Eribulin versus S-1 as first or second-line chemotherapy to assess health-related quality of life and overall survival in HER2-negative metastatic breast cancer (RESQ study): a non-inferiority, randomised, controlled, open-label, phase 3 trial.

Background: Eribulin prolongs overall survival (OS) of patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), particularly in later chemotherapy (ChT) treatment. However, the health-related quality of life (HRQoL) and efficacy of first or second-line therapy in eribulin-treated patients remain unknown. Using eribulin in the first- or second-line may demonstrate the non-inferiority of HRQoL compared to S-1, an oral 5-fluorouracil derivative, while maintaining OS. Methods: This randomised, controlled, open-label, phase III trial was conducted at 50 hospitals in Japan. Patients were enrolled from June 2016 and October 2019. Patients with HER2-negative MBC once under or no previous ChT were randomly assigned (1:1) to receive eribulin or S-1. HRQoL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) every six weeks until week 24 and every nine weeks until week 42. The primary endpoint was the deterioration defined as more than 10 points worsening of the general health score of QLQ-C30 or death within one year after randomisation. The secondary endpoints included OS. (Trial ID: UMIN000021398). Findings: Three hundred and two patients were enrolled, with 152 and 148 assigned to the eribulin and S-1 groups, respectively. The questionnaire compliance rate was 85.6%. Risk difference of global health status deterioration through one year was -0.66% (95% CI: -12.47-11.16; non-inferiority P = 0.077) for eribulin compared to S-1 groups. Median time to first deterioration for global health status score was 5.64 (95% CI: 3.51-8.00) and 5.28 months (95% CI: 3.28-7.80) in the eribulin and S-1 groups, respectively. The median OS was 34.7 and 27.8 months, (HR: 0.72, 95% CI: 0.54-0.96; P = 0.026); the median progression-free survival was 7.57 and 6.75 months in the eribulin and S-1 groups, (HR: 0.88, 95% CI: 0.67-1.16; P = 0.35), respectively. No new adverse events occurred. Interpretation: The time of the first clinical deterioration was similar between the two groups and OS significantly increased in eribulin-treated patients. Funding: This study was funded by CSPOR-BC and Eisai CO., Ltd.

How to select and understand guidelines for patient-reported outcomes: a scoping review of existing guidance.

BACKGROUND: Over the past few decades, patient-reported outcomes (PROs) have been used to understand patient health conditions better. Therefore, numerous PRO measures (questionnaires) and guidelines or guidance have been developed. However, it is challenging to select target guidance from among the many available guidance and to understand the chosen guidance. This study comprehensively collected the existing PRO guidance for clinical trials or studies and practices to support novice PRO users in academia, industry, clinical practice, and regulatory and reimbursement decision-making. METHODS: For the scoping review, we searched the MEDLINE, Embase, Google Books, WorldCat, and the National Library of Medicine (NLM) Bookshelf databases from 2009 to 2023. The eligibility criteria were PRO guidance for clinical trials, clinical practice, or application such as health technology assessment. Those guidance cover aspects such as quality of life (QOL), PRO, health-related QOL, health state utilities, psychometric requirements, implementation methods, analysis and interpretation, or clinical practice applications. After the systematic search, three researchers individually reviewed the collected data, and the reviewed articles and books were scrutinized using the same criteria. RESULTS: We collected the PRO guidance published in articles and books between 2009 and 2023. From the database searches, 1,455 articles and 387 books were identified, of which one book and 33 articles were finally selected. The collected PRO guidance was categorized into the adoption of PRO measures, design and reporting of trials or studies using PROs, implementation of PRO evaluation in clinical trials or studies or clinical practice, analysis and interpretation of PROs, and application of PRO evaluation. Based on this categorization, we suggest the following for novices: When selecting guidance, novices should clarify the "place" and "purpose" where the guidance will be used. Additionally, they should know that the terminology related to PRO and the scope and expectations of PROs vary by "places" and "purposes". CONCLUSIONS: From this scoping review of existing PRO guidance, we provided summaries and caveats to assist novices in selecting guidance that fits their purpose and understanding it.

Cost-Effectiveness Analysis of Nivolumab Plus Ipilimumab Combination Therapy as First-line Treatment for Advanced Renal Cell Carcinoma in Japan.

OBJECTIVES: The purpose of this study is to examine the cost-effectiveness of nivolumab (NIVO) plus ipilimumab (IPI) combination therapy (NIVO + IPI) compared with the sunitinib (SUN) therapy for Japanese patients with advanced renal cell carcinoma from the perspective of a Japanese health insurance payer. METHODS: A lifetime horizon was applied, and 2% per annum was set as the discount rate. The threshold was set as $ 75 000 per quality-adjusted life-year (QALY) gained. For the analytical method, we used a partitioned survival analysis model to estimate the incremental cost-effectiveness ratio (ICER), which is calculated by dividing incremental costs by incremental QALYs. Progression-free survival, progressive disease, and death were set as health states. Additionally, cost parameters and utility weights were set as key parameters. We set the intermediate/poor-risk population as the base case. Scenario analysis was conducted for the intention-to-treat population and the favorable risk population. Furthermore, one-way sensitivity analysis and probabilistic sensitivity analysis were conducted for each population. RESULTS: In the base-case analysis, the QALYs of NIVO + IPI and SUN were 4.32 and 2.99, respectively. NIVO + IPI conferred 1.34 additional QALYs. Meanwhile, the total costs in the NIVO + IPI and SUN were $692 288 and $475 481, respectively. As a result, the ICER of NIVO + IPI compared with SUN was estimated to be $162 243 per QALY gained. The parameter that greatly affected the ICER was the utility weight of progression-free survival in NIVO + IPI. CONCLUSIONS: NIVO + IPI for advanced renal cell carcinoma seems to be not cost-effective compared with the SUN in the Japanese healthcare system.

Perceptions regarding the concept and definition of patient-reported outcomes among healthcare stakeholders in Japan with relation to quality of life: a cross-sectional study.

Patient-reported outcomes (PROs) are frequently used in a variety of settings, including clinical trials and clinical practice. The definition of PRO and quality of life (QOL) and their relationship have been concluded through discussions among experts that has been the premise of PRO guidelines are not clearly stated in the guidelines. Therefore, the definition of PRO, especially in relation to QOL, is sometimes explained simply, as "PRO includes QOL," but this complicated matters. This study investigated the perceptions of PRO among various stakeholders (including patients and their families, the industry, clinicians, regulatory or health technology assessment personnel, and academic researchers) in Japan to clarify its definitions and that of QOL, including their relationship.We conducted a two-step survey: a qualitative interview survey and a web-based survey to ensure the validity of the survey. During the interviews, eight stakeholders described their perceptions and thoughts on PRO and its relationship to QOL, and their experience of using PRO. Overall 253 clinicians, 249 company employees, and 494 patients participated in the web survey to confirm how the findings of the interview survey supported the results.In the interview survey, patient advocates described various perspectives of PRO and QOL, including unexpected dynamic relationships, while the most other stakeholders explained PRO and QOL with the language used in the guidelines, but their responses were split. The web-based survey revealed that all stakeholders had a lower awareness of PRO than QOL. The most common perception of PRO, especially in the relationship to QOL, was "they did not fully overlap." Although there were differences in perceptions of the relationship between PRO and QOL among clinicians, company employees, and patients, all perceived PRO as a tool to facilitate communication in clinical practice.The present results are inconsistent with the simplified explanation of PRO, but consistent with the original PRO guideline definitions, which also considered the role of PRO in clinical practice. To make PRO a more potent tool, all stakeholders using PRO should confirm its definition and how it differs from QOL, have a unified recognition in each PRO use, and avoid miscommunication.

Cost-effectiveness analysis of nivolumab plus chemotherapy vs chemotherapy for patients with unresectable advanced or metastatic HER2-negative gastric or gastroesophageal junction or esophageal adenocarcinoma in Japan.

BACKGROUND: This study aimed to evaluate the cost-effectiveness of nivolumab plus chemotherapy (NIVO + Chemo) compared with chemotherapy monotherapy (Chemo) for patients with advanced or metastatic HER2-negative gastric or gastroesophageal junction or esophageal adenocarcinoma (GC/GEJC/EAC) in Japan from the perspective of healthcare payer. METHODS: A partitioned survival analysis model was developed to predict costs and quality-adjusted life years (QALYs) for NIVO + Chemo and Chemo. The time horizon of the model was set to 38 years. An annual discount rate of 2% for both costs and QALYs was applied. Data on overall survival and progression-free survival were derived from the CheckMate649 trial. Cost parameters were estimated from a Japanese medical claims database. The incremental cost-effectiveness ratio (ICER) of NIVO + Chemo compared with Chemo was estimated. A subgroup analysis on the level of PD-L1 CPS expression was conducted. In addition, sensitivity analysis was performed to assess the uncertainty in the parameter settings. RESULTS: The incremental cost and QALY of NIVO + Chemo compared with Chemo were USD99,416 and 0.30 QALY, respectively. The ICER of NIVO + Chemo was estimated to be USD327,161 per QALY gained. The results of the subgroup analysis showed that ICER was USD247,403/QALY and USD302,183/QALY for PD-L1 CPS ≧ 5 and ≧ 1, respectively. Sensitivity analyses showed a relatively robust result that the ICER remained higher than the Japanese cancer threshold of USD75,000-150,000/QALY. CONCLUSIONS: Applying the Japanese cancer threshold of USD75,000-150,000/QALY, NIVO + Chemo was not cost-effective for patients with advanced or metastatic HER2-negative GC/GEJC/EAC in Japan from the perspective of healthcare payer.

Impacts of the preceding cancer-specific health-related quality of life instruments on the responses to the subsequent EQ-5D-5L.

BACKGROUND: In clinical studies, the EQ-5D-5L is often employed with disease-specific health-related quality of life instruments. The questions in the former are more general than the latter; however, it is known that responses to general questions can be influenced by preceding specific questions. Thus, the responses to the EQ-5D-5L have the possibility of being influenced by the preceding disease-specific health-related quality of life instruments. This may lead to bias in the cost-effectiveness analysis results. Therefore, this study aimed to evaluate the impact of the preceding cancer-specific health-related quality of life instruments on the EQ-5D-5L responses. METHODS: We prepared questionnaire booklets containing the EQ-5D-5L, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, and the Functional Assessment of Cancer Therapy General with different orders. Using a quasi-randomized design, they were distributed to the patients undergoing drug therapy for advanced cancer, who were classified into three groups: Groups 1, 2, and 3 (the EQ-5D-5L placed first, second, and last, respectively). We compared the EQ-5D-5L index and the missingness of EQ-5D-5L among the groups. RESULTS: The mean EQ-5D-5L index was 0.796, 0.760, and 0.789 for groups 1 (n = 300), 2 (n = 306), and 3 (n = 331), respectively. The difference between Groups 2 and 1 was - 0.036 (95% CI - 0.065 to - 0.007; p = 0.015). The proportion of patients with an incomplete EQ-5D-5L was 0.11, 0.11, and 0.05 for Groups 1, 2, and 3, respectively. The difference of the proportions between group 3 and 1 and between 3 and 2 was - 0.06 (95% CI - 0.10 to - 0.02; p = 0.003) and - 0.06 (95% CI - 0.10 to - 0.02; p = 0.003), respectively. CONCLUSIONS: Although the EQ-5D-5L index differed according to the instrument orders, the difference size would not be considerably larger than the minimally important difference. The patients tended to complete the EQ-5D-5L when they were placed at the end of the questionnaire.

Gradient Boosted Tree Approaches for Mapping European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Onto 5-Level Version of EQ-5D Index for Patients With Cancer.

OBJECTIVES: This study aimed to develop direct and response mapping algorithms from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 onto the 5-level version of EQ-5D index based on the gradient boosted tree (GBT), a promising modern machine learning method. METHODS: We used the Quality of Life Mapping Algorithm for Cancer study data (903 observations from 903 patients) for training GBTs and testing their predictive performance. In the Quality of Life Mapping Algorithm for Cancer study, patients with advanced solid tumor were enrolled, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and 5-level version of EQ-5D were simultaneously evaluated. The Japanese value set was used for direct mapping, whereas the Japanese and US value sets were used for response mapping. We trained the GBTs in the training data set (80%) with cross-validation and tested the predictive performance measured by the root mean squared error (RMSE), mean absolute error (MAE), and mean error in the test data set (20%). RESULTS: The RMSE and MAE in the test data set were larger in the GBT approaches than in the previously developed regression-based approaches. The mean error in the test data set tended to be smaller in the GBT approaches than in the previously developed regression-based approaches. CONCLUSIONS: The predictive performances in the RMSE and MAE did not improve by the GBT approaches compared with regression approaches. The flexibility of the GBT approaches had the potential to reduce overprediction and underprediction in poor and good health, respectively. Further research is needed to establish the role of machine learning methods in mapping a nonpreference-based measure onto health utility.

Cost-Effectiveness Analysis of Universal Screening for Biliary Atresia in Japan.

OBJECTIVE: To evaluate the cost-effectiveness of universal newborn screening using stool color card or direct bilirubin (DB) testing when comparing with no screening for biliary atresia in Japanese setting. STUDY DESIGN: A decision analytic Markov microsimulation model was developed to evaluate the universal screening for biliary atresia. Our screening strategies included stool color card, DB, or no screening. The outcomes of all newborns undergoing 3 strategies were simulated to analyze event-free life-years defined as liver transplant-free survival, costs, and incremental cost-effectiveness ratio (ICER) over a 25-year period with an annual discount rate of 2% applied for both costs and outcomes. A 1-way sensitivity analysis was performed to assess the uncertainty. RESULTS: There were 941 000 newborn infants in our cohort and 114 cases of biliary atresia. The base case analysis showed that the stool color card strategy was $14 927 337 higher than no screening with an increase in 44 more event-free life-years gained, resulting in an ICER of $339 258 per event-free life-year gained. The DB screening strategy compared with stool color card was $138 994 060 higher with an increase in 271 more event-free life-years gained and an ICER of $512 893 per event-free life-year gained. The DB screening strategy compared with no screening resulted in an ICER of $488 639 per event-free life-year gained. The DB screening resulted in 16 fewer liver transplants than stool color card and stool color card had 2 fewer liver transplants than no screening. CONCLUSIONS: Universal screening for biliary atresia could be cost-effective depending on the willingness to pay thresholds for health benefits.

Cost-Effectiveness of First-Line Nivolumab Plus Ipilimumab Combination Therapy in Advanced Non-Small-Cell Lung Cancer in Japan.

BACKGROUND AND OBJECTIVE: In Japan, indications for nivolumab have been expanded to include the combination therapy with ipilimumab in various cancers. This study aimed to evaluate the cost-effectiveness of combination therapy of nivolumab plus ipilimumab (NIV + IPI) for patients with advanced non-small-cell lung cancer (NSCLC), comparing it with platinum-doublet chemotherapy in Japanese settings. METHODS: A partitioned survival model was developed to predict costs and quality-adjusted life-years (QALYs) in a NIV + IPI arm and a chemotherapy arm. Data on overall survival and progression-free survival were derived from the CheckMate 227 trial. Cost estimates were based on a Japanese healthcare system perspective using real-world data from the JMDC claims database. Utilities were derived from published sources outside Japan. The incremental cost-effectiveness ratio (ICER) of NIV + IPI therapy compared with chemotherapy was estimated. A scenario analysis on the level of programmed death-ligand 1 (PD-L1) expression was conducted. In addition, sensitivity analyses were performed to assess the uncertainty in parameter settings. RESULTS: Compared with chemotherapy, NIV + IPI therapy incurred an additional cost of USD102,623 and conferred an additional 1.007 QALY, which resulted in an ICER of USD101,950/QALY gained. Contrary to prior expectations, the ICER of patients with a PD-L1 expression level ≥ 1% was higher than that of patients with a PD-L1 expression level < 1% (USD145,868/QALY and USD127,737/QALY, respectively). Sensitivity analyses showed a relatively robust result with the ICERs remaining higher than a Japanese price adjustment threshold of USD75,000/QALY with a few exceptions. CONCLUSIONS: The combination of NIV + IPI as first-line therapy would not be cost effective under a willingness-to-pay threshold of USD75,000/QALY from the perspective of the Japanese healthcare system.

Cost-Effectiveness of Trastuzumab With or Without Chemotherapy as Adjuvant Therapy in HER2-Positive Elderly Breast Cancer Patients: A Randomized, Open-Label Clinical Trial, the RESPECT Trial.

BACKGROUND AND OBJECTIVE: Trastuzumab is a standard care as adjuvant chemotherapy (AdjCT) for patients with human epidermal growth factor receptor 2 (HER2)-positive primary breast cancer (BC) in Japan. However, no reports have evaluated its economics for patients with HER2-positive BC over 70 years of age. The objective of this study was to evaluate the cost-effectiveness of HER2-targeted trastuzumab + chemotherapy in Japan, comparing it with trastuzumab monotherapy. METHODS: A three-state-partitioned survival model was developed to evaluate the cost-effectiveness of trastuzumab + chemotherapy versus trastuzumab monotherapy for AdjCT in elderly patients with HER2-positive BC. We derived the efficacy data, utilities, and costs of both arms from individual patient data in the RESPECT trial (NCT01104935) and published studies. The costs and quality-adjusted life years (QALYs) were discounted at 2% per annum using a payer perspective. The respective cost estimates were reported in 2019 Japanese Yen (JPY) or US dollars (US$). The primary outcome was the incremental cost-effectiveness ratio (ICER). We assured robustness with deterministic and probabilistic sensitivity analyses. RESULTS: The cost per patient for trastuzumab + chemotherapy was JPY 14.6 million (US$137,000), and their QALYs were 9.308, compared with JPY 14.2 million (US$131,000) and 9.101, respectively, for trastuzumab monotherapy. The ICER of trastuzumab + chemotherapy versus trastuzumab monotherapy was JPY 2.7 milllion/QALY (US$17,200/QALY). The ICER for trastuzumab with chemotherapy varied from "Dominant" to "Dominated" in one-way sensitivity analysis. CONCLUSIONS: The base-case analysis suggests that AdjCT with trastuzumab + chemotherapy is likely to be a cost-effective choice for patients with HER2-positive BC aged 70 years or older. However, the sensitivity analysis suggested uncertainty regarding the cost-effectiveness of trastuzumab + chemotherapy.

Direct health care cost of treatment and medication of biliary atresia patients using the National Database of Health Insurance Claims and Specific Health Checkups.

BACKGROUND: Treatment of biliary atresia (BA), which typically requires an initial surgical intervention called the Kasai procedure (KP) and possible liver transplant (LT) afterwards, is quite resource-intensive and would affect patients and families for a lifetime; yet a comprehensive view of the economic burden has not been reported. We estimated direct health care costs from the public payer perspective using the National Database of Health Insurance Claims and Specific Health Checkups of Japan. METHODS: Children newly diagnosed at ages 0 days to 4 years between April 2010 and September 2019 were identified. Costs of treatment were estimated for six phases of care: prediagnosis, KP and inpatient hospitalization, follow-up after KP, pre-transplant checkup, LT and inpatient hospitalization, and follow-up after LT. RESULTS: Mean total prediagnosis medical cost was $6847 (USD) and KP and inpatient hospitalization was $42,157 per year. Follow-up after KP was $15,499, and pre-transplant checkup after KP was $36,015 per year. Mean cost for LT and inpatient hospitalization was $105,334, and follow-up after liver transplant was $25,459 per year. CONCLUSIONS: Treatment of BA requires extensive medical resource consumption. The use of the comprehensive national database allowed us to estimate the costs which will be useful for health service planning and cost-effectiveness analysis.

Randomized Controlled Trial of Paper-Based at a Hospital versus Continual Electronic Patient-Reported Outcomes at Home for Metastatic Cancer Patients: Does Electronic Measurement at Home Detect Patients' Health Status in Greater Detail?

PURPOSE: This study aimed to determine whether continual electronic patient-reported outcome (ePRO) measurements at home can capture the fluctuations in health-related quality of life (HRQOL) scores between visits. METHODS: We performed a randomized controlled trial to compare the scores obtained by standard practice (paper-based measurements in the hospital) to scores by continuous measurement of ePRO at home. Metastatic cancer patients were randomly assigned to either the paper-based (n = 50) or the ePRO group (n = 52). EQ-5D-5L and EORTC QLQ C-30 scores were obtained on 3 different chemotherapy days in the paper-based group. Meanwhile, scores were obtained on the chemotherapy day and on days 3, 7, 10, and 14 in the ePRO group during 2 cycles. The first hypothesis of our study was that both scores at the same time points would be equivalent despite different measurement frequency, place, or mode of measurement. The second hypothesis was that PRO score-adjusted time would be different between the groups. For equivalence, the endpoint was the mean EQ-5D-5L index value on the chemotherapy day before the outpatient treatment. Only if equivalence was shown, quality-adjusted life-days (QALDs) were considered using all the data. RESULTS: The adjusted mean difference in the EQ-5D-5L index was determined to be -0.013 (95% confidence interval [CI]: -0.049 to 0.022); the 95% CI did not exceed the equivalence margin. Similarly, the mean difference in global health status (2.28 [95% CI: -2.55 to 7.11]) also showed equivalence. However, the QALD by EQ-5D-5L was significantly lower in the ePRO group by 1.36 per 30 d (95% CI: -2.22 to -0.51; P = 0.0021). CONCLUSIONS: Continual measurements of the HRQOL at home by ePRO may yield more detailed profiles of the HRQOL.

Cost-Effectiveness of Nab-Paclitaxel and Gemcitabine Versus Gemcitabine Monotherapy for Patients with Unresectable Metastatic Pancreatic Cancer in Japan.

OBJECTIVES: The purpose of this study was to evaluate the cost-effectiveness of nab-paclitaxel and gemcitabine (GnP) compared with gemcitabine monotherapy (G) for patients with unresectable metastatic pancreatic cancer in Japan from the perspective of healthcare payer. METHODS: A partitioned survival analysis model was developed to predict costs and quality-adjusted life years (QALYs) for GnP and G. The time horizon of the model was set at 20 years. An annual discount rate of 2% for both costs and QALYs was applied. Data on overall survival and progression-free survival were derived from the Metastatic Pancreatic Adenocarcinoma Clinical Trial. Cost parameters were estimated from a Japanese medical claims database. The incremental cost-effectiveness ratio (ICER) of GnP compared with G was estimated. One-way sensitivity analysis was performed to assess the uncertainty in the parameter settings. In addition, scenario and probability sensitivity analyses were performed. RESULTS: The incremental cost and QALY of GnP compared with G were US$25 089 and 0.13 QALY, respectively. The ICER of GnP was estimated to be US$192 992 per QALY gained. Although the ICER was influenced by utility parameters and the survival curves, the ICERs remained higher than the willingness to pay (WTP) threshold of US$68 000 (JPY 7.5 million). The probability that GnP becomes cost-effective compared with G was estimated to be 29.2%. CONCLUSIONS: Applying the WTP threshold of US$68 000 per QALY, GnP was not cost-effective for patients with unresectable metastatic pancreatic cancer in Japan from the perspective of healthcare payer. Further research is needed to obtain utility data from Japanese patients with pancreatic cancer.

Impact of chemotherapy on cognitive functioning in older patients with HER2-positive breast cancer: a sub-study in the RESPECT trial.

PURPOSE: To investigate whether postoperative adjuvant trastuzumab plus chemotherapy negatively affected cognitive functioning during the post-chemotherapy period compared with trastuzumab monotherapy in older patients with HER2-positive breast cancer. METHODS: In the randomized RESPECT trial, women aged between 70 and 80 years with HER2-positive, stage I to IIIA invasive breast cancer who underwent curative operation were randomly assigned to receive either 1-year trastuzumab monotherapy or 1-year trastuzumab plus chemotherapy. Cognitive functioning was assessed using the Mini-Mental State Examination (MMSE) test at enrollment and 1 and 3 years after initiation of the protocol treatment. The primary outcome was change in the MMSE total score from baseline. Secondary outcomes included prevalence of suspected mild cognitive impairment (MMSE total score < 28) and suspected dementia (MMSE total score < 24). RESULTS: The analytical population consisted of 29 and 26 patients in the trastuzumab monotherapy and trastuzumab plus chemotherapy groups, respectively. The group differences in mean changes of the MMSE total score were 0.6 (95% confidence interval [CI] - 0.3 to 1.6) at 1 year and 0.9 (95% CI - 1.0 to 2.8) at 3 years (P = 0.136 for the group difference pooling the two visits). The prevalence of suspected mild cognitive impairment at 3 years was 41.7% in the trastuzumab monotherapy group and 28.6% in the trastuzumab plus chemotherapy group (P = 0.548). CONCLUSION: This randomized sub-study did not show worse cognitive functioning during the post-chemotherapy period with trastuzumab plus chemotherapy than with trastuzumab monotherapy in older patients with HER2-positive breast cancer. TRIAL REGISTRATION NUMBER: NCT01104935 (first posted April 16, 2010).

Economic Evaluation of First-Line Pertuzumab Therapy in Patients with HER2-Positive Metastatic Breast Cancer in Japan.

OBJECTIVE: The purpose of this analysis was to evaluate the cost effectiveness of the combination of pertuzumab, trastuzumab, and docetaxel (PTD) for the treatment of patients with human epidermal growth factor receptor-2 (HER2)-positive breast cancer in Japan. METHODS: A partitioned survival analysis model was developed to predict costs and quality-adjusted life-years (QALYs) in a PTD arm and a trastuzumab plus docetaxel (TD) arm. Direct medical costs were considered from the perspective of the Japanese healthcare system. The time horizon of the model was set to 20 years. Data on overall survival and progression-free survival were derived from the CLEOPATRA trial. Cost parameters were estimated using a real-world claims database. Utilities were derived from published sources outside Japan. The incremental cost-effectiveness ratio (ICER) of PTD therapy compared with TD therapy was estimated. Sensitivity analysis was conducted to assess the uncertainty in parameter settings. RESULTS: Compared with TD therapy, PTD therapy incurred an additional cost of $US174,479 and conferred an additional 0.949 QALYs. This resulted in an ICER of $US183,901 per QALY gained. Utility weights for progression-free survival and progressed disease had a relatively large impact on the base-case result, but the ICERs remained higher than $US75,000 per QALY over the full range of model parameters. Based on a probabilistic sensitivity analysis, the probability that PTD is cost effective was estimated to be 3.3%. CONCLUSIONS: Applying a willingness-to-pay threshold of $US75,000 per QALY, PTD therapy as first-line therapy would not be cost effective. Further research is required on utilities and clinical benefits for Japanese patients with breast cancer.

Mapping EORTC QLQ-C30 and FACT-G onto EQ-5D-5L index for patients with cancer.

BACKGROUND: To develop direct and indirect (response) mapping algorithms from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy General (FACT-G) onto the EQ-5D-5L index. METHODS: We conducted the QOL-MAC study where EQ-5D-5L, EORTC QLQ-C30, and FACT-G were cross-sectionally evaluated in patients receiving drug treatment for solid tumors in Japan. We developed direct and indirect mapping algorithms using 7 regression methods. Direct mapping was based on the Japanese value set. We evaluated the predictive performances based on root mean squared error (RMSE), mean absolute error, and correlation between the observed and predicted EQ-5D-5L indexes. RESULTS: Based on data from 903 and 908 patients for EORTC QLQ-C30 and FACT-G, respectively, we recommend two-part beta regression for direct mapping and ordinal logistic regression for indirect mapping for both EORTC QLQ-C30 and FACT-G. Cross-validated RMSE were 0.101 in the two methods for EORTC QLQ-C30, whereas they were 0.121 in two-part beta regression and 0.120 in ordinal logistic regression for FACT-G. The mean EQ-5D-5L index and cumulative distribution function simulated from the recommended mapping algorithms generally matched with the observed ones except for very good health (both source measures) and poor health (only FACT-G). CONCLUSIONS: The developed mapping algorithms can be used to generate the EQ-5D-5L index from EORTC QLQ-C30 or FACT-G in cost-effectiveness analyses, whose predictive performance would be similar to or better than those of previous algorithms.

Response Shift-Adjusted Treatment Effect on Health-Related Quality of Life in a Randomized Controlled Trial of Taxane Versus S-1 for Metastatic Breast Cancer: Structural Equation Modeling.

OBJECTIVE: We investigated the quantification of the response shift-adjusted treatment effect on quality-of-life (QOL) data in a randomized controlled trial of taxane versus S-1 for patients with metastatic breast cancer (SELECT-BC). METHODS: This study was a secondary data analysis of a previously published trial. The response shift-adjusted treatment effect on health-related QOL (HRQOL) data measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was estimated using structural equation modeling techniques in addition to quantifying the "true" treatment effect. Measurement invariances in the values of the common factor loadings, intercepts, and residual variances between before treatment and at the 3-, 6-, and 12-month visits were considered the response shift effects. RESULTS: In the taxane group, we observed positive recalibration effects for role functioning and positive reprioritization and negative recalibration effects for emotional functioning. The observed change of -4.56 for role functioning comprised +2.26 response shifts and -6.82 "true" change. The observed change of +9.41 for emotional functioning comprised +12.43 response shifts and -1.17 "true" change. In the S-1 group, we observed positive reprioritization and negative recalibration effects for emotional functioning and positive reprioritization effects for social functioning. The observed change of +10.54 for emotional functioning comprised +10.07 response shifts and +0.47 "true" change. The observed change of +2.43 for social functioning comprised +3.50 response shifts and -1.07 "true" change. CONCLUSION: Detailed analysis of the response shift effects will improve the evaluation reliability of observed HRQOL data during clinical trials.

Factors contributing to the ceiling effect of the EQ-5D-5L: an analysis of patients with prostate cancer judged "no-problems".

PURPOSE: The goal of the present study was to determine factors related to a ceiling effect (CE) on the EQ-5D-5L among Japanese patients with prostate cancer (PC). METHODS: An existent cross-sectional observational study dataset was used. Patients were ≥ 20 years of age and diagnosed with PC. For CE determinants on the EQ-5D-5L, we excluded possible "full-health" patients flagged by the EQ-VAS (score = 100) and/or FACT-P (score = 156) instruments. We then divided them into binary variables: A CE group (EQ-5D-5L score = 1) and others (< 1). The associations between CE, sociodemographic and medical characteristics, and FACT-P subscale scores were examined using a multivariate LASSO selection followed by a binomial logistic regression analysis performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 362 patients were analyzed. The LASSO selection variables, including all obtained variables, were as follows: age, palliative treatment, FACT-P physical well-being, and PC subscale score. Statistically significant variables predicting CE were palliative treatment (OR 0.23; 95% CI 0.09-0.60), physical well-being (OR 1.54; 95% CI 1.34-1.76), and PC subscale (OR 1.08; 95% CI 1.03-1.14). CONCLUSIONS: This study revealed that palliative treatment and two FACT-P physical well-being and PC subscale scores were positively related to CE on the EQ-5D-5L. To our knowledge, this is the first study to examine predictors of CE on the EQ-5D-5L. The present results may be helpful for facilitating the consideration of "bolt-on" studies from the standpoint of PC patients.

[Breast Cancer].

Patients' quality of life(QOL)and/or patient-reported outcomes(PRO)has recently been paid much attention as one of the major health outcomes of breast cancer treatments in Japan. In this report, through a systematic literature review for the evidence of QOL/PRO assessments in clinical study undergoing drug treatments of breast cancer in these several years, I introduced the results of the limited qualified papers from 2017. Moreover, I introduced the results of the large multi-center Japanese survey for alopecia induced by chemotherapy in the recent published paper.

Health utility and health-related quality of life of Japanese prostate cancer patients according to progression status measured using EQ-5D-5L and FACT-P.

PURPOSE: To obtain health utility data to allow for cost-effectiveness analysis in groups stratified by disease progression along with health-related quality of life (HRQoL) information in Japanese prostate cancer (PC) patients. METHODS: In this cross-sectional observational study, EuroQol-5 Dimension- 5 Level (EQ-5D-5L), EuroQol Visual Analog Scale (EQ-VAS), and Functional Assessment of Cancer Therapy-Prostate (FACT-P) measures were used to examine utility, VAS scores, and disease-specific HRQoL, respectively. Scores obtained were statistically examined for the correlation among measures and domains. Parameter estimates of statistically significant factors were assessed using generalized linear models (GLM). RESULTS: A total of 380 patients stratified by their disease progression status were analyzed. The numbers (%) of patients in groups stratified as having localized (L), localized progression (LP), distant metastatic (DM), and DM-castration-resistant PC (CRPC) were 275 (72.4), 40 (10.5), 27 (7.1), and 38 (10.0), respectively. EQ-5D-5L mean (standard deviation, SD) scores of L, LP, DM, and DM-CRPC in study participants were 0.87 (0.15), 0.86 (0.15), 0.85 (0.18), and 0.84 (0.17), respectively. The mean (SD) scores assessed by EQ-5D-5L, EQ-VAS, and FACT-P instruments were 0.86 (0.16), 74.6 (16.8), and 110.8 (19.6), respectively. Utility scores correlated well with FACT-P scores. Eastern Cooperative Oncology Group performance status had significant influences on all instruments' scores. CONCLUSIONS: We obtained health utility and HRQoL scores of Japanese PC patients stratified by disease progression in detail. Our results will be useful for establishing cost-effectiveness analyses in Japanese PC settings.