Systematic review of health state utility values in metastatic non-small cell lung cancer with a focus on previously treated patients

Background Health state utility values (HSUVs) are an important input to economic evaluations and the choice of HSUV can affect the estimate of relative cost-effectiveness between interventions. This systematic review identified utility scores for patients with metastatic non-small cell lung cancer (mNSCLC), as well as disutilities or utility decrements relevant to the experience of patients with mNSCLC, by treatment line and health state. Methods The MEDLINE®, Embase and Cochrane Library databases were systematically searched (September 2016) for publications describing HSUVs in mNSCLC in any treatment line. The EQ-5D website, the School of Health and Related Research Health Utilities Database (ScHARRHUD) and major pharmacoeconomic and clinical conferences in 2015–2016 were also queried. Studies in adults with previously treated mNSCLC were selected for further analysis. The information extracted included study design, description of treatment and health state, respondent details, instrument and tariff, HSUV or (dis) utility decrement estimates, quality of study, and appropriateness for use in economic evaluations. Results Of 1883 references identified, 36 publications of 34 studies were included: 19 reported EQ-5D scores; eight reported HSUVs from valuations of vignettes made by members of the public using standard gamble (SG) or time trade-off (TTO); two reported SG or TTO directly elicited from patients; two reported EQ-5D visual analogue scale scores only; one reported Assessment of Quality of Life instrument scores; one reported HSUVs for caregivers to patients with mNSCLC using the 12-item Short-Form Health Survey; and one estimated HSUVs based on expert opinion. The range of HSUVs identified for comparable health states showed how differences in study type, tariff, health state and the measures used can drive variation in HSUV estimates. Conclusions This systematic review provides a set of published HSUVs that are relevant to the experience of adult patients previously treated for mNSCLC. Our review begins to address the challenge of identifying reliable estimates of utility values in mNSCLC that are suitable for use in economic evaluations, and also highlights how varying estimates result from differences in methodology. Electronic supplementary material The online version of this article (10.1186/s12955-018-0994-8) contains supplementary material, which is available to authorized users.

Background Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, occurring in 85-90% of lung cancer cases [1], and includes adenocarcinoma (40% of all lung cancers), squamous cell carcinoma (25-30%) and large cell carcinoma (10-15%) [2]. NSCLC is staged according to the American Joint Committee on Cancer/ Union for International Cancer Control system [3], and measurement of lesions follows the Response Evaluation Criteria in Solid Tumors (RECIST) [4]. Approximately 40% of patients will have metastatic NSCLC (mNSCLC) at diagnosis [5], which includes cancers found in the lung and in the lymph nodes in the middle of the chest (defined as stage IIIA and IIIB; no distant metastasis), and cancers that have spread to both lungs or to another part of the body (defined as stage IV; distant metastasis) [6,7].
Treatment is recommended according to the stage of mNSCLC, but treatment options are limited in the later stages of disease [7,8]. Five-year survival rates are considerably lower in later than in earlier stages of NSCLC (stage IA, 45%; stage IIIA, 14%; stage IIIB, 5%; stage IV, 1%) [9]. Moreover, symptoms such as coughing and wheezing, chest pain, hoarseness and weight loss can severely reduce functional independence in patients with mNSCLC [10,11]. Patient-reported health-related quality of life (HRQoL) provides an overall evaluation of health, well-being and daily functioning, and is impaired in patients with mNSCLC owing both to the disease and to treatment sequelae. Maintenance or improvement of HRQoL is an important treatment goal [12].
HRQoL can be expressed as a health state utility value (HSUV) ranging from 0 (death) to 1 (full health). If the health state is considered to be worse than death, health states can be valued at less than 0. Utility values are key drivers in cost-effectiveness analyses because estimates of quality-adjusted life-years (QALYs) are obtained by multiplying HSUVs for each health state by the time spent in that health state. Estimates of cost per QALY are highly sensitive to the choice of HSUV. It is therefore important to identify specifically those HSUVs that have been derived using methods acceptable to health technology assessment (HTA) authorities [13].
HSUVs can be derived using a range of instruments and techniques [14,15]. In brief, instruments include: generic preference-based measures such as the EQ-5D-3 L [16] or EQ-5D-5 L [17], Health Utilities Index (HUI) [18], 6-dimension Short-Form Health Survey (SF-6D) [19], Assessment of Quality of Life instrument (AQoL) [20], 15-dimensional HRQoL measure [21], Quality of Well-Being scale [22], and multi-attribute utility instrument; as well as directly elicited standard gamble (SG), time trade-off (TTO) and visual analogue scale (VAS, e.g. EuroQoL VAS [EQ-VAS]). Mapping algorithms may also be used to convert values obtained from a condition-specific questionnaire to a generic preference-based measure; or to convert data from the 12-or 36-item Short-Form Health Survey (SF-12 or SF-36) to SF-6D [23]. Techniques may vary in terms of whose health is being measured (a patient's or a caregiver's), who responds to the questionnaire or, if using vignettes, who considers the health-state description (the patient regarding their own health, a patient with a different disease, the patient's closest caregiver, another caregiver, a physician or another healthcare provider). For preference-based measures, variation can stem from who values the health state (e.g. UK general population sample) and which choicebased method is used in this valuation (SG or TTO).
HTA bodies including the UK National Institute for Health and Care Excellence (NICE) [24,25], the Scottish Medicines Consortium (SMC) [26], the Canadian Agency for Drugs and Technologies in Health (CADTH) [27], the French Haute Autorité de Santé (HAS) [28] and the Australian Pharmaceutical Benefits Advisory Committee (PBAC) [29] have stated preferences for HSUV methodology. Across these agencies, there is a preference for HSUVs estimated using generic preference-based measures. NICE has a strong preference for EQ-5D, as this reduces variability induced when different instruments are used between different disease areas. Agencies also strongly prefer patients to be the respondents, as patients can best describe their own health state. Finally, valuation estimated using a country-specific general-population tariff via a choice-based elicitation technique such as SG or TTO is preferred, as this represents societal preferences.
This systematic review had three main aims: first, to identify HSUVs for adults with previously treated mNSCLC, by treatment line and health state, and to evaluate the relevance of each health state to patients, for example, line of treatment, adverse events (AEs), response status and prognostic factors; second, to identify relevant disutilities or utility decrements associated with adverse events (irrespective of line of treatment or health state). Finally, the suitability of the HSUVs according to HTA reference case was explored and the quality of the HSUVs assessed.

Study design and search strategy
A systematic review of HSUVs in mNSCLC was undertaken to identify HSUV studies in any treatment line. Studies, published either as full papers or as conference abstracts, in patients previously treated for mNSCLC were selected for further analysis. The following databases were searched: Embase (1974 to 7 September 2016); MEDLINE® (1966 to 7 September 2016); MED-LINE In-Process and e-publications ahead of print (database inception to 7 September 2016); and the Cochrane Library (including the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, the Cochrane Central Register of Controlled Trials, the National Health Service Economic Evaluation Database and the HTA database; 1968 to 7 September 2016).
Search strings are summarized in Additional file 1: Table S1, and were constructed not only to find utilities in mNSCLC (using a wide range of NSCLC and mNSCLC terms combined with the HSUV filter adapted from Arber et al. 2015 [30]) but also to identify all relevant disutilities or utility decrements associated with AEs/comorbidities. To ensure that estimates would be available from previously treated mNSCLC populations for all AEs or comorbidity health states relevant to the experience of such patients, the strings were designed to search for disutilities or decrements from a broader group of populations, as follows: from lung cancer; for progressive disease disutilities from advanced/metastatic cancer; for disutilities associated with the most common sites of metastasis from the lung (bone, respiratory system, nervous system, adrenal gland and liver) from advanced cancer; for disutilities associated with AEs or toxicities of cancer therapy; and disutilities associated with specific grade 3-4 AEs known to occur with cancer treatments from advanced cancer populations (pneumonia, pneumonitis, increased aspartate aminotransferase, febrile neutropenia, neutropenia, infection, sepsis, fatigue, lethargy, nausea, vomiting, ulcers, stomatitis, gastrointestinal disturbance, diarrhoea, visual disturbance, hearing loss, hair loss, psychological/self-esteem changes, rash, anaemia, bleeding and hypertension). From the identified disutilities/decrements for each AE/co-morbidity health state, those from the most relevant population available could be selected following an order of decreasing population specificity from first-line mNSCLC to NSCLC, lung cancer and advanced/metastatic cancer ( Fig. 1). The PICOS (patient, intervention, comparator, outcome, study) statements for study inclusion and exclusion criteria are summarized in Table 1. Although, second-and later-line data were of primary interest, studies that reported utilities for patients with mNSCLC who were either treatment-naïve or in receipt of maintenance first-line treatment were included for reference at the first screening but data were not extracted. These studies are listed in Additional file 2: Table S2.
Mapping from condition-specific to preference-based studies was not sought because it was anticipated that sufficient published utility and EQ-5D data would be available to populate the health states of an economic model, and because results based on mapping algorithms sit lower in the acceptance hierarchy used by some HTA authorities (Additional file 3: Figure S1). We have acknowledged NICE's stated preference for EQ-5D-3 L data over EQ-5D-5 L (Additional file 3: Figure  S1) and provide detailed information of the instrument used for generating data for each identified study in Table 2 [31].

Study selection
The screening process complied with the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [32]. Publications were de-duplicated using EndNote (Clarivate Analytics, Philadelphia, PA, USA) and using Rayyan (Qatar Computing Research Institute, Doha, Qatar) [33], an internet-based reference management system endorsed as suitable for systematic review screening by the European Network for HTA [34]. Abstracts and titles of papers were screened by one reviewer, and a 50% sample check conducted by a second reviewer; exclusion criteria are summarized in Table 1. The full texts of papers potentially meeting the selection criteria were screened by one reviewer, and a 50% sample check was conducted by a second reviewer. Discrepancies were discussed between reviewers, and any unresolved disputes were referred to a third reviewer.

Data extraction
Data were collected using a piloted data-extraction sheet. Extraction was conducted by one reviewer, and priority data elements were quality checked by a second reviewer. The information extracted included study design, whether the selection criteria yielded a population that matched the target population (i.e. previously treated adult patients with mNSCLC), health state description, instrument type, instrument scale, HSUV or (dis) utility or decrement estimates and measure of variability (median with interquartile range or mean with standard error, standard deviation or 95% confidence interval), derivation methods and if the data presented were appropriate for use in HTA submissions to NICE, SMC, CADTH, HAS and PBAC.

Quality and relevance assessment
The appropriateness of utilities reported for use in economic evaluations was determined by whether data met the requirements of the HTA body reference case; and the quality of utility estimates (based on sample size, response to the questionnaire, loss to follow-up, handling of missing data, and reporting of point and variance estimates, as discussed in NICE Decision Support Unit Technical Support Document 11 and its related publication [25,35]; Additional file 4: Table S3). Any recommendation for, or rationale against, the use of specific utilities in a cost-utility analysis model in previously treated patients with mNSCLC was also taken into consideration in line with preliminary guidance from the ISPOR Health State Utility Good Practices Task Force [36].

Search yields
Electronic database searches identified 1883 citations (1521 from MEDLINE/Embase, 144 from MEDLINE In-Process/e-publications and 218 from the Cochrane Library databases). After de-duplication (51 citations: 30 via Endnote and 21 via Rayyan) and title/abstract screening (1557 exclusions), 275 full-text papers were reviewed. Of these, 250 were excluded (21 of which were tagged as reporting first-line treatment; Additional file 2: Table S2), yielding 25 citations that were included from electronic sources. Manual searching identified 11 citations. In total, 36 articles were included, reporting 34 studies (Table 2). Two articles [37,38] were linked to other publications [39,40], and were retained because they provided additional information. The study selection is summarized in a PRISMA flow chart in Fig. 2.

Relevant HSUVs by line of treatment
Utilities were reported for a range of health state types: treatment-specific or not, RECIST response-based or not, time-on-treatment, time-till-death, or a combination of these. Details of HSUV estimates by treatment line are given in Table 3. Among patients receiving second-line or subsequent treatment for advanced NSCLC or mNSCLC, mean HSUV estimates based on EQ-5D for stable/progression-free disease and for patients at baseline or pre-treatment were in the range 0.66-0.76 [38,39,41,45,49,50]; in the same group, mean values for patients with progressive disease were generally lower (0.55-0.69) [38,39,45]. Among patients on treatment at this stage of disease and treatment line, the range of mean HSUVs based on EQ-5D was broad (0.53-0.82) [40,41,46,51,56], the highest value being associated with treatment with tyrosine kinase inhibitors [41,56]. A similar range of HSUV values was seen among patients being treated for advanced NSCLC or mNSCLC when the treatment line was unspecified (0.53-0.77) [42,47,52,53]. Only three papers specified using EQ-5D-3 L [39,41,56] and only two EQ-5D-5 L [44,57].
Disutilities for progression from a stable state were − 0.056 or − 0.065 by EQ-5D, both from Griebsch et al. [37], or − 0.1798 by general population-derived SG [69]. Overall, HSUVs varied not only by treatment line and disease state, but also by the treatment received under the same health state (potentially reflecting differences in safety profiles) and by the instrument/tariff used to derive the HSUV.

Relevant disutilities and decrements
Eleven studies identified in this systematic review reported disutilities or decrements for AE health states [44,52,55,58,59,65,[67][68][69][70][71]. Only two studies reported disutilities specifically associated with second-line treatment [69,71], and another two studies did not specify the treatment line [44,65]; disutility and decrement data are summarized in Table 4. Utility-incorporating decrements were identified for the following AEs in the context of second-line "stable disease" or second-line "responding": diarrhoea, fatigue, febrile neutropenia, hair loss and nausea/vomiting. Disutilities associated with second-line treatment were reported for the following events [69]: "moving from stable to progressive state" (− 0. (expert-opinion-derived utilities from this study were included, as they are the only source of estimates for pneumothorax, thrombocytopenia and thrombosis disutilities) [70]; and anaemia from general population SG or from patient-derived TTO in Lloyd et al. 2008 [59].

Discussion
Economic evaluation, particularly cost-utility analysis, provides important information for guiding decisionmaking in health care, and its use in HTA is increasing globally. Such evaluation includes examination of the time spent in different disease states and uses an HSUV for each disease state to calculate QALYs; HSUVs therefore play a key role in economic evaluation. As summarized in Additional file 3: Figure S1, NICE, SMC, CADTH, HAS and PBAC prefer utilities to be estimated using a generic preference-based instrument, with health states described by patients through use of a questionnaire, and with the health state valued using a country-specific tariff that reflects societal preferences. As the aim of this systematic review was to evaluate the experience of adults with previously treated mNSCLC, the synthesis of health state utility estimates was outside its scope. However, the findings presented here may provide a basis for generation of an accurate estimate of the mean HSUV for use in economic evaluations [74,75].
This systematic review identified HSUVs relevant to the experience of previously treated adult patients with mNSCLC. Search strings were designed to allow (dis) utilities from a broader population (including lung cancer, advanced/metastatic cancer and specific metastases common in patients with lung cancer). In the absence of second-line mNSCLC (dis) utilities, alternatives were selected with decreasing population specificity and relevance from first-line mNSCLC, NSCLC, lung cancer or advanced/metastatic cancer, as outlined in Fig. 1. Ordering the HSUVs by line of treatment reflects the practice of switching treatment at progression. However, for the newer immunotherapies, patients may remain on treatment post-progression, and their HRQoL may remain at pre-progression levels. Thus, HSUVs estimated for progression status-specific health states from patients receiving chemotherapy may not be suitable to apply to the equivalent health states when patients receive immunotherapy.
In total, the 36 identified articles reported 591 HSUVs relevant to the experience of previously treated adult patients with mNSCLC, and 11 of these studies reported a total of 195 disutilities or decrements for AE health states that are relevant to the experience of patients with mNSCLC. The range of HSUVs identified for comparable health states, such as progression-free/stable disease among patients treated second-line for advanced/metastatic NSCLC [39,45], highlights how differences in study type, tariff, health state and the measures used can drive variation in HSUV estimates. For instance, disutilities for progression from a stable state were − 0.056 or − 0.065 using EQ-5D, [37] or − 0.1798 by general-population-derived SG. [69] To overcome such variations, where possible, HSUV studies should seek to use instruments, respondents and valuation populations that are most acceptable to HTA bodies. However, there are instances where variation in methods can be justified. For example, disutility values derived from vignettes and a general public sample were used by Nafees et al. [69],       • You have a life-threatening illness that is stable on treatment. You are receiving cycles of treatment that require you to go to the outpatient clinic • You have lost weight, and your appetite is reduced. You sometimes experience pain or discomfort in your chest or under your ribs, which can be treated with painkillers. You have shortness of breath, and breathing can be painful. You have a persistent nagging cough • You are able to wash and dress yourself and do jobs around the home. Shopping and daily activities take more effort than usual • You are able to visit family and friends but often have to cut it short because you get tired • You sometimes feel less physically attractive than you used to. Your illness has affected your sex drive • You worry about dying and how your loved ones will cope f Second-line responding vignette: • You have a life-threatening illness that is responding to treatment. You are receiving cycles of treatment which require you to go to the outpatient clinic • You are gaining back your weight and your appetite is returning. You occasionally experience pain or discomfort in your chest or under your ribs which can be treated with painkillers. You sometimes have shortness of breath. You occasionally have a nagging cough • You are able to wash and dress yourself and do jobs around the home. Shopping and daily activities can sometimes be tiring • You are able to visit family and friends but sometimes have to cut it short because you get tired • You occasionally feel less physically attractive than you used to. Your illness has somewhat affected your sex drive • You sometimes worry about dying and how your loved ones will cope g Second-line PD vignette: • You have a life-threatening illness, and your condition is getting worse • You have lost your appetite and have experienced significant weight loss. You experience pain and discomfort in your chest or under your ribs. You frequently have shortness of breath, and breathing is often painful. You have a persistent nagging cough and sometimes cough up blood. You may experience some difficulty swallowing • You experience severe fatigue and feel too tired to go out or to see family and friends. It has affected your relationships with them • You need assistance to wash and dress yourself. You are often unable to do jobs around the house or other daily activities. You are dependent on others to do your shopping and are unable to do your usual daily activities • You often feel less physically attractive than you used to. You have little or no sexual drive • You are depressed, and dying is always on your mind. You worry about how your loved ones will cope h This study also has utilities available every 3 weeks between week 0 and week 30 for all treatments i All utilities in this paper assumed to be the mean, although it is not clearly stated in the paper        As reported in Shabarruddin 2013 [79], base state and utility increments were presented on different scales: base state was based on standard gamble scale between perfect health (arbitrary score of 100) or immediate death (arbitrary score of 0) while the utility increments were based on a scale between perfect health (arbitrary score of 100) and the surrogate negative anchor of continuous nausea/vomiting (re-set to an arbitrary score of 0) g Values are presented for global population (United Kingdom, Australia, France, China, Taiwan, Korea). Note that country-specific data are also available Abbreviations: 1 L first line, BL baseline, CI confidence interval, D decrement, ERL erlotinib, HSUV health state utility value, HTA health technology assessment, i.v. intravenous, LC lung cancer, mLC metastatic lung cancer, mNSCLC metastatic non-small cell lung cancer, NICE National Institute for Health and Care Excellence, NR not reported, NSCLC non-small cell lung cancer, SCLC small cell lung cancer, SD standard deviation, SE standard error, SG standard gamble, TTO time trade-off, U utility, UID utility incorporating decrement for adverse events, VAS visual analogue scale because asking patients suffering such toxicities to complete HRQoL questionnaires was considered to be too burdensome for patients and potentially unethical. Moreover, although the variation may be large, it helps decision makers to identify where variability exists and informs the design of sensitivity analyses.
In the 36 publications identified, 13 provided HSUVs that meet the NICE reference case or are considered acceptable to the HTA agencies of interest [37-40, 42, 45, 46, 49, 53, 56, 58, 64, 69]. These were deemed suitable because HRQoL was measured using the EQ-5D [37-40, 42, 45, 46, 49, 53, 56] or SG [58,64,69], both measures preferred or accepted by several HTA authorities. This endeavour fills an important gap in the field because hitherto, only two reports had described HSUVs in mNSCLC [68,69]; neither was a systematic review of the literature, nor did they assess their appropriateness for use in economic evaluations.
This systematic review did not identify an HSUV report based on data from the OAK trial (NCT02008227), because it was published as a congress abstract after the cut-off date for literature searching [76]. However, the HSUVs are relevant to the aims of this systematic review, and a brief description is provided below for completeness. Patients with locally advanced NSCLC or mNSCLC after failure of platinum-containing chemotherapy were randomized in a phase 3 trial to receive atezolizumab or docetaxel [76,77]. As part of the trial, patients completed the EQ-5D, and the resultant HSUVs were presented by time point before death. This study is similar to Huang et al. 2016, which also presented time-to-death EQ-5D utilities for a similar patient group receiving immunotherapy, except comparing pembrolizumab and docetaxel [45]. Overall, HSUVs were very similar between studies at approximately equivalent time points. In the OAK study, the following HSUVs were reported by time point before death  ). A further study evaluating the efficacy of immunotherapy in patients with NSCLC showed that baseline mean EQ-VAS and EQ-5D index scores were similar for nivolumab (63.7 and 0.68, respectively) and docetaxel (66.3 and 0.66, respectively) [50].
Strengths of this systematic review include the wide range of data sources searched and the search string design, which enabled identification of disutilities and utility decrements for a wide range of AEs and progressive disease states (e.g. common sites of metastasis from lung cancer) of relevance to the experience of patients previously treated for mNSCLC. We have presented HSUVs by line of treatment, allowing use in economic modelling, and have discussed HSUVs likely to be accepted by the HTA bodies of interest. Inadequate or inconsistent reporting is common, and low sample sizes and response rates considerably impact on the reported confidence intervals of the reported results. However, among the studies identified here, most reported sample size (over 100 respondents in most cases), many provided a measure of variability for the values reported, and several were based on response rates greater than 80% (although response rates were unreported in more than half of the studies). Moreover, the use of only published HSUVs can be a limitation, as HTA submissions may use HSUVs that have not been previously published. As part of this systematic review, we have therefore searched HTA submissions for any relevant utilities; most HTAs use data reported by Nafees et al. [69] Limitations of this review include that the label for the upper bound of the utility scale (e.g. "full health" or "perfect health") was not recorded. This has been shown to be a significant predictor of utility in lung cancer [78], so variation in utilities due to a different upper bound label cannot be explored. A further limitation concerns data extraction from some studies presented as congress abstracts or posters. Owing to the word restrictions placed on conference proceedings they may not be considered a robust data source in comparison with full publications. Furthermore, both screening and data extraction were conducted primarily by a single reviewer, and only 50% of studies were checked by a second reviewer. The exclusion of studies that used mapping to derive EQ-5D and utility values is a further limitation of this study; however, sufficient data obtained through direct measurement were identified to be informative.

Conclusions
This systematic review begins to address the challenge of identifying reliable estimates of utility values in mNSCLC that are suitable for use in economic evaluations. Our work has also highlighted that these estimates are vulnerable to variations in study type, tariff, health state and the measures used, and that shortcomings in reporting are common.

Additional files
Additional file 1: Table S1. Search strings. (DOCX 90 kb) Additional file 2: Table S2. Listing of first-line mNSCLC studies with utility data excluded at second pass . (DOCX 84 kb) Additional file 3: Figure S1. Hierarchy of preferred methodology for generation of HSUVs for different HTA agencies. (PDF 1172 kb) Additional file 4: Table S3. Quality assessment of identified studies. (DOCX 111 kb)