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Purpose: Imatinib is an inhibitor of the Bcr-Abl tyrosine kinase; however, resistance is common. Flavopiridol, a cyclin-dependent kinase (CDK) inhibitor, down-regulates short-lived anti-apoptotic proteins via inhibition of transcription. In preclinical studies, flavopiridol synergizes with imatinib to induce apoptosis. We investigated this novel combination regimen in patients with Bcr-Abl(+) malignancies.Methods: In a phase I dose-escalation study, imatinib was administered orally daily, and flavopiridol by 1 h intravenous infusion weekly for 3 weeks every 4 weeks. Adults with chronic myelogenous leukemia or Philadelphia chromosome-positive acute leukemia were eligible. Patients were divided into two strata based on peripheral blood and bone marrow blast counts. The primary objective was to identify the recommended phase II doses for the combination. Correlative pharmacokinetic and pharmacodynamic studies were also performed.Results: A total of 21 patients received study treatment. Four dose levels were evaluated before the study was closed following the approval of the second-generation Bcr-Abl tyrosine kinase inhibitors (TKIs). Five patients responded, including four sustained responses. Four patients had stable disease. All but one responder, and all patients with stable disease had previously been treated with imatinib. One patient had a complete response sustained for 30 months. Changes in expression of phospho-Bcr/Abl, -Stat5, and Mcl-1 were monitored. No major pharmacokinetic interaction was observed.Conclusions: This is the first study to evaluate the combination of a CDK inhibitor and a TKI in humans. The combination of flavopiridol and imatinib is tolerable and produces encouraging responses, including in some patients with imatinib-resistant disease. [ABSTRACT FROM AUTHOR]

Background: Olanzapine is an atypical antipsychotic drug used for chemotherapy-induced nausea and vomiting. It is particularly effective in preventing delayed nausea and vomiting induced by highly emetogenic chemotherapy (HEC). However, it has side effects, such as hyperglycemia and somnolence, the efficacy and safety of adding olanzapine to triplet antiemetic therapy (5-HT 3 receptor antagonist, NK 1 receptor antagonist, and dexamethasone) must be verified., Methods: We performed a systematic review and meta-analysis to compare the effectiveness of olanzapine combined with triplet antiemetic therapy and triplet antiemetic therapy in preventing nausea and vomiting for HEC. We set five items (hyperglycemia, prevention of vomiting, prevention of nausea, adverse events, and cost (drug costs)) as outcomes and conducted a systematic review., Results: Five randomized controlled trials was extracted and they showed that the addition of olanzapine was effective in control of nausea and vomiting, especially in the delayed phase. Complete response of acute and delayed phase were significantly higher in the olanzapine group. Risk difference was - 0.14 [95% CI - 0.26, - 0.03; p = 0.02] and - 0.14 [95% CI - 0.19, -0.09; p < 0.00001], respectively. Additionally, we evaluated hyperglycemia and somnolence, which are typical side effects of olanzapine. However, the incidence of grade ≥ 2 was low in both events, and there was no significant difference between olanzapine and control groups., Conclusions: Adding olanzapine to triplet antiemetic therapy is useful in preventing nausea and vomiting induced by HEC and there would be minimal adverse effects from the combination use., Competing Interests: Declarations. Conflicts of interest: Michiyasu Murakami received honoraria from Taiho Pharmaceutical Co. Ltd. Kazuhisa Nakashima received honoraria from Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., and Eli Lilly Japan K.K. Junichi Nishimura received honoraria from Taiho Pharmaceutical Co. Ltd. Eriko Satomi received honoraria from Shionogi & Co. Ltd. Masayuki Takeda received honoraria from Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., and Bayer. Narikazu Boku received honoraria from Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb, Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Eli Lilly Japan K.K. Koji Matsumoto received honoraria from MSD K.K., Kyowa Kirin Co., Ltd., and Chugai Pharmaceutical Co., Ltd., as well as research funding from Daiichi Sankyo Co., Ltd., MSD K.K., Gilead Sciences, Inc., and Eli Lilly Japan K.K. Nobuyuki Yamamoto received honoraria from MSD K.K., Accuray Japan K.K., AstraZeneca K.K., Abbvie Inc., Amgen Inc., Ono Pharmaceutical Co., Ltd., Guardant Health Japan Corp., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Chugai Foundation for Innovative Drug Discovery Science, Lao Tsumura Co., Ltd., Terumo Corporation, Eli Lilly Japan K.K., Nippon Kayaku Co., Ltd., Novartis AG, Pfizer Global Supply Japan Inc., Merck Biopharma Co., Ltd, Pfizer Global Supply Japan Inc., Merck Biopharma Co., Ltd., Janssen Pharmaceutical K.K., and USACO Corporation, as well as legal fees in case of iawsuit from Taiho Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan, Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Nippon Kayaku Co., Ltd., Prime Research Institute for Medical RWD, Inc., AstraZeneca K.K., and A2 Healthcare Corporation. Takako Eguchi Nakajima received research funding from KBBM, Inc. and Takeda Pharmaceutical Co., Ltd. Ethical approval: Not applicable. Informed consent: Formal consent was not required for this type of study. Consent to participate: Not applicable. Consent for publication: All authors consented to the publication of this study., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: A standardized multi-day antiemetic regimen for multi-day chemotherapy remains elusive. This systematic review evaluated the efficacy and safety of multi-day antiemetic regimens in patients undergoing multi-day intravenous chemotherapy., Methods: We conducted a comprehensive search of PubMed, Cochrane Library, and Ichushi-Web databases for relevant studies published from January 1990 to December 2020. We included studies comparing multi-day and single-day antiemetic regimens for preventing chemotherapy-induced nausea and vomiting., Results: No studies directly comparing multi-day versus single-day antiemetic regimens were found. Despite expanding control group criteria beyond "single-day antiemetic therapy" limited high-quality studies and variations in cancer types, chemotherapy regimens, and antiemetic treatments precluded meta-analysis. Among the included studies, some randomized controlled trials (RCTs) focused on complete response and vomiting rates. Two studies comparing two- and three-drug combinations reported higher complete response and no-vomiting rates with the three-drug regimen. Limited RCTs explored "nausea control" and "cost," and assessing "adverse events" proved challenging due to inconsistent reporting., Conclusion: The research on multi-day antiemetic therapy is limited, necessitating further investigation. Nonetheless, our findings suggest that three-drug combination therapy, including aprepitant, may offer superior antiemetic efficacy compared to two-drug regimens. Multi-day antiemetic therapy is strongly recommended during multi-day intravenous administration of cytotoxic anticancer drugs., Competing Interests: Declarations Conflict of interest Kazuhisa Nakashima received honoraria from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., and Eli Lilly Japan K.K. Eriko Satomi received honoraria from Shionogi & Co., Ltd. Masayuki Takeda received honoraria from Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., and Bayer. Takako Eguchi Nakajima received research funding from KBBM, Inc. and Takeda Pharmaceutical Co., Ltd. Junichi Nishimura received honoraria from Taiho Pharmaceutical Co., Ltd. Narikazu Boku received honoraria from Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb, Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Eli Lilly Japan K.K. Koji Matsumoto received honoraria from MSD K.K., Kyowa Kirin Co., Ltd., and Chugai Pharmaceutical Co., Ltd. as well as research funding from Daiichi Sankyo Co., Ltd., MSD K.K., Gilead Sciences, Inc., and Eli Lilly Japan K.K. Nobuyuki Yamamoto received honoraria from MSD K.K., Accuray Japan K.K., AstraZeneca K.K., Abbvie Inc., Amgen Inc., Ono Pharmaceutical Co., Ltd., Guardant Health Japan Corp., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Chugai Foundation for Innovative Drug Discovery Science, Lao Tsumura Co., Ltd., Terumo Corporation, Eli Lilly Japan K.K., Nippon Kayaku Co., Ltd., Novartis AG, Pfzer Global Supply Japan Inc., Merck Biopharma Co., Ltd, Pfzer Global Supply Japan Inc., Merck Biopharma Co., Ltd., Janssen Pharmaceutical K.K., and USACO Corporation, as well as legal fees in case of lawsuit from Taiho Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan, Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Nippon Kayaku Co., Ltd., Prime Research Institute for Medical RWD, Inc., AstraZeneca K.K., and A2 Healthcare Corporation. Other authors declare that they have no conflict of interest. Ethical approval Not applicable. Informed consent Formal consent was not required for this type of study. Consent to participate Not applicable. Consent for publication All authors consented to the publication of this study., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Chemotherapy-induced nausea and vomiting (CINV) are common side effects, classified according to timing and severity. Conventional agents such as dexamethasone are effective but have various side effects. For moderately emetogenic chemotherapy, dexamethasone-sparing antiemetic therapies have been developed to minimize these side effects. This systematic review evaluated the efficacy and safety of dexamethasone-sparing antiemetic therapy for highly emetogenic chemotherapy (HEC)., Methods: We performed a thorough literature search for studies related to dexamethasone-sparing antiemetic therapy with neurokinin-1 antagonists (NK 1 RA) for HEC using the PubMed, Cochrane Library, and Ichushi-Web databases. A qualitative analysis of the combined data was performed and risk differences with confidence intervals were calculated., Results: Two reviewers independently assessed the 425 records and 12 full-text articles were evaluated for eligibility. Two studies were included in the qualitative and meta-analyses. These studies included anthracycline-cyclophosphamide (AC) regimens and cisplatin-based regimens, with palonosetron as the serotonin receptor antagonist. In the two studies, no difference was found in the prevention of vomiting (delayed complete response). However, non-inferiority was not demonstrated in the subgroup that received cisplatin-containing regimens. Delayed complete control showed different results for nausea prevention; however, there was no significant difference in the meta-analysis. Only one report has shown non-inferiority for delayed total control. Although the strength of evidence for individual outcomes varied, there was no difference in the duration of dexamethasone administration., Conclusions: This systematic review and meta-analysis revealed that dexamethasone-sparing antiemetic therapy with NK 1 RA and palonosetron can be used to prevent CINV in HEC, limited to AC combination therapy., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Chemotherapy-induced nausea and vomiting (CINV) commonly affects patient quality of life and the overall effectiveness of chemotherapy. This study aimed to evaluate whether adding neurokinin-1 receptor antagonists (NK1RAs) to 5-hydroxytryptamine-3 receptor antagonists (5-HT 3 RAs) and corticosteroids provides clinically meaningful benefits in preventing CINV in patients receiving moderately emetogenic chemotherapy (MEC)., Methods: We conducted a systematic review of PubMed, Cochrane Library, and Ichushi-Web to identify clinical studies evaluating NK1RAs combined with 5-HT 3 RAs and dexamethasone for managing CINV in MEC. The endpoints were complete response (CR), complete control (CC), total control (TC), adverse events, and costs. The data were analyzed using a random effects model., Results: From 142 articles identified, 15 randomized controlled trials (RCTs), involving 4,405 patients, were included in the meta-analysis. Approximately 60% of the patients received carboplatin (CBDCA)-based chemotherapy. The meta-analysis showed that triplet antiemetic prophylaxis with NK1RA was significantly more effective for achieving CR than doublet prophylaxis in each phase. Regarding CC, the triplet antiemetic prophylaxis was significantly more effective than the doublet in the overall (risk difference [RD]: 0.11, 95% confidence interval [CI]: 0.06-0.17) and delayed (RD: 0.08, 95% CI: 0.02-0.13) phases. For TC, no significant differences were observed in any phase. Adding NK1RA did not cause adverse events., Conclusions: Adding NK1RA to CBDCA-based chemotherapy has shown clinical benefits. However, the clinical benefits of NK1RA-containing regimens for overall MEC have not yet been established and require RCTs that exclusively evaluate MEC regimens other than CBDCA-based chemotherapy., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Palonosetron, a second-generation 5-HT 3 receptor antagonist (5-HT 3 RA), is more effective than first-generation 5-HT 3 RA. Several studies have investigated whether dexamethasone (DEX), when combined with palonosetron as a 5-HT 3 RA, can be spared in the delayed phase after moderately emetogenic chemotherapy (MEC). In this systematic review, we aimed to determine which between 1- and 3-day DEX administration, when combined with palonosetron, is more useful in patients receiving MEC., Methods: The PubMed, Cochrane Library, and Ichushi-Web databases were searched for relevant studies published between 1990 and 2020. We included studies that compared the efficacy of 1- and 3-day DEX administration in preventing nausea and vomiting associated with MEC. Outcomes were "prevention of vomiting (complete response rate and no vomiting rate)," "prevention of nausea" (complete control rate, total control rate, no nausea rate, and no clinically significant nausea rate)" in the delayed phase, "prevention of blood glucose level elevation," and "prevention of osteoporosis.", Results: Eight studies were included in this systematic review. The no vomiting rate was significantly higher in the 3-day DEX group than in the 1-day DEX group. However, the other efficacy items did not significantly differ between the two groups. Meanwhile, insufficient evidence was obtained for "prevention of blood glucose level elevation" and "prevention of osteoporosis.", Conclusions: No significant differences in most antiemetic effects were found between 1- and 3-day DEX administration. Thus, DEX administration could be shortened from 3 days to 1 day when used in combination with palonosetron., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Nausea and vomiting are common adverse events associated with trastuzumab deruxtecan (T-DXd). We evaluated the efficacy of an olanzapine-based triplet regimen for preventing nausea and vomiting in patients receiving their first cycle T-DXd., Patients and Methods: This multi-institutional, randomized, double-blind, placebo-controlled (ERICA) phase II study enrolled patients with human epidermal growth factor receptor 2-positive/human epidermal growth factor receptor 2-low metastatic breast cancer receiving their first cycle of T-DXd. Patients were randomized to olanzapine 5 mg or placebo once daily (1 : 1 ratio) from day 1 to day 6, plus a 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone 6.6 mg intravenously or 8 mg orally on day 1. The total observation period was 504 h (21 days) from the first T-DXd administration. The primary endpoint was complete response (CR), defined as no emetic events and no rescue medications, in the delayed phase (24-120 h after T-DXd), with the type I error rate of 0.2 (one-sided) for the comparison. Secondary endpoints included no nausea rate in the delayed and persistent phases (120-504 h), adverse event by Common Terminology Criteria for Adverse Events (CTCAE) and patient-reported outcomes version of the CTCAE (PRO-CTCAE)., Results: In total, 168 patients were enrolled at 43 sites in Japan (November 2021-September 2023) with 162 patients (olanzapine, n = 80; placebo, n = 82) included in the per protocol set. The primary endpoint was met as the delayed phase CR rate was significantly greater with olanzapine than placebo (70.0% versus 56.1%, P = 0.047). Efficacy was maintained in the persistent phase (63.9% versus 44.4%). No nausea rate was also greater with olanzapine (delayed phase: 57.5% versus 37.8%; persistent phase: 51.4% versus 31.9%). CR rates in the delayed phase favored olanzapine across subgroups. Appetite loss was also decreased with olanzapine. Hyperglycemia and somnolence were mostly of low-grade severity., Conclusion: Olanzapine 5 mg for 6 days with 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone appears effective for T-DXd-treated patients to prevent delayed and persistent nausea and vomiting., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: In older patients, esophageal squamous cell carcinoma (ESCC) is difficult to treat using standard therapies, including surgery and cisplatin-based chemoradiotherapy. Paclitaxel (PTX) has radiosensitizing activity. We conducted a phase I trial of PTX combined with radiotherapy to establish a standard therapy for locally advanced ESCC in older patients., Methods: Enrollment was conducted at six centers in Japan from April 2016 to September 2019. The participants were aged ≥ 70 years, had locally advanced ESCC, and were intolerant to surgery or unwilling. A fixed 60-Gy radiation dose was administered in 30 fractions. PTX dosing levels started at 30 mg/m 2 weekly for 6 weeks. Depending on the number of DLTs, the dose was set to be increased by 10 mg/m 2 or switched to biweekly. A geriatric assessment was performed before treatment using the Geriatric-8 screening tool. The primary endpoint was dose-limiting toxicity (DLT)., Results: We enrolled 24 patients (6 per group); DLT was observed in one (grade 4 hypokalemia), one (grade 3 aspiration), two (grade 3 radiodermatitis, grade 3 esophageal hemorrhage), and two (grade 3 anorexia, grade 5 pneumonitis) patients in the weekly PTX 30, 40, 50, and 60 mg/m 2 groups, respectively. All adverse events, except death in the 60 mg/m 2 group, showed reversible improvement, and the safety profile was considered acceptable. The 2-year survival and complete response rates were 40.0% and 54.2%, respectively. There was a significant difference in survival between favorable and unfavorable Geriatric-8 scores., Conclusions: The recommended PTX dose with concomitant radiation was determined to be 50 mg/m 2 weekly. Phase II trials at this dose are underway., (© 2024. The Author(s).)

Background: Anticipatory chemotherapy-induced nausea and vomiting (CINV) is a conditioned response influenced by the severity and duration of previous emetic responses to chemotherapy. We aimed to evaluate the efficacy of non-pharmacologic interventions for anticipatory CINV among patients with cancer., Methods: We conducted a systematic search in databases, including PubMed, the Cochrane Library, CINAHL, and Ichushi-Web, from January 1, 1990, to December 31, 2020. Randomized controlled trials, non-randomized designs, observational studies, or case-control studies that utilized non-pharmacological therapies were included. The primary outcomes were anticipatory CINV, with an additional investigation into adverse events and the costs of therapies. The risk-of-bias for each study was assessed using the Cochrane risk-of-bias tool, and meta-analysis was performed using Revman 5.4 software., Results: Of the 107 studies identified, six met the inclusion criteria. Three types of non-pharmacological treatments were identified: systematic desensitization (n = 2), hypnotherapy (n = 2), and yoga therapy (n = 2). Among them, systematic desensitization significantly improved anticipatory CINV as compared to that in the control group (nausea: risk ratio [RR] = 0.60, 95% confidence interval [CI] = 0.49-0.72, p < 0.00001; vomiting: RR = 0.54, 95% CI = 0.32-0.91, p = 0.02). However, heterogeneity in outcome measures precluded meta-analysis for hypnotherapy and yoga. Additionally, most selected studies had a high or unclear risk of bias, and adverse events were not consistently reported., Conclusions: Our findings suggest that systematic desensitization may effectively reduce anticipatory CINV. However, further research is warranted before implementation in clinical settings., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: The Japan Society of Clinical Oncology Clinical Practice Guidelines for Antiemesis 2023 was extensively revised to reflect the latest advances in antineoplastic agents, antiemetics, and antineoplastic regimens. This update provides new evidence on the efficacy of antiemetic regimens., Methods: Guided by the Minds Clinical Practice Guideline Development Manual of 2017, a rigorous approach was used to update the guidelines; a thorough literature search was conducted from January 1, 1990, to December 31, 2020., Results: Comprehensive process resulted in the creation of 13 background questions (BQs), 12 clinical questions (CQs), and three future research questions (FQs). Moreover, the emetic risk classification was also updated., Conclusions: The primary goal of the present guidelines is to provide comprehensive information and facilitate informed decision-making, regarding antiemetic therapy, for both patients and healthcare providers., (© 2024. The Author(s).)

Background: Hormone receptor (HR)-positive breast cancer is a disease for which no immune checkpoint inhibitors have shown promise as effective therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors synergistically increased the effectiveness of antiprogrammed cell death protein-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibodies in preclinical studies., Methods: This non-randomized, multicohort, phase II study evaluated the efficacy and safety of the anti-PD-1 antibody nivolumab 240 mg administered every 2 weeks in combination with the CDK4/6 inhibitor abemaciclib 150 mg twice daily and either fulvestrant (FUL) or letrozole (LET) as a first-line or second-line treatment for HR-positive HER2-negative metastatic breast cancer. The primary end point was the objective response rate (ORR), and secondary end points were toxicity, progression-free survival, and overall survival. Blood, tissue, and fecal samples were collected at multiple points for correlative studies to evaluate immunity biomarkers., Results: From June 2019 to early study termination due to safety concerns on July 2020, 17 patients were enrolled (FUL: n=12, LET: n=5). One patient with a prior treatment history in the FUL cohort was excluded. ORRs were 54.5% (6/11) and 40.0% (2/5) in the FUL and LET cohorts, respectively. Treatment-emergent (TE) adverse events (AEs) of grade ≥3 occurred in 11 (92%) and 5 (100%) patients in the FUL and LET cohorts, respectively. The most common grade ≥3 TEAEs were neutropenia (7 (58.3%) and 3 (60.0%) in the FUL and LET cohorts, respectively), followed by alanine aminotransferase elevation (5 (41.6%) and 4 (80.0%)). One treatment-related death from interstitial lung disease occurred in the LET cohort. Ten patients developed liver-related grade ≥3 AEs. Liver biopsy specimens from 3 patients showed hepatitis characterized by focal necrosis with predominant CD8+ lymphocyte infiltration. Marked elevation of tumor necrosis factor-related cytokines and interleukin-11, and a decrease in peripheral regulatory T cells (Tregs), were observed in patients with hepatotoxicity. These findings suggest that treatment-related toxicities were immune-related AEs likely caused by proinflammatory cytokine production and suppression of Treg proliferation due to the addition of abemaciclib to nivolumab therapy., Conclusions: Although the combination of nivolumab and abemaciclib was active, it caused severe and prolonged immune-related AEs., Trial Registration Number: JapicCTI-194782, jRCT2080224706, UMIN000036970., Competing Interests: Competing interests: HS reports grants from Eisai and lecture fees from Daiichi Sankyo and Eisai to her institution outside the submitted work. JT reports grants from Daiichi Sankyo, Eli Lilly, and FSJD to his institution outside the submitted work; consulting fees, support for attending a meeting, and fees for an advisory board from Daiichi Sankyo; lecture fee from Eli Lilly; and payments for an advisory board from AstraZeneca. YT reports grants from Ono Pharmaceuticals, Taiho, Eli Lilly, Daiichi Sankyo, and MSD. NM reports grants from Chugai, Eli Lilly, AstraZeneca, Daiichi Sankyo, MSD, Eisai, Novartis Pharma, Sanofi, Kyowa-Kirin, and Nippon-Kayaku to his institution outside the submitted work; and lecture fees from Chugai, Pfizer, AstraZeneca, and Eli Lilly. MT reports lecture fees from AstraZeneca, Daiichi Sankyo, Eisai, and Eli Lilly, and MSD. KM reports contracts from MSD, Chugai, Eisai, Daiichi Sankyo, Eli Lilly, and ICON Japan to his institution; lecture fees from Daiichi Sankyo, Chugai, Kyowa-Kirin, and MSD; and fees for an advisory board from Daiichi Sankyo. KA reports grants from Chugai, Eisai, and Takeda Pharmaceutical; lecture fees from AstraZeneca, Daiichi Sankyo, Taiho, Pfizer, Novartis Pharma, Eli Lilly, and Chugai. HI reports grants from Chugai, Eli Lilly, Nihon Kayaku, Daiichi Sankyo, AstraZeneca, Taiho, Pfizer, MSD, Sanofi, Novartis, Bayer, and Boehringer Ingelheim to his institution outside submitted work; consulting fees from Chugai, Kyowa Kirin, AstraZeneca, Eli Lilly, Pfizer, and Daiichi Sankyo; and lecture fees from Chugai, AstraZeneca, Eli Lilly, Pfizer, Taiho, Daiichi Sankyo, Eisai, and Kyowa Kirin. TM reports grants from Sysmex, Eisai, MSD, Pfizer, Novartis Pharma, Sanofi, Chugai, AstraZeneca, and Ono Pharmaceuticals outside submitted work; lecture fees from Eisai, Pfizer, Novartis Pharma, Chugai, Eli Lilly, AstraZeneca, Kyowa-Kirin, and Taiho. KIY reports lecture fees from Chugai and Bristol Myers Squibb outside the submitted work. CKI reports research funding from Otsuka Pharmaceutical and Eli Lilly outside the submitted work; lecture fees from Taiho. HK reports grants from Chugai, Taiho, and Mochida Pharmaceutical; lecture fees from AstraZeneca, Daiichi Sankyo, Taiho, Pfizer, and Novartis. KEY reports a grant from Boehringer Ingelheim; lecture fees from Chugai, Eli Lilly, AstraZeneca, Pfizer, and Boehringer Ingelheim. TT reports lecture fees from Chugai, Daiichi Sankyo, Eisai, Eli Lilly, and Celltrion Healthcare. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The number of older patients with cancer is expected to continue to increase owing to the aging population. Recently, the usefulness of geriatric assessment (GA) conducted by multiple staff members from different medical backgrounds has been reported; however, a consensus on the effectiveness of GA has not yet been achieved., Materials and Methods: We, as the Japanese Geriatric Oncology Guideline Committee for elderly patients with cancer, conducted a literature search of randomized controlled trials published before August 2021 that used GA or comprehensive GA (CGA) as an intervention for patients with cancer undergoing chemotherapy. As the key outcomes for answering the clinical question, we focused on survival benefit, adverse events, and quality of life (QOL). After a systematic review of these studies, the expert panel member developed recommendations according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system., Results: For older patients with cancer, GA or CGA is suggested during or before chemotherapy (weakly recommended). Chemotherapy-induced adverse events were significantly reduced by GA/CGA interventions without any adverse effects on survival. Health-related QOL tended to improve with the GA/CGA interventions., Discussion: Although, in our opinion, GA/CGA does require time and resources, it poses no harm patients. Therefore, we suggest expanding the human resources and educating skills of medical providers for clinical implementation of GA/CGA., Competing Interests: Declaration of Competing Interest The authors whose names are listed immediately below report the following details of affiliation or involvement in an organization or entity with financial or non-financial interest in the subject matter or materials discussed in this manuscript. KS has received honoraria outside the current work from Sanofi, Kyowa Kirin, and Mitsubishi Tanabe Pharma. KS has also received research funding outside of the current work from Teijin Pharma. KS has also received donations outside of the current work from Takeda Pharma, Boehringer Ingelheim, Daiichi Sankyo, Astellas, Kyowa Kirin, Mitsubishi Taname Pharma, Teijin Pharma, and Sumitomo Pharma. CKI has received research funding outside of the current work from Otsuka Pharma and Lilly. NS has received honoraria outside the current work from Cancer Solutions. KT has received honoraria outside the current work from Ono Pharmaceutical, EP-Force, SymBio Pharmaceuticals and Eisai. KT has also received research funding outside of the current work from EP-Force, Eisai, and Ono Pharmaceutical., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has led to a change in the clinical management of breast cancer. Nausea and vomiting are the most common adverse events of T-DXd, which cannot be completely alleviated by standard prophylactic regimens. Olanzapine is particularly effective in preventing delayed nausea caused by chemotherapy. In this study, we will evaluate the efficacy of olanzapine in managing persistent nausea and vomiting during T-DXd treatment., Methods and Analysis: The ERICA study is a multicentre, placebo-controlled, double-blind, randomised phase II study with the aim to evaluate the antiemetic effects of the prophylactic olanzapine (5 mg orally, on days 1-6) or placebo combined with a 1,5-hydroxytryptamine-3 (5-HT 3 )-receptor antagonist and dexamethasone in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer undergoing T-DXd treatment. For a period of 22 days from the day of T-DXd treatment, patients will document their experience in an electronic symptom diary daily during observational periods. The primary endpoint is the complete response rate, defined as no vomiting and no rescue medications during the 'delayed phase' of 24-120 hours post-T-DXd administration. In addition, we define 120-504 hour as the 'persistent phase' and 0-504 hours as the 'overall phase' for secondary endpoint analysis. We have estimated that a total sample size of at least 156 patients is needed to allow a power of 80% at a one-sided significance level of 20% in this study. The target sample size is set to 166 to account for possible case exclusions., Ethics and Dissemination: The study protocol is approved by the West Japan Oncology Group protocol review committee and the SHOWA University Clinical Research Review Board. The study results will be presented at international conferences and published in a peer-reviewed journal., Trial Registration Number: jRCTs031210410., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form and declare that this research is supported by Daiichi Sankyo. HS has received speaker’s honorarium and medical writing support from Daiichi Sankyo as well as research funding from Eisai. JT has received consulting/advisory fees, conference support, speaker’s honoraria, research funding, and other fees from Daiichi Sankyo, research funding and speaker’s honoraria from Eli Lilly, research funding from Sant Joan de Déu Research Foundation, and consulting/advisory fees from AstraZeneca. YO has received speaker’s honoraria from Chugai and Daiichi Sankyo. KM has received speaker’s honoraria from Daiichi Sankyo, Chugai, Kyowa-Kirin and MSD, and advisory fees from Daiichi Sankyo and contracts for registration trials from MSD, Chugai, Eisai, Daiichi Sankyo, Eli Lilly, ICON Japan. KN, TY, SM, TI and YC have no conflicts of interest to disclose. HI has received speaker’s honoraria from Pfizer Japan, Eisai, Chugai Pharmaceutical, Kyowa Kirin, JMS, Taiho and Daiichi Sankyo. KW has received speaker’s honoraria from Chugai, Eli Lilly, Nippon-Kayaku, Kyowa Kirin, Novartis, Taiho, Eisai, Pfizer, Shionogi, Daiichi Sankyo and AstraZeneca. CMI has received research funding from Otsuka and Eli Lilly, in addition to speaker’s honorarium from Taiho. DT is an employee of Daiichi Sankyo. TT has received speaker’s honoraria from Daiichi Sankyo, Chugai, Eisai, Eli Lilly, and Celltrion Healthcare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations., Patients and Methods: EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated., Results: Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683-63,257 ng·h/mL) and 2338 ng·h/mL (581-5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound AUC 0-24 on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state (C trough,ss ) at each visit for 3 months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound C trough,ss on day 7-15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchanged for 3 months (P = 0.0046, 0.0008)., Conclusion: The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction., Clinical Trials Registration Number: UMIN000012862., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The aim of this study was to evaluate clinical validity of the S-1 dosage formula based on body surface area (BSA) and creatinine clearance (CLcr) to achieve the target area under the concentration-time curve of 5-FU, which we had developed and refined in each prospective pharmacokinetic study., Methods: The recommended dose determined by the refined formula was assessed using data of the SPIRITS (S-1 vs. S-1 plus cisplatin [SP]) and the G-SOX (SP vs. S-1 plus oxaliplatin [SOX]) trials. Nine hundred and thirty-eight patients in these trials were classified into three groups according to their actual S-1 starting doses compared with the recommended doses (under-dosed, recommended dose)., Results: The patients in the under-dosed group in both trials showed similar tendencies: male, younger, higher BSA, and higher CLcr. The incidence of any grade neutropenia was significantly greater in the over-dosed group compared with the equal-dosed group in the S-1 and the SOX arms. The hazard ratios (HR) of overall survival (OS) (under-dosed vs. equal-dosed) were 1.361 (S-1 arm), 1.259 (SP arm) in the SPIRITS trial, and 1.381 (SOX arm), 0.999 (SP arm) in the G-SOX trial. Multivariate analysis in all the patients demonstrated that OS of the over-dosed group was equivalent (HR 1.002, 95% confidence interval [CI] 0.850-1.182, p = 0.980) and that of the under-dosed group was inferior (HR 1.267, 95% CI 1.005-1.597, p = 0.045) to the equal-dosed group., Conclusions: It is suggested that the refined S-1 dosage formula can recommend optimal dose in terms of safety and efficacy., (© 2022. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Introduction: Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 antibody, have dramatically changed cancer treatment; however, fatal immune-related adverse events (irAEs) can develop. Here, we describe a severe case of sclerosing cholangitis-like irAE. We report the use of 3 immunosuppressive agents that resulted in the death of the patient due to treatment inefficacy. According to a postmarketing study of nivolumab, the frequency of ICI-related sclerosing cholangitis is 0.27% and that of ICI-related cholangitis is 0.20%. There have been 4 case reports of sclerosing cholangitis-like irAE, with imaging findings, including typical intrahepatic bile duct beaded constriction in primary sclerosing cholangitis. Treatment starts with prednisolone and is combined with an immunosuppressant in refractory cases. There are no reports of severe cases that ultimately led to death., Patients Concerns: The patient is a 64-year-old male with Stage IV squamous cell lung carcinoma; he was hospitalized with abdominal pain and elevation of aspartate transaminase and alanine transaminase, approximately 4 months after ICI administration was suspended. This occurred because the patient treated with nivolumab as the second-line chemotherapy and developed type 1 diabetes mellitus after 11 courses., Diagnosis: A grade 3 increase in bilirubin was observed and he was diagnosed with sclerosing cholangitis, based on magnetic resonance cholangiopancreatography imaging and pathological findings of the liver and bile duct., Interventions: Prednisolone, mycophenolate mofetil, and tacrolimus combination therapy was administered., Outcomes: The treatment was difficult and failed. He died from liver failure 8 months after diagnosis. In this case, hepatitis and cholangitis, mainly alanine transaminase-dominant liver disorder, developed in the early stages of irAEs. Although he showed some improvement after prednisolone administration, bilirubin levels began rising again, and sclerosing cholangitis did not improve even with the use of 3 immunosuppressive agents recommended by the ESMO Clinical Practice Guidelines for immune-related hepatotoxicity management. Although the antitumor effect showed a complete response, liver failure led to death., Conclusion: This is the first case report on the ineffectiveness of triple immunosuppressant combination therapy recommended by the guidelines for immune-related hepatotoxicity. It is necessary to develop more appropriate treatment for severe sclerosing cholangitis-like irAE based on the robust evidence., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

In patients with impaired renal function, S-1-related toxicities increase due to higher exposure of 5-fluorouracil (5-FU). Our previous pharmacokinetic study in 16 cancer patients with various renal functions developed an S-1 dosage formula based on individual creatinine clearance (CLcr) and body surface area (BSA). To evaluate and refine the formula, this prospective study was conducted. Thirty-three patients with various renal functions received S-1 for 4 weeks at doses determined by the nomogram derived from the previously developed formula. A series of blood samples were collected after the first dose to calculate the area under the concentration-time curve (AUC) of 5-FU. Thirty patients with BSA of 1.14-1.84 m 2 and CLcr of 23.8-96.4 mL/min were assessable for pharmacokinetics. The observed daily AUC ranged from 712.6 to 2868.7 ng·h/mL, and 18 patients achieved the target AUC (1447.8 ± 545.4 ng·h/mL). Three patients experienced S-1-related grade 3 adverse events during the first course. In the population pharmacokinetic analysis from the combined data of 46 patients in this study and the previous study, sex was identified as a statistically significant covariate for 5-FU clearance. Hence, the refined formula includes sex as an additional factor: Recommended daily dose = target AUC × (14.5 + 8.23 × SEX [0 for female and 1 for male] + 0.301 × CLcr) × BSA. Revised nomograms for recommended daily doses derived from the refined formula can be used in clinical practice to achieve the target AUC ensuring efficacy and safety of S-1., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Afatinib is a second-generation epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor (TKI). Combination therapies with first-generation EGFR-TKIs and bevacizumab have been reported to prolong progression-free survival (PFS). However, there are few data on the combination of afatinib and bevacizumab., Methods: In this phase I trial, we evaluated the safety of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations. This study consisted of two cohorts. In the dose-finding cohort, enrolled patients were treated with afatinib at a dose of 20, 30, or 40 mg/day (days 1-21) plus bevacizumab at a dose of 15 mg/kg (day 1) in 21-day cycles. This cohort was performed according to a 3 + 3 manner. In the expansion cohort, enrolled patients received the recommended dose (RD) based on the results of the dose-finding cohort. The serum trough concentration of afatinib was determined at the steady state., Results: Seventeen patients were enrolled in this study (6 patients in the dose-finding cohort and 11 patients in the expansion cohort). There were no dose-limiting toxicities (DLTs) with afatinib at a dose of 30 mg/day. With afatinib at a dose of 40 mg/day, two of two patients experienced DLTs (grade 3 diarrhea) in cycle 1. With these results, afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg was determined as the RD. Eleven patients in the expansion cohort were treated with the RD. Common treatment-related adverse events (AEs) with the RD were diarrhea (79%), rash (71%), perionychia (64%), and stomatitis (50%). Grade 3 AEs with the RD were diarrhea (7%), perionychia (7%), and hypertension (7%). There were no grade 4/5 AEs or cases of interstitial lung disease. Dose-proportional increases in serum afatinib trough concentrations at steady state were not observed. The response rates (RRs) and disease control rates were 55% and 100% in EGFR-TKI-naïve patients. Re-biopsy was performed in eight patients after progressive disease following the study treatment, and three patients acquired a T790M mutation., Conclusions: Afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg q3w is well tolerated., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-824). RK reports grants and personal fees from Boehringer Ingelheim and AstraZeneca, personal fees from Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, and Pfizer, outside the submitted work. TS reports grants and personal fee from MSD and Boehringer Ingelheim, personal fees from Nichi-Iko Pharmaceutical Co., Daiichi Sankyo, Ono Pharmaceutical, Bristol-Myers Squibb, Eli Lilly, Novartis, and Taiho Pharmaceutical, outside the submitted work. CKI reports personal fees from Chugai Pharmaceutical and Ono Pharmaceutical, outside the submitted work. TT reports personal fees from AstraZeneca, Chugai Pharmaceutical, MSD and Boehringer Ingelheim, outside the submitted work. KY reports personal fees from Chugai Pharmaceutical, outside the submitted work. HI reports grants and personal fees from Boehringer Ingelheim, personal fees from Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca and MSD, outside the submitted work. KA reports personal fees from Chugai Pharmaceutical, AstraZeneca, Merck Sharp and Dohme, Bristol-Myers Squibb, and Ono Pharmaceutical, outside the submitted work. KT reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, and Chugai Pharmaceutical, grants from MSD, and Bristol-Myers Squibb, personal fees from Eli Lilly, Astellas, Ono Pharmaceutical, Taiho Pharmaceutical, Shionogi, Novartis, Pfizer, Glaxo Smith Kline, and Actelion, outside the submitted work. The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Patients with cancer should appropriately receive antiemetic therapies against chemotherapy-induced nausea and vomiting (CINV). Antiemetic guidelines play an important role in managing CINV. Accordingly, the first Japanese antiemetic guideline published in 2010 by the Japan Society of Clinical Oncology (JSCO) has considerably aided Japanese medical staff in providing antiemetic therapies across chemotherapy clinics. With the yearly advancements in antiemetic therapies, the Japanese antiemetic guidelines require revisions according to published evidence regarding antiemetic management worldwide. A revised version of the first antiemetic guideline that considered several upcoming evidences had been published online in 2014 (version 1.2), in which several updated descriptions were included. The 2015 JSCO clinical practice guideline for antiemesis (version 2.0) (in Japanese) has addressed clinical antiemetic concerns and includes four major revisions regarding (1) changes in emetogenic risk categorization for anti-cancer agents, (2) olanzapine usage as an antiemetic drug, (3) the steroid-sparing method, and (4) adverse drug reactions of antiemetic agents. We herein present an English update summary for the 2015 JSCO clinical practice guideline for antiemesis (version 2.0).

Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR -mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients' reported outcomes. For patients with NSCLC harboring EGFR -activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients., (© 2020 The Authors.)

Background: Ramucirumab (RAM) with weekly paclitaxel (wPTX) is a standard second-line therapy for advanced or recurrent gastric cancer. Nanoparticle albumin-bound paclitaxel (nab-PTX), an albumin-bound form of PTX, was developed to improve the therapeutic index of taxane treatment. However, the ABSOLUTE trial showed the non-inferiority of weekly nab-PTX (w-nab-PTX) to wPTX with respect to overall survival (OS) as second-line therapy for advanced or recurrent gastric cancer, and subgroup analysis of patients with peritoneal dissemination showed favourable OS and progression-free survival (PFS) in the w-nab-PTX arm compared to those in the wPTX arm. This study evaluated whether w-nab-PTX plus RAM is more effective than wPTX plus RAM for patients with peritoneal dissemination., Methods: The P-SELECT trial (WJOG10617G) is a prospective, open-label, multicentre, randomised phase II study evaluating wPTX plus RAM (arm A) versus w-nab-PTX plus RAM (arm B). Key eligibility criteria include the following: 1) histologically proven adenocarcinoma, 2) unresectable or recurrent gastric cancer, 3) peritoneal dissemination, 4) intolerance or refractory to first-line therapy including fluoropyrimidines, and 5) ECOG Performance Status (PS) 0-2. Patients are randomised to either arm at a 1:1 ratio stratified by institution, PS, and severity of ascites. PTX (80 mg/m 2 ; days 1, 8, and 15) and RAM (8 mg/kg; days 1 and 15) are administered every 4 weeks in arm A, while nab-PTX (100 mg/m 2 ; days 1, 8, and 15) instead of PTX is administered in arm B. The primary endpoint is OS, and the main secondary endpoints are PFS, objective response rate, safety, neuropathy-specific quality of life, and biomarkers. To maintain a probability of ≥70% to ensure the hazard ratio for OS in arm B is lower than 0.90, 105 subjects are required. The study was initiated in October 2018 and is being conducted in 58 centres of the West Japan Oncology Group., Discussion: The results of this study will determine whether w-nab-PTX plus RAM has the potential to be a preferred therapeutic option for advanced and recurrent gastric cancer with peritoneal dissemination, compared to wPTX plus RAM., Trial Registration: This study was prospectively registered in the Japan Registry of Clinical Trials (jRCTs031180022, October 1, 2018).

Purpose: To investigate whether palonosetron is better than granisetron in preventing chemotherapy-induced nausea and vomiting (CINV) in a three-drug combination with dexamethasone and fosaprepitant (Fos) in patients with breast cancer who are placed on anthracycline and cyclophosphamide (AC-based regimen)., Patients and Methods: Chemo-naive women with primary breast cancer were randomly administered either palonosetron 0.75 mg (day 1) or granisetron 1 mg (day 1) combined with dexamethasone (12 mg at day 1, 8 mg at day 2 and day 3) and Fos 150 mg (day 1) before receiving AC-based regimen in a double-blind study. The primary endpoint was the complete response (CR) rate of emesis in cycle 1 in the delayed phase. This was defined as neither vomiting nor rescue drug usage for emesis at >24-120 hours after chemotherapy. Secondary endpoints were the CR in the acute/overall phase (0-24/0-120 hours, respectively, after chemotherapy), no nausea and vomiting, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and safety., Results: From December 2012 to October 2014, 326 patients were treated and evaluated (164/162 evaluable patients in granisetron/palonosetron arm, respectively). The CR during the delayed phase was 60.4% in the granisetron regimen and 62.3% in the palonosetron regimen. The CR during acute phase (73.2% vs 75.9%, respectively) and the CR during overall phase (54.9% in both regimens) were very identical. A significantly higher number of patients in the palonosetron arm were free from nausea during the delayed phase (28% vs 40.1%; P = .029). Adverse events were also identical, although infusion site reactions (ISR) were higher (20.3%-23.3%) than preceding studies in both regimens., Conclusion: In combination with dexamethasone and Fos, this study suggests that palonosetron is not better than granisetron in chemo-naive patients with primary breast cancer receiving AC-based regimen. Administration of Fos in peripheral veins after AC-based regimen increased ISR., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Regorafenib demonstrated survival benefits as salvage therapy for patients with metastatic colorectal cancer. However, severe toxicities frequently occurred early in the treatment with the standard dose (160 mg/day), resulting in a dose reduction or interruption. To improve the tolerability and maintain sufficient efficacy, we conducted a phase II study of regorafenib with a lower starting dose (120 mg/day)., Patients and Methods: Regorafenib was initiated at 120 mg/day, and the dosage was increased to 160 mg/day on day 15 of the first cycle for patients who had met the dose escalation criteria. The primary endpoint was the disease control rate (DCR). The pharmacokinetics of the total and unbound regorafenib and its active metabolites (M2, M5) were assessed., Results: A total of 70 patients were enrolled from September 2016 to December 2017. Only 6 patients achieved dose escalation to 160 mg on day 15 as planned. For the 68 evaluable patients, the DCR was 32.4% (95% confidence interval, 21.5%-44.8%), which was less than the threshold (30%) of our statistical hypothesis. The serum concentrations of total regorafenib for patients whose dose was escalated to 160 mg/day were significantly lower than those of the patients whose dose was not escalated (median, 3978 vs. 7244 nM; P = .027). The serum unbound concentrations of the sum of regorafenib and the active metabolites correlated significantly with the maximum grade of regorafenib-related symptomatic adverse events in the first cycle (11,138 vs. 19,096 pM; P = .035)., Conclusion: Regorafenib with a low starting dose of 120 mg/day did not achieve the expected DCR. A relationship of unbound exposure with toxicity was found., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Severe hepatotoxicity induced by the standard dose of gefitinib (250 mg daily) often becomes manageable by dose reduction to 250 mg every other day. Thus, we hypothesized that systemic exposure of standard-dose gefitinib in patients with experience of severe hepatotoxicity might be higher than that in patients without severe hepatotoxicity., Methods: Patients with advanced epidermal growth factor receptor-mutated non-small cell lung cancer who were receiving gefitinib either at a reduced dose (250 mg every other day) because of intolerable severe toxicity or at a standard dose (250 mg daily) were enrolled. A series of blood samples were collected to estimate pharmacokinetic parameters and calculate systemic exposure of standard-dose gefitinib (area under the concentration-time curve from 0 to 24 h at steady state, AUC 0-24,ss ). Systemic exposure of unbound gefitinib (fu·AUC 0-24,ss ) was also assessed, because gefitinib is extensively bound to serum proteins., Results: Of the 38 enrolled patients, 34 (23 patients without experience of severe hepatotoxicity, 11 patients with experience of severe hepatotoxicity) were evaluable. There was no significant differences in total AUC 0-24,ss or unbound fu·AUC 0-24,ss between patients with and without experience of severe hepatotoxicity. Analysis of the time to severe hepatotoxicity indicated no difference between patients with a high AUC 0-24,ss and those with a low AUC 0-24,ss of either total or unbound gefitinib., Conclusion: This study suggests that reversible severe hepatotoxicity is not caused by high systemic exposure of gefitinib.

Purpose: In patients taking tamoxifen, the CYP2D6 genotype causes different exposure of active metabolite endoxifen. The objective of this randomized, open-label, multicenter, phase II study was to prospectively evaluate whether CYP2D6 genotype-guided tamoxifen dosing in patients with hormone receptor-positive metastatic breast cancer could have an impact on the clinical outcome., Methods: Patients who needed first-line tamoxifen therapy were enrolled. Based on individual CYP2D6 genotype, patients heterozygous (wild type [wt]/variant [V]) or homozygous (V/V) for variant alleles of decreased or no function were randomly assigned to receive tamoxifen at an increased dose (ID arm; 40 mg daily) or regular dose (RD arm; 20 mg daily), and patients homozygous for wild-type alleles (wt/wt) received tamoxifen at 20 mg daily. The primary endpoint was the progression-free survival (PFS) rate at 6 months. The secondary endpoints included PFS and correlation of Z-endoxifen concentration with clinical outcomes., Results: Between December 2012 and July 2016, 186 patients were enrolled in Japan. Of 184 evaluable patients, 136 carried wt/V or V/V (ID arm, 70; RD arm, 66), and 48 carried wt/wt. PFS rates at 6 months were not significantly different between the ID and RD arms (67.6% v 66.7%). The serum trough concentrations of Z-endoxifen in the ID arm were significantly higher than those in the RD arm (median, 89.2 nM v 51.1 nM; P < .0001) and were also higher compared with wt/wt patients (72.0 nM; P = .045). No significant difference in Z-endoxifen concentrations was observed between patients with disease progression and those who were progression free at 6 months ( P = .43)., Conclusion: In patients with CYP2D6 -variant alleles, increasing tamoxifen dosing did not achieve a higher PFS rate at 6 months. The CYP2D6 genotype solely cannot explain individual variability in the efficacy of tamoxifen.

Background: Adjuvant capecitabine and oxaliplatin (CAPOX) is a standard treatment for resected colon cancer; however, in patients with moderate renal impairment, the incidence of CAPOX-related adverse events (AEs) and the rate of early discontinuation are higher than in patients with no or mild renal impairment. The aim of this retrospective study was to assess the impact of baseline renal function on the safety and discontinuation of adjuvant CAPOX therapy started with the standard dose of capecitabine in elderly patients with colon cancer., Methods: Data from patients aged ≥65 years old who received CAPOX at the standard starting dose as adjuvant therapy for stage II/III colon cancer were collected and analyzed retrospectively. Patients were divided into two groups based on their renal function: CLcr-H (patients with a creatinine clearance [CLcr] ≥50 ml/min) and CLcr-L (CLcr <50 ml/min), and AEs and discontinuations were assessed., Results: Overall, 189 patients were assessed (CLcr-H group = 137 and CLcr-L group = 52). No patients experienced grade 4 AEs. The incidence of grade 3 CAPOX-related AEs was higher in the CLcr-L group (42.3%) than in the CLcr-H group (31.3%). The proportion of patients who discontinued treatment within four cycles due to AEs was also higher in the CLcr-L group (21.1%) than in the CLcr-H group (2.9%). Multivariate analysis identified that CLcr <50 ml/min was the only significant risk factor for CAPOX therapy discontinuation due to AEs (P = 0.0008)., Conclusions: This study demonstrates that the tolerability of adjuvant CAPOX therapy was decreased in elderly patients with impaired renal function., Clinical Trial Registration: University Hospital Medical Information Network Clinical Trials Registry number UMIN000016446., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

According to rapid development of chemotherapy in advanced non-small cell lung cancer (NSCLC), the Japan Lung Cancer Society has been updated its own guideline annually since 2010. In this latest version, all of the procedure was carried out in accordance with grading of recommendations assessment, development and evaluation (GRADE) system. It includes comprehensive literature search, systematic review, and determination of the recommendation by multidisciplinary expert panel which consisted of medical doctors, pharmacists, nurses, statisticians, and patients from patient advocacy group. Recently, we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors. Thus, the guideline proposes to categorize patients into three entities: (1) driver oncogene-positive, (2) PD-L1 ≥ 50%, and (3) others. Based on this subgroup, 31 clinical questions were described. We believe that this attempt enables clinicians to choose appropriate treatment easier. Here, we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC, stages IV.

Background: Previous studies have revealed that higher exposure of axitinib leads to better prognosis in metastatic renal-cell carcinoma. We thus assessed individualized dosing of axitinib on the basis of the first-dose area under the concentration-time curve from 0 to 12 hours (AUC 0-12 ) for sunitinib-pretreated metastatic renal-cell carcinoma patients., Patients and Methods: In this prospective single-arm trial, the starting dose of axitinib was 5 mg twice daily. A series of blood samples were taken at predetermined times after the first dose to calculate AUC 0-12 . On day 15 of axitinib administration, the dose was adjusted to ensure ≥ 150 ng·h/mL AUC 0-12 at steady state according to first-dose AUC 0-12 . The primary end point was the 6-month progression-free survival rate., Results: Twenty-six Japanese patients were enrolled. The median recommended dose based on the first-dose AUC 0-12 was 2.5 mg (range, 1-16 mg) twice daily. The 6-month progression-free survival rate for all enrolled patients and per-protocol set, from which 3 patients were excluded for not adjusting to the recommended dose on day 15, was 84.6% (95% confidence interval, 65.5-94.1) and 82.6% (95% confidence interval, 61.8-93.3), respectively. The most common nonhematologic adverse events were hypertension, hand-foot syndrome, fatigue, and decreased appetite. Eighteen patients (75%) developed grade 3 hypertension; however, actual blood pressure could be controlled using antihypertensive agents. Other adverse events were manageable during the protocol treatment., Conclusion: Individualized dosing of axitinib based on the first-dose AUC 0-12 might have promising efficacy and manageable toxicity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Monoclonal antibodies (mAbs) have dramatically improved clinical outcomes for inflammatory and malignant diseases. The elimination route of mAbs is cellular uptake by nonspecific pinocytosis or receptor-mediated endocytosis followed by proteolytic degradation which is protected by neonatal Fc-receptor or mediated by antigenic target. There is a wide-interindividual variability in mAbs exposure due to target burden and other factors affecting unique their pharmacokinetics. It has been reported that higher exposures are correlated with better clinical outcomes of various therapeutic mAbs. On the other hand, flat exposure-efficacy relationships of anti-PD-1 antibodies nivolmab and pembrolizumab mean ensuring absolute maximum efficacy in each patient by the approved dose regardless of their large interpatient variability in pharmacokinetics. Administration of mAbs can induce production of anti-drug antibodies (ADAs), which impact on their pharmacokinetics and pharmacodynamics. In therapeutic drug monitoring (TDM) of mAbs, when total (free, soluble target bound and ADAs bound) mAbs concentration is measured, ADAs content (concentration/titer) should be also monitored because mAbs exists in inactive complex with ADAs. Along with determination of appropriated therapeutic windows taking into account ADAs content, treatment algorithms for TDM-guided clinical decision-making must be developed and prospectively shown to be superior to traditional clinical care for each mAb in each indication., (Copyright © 2018 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

The Tamoxifen Response by CYP2D6 Genotype-based Treatment-1 (TARGET-1) study (n = 180) was conducted from 2012-2017 in Japan to determine the efficacy of tamoxifen dosing guided by cytochrome P450 2D6 (CYP2D6) genotypes. To predict its outcomes prior to completion, we constructed the comprehensive physiologically based pharmacokinetic (PBPK) models of tamoxifen and its metabolites and performed virtual TARGET-1 studies. Our analyses indicated that the expected probability to achieve the end point (demonstrating the superior efficacy of the escalated tamoxifen dose over the standard dose in patients carrying CYP2D6 variants) was 0.469 on average. As the population size of this virtual clinical study (VCS) increased, the expected probability was substantially increased (0.674 for n = 260). Our analyses also informed that the probability to achieve the end point in the TARGET-1 study was negatively impacted by a large variability in endoxifen levels. Our current efforts demonstrate the promising utility of the PBPK modeling and VCS approaches in prospectively designing effective clinical trials., (© 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Chemotherapy has been reported to increase the proportion of cancer stem cells (CSCs) and to promote epithelial-mesenchymal transition (EMT) phenotype changes. Anti-HER2 therapy may provide a strategy for eliminating CSC and EMT, which contribute to therapeutic resistance. No study has determined the changes in the quantity or characteristics of CSCs or circulating tumor cells (CTCs) with EMT phenotype during preoperative anti-HER2 therapy, and whether these changes correlate to response to dual anti-HER2 therapy. In a prospective clinical trial to evaluate pharmacodynamic biomarkers, 18 patients with operable primary HER2-positive breast cancer received dual anti-Her2 preoperative therapy with trastuzumab and lapatinib with paclitaxel. Proportions of tumor cells with CSC characteristics and EMT markers in CTC's were estimated at baseline, after 6 and 18 weeks of preoperative therapy to determine the quantitative cutoff value to predict pathologic complete response (pCR). Out of 18 patients, 8 (44%) had a pCR; 5 of these 8 patients (62%) were positive for CD44v at baseline and none were positive on the 6-week biopsy. In contrast, 6 of the 10 patients without pCR exhibited persistent levels, or enrichment of CD44v proportion and expression at 6 and 18 weeks (p=0.0128). Other biomarkers were not statistically significant predictors of pCR. Enrichment of CD44v-positive tumor cells after dual anti-HER2 therapy alone may predict poor response to dual anti-HER2 therapy plus chemotherapy., Competing Interests: CONFLICTS OF INTEREST Teruo Yamauchi declares intent to reference unlabeled/unapproved uses of drugs or products and declares contracted research with Novartis. Hideko Yamauchi declares intent to reference unlabeled/unapproved uses of drugs or products and declares contracted research with Novartis. Hiromitsu Jinno declares intent to reference unlabeled/unapproved uses of drugs or products and declares contracted research with Novartis. Debasish Tripathy declares intent to reference unlabeled/unapproved uses of drugs or products and declares contracted research with Novartis. Naoto Ueno declares contracted research with Novartis and ApoCell. The other authors declare no potential conflicts of interest.

Aim: α 1 -Acid glycoprotein (AAG), which is a major binding protein of docetaxel, is considered to be a determinant for docetaxel pharmacokinetics. However, there are no reports about the impact of serum AAG on pharmacokinetics and pharmacodynamics in elderly patients treated with docetaxel. The aim of this prospective study was to elucidate the effects of advanced age and serum AAG on docetaxel unbound exposure and neutropenia, dose-limiting toxicity, in cancer patients., Methods: Docetaxel was administered at 60 mg m -2 to 51 patients with non-small cell lung cancer, 17 of whom were ≥75 years of age. Pharmacokinetics, unbound fraction (fu), neutropenia, serum protein levels of AAG and albumin, as well as baseline absolute neutrophil count (ANC) were assessed during the first course. Population pharmacokinetic and pharmacodynamic analyses were performed to evaluate the influence of clinically relevant factors on docetaxel pharmacokinetics and neutropenia., Results: Clearance of docetaxel and degree of fu were significantly associated with serum AAG level, but not with age. Area under the concentration-time curve of unbound docetaxel (fu·AUC) was significantly higher in patients aged ≥75 years (0.389 μg·h ml -1 , 95% CI; 0.329-0.448 μg·h ml -1 ) compared with patients aged <75 years (0.310 μg·h ml -1 , 95% CI; 0.268-0.352 μg·h ml -1 ). Percent decrease in ANC at nadir related to fu·AUC, and was dependent on baseline ANC., Conclusion: Regardless of ageing, serum level of AAG determines docetaxel unbound exposure and related dose-limiting toxicity. Serum AAG level and ANC at baseline appear to be predictive of neutropenia for patients of all ages following the administration of docetaxel., (© 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Spliced variant isoforms of CD44 (CD44v) are a marker of cancer stem cells in solid tumors. They stabilize the xCT subunit of the transporter system xc(-) and thereby promote synthesis of the antioxidant glutathione. Salazosulfapyridine (SASP) is an inhibitor of xCT and suppresses the proliferation of CD44v-positive cancer cells. Chemotherapy-naïve patients with advanced non-squamous non-small-cell lung cancer were enrolled in a dose-escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed. The primary end-point was the percentage of patients who experience dose-limiting toxicity. Fifteen patients were enrolled in the study. Dose-limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day (elevation of aspartate and alanine aminotransferase levels, each of grade 3), two of five patients at 3 g/day (hypotension or pneumonitis, each of grade 3), and two of three patients at 4.5 g/day (anorexia of grade 3). The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression-free survival was 11.7 months, much longer than that for cisplatin-pemetrexed alone in previous studies. Exposure to SASP varied markedly among individuals according to ABCG2 and NAT2 genotypes. The serum concentration of free CD44v protein was increased after the first cycle of treatment, possibly reflecting death of cancer stem cells. Salazosulfapyridine was thus given safely in combination with cisplatin-pemetrexed, with the addition of SASP tending to prolong progression-free survival. This trial is registered in the UMIN Clinical Trials Registry as UMIN000017854., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Cancer stem cells (CSCs) have enhanced mechanisms of protection from oxidative stress. A variant form of CD44 (CD44v), a major CSC marker, was shown to interact with xCT, a subunit of cystine-glutamate transporter, which maintains high levels of intracellular reduced glutathione (GSH) which defend the cell against oxidative stress. Sulfasalazine (SSZ) is an inhibitor of xCT and was shown to suppress the survival of CD44v-positive stem-like cancer cells both in vitro and in vivo. To find the dose of SSZ which can safely reduce the population of CD44v-positive cells in tumors, a dose-escalation study in patients with advanced gastric cancer was conducted., Methods: SSZ was given four times daily by oral administration with 2 weeks as one cycle. Tumor biopsies were obtained before and after 14 days of administration of SSZ to evaluate expression of CD44v and the intratumoral level of GSH., Results: Eleven patients were enrolled and received a dosage from 8 to 12 g/day. Safety was confirmed up to a dosage of 12 g/day, which was considered the maximum tolerated dose. Among the eight patients with CD44v-positive cells in their pretreatment biopsy samples, the CD44v-positive cancer cell population appeared to be reduced in the posttreatment biopsy tissues of four patients. Intratumoral GSH levels were also decreased in two patients, suggesting biological effectiveness of SSZ at 8 g/day or greater., Conclusions: This is the first study of SSZ as an xCT inhibitor for targeting CSCs. Reduction of the levels of CD44v-positive cells and GSH was observed in some patients, consistent with the mode of action of SSZ in CSCs.

Introduction: Everolimus selectively inhibits mammalian target of rapamycin complex 1 (mTORC1) and exerts an antineoplastic effect. Metabolic disturbance has emerged as a common and unique side effect of everolimus., Objectives: We used targeted metabolomic analysis to investigate the effects of everolimus on the intracellular glycometabolic pathway., Methods: Mouse skeletal muscle cells (C2C12) were exposed to everolimus for 48 h, and changes in intracellular metabolites were determined by capillary electrophoresis time-of-flight mass spectrometry. mRNA abundance, protein expression and activity were measured for enzymes involved in glycometabolism and related pathways., Results: Both extracellular and intracellular glucose levels increased with exposure to everolimus. Most intracellular glycometabolites were decreased by everolimus, including those involved in glycolysis and the pentose phosphate pathway, whereas no changes were observed in the tricarboxylic acid cycle. Everolimus suppressed mRNA expression of enzymes related to glycolysis, downstream of mTOR signaling enzymes and adenosine 5'-monophosphate protein kinases. The activity of key enzymes involved in glycolysis and the pentose phosphate pathway were decreased by everolimus. These results show that everolimus impairs glucose utilization in intracellular metabolism., Conclusions: The present metabolomic analysis indicates that everolimus impairs glucose metabolism in muscle cells by lowering the activities of glycolysis and the pentose phosphate pathway.

Background: S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-fluorouracil, 5-FU), 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. As renal dysfunction is known to increase exposure of 5-FU following S-1 administration, the incidence of severe adverse reactions is increased in patients with impaired renal function. However, no reliable information on its dose modification for patients with renal dysfunction has been provided., Methods: We conducted a prospective pharmacokinetic study to develop an S-1 dosage formula based on renal function. Sixteen cancer patients with various degrees of renal function received a single dose of S-1 at 40 mg/m(2). A series of blood samples were collected at predefined times within 24 h to assess the plasma concentration profiles of 5-FU, 5-chloro-2,4-dihydroxypyridine, and tegafur. A mathematical model for the relationship between renal function and exposure of 5-FU was constructed by a population pharmacokinetic analysis., Results: The clearance of 5-FU following S-1 administration was related to body surface area and creatinine clearance in the range 15.9-108.8 mL/min as estimated by the Cockcroft-Gault equation. The S-1 dosage formula was derived as follows:[Formula: see text]where AUC is the area under the concentration-time curve, CLcr is creatinine clearance, and BSA is body surface area. The recommended daily doses of S-1 in Asia and Europe were also proposed as nomograms according to exposure matching to the previously reported area under the concentration-time curve of 5-FU, which confirmed the efficacy and toxicity in pivotal registration studies., Conclusions: We have developed a novel formula for determining the S-1 dosage on the basis of renal function. Further validation is needed to confirm the formula for practical application.

This study evaluated the effects of cytochrome P450 (CYP) 2C19 polymorphisms on tacrolimus pharmacokinetics when coadministered with voriconazole. Eighteen healthy volunteers, including 6 individuals in each CYP2C19 genotype (extensive metabolizers [EMs], intermediate metabolizers [IMs], and poor metabolizers [PMs]), received a single oral dose of 3 mg tacrolimus alone or in combination with 200 mg voriconazole twice daily at steady state. When tacrolimus was coadministered with voriconazole, a significant increase in area under its concentration-time curve (AUC0-24 ) was observed for all genotypes. AUC0-12 of voriconazole in IMs and PMs were significantly higher than that in EMs (P < .05 and P < .01, respectively). Consequently, AUC0-24 of tacrolimus in combination with voriconazole in IMs and PMs were also significantly higher than that in EMs (P < .05). These results demonstrate that CYP2C19 genotypes influenced the exposure of tacrolimus when coadministered with voriconazole, although tacrolimus is mainly metabolized by CYP3A., (© 2015, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Age-related physiological changes affect pharmacokinetics and pharmacodynamics in elderly individuals. Cancer treatment in the elderly requires a careful and multidisciplinary assessment of each patient prior to therapy initiation with respect to treatment decisions and dose optimization considerations, given the wide interpatient variability in this population. As renal function declines with age, renal function assessments are necessary when drugs increasing exposure in renal impairment will be administered to elderly patients. Serum creatinine is an insufficient marker for evaluating renal function in elderly patients because muscle mass decreases with age. Renal function should be assessed according to the index used for dosing recommendation at drug administration planning; in most of drugs, does adjustment is recommended according to the creatinine clearance (Ccr) calculated using the Cockcroft-Gault equation. Elderly patients are apparently more sensitive to cytotoxic agent-induced neutropenia and therefore should be monitored closely. Following the first cycle, a proper assessment of tolerability should be conducted before the second cycle; such assessments are required to discuss the appropriateness of the initiation dose and determine doses during the following cycles for each patient.

Background: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor that acts against receptors for vascular endothelial growth factor and platelet-derived growth factor. Common toxicities of sunitinib treatment include hypertension, hand-foot syndrome, vomiting, and diarrhea, and the proportion of grade 3 or 4 adverse events relating to sunitinib treatment range from 1 to 13% for all categories. It is reported that increased exposure to sunitinib is associated with improved clinical outcomes but also carries an increased risk of adverse effects., Case Presentation: A 73-year-old Japanese woman with metastatic renal cell carcinoma who received sunitinib at a dose of 50 mg once daily suffered a high-grade fever on day 11 of treatment. Sunitinib treatment was discontinued on day 12; however, severe thrombocytopenia and transaminase elevation occurred and persisted more than a week. Additionally, severe hypoxia due to pleural effusion and pulmonary edema developed despite immediate discontinuation of sunitinib. On day 14, three days after the discontinuation of sunitinib, the plasma concentrations of sunitinib and its major active metabolite N-desethyl sunitinib (SU12662) were extremely high (131.9 ng/mL and 28.4 ng/mL, respectively). By day 25, all toxicities had resolved, and a CT scan revealed marked tumor shrinkage. Genotyping of seven single-nucleotide polymorphisms that are potentially relevant to the pharmacokinetics of sunitinib was performed. The patient's genotype of ABCG2 (ATP-binding cassette, sub-family G (WHITE), member 2) 421C > A was homozygous for the variant allele (AA), which was reported to be associated with high exposure to sunitinib. Therefore, we speculated that the extremely high plasma concentrations of sunitinib and SU12662 caused by the ABCG2 421 AA genotype might have resulted in severe toxicities to the patient., Conclusion: The minor allele frequencies of ABCG2 421C > A are approximately three-fold higher in Asians than in Caucasians. Our report suggests that pharmacogenetic factors should be considered when severe and rapid-onset adverse drug reactions occur in Asian patients, including Japanese treated with sunitinib.

Background: Academic/institutional investigator-initiated clinical trials benefit individuals and society by supplementing gaps in industry-sponsored clinical trials., Materials: In May 2010, experts from Japan, the Republic of Korea, the UK, and the United States, met at a symposium in Tokyo, Japan, to discuss how policies related to the conduct of clinical trials, which have been shown to be effective, may be applied to other regions of the world., Results: In order to increase the availability of anticancer drugs world-wide, nations including Japan should examine the benefits of increasing the number of investigator-initiated clinical trials. These trials represent one of the most effective ways to translate basic scientific knowledge into clinical practice. These trials should be conducted under GCP guidelines and include Investigational New Drug application submissions with the ultimate goal of future drug approval., Conclusions: To maximize the effectiveness of these trials, a policy to educate health care professionals, cancer patients and their families, and the public in general on the benefits of clinical trials should be strengthened. Finally, policies that expedite the clinical development of novel cancer drugs which have already been shown to be effective in other countries are needed in many nations including Japan to accelerate drug approval.

Genetic differences in individuals with regard to opioid-receptor signaling create clinical difficulties for opioid treatment; consequently, useful pharmacodynamic and predictive biomarkers are needed. In this prospective study, we studied gene expression changes in peripheral blood leukocytes using a microarray and real-time RT-PCR analysis to identify pharmacodynamic biomarkers for monitoring the effect of morphine in a cohort of opioid-treatment-naïve cancer patients. We also examined genetic variations in opioid receptor mu 1 (OPRM1, 118A→G) and catechol-O-methyltransferase (COMT, 472G→A) to evaluate predictive biomarkers of the treatment outcome of morphine. The plasma concentration of morphine was measured using a liquid chromatography-tandem mass spectrometry method. Microarray analysis revealed that the mRNA expression levels of arrestin β 1 (ARRB1) were significantly down-regulated by morphine treatment. Real-time RT-PCR analysis against independent samples confirmed the results (P=0.003) and changes during treatment were negatively correlated with the plasma morphine concentration (R=-0.42). No correlation was observed between the genotype of OPRM1 and morphine treatment; however, the plasma concentration of morphine and the required dose of morphine were significantly lower for the A/A genotype of COMT (vs. A/G+G/G, P=0.008 and 0.03). We found that changes in the expression of ARRB1 may be a novel pharmacodynamic biomarker and the COMT 472G→A genotype may be a predictive biomarker of the response to morphine treatment.

Although many association studies of polymorphisms in candidate genes with the clinical outcomes of breast cancer patients receiving adjuvant tamoxifen therapy have been reported, genetic factors determining individual response to tamoxifen are not fully understood. To identify genetic polymorphisms associated with clinical outcomes of patients with tamoxifen treatment, we conducted a genome-wide association study (GWAS). We studied 462 Japanese patients with hormone receptor-positive, invasive breast cancer receiving adjuvant tamoxifen therapy. Of them, 240 patients were analyzed by genome-wide genotyping using the Illumina Human610-Quad BeadChips, and two independent sets of 105 and 117 cases were used for replication studies. In the GWAS, we detected significant associations with recurrence-free survival at 15 single-nucleotide polymorphisms (SNPs) on nine chromosomal loci (1p31, 1q41, 5q33, 7p11, 10q22, 12q13, 13q22, 18q12 and 19p13) that satisfied a genome-wide significant threshold (log-rank P= 2.87 × 10(-9)-9.41 × 10(-8)). Among them, rs10509373 in C10orf11 gene on 10q22 was significantly associated with recurrence-free survival in the replication study (log-rank P= 2.02 × 10(-4)) and a combined analysis indicated a strong association of this SNP with recurrence-free survival in breast cancer patients treated with tamoxifen (log-rank P= 1.26 × 10(-10)). Hazard ratio per C allele of rs10509373 was 4.51 [95% confidence interval (CI), 2.72-7.51; P= 6.29 × 10(-9)]. In a combined analysis of rs10509373 genotype with previously identified genetic makers, CYP2D6 and ABCC2, the number of risk alleles of these three genes had cumulative effects on recurrence-free survival among 345 patients receiving tamoxifen monotherapy (log-rank P= 2.28 × 10(-12)). In conclusion, we identified a novel locus associated with recurrence-free survival in Japanese breast cancer patients receiving adjuvant tamoxifen therapy.

CYP2D6 is a key enzyme responsible for the metabolism of tamoxifen to active metabolites, endoxifen, and 4-hydroxytamoxifen. The breast cancer patients who are heterozygous and homozygous for decreased-function and null alleles of CYP2D6 showed lower plasma concentrations of endoxifen and 4-hydroxytamoxifen compared to patients with homozygous-wild-type allele, resulting in worse clinical outcome in tamoxifen therapy. We recruited 98 Japanese breast cancer patients, who had been taking 20 mg of tamoxifen daily as adjuvant setting. For the patients who have one or no normal allele of CYP2D6, dosages of tamoxifen were increased to 30 and 40 mg/day, respectively. The plasma concentrations of tamoxifen and its metabolites were measured at 8 weeks after dose-adjustment using liquid chromatography-tandem mass spectrometry. Association between tamoxifen dose and the incidence of adverse events during the tamoxifen treatment was investigated. In the patients with CYP2D6*1/*10 and CYP2D6*10/*10, the mean plasma endoxifen levels after dose increase were 1.4- and 1.7-fold higher, respectively, than those before the increase (P < 0.001). These plasma concentrations of endoxifen achieved similar level of those in the CYP2D6*1/*1 patients receiving 20 mg/day of tamoxifen. Plasma 4-hydroxytamoxifen concentrations in the patients with CYP2D6*1/*10 and CYP2D6*10/*10 were also significantly increased to the similar levels of the CYP2D6*1/*1 patients according to the increasing tamoxifen dosages (P < 0.001). The incidence of adverse events was not significantly different between before and after dose adjustment. This study provides the evidence that dose adjustment is useful for the patients carrying CYP2D6*10 allele to maintain the effective endoxifen level.

Cytokine signaling is involved in pain and opioid-receptor signaling. In this prospective study, we studied the plasma cytokine levels in order to identify candidate biomarkers for predicting resistance to morphine treatment in a cohort of opioid-treatment-naïve cancer patients. We analyzed pain rating and the plasma concentrations of 26 cytokines at baseline and after morphine treatment using a multiplex immunoassay system for the following cytokines: eotaxin, colony stimulating factor, granulocyte (G-CSF), colony stimulating factor granulocyte-macrophage (GM-CSF), interferon α2 (IFN-α2), IFN-γ, interleukin 1α (IL-1α), IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IP-10, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, tumor necrosis factor-α (TNF-α) and TNF-β. No correlation was observed between the clinical characteristics and the numerical rating scale for pain at baseline or among patients who developed resistance to morphine treatment. Interestingly, the plasma concentration of MIP-1α significantly decreased during morphine treatment (day 8 vs. baseline, p=0.03). Regarding the baseline plasma cytokine concentrations, none of the cytokine levels were correlated with the numerical rating scale for pain at baseline; however, the baseline plasma concentrations of eotaxin, IL-8, IL-12 (p40), IL-12 (p70), MIP-1α and MIP-1β were significantly lower in patients who required a high dose of morphine or who developed resistance to morphine treatment. In conclusion, this is the first report revealing that the plasma concentrations of several cytokines were significantly modulated during treatment and were correlated with treatment outcome of morphine. Our results suggest that plasma cytokine levels may be promising biomarkers for morphine treatment and that they warrant further study.

Purpose: The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen., Patients and Methods: We studied 282 patients with hormone receptor-positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d., Results: CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with

Background: Carboxyamido-triazole (CAI) is a calcium influx inhibitor with anti-angiogenic and anti-invasive properties and stabilizes tumor progression in patients. We hypothesized daily oral micronized CAI with q3 week paclitaxel would be well-tolerated and active., Results: Twenty-nine heavily pretreated patients [median 3 [0-7]] were enrolled on five dose levels. No additive or cumulative toxicity was observed, and grade III nonhematological toxicity was rare. Neutropenia was the most common hematologic toxicity, seen in 79% of patients, with a trend towards increasing grade with higher paclitaxel doses. The recommended phase II dose defined by the maximum tolerated dose (MTD) was CAI 250 mg daily and paclitaxel 200 mg/m(2) q3weeks. Pharmacokinetic analysis revealed paclitaxel increases CAI trough concentration at all dose levels by over 100% (p < 0.0001). A trend towards higher steady-state CAI trough concentrations was found in patients with a partial response (PR; p = 0.09). Six patients had confirmed PR (24%; 4-67 cycles, median 10); two patients had minor responses., Patients and Methods: Eligible patients with solid tumors received micronized CAI daily (150-250 mg PO) and paclitaxel intravenously q3weeks (175-250 mg/m(2)), sequentially escalating each drug. CAI preceded paclitaxel by one week to permit pharmacokinetic analysis. Patients were assessed for toxicity, pharmacokinetics and disease outcome., Conclusions: The MTD of the combination of CAI and paclitaxel is 250 mg daily and 200 mg/m(2) q3weeks, respectively. The combination is tolerable and has potential antitumor activity.