Japanese value set for the EORTC QLU-C10D: A multi-attribute utility instrument based on the EORTC QLQ-C30 cancer-specific quality-of-life questionnaire.

PURPOSE: This study aimed to develop a Japanese value set for the EORTC QLU-C10D, a multi-attribute utility measure derived from the cancer-specific health-related quality-of-life (HRQL) questionnaire, the EORTC QLQ-C30. The QLU-C10D contains ten HRQL dimensions: physical, role, social and emotional functioning, pain, fatigue, sleep, appetite, nausea, and bowel problems. METHODS: Quota sampling of a Japanese online panel was used to achieve representativeness of the Japanese general population by sex and age (≥ 18 years). The valuation method was an online discrete choice experiment. Each participant considered 16 choice pairs, randomly assigned from 960 choice pairs. Each pair included two QLU-C10D health states and life expectancy. Data were analyzed using conditional logistic regression, parameterized to fit the quality-adjusted life-year framework. Preference weights were calculated as the ratio of each dimension-level coefficient to the coefficient for life expectancy. RESULTS: A total of 2809 eligible panel members consented, 2662/2809 (95%) completed at least one choice pair, and 2435/2662 (91%) completed all choice pairs. Within dimensions, preference weights were generally monotonic. Physical functioning, role functioning, and pain were associated with the largest utility weights. Intermediate utility weights were associated with social functioning and nausea; the remaining symptoms and emotional functioning were associated with smaller utility decrements. The value of the worst health state was - 0.221, lower than that seen in most other existing QLU-C10D country-specific value sets. CONCLUSIONS: The Japan-specific QLU-C10D value set is suitable for evaluating the cost and utility of oncology treatments for Japanese health technology assessment and decision-making.

Psychometric properties of the Japanese version of the EQ-5D-Y by self-report and proxy-report: reliability and construct validity.

PURPOSE: This study aimed to assess psychometric properties of the Japanese version of the EQ-5D-Y (3 levels) with a focus on feasibility, reliability, and construct validity. METHODS: Respondents were recruited from the general populations of three cities in Japan. First, children and adolescents responded to the EQ-5D-Y and PedsQL by self-report. Parents were also asked to evaluate the health states of their children/adolescents using proxy versions of these questionnaires. Next, the EQ-5D-Y was mailed to their residence approximately 2 weeks later, and both children/adolescents and their parents responded to the questionnaire. Reliability was confirmed by self-report test-retest methods and a comparison of self-report responses with proxy responses. Spearman's correlation coefficients were calculated between responses to the EQ-5D-Y and both responses to and scores of the PedsQL in order to assess construct validity. RESULTS: A total of 654 children/adolescents from aged 8 to 15 (median age: 11) responded to the questionnaires at both the first- and second-stage surveys. Test-retest agreement was sufficiently high and was influenced by age. Proxy test-retest results revealed that parents' responses were more reliable compared to the self-report results. Some correlations (|r| > 0.3) between items of the EQ-5D-Y and PedsQL were found. Meanwhile, no correlations were found between proxy responses to the EQ-5D-Y and self-report responses to the PedsQL. CONCLUSIONS: The EQ-5D-Y demonstrates reliability and validity among children/adolescents and their parents in Japan. Construct validity of the EQ-5D-Y by self-report was confirmed through comparisons with the PedsQL. Proxy responses to the EQ-5D-Y were more reliable compared to the self-report results, but construct validity was not confirmed in the proxy version.

Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial.

PURPOSE: The goal of chemotherapy for metastatic breast cancer (MBC) is to prolong survival and maintain health-related quality of life. This study aimed to evaluate long-term health status of patients with MBC who participated in the phase III randomized SELECT BC trial. METHODS: In the SELECT BC trial, patients were randomly allocated to the S-1 or taxane (paclitaxel or docetaxel) arm. Health status was assessed by EQ-5D at pre-treatment, 3 and 6 months after randomization, and every 6 months thereafter to the extent possible. Least square mean scores were assessed to compare EQ-5D index values between groups. Time to deterioration analysis was also performed by defining the minimally important difference of EQ-5D as 0.05 or 0.1. RESULTS: The number of patients for EQ-5D analysis was 175 and 208 in the taxane and S-1 arms, respectively. Least square mean EQ-5D index values up to 60 months were 0.741 (95 % CI [0.713-0.769]) in the taxane arm and 0.748 [0.722-0.775] in the S-1 arm. The EQ-5D index value during PFS up to 12 months in the S-1 was superior to the corresponding index value in the taxane (0.812 [0.789-0.834] vs. 0.772 [0.751-0.792], P = 0.009). Time to deterioration analysis also revealed that S-1 significantly delayed the deterioration of EQ-5D index value during the period before progression (P = 0.002 and 0.003). CONCLUSIONS: Our findings suggest that the EQ-5D index value was higher in patients treated with S-1 during first-line chemotherapy. Considering non-inferiority of S-1 in terms of OS, obtained quality-adjusted life years may be greater in the S-1 arm.

Cost-effectiveness analysis of trastuzumab to treat HER2-positive advanced gastric cancer based on the randomised ToGA trial.

BACKGROUND: We performed a cost-effectiveness analysis of trastuzumab plus chemotherapy for human epidermal growth factor type-2 (HER2)-positive advanced gastric cancer (GC) based on data obtained from the Trastuzumab for Gastric Cancer (ToGA) trial from a Japanese perspective. METHODS: The following Japanese and Korean populations of the ToGA trial were analysed to obtain mean overall and progression-free survival times: (1) all HER2-positive populations, (2) immunohistochemical (IHC) 2+/fluorescence in situ hybridisation (FISH)+ or IHC 3+ populations, and (3) IHC 3+ only population. The effect of trastuzumab treatment on mean survival time was estimated by fitting a Weibull parametric function. Costs were calculated from the perspective of health-care payer. Neither costs nor outcomes were discounted because of short life expectancy. RESULTS: In the base-case analysis, the incremental cost-effectiveness ratio was (1) JPY 12 million (€110,000) per quality-adjusted life year (QALY) gained and JPY 8.9 million (€81,000) per life-year gained (LYG) for all HER2-positive populations, (2) JPY 9.1 million (€83,000) per QALY gained and JPY 6.6 million (€60,000) per LYG for the IHC 2+/FISH+ or IHC 3+ population, and (3) JPY 6.1 million (€55,000) per QALY gained and JPY 4.3 million (€39,000) per LYG for the IHC 3+ population. CONCLUSION: Trastuzumab treatment for IHC 3+ populations is cost effective. Our analysis can find a cost-effective subgroup when advanced GC is treated by trastuzumab.

Effect of CGS 16949A plus tamoxifen on induced mammary tumours in rats.

The antitumour effect of CGS 16949A, an aromatase inhibitor, was investigated in rats with mammary tumours induced by 7,12-dimethylbenz[a]anthracene. A dose-dependent antitumour effect was observed after daily oral administration of CGS 16949A for 3 weeks. The tumour did not recur in the groups treated with 4.0 and 8.0 mg/kg per day. The complete remission rate increased and the time required to achieve complete remission became shorter with increasing daily doses. After daily administration for 3 weeks, a significant antitumour effect was observed in the group treated with CGS 16949A plus tamoxifen compared with that seen either with CGS 16949A or with tamoxifen alone. At the end of treatment, the group treated with CGS 16949A had significantly decreased oestradiol-17 beta and prolactin levels and increased levels of follicle stimulating hormone, but oestrone was not affected.

Semi-quantitative comparison of the differentiation markers and sodium iodide symporter messenger ribonucleic acids in papillary thyroid carcinomas using RT-PCR.

OBJECTIVE: To investigate the levels of expression of the sodium iodide symporter (NIS) and three differentiation markers (thyroglobulin (Tg), thyroid peroxidase (TPO) and thyrotrophin receptor (TSH-R)) in 35 patients with primary (n=31) or recurrent (n=4) papillary thyroid carcinoma, and to compare the findings with clinical data. METHODS: We performed a multiplex semi-quantitative RT-PCR to analyse the relative levels of expression of Tg, TPO and TSH-R mRNAs, and a separate semi-quantitative RT-PCR for NIS mRNA. RESULTS: Tg, TPO and TSH-R mRNAs were expressed in all the patients, whereas NIS mRNA was expressed in all but eight. Analysis of the expression of the differentiation markers in all patients showed a significant correlation among Tg, TPO and NIS. With regard to the relationship between the expression of each gene and the MACIS score, there was significant correlation only for the Tg gene (P<0.05). CONCLUSIONS: The levels of expression of NIS mRNA correlated significantly with those of Tg and TPO mRNAs, but not with those of TSH-R mRNA. The relationship with clinical stage and prognostic score, however, varied among these differentiation markers.

Lithium associated autoimmune thyroiditis.

A case of autoimmune thyroiditis after long term treatment with lithium is described in a 29 year old Japanese woman with manic depression. Positive serum antithyroglobulin and antimicrosomal antibodies, diffuse goitre, and microscopic chronic thyroiditis, as well as the clinical history of long term lithium treatment were suggestive of lithium associated autoimmune thyroiditis. Microscopically, there was a mild degree of interstitial fibrosis and a moderate degree of lymphocytic infiltration. Some areas showed a moderate degree of stromal fibrosis and atrophic thyroid follicles. Lymphoid follicles with germinal centres, disrupted thyroid follicles with lymphocytic infiltration, and Hürthle cells were also observed. The differential diagnosis in patients presenting with these histological features includes painless (silent) thyroiditis, autoimmune thyroiditis and lithium associated autoimmune thyroiditis. A detailed clinical history is essential if the correct diagnosis is to be reached.

Analyses of the outcome of locally invasive papillary thyroid carcinomas.

We retrospectively analyzed the outcome for patients with locally invasive papillary carcinoma. The study group comprised 40 patients with locally invasive papillary thyroid carcinoma first diagnosed between 1981 and 1995. The enrolled patients were divided into two groups according to whether they underwent complete resection (n = 19) or not (n = 21). All patients were followed-up for a maximum of 206 months and a minimum of 33 months until 1998. There were no significant differences among these two groups with regard to age, sex, or tumor size. Recurrence of the disease was recognized in four patients in the complete resection group and ten in the incomplete group. There were no significant differences in the recurrence rate between both groups. Five patients from the incomplete resection group died of disease, and all patients from the complete resection group were alive. The percentage of surviving patients in the complete resection group was significantly higher than that in the incomplete group. The 15-year survival rates of the complete resection group and incomplete resection group were 100% and 74.2%, respectively. The 15-year survival rate of patients younger than 45 years in the incomplete resection group was 100%. The 15-year survival rate of the complete resection group was significantly higher than that of the incomplete group. In conclusion, complete resection without tumor residue should be performed for patients older than 45 years.

Interstitial brachytherapy for recurrent breast cancer using a high dose rate Ir-192 remote afterloading system: a report of two cases.

We employed interstitial brachytherapy using a high dose rate Ir-192 remote afterloading unit in two breast cancer patients with locoregional recurrence. In the first case, skin metastasis was treated, with favorable control of the infield tumor but subsequent persistent sequelae and multiple outfield metastases. This experience caused us to be cautious when choosing brachytherapy for the second case, in whom a solitary metastasis to an axillary lymph node was successfully treated. Although this method is still investigational, it may play a critical role in the treatment of locoregional recurrence resistant to other treatment modalities.

[Significance and problems of quality-of-life assessment in clinical trials].

The importance of quality of life (QOL), as an outcome variable of cancer treatments, has rapidly become recognized not only in western countries but also in Japan. However, many problems remain to be resolved for QOL assessment methods. In this paper, we give outlines for the position of QOL as an outcome variable, the standpoint and purpose for QOL assessment, the appropriate range of QOL domains to be assessed, and the appropriate QOL measures. Furthermore, we introduce key points for the success of QOL assessment in clinical trials, the appropriate way to deal with missing data and appropriate methods for analysis in longitudinal studies.

[Analysis of factors that improve quality of life of patients with advanced or recurrent breast cancer].

The quality of life (QOL) of 21 patients with advanced or recurrent breast cancer was assessed using a QOL measure developed by the Ministry of Welfare in Japan: The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs (QOL-ACD). The factors that improve the QOL were analyzed by multiple regression analysis. The difference of the QOL score between pre- and post-treatment was set as a dependent variable, and sociodemographic and therapeutic characteristics were set as independent variables. The results revealed that the improvement of the QOL score had close associations with therapeutic efficacy (TE) and shorter disease-free interval (DFI). In the analysis using the mean scores of the four categories of the QOL (activity, physical, psychological and social aspects) as dependent variables, activity had a close association with shorter DFI; physical aspect had close associations with TE and shorter DFI; and the psychological aspect had close associations with chemoendocrine therapy and less lines of previous therapies. The results suggest that, to improve the QOL of patients with advanced or recurrent breast cancer, we should attempt to obtain higher efficacy of treatments such as endocrine therapy for patients with shorter DFI in the earlier period of their clinical course.

[Subrenal capsule (SRC) assay as a chemosensitivity test (IV)--Evaluation of the SRC assay method as a system for growing implanted tumor-xenografts].

Using tumor specimens of human cancer serially transplanted in nude mice, we examined fundamentally the subrenal capsule assay method in order to improve the subrenal space as an area where implanted tumor-xenografts persistently grow. Host reaction in immunocompetent mice treated with cyclosporin A (CsA) (60 mg/kg subcutaneously, daily) was suppressed almost completely, and tumor-xenografts persistently grew similarly to those implanted under the renal capsule of BALB/c-nu/nu mice. CsA treatment, 30 mg/kg given subcutaneously; daily, or 60 mg/kg subcutaneously; every other day, could not suppress the host reaction. Bredinin treatment, 200 mg/kg subcutaneously; every other day, or 100 mg/kg subcutaneously; daily, could not suppress the host reaction also, and tumor-xenografts implanted under the renal capsule were rejected.

[Notification of cancer in breast cancer patients].

The notification of the name of disease is a premise for making the system of informed consent more complete in case of cancer treatment. In Japan, however, the notification of cancer can hardly be said to have an attained social consensus. Considering that the notification can ultimately improve patients quality of life (QOL), the breast cancer group of our department informs all breast cancer patients of their diseases in principle. This paper reports and discusses the results of a survey by questionnaire on the notification of cancer in 100 patients with breast cancer. The notification of cancer was received favorably in 83% of the patients. For those who answered, the explanation on the notification was convincing and it accounted for 81%. An examination of background factors of patients who had not been convinced revealed that many of them were suffered from advanced cancer. After the notification, a human relationship with the family and friends aggravated few of them and improved in 30% (family) and 18% (friends), respectively. The notification of cancer was thus suggested to contribute to the improvement of QOL. Although 83% well received the notification of their own diseases, only 21% were affirmative for the notification of cancer in case of a member of the family. We medical professionals should make a further effort not to make the notification of cancer the pronouncement death but to make it an aid for patients to live better.

[Analyses of factors influencing the chemosensitivity of human tumors xenografted into nude mice (I)].

Experimental single-agent chemotherapies using 11 anticancer agents for 15 human cancers xenografted into nude mice revealed that each cancer line seemed to retain a degree of individuality in its spectrum of chemosensitivity irrespective of whether it originated from the same organ or whether it was of a similar histologic type. As possibly factors relevant to this chemosensitivity, we investigated the following 9 parameters in cancer tissue or cancer-bearing mice, i.e., grade of differentiation, vascularity, percentage necrosis, volume doubling time, labeling index (LI), LDH activity, tissue/serum LDH ratio, thymidine phosphorylase activity, and serum CEA. Values of these parameters remained markedly constant within each cancer line. The relationships between these 9 parameters and chemosensitivities to the 11 drugs were investigated in 15 cancer lines. A statistically significant relationship was noted in 22% of the 99 such combinations. Parameters showing a close correlation to chemosensitivity differed from drug to drug, such as ADR vs LI and vascularity, 5'-DFUR vs CEA and vascularity, and MMC vs LDH ratio and grade of differentiation. It was concluded that the chemosensitivity of cancer lines to each drug is a result of various interacting factors.

[Systemic therapy, pain relief and quality of life of breast cancer patients with bone metastasis].

Systemic therapy, pain relief and the quality of life (QOL) of breast cancer patients with bone metastasis were described. QOL was measured using a "QOL questionnaire" developed by the Ministry of Welfare in Japan. It was proved objectively that QOL scores in the cases with bone metastasis were significantly low in terms of activity, physical psychological conditions. Chemoendocrine therapy, endocrine therapy and outpatient therapy showed a high QOL score. The cases with bone pain showed a low QOL scores. In the 45 cases whose first metastatic site was bone only, there were no differences between endocrine therapy and chemoendocrine therapy in the rate and period of response or the total QOL score. MPA showed a higher response rate and a higher pain relief rate than TAM. In the cases with bone metastasis but without severe visceral metastasis, MPA monotherapy showed an excellent response when the tumor was ER or PgR positive, or when there was a long disease-free interval of more than three years, or if there was no previous therapy. MPA monotherapy is a suitable firstline therapy in such cases. Radiation therapy was more effective for bone pain (response rate 96.3%), and it was also effective in cases in which systemic therapy was not.

[Chemosensitivity of human gastrointestinal and breast cancer xenografts in nude mice].

Experimental chemotherapies for 15 human cancers xenografted into nude mice were performed using 14 anticancer agents including 6 drugs in clinical use. Treatment with each single agent was performed for every cancer line using the maximum tolerated dose through continuous daily (antimetabolites) or intermittent (cytocidal agents) schedules. Effectiveness of each drug was evaluated by inhibition rate (IR) calculated from mean tumor weights of both treated and untreated groups. Response to a treatment was judged as effective when the IR was higher than 58%. Response rate of each drug was as follows; MMC was 67%, UFT 67%, CPA 47%, FT-207 40%, ACNU 33%, ADR 27%, SOAz 87%, 5'-DFUR 80%, MXT 20%, Leakadine 17%, M-83 17%, CAM 0% and GANU 0%. Generally, the experimental results for each drug on the xenografts was in good accordance with the known clinical effect of each drug on the same type of cancer. On the other hand, individual cancer xenografts showed considerable differences in chemosensitivity. Some tumors were sensitive to a majority of the drugs, whereas some were resistant to many of them. Each cancer line seemed to retain individuality in its spectrum of chemosensitivity irrespective of whether it originated from the same organ or whether it was of similar histologic type. This fact suggests the necessity of selecting drugs effective to the individual tumor when considering a patients chemotherapy regime.

[A case of advanced breast cancer associated with humoral hypercalcemia that responded to medroxyprogesterone acetate and docetaxel].

A 67-year-old woman with a left advanced breast cancer was admitted to our hospital. Chest CT revealed a parasternal lymph nodal metastasis invading into the sternum, an axillary lymph nodal metastasis, and a lung metastasis. The clinical stage of the patient was i.v. (T4bN2M1). Laboratory examination showed humoral hypercalcemia. After controlling the hypercalcemia with alendronate, sodium hydrate she received chemoendocrine therapy with medroxyprogesterone acetate (MPA) (800 mg/day) and docetaxel (60 mg/body once every three weeks). A complete response was obtained in the primary and metastatic lesions after 3 cycles of docetaxel. This case suggests the efficacy of the combined therapy with MPA and docetaxel on advanced breast cancers.

[Predictability of preclinical evaluation of anticancer drugs by human gastrointestinal cancer--nude mouse panel].

We evaluated the predictability to clinical response of experimental effects of various anticancer agents on human cancer--nude mouse panel established in our department. The human cancer lines used were 12 gastric, 4 colorectal, 3 breast, 2 pancreatic cancers and 1 melanoma xenografted into BALB/c athymic nude mice under SPF conditions. Seven mice each with equivalent mean volume of sc inoculated tumor (about 100 mm3) were subjected to the treatment and control groups. Experimental treatment was conducted daily 25 times for antimetabolites, and intermittently 5 times once or twice a week for other drugs. Dosage of each drug adopted was maximal tolerated dose predetermined for the treatment schedule. Four weeks after the initiation of treatment, the therapeutic effect of each experiment was evaluated by the tumor growth inhibition rate (IR) based on the comparison of mean tumor weight between the 2 groups. When the IR was greater than 58%, the drug was evaluated as effective. The clinical response rate of each drug was referred from the result of the phase II study. Direct comparison of effects on 16 experimental chemotherapies in xenografts with responses to the corresponding clinical therapy of each donor patient revealed a fairly high accordance rate (94%). To elucidate the value of human cancer--nude mouse panel as the preclinical secondary screening, the response rates of 8 anticancer drugs treated to 15 cancer xenografts were compared with the cumulative clinical data available in each drug. Generally, the response rates of the human cancer xenografts to the drugs showed fairly good correlations with the cumulative clinical response rates of the corresponding drugs to the same organs. Using this panel, preclinical examinations of 6 new agents under development, including 254 S and other 2 CDDP derivatives, were performed in expectation the positive correlation with further clinical data.