REVIEW
Patient and Healthcare Provider Perspectives of First-Generation Somatostatin Analogs in the Managementof Neuroendocrine Tumors and Acromegaly:A Systematic Literature Review
David Cella . Jennifer Evans . Marion Feuilly . Sebastian Neggers .
Dirk Van Genechten . Jackie Herman . Mohid S. Khan
Received: October 22, 2020 / Accepted: December 5, 2020 / Published online: January 11, 2021� The Author(s) 2021
ABSTRACT
Introduction: Somatostatin analogs (SSAs) areused to treat neuroendocrine tumors (NETs) andacromegaly. Two first-generation SSAs, octreo-tide long-acting release (OCT LAR) and lan-reotide autogel/depot (LAN), are available. Asystematic literature review (SLR) was con-ducted to investigate which characteristicsbeyond efficacy are most important in patientand healthcare practitioner (HCP) experience of
LAN and OCT when used to treat acromegalyand NETs.Methods: MEDLINE, Embase, the CochraneLibrary, and Database of Abstracts of Reviews ofEffect were searched from database inception toJanuary 2019 with terms for first-generationSSAs, NETs, acromegaly, preferences, decision-making, and human factors. Key congresses in2016–2018 and SLR bibliographies were hand-searched. Two independent reviewers screenedarticles at title/abstract and full-text stage.Publications fulfilling pre-specified inclusioncriteria reported patient or HCP perspectives ofLAN or OCT, or any factors affecting treatmentperspectives for NETs or acromegaly.Results: A total of 1110 unique records werescreened, of which 21 studies were included,reporting from the perspectives of patients(n = 18) and/or HCPs (n = 9). Perspectives were
Marion Feuilly was an employee of Ipsen at the time ofthese analyses.
Supplementary Information The online versioncontains supplementary material available at https://doi.org/10.1007/s12325-020-01600-x.
D. Cella (&)Department of Medical Social Sciences,Northwestern University Feinberg School ofMedicine, Chicago, IL, USAe-mail: [email protected]
J. EvansCostello Medical, Cambridge, UK
M. FeuillyIpsen Pharma, Boulogne Billancourt, France
S. NeggersDepartment of Medicine, Section Endocrinology,Erasmus University Medical Center, Rotterdam, TheNetherlands
D. Van GenechtenBelgian Neuroendocrine Tumour (NET) andMultiple Endocrine Neoplasia (MEN) Association,Blankenberge, Belgium
D. Van GenechtenInternational Neuroendocrine Cancer Alliance(INCA), Boston, MA, USA
J. HermanCanadian Neuroendocrine Tumour Society,Cornwall, ON, Canada
M. S. KhanUniversity Hospital of Wales, Cardiff, UK
Adv Ther (2021) 38:969–993
https://doi.org/10.1007/s12325-020-01600-x
collected using shared decision-making frame-works, questionnaires, informal patient opin-ion, and a Delphi panel. Where patientpreference was specifically reported, LAN waspreferred in 4/5 studies and OCT LAR in 1/5.Common factors underlying treatment experi-ence included technical problems with injec-tions and associated pain, emotional quality/anxiety of injections, time and convenience oftreatment administration, and independence.Immediate aspects of injections appeared mostimportant to patients, though the possibilitiesof extended dosing intervals and self-/partner-injection with LAN were also notable factors.Conclusions: Study outcomes favored LAN inthis SLR, with factors surrounding injectionadministration most influential in treatmentexperience. The findings of this SLR provide abasis that could inform development of deci-sion-making criteria, with patient and HCPtreatment perspectives considered. Future stud-ies should utilize a common method to reportpreference and associated drivers.
Keywords: Acromegaly; Neuroendocrinetumors; Preference; Somatostatin analogs;Treatment perspectives
Key Summary Points
Why carry out this study?
This manuscript reports the findings of asystematic literature review (SLR) toinvestigate which characteristics of first-generation somatostatin analogs (SSAs),beyond efficacy, are most important frompatient and healthcare practitioner (HCP)perspectives, when used to treatacromegaly and neuroendocrine tumors.
What was learned from the study?
A total of 26 publications reporting on 21studies were included in this SLR,reporting from the perspectives of patients(n = 18) and HCPs (n = 9), using shareddecision-making frameworks,questionnaires, informal patient opinion,and a Delphi panel.
Common factors underlying treatmentexperience with long-acting lanreotideand octreotide included technicalproblems with injections and associatedpain, emotional quality/anxiety ofinjections, time and convenience oftreatment administration, and patientindependence; immediate aspects ofinjection administration appeared mostimportant to patients.
Where study participants had directexperience of both SSAs, four of the fivestudies reporting patient preference, andthe only study reporting preference ofHCPs, reported preference for lanreotideautogel over octreotide long-actingrelease.
DIGITAL FEATURES
This article is published with digital features,including a summary slide, to facilitate under-standing of the article. To view digital featuresfor this article go to https://doi.org/10.6084/m9.figshare.13333565.
INTRODUCTION
Long-acting somatostatin analogs (SSAs) areused to treat neuroendocrine tumors (NETs)with and without features of carcinoid syn-drome (CS), the latter resulting from thehypersecretion of serotonin and other vasoac-tive substances from NETs [1–3]. The EuropeanNeuroendocrine Tumor Society (ENETS) andNational Comprehensive Cancer Network(NCCN) guidelines recommend SSAs as first-linesystemic therapy for unresectable and/or meta-static gastroenteropancreatic neuroendocrinetumors (GEP-NETs) following surgery [4, 5].SSAs are also indicated as primary and adjuvanttreatment for acromegaly, a disorder resultingfrom the overproduction of growth hormonefrom adenomas, for patients who are unable toundergo surgery, are not cured by surgery, orotherwise require medical treatment [6–8]. The
970 Adv Ther (2021) 38:969–993
clinical efficacy and safety of the two first-gen-eration SSAs lanreotide autogel/depot (LAN)and octreotide long-acting release (OCT LAR)has been previously demonstrated; both SSAshave been shown to decrease growth hormoneand insulin-like growth factor 1 levels inpatients with acromegaly [9–13], as well as tocontribute to progression-free survival inpatients with NETs [14–19].
LAN is approved in countries including Eur-ope and the USA for long-term treatment ofacromegaly, treatment of gastrointestinal (GI)NETs and pancreatic NETs, and of symptomsassociated with NETs (EU only) [8, 18]. In Eur-ope, LAN is also indicated for NETs of unknownorigin and NETs with a Ki-67 index of up to 10%[8]. LAN is supplied in a pre-filled syringe,administered by deep subcutaneous injectiononce every 4 weeks [20, 21]. Additionally,extended dosing intervals (EDIs) are availablefor patients with acromegaly when symptomcontrol is stable [18], and this ready-to-use for-mulation allows for the possibility of self-in-jection by patients with NETs and acromegalyin most geographies (self-injection not yetapproved in the USA) [8, 18].
OCT LAR is indicated for long-term treat-ment of acromegaly in Europe and the USA[19, 22]. OCT LAR is also approved in Europe forsymptom and tumor control in GI NETs or NETsof unknown primary origin, and in the USA it isapproved for the treatment of symptoms inmetastatic carcinoid tumors [19, 22]. A short-acting OCT daily subcutaneous injection for-mulation was previously used in long-termtreatment of acromegaly and GEP-NETs [23],though this is now mainly used for prophylaxisof carcinoid crises prior to surgeries, or as rescuetreatment in the case of acute symptoms. OCTLAR is provided as a powder that requiresreconstitution in a solvent by a healthcarepractitioner (HCP) before intramuscular injec-tion [19, 22].
Despite their therapeutic benefits and wideuse in clinical practice over the last two decades,understanding of which SSA product charac-teristics beyond efficacy and safety impact thetreatment experience of patients and HCPs iscurrently limited. The objective of this SLR wasto identify treatment characteristics that
influence patient and HCP experience of LANand OCT LAR when used to treat acromegalyand NETs. As such, this SLR sought to determinedistinguishing factors between the two SSAsthat could be considered in treatment decision-making.
METHODS
Search Strategy
Databases including MEDLINE, Embase, theCochrane Database of Systematic Reviews, theDatabase of Abstracts of Reviews of Effect, andthe Cochrane Central Register of ControlledTrials were searched from database inception to11 January 2019 using terms for SSAs, NETs oracromegaly, preferences, decision-making, andhuman factors (a full list of search terms can befound in Tables S1–S4). Terms were decidedthrough consultation with independent expertsin SLR design and development. Congressesthat had taken place in 2016–2018 includingthe North American Neuroendocrine TumorSociety, European Neuroendocrine TumourSociety, European Congress of Endocrinology,Pituitary Society International Congress, andUK and Ireland Neuroendocrine Tumour Soci-ety were hand-searched for further evidenceusing the search terms based on those used inthe electronic databases, and strategies werebased on the search functions of the individualconferences. Bibliographies of relevant SLRswere also hand-searched.
Study Selection and Data Extraction
Abstracts and full texts eligible for inclusion inthis SLR must have been published in Englishand reported data pertaining to adult patientswith NETs or acromegaly receiving treatmentwith long-acting formulations of LAN or OCT,or to their HCPs. Studies reported informationregarding treatment experience or SSA prefer-ence, including but not limited to opinion ofsafety, efficacy, direct costs; indirect costs; non-utility quantitative measures; and qualitativefindings in interviews or focus groups. Full
Adv Ther (2021) 38:969–993 971
eligibility criteria are detailed in Table S5. Twoindependent reviewers screened records forinclusion using the pre-specified criteria at thetitle/abstract stage and full-text stage, and anydiscrepancies were resolved by discussion untila consensus was met. If necessary, a thirdreviewer made the final decision. Where theapplicability of the inclusion criteria wasunclear, articles were included at the abstractstage to ensure that all potentially relevantstudies were captured. Articles of unclear rele-vance could then be excluded at the full-textstage to ensure that only relevant articles wereultimately included. Relevant data pertaining tostudy design, location, date and duration,treatment arms, funding, study aims and eligi-bility criteria, interventions, and results fromthe included studies were extracted into pre-specified Microsoft Word extraction grids.
Quality Assessment
The quality of the included studies was assessedusing the Purpose, Respondents, Explanation,Findings, Significance (PREFS) checklist, a toolspecifically designed to assess the quality ofpreference studies [24]. The quality of eachstudy was assessed by a single individual, withthe conclusions regarding quality confirmedindependently by a second individual; any dis-crepancies were discussed, and final decisionswere made by a third individual wherenecessary.
Compliance with Ethics Guidelines
This article is based on previously conductedstudies and does not contain any new studieswith human participants or animals performedby any of the authors.
RESULTS
Study Selection
A total of 1110 records from database searchesand 990 records from congresses and SLR bibli-ographies were screened. In total, 26
publications reporting on 21 unique studieswere included in this SLR (Fig. 1).
Study Characteristics
Of the 21 included studies, 10 reported on thetreatment of NETs [25–33], 10 reported thetreatment of acromegaly [34–43], and onereported both [44]. The included studies wereconducted using a range of study designs, mostcommonly including open-label trials[25, 27, 34, 37], and prospective observationalstudies [25, 31, 39, 43] among others (Table 1).Group comparison studies compared experi-ence between patients on parallel treatmentarms [25, 26, 28, 29, 31, 32, 36, 41–44] whereascrossover studies reported the experience ofpatients who switched from one SSA to theother [34, 35, 37, 38, 40]. Patients switchedfrom OCT LAR to LAN treatment in all crossoverstudies. Most studies (n = 19) were conducted inthe USA and/or Europe (Table 1).
All but one of the studies included LAN[25–44]; 17 compared LAN with OCT[25, 26, 28, 29, 31–38, 40–42, 44], four studiesinvestigated different formulations or adminis-tration methods of LAN exclusively[30, 33, 39, 43], and a single study exclusivelyinvestigated different formulations of OCT [27].Most studies did not specifically aim to inves-tigate patient or HCP perspectives of SSA treat-ments; efficacy and tolerability of treatmentwere often the primary outcomes in these cases,and treatment perspective was collected as asecondary or exploratory outcome. The major-ity of studies (n = 12) used structured ques-tionnaires or surveys to elicit patient or HCPtreatment perspectives or preference[25, 26, 28, 30, 31, 36, 38–41, 43, 44], thoughthese were not validated instruments, andinformal patient questioning was also a com-mon approach (n = 5 ) [27, 34, 35, 37, 42].Methods less frequently employed included useof a patient–clinician shared decision-makingframework [29, 33], and a Delphi panel [32]. Assuch, where preference was not explicitlyreported, the independent investigatorsreviewing the studies in this SLR assessed thestatistical and numerical comparisons presented
972 Adv Ther (2021) 38:969–993
in each study. These comparisons were used todetermine which, if any, of the two treatmentswas associated with the more favorable out-come, such as lowest level of anxiety or fewesttechnical problems, for example. Includingpreference, nine key outcomes in treatmentexperience were identified (Table 2). Here, wefocus on studies in which respondents haddirect experience of SSA treatment (rather thananticipated preference) and where statistical ornumerical comparisons were provided (ratherthan qualitative comparisons).
Treatment-Specific Preference
Of the 21 studies included in this SLR, fivecrossover studies explicitly reported the prefer-ences of patients who had direct experience ofboth LAN and OCT LAR treatment (Table 3)
[34, 35, 37, 39, 40]. LAN was preferred in four ofthe five studies that reported patient preferenceas an outcome [34, 37, 39, 40]. All crossoverstudies included patients who switched fromOCT LAR to LAN with the standard 28-daydosing interval for each treatment.
Salvatori et al. reported that 81.3% ofpatients preferred LAN in comparison with12.5% for OCT LAR (n = 33, p = 0.0001), basedon a structured questionnaire, though reasonsfor preference were not reported [38]. Alex-opoulou et al. reported that 17/25 (68%)patients with acromegaly chose LAN by infor-mal opinion, whereas 2/25 (8%) preferred OCTLAR; 6/25 (24%) patients did not report treat-ment preference [34]. Reduced pain at theinjection site and fewer technical problemsfollowing LAN injection were deemed byinvestigators in this study to influence patientchoice [34].
Fig. 1 PRISMA diagram for included studies. CDSRCochrane Database of Systematic Reviews, CENTRALCochrane Central Register of Controlled Trials, DAREDatabase of Abstracts of Reviews of Effects, HCPs
healthcare practitioners, NETs neuroendocrine tumors,PRISMA Preferred Reporting Items for SystematicReviews and Meta-Analyses
Adv Ther (2021) 38:969–993 973
Table1
Characteristics
ofthe21
studiesincluded
intheSL
R
Stud
yDesign
Dateof
stud
yLocation
Stud
ydu
ration
Stud
ypo
pulation
Stud
yarms
Stud
yfund
ing
Adamset
al.
2018
[25]
Prospective,
observational
cohortstudy
NR
USA
12weeks
120patientsenrolledvia
theCarcinoid
Cancer
Foun
dation,o
fwhom
82completed
all
assessments
OCT
LAR
LAN
depot
Ipsen
Adelman
etal.2
012
[44]
Multicenter
opinionstudy
2010
France,G
ermany,
UK,U
SA
NR
77registered
nurses,o
f
whom
61/77(79%
)
and33/77(43%
)
injected
patientswith
acromegalyandGEP-
NETs,respectively
OCT
LAR
LAN
autogel/
depot,delivered
usinganew
syringe
Ipsen
Alexopoulou
etal.2
004
[34]
Prospective,
open-label,
crossover,
within-subject
controlled
study
NR
Belgium
24weeks
25patientswith
acromegalywho
had
previouslybeen
treated
withOCT
forC
6months,allof
whom
completed
the
study
Patientswho
previously
received
OCT
LARwere
switched
to
LAN
autogel
NR
Almquist
etal.2
017
[26]
Cross-section
al
study
NR
Sweden
NR
156patientswithGEP-
NETsidentifiedfrom
hospitaldatabases,of
whom
119(76%
)
returned
avalid
questionnaire
OCT
LAR
LAN
autogel
NR
974 Adv Ther (2021) 38:969–993
Table1
continued
Stud
yDesign
Dateof
stud
yLocation
Stud
ydu
ration
Stud
ypo
pulation
Stud
yarms
Stud
yfund
ing
And
ries
etal.
2008
[35]
Randomized
crossovertrial
2002–2
003
Denmark
12months
12patientswith
acromegalywere
included
from
the
outpatient
clinicof
OdenseUniversity
Hospital,of
whom
10
completed
thestudy
OCT
LAR
LAN
autogel
Ipsen
Apaydin
etal.
2017
[36]
NR
Novem
berand
Decem
ber
2015
Turkey
6weeks
528endocrinologistsin
Turkey,of
whom
196
(37.4%
)answered
the
questionnaire
LAN
autogel
OCT
LAR
Cabergolin
e
Pegvisom
ant
Pasireotide
None
Garland
etal.
2003
[27]
Retrospective
cohortstudy
NR
UK
3years
27patientswith
carcinoidsynd
rome
andbiopsy-confirmed
metastaticcarcinoid
tumor
OCT
LAR
NR
Geilvoetetal.
2017
[28]
NR
NR
Netherlands
NR
51patientswithNETs
usingdepotSSA
anda
homeinjectionservice
forC
3months
OCT
LAR
LAN
autogel
NR
Goetghebeur
etal.2
017
[29]
Multicriteria
decision
analysis
March
2016
NR
NR
5patientswithGEP-
NETsand6physicians
LAN
autogel
OCT
LAR
Watch
andwait
Ipsen
Adv Ther (2021) 38:969–993 975
Table1
continued
Stud
yDesign
Dateof
stud
yLocation
Stud
ydu
ration
Stud
ypo
pulation
Stud
yarms
Stud
yfund
ing
Johanson
etal.2
012
[30]
Randomized,
open-label
crossovertrial
June
2008
to
Janu
ary2010
(recruitment
period)
Sweden,N
orway,
Denmark
34weeks
62patientswithNETs,
ofwhom
26were
included
inthestudy
LAN
autogel,
HCP-
administered
LAN
autogel,
self/partner-
administered
Ipsen
Neggerset
al.
2015
[37]
Open-label,
crossover,
non-
comparative
trial
6October
2008
to
20May
2013
Brazil,Denmark,
Finland,
France,
Greece,Latvia,
Netherlands,
Norway,P
oland,
Rom
ania,R
ussia,
Serbia,S
outh
Korea,and
Sweden
48weeks
(29
24-
week
phases)
124patientswith
acromegalywho
previouslyreceived
OCT
LARentered
phase1;
109of
these
patientsentered
phase2,
ofwhom
107
completed
thestudy
Patientswho
previously
received
OCT
LARwere
switched
to
LAN
autogel,
somewith
extend
ed-
dosing
intervals
Ipsen
Ryanet
al.
2018
[31]
Prospective
observational
timeand
motionstudy
NR
USA
NR
44patientswithGEP-
NETsandtheirHCPs
LAN
depot
OCT
LAR
Ipsen
976 Adv Ther (2021) 38:969–993
Table1
continued
Stud
yDesign
Dateof
stud
yLocation
Stud
ydu
ration
Stud
ypo
pulation
Stud
yarms
Stud
yfund
ing
Salvatori
etal.2
010
[38]
Single-arm
,
open-label
crossover
study
June
2007
to
May
2008
USA
6months
59patientswith
acromegalyenrolledvia
oneof
13centersin
the
USA
[33patients
switched
directlyfrom
OCT
(‘‘switch
patients’’);26
patients
wereSSA
treatm
ent
naıveor
notcurrently
receivingOCT
(‘‘other
patients’’)]
LAN
depot
IpsenPh
arma(via
subsidiary)
Salvatori
etal.2
014
[39]
Prospective
cohortstudy
May
2008
to
April2012
(datacutoff)
USA
NR
166patientswith
acromegalyrecruited
from
academ
iccenters
andprivatepractice
sitesacross22
states
in
theUSA
LAN
depot
Ipsen
Biopharmaceuticals
Schopohl
etal.2
011
[40]
Single-arm
,
open-label
crossover
study
Janu
ary2005
toJuly2007
Germany
NR
37patientswith
acromegalyrecruited
from
13centersin
Germanywho
had
previouslyreceived
OCT
LAR
forC
6months,of
whom
33completed
thestudy
Patientswho
previously
received
OCT
LARwere
switched
to
LAN
autogel
IpsenPh
arma
Adv Ther (2021) 38:969–993 977
Table1
continued
Stud
yDesign
Dateof
stud
yLocation
Stud
ydu
ration
Stud
ypo
pulation
Stud
yarms
Stud
yfund
ing
Sevilla
etal.
2016
[32]
Delphipanel
October
to
Novem
ber
2015
Spain
NA
65oncologistswith
experience
inthe
managem
entof
NETs
answered
thefirst
roun
d;57
ofthe65
answered
thesecond
roun
d
LAN
autogel
OCT
LAR
IpsenPh
arma
Strasburger
etal.2
016
[41]
Observational
survey
Novem
ber
2012
toJune
2013
Germany,UK,
Netherlands
NR
195patientswith
acromegalydistributed
betweenfivesitesin
Germany(n
=102),
threesitesin
theUK
(n=70),andonesite
intheNetherlands
(n=23)
LAN
autogel
OCT
LAR
Chiasma
Verhelst
etal.
2000
[42]
Prospective,
open-label
study
NR
Belgium
,Italy
48weeks
66patientswithactive
acromegalyfrom
eight
centersin
Belgium
(n=37)andone
centerin
Italy(n
=29)
LAN
microsphere
NR
Wagneret
al.
2018a[33]
Decision
support
workshop
NR
Spain
NR
Five
patientswithNETs
recruitedfrom
patient
associations
andsix
clinicians
from
differentregionsof
Spain
LAN
autogel
Watch
andwait
IpsenPh
arma
978 Adv Ther (2021) 38:969–993
Table1
continued
Stud
yDesign
Dateof
stud
yLocation
Stud
ydu
ration
Stud
ypo
pulation
Stud
yarms
Stud
yfund
ing
Wagneret
al.
2018b[33]
Decision
support
workshop
NR
USA
NR
Sixclinicians
specializing
intreating
NETsand
fivepatientswith
NETsrecruitedfrom
patientassociations
and
supportgroups
LAN
autogel
OCT
LAR
Watch
andwait
IpsenPh
arma
Witek
etal.
2016
[43]
Prospective,
observational,
multicenter,
patient-
reported
outcom
e
study
2012
Poland
*12
months
113patientswith
acromegaly,of
whom
102completed
the
study,plus
50
investigators.
RecruitmentNR
LAN
autogel
OCT
LAR
IpsenPo
land
and
Novartis
GEPgastroenteropancreatic,HCPhealthcare
practitioner,LAN
lanreotide,LARlong-actingrelease,NAnotapplicable,N
Dnewdevice,N
ETsneuroend
ocrine
tumors,NRnotreported,O
CToctreotide,S
SAsomatostatinanalog
Adv Ther (2021) 38:969–993 979
Neggers et al. included three study arms,whereby patients with acromegaly were swit-ched from OCT LAR 4-week dosing interval toLAN with either a 4-week dosing interval or a 6-or 8-week extended dosing interval (EDI) [37].LAN was preferred over OCT LAR in all treat-ment regimens. At week 48, 53/68 (77.9%)patients in the 6-week EDI group preferred LAN,vs 10/68 (14.7%) who preferred OCT LAR; and24/26 (92.3%) patients in the 8-week EDI grouppreferred LAN, vs 2/26 who preferred the OCTLAR 4-week interval [37]. Although this study
sought to investigate the impact of EDIs ontreatment preference, notably, 10/13 (76.9%)patients chose LAN when administered with thesame 4-week dosing interval used for their pre-vious OCT LAR treatment; just 2/13 (15.3%)patients chose OCT LAR and 1/13 (7.7%) had nopreference (reasons for preference were notreported) [37]. Schopohl et al. conducted asimilar study in which patients with acromegaly(n = 33) switched from OCT LAR with standarddosing interval to LAN with standard dosinginterval and EDI groups [40]. Preference for LAN
Table 2 Key outcomes relating to patient treatment experience
Outcome Number of studies Number ofpatients
Favored SSAb
Patient preference 5 (all switch)a 10–112 LAN (9 4)
[34, 37, 39, 40]
OCT LAR (9 1) [35]
Anxiety/‘‘emotional quality’’ of
injections
2 (group comparisons) 119–120 LAN (9 2) [25, 26]
Technical problems with injections 4 (2 switch, 2 group
comparisons)
25–119 LAN (9 4)
[26, 28, 34, 43]
Satisfaction/‘‘expectations met’’ 2 (group comparisons) 44–102 LAN (9 1) [43]
NP (9 1) [31]
Time associated with injections 2 (group comparisons) 44–51 LAN (9 1) [28]
NP (9 1) [31]
Injection-associated pain 3 (2 switch, 1 group
comparison)
33–195 LAN (9 3) [34, 38, 41]
Convenience of injections 2 (1 switch, 1 group
comparison)
33–119 LAN (9 2) [26, 38]
Perceived effectiveness 1 (switch) 102 LAN [43]
Indirect costs 1 (switch) 26 LAN [30]
LAN lanreotide autogel/depot, NP no preference/favored SSA, OCT LAR octreotide long-acting release, SSA somatostatinanaloga Switch refers to studies where patients had direct experience with both LAN and OCT, having switched from onetreatment to the other either prior to or during the studyb Aside from preference, the favored SSA was determined by the independent reviewers on the basis of the data includedwithin each study. Where statistical comparisons were performed and found to be non-significant, this was reported as NP;a favored SSA was determined on the basis of numerical comparisons in studies where statistical analyses were notperformed
980 Adv Ther (2021) 38:969–993
Table 3 Treatment specific preference outcomes
Adv Ther (2021) 38:969–993 981
Table 3 continued
EDI extended dosing interval, GEP gastroenteropancreatic, HCP healthcare practitioner, ITT intention-to-treat, LANlanreotide, LAR long-acting release, NETs neuroendocrine tumors, NR not reported, OCT octreotide, SSA somatostatinanalog
982 Adv Ther (2021) 38:969–993
was higher overall; LAN was preferred in boththe 6- and 8-week EDI groups compared withOCT LAR (63.6% vs 18.2%, and 57.1% vs 28.6%,respectively) [40]. However, preference washigher for OCT LAR over the standard LAN4-week dosing interval group (41.2% vs 11.8%)[40].
OCT LAR was preferred overall in one cross-over study, where 6/10 patients with acrome-galy cited fewer adverse effects (such as nodulesat the administration site) and greater perceivedefficacy compared with LAN [35].
Just two studies specifically reported HCPpreferences (Table 3) [36, 44]. A multicenteropinion study in patients with NETs or acro-megaly reported HCP preference when HCPshad experience administering both SSAs [44].LAN was preferred in this study because of theattributes of a LAN injection syringe over OCTLAR, such as faster and smoother administra-tion with lower risk of needle clogging, as wellas the option for patients to self-inject usingthis syringe [44]. Though direct experience witheither SSA was unclear, in one study whereendocrinologists (n = 196) completed an onlinesurvey, HCPs reported preference for OCT LAR(47.1%; n = 92) over LAN (32.2%; n = 63) astheir postoperative adjunctive medical therapyof choice, deemed by the study’s authors to bebased on the longer period of market autho-rization of OCT LAR compared with LAN,although this varies between continents [36].
Proximal Factors in Treatment Experience
Outcomes commonly emerging as aspects thatinfluence preference or treatment experiencemay be divided into proximal and distal factors.Proximal factors refer to the practicalities andimmediate aspects of treatment, such as thosesurrounding method of administration, whiledistal factors are more conceptual and includeemotional aspects of treatment experience, andpreference itself.
Injection-Associated PainInjection-associated pain was reported as anoutcome in three studies [34, 38, 41], all ofwhich reported LAN as the favored treatment as
a result of less injection-associated pain com-pared with OCT LAR injections. Of 33 patientswith acromegaly who switched from OCT LARto LAN treatment in the Salvatori et al. study,more patients reported that LAN injection wasnot painful at week 24 vs the OCT injection atweek 0 (the final OCT injection prior toswitching), compared using a McNemar’s test(50.0% vs 25.0% of patients, respectively;p = 0.0201) [38]. Among those who did reportpain, patients described the LAN and OCT LARinjections as ‘‘somewhat painful’’ (43.8% vs59.4%; p = NR), ‘‘moderately painful’’ (6.3% vs6.3%; p = NR), or ‘‘very painful’’ (0.0% vs 9.4%;p = NR) [38].
One group comparison study found thatpatients with acromegaly (n = 83 prescribedLAN; n = 112 prescribed OCT LAR) consideredthe overall injection burden to be similar for thetwo treatments [41]. The authors found smallbut statistically significant differences in painand other injection site reactions; OCT LARinjections were associated with slightly greaterpain at the injection site hours and days afterthe injection (hours mean score [scale 0–3], 0.7vs 0.6 for LAN, p = 0.05; days mean score [scale0–3], 0.5 vs 0.3 for LAN, p = 0.0007). However,LAN injections were associated with the devel-opment of nodules, swelling, bruising, anddermatitis (mean score [scale 0–3], 0.8 vs 0.5 forOCT, p = 0.0008) [41]. In one crossover studyalso in acromegaly, patients reported signifi-cantly superior immediate local tolerability atthe injection site with LAN injections comparedwith OCT LAR [34]; 76% (n = 19) of patientsreported mild-to-moderate pain at the injectionsite with OCT LAR, vs 12% (n = 3) reportinglocal pain after LAN injection.
Technical Problems with InjectingTechnical problems with injecting, such asneedle clogging and difficulty in completingdose administration, were reported as an out-come in four studies [26, 28, 34, 43]. LANinjections were favorable in all four studies,with markedly fewer technical problems repor-ted compared with OCT LAR injections. Alex-opoulou et al. reported results from 25 patientswith acromegaly who experienced treatmentwith LAN after switching from OCT LAR [34].
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Patients informally gave their opinion, with themajority recalling the occurrence of minor ormajor technical problems for at least one oftheir six most recent OCT LAR injections,despite injections being administered by expe-rienced paramedical staff (60/150 injectionsreported by 19 patients) [34]. By contrast, notechnical problems were reported during anyLAN injections (p\0.001) [34]. Geilvoet et al.carried out a survey designed for patients withNETs with satisfaction-related theorems with afive-point Likert scale, multiple choice, and freetext [28]. The survey revealed that 52% ofpatients treated with OCT LAR (n = 23) experi-enced injection problems, compared to 17% ofpatients treated with LAN (n = 28) [28].
Witek et al. used a crossover study forpatients with acromegaly to assess technicalproblems related to treatment administration[43]. Measured by a visual analog scale (VAS),whereby ‘‘no technical problems’’ was coded as0, and ‘‘technical problems’’ was coded as 100,patients (n = 102) reported fewer technicalproblems related to the administration of LAN(final mean VAS 5.3) compared with OCT LAR(mean VAS 37.6) [43]. Almquist et al. used asurvey questionnaire to assess recent SSA injec-tion experiences of patients with GEP-NETs,including technical problems with injecting[26]. Twelve out of 66 (18%) patients treatedwith OCT LAR reported problems with theirmost recent injection, whereas none of the 53patients receiving LAN treatment reported anyproblems with their most recent injection(p = 0.001) [26]. From the HCP perspective,HCPs in one time and motion study involvedwith treatment administration indicated con-cerns over OCT LAR, due to longer time toprepare as well as increased risk of needle clog-ging (p = 0.034) and device failures (p = 0.057)[31].
Distal Factors in Treatment Experience
Anxiety/‘‘Emotional Factors’’Emotional factors were a notable outcomereported among patients when examining SSAtreatment perspectives. Two studies were iden-tified reporting such outcomes, both of which
reported group comparisons, with patientsexperiencing either LAN or OCT LAR treatment;both studies favored LAN [25, 26]. Adams et al.asked 120 patients to grade the ‘‘emotionalquality’’ of their injection experience, whereLAN injections were significantly associatedwith a positive injection experience vs OCT LARinjections (p\0.001) [25]. The questionnaireused by Almquist et al. also assessed levels ofanxiety prior to injection [26]. Fewer patientsreported moderate-to-high anxiety with LANinjections vs OCT LAR (2% vs 11%, n = 119;p = NR) [26].
Satisfaction/‘‘Expectations Met’’One time and motion study reported statisticalcomparisons for satisfaction between LAN andOCT LAR in terms of treatment delivery attri-butes from the perspective of both patients andHCPs [31]. Of the 22 patients included for eachtreatment arm, 20 (90.9%) patients treated withLAN reported that all or most of their expecta-tions had been met compared with 18 (81.8%)patients treated with OCT LAR (p = 0.25) [31].HCPs involved in preparing and delivering SSAsindicated significantly higher satisfaction withLAN vs OCT LAR (median satisfaction score 5 vs4, p = 0.006) [31].
ConvenienceThree studies reported statistical comparisonsbetween LAN and OCT regarding the time takenfor treatment administration and patient wait-ing time in the clinic prior to their injection[28, 31, 44]. Geilvoet et al. concluded from apatient survey that visits by nurses administer-ing LAN (n = 28) were significantly shorter thanfor OCT LAR (n = 23; p = 0.048) [28]. Ryan et al.,using a time and motion study comparingtreatment delivery attributes between SSAs,reported that patient waiting times (from cliniccheck-in to check-out) were similar for LAN andOCT LAR. The median total waiting time pervisit was 6.2 min shorter for patients receivingLAN than for those receiving OCT LAR(25.0 min vs 31.2 min, respectively), thoughthis comparison did not reach statistical signif-icance (p = 0.734; n = 43) [31].
984 Adv Ther (2021) 38:969–993
From the HCP perspective, Ryan et al. alsoreported that there was a mean reduction of3.7 min of treatment delivery time in favor ofLAN (2.5 [95% confidence interval (CI)2.0–3.1] min) vs OCT LAR (6.2 [95% CI4.4–7.9] min, p = 0.001) [31]. In an opinionstudy where syringe attributes were rated by 77nurses via a questionnaire, Adelman et al. foundthat injection preparation and administrationtime were significantly shorter with the LANsyringe than OCT LAR (p\0.01) [44]. Thisstudy also reported a significant difference inmean score for ease/convenience of preparationand injection, ranked among the most impor-tant attributes by 70% of nurses, for the LANsyringe (rated 9.4/10) and OCT LAR (rated 3.8/10, p\0.05) [44]. In another study, comparingHCP-administered injections with LAN vs OCTLAR, LAN injections were judged by the studyinvestigators to be ‘‘much easier’’ or ‘‘easier’’ for57.1% of 37 patients, ‘‘the same’’ for 17.1%,‘‘more difficult’’ for 22.9%, and ‘‘much moredifficult’’ for 0.0% [40]. The most frequentlycited reasons for investigator preference for LANwere ease of injection (51.4%), being time-sav-ing (45.7%) and patient preference (45.7%) [40].
EDIsFour studies reported that patients with acro-megaly indicated a greater preference for longerdosing intervals vs shorter intervals[27, 37, 40, 42]. In two studies in patients withacromegaly initially treated with OCT LAR(dosing interval of 28 days) who then switchedto LAN (42- or 56-day intervals), over 55% ofpatients in both studies expressed a preferencefor the EDIs of LAN (numerical comparisonsonly) [37, 40]. However, one of these studiesalso reported that a higher proportion ofpatients demonstrated a preference for a LANdosing interval of 42 days compared with56 days (63.6% vs 57.1%), although no statisti-cal comparisons were performed [40]. Thepreference for the 56-day interval was higherwhen investigator preference was also takeninto account [40]. The remaining two olderstudies compared short-acting with long-actingformulations; one study included patientsswitching from daily subcutaneous octreotideinjections to monthly intramuscular octreotide
LAR [27], and the other included patientsswitching from daily subcutaneous octreotideinjections to a lanreotide sustained releasemicrosphere formulation, administered byintramuscular injection every 7–14 days [42].The longer-acting formulations with longerintervals between doses were preferred in bothstudies [27, 42].
Self-/Partner-Injectable Treatment with LANSelf- or partner-injection with LAN was investi-gated in two studies in patients with acrome-galy and one in NETs [30, 38, 39]. Self- orpartner-injectable treatment was generallyfavored compared with attending a medical siteor receiving LAN injections administered byHCPs. Johanson et al. reported that reasonspertained to increased independence and con-venience, especially for patients living inremote locations. Indirect costs associated withSSA treatments for patients or their caregiverswere also estimated on the basis ofpatient/partner time for travel and injection;one HCP-administered LAN injection was esti-mated to cost €7.95, while one self-injectionwas estimated to cost €0.10, on account ofpatients not having to travel or take time offwork to be treated [30].
Quality Assessment
A quality assessment was conducted for eachstudy using the PREFs checklist (Table 4) [24].Just one of the included studies sufficientlyanswered all domains of the checklist [44], andsix studies answered four out of the fivedomains [29, 31, 33, 41, 43, 45], most com-monly not including statistical comparisons[29, 33, 43, 45]. Most of the included studies didnot explicitly aim to investigate SSA preferenceand, as such, purpose in relation to preferencesand significance was not a strong domain acrossstudies. Methods of assessment in the context oftreatment experience and preferences werereported inconsistently; some studies specifi-cally stated their assessments as part of theirmethodology, while several did not, or assess-ment methods were unclear. Statistical com-parisons were used to assess differences between
Adv Ther (2021) 38:969–993 985
the SSAs in only 8/21 studies, with the majorityof studies making numerical comparisons. Aminority of studies explicitly reported prefer-ence between SSAs, and the remainder often didnot report sufficient information relevant toSSA treatment experience to clearly determinewhich SSA was favored.
DISCUSSION
This SLR aimed to identify relevant evidencedescribing treatment characteristics that impactpatient and HCP experience of long-acting,first-generation SSAs in the treatment of NETsor acromegaly. The 21 included studies hadvaried scopes and used a wide range of quanti-tative and qualitative designs, leading to con-siderable heterogeneity across the reportedresults. Within these studies, factors identifiedto potentially impact treatment experienceincluded ease of administration and fewerproblems with injecting [26, 28, 35], less pain atthe injection site [34, 38], and emotional expe-rience, or less anxiety, associated with injecting[25, 26]. It is perhaps likely that these factors arelinked. For example, more problems withinjecting may cause pain at the injection sitedue to re-injection, and more pain could lead toincreased anxiety when injecting.
Several factors surrounding mode of admin-istration were identified as contributors to SSAtreatment experience, indicating that comfort,convenience, and independence may also be ofparticular importance in the management ofdisease and treatment, especially amongpatients. However, a large proportion ofpatients who participated in the studies inclu-ded in this SLR were prescribed LAN at thestandard 4-week interval, and their injectionswere administered by HCPs; notably, threestudies reported patient preference for LAN overOCT LAR when patients were receiving HCPinjections at the same dosing interval[34, 37, 39]. It is therefore likely that the prox-imal factors surrounding injections, such astechnical problems with injecting and injec-tion-associated pain, are currently greater con-tributors to patients’ treatment experience;when distal factors did not differ between
treatment groups, LAN was most commonlypreferred or favored. It is interesting to considerthat future studies might reveal a shift towardshome-based healthcare, especially in the era ofthe coronavirus disease 2019 (COVID-19) pan-demic, and, as such, the option for self- orpartner-injection may become a more promi-nent feature in treatment decision-making.Furthermore, a recent study evaluating patientexperience using a LAN syringe introduced in2019 indicated that use of newer injectiondevices could further reduce pain and anxietyfor patients [46, 47].
Where study participants had direct experi-ence of both SSAs, four of the five studiesreporting patient preference, and the only studyreporting HCP preference, reported preferencefor LAN over OCT LAR. Among HCPs, prepara-tion and administration of LAN were reportedto be quicker and simpler, presenting fewertechnical problems such as device clogging, incomparison with OCT LAR [28, 31, 34, 40, 44].An important caveat of the comparisons maderegarding technical problems in the studiesincluded in this SLR is that, since these studieswere conducted, a new solvent for OCT LARreconstitution and a LAN new syringe havebecome available [18, 19]. However, in a recentobservational study, 4% of nurses (n = 96)reported that purge problems (clogging) per-sisted when injecting OCT LAR reconstitutedwith the new solvent [48]. Further, in an inter-national simulated-use study (PRESTO), alsocompleted since this SLR was conducted, mostnurses (88/90) expressed a ‘‘slight’’ or ‘‘strong’’preference for the LAN new syringe vs the OCTLAR syringe (with the latest excipient), citing‘‘confidence the syringe will not be clogged’’ asthe most important attribute [49]. This factormay also impact patients’ treatment experience;a recent survey conducted in 2019 found thatpatients’ overall SSA injection experience is alsoimpacted by the training and process knowl-edge of their HCP, leading to variation inpatient satisfaction depending on the nurseadministering the SSA [50]. Advancements indevice usability and functionality for HCPs maytherefore help improve patient satisfaction withinjections.
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Table 4 Quality assessment
Study Purpose: is thepurpose of thestudy in relationto preferencesclearly stated?
Respondents:are theresponderssimilar to thenon-responders?
Explanation: aremethods ofassessingpreferencesclearlyexplained?
Findings: were allrespondents included inthe reported findingsand analysis ofpreference results?
Significance:were significancetests used toassess thepreferenceresults?
Adams et al.
2018 [25]
N U Y Y Y
Adelman
et al. 2012
[44]
Y Y Y Y Y
Alexopoulou
et al. 2004
[34]
N Y N Y Y
Almquist
et al. 2017
[26]
N Y N Y Y
Andries et al.
2008 [35]
N Y N Y N
Apaydin et al.
2017 [36]
N U N U N
Garland et al.
2003 [27]
N U N U N
Geilvoet et al.
2017 [28]
N U N U Y
Goetghebeur
et al. 2017
[29]
Y Y Y Y N
Johanson
et al. 2012
[30]
Y U Y N N
Neggers et al.
2015 [37]
N U N N N
Ryan et al.
2018 [31]
Y Y N Y Y
Salvatori
et al. 2010
[38]
N U N Y Y
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Habit, effectiveness, and adverse effects ofLAN were found to contribute to patient pref-erence for OCT LAR in one study [35]. Althoughexperience with LAN was unclear, HCPs repor-ted preference for OCT LAR in a study con-ducted in 2017, based on a longer period ofmarket authorization compared with LAN [36].Overall, however, perceived efficacy was notone of the main factors contributing to patientor HCP preference in the majority of studies.This finding aligns with previously reporteddata indicating that the efficacy of the two SSAsmay be comparable in both acromegaly andNETs [40, 51, 52], or other factors beyondtreatment efficacy, such as technical problemswhen administering treatment and injection-
associated pain, may be more important topatients’ overall treatment experience.
Several limitations within the capturedstudies and SLR methodology should be con-sidered when interpreting the results. In termsof the assessment tools used in the identifiedstudies, there was a lack of standardizationacross the included studies, and none employedvalidated quality of life or utility measures,limiting the conclusions that can be drawnfrom any comparisons made. Although ninestudies did include statistical analyses, some ofthese may not have used robust statisticalmethods to ascertain significant differences,and differences may not necessarily be clinicallysignificant in certain instances, despite
Table 4 continued
Study Purpose: is thepurpose of thestudy in relationto preferencesclearly stated?
Respondents:are theresponderssimilar to thenon-responders?
Explanation: aremethods ofassessingpreferencesclearlyexplained?
Findings: were allrespondents included inthe reported findingsand analysis ofpreference results?
Significance:were significancetests used toassess thepreferenceresults?
Salvatori
et al. 2014
[39]
N Y Y Y N
Schopohl
et al. 2011
[40]
N U Y Y N
Sevilla et al.
2016 [32]
N Y Y Y N
Strasburger
et al. 2016
[41]
N Y Y Y Y
Verhelst et al.
2000 [42]
N U N U N
Wagner et al.
2018a [33]
Y Y Y Y N
Wagner et al.
2018b [33]
Y Y Y Y N
Witek et al.
2016 [43]
Y Y Y Y N
N no, U unable to determine, Y yes
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statistical significance. Additionally, for severalof the outcomes assessed, including pain, anxi-ety, and nodules, there was a lack of informa-tion to clarify the relative burden of thosefactors for patients. When assessing differentinterventions experienced by the same patient,recall of the first treatment is subject to bias.This may be important when considering thatpatients switched in the direction of OCT LARto LAN in all crossover studies and were notblinded to the treatment received. This possiblebias would not be a concern in the 11 studieswith treatment arms running in parallel.
While seven of the studies included in thisSLR reported preference as an outcome, none ofthe included studies specifically aimed to assesspatient/HCP preference. For the purpose of thisSLR, favored treatment among patients or HCPsin a number of studies was inferred throughstatistical significance or numerical compar-isons of data on factors such as treatmentpreparation and administration time, visittimes, technical problems, and side effects.Although such factors are advantageous andmay drive preference, they are not necessarilycorrelated with patient/HCP preference for oneintervention over another and, as such, shouldbe interpreted with caution. The SLR searchstrategy excluded non-English-language fulltexts, potentially restricting the identificationof all relevant evidence and limiting the globalrelevance of the review findings; the includedstudies were conducted in Western countriesand the conclusions of this SLR may not beapplicable for patients in Asian countries andother global regions. Finally, as is to be expec-ted, the manufacturers of the two SSAs havesponsored much of the research identified inour review. Truly independent research intopatient preferences is difficult to obtain.
CONCLUSIONS
This SLR has identified a moderate volume ofevidence describing the treatment perspectivesof patients with acromegaly and NETs, as well astheir HCPs. While highlighting the hetero-geneity in the way that treatment preferenceshave previously been reported, a number of
common outcomes underlying treatmentexperience, including injection-associated pain,emotional quality of injections, time and con-venience of treatment administration, andpatient independence and autonomy, wereidentified. Future research should be specificallydesigned to assess patient preference and todetermine which factors contribute the most topositive patient and HCP experience. Studiesshould also utilize a common framework orvalidated reporting instrument to allow out-comes reported across studies to be pooled andanalyzed more robustly. The findings of this SLRprovide a basis that could be used to informdevelopment of decision-making criteria, con-sidering the patient perspective when initiatinglong-acting SSA treatment.
ACKNOWLEDGEMENTS
The authors thank Daphne T. Adelman for hercontributions to the analysis and interpretationof the data and critically revising drafts forimportant intellectual content.
Funding. This study was sponsored by Ipsen.The study sponsor is also funding the journal’sRapid Service and Open Access Fees.
Medical Writing and Editorial Assis-tance. The authors thank Oliver Palmer, BSc(Hons), and Amelia Frizell-Armitage, PhD, ofCostello Medical, UK, for medical writing andeditorial support, which was sponsored by Ipsenin accordance with Good Publication Practiceguidelines.
Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.
Authorship Contributions. Substantial con-tributions to study conception and design: DC,JE, MF, SN, DVG, JH, MSK; substantial contri-butions to analysis and interpretation of the
Adv Ther (2021) 38:969–993 989
data: DC, JE, MF, SN, DVG, JH, MSK; draftingthe article or revising it critically for importantintellectual content: DC, JE, MF, SN, DVG, JH,MSK; final approval of the version of the articleto be published: DC, JE, MF, SN, DVG, JH, MSK.
Prior Presentation. This manuscript is basedon work that has been previously presented atthe 17th Annual ENETS Conference for theDiagnosis and Treatment of NeuroendocrineTumor Disease, in Barcelona, Spain, on March11–13, 2020.
Disclosures. DC received research grantsand consulting honoraria from Ipsen andNovartis.DVG is Vice-President of the Belgian NET and
MEN Association and board member of INCA.Both organizations receive grants from Ipsenand Novartis. No personal fees or renumerationhave been received.JE has nothing to disclose.JH is the President of CNETS. The organization
receives grants annually from Ipsen and Novar-tis. JH personally received one small honorar-ium from Novartis.MF was an employee of Ipsen at the time of
these analyses. MF is now an employee of BayerPharmaceuticals.MSK received consulting honoraria and speak-
er fees from Ipsen and Novartis.SN received speaker/consultancy fees from
Pfizer and Ipsen, and research grants fromPfizer.
Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any new studies withhuman participants or animals performed byany of the authors.
Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.All data included in this manuscript have beenreported in published studies.
Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permits
any non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.
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