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: d-cella@northwestern.edu

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].

Adv Ther (2021) 38:969–993 983

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.

986 Adv Ther (2021) 38:969–993

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

Adv Ther (2021) 38:969–993 987

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

988 Adv Ther (2021) 38:969–993

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/.

REFERENCES

1. Delle Fave G, O’Toole D, Sundin A, et al. ENETSconsensus guidelines update for gastroduodenalneuroendocrine neoplasms. Neuroendocrinology.2016;103:119–24.

2. Matfin G. Endocrine and metabolic medical emer-gencies: a clinician’s guide. New York: Wiley; 2018.

3. Dimitriadis GK, Weickert MO, Randeva HS, et al.Medical management of secretory syndromes rela-ted to gastroenteropancreatic neuroendocrinetumours. Endocr Relat Cancer. 2016;23:R423.

4. Pavel M, O’Toole D, Costa F, et al. ENETS consensusguidelines update for the management of distantmetastatic disease of intestinal, pancreatic, bron-chial neuroendocrine neoplasms (NEN) and NEN ofunknown primary site. Neuroendocrinology.2016;103:172–85.

5. Shah MH. J Natl Compr Canc Netw (2019). http://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. Accessed 22 Dec 2020.

6. Katznelson L, Laws ER Jr, Melmed S, et al. Acro-megaly: an Endocrine Society clinical practiceguideline. J Clin Endocrinol Metab. 2014;99:3933–51.

7. Brue T, Castinetti F. The risks of overlooking thediagnosis of secreting pituitary adenomas. Orpha-net J Rare Dis. 2016;11:135–135.

990 Adv Ther (2021) 38:969–993

8. Somatuline Autogel. Summary of product charac-teristics (2018). https://www.medicines.org.uk/emc/product/8258/smpc. Accessed 22 Dec 2020.

9. Ezzat S, Snyder PJ, Young WF, et al. Octreotidetreatment of acromegaly. A randomized, multicen-ter study. Ann Intern Med. 1992;117:711–8.

10. Lombardi G, Minuto F, Tamburrano G, et al. Effi-cacy of the new long-acting formulation of lan-reotide (lanreotide autogel) in somatostatinanalogue-naive patients with acromegaly. J En-docrinol Investig. 2009;32:202–9.

11. Melmed S, Popovic V, Bidlingmaier M, et al. Safetyand efficacy of oral octreotide in acromegaly: resultsof a multicenter phase III trial. J Clin EndocrinolMetab. 2015;100:1699–708.

12. Newman CB, Melmed S, Snyder PJ, et al. Safety andefficacy of long-term octreotide therapy of acro-megaly: results of a multicenter trial in 103patients—a clinical research center study. J ClinEndocrinol Metab. 1995;80:2768–75.

13. Shimatsu A, Teramoto A, Hizuka N, et al. Efficacy,safety, and pharmacokinetics of sustained-releaselanreotide (lanreotide autogel) in Japanese patientswith acromegaly or pituitary gigantism. Endocr J.2013;60:651–63.

14. Caplin ME, Pavel M, Cwikła JB, et al. Lanreotide inmetastatic enteropancreatic neuroendocrinetumors. NEJM. 2014;371:224–33.

15. Lau SC, Abdel-Rahman O, Cheung WY. Improvedsurvival with higher doses of octreotide long-actingrelease in gastroenteropancreatic neuroendocrinetumors. Med Oncol. 2018;35:123.

16. Rinke A, Muller HH, Schade-Brittinger C, et al.Placebo-controlled, double-blind, prospective, ran-domized study on the effect of octreotide LAR inthe control of tumor growth in patients withmetastatic neuroendocrine midgut tumors: a reportfrom the PROMID Study Group. J Clin Oncol.2009;27:4656–63.

17. Wymenga AN, Eriksson B, Salmela PI, et al. Efficacyand safety of prolonged-release lanreotide inpatients with gastrointestinal neuroendocrinetumors and hormone-related symptoms. J ClinOncol. 1999;17:1111.

18. Somatuline Depot (lanreotide) injection prescribinginformation (2019). https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022074s024lbl.pdf. Accessed 4 Jan 2021.

19. Sandostatin LAR Depot prescribing information(2019). https://www.accessdata.fda.gov/drugsatfda_

docs/label/2019/021008s043lbl.pdf. Accessed 4 Jan2021.

20. Troconiz IF, Cendros JM, Peraire C, et al. Populationpharmacokinetic analysis of lanreotide autogel inhealthy subjects: evidence for injection interval ofup to 2 months. Clin Pharmacokinet. 2009;48:51–62.

21. Valery C, Paternostre M, Robert B, et al. Biomimeticorganization: octapeptide self-assembly into nan-otubes of viral capsid-like dimension. Proc NatlAcad Sci USA. 2003;100:10258–62.

22. Sandostatin LAR. Summary of product characteris-tics (2018). https://www.medicines.org.uk/emc/product/1038/smpc. Accessed 4 Jan 2021.

23. EMC. Octreotide 100 micrograms/1ml solution forinjection SmPC (2019). https://www.medicines.org.uk/emc/product/373/smpc. Accessed 4 Jan 2021.

24. Joy SM, Little E, Maruthur NM, et al. Patient pref-erences for the treatment of type 2 diabetes: ascoping review. Pharmacoeconomics. 2013;31:877–92.

25. Adams J, Ray D, Willmon R, et al. Living withneuroendocrine tumors: assessing quality of life(QoL) through a mobile application. J Clin Oncol.2018;36. https://doi.org/10.1200/JCO.2018.36.4_suppl.359.

26. Almquist M, Myrenfors P, Strom T, et al. STREET—somatostatin treatment experience trial. Neuroen-docrinology. 2017;105(Suppl 1):191.

27. Garland J, Buscombe JR, Bouvier C, et al. Sando-statin LAR (long-acting octreotide acetate) formalignant carcinoid syndrome: a 3-year experience.Aliment Pharmacol Ther. 2003;17:437–44.

28. Geilvoet W, Feelders R, De Herder WW. Patientsatisfaction regarding home injection service forsomatostatin analogues: a survey among patientswith a neuroendocrine tumour. Neuroendocrinol-ogy. 2017;105(Suppl 1):198.

29. Goetghebeur M, Samaha D, Khoury H, et al. Totreat or watch? Identifying drivers of decisions forpatients with GEP-NET using reflective multi-crite-ria decision analysis. Neuroendocrinology.2017;105(Suppl 1):235.

30. Johanson V, Wilson B, Abrahamsson A, et al. Ran-domized crossover study in patients with neuroen-docrine tumors to assess patient preference forlanreotide autogel given by either self/partner or ahealth care professional. Patient Prefer Adherence.2012;6:703–10.

Adv Ther (2021) 38:969–993 991

31. Ryan P, McBride A, Ray D, et al. Lanreotide depot/autogel vs. octreotide LAR for patients withadvanced gastroenteropancreatic neuroendocrinetumours: an observational time and motion analy-sis. In: NANETS 11th annual multidisciplinary NETsymposium, 04–06 Oct 2018, Seattle, WA, USA.2018;P-12:211–2. https://nanets.net/abstracts-archive/2018/948-abstract-p12/file. Accessed 4 Jan2021.

32. Sevilla I, Segura A, Capdevila J, et al. Managementof controversial gastroenteropancreatic neuroen-docrine tumour clinical situations with somato-statin analogues: results of a Delphi questionnairepanel from the NETPraxis program. BMC Cancer.2016;16:858.

33. Wagner M, Samaha D, Cuervo J, et al. Applyingreflective multicriteria decision analysis (MCDA) topatient-clinician shared decision-making on themanagement of gastroenteropancreatic neuroen-docrine tumors (GEP-NET) in the Spanish context.Adv Ther. 2018;35:1215–31.

34. Alexopoulou O, Abrams P, Verhelst J, et al. Efficacyand tolerability of lanreotide autogel therapy inacromegalic patients previously treated withoctreotide LAR. Eur J Endocrinol. 2004;151:317–24.

35. Andries M, Glintborg D, Kvistborg A, et al. A12-month randomized crossover study on theeffects of lanreotide autogel and octreotide long-acting repeatable on GH and IGF-l in patients withacromegaly. Clin Endocrinol. 2008;68:473–80.

36. Apaydin T, Ozkaya HM, Keskin FE, et al. Daily lifereflections of acromegaly guidelines. J EndocrinolInvestig. 2017;40:323–30.

37. Neggers SJ, Pronin V, Balcere I, et al. Lanreotideautogel 120 mg at extended dosing intervals inpatients with acromegaly biochemically controlledwith octreotide LAR: The LEAD study. Eur J Endo-crinol. 2015;173:313–23.

38. Salvatori R, Nachtigall LB, Cook DM, et al. Effec-tiveness of self- or partner-administration of anextended-release aqueous-gel formulation of lan-reotide in lanreotide-naive patients with acrome-galy. Pituitary. 2010;13:115–22.

39. Salvatori R, Woodmansee WW, Molitch M, et al.Lanreotide extended-release aqueous-gel formula-tion, injected by patient, partner or healthcareprovider in patients with acromegaly in the UnitedStates: 1-year data from the SODA registry. Pitu-itary. 2014;17:13–21.

40. Schopohl J, Strasburger CJ, Caird D, et al. Efficacyand acceptability of lanreotide autogel 120 mg atdifferent dose intervals in patients with acromegaly

previously treated with octreotide LAR. Exp ClinEndocrinol Diabetes. 2011;119:156–62.

41. Strasburger CJ, Karavitaki N, Stormann S, et al.Patient-reported outcomes of parenteral somato-statin analogue injections in 195 patients withacromegaly. Eur J Endocrinol. 2016;174:355–62.

42. Verhelst JA, Pedroncelli AM, Abs R, et al. Slow-re-lease lanreotide in the treatment of acromegaly: astudy in 66 patients. Eur J Endocrinol. 2000;143:577–84.

43. Witek P, Mucha S, Ruchala M. Patient satisfactionand preferences of lanreotide autogel treatment inacromegaly. Endokrynologia Polska. 2016;67:572–9.

44. Adelman DT, Burgess A, Davies PR. Evaluation oflong-acting somatostatin analog injection devicesby nurses: a quantitative study. Med Devices(Auckl). 2012;5:103–9.

45. Wagner M, Samaha D, Khoury H, et al. Develop-ment of a framework based on reflective MCDA tosupport patient-clinician shared decision-making:the case of the management of gastroenteropan-creatic neuroendocrine tumors (GEP-NET) in theUnited States. Adv Ther. 2018;35:81–99.

46. Adelman DT, Van Genechten D, Megret CM, et al.Co-creation of a lanreotide autogel/depot syringefor the treatment of acromegaly and neuroen-docrine tumours through collaborative humanfactor studies. Adv Ther. 2019;36:3409–23.

47. Walter T, Eskenazi M, Rama N, et al. Patient andnurse satisfaction with the new lanreotide autogelpre-filled syringe in neuroendocrine tumors (NET):a prospective study (SONATE). In: ENETS 17thannual conference, 11–13 Mar 2020, Barcelona,Spain. 2020;2824. https://www.enets.org/patient-and-nurse-satisfaction-with-the-new-lanreotide-autogel-prefilled-syringe-in-neuroendocrine-tumors-net-a-prospective-study-sonate.html. Accessed 4 Jan2021.

48. Cadiot G, Coriat R, Raverot G, et al. EvAluation deSatisfaction Infirmiere (Nurse satisfaction evalua-tion). Observational study of the preparation andintramuscular administration of the previous andnew long-acting release octreotide LAR formulation(EASI). In: ENETS 17th annual conference, 11–13Mar 2020, Barcelona, Spain. 2020;2802. https://www.enets.org/evaluation-de-satisfaction-infirmiere-nurse-satisfaction-evaluationobservational-study-of-the-preparation-and-intramuscular-administration-of-the-previousand-new-long-acting-release-octreotide-lar-formulation-easi.html. Accessed 4 Jan 2021.

49. Adelman DT, Truong-Thanh X, Feuilly M, et al.Evaluation of nurse preferences between the

992 Adv Ther (2021) 38:969–993

lanreotide autogel new syringe and the octreotidelong-acting release syringe: an international simu-lated-use study (PRESTO). Adv Ther. 2020;37:1608–19.

50. Darden C, Ray D, Goldstein G, et al. Satisfactionsurvey of administration modes for long-actingsomatostatin analog therapy in patients with neu-roendocrine tumors. In: NANETS 12th annualmultidisciplinary NET symposium, 03–05 Oct 2019,Boston, MA, USA. 2019;P-3:181-2. https://nanets.net/abstracts-archive/2019/1328-p3-satisfaction-survey-ofadministration-modes-for-long-acting-la-somatostatin-analog-ssa-therapy-in-patients-

withneuroendocrine-tumors-nets/file. Accessed 4Jan 2021.

51. Tutuncu Y, Berker D, Isik S, et al. Comparison ofoctreotide LAR and lanreotide autogel as post-op-erative medical treatment in acromegaly. Pituitary.2012;15:398–404.

52. Thiel SW, Romijn JA, Biermasz NR, et al. Octreotidelong-acting repeatable and lanreotide autogel areequally effective in controlling growth hormonesecretion in acromegalic patients. Eur J Endocrinol.2004;150:489–95.

Adv Ther (2021) 38:969–993 993