Although there is a lack of data on health-state utility values (HSUVs) for calculating quality-adjusted life years in Japan, Cost-utility analysis has been introduced by the Japanese government to inform decision-making in the medical field since 2016. This study aimed to determine whether the Lloyd model which was a predictive model of HSUVs for metastatic breast cancer (MBC) patients in the United Kingdom can accurately predict actual HSUVs for Japanese patients with MBC. The prospective observational study, followed by the validation study of the clinical predictive model. Forty-four Japanese patients with MBC were studied at 336 survey points. This study consisted of two phases. In the first phase, we constructed a database of clinical data prospectively and HSUVs for Japanese patients with MBC to evaluate the predictive accuracy of HSUVs calculated using the Lloyd model. In the second phase, Bland-Altman analysis was used to determine how accurately predicted HSUVs (based on the Lloyd model) correlated with actual HSUVs obtained using the EuroQol 5-Dimension 5-Level questionnaire, a preference-based measure of HSUVs in patients with MBC. In the Bland-Altman analysis, the mean difference between HSUVs estimated by the Lloyd model and actual HSUVs, or systematic error, was -0.106. The precision was 0.165. The 95% limits of agreement ranged from -0.436 to 0.225. The t value was 4.6972, which was greater than the t value with 2 degrees of freedom at the 5% significance level (p=0.425). There were acceptable degrees of fixed and proportional errors associated with the prediction of HSUVs based on the Lloyd model for Japanese patients with MBC. We recommend that sensitivity analysis be performed when conducting cost-effectiveness analyses with HSUVs calculated using the Lloyd model.

We validated the predictive accuracy of HSUVs estimated by including clinical data from Japanese patients with MBC into the Lloyd model. The study consisted of two phases. In the first phase, we constructed a database of clinical data and HSUVs for Japanese patients with MBC in a real-world setting to evaluate the predictive accuracy of HSUVs calculated using the Lloyd model. In the second phase, we assessed how accurately predicted HSUVs (based on the Lloyd model) correlated with actual HSUVs obtained using preference-based health status measures in Japanese patients with MBC.

Health-state utility values and patient-reported outcomes (PROs)

The first phase of our study involved developing a comprehensive database of HSUVs and PROs for Japanese patients with MBC, which is linked to patients’ social background and treatment history, and PRO surveys of adverse events from anti-cancer agents using a questionnaire. The study sample included patients who attended the Outpatient Breast Clinic at the Department of Breast and Endocrine Surgery, St. Marianna University School of Medicine, Kawasaki, Japan, between May 2016 and September 2018. The inclusion criteria were (i) Japanese women aged >20 years, (ii) a histopathological diagnosis of breast cancer, and (iii) provision of written informed consent for study participation. Exclusion criteria were (i) undergoing active treatment for mental disorders, and (ii) participation in other clinical trials.

We developed this longitudinal study to collect clinical data on patients’ disease conditions and treatments. Patients’ social background factors (age, educational level, marital status, residential environment, employment status, and household income) were examined; and breast cancer condition survey (including breast cancer subtypes, number of metastatic organs, metastatic organ sites, and treatment response), and HSUVs (measured using the EuroQol 5-Dimension 5-Level [EQ-5D-5L] questionnaire) were completed at entry, as per the study schedule.

The EuroQol-5-dimension questionnaire [EQ-5D-5L] is a preference-based measurement scale developed by the EuroQol groups [8], and this is a target measure of how accurately the Lloyd's model predicts the HSUV, measured by this questionnaire, in our study. This descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has five levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Using this questionnaire form, 3,125 health-state patterns, ranging from 11111 (representing the best health-state) to 55555 (worst health-state), can be defined. These 3,125 health-state patterns may be converted into a country-specific single index value (so-called HSUVs) using country-specific value sets, which have been derived from large country-specific validation studies using time-trade-off/discrete choice methodology and which anchor 1 for ‘perfect health’ and 0 for ‘dead,’ respectively [10]. In other words, the HSUVs calculated using the EQ-5D-5L are a value of the respondent’s health status from the general public’s perspective.

The results of a PRO survey of drug therapy-related (hormone therapy, chemotherapy, and targeted molecular therapy) adverse events were also evaluated with treatment response. Drug therapy-related adverse events questionnaires were completed following the Common Terminology Criteria for Adverse Events v4.0 [11]. The questionnaire included five levels of severity: “none” to Grades 1–4. The 21 items surveyed were: diarrhoea, constipation, nausea, vomiting, headache, hot flashes, oral mucositis, dry mouth, dysgeusia, anorexia, concentration imaging, arrhythmia, peripheral sensory neuropathy, vaginal dryness, fever, fatigue, limb oedema, insomnia, dyspnoea, restlessness, and hand-foot syndrome.

Patients receiving hormone therapy for the treatment of MBC were surveyed every 9 ± 3 weeks using HSUVs and PRO surveys of adverse events. Patients receiving chemotherapy or molecular targeted therapy were interviewed every 6 ± 3 weeks using HSUVs and PRO surveys of adverse events. Patients receiving radiation therapy were evaluated once during the treatment period using HSUVs.

Research assistants distributed the questionnaires to the participants before the physician’s examination and collected them approximately 30 minutes later. All data were collected in the same manner. All data were collected in accordance with the protocol. There were no missing data in the repeated measures.

Validation of the predictive accuracy of HSUVs based on the Lloyd model

The Lloyd model evaluated the clinical data of Japanese patients with MBC to predict HSUVs [9]. The model consisted of population-based societal preferences for distinct stages of MBC and six common toxicities. Health states were developed based on literature review, iterative cycles of interviews and a focus group with clinical experts. This predictive model established as a base, one hundred members of the UK general public who rated the burden of progressive, responding and stable disease on treatment; and also, febrile neutropenia, stomatitis; diarrhoea/vomiting; fatigue; hand-foot syndrome (grade 3/4 toxicities); and hair loss, using SG to determine HSUVs. The Lloyd model was based on the logistic model using the linear combination of disease states and toxicities. Stable disease on treatment had a utility value of 0.72, with a corresponding gain of þ0.07 following a treatment response and a decline by 0.27 for disease progression. Toxicities led to declines in utility between 0.10 (diarrhoea/vomiting) and 0.15 (febrile neutropenia). The Lloyd model’s estimated HSUVs were compared with those measured using the EQ-5D-5L questionnaire to verify the Lloyd model’s reliability.