Open Access

Systematic review reveals lack of quality in reporting health-related quality of life in patients with gastroenteropancreatic neuroendocrine tumours

  • Caroline Martini1,
  • Eva-Maria Gamper1, 2Email author,
  • Lisa Wintner1,
  • Bernhard Nilica2,
  • Barbara Sperner-Unterweger1,
  • Bernhard Holzner1 and
  • Irene Virgolini2
Health and Quality of Life Outcomes201614:127

https://doi.org/10.1186/s12955-016-0527-2

Received: 22 January 2016

Accepted: 2 September 2016

Published: 10 September 2016

Abstract

Background

Gastroenteropancreatic neuroendocrine tumours (GEP-NET) are often slow-growing and patients may live for years with metastasised disease. Hence, along with increasing overall and progression-free survival, treatments aim at preserving patients’ well-being and health-related quality of life (HRQoL). However, studies on systematic HRQoL assessment in patients with GEP-NET are scarce. Therefore, the purpose of the current review is to systematically evaluate the methodological quality of the identified studies.

Methods

A targeted database search was performed in PubMed, EMBASE, and CENTRAL. Data extraction was conducted by two independent researchers according to predefined criteria. For study evaluation, the Minimum Standard Checklist for Evaluating HRQoL Outcomes in Cancer Clinical Trials and the CONSORT Patient-Reported Outcome extension were adapted.

Results

The database search yielded 48 eligible studies. We found the awareness for the need of HRQoL measurement to be growing and application of cancer-specific instruments gaining acceptance. Overall, studies were too heterogeneous in terms of patient characteristics and treatment interventions to draw clear conclusions for clinical practice. More importantly, a range of methodological shortcomings has been identified which were mainly related to the assessment and statistical analysis, as well as the reporting and interpretation of HRQoL data.

Conclusion

Despite an increasing interest in HRQoL in GEP-NET patients, there is still a lack of knowledge on this issue. A transfer of HRQoL results into clinical practice is hindered not only by the scarceness of studies, but also by the often limited quality of HRQoL processing and reporting.

Keywords

Health-related quality of life Gastroenteropancreatic neuroendocrine tumours Patient-reported outcomes Systematic review Methodological quality

Background

With an incidence of 5.25 per 100,000 [1] gastroenteropancreatic neuroendocrine tumours (GEP-NET) are a relatively rare disease. They are usually slow-growing and often do not produce clear symptoms until they are metastasised. Currently, surgical tumour resection is the only curative treatment, and usually only in patients with localised disease [14]. The primary aims of available therapeutic options are to provide symptom relief, control tumour growth, improve long-term survival, and, not least, preserve psychosocial well-being and health-related quality of life (HRQoL) [2, 4].

The past two decades have shown that the patient’s subjective perspective on his/her own health, quality of life, and treatment-related aspects plays an essential role in treatment evaluation. Traditional physician proxy ratings on morbidity correlate only poorly with several self-reported functional capacity and well-being domains [5] – areas which are of utmost importance for the individual patient in managing his/her everyday life with the disease. These aspects are represented in the concept of HRQoL. There is agreement that HRQoL describes “the extent to which one’s usual or expected physical, emotional, and social well-being is affected by a medical condition or its treatment” ([6], p. 73) and needs to be assessed as a patient-reported outcome (PRO). PROs comprise any self-report of a patient’s health status without interpretation by a third person [7].

The assessment of HRQoL as an important secondary outcome in clinical studies, using reliable and valid self-report instruments, has become the criterion standard in oncology [810]. To date, systematic assessments of HRQoL in patients with GEP-NET have hardly been performed. High-quality information on HRQoL serves a variety of purposes, from the development of targeted interventions to informed decision making about treatment options to the allocation of healthcare resources [11].

Based on the assumptions above, we conducted a systematic review on studies incorporating HRQoL in patients with GEP-NET to evaluate the methodological quality of HRQoL processing and reporting. In detail, this review aims at investigating (i) the amount of available information on HRQoL in patients with GEP-NET, (ii) how HRQoL was assessed and reported, and (iii) if the quality of HRQoL information provided meets agreed standards.

Methods

We applied a systematic approach to identify and appraise studies on HRQoL in GEP-NET patients. Criteria for the selection, description and evaluation of studies were based on the PRISMA (Preferred Reporting Items of Systematic Reviews and Meta-Analyses) checklist [12], the Cochrane Consumers and Communication Review Group’s Extraction Template [13], and the Minimum Standard Checklist for Evaluating HRQoL Outcomes in Cancer Clinical Trials [14].

Search strategy

A systematic literature search was conducted in September 2014 and updated in July 2016 using PubMed, EMBASE, and CENTRAL. We searched for original research articles published in English, Italian, French, or German and restricted the search to studies on humans. Combinations of the following MeSH and free text terms were used: neuroendocrine tumors, digestive system neoplasms, neuroendocrine, endocrine, NET, foregut, midgut, hindgut, quality of life, patient-reported, self-reported, well-being, psycho*. An exemplary search history for PubMed is provided in Appendix.

In addition, we also searched OpenGrey (http://www.opengrey.eu) and BIOSIS previews (http://www.dimdi.de/static/de/db/dbinfo/ba70.htm) for the identification of grey literature. Database searches were augmented by a manual search of reference lists of included articles to identify further eligible studies not detected by our search terms.

Inclusion criteria and data extraction

Due to the scarceness of studies on the topic of HRQoL in patients with GEP-NET, it was decided not to impose restriction criteria concerning study design in order to comprehensively capture the available information. Any study with a quantitative approach assessing self-reported HRQoL was considered eligible. Publications that were letters, editorials, narrative reviews, and case reports were excluded. Methodological studies on HRQoL in this patient group (e.g., instrument development) were considered not eligible. A data collection form was based on the Cochrane Consumers and Communication Review Group’s Extraction Template, adapted to study requirements, pilot tested on five randomly selected reports and refined accordingly.

Eligibility assessment and data extraction were performed by two independent researchers. In the case of disagreement, a third reviewer was consulted to reach final consensus. For the assessment of interrater agreement a simple Kappa calculation was performed, with values between .61 and .80 indicating substantial and of > .81 almost perfect agreement [15].

Study evaluation

For study evaluation we adapted the Minimum Standard Checklist for Evaluating HRQoL Outcomes in Cancer Clinical Trials [14] and the Consolidated Standards of Reporting Trials (CONSORT) PRO extension checklist [16] for our requirements (i.e., applicable to a range of different study designs in addition to randomised controlled trials (RCTs)). Multiple reports on the same study were linked together and were subsequently defined as one study.

Quality criteria were defined according to study design

For all studies it was documented if:
  • HRQoL was identified as primary or secondary outcome in the abstract (for studies with more than one outcome parameter),

  • there was an a priori hypothesis concerning HRQoL (not applicable if explorative),

  • an explicit rationale for HRQoL instrument selection was provided,

  • the instrument was validated or psychometric properties were reported or referenced,

  • the HRQoL instrument was cancer-specific,

  • the instrument administration was reported,

  • missing data was documented or discussed,

  • statistical considerations for dealing with missing data were provided,

  • reports on HRQoL results were complete and scoring was correct,

  • the issue of clinical significance had been addressed.

For cross-sectional studies it was additionally documented if:
  • compliance was reported.

For all kinds of prospective studies it was additionally documented if:
  • baseline compliance was documented,

  • the timing of assessment was reported.

For prospective and comparative studies it was additionally documented if:
  • statistical power or effect sizes for HRQoL results were reported.

For studies with HRQoL as secondary outcome it was additionally documented if:
  • HRQoL results were considered in discussion section.

Results

Study selection and study characteristics

The literature search yielded a total of 1506 records (after removing duplicates). Figure 1 shows the flow-diagram of the selection process. We screened titles and abstracts and excluded 88 case-reports and non-original research reports such as comments and letters. Subsequently, 791 studies were excluded for not investigating GEP-NET, and 566 were excluded for not investigating HRQoL. Grey literature search yielded five conference abstracts reporting on studies dealing with HRQoL issues which were not (or not yet) published as full reports and, therefore, not included in the review. Four additional studies were identified by hand search of reference lists of relevant articles. After these selection steps, 65 potentially relevant full-text articles remained and were assessed for eligibility. Out of these, 14 articles were excluded from the review for the following reasons: ten did not measure self-reported HRQoL (e.g., used the Karnofsky Performance Score), and four were methodological studies either on HRQoL instrument development or comparison of instruments. With a Kappa of .818 (p ≤ .001) the level of agreement between the two reviewers concerning inclusion or exclusion of a full-text article assessed for eligibility was high.
Fig. 1

Flow-diagram of study selection process

In total, 51 articles, which reported on 48 separate studies, were included. Eight were RCTs which assessed HRQoL as a secondary outcome to the primary endpoints response, progression-free survival, or time to progression. Additionally, 25 prospective studies, including 15 phase II trials, and 15 observational cross-sectional studies were identified.

Sample sizes ranged between 9 and 663 patients with a median of 51. Most of the studies investigated patients in an advanced stage of disease and administered the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) for assessing HRQoL. In total, 22 studies used either HRQoL or another PRO (e.g., fear of recurrence) as a primary outcome measure. Eight studies compared HRQoL scores with normative values from the national general population. For details on study characteristics see Table 1.
Table 1

Study characteristics of identified studies

Author, year

Sample size, diagnosis (disease severity)

Treatment modality/intervention

Comparison

PRO primary outcome

HRQoL measure

Randomised controlled trials

Arnold et al., 2005 [52]

N = 109, foregut, midgut NET, CUP (locally advanced, metastatic)

octreotide

octreotide + INT

no

QLQ-C30

Bajetta et al., 2006 [53]

N = 60, well-differentiated intestinal, pancreatic, bronchial NET, other, CUP (low-grade malignancy)

lan ATG

lan MP

no

QLQ-C30

Caplin et al., 2014 [42] (CLARINET)

N = 204, well- or moderately differentiated pancreatic, midgut, hindgut NET, other, CUP (progressive, metastatic)

lan ATG

placebo

no

QLQ-C30, QLQ-GI.NET21

Jacobsen & Hanssen, 1995 [54]

N = 11, intestinal NET, PNET (liver metastases)

octreotide

placebo (cross-over design)

no

GHQ-30, PAIS

Meyer et al., 2014 [55]

N = 86, PNET, GI foregut NET, CUP (advanced, metastatic)

capecitabine + streptozocin + cisplatine

capecitabine + streptozocin

no

QLQ-C30

Raymond et al., 2011 [56]

N = 171, well-differentiated PNET (advanced, metastatic)

sunitinib

placebo

no

QLQ-C30

Rinke et al., 2009 [57] (PROMID)

N = 85, well-differentiated midgut NET (metastatic)

octreotide LAR

placebo

no

QLQ-C30

Yao et al., 2016 [45] (RADIANT-4)

N = 302, well-differentiated GI-NET, bronchopulmonary NET (advanced, progressive)

everolimus

placebo

no

FACT-G

Phase II studies

Bodei et al., 2011 [58]

N = 51, bronchial, pancreatic, duodenal, ileal, appendicular, sigma-rectal NET, CUP (progressive, other)

177Lu-DOTATATE

-

no

QLQ-C30

Bushnell et al., 2010 [59]

N = 90, carcinoid (metastatic, refractory to octreotide)

90Y-DOTADOC

-

no

EQ-5D

Claringbold et al., 2011 [60]

N = 33, well-differentiated NET (progressive)

177Lu-DOTATATE

-

no

QLQ-C30

Cwikla et al., 2010 [61]

N = 60, GEP-NET (progressive, metastatic)

90Y-DOTATATE

-

no

QLQ-C30, QLQ-GI.NET21

Delpassand et al., 2014 [62]

N = 37, GEP-NET (progressive)

177Lu-DOTATATE

-

no

QLQ-C30

Ducreux et al., 2014 [43];

Mitry et al., 2014 [44] (BETTER)

N = 34, well-differentiated PNET (progressive, metastatic)

N = 49, well-differentiated GI-NET (progressive, metastatic)

bevacizumab + 5-FU/streptozocin;

bevacizumab + capecitabine

-

no

QLQ-C30

Frilling et al., 2006 [63]

N = 18, ileal, pancreatic NET, paraganglioma, gastrinoma, CUP (progressive, metastatic)

90Y-DOTATOC; 177Lu-DOTATOC

-

no

SF-36

Khan et al., 2011 [64]

N = 256, carcinoid, PNET, CUP, gastrinoma, glucagonoma, insulinoma, VIPoma (with and without metastases)

177Lu-DOTATATE

-

yes

QLQ-C30

Korse et al., 2009 [65]

N = 39, GI-NET (advanced, metastatic)

octreotide LAR

-

no

QLQ-C30

Kulke et al., 2008 [66]

N = 107, carcinoid, PNET (advanced)

sunitinib

-

no

EQ-5D, FACIT-Fatigue scale

Kvols et al., 2012 [67]

N = 45, GI-NET (advanced, metastatic)

pasireotide

-

no

FACIT-D

Martin-Richard et al., 2013 [68]

N = 30, well-differentiated GEP-NET, bronchopulmonary NET, CUP (progressive)

lan ATG

-

no

QLQ-C30

Ruszniewski et al., 2004 [69]

N = 71, foregut, midgut, hindgut NET, other (not terminally ill)

lan PR

-

no

QLQ-C30

Wymenga et al., 1999 [70]

N = 55, carcinoid, gastrinoma, VIPoma (tumour stages III and IV)

lan PR

-

no

QLQ-C30

Zuetenhorst et al., 2004 [71]

N = 26, well-differentiated ileo-cecal, gastric, bronchopulmonary NET, CUP (metastatic)

INT followed by unlabelled MIBG followed by 131I-MIBG

-

no

QLQ-C30

Prospective studies

Fröjd et al., 2007 [72];

Fröjd et al., 2009 [73]

N = 36, carcinoid (metastatic, other)

INT; octreotide; INT + octreotide; CTX; octreotide + CTX; no treatment

normative data (subsample)

yes

QLQ-C30

Haugland et al., 2013 [74]

N = 37, GI-NET (not terminally ill)

medical treatment (n.s.)

-

yes

SF-36

Kalinowski et al., 2009 [75]

N = 9, bronchial, jejunal, ileal, gastric NET, PNET, insulinoma (liver metastases)

90Y microspheres

-

no

QLQ-C30, QLQ-LMC21

Kwekkeboom et al., 2003 [76]

N = 35, GEP-NET (progressive, other)

177Lu-DOTATATE

-

no

QLQ-C30

Larsson & Janson, 2008 [77]

N = 18, midgut carcinoid (n.s.)

INT

-

yes

QLQ-C30, FACT-An

Larsson et al., 2001 [78]

N = 24, midgut carcinoid (metastatic, other)

INT; SSA; INT + SSA

normative data

yes

QLQ-C30

O’Toole et al., 2000 [79]

N = 33, intestinal NET, PNET, other (metastatic)

octreotide followed by lanreotide

lanreotide followed by octreotide

no

ISPN

Pasieka et al., 2004 [80]

N = 24, small bowel carcinoid, medullary thyroid cancer, CUP (progressive, metastatic)

131I-MIBG; 111In-octreotide

-

no

ad hoc questionnaire

Spolverato et al., 2015 [81]

N = 85, intestinal, pancreatic, bronchial NET, CUP (neuroendocrine liver metastasis)

surgical vs. nonsurgical treatment

-

yes

self-constructed questionnaire

Teunissen et al., 2004 [82]

N = 50, carcinoid, PNET, CUP, gastrinoma, insulinoma (metastatic)

177Lu-DOTATATE

-

yes

QLQ-C30

Cross-sectional studies

Beaumont et al., 2012 [83];

N = 663, carcinoid, islet cell, “do not know or not sure which type” (local, regional, distant, currently not present)

surgery; surgery + SSA; other; no past/current treatment

normative data

yes

SF-36, PROMIS global health short form, PROMIS-29

Pearman et al., 2016 [84]

-

Gelhorn et al., 2016 [85]

N = 11, midgut, hindgut NET (metastatic)

telotristat etiprate

normative data

yes

QLQ-C30, QLQ-GI.NET21

Haugland et al., 2009 [86]

N = 96, GI-NET (not terminally ill)

INT; SSA; INT + SSA; CTX; no treatment

normative data

yes

SF-36

Haugland et al., 2016 [87]

N = 196, GI-NET (not terminally ill)

medical treatment (n.s.)

normative data

yes

SF-36

Larsson et al., 1998 [88]

N = 17, carcinoid, PNET (not terminally ill) (+ staff, N = 17)

INT; SSA; INT + SSA

-

yes

QLQ-C30

Larsson, Sjöden et al., 1999 [89]

N = 119, carcinoid, PNET (n.s.)

INT + octreotid; INT; octreotide; CTX; XTR; omeprazol; no treatment

-

yes

QLQ-C30

Larsson, von Essen et al., 1999 [90]

N = 99, carcinoid, PNET (not terminally ill)

INT; SSA; INT + SSA

-

yes

QLQ-C30

Larsson et al., 2003 [91]

N = 19, carcinoid (n.s.) (+ staff, N = 19)

INT; SSA; INT + SSA

-

yes

semi-structured interviews

Larsson et al., 2007 [92]

N = 83, carcinoid, PNET (n.s.)

INT/octreotide; CTX; XTR; omeprazol; no treatment

-

yes

QLQ-C30

Petzel et al., 2012 [93]

N = 240, PNET, periampullary neoplasms (disease-free after surgery)

no current treatment

-

yes

FACT-Hep

Pezzilli et al., 2009 [94]

N = 44 PNET (disease free, advanced)

SSA; SSA + other; no treatment

normative data

yes

SF-12, GHQ-12

Pezzilli et al., 2010 [95]

N = 44 ileal NET (disease free, advanced)

SSA; INT; CTX; SSA + other; no treatment

 

yes

SF-12

Ruszniewski et al., 2016 [96] (SYMNET)

N = 273, small bowel carcinoid, appendicular, colonic, bronchopulmonary NET, CUP (92 % with metastases)

lan ATG

-

yes

QLQ-C30, QLQ-GI.NET

van der Horst-Schrivers et al., 2009 [97]

N = 43, midgut NET (metastatic)

SSA; INT; SSA + INT

normative data

yes

QLQ-C30

von Essen et al., 2002 [98]

N = 85, GI-NET (n.s.)

INT; SSA; INT + SSA

-

yes

QLQ-C30

Grey literature

Garcia-Hernandez et al., 2012 [99]

N = 74, GI-NET (n.a.)

n.a.

-

yes

QLQ-C30, QLQ-GI.NET21

Gyökeres et al., 2010 [100]

N = 93, GI-NET (59 % with metastases)

SSA

-

yes

QLQ-C30, QLQ-GI.NET21

Marinova et al., 2016 [101]

N = 68, PNET (n.a.)

PRRT (n.s.)

-

yes

QLQ-C30

Pavel et al., 2013 [102]

N = 126, PNET (advanced)

everolimus

-

no

QLQ-C30, QLQ-GI.NET21

Strosberg et al., 2015 [103]

N = 230, midgut NET (advanced, progressive, metastatic)

177Lu-DOTATATE

octreotide LAR

no

QLQ-C30, QLQ-GI.NET21

Note. CUP cancer with unknown primary, CTX chemotherapy, GEP-NET gastroenteropancreatic NET, GI-NET gastrointestinal NET, INT interferon-α, lan ATG lanreotide autogel, lan MP lanreotide microparticles, lan PR lanreotide prolonged-release, MIBG meta-iodbenzylguanidin, NET neuroendocrine tumours, n.a. not available, n.s. not specified, octreotide LAR octreotide long-acting repeatable, PNET pancreatic NET, XTR radiotherapy, SSA somatostatin analogues

Applied instruments for measuring health-related quality of life

The majority of the reviewed studies (31/48) used the EORTC QLQ-C30 [17], which is one of the most widely used HRQoL questionnaire in oncology in Europe. It has been shown to have good validity and reliability and consists of 30 items incorporating five functional scales (physical, role, emotional, cognitive, social), three symptom scales (fatigue, nausea/vomiting, pain), six single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, financial difficulties) and one scale assessing global health status/QoL. Scores are linearly transformed to a 0–100 scale with higher scores representing a higher level of functioning and a higher level of symptomatology, respectively. As defined by Osoba et al. [18], mean changes in HRQoL scores over time of 5 to 10 points are considered as “small”, 10 to 20 points as “moderate”, and more than 20 points as “large” with regard to clinical relevance. The QLQ-C30 can be supplemented with disease- and treatment-specific modules. The NET-specific module, the QLQ-GI.NET21 [19], was used in four of the reviewed studies. It covers issues specific for GEP-NET and is applicable to patients suffering from endocrine or gastrointestinal symptoms. One study used the QLQ-LMC21, which is a module for patients with liver metastases from a colorectal tumour.

The same principle of adding disease- and treatment-specific modules to a generic questionnaire is applied by the Functional Assessment of Chronic Illness Therapy (FACIT) measures, which is one of the most frequently used HRQoL measurement systems in the US and Canada. The core questionnaire, the Functional Assessment of Cancer Therapy-General (FACT-G) [20], is composed of 27 items assessing physical, emotional, functional and social well-being. The FACT-G was used in five studies; applied modules were the FACT-Hepatobiliary, the FACT-Anemia, the FACIT-Diarrhea, and the FACIT-Fatigue.

One study used the Patient-Reported Outcome Measurement Information System 29-item Health Profile (PROMIS-29) which measures HRQoL in seven domains (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, ability to participate in social roles and activities) and was designed for patients with a wide range of chronic diseases [21]. In another study the Psychosocial Adjustment to Illness Scale (PAIS) was used. The PAIS was designed as a semi-structured clinical interview assessing a patient’s psychosocial adjustment to medical illness in terms of multiple domains (health care orientation, vocational environment, domestic environment, sexual relationships, extended family relationships, social environment, psychological distress) [22].

Generic instruments, namely the 36-Item Short Form Health Survey (SF-36), the 12-Item Short Form Health Survey (SF-12), the Euroqol-5 Dimension (EQ-5D), the General Health Questionnaire 30 (GHQ-30) and 12 (GHQ-12), and the French version of the Nottingham Health Profile (ISPN), were used in 10 studies. These instruments assess physical, emotional, functional and social aspects that are applicable across patient groups and diseases and are therefore less suitable for the identification of cancer site- or problem-specific concerns [23].

Evaluation of methodological quality of HRQoL reporting

Detailed information for each study based on the Minimum Standard Checklist for Evaluating HRQoL Outcomes in Cancer Clinical Trials and the CONSORT PRO extension checklist is provided in Table 2. Figure 2 shows the percentage of studies meeting the CONSORT PRO reporting criteria. The percentage of studies meeting additional quality criteria is depicted in Fig. 3. It should be noted that stated percentages do not always refer to all 48 extracted studies, but to the total number of studies that met the defined criteria.
Table 2

Study evaluation according to defined quality criteria

Author, year

HRQoL stated as prim./sec. aima

A priori hypothesis

Instrument rational

Instrument validationb

Cancer-specific instrument

Instrument administration

(Baseline) compliance

Timing of assessments

Missing data reported

Statistical methods for missing data

Power or effect sizes (HRQoL)

Presentation of results adequatec

Clinical significance addressed

HRQoL results discussed

Randomised controlled trials

Arnold et al., 2005 [52]

-

-

+

+

+

-

+

+

+

-

-

-

-

+

Bajetta et al., 2006 [53]

-

-

-

+

+

+

-

+

+

+

-

-

-

+

Caplin et al., 2014 [42] (CLARINET)

+

-

-

+

+

-

-

+

+

+

-

+

-

-

Jacobsen & Hanssen, 1995 [54]

+

-

-

+

-d

-

+

+

+

-

-

-

+

+

Meyer et al., 2014 [55]

+

-

-

+

+

-

+

+

+

-

-

-

-

-

Raymond et al., 2011 [56]

-

-

-

+

+

+

-

+

+

-

-

-

+

+

Rinke et al., 2009 [57] (PROMID)

-

-

-

+

+

-

+

+

-

-

-

-

-

-

Yao et al., 2016 [45] (RADIANT-4)

-

-

+

+

+

+

+

+

-

+

-

n.r.

+

n.r.

Phase II studies

Bodei et al., 2011 [58]

-

-

-

+

+

-

-

+

-

-

-

-

-

+

Bushnell et al., 2010 [59]

-

-

-

+

-

-

+

+

+

-

-

-

-

-

Claringbold et al., 2011 [60]

-

-

-

+

+

-

-

+

+

-

-

-

-

+

Cwikla et al., 2010 [61]

-

-

-

+

+

+

-

+

+

-

-

-

-

-

Delpassand et al., 2014 [62]

-

-

-

+

+

-

-

+

+

-

-

-

-

-

Ducreux et al., 2014 [43];

Mitry et al., 2014 [44] (BETTER)

+

-

-

+

+

-

-

+

+

-

-

-

-

-

Frilling et al., 2006 [63]

-

-

-

+

-

-

-

+

+

-

-

-

-

-

Khan et al., 2011 [64]

N/A

-

+

+

+

+

+

+

+

-

-

-

+

+

Korse et al., 2009 [65]

N/A

-

+

+

+d

-

-

-

+

-

-

-

-

N/A

Kulke et al., 2008 [66]

-

-

-

+

-

+

-

+

+

-

-

-

-

+

Kvols et al., 2012 [67]

-

-

-

+

+

-

-

+

+

-

-

-

-

+

Martin-Richard et al., 2013 [68]

+

-

-

+

+

-

-

+

-

-

-

+

-

-

Ruszniewski et al., 2004 [69]

-

-

-

+

+

-

+

+

+

-

-

-

-

+

Wymenga et al., 1999 [70]

-

-

-

+

+

-

-

+

-

+

-

+

-

+

Zuetenhorst et al., 2004 [71]

-

+

-

+

+d

-

-

+

+

-

-

-

-

+

Prospective studies

Fröjd et al., 2007 [72];

Fröjd et al., 2009 [73]

N/A

N/A

-

+

+d

+

+

+

+

+

-

+

+

N/A

Haugland et al., 2013 [74]

N/A

-

-

+

-

+

+

+

+

+

+

+

-

N/A

Kalinowski et al., 2009 [75]

-

-

+

+

+

-

-

+

-

-

-

-

-

+

Kwekkeboom et al., 2003 [76]

-

-

-

+

+

+

-

+

+

-

-

-

-

+

Larsson & Janson, 2008 [77]

N/A

N/A

+

+

+

-

-

+

+

-

-

+

+

N/A

Larsson et al., 2001 [78]

N/A

-

-

+

+d

+

+

+

+

-

-

+

+

N/A

O’Toole et al., 2000 [79]

-

+

-

+

-d

+

-

+

-

-

-

+

-

+

Pasieka et al., 2004 [80]

-

-

-

-

-

+

+

+

+

-

-

-

+

+

Spolverato et al., 2015 [81]

N/A

+

+

-

+

+

+

+

+

-

-

-

-

N/A

Teunissen et al., 2004 [82]

N/A

N/A

+

+

+

+

-

+

+

+

-

+

+

N/A

Cross-sectional studies

Beaumont et al., 2012 [83];

N/A

N/A

-

+

-

+

+

N/A

+

-

+

+

+

N/A

Pearman et al., 2016 [84]

-

Gelhorn et al., 2016 [85]

-

N/A

-

+

+

+

+

N/A

+

-

N/A

-

+

+

Haugland et al., 2009 [86]

N/A

N/A

+

+

-

+

+

N/A

+

-

+

+

+

N/A

Haugland et al., 2016 [87]

N/A

+

-

+

-

+

+

N/A

+

+

-

-

-

N/A

Larsson et al., 1998 [88]

N/A

N/A

+

+

+d

+

+

N/A

+

-

N/A

-

-

N/A

Larsson, Sjöden et al., 1999 [89]

N/A

N/A

+

+

+

+

-

N/A

+

-

N/A

+

+

N/A

Larsson, von Essen et al., 1999 [90]

N/A

N/A

+

+

+d

+

+

N/A

+

-

N/A

+

+

N/A

Larsson et al., 2003 [91]

N/A

N/A

N/A

N/A

N/A

+

-

N/A

+

N/A

N/A

N/A

N/A

N/A

Larsson et al., 2007 [92]

N/A

N/A

+

+

+d

+

+

N/A

+

-

N/A

+

-

N/A

Petzel et al., 2012 [93]

N/A

+

+

+

+

+

-

N/A

+

+

N/A

+

-

N/A

Pezzilli et al., 2009 [94]

N/A

-

-

+

-

+

+

N/A

+

-

-

-

-

N/A

Pezzilli et al., 2010 [95]

N/A

-

-

+

-

+

-

N/A

-

-

-

-

-

N/A

Ruszniewski et al., 2016 [96] (SYMNET)

-

N/A

-

+

+

+

-

N/A

-

+

+

-

-

+

van der Horst-Schrivers et al., 2009 [97]

N/A

N/A

-

+

+

+

+

N/A

-

-

-

+

-

N/A

von Essen et al., 2002 [98]

N/A

N/A

-

+

+

+

+

N/A

+

-

-

-

-

N/A

Note. ain the abstract of the article; bor psychometric properties reported; cconsidered adequate if scoring has been performed correctly and if all assessed HRQoL domains were reported (including relevant p-values); dadditional ad hoc questions on symptoms added; N/A not applicable due to study design, n.r. not reported

Fig. 2

Percentage of studies meeting CONSORT PRO extension criteria

Fig. 3

Percentage of studies meeting additional quality criteria from HRQoL checklist

Study evaluation revealed three major topics of concern. The first is a lack of knowledge on how to assess and process HRQoL data, and here particularly the absence of a priori hypotheses on HRQoL outcomes in 85 % and missing rationales for applied questionnaires in 70 % of studies. The second is a lack of adequate reporting of HRQoL results. For 65 % of studies, the presentation of results was rated inadequate, either due to incomplete reporting of HRQoL scores (only single scales or statistical significant results) or due to invalid score calculation (i.e., not according to the respective scoring manual). The third is related to the statistical methods as well as interpretation and discussion of HRQoL results. Information on the handling of missing data was not given in 79 % of studies. Less than one third of the studies (30 %) addressed the issue of clinical significance of findings. Further evaluation revealed that studies which investigated HRQoL as a primary outcome showed higher methodological quality of HRQoL data than those that included HRQoL as a secondary outcome measure. This was especially true for presentation and interpretation of results.

Overview on HRQoL outcomes

From our literature search, we identified 8 RCTs investigating a broad range of patient groups regarding cancer site and stage, disease duration, as well as treatment modality. According to the predefined criteria, reporting of HRQoL data was of moderate to poor quality, especially in terms of completeness and adequate presentation of results. Thus, due to heterogeneity and methodological limitations of studies, no firm conclusions for clinical practice can be drawn.

There is evidence from non-RCTs including HRQoL as a primary outcome that patients with GEP-NET perceive their overall HRQoL as relatively good and stable. However, in-depth evaluation of these studies revealed a range of physical and psychosocial complaints primarily related to diarrhoea, flushing, and fatigue, as well as emotional, social, and role functioning when compared to the general population. Again, it has to be noted that these results should be interpreted with caution and not be considered as a basis for informing clinical practice and decision making. A brief summary of primary outcomes and HRQoL results of the reviewed studies is provided in Additional file 1.

Discussion

The evaluation of HRQoL in patients with GEP-NET has attracted increasing interest in recent years. Despite this positive trend, however, there is still little knowledge available on this topic, and existing studies have major methodological limitations that hinder the application of HRQoL findings in daily clinical practice. The aim of this review was to evaluate the methodological quality of studies on HRQoL in GEP-NET patients, from data collection through to interpretation of results.

Our literature search yielded 58 abstracts ostensibly dealing with HRQoL issues in GEP-NET patients. However, further evaluation reveals that ten of these studies did not assess HRQoL at all but rather performed proxy ratings on physical functioning and self-care abilities. As the agreed definition of HRQoL is that it assesses a range of health issues beyond physical abilities and inevitably comprises patients’ self-reports [7, 2426], these studies were excluded from the systematic review.

The evaluation of the remaining 48 studies, on a positive note, revealed a consistent application of appropriate HRQoL instruments. The majority of studies (35/48) used a cancer-specific questionnaire with already proven reliability and validity. This finding is in line with previous studies on the quality of PRO reporting in oncology RCTs, indicating that a majority of studies including PROs used validated disease- or at least cancer-specific instruments [2729]. In the current review, nine studies amended these questionnaires with ad hoc questions on NET-specific symptoms, such as diarrhoea and hot flushes. It should be noted, however, that this was done in the absence of validated NET-specific PRO instruments. One study, however, administered an ad hoc instrument alone (i.e., not in combination with another validated measure) and another study used a self-constructed questionnaire comprising elements of validated measures. The term ‘ad hoc’ refers to the fact that these questions were not formally developed and had not undergone psychometric testing. In order to ensure high methodological quality and improve comparability of data across different studies, ad hoc questions should be considered only, if there are no appropriate validated PRO instruments [30, 31]. There is awareness of the fact that novel treatment agents may entail a range of symptoms not currently covered by validated PRO/HRQoL instruments [3234] and methodological approaches of addressing this issue are being discussed. The EORTC Quality of Life Group (QLG) runs a database with an item pool including all questions from the disease-specific supplementary modules of the QLQ-C30, validated for cancer patients and different languages. Selecting suitable questions from such an item bank should be preferred over designing ad hoc questions. For patients with GEP-NET, two disease-specific questionnaires, the EORTC QLQ-GI.NET21 [19], a module to be applied together with the core questionnaire QLQ-C30, and the Norfolk QOL-NET [35], a NET-specific stand-alone measure, have become available only recently.

A range of methodological shortcomings were identified in assessing and processing as well as in reporting and interpreting HRQoL data. Most of the reviewed studies were heterogeneous in terms of study design and quality making it impossible to draw meaningful conclusions for clinical practice at this point. This refers primarily to studies investigating HRQoL as a secondary outcome. A large percentage of these studies provided only crude or incomplete presentations of HRQoL results or did not apply correct scoring procedures as prescribed by respective manuals. One of the included RCTs used HRQoL as a secondary outcome, as indicated in the clinical trial protocol as well as in the Methods section of the respective main publication, but failed to report on these issues both in the Results and Discussion section. Another common limitation was the lack of information on the statistical approach of handling missing HRQoL data, which was also found in previous reviews including different malignancies such as brain, bladder, prostate, and gynaecological cancers [27, 28, 36, 37]. These limitations were apparent even in high-evidence studies that are likely to impact on health policy and practice. None of the eight RCTs included in this review could provide HRQoL information in a way that would allow its use for informed decision making and planning future trials. Thus, while acknowledging the need for assessing HRQoL as an important secondary outcome in clinical studies, there seems to be an uncertainty about the processing of the collected data [14, 3840]. Similar to the results of previous studies investigating the methodological quality of PRO reporting in patients with brain [27], prostate [36], and gynaecological [28] cancers, further problems were related to the interpretation of HRQoL results, especially regarding the clinical significance of HRQoL findings (e.g., changes over time, differences between treatment arms). Studies included in this review that used HRQoL as a primary outcome provided evidence that patients present with impairments in multiple domains such as emotional, role, and social functioning when compared to general population norms. This is in contrast to findings showing that GEP-NET patients generally perceived their HRQoL as relatively good. As mentioned above, to date, existing studies do not allow for firm conclusions and call for further research to elucidate the time course of HRQoL in this patient group.

Two recent review articles [29, 39] evaluating the methodological quality of PRO reporting in high-evidence studies on different cancer types indicated that the overall level of reporting according to the CONSORT PRO extension criteria was poor. Exceptions were studies assessing HRQoL as a primary outcome and/or presenting a supplementary report on HRQoL issues which showed a better performance. The overall quality of PRO reporting might benefit from increasing familiarity with HRQoL issues and the development of the above mentioned guidelines [29, 36, 39]. However, in spite of this development, a recent review on the consistency of available PRO-specific guidance has identified a clear lack of respective recommendations for the appropriate implementation of PROs in clinical research [41]. Although the checklists applied in this review [14, 16] do not represent an exhaustive set of criteria for high-quality HRQoL assessment for studies including HRQoL either as a primary or secondary outcome, their application both during study planning and reporting would substantially enhance the quality of the assessed data.

Therefore, while agreeing that further guidance is required to make HRQoL assessment more feasible and – with increasing quality – accessible for clinical use, we emphasise the need to adhere to already existing quality standards. Important scientific societies that have shaped the field of HRQoL research in oncology over the past two decades, such as the EORTC QLG, the FACIT group and the International Society for Quality of Life Research (ISOQOL), provide a well-informed basis for the application of PROs and should therefore be consulted when considering their incorporation into clinical trials.

In the field of GEP-NET research, there is a growing number of clinical trials considering HRQoL as an outcome measure [4248]. However, two recent, not yet published, phase III trials fail to incorporate PRO or HRQoL assessments, as indicated in the respective study protocols [49, 50]. Furthermore, the methodological quality of information derived thus far is not satisfactory. Considering the fact that such studies have the potential to impact on health policy and practice, the importance of generating high-quality HRQoL data cannot be overstated. Poorly designed and/or reported PROs are likely to undermine the credibility of the results, which in turn hinders their application in daily clinical practice [9, 14, 27, 29, 37, 39, 40]. Especially with the movement towards a more patient-centred health care system, the incorporation of the patient’s subjective perspective plays a pivotal role in facilitating patient involvement in health care, thereby enhancing patient empowerment and satisfaction [51].

Conclusions

Despite an increasing interest in assessing HRQoL in patients with GEP-NET, there is still little knowledge on the course of HRQoL over time, highlighting the need for high-quality longitudinal studies. Existing studies show methodological shortcomings in both processing and reporting of HRQoL data, especially when included as a secondary outcome in clinical trials. Methodological limitations were identified even for studies with high evidence level, which is considered problematic given their impact on health policy and medical practice. Thus, the valid application of HRQoL findings in clinical practice is hampered not only by lack of studies, but also by various methodological limitations of the existing ones. High-quality, well-reported HRQoL data is of utmost importance to make results accessible and useful to patients and their treating physicians. Therefore, it is strongly recommended to adhere to existing guidelines on the incorporation of PROs into clinical research.

Abbreviations

CONSORT: 

Consolidated standards of reporting trials

EORTC: 

European Organisation for research and treatment of cancer

FACIT: 

Functional assessment of chronic illness therapy

GEP-NET: 

Gastroenteropancreatic neuroendocrine tumours

HRQoL: 

Health-related quality of life

ISOQOL: 

International society for quality of life research

Norfolk QOL-NET: 

Norfolk quality of life – neuroendocrine tumor questionnaire

PRISMA: 

Preferred reporting items of systematic reviews and meta-analyses

PRO: 

Patient-reported outcome

QLG: 

Quality of life group

QLQ-C30: 

Quality of life questionnaire core 30

QLQ-GI.NET21: 

Quality of life questionnaire – neuroendocrine carcinoid

Declarations

Acknowledgements

The work of CM was funded by the Austrian Science Fund (FWF): P269300.

Funding

The work of CM was funded by the Austrian Science Fund (FWF): P269300.

Availability of data and material

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Authors’ contributions

CM and EMG performed eligibility assessment and data extraction and drafted the manuscript. LW participated in eligibility assessment and data extraction and contributed to the revision of the manuscript. BN participated in drafting and revising the manuscript. BSU, BH, and IV made substantial contributions to conception and design and were involved in revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department for Psychiatry, Psychotherapy and Psychosomatics, Medical University of Innsbruck
(2)
Department for Nuclear Medicine, Medical University of Innsbruck

References

  1. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, et al. One hundred years after “carcinoid”: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063–72.View ArticlePubMedGoogle Scholar
  2. Scarsbrook AF, Ganeshan A, Statham J, Thakker RV, Weaver A, Talbot D, Boardman P, Bradley KM, Gleeson FV, Phillips RR. Anatomic and functional imaging of metastatic carcinoid tumors. RadioGraphics. 2007;27:455–76.View ArticlePubMedGoogle Scholar
  3. Tomassetti P, Campana D, Piscitelli L, Casadei R, Santini D, Nori F, Morselli-Labate AM, Pezzilli R, Corinaldesi R. Endocrine pancreatic tumors: factors correlated with survival. Ann Oncol. 2005;16:1806–10.View ArticlePubMedGoogle Scholar
  4. Vinjamuri S, Gilbert TM, Banks M, McKane G, Maltby P, Poston G, Weissman H, Palmer DH, Vora J, Pritchard DM, et al. Peptide receptor radionuclide therapy with 90Y-DOTATATE/90Y-DOTATOC in patients with progressive metastatic neuroendocrine tumours: assessment of response, survival and toxicity. Br J Cancer. 2013;108:1440–8.View ArticlePubMedPubMed CentralGoogle Scholar
  5. Basch E, Iasonos A, McDonough T, Barz A, Culkin A, Kris MG, Scher HI, Schrag D. Patient versus clinician symptom reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events: results of a questionnaire-based study. Lancet Oncol. 2006;7:309–909.View ArticleGoogle Scholar
  6. Cella DF. Measuring quality of life in palliative care. Semin Oncol. 1995;22:73–81.PubMedGoogle Scholar
  7. U.S. Department of Health and Human Services FDA Center for Drug Evaluation and Research. Guidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims: draft guidance. Health Qual Life Outcomes. 2006;4:79.View ArticlePubMed CentralGoogle Scholar
  8. Brundage M, Blazeby J, Revicki D, Bass B, de Vet H, Duffy H, Efficace F, King M, Lam CL, Moher D, et al. Patient-reported outcomes in randomized clinical trials: development of ISOQOL reporting standards. Qual Life Res. 2013;22:1161–75.View ArticlePubMedGoogle Scholar
  9. Efficace F, Rees J, Fayers P, Pusic A, Taphoorn M, Greimel E, Reijneveld J, Whale K, Blazeby J. Overcoming barriers to the implementation of patient-reported outcomes in cancer clinical trials: the PROMOTION Registry. Health Qual Life Outcomes. 2014;12:86.View ArticlePubMedPubMed CentralGoogle Scholar
  10. Reeve BB, Mitchell SA, Dueck AC, Basch E, Cella D, Reilly CM, Minasian LM, Denicoff AM, O’Mara AM, Fisch MJ, et al.: Recommended patient-reported core set of symptoms to measure in adult cancer treatment trials. J Natl Cancer Inst. 2014;106(7). doi:https://doi.org/10.1093/jnci/dju129.
  11. Ramage JK, Ahmed A, Ardill J, Bax N, Breen DJ, Caplin ME, Corrie P, Davar J, Davies AH, Lewington V, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut. 2012;61:6–32.View ArticlePubMedGoogle Scholar
  12. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann Intern Med. 2009;151:264–9.View ArticlePubMedGoogle Scholar
  13. Cochrane Consumers and Communication Group: Consumers and Communication Group resources for authors. Data extraction template. 2013. https://cccrg.cochrane.org/author-resources. Accessed 25 Sep 2014
  14. Efficace F, Bottomley A, Osoba D, Gotay C, Flechtner H, D’haese S, Zurlo A. Beyond the development of health-related quality-of-life (HRQOL) measures: a checklist for evaluating HRQOL outcomes in cancer clinical trials--does HRQOL evaluation in prostate cancer research inform clinical decision making? J Clin Oncol. 2003;21:3502–11.View ArticlePubMedGoogle Scholar
  15. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:159–74.View ArticlePubMedGoogle Scholar
  16. Calvert M, Brundage M, Jacobsen PB, Schünemann HJ, Efficace F. The CONSORT patient-reported outcome (PRO) extension: implications for clinical trials and practice. Health Qual Life Outcomes. 2013;11:184.View ArticlePubMedPubMed CentralGoogle Scholar
  17. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365–76.View ArticlePubMedGoogle Scholar
  18. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol. 1998;16:139–44.PubMedGoogle Scholar
  19. Yadegarfar G, Friend L, Jones L, Plum LM, Ardill J, Taal B, Larsson G, Jeziorski K, Kwekkeboom D, Ramage JK. Validation of the EORTC QLQ-GINET21 questionnaire for assessing quality of life of patients with gastrointestinal neuroendocrine tumours. Br J Cancer. 2013;108:301–10.View ArticlePubMedPubMed CentralGoogle Scholar
  20. Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, Silberman M, Yellen SB, Winicour P, Brannon J, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol. 1993;11:570–9.PubMedGoogle Scholar
  21. Cella DF, Riley W, Stone A, Rothrock N, Reeve B, Yount S, Amtmann D, Bode R, Buysse D, Choi S, et al. Initial adult health item banks and first wave testing of the Patient-Reported Outcomes Measurement Information System (PROMIS) Network: 2005–2008. J Clin Epidemiol. 2010;63:1179–94.View ArticlePubMedPubMed CentralGoogle Scholar
  22. Derogatis LR. The psychosocial adjustment to illness scale (PAIS). J Psychosom Res. 1986;30:77–91.View ArticlePubMedGoogle Scholar
  23. Lipscomb J, Gotay CC, Snyder CF. Patient-reported outcomes in cancer: A review of recent research and policy initiatives. CA Cancer J Clin. 2007;57:278–300.View ArticlePubMedGoogle Scholar
  24. Reeve BB, Wyrwich KW, Wu AW, Velikova G, Terwee CB, Snyder CF, Schwartz C, Revicki DA, Moinpour CM, McLeod LD, et al. ISOQOL recommends minimum standards for patient-reported outcome measures used in patient-centered outcomes and comparative effectiveness research. Qual Life Res. 2013;22:1889–905.View ArticlePubMedGoogle Scholar
  25. Velikova G, Stark D, Selby P. Quality of life instruments in oncology. Eur J Cancer. 1999;35:1571–80.View ArticlePubMedGoogle Scholar
  26. Wilson KA, Dowling AJ, Abdolell M, Tannock IF. Perception of quality of life by patients, partners and treating physicians. Qual Life Res. 2000;9:1041–52.View ArticlePubMedGoogle Scholar
  27. Dirven L, Taphoorn MJ, Reijneveld JC, Blazeby J, Jacobs M, Pusic A, La Sala E, Stupp R, Fayers P, Efficace F. The level of patient-reported outcome reporting in randomised controlled trials of brain tumour patients: a systematic review. Eur J Cancer. 2014;50:2432–48.View ArticlePubMedGoogle Scholar
  28. Efficace F, Jacobs M, Pusic A, Greimel E, Piciocchi A, Kieffer JM, Gilbert A, Fayers P, Blazeby J. Patient-reported outcomes in randomised controlled trials of gynaecological cancers: investigating methodological quality and impact on clinical decision-making. Eur J Cancer. 2014;50:1925–41.View ArticlePubMedGoogle Scholar
  29. Efficace F, Fayers P, Pusic A, Cemal Y, Yanagawa J, Jacobs M, la Sala A, Cafaro V, Whale K, Rees J, Blazeby J. Quality of patient-reported outcome reporting across cancer randomized controlled trials according to the CONSORT patient-reported outcome extension: A pooled analysis of 557 trials. Cancer. 2015;121:3335–42.View ArticlePubMedPubMed CentralGoogle Scholar
  30. Pusic AL, Chen CM, Cano S, Klassen A, McCarthy C, Collins ED, Cordeiro PG. Measuring quality of life in cosmetic and reconstructive breast surgery: a systematic review of patient-reported outcomes instruments. Plast Reconstr Surg. 2007;120:823–37. discussion 838–829.View ArticlePubMedGoogle Scholar
  31. Sears ED, Chung KC. A guide to interpreting a study of patient-reported outcomes. Plast Reconstr Surg. 2012;129:1200–7.View ArticlePubMedPubMed CentralGoogle Scholar
  32. Basch E, Reeve BB, Mitchell SA, Clauser SB, Minasian LM, Dueck AC, Mendoza TR, Hay J, Atkinson TM, Abernethy AP, et al.: Development of the National Cancer Institute’s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). J Natl Cancer Inst 2014, 106Google Scholar
  33. Kluetz PG, Chingos DT, Basch EM, Mitchell SA. Patient-Reported Outcomes in Cancer Clinical Trials: Measuring Symptomatic Adverse Events With the National Cancer Institute’s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Am Soc Clin Oncol Educ Book. 2016;35:67–73.View ArticlePubMedGoogle Scholar
  34. Kluetz PG, Slagle A, Papadopoulos EJ, Johnson LL, Donoghue M, Kwitkowski VE, Chen W-H, Sridhara R, Farrell AT, Keegan P, et al. Focusing on Core Patient-Reported Outcomes in Cancer Clinical Trials: Symptomatic Adverse Events, Physical Function, and Disease-Related Symptoms. Clin Cancer Res. 2016;22:1553–8.View ArticlePubMedGoogle Scholar
  35. Vinik E, Carlton CA, Silva MP, Vinik AI. Development of the Norfolk quality of life tool for assessing patients with neuroendocrine tumors. Pancreas. 2009;38:e87–95.View ArticlePubMedGoogle Scholar
  36. Efficace F, Feuerstein M, Fayers P, Cafaro V, Eastham J, Pusic A, Blazeby J. Patient-reported outcomes in randomised controlled trials of prostate cancer: methodological quality and impact on clinical decision making. Eur Urol. 2014;66:416–27.View ArticlePubMedGoogle Scholar
  37. Feuerstein MA, Jacobs M, Piciocchi A, Bochner B, Pusic A, Fayers P, Blazeby J, Efficace F. Quality of life and symptom assessment in randomized clinical trials of bladder cancer: A systematic review. Urol Oncol. 2015;33:331. e317-323.View ArticlePubMedPubMed CentralGoogle Scholar
  38. Brundage M, Bass B, Davidson J, Queenan J, Bezjak A, Ringash J, Wilkinson A, Feldman-Stewart D. Patterns of reporting health-related quality of life outcomes in randomized clinical trials: implications for clinicians and quality of life researchers. Qual Life Res. 2011;20:653–64.View ArticlePubMedGoogle Scholar
  39. Bylicki O, Gan HK, Joly F, Maillet D, You B, Péron J. Poor patient-reported outcomes reporting according to CONSORT guidelines in randomized clinical trials evaluating systemic cancer therapy. Ann Oncol. 2015;26:231–7.View ArticlePubMedGoogle Scholar
  40. Rees JR, Whale K, Fish D, Fayers P, Cafaro V, Pusic A, Blazeby JM, Efficace F. Patient-reported outcomes in randomised controlled trials of colorectal cancer: an analysis determining the availability of robust data to inform clinical decision-making. J Cancer Res Clin Oncol. 2015;141:2181–92.View ArticlePubMedGoogle Scholar
  41. Calvert M, Kyte D, Duffy H, Gheorghe A, Mercieca-Bebber R, Ives J, Draper H, Brundage M, Blazeby J, King M. Patient-reported outcome (PRO) assessment in clinical trials: a systematic review of guidance for trial protocol writers. PLoS One. 2014;9:e110216.View ArticlePubMedPubMed CentralGoogle Scholar
  42. Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlackova E, Cadiot G, Wolin EM, Capdevila J, Wall L, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371:224–33.View ArticlePubMedGoogle Scholar
  43. Ducreux M, Dahan L, Smith D, O’Toole D, Lepère C, Dromain C, Vilgrain V, Baudin E, Lombard-Bohas C, Scoazec JY, et al. Bevacizumab combined with 5-FU/streptozocin in patients with progressive metastatic well-differentiated pancreatic endocrine tumours (BETTER trial) – A phase II non-randomised trial. Eur J Cancer. 2014;50:3098–106.View ArticlePubMedGoogle Scholar
  44. Mitry E, Walter T, Baudin E, Kurtz JE, Ruszniewski P, Dominguez-Tinajero S, Bengrine-Lefevre L, Cadiot G, Dromain C, Farace F, et al. Bevacizumab plus capecitabine in patients with progressive advanced well-differentiated neuroendocrine tumors of the gastro-intestinal (GI-NETs) tract (BETTER trial) – A phase II non-randomised trial. Eur J Cancer. 2014;50:3107–15.View ArticlePubMedGoogle Scholar
  45. Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin EM, Tomasek J, Raderer M, Lahner H, Voi M, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387:968–77.View ArticlePubMedGoogle Scholar
  46. Ipsen. Efficacy and safety study in pancreatic or midgut neuroendocrine tumours having progressed radiologically while previously treated with Lanreotide Autogel® 120 mg (CLARINET FORTE). In: ClinicalTrialsgov [Internet]. Bethesda: National Library of Medicine (US); 2000. [cited 2016 Jul 11]. Available from: https://clinicaltrials.gov/ct2/show/NCT02651987.Google Scholar
  47. Vinik AI, Wolin EM, Liyanage N, Gomez-Panzani E, Fisher GA: Evaluation of lanreotide depot/autogel efficacy and safety as a carcinoid syndrome treatment (ELECT): A randomized, double-blind, placebo-controlled trial. Endocr Pract in press.Google Scholar
  48. Advanced Accelerator Applications. A study comparing treatment with 177Lu-DOTA0-Tyr3-octreotate to octreotide LAR in patients with inoperable, progressive, somatostatin receptor positive midgut carcinoid tumours (NETTER-1). In: ClinicalTrialsgov [Internet]. Bethesda: National Library of Medicine (US); 2000. [cited 2016 Jul 11]. Available from: https://clinicaltrials.gov/ct2/show/NCT01578239.Google Scholar
  49. Lexicon Pharmaceuticals L. Telotristat etiprate for carcinoid syndrome therapy (TELECAST). In: ClinicalTrialsgov [Internet]. Bethesda: National Library of Medicine (US); 2000. [cited 2016 Jul 11]. Available from: https://clinicaltrials.gov/ct2/show/NCT02063659.Google Scholar
  50. Lexicon Pharmaceuticals L. TELESTAR (Telotristat etiprate for somatostatin analogue not adequately controlled carcinoid syndrome). In: ClinicalTrialsgov [Internet]. Bethesda: National Library of Medicine (US); 2000. [cited 2016 Jul 11]. Available from: https://clinicaltrials.gov/ct2/show/NCT01677910.Google Scholar
  51. Greenhalgh J. The applications of PROs in clinical practice: what are they, do they work, and why? Qual Life Res. 2009;18:115–23.View ArticlePubMedGoogle Scholar
  52. Arnold R, Rinke A, Klose KJ, Müller HH, Wied M, Zamzow K, Schmidt C, Schade-Brittinger C, Barth P, Moll R, et al. Octreotide versus octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: A randomized trial. Clin Gastroenterol Hepatol. 2005;3:761–71.View ArticlePubMedGoogle Scholar
  53. Bajetta E, Procopio G, Catena L, Martinetti A, De Dosso S, Ricci S, Lecchi AS, Boscani PF, Iacobelli S, Carteni G, et al. Lanreotide Autogel every 6 weeks compared with lanreotide microparticles every 3 weeks in patients with well differentiated neuroendocrine tumors. Cancer. 2006;107:2474–81.View ArticlePubMedGoogle Scholar
  54. Jacobsen MB, Hanssen LE. Clinical effects of octreotide compared to placebo in patients with gastrointestinal neuroendocrine tumours. Report on a double-blind, randomized trial. J Intern Med. 1995;237:269–75.View ArticlePubMedGoogle Scholar
  55. Meyer T, Qian W, Caplin ME, Armstrong G, Lao-Sirieix SH, Hardy R, Valle JW, Talbot DC, Cunningham D, Reed N, et al. Capecitabine and streptozocin ± cisplatin in advanced gastroenteropancreatic neuroendocrine tumours. Eur J Cancer. 2014;50:902–11.View ArticlePubMedGoogle Scholar
  56. Raymond E, Dahan L, Raoul J-L, Bang Y-J, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501–13.View ArticlePubMedGoogle Scholar
  57. Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID Study Group. J Clin Oncol. 2009;27:4656–63.View ArticlePubMedGoogle Scholar
  58. Bodei L, Cremonesi M, Grana CM, Fazio N, Iodice S, Baio SM, Bartolomei M, Lombardo D, Ferrari ME, Sansovini, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE: The IEO phase I-II study. Eur J Nucl Med Mol Imaging. 2011;38:2125–35.View ArticlePubMedGoogle Scholar
  59. Bushnell DL, O’Dorisio TM, O’Dorisio MS, Menda Y, Hicks RJ, Van Cutsem E, Baulieu JL, Borson-Chazot F, Anthony L, Benson AB, et al. 90Y-Edotreotide for metastatic carcinoid refractory to octreotide. J Clin Oncol. 2010;28:1652–9.View ArticlePubMedPubMed CentralGoogle Scholar
  60. Claringbold PG, Brayshaw PA, Price RA, Turner JH. Phase II study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2011;38:302–11.View ArticlePubMedGoogle Scholar
  61. Cwikla JB, Sankowski A, Seklecka N, Buscombe JR, Nasierowska-Guttmejer A, Jeziorski KG, Mikolajczak R, Pawlak D, Stepien K, Walecki J. Efficacy of radionuclide treatment DOTATATE Y-90 in patients with progressive metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs): a phase II study. Ann Oncol. 2010;21:787–94.View ArticlePubMedGoogle Scholar
  62. Delpassand ES, Samarghandi A, Zamanian S, Wolin EM, Hamiditabar M, Espenan GD, Erion JL, O’Dorisio TM, Kvols LK, Simon J, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE for patients with somatostatin receptor-expressing neuroendocrine tumors. Pancreas. 2014;43:518–25.View ArticlePubMedGoogle Scholar
  63. Frilling A, Weber F, Saner F, Bockisch A, Hofmann M, Müller-Brand J, Brölsch CE. Treatment with 90Y- and 177Lu-DOTATOC in patients with metastatic neuroendocrine tumors. Surgery. 2006;140:968–77.View ArticlePubMedGoogle Scholar
  64. Khan S, Krenning EP, van Essen M, Kam BL, Teunissen JJ, Kwekkeboom DJ. Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumors treated with [177Lu-DOTA0, Tyr3]Octreotate. J Nucl Med. 2011;52:1361–8.View ArticlePubMedGoogle Scholar
  65. Korse CM, Bonfrer JM, Aaronson NK, Hart AA, Taal BG. Chromogranin A as an alternative to 5-hydroxyindoleacetic acid in the evaluation of symptoms during treatment of patients with neuroendocrine Tumors. Neuroendocrinology. 2009;89:296–301.View ArticlePubMedGoogle Scholar
  66. Kulke MH, Lenz H-J, Meropol NJ, Posey J, Ryan DP, Picus J, Bergsland E, Stuart K, Tye L, Huang X, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol. 2008;26:3403–10.View ArticlePubMedGoogle Scholar
  67. Kvols LK, Oberg KE, O’Dorisio TM, Mohideen P, de Herder WW, Arnold R, Hu K, Zhang Y, Hughes G, Anthony L, Wiedenmann B. Pasireotide (SOM230) shows efficacy and tolerability in the treatment of patients with advanced neuroendocrine tumors refractory or resistent to octreotide LAR: results from a phase II study. Endocr Relat Cancer. 2012;19:657–66.View ArticlePubMedGoogle Scholar
  68. Martín-Richard M, Massutí B, Pineda E, Alonso V, Marmol M, Castellano D, Fonseca E, Galán A, Llanos M, Sala MA, et al. Antiproliferative effects of lanreotide autogel in patients with progressive, well-differentiated neuroendocrine tumours: a Spanish, multicentre, open-label, single arm phase II study. BMC Cancer. 2013;13:427.View ArticlePubMedPubMed CentralGoogle Scholar
  69. Ruszniewski P, Ish-Shalom S, Wymenga M, O’Toole D, Arnold R, Tomassetti P, Bax N, Caplin M, Eriksson B, Glaser B, et al. Rapid and sustained relief from the symptoms of carcinoid syndrome: Results from an open 6-months study of the 28-day prolonged-release formulation of lanreotide. Neuroendocrinology. 2004;80:244–51.View ArticlePubMedGoogle Scholar
  70. Wymenga AN, Eriksson B, Salmela PI, Jacobsen MB, Van Cutsem EJ, Fiasse RH, Välimäki MJ, Renstrup J, de Vries EG, Oberg KE. Efficacy and safety pf prolonged-release lanreotide in patients with gastrointestinal neuroendocrine tumors and hormone-related symptoms. J Clin Oncol. 1999;17:1111–7.PubMedGoogle Scholar
  71. Zuetenhorst JM, Valdes Olmos RA, Muller M, Hoefnagel CA, Taal BG. Interferon and meta-iodobenzylguanidin combinations in the treatment of metastatic carcinoid tumours. Endocr Relat Cancer. 2004;11:553–61.View ArticlePubMedGoogle Scholar
  72. Fröjd C, Larsson G, Lampic C, von Essen L. Health related quality of life and psychosocial function among patients with carcinoid tumours. A longitudinal, prospective, and comparative study. Health Qual Life Outcomes. 2007;5:18.View ArticlePubMedPubMed CentralGoogle Scholar
  73. Fröjd C, Lampic C, Larsson G, von Essen L. Is satisfaction with doctors’ care related to health-related quality of life, anxiety and depression among patients with carcinoid tumours? A longitudinal report. Scand J Caring Sci. 2009;23:107–16.View ArticlePubMedGoogle Scholar
  74. Haugland T, Veenstra M, Vatn MH, Wahl AK. Improvement in stress, general self-efficacy, and health related quality of life following patient education for patients with neuroendocrine tumors: A pilot study. Nurs Res Pract. 2013;2013:695820.PubMedPubMed CentralGoogle Scholar
  75. Kalinowski M, Dressler M, König A, El-Sheik M, Rinke A, Höffken H, Gress TM, Arnold R, Klose KJ, Wagner HJ. Selective internal radiotherapy with Yttrium-90 microspheres for hepatic metastatic neuroendocrine tumors: A prospective single center study. Digestion. 2009;79:137–42.View ArticlePubMedGoogle Scholar
  76. Kwekkeboom DJ, Bakker WH, Kam BL, Teunissen JJ, Kooij PP, de Herder WW, Feelders RA, van Eijck CH, de Jong M, Srinivasan A, et al. Treatment of patients with gastro-entero-pancreatic (GEP) tumours with the novel radiolabelled somatostatin analogue [177Lu-DOTA0, Tyr3]octreotate. Eur J Nucl Med Mol Imaging. 2003;30:417–22.View ArticlePubMedPubMed CentralGoogle Scholar
  77. Larsson G, Janson ET. Anemia in patients with midgut carcinoid, treated with alpha interferon: effects by erythropoietin treatment on the perceived quality of life. Eur J Cancer Care (Engl). 2008;17:200–4.View ArticleGoogle Scholar
  78. Larsson G, Sjödén PO, Oberg K, Eriksson B, von Essen L. Health-related quality of life, anxiety and depression in patients with midgut carcinoid tumours. Acta Oncol. 2001;40:825–31.View ArticlePubMedGoogle Scholar
  79. O’Toole D, Ducreux M, Bommelaer G, Wemeau JL, Bouché O, Catus F, Blumberg J, Ruszniewski P. Treatment of carcinoid syndrome: A prospective crossover evaluation of lanreotide versus octreotide in terms of efficacy, patient acceptability, and tolerance. Cancer. 2000;88:770–6.View ArticlePubMedGoogle Scholar
  80. Pasieka JL, McEwan AJ, Rorstad O. The palliative role of 131I-MIBG and 111In-octreotide therapy in patients with metastatic progressive neuroendocrine neoplasms. Surgery. 2004;136:1218–26.View ArticlePubMedGoogle Scholar
  81. Spolverato G, Bagante F, Wagner D, Buettner S, Gupta R, Kim Y, Magsood H, Pawlik TM. Quality of life after treatment of neuroendocrine liver metastasis. J Surg Res. 2015;198:155–64.View ArticlePubMedGoogle Scholar
  82. Teunissen JJ, Kwekkeboom DJ, Krenning EP. Quality of life in patients with gastroenteropancreatic tumors treated with [177Lu-DOTA0, Tyr3]octreotate. J Clin Oncol. 2004;22:2724–9.View ArticlePubMedGoogle Scholar
  83. Beaumont JL, Cella D, Phan AT, Choi S, Liu Z, Yao JC. Comparison of health-related quality of life in patients with neuroendocrine tumors with quality of life in the general US population. Pancreas. 2012;41:461–6.View ArticlePubMedGoogle Scholar
  84. Pearman TP, Beaumont JL, Cella D, Neary MP, Yao J. Health-related quality of life in patients with neuroendocrine tumors: an investigation of treatment type, disease status, and symptom burden. Support Care Cancer. 2016;24:3695–703.View ArticlePubMedGoogle Scholar
  85. Gelhorn HL, Kulke MH, O’Dorisio T, Yang QM, Jackson J, Jackson S, Boehm KA, Law L, Kostelec J, Auguste P, Lapuerta P. Patient-reported Symptom Experiences in Patients With Carcinoid Syndrome After Participation in a Study of Telotristat Etiprate: A Qualitative Interview Approach. Clin Ther. 2016;38:759–68.View ArticlePubMedGoogle Scholar
  86. Haugland T, Vatn MH, Veenstra M, Wahl AK, Natvig GK. Health related quality of life in patients with endocrine tumors compared with the general Norwegian population. Qual Life Res. 2009;18:719–26.View ArticlePubMedGoogle Scholar
  87. Haugland T, Wahl AK, Hofoss D, DeVon HA. Association between general self-efficacy, social support, cancer-related stress and physical health-related quality of life: a path model study in patients with neuroendocrine tumors. Health Qual Life Outcomes. 2016;14:11.View ArticlePubMedPubMed CentralGoogle Scholar
  88. Larsson G, von Essen L, Sjödén PO. Quality of life in patients with endocrine tumors of the gastrointestinal tract: Patient and staff perceptions. Cancer Nurs. 1998;21:411–20.View ArticlePubMedGoogle Scholar
  89. Larsson G, Sjödén PO, Oberg K, von Essen L. Importance-satisfaction discrepancies are associated with health-related quality of life in five-year survivors of endocrine gastrointestinal tumours. Ann Oncol. 1999;10:1321–7.View ArticlePubMedGoogle Scholar
  90. Larsson G, von Essen L, Sjödén PO. Health-related quality of life in patients with endocrine tumours of the gastrointestinal tract. Acta Oncol. 1999;38:481–90.View ArticlePubMedGoogle Scholar
  91. Larsson G, Haglund K, von Essen L. Distress, quality of life and strategies to ‘keep a good mood’ in patients with carcinoid tumours: patient and staff perceptions. Eur J Cancer Care (Engl). 2003;12:46–57.View ArticleGoogle Scholar
  92. Larsson G, von Essen L, Sjödén PO. Are importance-satisfaction discrepancies with regard to ratings of specific health-related quality-of-life aspects valid indicators of disease- and treatment-related distress among patients with endocrine gastronintestinal tumours? Eur J Cancer Care (Engl). 2007;16:493–9.View ArticleGoogle Scholar
  93. Petzel MQ, Parker NH, Valentine AD, Simard S, Nogueras-Gonzalez GM, Lee JE, Pisters PW, Vauthey JN, Fleming JB, Katz MH. Fear of cancer recurrence after curative pancreatectomy: A cross-sectional study in survivors of pancreatic and periampullary tumors. Ann Surg Oncol. 2012;19:4078–84.View ArticlePubMedGoogle Scholar
  94. Pezzilli R, Campana D, Morselli-Labate AM, Fabbri MC, Brocchi E, Tomassetti P. Patient-reported outcomes in subjects with neuroendocrine tumors of the pancreas. World J Gastroenterol. 2009;15:5067–73.View ArticlePubMedPubMed CentralGoogle Scholar
  95. Pezzilli R, Campana D, Morselli-Labate AM, Galassi E, Brocchi E, Nori F, Cipollini ML, Tomassetti P. Patient-reported outcomes in patients with endocrine tumors of the ileum. Eur J Gastroenterol Hepatol. 2010;22:689–94.PubMedGoogle Scholar
  96. Ruszniewski P, Valle JW, Lombard-Bohas C, Cuthbertson DJ, Perros P, Holubec L, Delle Fave G, Smith D, Niccoli P, Maisonobe P, et al. Patient-reported outcomes with lanreotide Autogel/Depot for carcinoid syndrome: An international observational study. Dig Liver Dis. 2016;48:552–8.View ArticlePubMedGoogle Scholar
  97. van der Horst-Schrivers AN, van Ieperen E, Wymenga AN, Boezen HM, Weijmar-Schultz WC, Kema IP, Meijer WG, de Herder WW, Willemse PH, Links TP, de Vries EG. Sexual function in patients with metastatic midgut carcinoid tumours. Neuroendocrinology. 2009;89:231–6.View ArticlePubMedGoogle Scholar
  98. von Essen L, Larsson G, Oberg K, Sjödén PO. ‘Satisfaction with care’: associations with health-related quality of life and psychosocial function among Swedish patients with endocrine gastrointestinal tumours. Eur J Cancer Care (Engl). 2002;11:91–9.View ArticleGoogle Scholar
  99. Garcia-Hernandez J, Mohmaduvesh M, Davies P, Toumpanakis C, Goodhand JR, Caplin M: PMO-023 Assessment of quality of life, coping strategies and personal beliefs in neuroendocrine tumour patients. 2012. http://gut.bmj.com/content/61/Suppl_2/A82.2.short. Accessed 28 Sep 2015
  100. Gyökeres T: The use of validated quality of life questionnaries in patients with neuroendocrine tumors. The results of the national multicenter study (SAS-LAR-QOL) of 93 patients. Z Gastroenterol 2010, 48. https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0030-1254762. Accessed 28 Sep 2015.
  101. Marinova M, Muecke M, Mahlberg L, Essler M, Cuhls H, Radbruch L, Ahmadzadehfar H. Quality of life assessment following peptide receptor radionuclide therapy (PRRT) of pancreatic neuroendocrine tumor (P-NET). J Nucl Med. 2016;57:1462. http://jnm.snmjournals.org/content/57/supplement_2/1462. Accessed 12 Jul 2016.Google Scholar
  102. Pavel M: NANETS 2013, Safety and quality-of-life (QOL) assessments in the open-label, multicenter, phase 3b, expanded access study of everolimus in patients with advanced neuroendocrine tumors (NET). 2013. https://www.nanets.net/nanets_cd/2013/pdfs/C27-pavelabstract.pdf. Accessed 28 Sep 2015
  103. Strosberg J: NANETS 2015, Neuroendocrine Tumor Symposium Abstracts: 177-Lu-Dotatate significantly improves progression-free survival in patients with mid-gut neuroendocrine tumours: Results of the phase III NETTER-1 trial. 2015. https://www.nanets.net/nanets_cd/2015/pdfs/C39.pdf. Accessed 12 Jul 2016

Copyright

© The Author(s). 2016

Advertisement