The Challenges of Measuring and Valuing Quality of Life in Preschool Children: A Retrospective Review of NICE Appraisals

Health technology assessment agencies evaluate interventions across the lifespan. However, there is no consensus about best-practice methods to measure health-related quality of life (HRQoL) in preschool children (<5 years) and data are often scarce. We reviewed methods used to capture the HRQoL of preschool children in past National Institute for Health and Care Excellence (NICE) appraisals to establish whether there is a need for better methods in this area and if so, to identify priority research areas. We identified past NICE appraisals that included preschool children, examining the methods used to generate utility values and whether committees believed these captured HRQoL adequately. Of the 12 appraisals, most used generic HRQoL measures designed for adults. Measures were usually completed by adult patients or clinical experts. Committees frequently commented on limitations in the HRQoL data. While acknowledging that data collection may be challenging, committees would value evidence based on HRQoL data from parents or guardians collected as part of a clinical trial. We identified several research priorities including the psychometric properties of existing measures; the feasibility and validity of valuation studies; and mapping. Progress in these areas will help ensure that the aspects of HRQoL which matter to children and their families are captured in NICE evaluations.

Health-related quality of life in primary hepatic cancer: a systematic review assessing the methodological properties of instruments and a meta-analysis comparing treatment strategies

Purpose Patient-reported outcomes including health-related quality of life (HRQoL) are important oncological outcome measures. The validation of HRQoL instruments for patients with hepatocellular and cholangiocellular carcinoma is lacking. Furthermore, studies comparing different treatment options in respect to HRQoL are sparse. The objective of the systematic review and meta-analysis was, therefore, to identify all available HRQoL tools regarding primary liver cancer, to assess the methodological quality of these HRQoL instruments and to compare surgical, interventional and medical treatments with regard to HRQoL. Methods A systematic literature search was conducted in MEDLINE, the Cochrane library, PsycINFO, CINAHL and EMBASE. The methodological quality of all identified HRQoL instruments was performed according to the COnsensus-based Standards for the selection of health status Measurements INstruments (COSMIN) standard. Consequently, the quality of reporting of HRQoL data was assessed. Finally, wherever possible HRQoL data were extracted and quantitative analyses were performed. Results A total of 124 studies using 29 different HRQoL instruments were identified. After the methodological assessment, only 10 instruments fulfilled the psychometric criteria and could be included in subsequent analyses. However, quality of reporting of HRQoL data was insufficient, precluding meta-analyses for 9 instruments. Conclusion Using a standardized methodological assessment, specific HRQoL instruments are recommended for use in patients with hepatocellular and cholangiocellular carcinoma. HRQoL data of patients undergoing treatment of primary liver cancers are sparse and reporting falls short of published standards. Meaningful comparison of established treatment options with regard to HRQoL was impossible indicating the need for future research.

Health-related quality-of-life (HRQoL) analysis from the phase 3 CLEAR trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) for patients (pts) with advanced renal cell carcinoma (aRCC).

4502 Background: LEN + PEMBRO improved PFS, OS and ORR vs SUN in the first-line treatment of pts with aRCC; LEN + EVE improved PFS and ORR vs SUN (Motzer R et al. NEJM. 2021). We report results of a secondary objective of the CLEAR trial comparing the impact of LEN + PEMBRO or EVE vs SUN, on HRQoL. Methods: Pts (N=1069) were randomized (1:1:1) to receive LEN 20 mg PO QD + PEMBRO 200 mg IV Q3W; LEN 18 mg + EVE 5 mg PO QD; or SUN 50 mg PO QD (4 wks on/2 wks off). HRQoL was assessed per FKSI-DRS, EORTC QLQ-C30, and EuroQoL EQ-5D-3L, at baseline, on day 1 of subsequent 3 wk cycles starting with cycle 2, and at the off-treatment visit. HRQoL analyses (unless otherwise noted) were based on data from randomized pts with any HRQoL data who received ≥1 dose of study treatment. No adjustments for multiple testing or estimation were used; P-values and CIs are nominal and descriptive. Results: For comparisons of LEN + PEMBRO vs SUN, overall changes from baseline at mean follow-up (wk 46) favored LEN + PEMBRO with significant differences between treatments for physical functioning (least squares mean difference [LS MD] [95% CI]: 3.0 [0.5, 5.5]) and fatigue (−2.8 [−5.5, −0.1]), dyspnea (−2.8 [−5.3, −0.3]), and constipation (−2.2 [−4.2, −0.2]). LS MD of the FKSI-DRS total score was 0.2 (−0.4, 0.7). For comparisons of LEN + EVE vs SUN, overall changes from baseline at wk 46 favored SUN with significant differences in overall HRQoL (−2.8 [−5.1, −0.5] assessed by the EORTC QLQ-C30 GHS/QoL scale) and pain (2.8 [0.1, 5.5]), appetite loss (4.2 [1.3, 7.1]), and diarrhea (5.3 [2.6, 7.9]). LS MD of the FKSI-DRS total score was −0.4 (−1.0, 0.2). 14 of 18 scales for both LEN + PEMBRO and LEN + EVE vs SUN had no significant differences in LS MD comparisons. The LEN + PEMBRO arm is favored over SUN for the median time to first deterioration (TTD) for physical functioning, dyspnea, appetite loss and EQ-5D VAS (Table). 15 of 19 scales for both LEN + PEMBRO and LEN + EVE vs SUN had no significant differences in TTD comparisons. Conclusions: Compared with SUN, pts in LEN + PEMBRO group had similar or better symptoms and HRQoL. Clinical trial information: NCT02811861. [Table: see text]

Establishing anchor-based minimally important differences for the EORTC QLQ-C30 in glioma patients

Background Minimally important differences (MIDs) allow interpretation of the clinical relevance of health-related quality of life (HRQOL) results. This study aimed to estimate MIDs for all European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) scales for interpreting group-level results in brain tumor patients. Methods Clinical and HRQOL data from three glioma trials were used. Clinical anchors were selected for each EORTC QLQ-C30 scale, based on correlation (&gt;0.30) and clinical plausibility of association. Changes in both HRQOL and the anchors were calculated, and for each scale and time period, patients were categorized into one of the three clinical change groups: deteriorated by one anchor category, no change, or improved by one anchor category. Mean change method and linear regression were applied to estimate MIDs for interpreting within-group change and between-group differences in change over time, respectively. Distribution-based methods were applied to generate supportive evidence. Results A total of 1687 patients were enrolled in the three trials. The retained anchors were performance status and eight Common Terminology Criteria for Adverse Events (CTCAE) scales. MIDs for interpreting within-group change ranged from 4 to 12 points for improvement and −4 to −14 points for deterioration. MIDs for between-group difference in change ranged from 4 to 9 for improvement and −4 to −16 for deterioration. Most anchor-based MIDs were closest to the 0.3 SD distribution-based estimates (range: 3-10). Conclusions MIDs for the EORTC QLQ-C30 scales generally ranged between 4 and 11 points for both within-group mean change and between-group mean difference in change. These results can be used to interpret QLQ-C30 results from glioma trials.

Health-Related Quality of Life Data in Cancer Clinical Trials for Drug Registration: The Value Beyond Reimbursement

PURPOSE A review of the literature was performed to evaluate how quality of life measures are collected, analyzed, and reported in cancer clinical trials intended to support drug registration.Health-related quality of life (HRQoL) data points are one of the patient-reported outcome (PRO) assessments used in clinical trials to evaluate the effects of treatments from the patient perspective. The use of PROs has gained focus in cancer clinical trials as more options become available for greater longevity of patients on treatment. Standardization of PRO data is evolving and involves unique challenges when used for assessing biologic and chemotherapeutic agents for the treatment of cancer. METHODS In this study, a review of literature published between 2009 and 2019 was conducted using PubMed, COCHRANE Library, and Medline. The research focus was on the current guidance, implementation, and reporting as well as highlighting the issues, and recommendations for the inclusion of HRQoL end points in cancer clinical trials intended for use in drug registration. RESULTS Although there exist many levels of guidance for HRQoL measures in cancer drug trials, challenges to operational implementation, the current inconsistent adherence to reporting standards, and the lack of consensus and understanding of analyses limit the value and potential of the resulting data collected. CONCLUSION The results of HRQoL data collected from cancer clinical trials can be difficult to interpret and apply to inform clinical decision making. Increased reporting and access to these data can provide opportunities for potential applications to improve translatability of HRQoL data collected in clinical trials into practice.

Research Objectives, Statistical Analyses and Interpretation of Health-Related Quality of Life Data in Glioma Research: A Systematic Review

Background: Health-related quality of life (HRQoL) has become an increasingly important patient-reported outcome in glioma studies. Ideally, collected HRQoL data should be exploited to the full, with proper analytical methods. This systematic review aimed to provide an overview on how HRQoL data is currently evaluated in glioma studies, focusing on the research objectives and statistical analyses of HRQoL data. Methods: A systematic literature search in the databases PubMed, Embase, Web of Science and Cochrane was conducted up to 5 June 2020. Articles were selected based on predetermined inclusion criteria and information on study design, HRQoL instrument, HRQoL research objective and statistical methods were extracted. Results: A total of 170 articles describing 154 unique studies were eligible, in which 17 different HRQoL instruments were used. HRQoL was the primary outcome in 62% of the included articles, and 51% investigated ≥1 research question with respect to HRQoL, for which various analytical methods were used. In only 42% of the articles analyzing HRQoL results over time, the minimally clinical important difference was reported and interpreted. Eighty-six percent of articles reported HRQoL results at a group level only, and not at the individual patient level. Conclusion: Currently, the assessment and analysis of HRQoL outcomes in glioma studies is highly variable. Opportunities to maximize information obtained with HRQoL data include appropriate and complementary analyses at both the group and individual level, comprehensive reporting of HRQoL results in separate articles or supplementary material, and adherence to existing guidelines about the assessment, analysis and reporting of patient-reported outcomes.

Health-related quality of life of inpatients and outpatients with TB in rural Malawi

INTRODUCTION: Patients being treated for TB may suffer reductions in health-related quality of life (HRQoL). This study aims to assess the extent of such reductions and the trajectory of HRQoL over the course of treatment in rural Malawi.METHODS: We collected patient demographic and socioeconomic status, TB-related characteristics, and HRQoL data (i.e., EQ-5D and a visual analogue scale VAS) from adults (age ≥18 years) being treated for TB in 12 primary health centers and one hospital in rural Thyolo District, Malawi, from 2014 to 2016. Associations between HRQoL and patient characteristics were estimated using multivariable linear regression.RESULTS: Inpatients (n = 197) consistently showed lower median HRQoL scores and suffered more severe health impairments during hospitalization than outpatients (n = 156) (EQ5D and VAS: 0.79, 55 vs. 0.84, 70). Longer treatment duration was associated with higher HRQoL among outpatients (EQ5D: 0.034 increase per 2 months, 95%CI 0.012–0.057). We found no substantial associations between patients´ demographic and socioeconomic characteristics and HRQoL in this setting.CONCLUSION: HRQoL scores among patients receiving treatment for TB in rural Malawi differ by clinical setting and duration of treatment, with greater impairment among inpatients and those early in their treatment course.

Health-related quality of life trajectory of treatment-naive patients with Merkel cell carcinoma receiving avelumab

Aim: To evaluate changes in health-related quality of life (HRQoL) in a Phase II trial (NCT02155647) of treatment-naive patients with metastatic Merkel cell carcinoma treated with avelumab (15-month follow-up). Materials & methods: Mixed-effect Models for Repeated Measures were applied to HRQoL data (FACT-M; EQ-5D-5L) to assess changes over time. Clinically derived progression-free survival was compared with HRQoL deterioration-free survival. Results: Overall, we saw relative stability in HRQoL among 116 included patients, with nonprogression associated with statistically and clinically meaningful better HRQoL compared with progressive disease. Deterioration-free survival rates (49–72% at 6 months, 40–58% at 12 months) were consistently higher/better compared with progression-free survival rates (41/31% at 6/12 months). Conclusion: These findings show unique longitudinal HRQoL data for treatment-naive metastatic Merkel cell carcinoma patients treated with avelumab. Clinical trial registration: NCT02155647 ( ClinicalTrials.gov ).

Associations between safety and tolerability and reporting of health-related quality of life in phase III randomized trials in common solid tumors.

e19206 Background: Anti-cancer drugs are approved typically on the basis of efficacy and safety as evaluated in phase III randomized trials (RCTs). Health related quality of life (HRQoL) is a direct measure of patient benefit from drugs. Despite this, HRQoL is not reported universally for all anti-cancer drugs. Here we explore associations with reporting of HRQoL data in phase III RCTs in common solid tumors. Methods: We searched ClinicalTrials.gov to identify phase III oncology RCTs evaluating new drugs in adult patients with breast, colorectal, lung, or prostate cancers. We included all completed or active trials that completed accrual between January 1, 2005 and October 31, 2016. Data were extracted from published trials including HRQoL data and toxicity data on toxic death, treatment discontinuation and commonly reported grade 3 or 4 adverse events (AEs). Then, we explored associations between these safety and tolerability measures and the odds of reporting HRQoL data and whether HRQoL were favourable or not. Analysis comprised logistic regression and was performed in SPSS version 25. Results: A total of 377 phase III RCTs were initially identified. After excluding ineligible studies, a total of 143 studies were analysed. All trials (100%) were in the metastatic setting with 79 (55%) being positive trials. 40 (28%) were breast cancer trials, 38 (26%) were focused on evaluating chemotherapy, and 128 (90%) of trials were industry sponsored. 84 (59%) trials reported measuring HRQoL data, however of these, only 47 (56%) reported HRQoL data. In 14 (30%) HRQoL was improved with experimental therapy. There was no association between treatment related death (OR 1.25, 95%CI 0.74-2.12, p = 0.398) or treatment discontinuation (OR 1.12, 95%CI 0.73-1.72, p = 0.61) with reporting of HRQoL data. Associations with grade 3 or 4 AEs are shown in the Table. Conclusions: HRQoL is reported for only around a half of RCTs that collect such data. Reporting of HRQoL is not associated with safety and tolerability of anti-cancer drugs. [Table: see text]

Improving quality of health-related quality of life (HRQOL) reporting in phase III randomized controlled trials (RCTs) of metastatic urothelial carcinoma (mUC).

467 Background: HRQOL data are increasingly used to guide patient care and health policy. However, their utility can be compromised by inadequate quality of HRQOL reporting (QHR). We aimed to systematically evaluate QHR in phase III RCTs of mUC. Methods: A comprehensive systematic review following PRISMA guidelines identified published manuscripts of phase III RCTs of mUC in English between 1985 - 2019. Supplementary material, references and companion publications were reviewed. QHR was quantified using: 1) 2013 CONSORT-PRO extension (CPE), and 2) 2003 Minimum Standard Checklist for Evaluating HRQOL Outcomes in Cancer Clinical Trials (MSC). Both scores range from 0-11, with higher scores indicating higher QHR. QHR is “probably robust” if MSC score is ≥8 and all 3 mandatory items (baseline compliance, missing data, and psychometric properties) are reported; “limited” if MSC score is 5-7; and “very limited” if MSC score is ≤4. Results: HRQOL data was collected in 7/21 (33%) mUC phase III RCTs. All reported HRQOL data as secondary/exploratory endpoints. Generic instruments included EORTC QLQ-C30 alone (n=3) or combined with EQ-5D (n=2)/McGill pain questionnaire (n=1). Disease-specific FACT-Bl was used in 1 RCT. Both checklists showed strong correlation (Spearman coefficient 0.94, p=0.001). QHR was often limited, however has improved in recent years (Table). No RCT stated HRQOL-specific hypotheses. Only 1 reported instrument validity and mode of administration. Few provided domain specific results (n=2) and statistical methods for handling missing data (n=3). Implications for clinical practice were only discussed in 3 RCTs. Conclusions: QHR has improved over time however many critical methodological deficiencies remain in mUC phase III RCTs. The use of standard checklists are encouraged to further enhance QHR and promote high quality HRQOL research. [Table: see text]