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

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); MEDLINE 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).

Using the term “NSCLC” or “non-small cell lung cancer”, manual searching of the EQ-5D website, of the School of Health and Related Research Health Utilities Database (ScHARRHUD) and of major pharmacoeconomic and clinical conferences in 2015–2016 was conducted on 3 and 5 December 2016. Conferences included: the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) International Meetings and European Congresses; the HTA International Annual Meetings (HTAi); the Society for Medical Decision Making (SMDM) North American Meetings and European Conferences; the American Society of Clinical Oncology (ASCO) Meetings; and the European Society for Medical Oncology (ESMO) Congresses. Bibliographic reference lists of relevant systematic reviews from 2010 onwards were searched and of relevant cost-utility analyses, and HTA reports from various bodies identified in a parallel economic systematic review, including: NICE; SMC; All Wales Medicines Strategy Group (AWMSG); PBAC; CADTH; Institut National d’Excellence en Santé et en Services Sociaux; pan-Canadian Oncology Drug Review (pCODR); and HAS.

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].

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 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.

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].

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.

Among the 36 articles (34 studies) identified, 19 reported EQ-5D scores [37‐55] (three studies further specified the instrument as EQ-5D-3 L [39, 41, 56] and two as EQ-5D-5 L [44, 57]; Table 2), two reported SG or TTO directly elicited from patients [58, 59], two reported EQ-VAS scores only [57, 60], and one reported AQoL scores [61] (Table 2). Moreover, one study reported SF-12 scores for caregivers to patients with mNSCLC [62], eight reported HSUVs from valuations of vignettes made by members of the public using SG or TTO [59, 63‐69] (one of which reported both general public-elicited SG and patient-elicited TTO) [59], and one reported disutility estimates based on expert opinion for pneumothorax, thrombocytopenia and thrombosis, adverse event health states for which disutilities were not available from other HSUV derivation methods [70]. A further two articles reported HSUVs but were unclear about how these were derived; one reported disutilities used in previous NICE submissions, for anaemia and for oral and intravenous treatment modes [71], and one reported a “global quality of life index” for second-line NSCLC [72].

Among the dataset, two studies were retained despite reporting first-line treatment only, because they reported AE disutility estimates from populations broader than mNSCLC [68, 70]; three further studies that reported first-line data also reported on subsequent treatment lines [38, 39, 46]. Eleven studies focused exclusively on HSUVs associated with second-line treatment [41, 45, 48‐51, 57, 59, 69, 71, 72], and five reported HSUVs in second-line and subsequent treatment [37, 40, 56, 60, 73]. Line of treatment was unspecified in 15 studies [42‐44, 47, 52‐55, 58, 61‐63, 65‐67].

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.

Eleven studies identified in this systematic review reported disutilities or decrements for AE health states [44, 52, 55, 58, 59, 65, 67‐71]. 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” (− 0.18), neutropenia (− 0.09), febrile neutropenia (− 0.09), fatigue (− 0.07), nausea/vomiting (− 0.05), diarrhoea (− 0.05), hair loss (− 0.04) and rash (− 0.03).

Further recommended sources of AE health state (dis) utilities were as follows (Fig. 1): in 2 L from general population SG in Nafees et al. 2008 [69]; in metastatic NSCLC (line unspecified) from general population SG in Doyle et al. 2008 [65]; in 1 L from patients without NSCLC using directly elicited TTO in Nafees et al. 2016 [68]; in 2 L in NSCLC as reported in Westwood et al. 2014 [71]; in cancer with bone metastases for skeletal-related events from general population TTO in Matza et al. 2014 [67]; stage IV NSCLC in 1 L from expert opinion estimates in Handorf et al. 2012 (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].

Of the 36 publications, 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], based on the measurement technique for generation of HSUVs, as outlined in Additional file 3: Figure S1. The main characteristics of these studies are presented in Table 3. These 13 publications reported data from multinational studies [37‐40, 45, 49, 64], and from Canada [42, 56], France/Germany [46], USA [58], Italy [53] and the UK [69]. In these studies, HRQoL was measured using EQ-5D [37‐40, 42, 45, 46, 49, 53, 56], EQ-VAS [37, 39, 40, 49] and SG [58, 64, 69]. The HTA suitability of disutilities and decrements for AE health states in previously treated patients are reported in Table 4.