Search

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., (© 2022. The Author(s).)

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)., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

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.

Purpose: Many breast cancer patients suffer from chemotherapy-induced hair loss. Accurate information about temporal changes in chemotherapy-induced hair loss is important for supporting patients scheduled to receive chemotherapy, because it helps them to prepare. However, accurate information, on issues such as the frequency of hair loss after chemotherapy, when regrowth starts, the condition of regrown hair, and the frequency of incomplete hair regrowth, is lacking. This study aimed to clarify the long-term temporal changes in chemotherapy-induced hair loss using patient-reported outcomes for chemotherapy-induced hair loss., Methods: We conducted a multicenter, cross-sectional questionnaire survey. Disease-free patients who had completed adjuvant chemotherapy consisting of anthracycline and/or taxanes for breast cancer within the prior 5 years were enrolled from 47 hospitals and clinics in Japan. Descriptive statistics were obtained in this study. The study is reported according to the STROBE criteria., Results: The response rate was 81.5% (1511/1853), yielding 1478 questionnaires. Hair loss occurred in 99.9% of patients. The mean time from chemotherapy until hair loss was 18.0 days. Regrowth of scalp hair occurred in 98% of patients. The mean time from the completion of chemotherapy to the beginning of regrowth was 3.3 months. Two years after chemotherapy completion, the scalp-hair recovery rate was <30% in approximately 4% of patients, and this rate showed no improvement 5 years after chemotherapy. Eighty-four percent of the patients initially used wigs, decreasing to 47% by 1 year after chemotherapy and 15.2% after 2 years. The mean period of wig use was 12.5 months. However, a few patients were still using wigs 5 years after completing chemotherapy., Conclusions: Our survey focused on chemotherapy-induced hair loss in breast cancer patients. We believe these results to be useful for patients scheduled to receive chemotherapy., Competing Interests: The authors have declared that no competing interests exist.

Objective: The aim of this study was to investigate the impact of adverse events (AEs) on health utility and health-related quality of life (HRQOL) in patients with metastatic breast cancer undergoing first-line chemotherapy., Methods: We analyzed the data from the SELECT BC study, a multicenter, open-label, randomized, phase III study conducted in Japan, which compared first-line S-1 with taxane therapies. Heath utility and HRQOL were assessed using the EQ-5D-3L and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at baseline and 3, 6, and 12 months after treatment initiation. Health utility was calculated based on societal preferences, and AEs were reported at each cycle of the study treatment. Linear marginal mean models were used to quantify the impact of the last AEs (with 10 or more incidences) observed before HRQOL assessment on health utility and HRQOL., Results: Analysis included 380 patients and 12 (of 15) AEs. Grade 1 nausea and oral mucositis, grade 1 and 2 edema, and grade 2 fatigue, motor and sensory neuropathy, and myalgia were significantly associated with disutility, measured using the EQ-5D-3L. Grade 1 oral mucositis, grade 1 and 2 fatigue, and grade 2 sensory neuropathy were significantly associated with impaired global health status in the EORTC QLQ-C30. AEs associated with decrements in the five functioning scales included fatigue, oral mucositis, nausea, edema, motor and sensory neuropathy, and myalgia., Conclusions: We reported disutilities caused by AEs in patients with metastatic breast cancer under chemotherapy. These findings can be applied to future model-based cost-effectiveness analyses., Trial Registration Number: C000000416.

Objective: To evaluate the effects of S-1, an orally administered 5-FU agent, versus taxane on patient-reported outcomes (PROs) in the SELECT BC trial., Methods: Patients with HER2-negative and endocrine treatment-resistant breast cancer with metastasis or recurrence after surgery were randomly assigned to receive first-line taxane or S-1. PROs (secondary endpoint) were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Patient Neurotoxicity Questionnaire (PNQ) at baseline and at 3, 6, and 12 months. We conducted a responder analysis for the QLQ-C30 and PNQ and created cumulative distribution function (CDF) plots as a sensitivity analysis., Results: The questionnaire response rates were over 80% from 386 patients, who completed at least one baseline questionnaire. S-1 was significantly superior to taxane with respect to 6 scales (physical functioning [p = 0.03], role functioning [p = 0.04], social functioning [p < 0.01], financial difficulties [p = 0.01], global health status [p = 0.02], and constipation [p < 0.01]) and sensory neuropathy (p = 0.01). The CDF plots partially supported the conclusions and their robustness., Conclusion: First-line S-1 therapy has clinical benefits with respect to many aspects of health-related quality of life for metastatic breast cancer patients., (© 2017 The Author(s) Published by S. Karger AG, Basel.)

Background: This study evaluated the cost-effectiveness of replacing standard intravenous therapy (taxane) with oral S-1 therapy for first-line metastatic breast cancer treatment., Methods: This cost-effectiveness analysis was based on data from a randomized phase III trial (SELECT BC). As cost-effectiveness was a secondary endpoint of the SELECT BC trial, some of the randomized patients participated in an EQ-5D survey (N = 391) and health economic survey (N = 146). The EQ-5D responses, claims, and prescription data were collected for as long as possible until death. The expected quality-adjusted life years (QALY) obtained from each treatment were calculated using patient-level EQ-5D data, and the expected cost was calculated using patient-level claim data. The analysis was performed from the perspective of public healthcare payers., Results: The estimated EQ-5D least-square means and 95% CI up to 48 months were 0.764 (95% CI, 0.741-0.782) and 0.742 (95% CI, 0.720-0.764) in the S-1 and taxane arms, respectively. The expected QALY was 2.11 for the S-1 arm and 2.04 for the taxane arm, with expected costs of JPY 5.13 million (USD 46,600) and JPY 5.56 million (USD 50,500), respectively. These results show that S-1 is cost-saving. According to probabilistic sensitivity analysis, S-1 was dominant with a probability of 63%. When the willingness to pay (WTP) value was JPY 5 million (USD 45,500) per QALY, the probability of being cost-effective was 92%., Conclusions: Our results show that the introduction of oral S-1 therapy for metastatic breast cancer is highly likely to be cost-effective., Trial Registration: UMIN CTR C000000416 . Registered on May 10, 2006.

Background: An understanding of health-related quality of life (HRQOL) is of utmost importance in both oncological and esthetic breast surgery. The BREAST-Q is a patient-reported outcome (PRO) measure that investigates HRQOL and patient satisfaction before and after breast surgery. The aim of this study was to develop a Japanese version of the BREAST-Q including the mastectomy module, the reconstruction module, the augmentation module and the reduction/mastopexy module, and to assess the psychometric properties of the mastectomy module among Japanese women., Methods: The Japanese version of the BREAST-Q was developed through forward translation, backward translation and patient testing. Traditional psychometric testing of the mastectomy module was administered to 45 post-mastectomy patients., Results: The mastectomy, reconstruction, augmentation and reduction/mastopexy modules were formally developed into Japanese. Despite cultural difference between Japanese women and original target population, the contents were considered to be valid among Japanese woman. With the exception of the sexual well-being subscale, good reliability and validity were evident for the mastectomy module (Test-retest reliability 0.76-0.95, Chronbach's alpha coefficient 0.77-0.98)., Conclusions: The BREAST-Q Japanese version is a useful PRO measure for investigating the impact of breast surgery on HRQOL and patient satisfaction. Further validation in younger Japanese women is needed to determine the usefulness of the sexual well-being subscale.

Purpose: To assess the joint symptoms and the impact on patients' health-related quality of life (HRQOL) due to 5 years of anastrozole from the baseline data in the N-SAS BC 05 trial, a randomized clinical trial was designed to assess the efficacy of 5 additional years of anastrozole among women with breast cancer., Methods: Joint symptoms and HRQOL were evaluated using an original questionnaire for joint symptoms, the Short Form 36-item Health Survey (SF-36), the EuroQol EQ-5D-3L, and a subscale of the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES)., Results: Baseline joint symptom and HRQOL data were collected from 330 patients between November 2007 and March 2010. Joint pain and joint stiffness were reported by 61.6 and 59.1 % of patients, respectively, although these symptoms did not affect the activities of daily living in 96.0 and 97.9 % of patients, respectively. Joint pain was reported in the knee by 61.0 % of patients and in the hand by 36.0 % of patients. Joint stiffness mainly affected the hand (67.9 %), especially the proximal interphalangeal joint, and typically occurred upon waking up or in the morning. Most SF-36 domains had good average scores, although slight decreases in physical functioning and role-physical were observed (compared to the national standard scores). The mean EQ-5D utility score was 0.86, and the total FACT-ES subscale score was 62.2/76., Conclusions: After 5 years of anastrozole, many of the patients reported joint pain and stiffness in mainly the hand and knee with mild symptoms and good HRQOL.

Background: Oral fluoropyrimidines are used for the first-line treatment of metastatic breast cancer to avoid severe adverse effects, although firm supporting evidence is lacking. We aimed to establish whether S-1 is non-inferior to taxanes in this setting., Methods: We did an open-label, non-inferiority, phase 3 trial at 154 hospitals in Japan. We enrolled individuals who had HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease, and who were resistant to endocrine treatment. Patients were randomly assigned (1:1) either to taxane (docetaxel 60-75 mg/m(2) at intervals of 3-4 weeks; paclitaxel 80-100 mg/m(2) weekly for 3 of 4 weeks; or paclitaxel 175 mg/m(2) at intervals of 3-4 weeks) or to S-1 (40-60 mg twice daily for 28 consecutive days, followed by a 14-day break). Randomisation was done centrally with the minimisation method, with stratification by institution, liver metastasis, oestrogen and progesterone receptor status, previous treatment with taxanes or oral fluorouracil, and time from surgery to recurrence. The primary endpoint was overall survival, with a prespecified non-inferiority margin of 1·333 for the hazard ratio (HR). The primary efficacy analysis was done in the full analysis set, which consisted of all patients who took at least one study treatment and who had all data after randomisation. This trial is registered with the University Hospital Medical Information Network, Japan (protocol ID C000000416)., Findings: Between Oct 27, 2006, and July 30, 2010, we enrolled 618 patients (309 assigned to taxane; 309 assigned to S-1). The full analysis set consisted of 286 patients in the taxane group and 306 in the S-1 group. Median follow-up was 34·6 months (IQR 17·9-44·4). Median overall survival was 35·0 months (95% CI 31·1-39·0) in the S-1 group and 37·2 months (33·0-40·1) in the taxane group (HR 1·05 [95% CI 0·86-1·27]; pnon-inferiority=0·015). The most common grade 3 or worse adverse events were neutropenia (20 [7%] of 307 patients in the S-1 group vs nine [3%] of 290 patients in the taxane group), fatigue (ten [3%] vs 12 [4%]), and oedema (one [<1%] vs 12 [4%]). Treatment-related deaths were reported in two patients in the taxane group., Interpretation: S-1 is non-inferior to taxane with respect to overall survival as a first-line treatment for metastatic breast cancer. S-1 should be considered a new option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer., Funding: Comprehensive Support Project for Oncology Research of the Public Health Research Foundation, Japan; Taiho., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Trials of adjuvant endocrine therapy for breast cancer have shown that aromatase inhibitors have little impact on global health-related quality of life (HRQoL), but have significant effects on patient-reported endocrine symptoms (ESs). There are few studies of HRQoL and psychological distress during preoperative endocrine therapy performed to determine endocrine responsiveness. The NEOS trial is a multicenter, phase 3 randomized controlled trial in postmenopausal women with hormone receptor-positive breast cancer. The primary aim of the trial was to evaluate the need for adjuvant chemotherapy in patients with clinical T1c-T2N0M0, hormone receptor-positive tumors who responded to neoadjuvant letrozole (LET) administered for 24-28 weeks before surgery. The primary endpoint was disease-free survival and the secondary endpoints included adverse events, HRQoL, and cost-effectiveness. In a HRQoL sub-study, subjects were assessed at baseline and 4 and 16 weeks after starting neoadjuvant LET, using the functional assessment of cancer therapy-breast and its ES subscale, and the hospital anxiety and depression scale. HRQoL and psychosocial distress were analyzed in the uncontrolled phase during 24-28 weeks of neoadjuvant LET therapy in the NEOS trial. From May 16, 2008, to December 14, 2011, 503 patients were recruited into the HRQoL sub-study. The full analysis set included 497 patients with a mean age of 63-years old. The questionnaire response rates at enrollment and 4 and 16 weeks were 94.4, 90.7, and 89.1 %, respectively. There were no significant changes in the FACT-G or B-trial outcome index over time, but the social and family well-being score and the ES subscale deteriorated significantly, and the number of patients with clinically significant hot flush increased significantly. Anxiety, depression, and emotional well-being improved significantly after neoadjuvant LET. Neoadjuvant endocrine therapy with LET had no impact on global HRQoL, but did influence endocrine-related symptoms such as hot flush. This study is registered as UMIN000001090.

Background: Sensory loss or paresthesia due to division of the intercostobrachial nerve (ICBN) is a complication of axillary lymph node dissection (ALND). Preservation of the ICBN may be of value, but few prospective studies have shown an impact of preservation on sensory changes or health-related quality of life (HRQOL) after breast cancer surgery., Methods: This prospective study was performed to evaluate the association between ICBN preservation and sensory change and HRQOL at 1 (baseline), 6, 12, and 24 months after breast cancer surgery in 140 patients. The sensory examination included dysesthesia, paresthesia, and abnormal touch and pain sensation in the upper arm., Results: Division of the ICBN did not influence the frequency or severity of subjective dysesthesia and paresthesia. There was no marked difference in touch or pain sensation at baseline between patients with a preserved (group P) and divided (group D) ICBN. In group P, the percentage of patients aware of a sensory deficit or loss decreased with time, and that of patients aware of a hypersensitive sensation increased. These changes did not occur in group D, leading to a significant difference between the groups at 24 months. The main difference between the groups was the area with reduced touch or pain sensation. This area decreased with time in group P, but not in group D. ICBN preservation or division did not influence HRQOL., Conclusion: ICBN preservation in ALND has a benefit of a reduced area with long-term axillary hypoesthesia, but has no influence on improvement of pain and HRQOL.

The aim of healthcare providers is to help patients regain their health and/or maintain or increase their happiness. The quality of healthcare can be assessed objectively by using indices such as survival rates, but subjective assessment is sometimes more important than objective evaluation, because whether patients feel healthy or happy or not is their major concern. Quality of life (QOL) research is a typical approach to subjective assessment of health. Self-administered health-related QOL (HRQOL) questionnaires are used to obtain patient-reported outcome (PRO) data. PRO is defined by the US Food and Drug Administration (FDA) as any report of the status of a patient's health condition that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else. PRO data are regarded as more accurate than clinician-rated ones in terms of assessing patients' symptoms and HRQOL. The Comprehensive Support Project for Health Outcome Research of the Public Health Research Foundation has conducted much PRO research in collaboration with the Comprehensive Support Project for Oncology Research, especially in randomized controlled trials (RCTs). Here, we review the results of PRO research in RCTs conducted in Japan and examine future perspectives in this field.

Purpose: To elucidate whether adjuvant taxane monotherapy is a feasible and tolerable for postoperative breast cancer patients, we evaluated the severity of chemotherapy-induced peripheral neuropathy (CIPN) and the relative tolerability of regimens by health-related quality of life (HRQOL) assessment in node-positive breast cancer patients treated with taxane-containing regimens., Methods: We evaluated CIPN and HRQOL in the first 300 patients enrolled in a larger (1,060 total) multicenter phase III trial randomized to one of four adjuvant regimens: (1) anthracycline-cyclophosphamide followed by paclitaxel (ACP), (2) AC followed by docetaxel (ACD), (3) paclitaxel alone (PTX), or (4) docetaxel alone (DTX). CIPN was assessed by the Patient Neurotoxicity Questionnaire (PNQ) and the National Cancer Institute Common Toxicity Criteria, and HRQOL by Functional Assessment of Cancer Therapy-General (FACT-G). CIPN and HRQOL scores were compared between ACP and ACD vs. PTX and DTX, and ACP and PTX vs. ACD and DTX., Results: PNQ sensory scores were significantly higher in patients treated with taxane monotherapy compared to treatment with AC followed by taxane (P = .003). No significant differences in PNQ sensory scores were observed between the ACP and PTX vs. ACD and DTX regimens (P = .669). Regardless of taxane regimen, PNQ severity scores for CIPN appear to be largely reversible within 1 year of adjuvant treatment. No significant difference in FACT-G scores was observed between any regimens during the study treatments., Conclusions: Patient-reported CIPN was significantly more severe with single-agent adjuvant taxane compared to AC followed by taxane treatment; however, the HRQOL findings support that single-agent taxane treatment is tolerable.

Health-related quality of life (HRQOL), symptoms of depression, and adverse events (AEs) were compared between Japanese postmenopausal patients with hormone-sensitive breast cancer (BC) who received adjuvant tamoxifen, exemestane, or anastrozole in an open-labeled, randomized, multicenter trial designated as the National Surgical Adjuvant Study of Breast Cancer (N-SAS BC) 04 substudy of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. During the first year of treatment, HRQOL and symptoms of depression were analyzed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and its Endocrine Symptom Subscale (ES), and the Center for Epidemiologic Studies Depression Scale (CES-D), respectively. In addition, predefined AEs were analyzed. A total of 166 eligible patients were randomly assigned to receive adjuvant tamoxifen, exemestane, or anastrozole. FACT-B scores increased after treatment began and remained significantly higher in the tamoxifen group than in the exemestane group or anastrozole group during the first year (P = 0.045). FACT-B scores were similar in the exemestane group and anastrozole group. ES scores and CES-D scores were similar in all treatment groups. Arthralgia and fatigue were less frequent, but vaginal discharge was more frequent in the tamoxifen group than in the exemestane group or anastrozole group. HRQOL was better in Japanese postmenopausal women treated with tamoxifen than those treated with exemestane or anastrozole. HRQOL and AEs were similar with exemestane and anastrozole. Given the results of the TEAM trial, upfront use of tamoxifen followed by an aromatase inhibitor (AI) may be an important option for adjuvant endocrine therapy in Japanese postmenopausal women.

Objective: To elucidate the time course of taxane-induced edema which may affect the patients' quality of life (QOL)., Patients and Methods: Our study included the first 300 Japanese patients assigned to 1 of 4 regimens using docetaxel (DTX) or paclitaxel (PTX) by 1:1:1:1 in a randomized controlled trial to evaluate the efficacy of adjuvant therapies for node-positive breast cancer. Patients' QOL was prospectively assessed by the functional assessment of cancer therapy (FACT)-breast and -taxane (FACT-T) subscale. The scores of FACT items regarding edema and body weight were used as indicators of edema., Results: The scores for 'anasarca', 'edema of the hands' and 'edema of the legs and feet' of the FACT-T subscale worsened up to 1-2 months after chemotherapy, and body weights increased remarkably until cycle 8 in patients treated with DTX alone (75 mg/m(2), 8 cycles, every 3 weeks). Edema-related symptoms and body weight were relatively stable in the other treatment groups. There were statistically significant differences in the scores of those items and in the changes of body weight both between the DTX-alone group and the other three groups combined, and between the groups using DTX and those using PTX., Conclusion: Many patients receiving DTX for >4 cycles suffered significantly from edema., (Copyright © 2012 S. Karger AG, Basel.)

Provision of social support and rehabilitation for patients with physical, mental, and functional problems after cancer treatment is important for long-term health-related quality of life (HRQOL). Effective use of human and financial healthcare resources requires identification of patients requiring rehabilitation. The objectives of the current study were to clarify the patterns of physical and psychosocial recovery over time, to evaluate the associations among baseline variables, treatment-related factors and HRQOL at 6 months, 1, and 2 years after breast cancer surgery, and to identify the significant factors predicting HRQOL at each point. A multicenter longitudinal study was performed to evaluate physical conditions, anxiety, depression, and HRQOL at 1 month (baseline), 6 months, 1, and 2 years after surgery in 196 patients (mean age: 53.3 years old) with early breast cancer and no postoperative recurrence. Physical conditions were evaluated using a patient-reported symptom checklist. HRQOL was rated using the functional assessment of cancer treatment scale-general (FACT-G) and the breast cancer subscale (FACT-B). Anxiety and depression were rated using the hospital anxiety and depression scale (HADS). More than 50% of patients had local problems of "tightness", "arm weakness." and "arm lymphedema", and systemic problems of "reduced energy, fatigue, and general weakness" postoperatively. The HRQOL score significantly improved 1 year after surgery, and scores for physical, emotional and functional well-being also increased with time, whereas the score for social well-being was the highest at baseline and decreased with time. Depression and anxiety significantly improved with time. Concomitant disease, marital status, and the presence of a partner, anxiety and depression at baseline, pathological lymph node involvement, and adjuvant intravenous chemotherapy were significant factors predicting FACT-G scores at 6 months, 1, and 2 years after surgery. Depression at baseline was a strong predictor of HRQOL up to 2 years after surgery. These results suggest that physical rehabilitation is required for tightness and lymphedema to improve long-term postoperative physical function. A further study of psychosocial interventions is required to improve depression and social well-being after breast cancer surgery.

Objective: To examine health-related quality of life, we investigated the effect of adjuvant chemotherapy regimens on utility scores assessed by the EuroQoL-5D (EQ-5D) instrument in a randomized, controlled trial for breast cancer patients after surgery. We also investigated the relationship between Functional Assessment of Cancer Therapy (FACT) scale scores and EQ-5D utilities., Methods: Patients were randomly assigned to the following four chemotherapy regimens: four cycles of anthracycline followed by paclitaxel (ACP), four cycles of anthracycline-containing regimens followed by docetaxel (ACD), eight cycles of paclitaxel (PTX), and eight cycles of docetaxel (DTX). Of 1060 registered, the first 300 consecutive patients were included in the current utility study. Utility scores were assessed using the EQ-5D instrument at baseline; cycles 3, 5, and 7; 7 months; and 1 year. We also evaluated the correlation between these scores and FACT-G, -B, and -Taxane scores at each time point., Results: Utility scores were significantly lower in the DTX group than in the ACP and ACD groups. Mean utility scores in the DTX group were lowest at 7 months and tended to remain low for a long time. The combined anthracycline followed by taxane group had significantly higher utility scores that the taxane-alone group, with no significant difference depending on the type of taxane. Only the FACT-G social/family well-being subscale had no relationship with EQ-5D responses and utility scores., Conclusions: Although the regimens in this study were similar in that they included taxane, the mean utility scores and longitudinal patterns of utility scores were different among regimens., (Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

To investigate whether the health-related quality of life (HRQOL) of patients switching from tamoxifen to anastrozole in a randomized trial is identical to that of those who continued tamoxifen after 1-4 years of adjuvant tamoxifen in Japanese postmenopausal breast cancer patients. Eligible patients for the randomized trial, the National Surgical Adjuvant Study of Breast Cancer 03, were recurrence-free postmenopausal women who had received definitive surgery for primary breast cancer with positive hormone receptor(s), and had been taking tamoxifen for 1-4 years postoperatively. They were randomly assigned to continue tamoxifen or to switch to anastrozole for a total duration of five years. Subjects were asked to reply to a self-administered QOL questionnaire survey to assess HRQOL (FACT-B [breast cancer scale], FACT-ES [endocrine symptom scale]) and psychological distress (CES-D: Center for Epidemiologic Studies Depression scale) at randomization (baseline), 3 months, 1, and 2 years after randomization, respectively. At baseline 694 patients (346 in the tamoxifen group and 348 in the anastrozole group) responded to the survey. The total scores of FACT-G, FACT-ES, and those of the FACT-G physical well-being subscale were statistically significantly better in the tamoxifen group than in the anastrozole group (P = 0.042, 0.038, and 0.005, respectively). However, there was no statistically significant difference between the treatment groups in the CES-D scores. Continuation of tamoxifen treatment after adjuvant tamoxifen for 1-4 years may provide Japanese breast cancer patients with better HRQOL than by switching to anastrozole.

Treatment of elderly patients with breast cancer is limited by the lack of evidence-based medicine due to exclusion of elderly persons from clinical studies and the difficulty of decision-making in an elderly population comprising subjects with heterogeneous health backgrounds. Individual variation of health conditions is larger in elderly patients than in young people. Since the risk-benefit balance of treatment depends on the health background, judgment of the vulnerability of individual patients is required in treatment planning. The comprehensive geriatric assessment (CGA) is a tool for acquisition of information for design of a cancer treatment plan based on evaluation of the vulnerability of elderly patients from various perspectives. The domains of the CGA include physical function, comorbidity, cognitive function, psychological status, social support system, nutrition, and medication. The CGA can be used to predict survival and adverse events; to identify health problems that cannot be detected based on medical history or examination; to recognize new problems that emerge during course observation; and to improve psychological conditions. However, application of the CGA in routine clinical practice requires establishment of a consensus regarding the survey method, evaluation scale, and use of results in decision-making. A prospective investigation of the CGA as an outcome index in elderly breast cancer patients is required to address these issues.

Objective: To determine if health-related quality-of-life (QOL) differences existed between breast cancer (BC) survivors receiving mastectomy and those receiving breast-conserving treatment (BCT). Factors associated with QOL in long-term BC survivors were also identified., Methods: One hundred patients who had previously undergone BC surgery and were alive without recurrence for >5 years were asked to answer the patient-administered questionnaires to assess their QOL (Functional Assessment of Cancer Therapy scale-Breast: FACT-B) and psychological distress (Hospital Anxiety and Depression Scale: HADS). Of them, 93 responded to the questionnaires affirmatively., Results: Although none of the QOL scores were related to the surgical procedures, statistically significant relationships were found between age and the scores of FACT-General and social/family well-being (SWB), and between the educational status and scores of SWB in univariate analyses. There was no statistically significant relationship between psychological distress and each factor examined. In multivariate analyses, significant correlations were established between scores of the FACT-BC subscale (FACT-BCS) and the type of surgery and between those on the FACT SWB subscale and age at study or educational status. Namely, patients who had undergone BCT, younger patients and patients with higher educational background scored higher QOL., Conclusions: Among the BC survivors, those who underwent BCT experienced significantly but slightly better QOL than those who received mastectomy in FACT-BCS assessments. Younger patients and patients with higher educational backgrounds experienced significantly better SWB.

Purpose: The primary aim of this study was to compare the effectiveness of oral uracil-tegafur (UFT) with that of classical cyclophosphamide, methotrexate, and fluorouracil (CMF) given as postoperative adjuvant treatment to women with node-negative, high-risk breast cancer., Patients and Methods: Women with node-negative, high-risk breast cancer were randomly assigned to receive either 2 years of UFT or six cycles of CMF after surgery. The primary end point was relapse-free survival (RFS). Overall survival (OS), toxicity, and quality of life (QOL) were secondary end points. The hypothesis was that UFT was not inferior to CMF in terms of RFS., Results: Between October 1996 and April 2001, a total of 733 patients were randomly assigned to receive either treatment. The median follow-up time was 6.2 years. The RFS rates at 5 years were 88.0% in the CMF arm and 87.8% in the UFT arm. OS rates were 96.0% and 96.2%, respectively. The hazard ratios of the UFT arm relative to the CMF arm were 0.98 for RFS (95% CI, 0.66 to 1.45; P = .92) and 0.81 for OS (95% CI, 0.44 to 1.48; P = .49). The toxicity profiles differed between the two groups. The QOL scores were better for patients given UFT than those given CMF., Conclusion: RFS and OS with oral UFT were similar to those with classical CMF. Given the higher QOL scores, oral UFT is a promising alternative to CMF for postoperative adjuvant chemotherapy in women with node-negative, high-risk breast cancer.

Objective: Since there is now growing interest in the incorporation of patient-reported outcome measures in cancer clinical trials, a patient-based questionnaire, the Patient Neurotoxicity Questionnaire (PNQ) was developed to quantify the symptoms and severity of chemotherapy-induced peripheral neuropathy (CIPN). The aim of this study was to evaluate the physicians' perspectives regarding the utility and diagnostic value of PNQ., Methods: A questionnaire was sent to 61 physicians who participated in a Phase III randomized trial of adjuvant chemotherapy in breast cancer (AC followed by taxane versus taxane alone) that used the PNQ to assess CIPN., Results: Forty-seven out of 61 physicians (77%) responded. The majority considered neurosensory symptoms the diagnostic hallmark for CIPN and most regarded interference with activities of daily living (ADLs) as definite justification for treatment modifications. For neurosensory disturbance, the majority of physicians indicated that Grade D severity (moderate to severe symptoms interfering with ADLs) should result in treatment postponement and Grade E severity (severe symptoms preventing most ADLs) should result in treatment discontinuation. Similarly, for neuromotor disturbance, over half of the physicians replied that Grade C (moderate symptoms not interfering with ADLs), D and E severity should result in dose reduction, treatment postponement and treatment discontinuation, respectively. Eighty-four percentage of the physicians reported that the use of the PNQ was helpful in the diagnosis and assessment of patients at risk of CIPN., Conclusions: The PNQ appears to be a useful instrument for the diagnosis and grading of CIPN, as well as for clinical decision-making regarding treatment modifications secondary to CIPN.

Background: Several randomized controlled trials have confirmed the usefulness of trastuzumab as an adjuvant therapy for HER2-overexpressed breast cancer patients; however, the costs for 1-year treatment are high. Therefore, we performed an economic analysis regarding the efficient distribution of medical resources., Methods: To analyze the cost-effectiveness for a 1-year adjuvant trastuzumab treatment group compared with the observation group, we constructed a Markov model adopting a 3% per year discount rate for costs and outcomes. The time horizon was 50 years. The perspective was that of health-care payers, as only direct medical costs were calculated. The outcome was measured as life-year gained (LYG) from 2-year follow-up HERA trial data., Results: The ICER of the standard setting (5 years efficacy and 50-60 kg patient weight) was JPY 2,600,000 (17,000) per LYG. The calculation results of other weight class ICER were JPY 2,200,000 (15,000) and JPY 3,300,000 (22,000) per LYG for the patients, respectively, who weighed less than 50 kg, and 60-75 kg. In the sensitivity analysis, the period of trastuzumab efficacy was the most influential parameter for the result of cost-effectiveness. However, even if the trastuzumab efficacy were to continue for only 2 years, at least, which is a conservative setting judging from the joint analysis (NSABP B-31 and NCCTG N9831 trials), the ICER remains acceptable for any weight class., Conclusion: These results suggest that the 1-year adjuvant trastuzumab treatment is cost-effective. Both clinical and economic benefits were superior for the 1-year adjuvant trastuzumab treatment group compared with the observation group.

Since standard radical mastectomy was established by Halsted for breast cancer, surgical procedures for breast cancer have been changed according to the results of randomized controlled trials. Breast-conserving treatment is now regarded as a standard local treatment for early breast cancer. More recently, sentinel node biopsy is becoming popular as an alternative procedure to axillary node dissection for nodal staging. These new procedures have been believed to be better in terms of patients' quality of life in comparison with previous surgical procedures without impairing prognosis. Many studies regarding the quality of life (QOL) of patients after such procedures have been reported. Here we review those data, especially of studies comparing quality of life of patients after mastectomy and breast-conserving treatment, and of those after axillary node dissection and sentinel node biopsy. Viewpoints and issues on surgical treatment-related QOL are discussed.

Background: More effective methods of preventing and treating breast cancer are being sought by clinicians every day, and new drugs and interventions for overcoming this cancer are being energetically evaluated. At present, there are wide treatment options and many different objectives for breast cancer. These circumstances led us to seek information about the relative costs of the different medical options for the prevention and treatment of breast cancer and to try to ascertain whether one course of action is more efficient than other courses. Economic evaluation of healthcare is indispensable for selection of the best alternatives among medical interventions which are becoming more diverse day after day. The total medical expenditure continues to rise each year and some sort of evaluation from an objective and external viewpoint is required to provide the information with which to suppress this rise., Methods: This paper surveys the three major reports published on this topic to date, for the purpose of demonstrating the importance and necessity of performing an economic analysis of the treatment and prevention of breast cancer. The three reports to be surveyed pertain to: (1) cost-effectiveness analysis of adjuvant chemotherapy for patients with lymph node negative breast cancer, (2) cost utility analysis of first-line hormonal therapy in advanced breast cancer, namely comparison of two aromatase inhibitors to tamoxifen, and (3) cost-effectiveness analysis of tamoxifen in the prevention of breast cancer. In addition, this paper discusses the advantages, limitations and perspective for the future of the economic evaluation of healthcare for breast cancer., Results: (1) The authors concluded that if the average risk of all women of undergoing recurrence after this therapy is assumed to be 4% per year, adjuvant chemotherapy is definitely of benefit for node-negative, estrogen receptor-negative breast cancer patients. They additionally stated that this benefit decreases markedly if the changes in long-term survival are less than those in disease-free survival. In this connection, they pointed out that the benefit is considerably smaller among postmenopausal 60-year-old women. (2) The incremental cost per quality-adjusted progression-free life year (QAPFY) for letrozole and anastrozole, relative to tamoxifen, was Can $12,500-19,600, which was lower than the criterion level (US $50,000). On the basis of this result, the authors concluded that these two drugs are economically acceptable. Furthermore, when efficacy and cost effectiveness were analyzed together, it was concluded that letrozole is in fact preferable to anastrozole. (3) The model analysis of tamoxifen's cost effectiveness among women at increased risk for breast cancer yielded the following results. In the base-case analysis, involving the calculation of the costs and benefits of 5-year tamoxifen administration, the incremental cost effectiveness of tamoxifen was $41,372 per life-year gained for women age 35 to 49 years, whereas for women age 50 to 59 years and 60 to 69 years, these values were $68,349 and $74,981, respectively. For women who had undergone hysterectomy and thus had no risk of the onset of endometrial cancer, the incremental cost effectiveness of tamoxifen was $46,060 per life-year gained., Conclusion: Medico-economic evaluation of breast cancer is very significant and valuable and is expected to stimulate efficient utilization of healthcare resources. It can provide important information to physicians, patients, insurers, pharmaceutical and other industries, healthcare policy planners, and others.

Recent research has shown the importance of the patient's point of view on the goals of medical care, and now health-related quality of life (HR-QOL) has become an important endpoint of clinical studies. However, as HR-QOL is essentially a subjective, personal concept determined from the viewpoint of the patient, it is fundamentally important to understand the concept and use the HR-QOL assessment, to express both the subjective and qualitative concept of HR-QOL in an objective and quantitative way that meets the patient's true needs, and also to obtain high-quality information about HR-QOL. In this article, we describe the concept of HR-QOL, the purpose of HR-QOL measurement, the approach to the HR-QOL assessment, instruments used in the measurement of HR-QOL, and general principles of HR-QOL measurements. We also review the current status of HR-QOL assessment of medical treatment in breast cancer.

Background: Seroma is a common problem in breast surgery. The aim of this systematic review was to identify risk factors for seroma formation., Methods: Articles published in English were obtained from searches of Medline and additional references were found in the bibliographies of these articles. Risk factors were graded according to the quality and strength of evidence and to the direction of association., Results: One meta-analysis, 51 randomized controlled trials, 7 prospective studies and 7 retrospective studies were identified. There was no risk factor supported by strong evidence, but there was moderate evidence to support a risk for seroma formation in individuals with heavier body weight, extended radical mastectomy as compared with simple mastectomy, and greater drainage volume in the initial 3 days. On the other hand, the following factors did not have a significant influence on seroma formation: duration of drainage; hormone receptor status; immobilization of the shoulder; intensity of negative suction pressure; lymph node status or lymph node positivity; number of drains; number of removed lymph nodes; previous biopsy; removal of drains on the fifth postoperative day versus when daily drainage volume fell to minimal; stage; type of drainage (closed suction versus static drainage); and use of fibrinolysis inhibitor. In contrast, sentinel lymph node biopsy reduced seroma formation. Evidence was weak, or unproven, for other factors that were commonly cited in the literature., Conclusions: Although a number of factors have been correlated with seroma formation, strong evidence is still scarce. However, there is evidence showing that sentinel lymph node biopsy reduces seroma formation.

Seroma, a collection of serous fluid, is the most common problem after breast surgery. The aim of this study was to review the effect of mechanical closure of dead space on seroma formation after breast surgery. There are two mechanical methods for closure of the dead space beneath skin flaps: compression by external pressure, and fixation of the flaps with sutures. There is no evidence to suggest that the routine use of a pressure garment or compression dressing is beneficial. However, it appears that suture flap fixation does reduce seroma formation, simplify postoperative care and dressing, and thus allow early removal of drains and discharge. Drains are helpful for mechanical closure of dead space, but in breast-conserving surgery this technique may preclude the use of a drain. However, previous studies have often been small in scale and poor in quality. Further studies should examine the effect of this technique on quality of life, cosmesis, and medical economics.

The development of new chemotherapeutic agents and regimens has contributed to reduced risk of cancer recurrence and prolonged patient survival. However, mild cognitive impairment (MCI), also known as ''chemofog'' or ''chemobrain'' following adjuvant chemotherapy for breast cancer has been reported since the late 1980s. Unfortunately, little is known about it's mechanism, type, severity, and episode length. This article reviewed related studies on the subject, and found that chemotherapy-induced MCI appears to occur in 10-40% of patients, and memory loss and lack of concentration are the most frequent symptoms. The symptoms are apparently transient, but take at least several years to disappear. Reviewed studies show a lack of clear understanding of what causes MCI directly. There is also a lack of consistency in symptom measurement. We point to the need to conduct well-designed studies which begin with a proper hypothesis. Future research needs to be randomized and longitudinal with a base measurement point before the chemotherapy cycle starts. Future studies must adopt an effective and sensitive method to measure MCI. The latest imaging technique, positron emission tomography (PET) may be a powerful tool. Also, all confounding factors, such as age, education, intelligence quotient (IQ), fatigue and depression, hormonal therapy and other treatments should be controlled within the study design. It is hoped that the results of such future studies will allow medical professionals to contemplate effective prevention, treatment and rehabilitation for MCI.

Purpose: Seroma is the most common complication of mastectomy. The aim of this systematic review is to clarify the pathophysiology of seroma., Materials and Methods: A computer-assisted MEDLINE search was conducted, and additional references were found in the bibliographies of these articles. The reference terms ''breast cancer'', ''mastectomy'', ''seroma'', ''lymphocele'' and ''lymphocyst'' were used as both keyword and subject terms. The search was limited to studies published in English., Results: The definition of seroma was highly variable across studies, but was most commonly a seroma large enough to be noticed by the patient or medical staff and affecting the patient's satisfaction in the immediate or acute postoperative period. So far, only limited data are available on the severity of seroma. With respect to the pathophysiology of seroma, the data indicated that several anatomical factors, especially dead space, likely contribute to seroma formation. However, it was obscure whether seroma was due to lymph-like fluid or exudate., Conclusion: There is considerable variability in the way seroma is defined across studies, and its pathophysiology remains uncertain.

Background: Little is known about the availability and psychometric properties of instruments to measure quality of life (QOL) in clinical research on Japanese patients with breast cancer. The purpose of this systematic review is to find reliable and valid instruments available in Japan, and to summarize their characteristics., Methods: Instruments available in Japan were found through a systematic search of the literature. Each instrument identified was evaluated for item development, reliability, validity, interpretability and utility., Results: Six questionnaires to measure health-related QOL (the QOL-ACD, the EORTC QLQ-C30, the EORTC QLQ-BR23, the FACT-B, the SF-36, the WHO/QOL-26) and five scales to quantify the psychological burden (the STAI, the POMS, the SDS, the HADS, the GHQ), for which reliability and validity have been documented, are available in Japanese. All instruments were developed in foreign countries except for the QOL-ACD. Two of the QOL questionnaires were specific to breast cancer (the EORTC QLQ-BR23, the FACT-B). Though the measurements can be interpreted in some manner, the meaning of change scores over time has been documented for only three instruments (the EORTC QLQ-C30, the FACT-B, and the GHQ)., Conclusions: The review provides grounds for designing and implementing quantitative research on QOL of breast cancer patients in Japan. Methodological challenges, however, continue, particularly for validating instruments with regard to various study populations of Japanese people and demonstrating the clinical importance of change scores.

Health-related quality of life (HRQOL) has become one of the important endpoints in cancer treatments. However, a relatively small proportion of oncologists truly understand the concepts and uses of QOL assessments. In this article, I discuss psychometric properties that should be verified with QOL instruments, scope of the QOL concepts that should be assessed in oncology, how to choose the appropriate measures, and cross-cultural validation and statistical issues. Several examples of QOL assessments in recent clinical trials in oncology are also reviewed.

Background: The concept of quality of life (QOL) is essentially subjective, determined from the patient's point of view. Thus, an appropriate investigation and analysis of QOL as an indicator of medical treatment outcome is a task of some difficulty. The physician-led QOL assessment studies to date in Japan have suffered from insufficient knowledge and understanding of the diverse factors contributing to QOL, thereby contributing to a dearth of quality studies. Given this background, the Japanese Breast Cancer Society has established a Task Force for the development of guidelines to properly conduct QOL assessment studies. The present article reports the results of a large-scale systematic overview of QOL assessment studies for breast cancer patients that was undertaken as one part of this project., Methods: Six databases were used in this overview: MEDLINE, CINAHL, CANCERLIT, EMBASE, PsychINFO, and Japan Centra Revuo Medicina. The search period was 1982-1999 for CINAHL, and 1990-1999 for the others. Following a check of the titles, important information was recorded on relevance and data collection forms., Results: A systematic search was conducted of the literature on QOL assessment studies for breast cancer patients, and 1,954 articles were extracted from a check of titles. Using the relevance and data collection forms, the number of articles was further narrowed to 126. These articles were then classified according to the type and design of the study, the number of QOL and psychological measures used, frequency of use of each measure, and study focus and type of intervention. The results were then compiled., Conclusion: To date there have been almost no appropriate systematic overviews or guidelines issued for QOL assessment studies related to breast cancer, even on the international level. The results of the present study may contribute high-quality QOL information for evidence-based medicine, as it continues to gain global prevalence.

Background: This study evaluated the cost-effectiveness of replacing standard intravenous therapy (taxane) with oral S-1 therapy for first-line metastatic breast cancer treatment.Methods: This cost-effectiveness analysis was based on data from a randomized phase III trial (SELECT BC). As cost-effectiveness was a secondary endpoint of the SELECT BC trial, some of the randomized patients participated in an EQ-5D survey (N = 391) and health economic survey (N = 146). The EQ-5D responses, claims, and prescription data were collected for as long as possible until death. The expected quality-adjusted life years (QALY) obtained from each treatment were calculated using patient-level EQ-5D data, and the expected cost was calculated using patient-level claim data. The analysis was performed from the perspective of public healthcare payers.Results: The estimated EQ-5D least-square means and 95% CI up to 48 months were 0.764 (95% CI, 0.741-0.782) and 0.742 (95% CI, 0.720-0.764) in the S-1 and taxane arms, respectively. The expected QALY was 2.11 for the S-1 arm and 2.04 for the taxane arm, with expected costs of JPY 5.13 million (USD 46,600) and JPY 5.56 million (USD 50,500), respectively. These results show that S-1 is cost-saving. According to probabilistic sensitivity analysis, S-1 was dominant with a probability of 63%. When the willingness to pay (WTP) value was JPY 5 million (USD 45,500) per QALY, the probability of being cost-effective was 92%.Conclusions: Our results show that the introduction of oral S-1 therapy for metastatic breast cancer is highly likely to be cost-effective.Trial Registration: UMIN CTR C000000416 . Registered on May 10, 2006. [ABSTRACT FROM AUTHOR]