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

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 [1‐4]. 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 [8‐10]. 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.

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].

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, 24‐26], 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 [27‐29]. 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 [32‐34] 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, 38‐40]. 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 [42‐48]. 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].

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.