53
(0.38)
EQ-5D
UK
Fren
chandGerman
patients
MeetsNICEandSM
Crequ
iremen
ts
54.9(19.3)
EQ-5DVA
SN/A
No
Lang
ley2013
[48]
StageIV
NSC
LCwith
brain
metastases
NSC
LCwith
BM,p
reviou
stx
allowed
,OSC
+WBRT0days
0.63
EQ-5D
NRd
UKandAustralianNSC
LCpatientswith
brain
metastases
No,as
VAStariffused
NSC
LCwith
BM,p
reviou
stx
allowed
,OSC
+WBRT28
days
0.49
NSC
LCwith
BM,p
reviou
stx
0.39
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 12 of 30
Table
3Health
stateutility
values
bytreatm
entline,he
alth
stateandinstrumen
t(Con
tinued)
Stud
yHealth
state
Utility
valuea
Instrumen
tTariff
Respon
dent
details
HTA
suitability
allowed
,OSC
+WBRT56
days
NSC
LCwith
BM,p
reviou
stx
allowed
,OSC
+WBRT
112days
0.36
NSC
LCwith
BM,p
reviou
stx
allowed
,OSC
+WBRT
168days
0.16
NSC
LCwith
BM,p
reviou
stx
allowed
,OSC
alon
e0days
0.60
NSC
LCwith
BM,p
reviou
stx
allowed
,OSC
alon
e28
days
0.49
NSC
LCwith
BM,p
reviou
stx
allowed
,OSC
alon
e56
days
0.44
NSC
LCwith
BM,p
reviou
stx
allowed
,OSC
alon
e112days
0.38
NSC
LCwith
BM,p
reviou
stx
allowed
,OSC
alon
e168days
0.36
Lloyd2008
[59]
Cancerwith
chem
othe
rapy-
relatedanaemiaor
fatig
ue
Anaem
ia,H
blevel,≥12.0
g/dL
0.708(95%
CI,0.057)
SGN/A
Gen
eralpu
blicsample
from
UK
No
0.611(95%
CI,0.112)
TTO
UKcancer
patientswho
have
recentlyexpe
rienced
chem
othe
rapy-related
fatig
ueandanaemiacompleting
vign
ette-based
TTO
MeetsNICE/SM
Crequ
iremen
tsbu
tstill
vign
ette-based
health
state
rather
than
patient
ratin
gow
nhe
alth
Nafees2008
[59]
mNSC
LC2LStablediseasee
0.65
(SE,0.02)
SGN/A
100mem
bersof
gene
ral
publicin
UK
No,bu
tused
inmultip
leHTA
subm
ission
s2LRespon
ding
diseasef
0.67
2LRespon
segain
0.02
(SE,0.01)
2LProg
ressivediseaseg
0.47
Novello
2015
[49]
StageIII/IV
recurren
tNSC
LC(SQandNSQ
)h
2LNIN
+DOC,b
efore
treatm
ent(week0)
0.72
EQ-5D
UK
Multin
ationalp
atientswith
stageIII/IV
recurren
tNSC
LC(SQandNSQ
)in2Lafter
chem
othe
rapy
Ade
nocarcinom
a:50.1%
MeetsNICE/SM
Crequ
iremen
ts
2LNIN
+DOC,after
treatm
ent(week30)
0.61
2LPLA+DOC,b
efore
treatm
ent(week0)
0.72
2LPLA+DOC,after
treatm
ent(week30)
0.62
2LNIN
+DOC,b
efore
treatm
ent(week0)
69.0
EQ-5DVA
SN/A
No
2LNIN
+DOC,after
treatm
ent(week30)
63.2
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 13 of 30
Table
3Health
stateutility
values
bytreatm
entline,he
alth
stateandinstrumen
t(Con
tinued)
Stud
yHealth
state
Utility
valuea
Instrumen
tTariff
Respon
dent
details
HTA
suitability
2LPLA+DOC,b
efore
treatm
ent(week0)
69.0
2LPLA+DOC,after
treatm
ent(week30)
63.1
Reck
2015
[50]
AdvancedSQ
NSC
LC2LNIVOat
BL0.68
(0.208)
EQ-5D
NR
Multin
ationalp
atientswith
advanced
SQNSC
LCUnclear
astariffNR
2LDOCat
BL0.66
(0.284)
2LNIVOat
BL63.7(18.2)
EQ-5DVA
SN/A
No
2LDOCat
BL66.3(20.5)
Rude
ll2016
c[57]
AdvancedNSC
LC,EGFR+
2LOSIat
BL65.2(20.33)
EQ-5D-5
LVA
SN/A
Multin
ationalp
atientswith
EGFR+advanced
NSC
LC,
2Lafterprevious
TKI
No
2LOSIat
36weeks
73.7(17.33)
Schu
ette
2012
[51]
NSC
LCStageIIIB–IV
2L,PEM
atBL
0.66
(0.256)
EQ-5D
UKTTO
AustrianandGerman
advanced
/mNSC
LC2L
patientsmainlyafterprior
platinum
treatm
ent
(IIIa,6.7%;IIIb,19.8%
;IV,73.5%
)
MeetsNICE/SM
Crequ
iremen
ts2L,PEM
at6weeks
(2nd
cycle)
0.02
(0.214)
EQ-5Dgain
2L,PEM
at6thcycle
0.11
(0.228)
2L,PEM
atBL
59.3(17.8)
EQ-5DVA
SN/A
No
2L,PEM
at6weeks
(2nd
cycle)
3.3(12.58)
EQ-5DVA
Sgain
N/A
2L,PEM
at6thcycle
12.8(17.62)
Vargas
2009
c[72]
AdvancedNSC
LC2L,on
ERL
0.81
GlobalQ
oLinde
xNR
Patientswith
advanced
NSC
LC,2
Lafterprevious
chem
othe
rapy
No
2L,on
taxane
s0.62
≥2n
dline
Che
n2010
c[73]
AdvancedNSC
LCd
2L,DOC,d
uringtreatm
ent
0.45
iSG
N/A
UKge
neralp
ublic
(as
algo
rithm
basedon
Nafees
2008
data
used
tocalculate
utilities)
Accep
tabledata
forSM
C
2L,DOC,after
treatm
ent
0.57
2L,PEM,d
uringtreatm
ent
0.54
2L,PEM,after
treatm
ent
0.59
3L,ERL,du
ringtreatm
ent
0.48
BSC,d
uringtreatm
ent
0.47
Che
valier2013
[38]
Advanced/metastatic
NSC
LC3/4LPF
0.61
(0.3)
EQ-5D
Fren
ch(TTO
)StageI–StageIII/IV
PFandPD
MeetsHASrequ
iremen
ts
3/4LPD
0.42
(0.40)
Griebsch
2014
[37]
StageIIIb(with
pleural
effusion
)/IV
NSC
LCaden
ocarcino
ma
(LUX-LU
NG1)j
Week4,prog
ressioneffect
long
itudinalm
odel
−0.1
EQ-5D
UK
Multin
ationaladvanced/
metastatic
NSC
LC,2
LLMeetsNICErequ
iremen
ts
Mixed
effect
long
itudinal
mod
elIRC
−0.056(95%
CI,
−0.083to
−0.028)
Mixed
effect
long
itudinal
mod
elIN
−0.065(95%
CI,
−0.092to
−0.039)
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 14 of 30
Table
3Health
stateutility
values
bytreatm
entline,he
alth
stateandinstrumen
t(Con
tinued)
Stud
yHealth
state
Utility
valuea
Instrumen
tTariff
Respon
dent
details
HTA
suitability
Mixed
effect
long
itudinal
mod
elIRC,A
FA−0.06
Mixed
effect
long
itudinal
mod
elIRC,BSC
−0.046
Mixed
effect
long
itudinal
mod
elIIN
V,AFA
−0.081
Mixed
effect
long
itudinal
mod
elIIN
V,BSC
−0.033
Week4,prog
ressioneffect
long
itudinalm
odel
−7.3
EQ-5DVA
SN/A
No
Mixed
effect
long
itudinal
mod
elIRC
−3.76
(95%
CI,−5.19
to−2.32)
Mixed
effect
long
itudinal
mod
elINV
−3.83
(95%
CI,−5.21
to−2.44)
Mixed
effect
long
itudinal
mod
elIRC,A
FA3.63
Mixed
effect
long
itudinal
mod
elIRC,BSC
−4.11
Mixed
effect
long
itudinal
mod
elINV,AFA
−4.42
Mixed
effect
long
itudinal
mod
elINV,BSC
−2.55
Hirsh2013
[40]
StageIIIB/IV
NSC
LC3LL
onAFA
+BSC
0.71
EQ-5D
UK
98%
aden
ocarcino
ma
PDfollowingtreatm
entlines
1–2,on
eof
which
was
platinum
based,
plus
PDafter
atleast12
weeks
ofERLor
GEF
MeetsNICErequ
iremen
ts
3LL
onPLA+BSC
0.67
3LL
onAFA
+BSC
67.4
EQ-5DVA
SN/A
No
3LL
onPLA+BSC
65.2
Schw
artzbe
rgc2015
[60]
StageIIIb/IV
NSC
LC(SQ
&NSQ
)
Allpatientswk6
1.0(21.7)
EQ-5DVA
SN/A
Patients,2LL,N
IVO3mg/kg
i.v.q
2wNo
wk12
5.8(21.3)
wk18
8.2(22.3)
wk24
8.2(23.9)
wk30
8.4(29.2)
SDiswk6
3.8(19.8)
wk12
6.4(21.9)
wk18
8.2(20.9)
wk24
5.2(21.9)
wk30
7.2(28.5)
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 15 of 30
Table
3Health
stateutility
values
bytreatm
entline,he
alth
stateandinstrumen
t(Con
tinued)
Stud
yHealth
state
Utility
valuea
Instrumen
tTariff
Respon
dent
details
HTA
suitability
PRwk6
7.3(22.4)
wk12
6.6(24.7)
wk18
8.1(27.6)
wk24
18.1(31.0)
wk30
13.7(38.2)
PDwk6
−5.8(21.1)
wk12
−3.0(19.8)
wk18
3.9(24.3)
wk24
6.8(12.2)
wk30
5.5(15.7)
Treatm
entlineno
tspecified
Bradbu
ry2008
c[42]
AdvancedNSC
LCOnERL
0.772
EQ-5D
NR(possibly
Canadian)
Canadianpatients
Potentially
relevant
toCADTH
OnBSC
0.754
Chang
2016
c[63]
AdvancedNSC
LC>360days
from
death
0.904
(95%
CI,0.892–0.917)
TTO
NR
Gen
eralpu
blic,Sou
thKo
rea
No
180–360days
from
death
0.720
(95%
CI,0.692–0.748)
90–180
days
from
death
0.627
(95%
CI,0.598–0.655)
30–90days
from
death
0.379
(95%
CI,0.349–0.409)
<30
days
from
death
0.195
(95%
CI,0.172–0.218)
Dansk
2016
c[43]
AdvancedNSC
LCSynthe
sizedPF
Med
ian,0.706
Rang
e,0.620–0.815
Synthe
sizedutility
across
>1
instrumen
ttype
NR
Utilities
synthe
sizedinclud
edthosewhe
rerespon
dents
werepatientsandthose
whe
rethey
werethege
neral
publicconsideringa
hypo
theticalhe
alth
state
No
Synthe
sizedPF
trial-b
ased
Med
ian,0.750
Rang
e,0.627–0.815
Synthe
sizedPF
non-trial-
based
Med
ian,0.653
Rang
e,0.620–0.653
Synthe
sizedPD
Med
ian,0.565
Rang
e,0.470–0.688
Synthe
sizedPD
trial-b
ased
Med
ian,0.599
Rang
e,0.550–0.688
Synthe
sizedPD
non-trial-
based
Med
ian,0.473
Rang
e,0.470–0.530
Doyle2008
[65]
Metastatic
NSC
LCSD
is,noadditio
nalsym
ptom
s0.626
SGN/A
Gen
eralpu
blic
No
Treatm
entrespon
se,no
0.712
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 16 of 30
Table
3Health
stateutility
values
bytreatm
entline,he
alth
stateandinstrumen
t(Con
tinued)
Stud
yHealth
state
Utility
valuea
Instrumen
tTariff
Respon
dent
details
HTA
suitability
additio
nalsym
ptom
s
Grunb
erg2009
c[58]
BC/LC
Che
mothe
rapy-in
duced
nausea
andvomiting
ofdifferin
gseverity
Repo
rted
graphically
SGN/A
PatientsBC
/LC
MeetsNICErequ
iremen
ts
Grutters2010
c[44]
NSC
LC(stage
unspecified
)NSC
LCwith
grade3+
dyspno
ea,stage
unspecified
Med
ian,0.52
EQ-5D-5
LNR
Patientsat
anearly
treatm
ent
stage
No
Jang
2010
[47]
StageIV
NSC
LCStageIV
NSC
LC0.75
(0.15)
EQ-5D
US
Patientswith
NSC
LCattend
ingamajor
Canadian
cancer
center
outpatient
clinic
No
Linn
et2015
c[62]
StageIV
NSC
LCon
oralVINO
PCS,cycle2
37.0
SF-12
N/A
Patients
No
PCS,cycle3
38.6
MCS
,cycle2
47.7
MCS
,cycle3
44.2
PCS,cycle2
52.9
Careg
ivers
Potentialtoestim
ateSF-6D
forcaregiversto
mNSC
LCpatients,forSM
Cor
CADTH
PCS,cycle3
53.4
MCS
,cycle2
46.2
MCS
,cycle3
44.6
Lloyd2005
c[66]
StageIV
NSC
LCRES
0.70
SGk
N/A
Gen
eralpu
blic
No
SDis,oraltreatmen
t0.63
SDis,i.v.treatmen
t0.58
PD0.42
Endof
life
0.33
Manser2006
[61]
StageIV
NSC
LCStageIV
Med
ian,0.68
(IQR,0.54–0.82)
AQoL
Australia
Mixed
stageen
rolled:
I,31.5%;II,17.4%;IIIa,16.3%
;IIIb,
7.6%
;IV,25.0%
No
Matza
2014
[67]
StageIV
cancer
with
bone
metastases
Cancerwith
bone
metastases
andno
SRE
0.47
(0.41)
TTO
N/A
Gen
eralpu
blic,U
K(Edinb
urgh
andLond
on)
No
0.47
(0.45)
Gen
eralpu
blic,C
anada
(Mon
trealand
Toronto)
0.47
(0.42)
Gen
eralpu
blic,U
Kand
Canada
Stew
art2015
[56]
EGFR+StageIV
NSC
LCPR/SDison
EGFR
TKIs
(GEF,ERL,A
ZD9291)
0.82
(SE,0.16)
EQ-5D-3
LNR
Patients,eligibleforor
onTKI
tx,55%
Asian,45%
male,
med
ianage60,66%
never
smokers.StageIV:
atdiagno
sis,80%
whe
nsurveyed
,100%
Unclear
Respon
dedto
standard
chem
othe
rapy
0.80
(SE,0.12)
EGFR+,respo
nded
toGEF
0.84
(SE,0.14)
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 17 of 30
Table
3Health
stateutility
values
bytreatm
entline,he
alth
stateandinstrumen
t(Con
tinued)
Stud
yHealth
state
Utility
valuea
Instrumen
tTariff
Respon
dent
details
HTA
suitability
EGFR+,respo
nded
toERL
0.82
(SE,0.17)
EGFR+,respo
nded
toAZD
9291
0.83
(SE,0.16)
EGFR+,PDdu
ringTKI
treatm
ent(GEF,ERL,
AZD
9291)
0.74
(SE,0.08)
EGFR+,allpatients(PR/SD
is/
PD),25%
3LL
0.802
Tabb
erer
2006
[52]
AdvancedNSC
LCRES
0.49
EQ-5D
NR
Gen
eralpu
blic,U
K(Cardiff,Glasgow
,Lon
don
andOxford)
No
SDis
0.46
SDis+oraltreatm
ent
0.45
SDis+i.v.treatmen
t0.43
PD0.22
Nearde
ath
0.15
Trippo
li2001
[53]
Metastatic
NSC
LCMetastatic
NSC
LC0.53
(0.36)
EQ-5D
UK(TTO
)Italianpatients
MeetsNICEandSM
Creferencecases
0.55
(0.22)l
EQ-5DVA
SN/A
No
Yang
2014
[54]
StageIIIB/IV
NSC
LCStageIV
inop
erable,
perfo
rmance
status
0–1
0.75
(0.22)
EQ-5D
Taiwan
Patients,mixed
NSC
LCstages:
I,0.8%
;II,0%
;IIIA,4.5%;
IIIB,16.9%;IV,77.8%
No
StageIV
inop
erable,
perfo
rmance
status
0–4
0.75
(0.22)
Yokoyama2013
c[55]
AdvancedNSC
LC/SCLC
StageIIIB/IV
NSC
LC/SCLC
with
bone
metastasisand
SRE
NR
EQ-5D
NR
Patients,advanced
NSC
LC,
72%,SCL
C,28%
NSC
LCandSC
LC:IIIB,37%
;IV,63%
No
a Mean,
ormean(SD)un
less
stated
othe
rwise
bVA
Sscores
werealso
repo
rted
inthisstud
ybu
tun
clearwhe
ther
thiswas
EQ-VAS
c The
sestud
ieswerepu
blishe
das
abstractsor
posters
dTh
isreferenced
article
(https://www.ncb
i.nlm
.nih.gov
/pub
med
/101
0980
1)isforaVA
Svaluation
e SDisvign
ette:
•Yo
uha
vealife-threaten
ingillne
ssthat
isstab
leon
treatm
ent.Yo
uarereceivingcycles
oftreatm
entthat
requ
ireyo
uto
goto
theou
tpatient
clinic
•Yo
uha
velost
weigh
t,an
dyo
urap
petiteisredu
ced.
Yousometim
esexpe
riencepa
inor
discom
fortin
your
chestor
unde
ryo
urrib
s,which
canbe
treatedwith
painkillers.Y
ouha
veshortnessof
breath,and
breathing
canbe
painful.Yo
uha
veape
rsistent
nagg
ingcoug
h•Yo
uareab
leto
washan
ddressyo
urselfan
ddo
jobs
arou
ndtheho
me.
Shop
ping
andda
ilyactiv
ities
take
moreeffortthan
usua
l•Yo
uareab
leto
visitfamily
andfriend
sbu
toftenha
veto
cutitshortbe
causeyo
uge
ttired
•Yo
usometim
esfeel
less
physically
attractiv
ethan
youused
to.Y
ourillne
ssha
saffected
your
sexdrive
•Yo
uworry
abou
tdy
ingan
dho
wyo
urlovedon
eswillcope
f Secon
d-linerespon
ding
vign
ette:
•Yo
uha
vealife-threaten
ingillne
ssthat
isrespon
ding
totreatm
ent.Yo
uarereceivingcycles
oftreatm
entwhich
requ
ireyo
uto
goto
theou
tpatient
clinic
•Yo
uarega
iningba
ckyo
urweigh
tan
dyo
urap
petiteisreturning.
Youoccasion
ally
expe
riencepa
inor
discom
fortin
your
chestor
unde
ryo
urrib
swhich
canbe
treatedwith
painkillers.Y
ousometim
esha
veshortness
ofbreath.Y
ouoccasion
ally
have
ana
ggingcoug
h•Yo
uareab
leto
washan
ddressyo
urselfan
ddo
jobs
arou
ndtheho
me.
Shop
ping
andda
ilyactiv
ities
cansometim
esbe
tiring
•Yo
uareab
leto
visitfamily
andfriend
sbu
tsometim
esha
veto
cutitshortbe
causeyo
uge
ttired
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 18 of 30
•Yo
uoccasion
ally
feel
less
physically
attractiv
ethan
youused
to.Y
ourillne
ssha
ssomew
hataffected
your
sexdrive
•Yo
usometim
esworry
abou
tdy
ingan
dho
wyo
urlovedon
eswillcope
gSecond
-line
PDvign
ette:
•Yo
uha
vealife-threaten
ingillne
ss,and
your
cond
ition
isge
ttingworse
•Yo
uha
velost
your
appe
titean
dha
veexpe
rienced
sign
ificant
weigh
tloss.Y
ouexpe
riencepa
inan
ddiscom
fortin
your
chestor
unde
ryo
urrib
s.Yo
ufreq
uently
have
shortnessof
breath,and
breathingisoften
painful.Yo
uha
veape
rsistent
nagg
ingcoug
han
dsometim
escoug
hup
bloo
d.Yo
umay
expe
riencesomedifficulty
swallowing
•Yo
uexpe
riencesevere
fatig
uean
dfeel
tootired
togo
outor
toseefamily
andfriend
s.Itha
saffected
your
relatio
nships
with
them
•Yo
une
edassistan
ceto
washan
ddressyo
urself.
Youareoftenun
able
todo
jobs
arou
ndtheho
useor
othe
rda
ilyactiv
ities.Y
ouarede
pend
enton
othe
rsto
doyo
urshop
ping
andareun
able
todo
your
usua
lda
ilyactiv
ities
•Yo
uoftenfeel
less
physically
attractiv
ethan
youused
to.Y
ouha
velittle
orno
sexual
drive
•Yo
uarede
pressed,
anddy
ingisalwayson
your
mind.
Youworry
abou
tho
wyo
urlovedon
eswillcope
hTh
isstud
yalso
hasutilitie
savailableevery3weeks
betw
eenweek0an
dweek30
foralltreatmen
tsi Allutilitie
sin
thispa
perassumed
tobe
themean,
althou
ghitisno
tclearly
stated
inthepa
per
j 1Lda
taalso
repo
rted
from
LUX-LU
NG3
k Ind
ividua
lcou
ntry
values
arealso
availablein
thispu
blication
l Thisvalueisrepo
rted
asin
theoriginal
publication
Abb
reviations:1
Lfirst
line,
2Lsecond
line,
2LL
second
andsubseq
uent
line,3LL
third
andsubseq
uent
line,
AFA
afatinib,A
LK+an
aplasticlymph
omakina
semutationpo
sitiv
e,AQoL
Assessm
entof
Qua
lityof
Life
instrumen
t,BC
breast
cancer,B
Lba
selin
e,BSCbe
stsupp
ortiv
ecare,C
ADTH
Can
adianAge
ncyforDrugs
andTechno
logies
inHealth
,CIcon
fiden
ceinterval,C
RZcrizotinib,D
OCdo
cetaxel,EG
FRep
idermal
grow
thfactor
receptor,EGFR+ep
idermal
grow
thfactor
receptor
mutationpo
sitiv
e,EO
RTCQLQ
Europe
anOrgan
isationfortheRe
search
andTreatm
entof
Can
cerQua
lityof
Life
Que
stionn
aire,EQ-VASEu
roQol
visual
analog
uescale,
ERLerlotin
ib,G
EFge
fitinib,H
ASHau
teAutorité
deSanté,
HTA
health
techno
logy
assessmen
t,IQRinterqua
rtile
rang
e,i.v.intraveno
us,LClung
cancer,M
CSmen
talcom
pone
ntsummary,mNSC
LCmetastatic
non-sm
all
celllung
cancer,N
/Ano
tap
plicab
le,N
ICENationa
lInstituteforHealth
andCareExcellence,
NIN
ninted
anib,N
IVOnivo
lumab
,NRno
trepo
rted
,NSC
LCno
n-sm
allcelllun
gcancer,N
SQno
n-squa
mou
s,NTS
nottreatm
ent-
specific,OSC
optim
alstan
dard
care,O
SIosim
ertin
ib,P
CSph
ysical
compo
nent
summary,PD
prog
ressivedisease,
PEM
pemetrexed,
PFprog
ression-free,P
LAplaceb
o,PR
partialrespo
nse,
PSSprog
ression-status
specific,
q2won
ceevery2weeks,Q
oLqu
ality
oflife,
RESrespon
se,SCLCsm
all-celllun
gcancer,SDstan
dard
deviation,
SDisstab
ledisease,
SEstan
dard
error,SF-6D6-dimen
sion
Short-Fo
rmHealth
Survey,SF-12/3612
-/36
-item
Short-Fo
rmHealth
Survey,SGstan
dard
gamble,
SMCScottishMed
icines
Con
sortium,SQsqua
mou
s,SREskeletal-related
even
t,TKItyrosinekina
seinhibitor,TTOtim
etrad
e-off,VA
Svisual
analog
uescale,
VINO
vino
relbine,
WBR
Twho
le-brain
radiothe
rapy
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 19 of 30
Table
4Disutilitiesandde
crem
entsforadverseeven
the
alth
states
inpatientswith
previouslytreatedmNSC
LC
Relevance
Autho
r,year,cou
ntry,
referencea
Instrumen
tand
respon
dent
Utility
type
Health
state/disutility
MeanHSU
V(SD)[SE]
{95%
CI}
HTA
suitability
Advanced/mNSC
LCNafees2008,U
K[69]
SG Gen
eralpu
blic
UID
StageIV
NSC
LC,2
L,stable
disease
Doe
sno
tmeetHTA
body
referencecase
asvign
ette-
basedutility
completed
byge
neralp
ublic
respon
dents.
Has
been
used
inmultip
leHTA
subm
ission
s,ho
wever.
Specifically
2LandUK,go
odsamplesize
(n=100)
and
measure
ofdispersion
available.
+Diarrho
ea0.61
+Fatig
ue0.58
+Febrile
neutrope
nia
0.56
+Hairloss
0.61
+Nausea/vomiting
0.61
+Neutrop
enia
0.56
+Rash
0.62
StageIV
NSC
LC,2
L,respon
ding
disease
+Diarrho
ea0.63
+Fatig
ue0.60
+Febrile
neutrope
nia
0.58
+Hairloss
0.63
+Nausea/vomiting
0.62
+Neutrop
enia
0.58
+Rash
0.64
DStageIV
NSC
LC,2
L,movingfro
mstableto
prog
ressive
−0.18
[0.022]
Neutrop
enia
−0.09
[0.015]
Febrile
neutrope
nia
−0.09
[0.016]
Fatig
ue−0.07
[0.018]
Nauseaandvomiting
−0.05
[0.016]
Diarrho
ea−0.05
[0.016]
Hairloss
−0.04
[0.015]
Rash
−0.03
[0.012]
Respon
segain
0.02
[0.007]
Tabb
erer
2006,U
K[52]
EQ-5D(tariff
NRbu
tlikelyUKTTOtariffas
UKsample)
Gen
eralpu
blic
DCom
paredwith
stable
disease(advancedNSC
LC,
lineno
tspecified
)
Not
suitableas
gene
ralp
ublic
respon
dents,lineof
treatm
entno
tspecified
,and
nomeasure
ofdispersion
repo
rted
.Goo
dsamplesize,
however
(n=154)
andNafees
etal.2008in
2Ldo
esno
t
Febrile
neutrope
nia
−0.27
Rash
−0.06
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 20 of 30
Table
4Disutilitiesandde
crem
entsforadverseeven
the
alth
states
inpatientswith
previouslytreatedmNSC
LC(Con
tinued)
Relevance
Autho
r,year,cou
ntry,
referencea
Instrumen
tand
respon
dent
Utility
type
Health
state/disutility
MeanHSU
V(SD)[SE]
{95%
CI}
HTA
suitability
providedisutilities
for
neurop
athy
orstom
atitisso
thesevalues
from
Tabb
erer
etal.m
aybe
thebe
stavailable.
Neuropathy
−0.15
Neutrop
enia
−0.14
Nausea
−0.14
Stom
atitis
−0.14
Diarrho
ea−0.13
Doyle2008,U
K[65]
SG Gen
eralpu
blic
UID
Metastatic
NSC
LC,lineno
tspecified
,SDisno
additio
nal
symptom
s
Doe
sno
tmeetreference
case
asge
neralp
ublic
respon
dents.How
ever,the
searetheon
lydisutilities
for
severe
symptom
sforcoug
h,dyspno
eaandpain
inmNSC
LC,soarebe
stop
tion
inspite
ofno
tmeetin
gHTA
derivationmetho
dpreferen
ces(n=101)
+Cou
gh0.58
+Dyspn
oea
0.58
+Pain
0.56
+Cou
gh,d
yspn
oeaandpain
0.46
DCou
gh−0.05
[0.011]
Dyspn
oea
−0.05
[0.012]
Pain
−0.07
[0.012]
Cou
gh,d
yspn
oeaandpainc
−0.17
b
Respon
ding
diseasegain
vsSD
is0.09
[0.015]
Aslineno
tspecified
,data
from
Nafeeset
al.2008
shou
ldbe
used
inpreferen
ce.
Hando
rf2012,U
SA[70]
Expe
rtop
inion
UID
StageIV
NSC
LCaden
ocarcino
ma(1
LSD
is)
+ne
utrope
nia
0.67
Doe
sno
tmeetreference
case
asexpe
rtop
inion-
derived
.ThisAEiscoveredby
Nafeeset
al.2008,which
uses
abe
tter
derivationmetho
dthan
expe
rtop
inion.
+pn
eumotho
rax
0.63
Doe
sno
tmeetreference
case
asexpe
rtop
inion-
derived
,but
thesearethe
onlyestim
ates
fortheseAE
health
states.SDisestim
ate
was
0.670(oralthe
rapy)and
0.653(i.v.chem
othe
rapy)for
disutility
calculation.
+haem
orrhage
0.63
+thrombo
cytope
nia
0.65
+thrombo
sis
0.56
Earlier
stageNSC
LC(curativeintent)
Grutters2010,cou
ntry
NR[44]
EQ-5D-5
L(tariff
NR)
Patients
UID
NSC
LC,curativeintent
stage,
lineno
tspecified
,grade
III+
dyspno
ea
0.52
(med
ian)
Patient-derived
EQ-5Dbu
ttariffandmeasure
ofdisper
sion
NR.Onlysource
ofgrade
III+dyspne
a.Utility
forNSC
LC
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 21 of 30
Table
4Disutilitiesandde
crem
entsforadverseeven
the
alth
states
inpatientswith
previouslytreatedmNSC
LC(Con
tinued)
Relevance
Autho
r,year,cou
ntry,
referencea
Instrumen
tand
respon
dent
Utility
type
Health
state/disutility
MeanHSU
V(SD)[SE]
{95%
CI}
HTA
suitability
patientswith
outdyspno
eain
thissamplewas
0.81,i.e.
disutility
−0.29
Advanced/mLC
(NSC
LC+SC
LC)
Yokoyama2013,Japan
[55]
EQ-5D(tariff
NR)
Patients
DStageIIIB/IV
NSC
LC/SCLC
with
bone
metastases+
skeletalrelatedeven
t(patho
logicfracture,radiation
orsurgeryto
bone
lesion
,spinalcord
compression
orhype
rcalcaem
ia)
−0.05
dProvides
NSC
LC/SCLC
(mixed
)patient-derived
EQ-5Dde
cre
men
tfor(m
ixed
)SREs.D
ata
fortheseAEs
arelim
ited,
soalthou
ghthisestim
ateisno
trobu
st(n=9andrespon
se%
low
at32%)itdo
esprovide
anindicatio
n.Novariability
measure
repo
rted
Breastcancer
and
lung
cancer
Grunb
erg2009,U
SA[58]
SG Patients
UID
Base
state:continuo
usnausea
andvomiting
0.53
fNafeeset
al.2008provide
data
fornausea
andvomiting
butifdifferent
levelsof
nausea
andvomiting
need
tobe
discerne
dthen
these
utilitiescanbe
considered
.Patient-derived
SGbu
tmixed
lung
/breastcancers.Goo
dsamplesize
(n=96)bu
tno
measure
ofdispersion
.Asthe
Cop
yright
feeforGrunb
erg
2009
was
high
,the
sedata
arerepo
rted
from
Shabarud
din2013
[79]
(aprevious
SRthat
extractedthegraphical
data
from
Grunb
erg2009)
Increm
ent
Limitednausea
andlim
itvomiting
vscontinuo
usnausea
andvomiting
+0.53
f
Increm
ent
Limitednausea
vscontinuo
usnausea
andvomiting
+0.55
f
Increm
ent
Limitedvomiting
vscontinuo
usnausea
and
vomiting
+0.50
f
AdvancedCancer
Matza
2014,U
K[67]
TTO
Gen
eralpu
blic
UStageIV
cancer
with
bone
metastases(noskeletal-
relatedeven
ts)
0.47
(0.41)
Doe
sno
tmeetreference
case
asge
neralp
opulation
respon
dents.How
ever,as
thereareno
alternative
utilitiesforbo
nemetastases
theseUKutilitiescouldbe
considered
forNICEor
SMC.
Goo
dsamplesize
(n=126),
SDavailable.
UID
+spinalcord
compression
with
outparalysis
0.25
(0.50)
+spinalcord
compression
with
paralysis
0.13
(0.49)
+fractureof
theleg
0.42
(0.41)
+fractureof
therib
0.44
(0.42)
+fractureof
thearm
0.44
(0.41)
+radiationtreatm
ent
(2weeks,5
appo
intm
ents/
week)
0.42
(0.42)
+radiationtreatm
ent
(2appo
intm
ents)
0.45
(0.41)
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 22 of 30
Table
4Disutilitiesandde
crem
entsforadverseeven
the
alth
states
inpatientswith
previouslytreatedmNSC
LC(Con
tinued)
Relevance
Autho
r,year,cou
ntry,
referencea
Instrumen
tand
respon
dent
Utility
type
Health
state/disutility
MeanHSU
V(SD)[SE]
{95%
CI}
HTA
suitability
+surgeryto
stabilize
bone
0.40
(0.44)
Matza
2014,C
anada[67]
TTO
Gen
eralpu
blic
UStageIV
cancer
with
bone
metastases(noskeletal-
relatedeven
ts)
0.47
(0.45)
Doe
sno
tmeetreference
case
asge
neralp
opulation
respon
dents.How
ever,as
thereareno
alternative
utilitiesforbo
nemetastases
theseCanadianutilitiescould
beconsidered
forCADTH
.Reason
ablesamplesize
(n=61),SD
available.
UID
+spinalcord
compression
with
outparalysis
0.25
(0.54)
+spinalcord
compression
with
paralysis
0.19
(0.53)
+fractureof
theleg
0.40
(0.48)
+fractureof
therib
0.43
(0.47)
+fractureof
thearm
0.43
(0.48)
+radiationtreatm
ent
(2weeks,5
appo
intm
ents/
week)
0.41
(0.50)
+radiationtreatm
ent
(2appo
intm
ents)
0.45
(0.45)
+surgeryto
stabilize
bone
0.39
(0.50)
Matza
2014,U
Kand
Canada[67]
TTO
Gen
eralpu
blic
UStageIV
cancer
with
bone
metastases(noskeletal-
relatedeven
ts)
0.47
(0.42)
Doe
sno
tmeetreference
case
asge
neralp
opulation
respon
dents.How
ever,as
thereareno
alternative
utilitiesforbo
nemetastases
theseUK+
Canadianutilities
couldbe
considered
forNICE,
SMCor
CADTH
.Goo
dsample
size
(n=187),SDavailable.
UID
+spinalcord
compression
with
outparalysis
0.25
(0.21)
+spinalcord
compression
with
paralysis
0.15
(0.50)
+fractureof
theleg
0.41
(0.43)
+fractureof
therib
0.44
(0.43)
+fractureof
thearm
0.43
(0.43)
+radiationtreatm
ent
(2weeks,5
appo
intm
ents/
week)
0.41
(0.45)
+radiationtreatm
ent
(2appo
intm
ents)
0.45
(0.42)
+surgeryto
stabilize
bone
0.40
(0.46)
Matza
2014,U
K[67]
TTO
Gen
eralpu
blic
DStageIV
cancer
with
bone
metastases
Asabove
+spinalcord
compression
with
outparalysis
−0.22
(0.31)
+spinalcord
compression
−0.34
(0.36)
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 23 of 30
Table
4Disutilitiesandde
crem
entsforadverseeven
the
alth
states
inpatientswith
previouslytreatedmNSC
LC(Con
tinued)
Relevance
Autho
r,year,cou
ntry,
referencea
Instrumen
tand
respon
dent
Utility
type
Health
state/disutility
MeanHSU
V(SD)[SE]
{95%
CI}
HTA
suitability
with
paralysis
+fractureof
theleg
−0.05
(0.09)
+fractureof
therib
−0.03
(0.08)
+fractureof
thearm
−0.03
(0.07)
+radiationtreatm
ent
(2weeks,5
appo
intm
ents/
week)
−0.05
(0.12)
+radiationtreatm
ent
(2appo
intm
ents)
−0.02
(0.07)
+surgeryto
stabilize
bone
−0.07
(0.17)
Matza
2014,C
anada[67]
TTO
Gen
eralpu
blic
DStageIV
cancer
with
bone
metastases
Asabove
+spinalcord
compression
with
outparalysis
−0.22
(0.32)
+spinalcord
compression
with
paralysis
−0.28
(0.30)
+fractureof
theleg
−0.07
(0.19)
+fractureof
therib
−0.04
(0.17)
+fractureof
thearm
−0.04
(0.07)
+radiationtreatm
ent
(2weeks,5
appo
intm
ents/
week)
−0.06
(0.21)
+radiationtreatm
ent
(2appo
intm
ents)
−0.02
(0.11)
+surgeryto
stabilize
bone
−0.08
(0.21)
Matza
2014,U
Kand
Canada[67]
TTO
Gen
eralpu
blic
DStageIV
cancer
with
bone
metastases
Asabove
+spinalcord
compression
with
outparalysis
−0.22
(0.31)
+spinalcord
compression
with
paralysis
−0.32
(0.34)
+fractureof
theleg
−0.06
(0.13)
+fractureof
therib
−0.03
(0.12)
+fractureof
thearm
−0.04
(0.11)
+radiationtreatm
ent
(2weeks,5
appo
intm
ents/
week)
−0.06
(0.15)
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 24 of 30
Table
4Disutilitiesandde
crem
entsforadverseeven
the
alth
states
inpatientswith
previouslytreatedmNSC
LC(Con
tinued)
Relevance
Autho
r,year,cou
ntry,
referencea
Instrumen
tand
respon
dent
Utility
type
Health
state/disutility
MeanHSU
V(SD)[SE]
{95%
CI}
HTA
suitability
+radiationtreatm
ent
(2appo
intm
ents)
−0.02
(0.08)
+surgeryto
stabilize
bone
−0.07
(0.18)
Cancer,un
clearstage
Lloyd2008,U
K[59]
SG Gen
eralpu
blic
UID
Anaem
iaassociated
with
cancer
treatm
ent
Doe
sno
tmeetreference
case
asge
neralp
opulation
samplerespon
dent
forSG
exercise.
Haemog
lobinlevel(g/dL)
7.0–8.0
0.58
{0.067}
8.0–9.0
0.61
{0.064}
9.0–10.0
0.64
{0.060}
10.0–10.5
0.64
{0.062}
10.5–11.0
0.66
{0.061}
11.0–12.0
0.70
{0.056}
>12.0
0.71
{0.057}
VAS
Gen
eralpu
blic
UID
Haemog
lobinlevel(g/dL)
7.0–8.0
16.9{2.6}
8.0–9.0
22.3{3.0}
9.0–10.0
27.6{2.9}
10.0–10.5
32.9{3.4}
10.5–11.0
38.8{3.6}
11.0–12.0
45.9{4.2}
>12.0
51.2{4.3}
TTO
Cancerpatientswith
recent
expe
rienceof
chem
othe
rapy-related
anaemiaor
fatig
ue
UID
Haemog
lobinlevel(g/dL)
7.0–8.0
0.30
{0.127}
8.0–9.0
0.36
{0.126}
9.0–10.0
0.41
{0.125}
10.0–10.5
0.45
{0.122}
10.5–11.0
0.45
{0.111}
11.0–12.0
0.55
{0.105}
>12.0
0.61
{0.112}
UOwncurren
the
alth
0.85
{0.034}
EQ-5Dcurren
the
alth
0.87
{0.076}
VAS
Cancerpatientswith
recent
expe
rienceof
chem
othe
rapy-related
anaemiaor
fatig
ue
UID
Haemog
lobinlevel(g/dL)
7.0–8.0
21.7{5.7}
8.0–9.0
32.4{6.6}
9.0–10.0
34.2{6.7}
10.0–10.5
41.9{6.6}
10.5–11.0
44.7{6.6}
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 25 of 30
Table
4Disutilitiesandde
crem
entsforadverseeven
the
alth
states
inpatientswith
previouslytreatedmNSC
LC(Con
tinued)
Relevance
Autho
r,year,cou
ntry,
referencea
Instrumen
tand
respon
dent
Utility
type
Health
state/disutility
MeanHSU
V(SD)[SE]
{95%
CI}
HTA
suitability
11.0–12.0
52.2{6.8}
>12.0
62.4{7.9}
UOwncurren
the
alth
87.6{4.9}
EQ-5Dcurren
the
alth
84.2{4.57}
NR
Westw
ood2014,N
R[71]
NR
DAnaem
ia0.073[0.018]
Disutilitiesforanaemiaand
treatm
entmod
ehave
been
used
inprevious
NICE
subm
ission
s.How
ever,the
reisno
inform
ationconcerning
theirde
rivation.
2LNSC
LCOralthe
rapy
(ERL)
0.014[0.012]
2LNSC
LCi.v.the
rapy
0.043[0.020]
Patientswith
out
NSC
LC1Lsetting
Nafees2016,
Multin
ationaland
UK
[68]g
TTO
Patients(but
not
NSC
LCpatients)fro
mthege
neralp
ublic
inUK,Australia,France,
China,S.Korea,
Taiwan
DBleeding
vsBL
(stableno
side
effects)
−0.25
No
Hypertensionvs
BL(stableno
side
effects)
−0.03
UID
Respon
ding
+bleeding
vsBL
0.534
Respon
ding
+hype
rten
sion
vsBL
0.749
Stable+bleeding
vsBL
0.508
Stable+hype
rten
sion
vsBL
0.729
a Som
estud
iesiden
tifiedin
thissystem
aticreview
wereno
tinclud
edin
thistableforthefollowingreason
s:Grunb
erg20
09[58]
andGrutters20
10[44]
didno
trepo
rtvalues
bTh
eita
licsindicate
acalculated
utility.Thisiscalculated
from
thevalues
repo
rted
inDoy
le20
08[65]
Table3(differen
cebe
tweenstab
lediseaseno
othe
rsymptom
san
dstab
lediseasewith
coug
h,dy
spno
eaan
dpa
in,
toob
tain
thedisutility
).Itisno
tcalculated
byad
ding
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Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 26 of 30
because asking patients suffering such toxicities tocomplete HRQoL questionnaires was considered to betoo burdensome for patients and potentially unethical.Moreover, although the variation may be large, it helpsdecision makers to identify where variability exists andinforms the design of sensitivity analyses.In the 36 publications identified, 13 provided
HSUVs that meet the NICE reference case or areconsidered acceptable to the HTA agencies of interest[37–40, 42, 45, 46, 49, 53, 56, 58, 64, 69]. These weredeemed suitable because HRQoL was measured using theEQ-5D [37–40, 42, 45, 46, 49, 53, 56] or SG [58, 64, 69],both measures preferred or accepted by several HTA au-thorities. This endeavour fills an important gap in the fieldbecause hitherto, only two reports had described HSUVsin mNSCLC [68, 69]; neither was a systematic review ofthe literature, nor did they assess their appropriateness foruse in economic evaluations.This systematic review did not identify an HSUV
report based on data from the OAK trial(NCT02008227), because it was published as a congressabstract after the cut-off date for literature searching[76]. However, the HSUVs are relevant to the aims ofthis systematic review, and a brief description isprovided below for completeness. Patients with locallyadvanced NSCLC or mNSCLC after failure ofplatinum-containing chemotherapy were randomized ina phase 3 trial to receive atezolizumab or docetaxel [76,77]. As part of the trial, patients completed the EQ-5D,and the resultant HSUVs were presented by time pointbefore death. This study is similar to Huang et al. 2016,which also presented time-to-death EQ-5D utilities fora similar patient group receiving immunotherapy, ex-cept comparing pembrolizumab and docetaxel [45].Overall, HSUVs were very similar between studies atapproximately equivalent time points. In the OAKstudy, the following HSUVs were reported by timepoint before death: 0.77 (> 210 days), 0.71 (105–210 days), 0.61 (35–105 days) and 0.39 (< 35 days). Forcomparison, HSUVs published by Huang et al. 2016were 0.73 (180–360 days), 0.69 (90–180 days), 0.60(30–90 days) and 0.40 (< 30 days). A further studyevaluating the efficacy of immunotherapy in patientswith NSCLC showed that baseline mean EQ-VAS andEQ-5D index scores were similar for nivolumab (63.7and 0.68, respectively) and docetaxel (66.3 and 0.66,respectively) [50].Strengths of this systematic review include the wide
range of data sources searched and the search stringdesign, which enabled identification of disutilities andutility decrements for a wide range of AEs and progres-sive disease states (e.g. common sites of metastasis fromlung cancer) of relevance to the experience of patientspreviously treated for mNSCLC. We have presented
HSUVs by line of treatment, allowing use in economicmodelling, and have discussed HSUVs likely to be ac-cepted by the HTA bodies of interest. Inadequate or in-consistent reporting is common, and low sample sizesand response rates considerably impact on the reportedconfidence intervals of the reported results. However,among the studies identified here, most reported samplesize (over 100 respondents in most cases), many pro-vided a measure of variability for the values reported,and several were based on response rates greater than80% (although response rates were unreported in morethan half of the studies). Moreover, the use of only pub-lished HSUVs can be a limitation, as HTA submissionsmay use HSUVs that have not been previously published.As part of this systematic review, we have thereforesearched HTA submissions for any relevant utilities;most HTAs use data reported by Nafees et al. [69]Limitations of this review include that the label for the
upper bound of the utility scale (e.g. “full health” or “per-fect health”) was not recorded. This has been shown tobe a significant predictor of utility in lung cancer [78],so variation in utilities due to a different upper boundlabel cannot be explored. A further limitation concernsdata extraction from some studies presented as congressabstracts or posters. Owing to the word restrictionsplaced on conference proceedings they may not be con-sidered a robust data source in comparison with fullpublications. Furthermore, both screening and dataextraction were conducted primarily by a single re-viewer, and only 50% of studies were checked by asecond reviewer. The exclusion of studies that usedmapping to derive EQ-5D and utility values is a fur-ther limitation of this study; however, sufficient dataobtained through direct measurement were identifiedto be informative.
ConclusionsThis systematic review begins to address the challengeof identifying reliable estimates of utility values inmNSCLC that are suitable for use in economic evalua-tions. Our work has also highlighted that these estimatesare vulnerable to variations in study type, tariff, healthstate and the measures used, and that shortcomings inreporting are common.
Additional files
Additional file 1: Table S1. Search strings. (DOCX 90 kb)
Additional file 2: Table S2. Listing of first-line mNSCLC studies withutility data excluded at second pass [80–100]. (DOCX 84 kb)
Additional file 3: Figure S1. Hierarchy of preferred methodology forgeneration of HSUVs for different HTA agencies. (PDF 1172 kb)
Additional file 4: Table S3. Quality assessment of identified studies.(DOCX 111 kb)
Paracha et al. Health and Quality of Life Outcomes (2018) 16:179 Page 27 of 30
AbbreviationsAE: Adverse event; AQoL: Assessment of Quality of Life instrument;CADTH: Canadian Agency for Drugs and Technologies in Health; HAS: HauteAutorité de Santé; HRQoL: Health-related quality of life; HSUV: Health stateutility value; HTA: Health technology assessment; mNSCLC: Metastatic non-small cell lung cancer; NICE: National Institute for Health and Care Excellence;NSCLC: Non-small cell lung cancer; PBAC: Australian Pharmaceutical BenefitsAdvisory Committee; PICOS: Patient, intervention, comparator, outcome,study; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; QALY: Quality-adjusted life-year; RECIST: Response EvaluationCriteria in Solid Tumors; SF-12/SF-36: 12-/36-item Short-Form Health Survey;SF-6D: 6-dimension Short-Form Health Survey; SG: Standard gamble;SMC: Scottish Medicines Consortium; TTO: Time trade-off; VAS: Visualanalogue scale
AcknowledgementsMedical writing support was provided by Christian Eichinger ofPharmaGenesis London, London, UK and was funded by Roche.
Availability of data and materialsNot applicable. The data presented in this systematic review are publishedand can be found in the cited original references.
DisclosuresNP is an employee of F. Hoffmann-La Roche. AA was an employee of F.Hoffman-La Roche at the time the study was conducted. KSM is anemployee of Epidemica Ltd.
Authors’ contributionsNP, AA and KSM carried out the conception and design, participated in thereview and critique process, drafted the manuscript, and revised it criticallyfor intellectual content. The systematic review was carried out by KSM fromEpidemica Ltd., UK and was funded by Roche. All authors read and approvedthe final manuscript.
Ethics approval and consent to participateNot applicable.
Consent for publicationNot applicable.
Competing interestsThe authors declare that they have no competing interests.
Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.
Author details1F. Hoffmann-La Roche AG, Basel, Switzerland. 2Epidemica Ltd, Bicester,Oxfordshire, UK. 3Present address: Digipharm, Zug, Switzerland.
Received: 8 February 2018 Accepted: 8 August 2018
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