Definitive chemoradiotherapy with paclitaxel for locally advanced esophageal squamous cell carcinoma in older patients (PARADISE-1): a phase I trial.

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/m2 weekly for 6 weeks. Depending on the number of DLTs, the dose was set to be increased by 10 mg/m2 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/m2 groups, respectively. All adverse events, except death in the 60 mg/m2 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/m2 weekly. Phase II trials at this dose are underway.

2023 Japan Society of clinical oncology clinical practice guidelines update for antiemesis.

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.

Non-pharmacological treatments for anticipatory nausea and vomiting during chemotherapy: a systematic review and meta-analysis of the Clinical Practice Guidelines for Antiemesis 2023.

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.

Evaluation of clinical validity of an S-1 dosage formula based on renal function using data of the SPIRITS and the G-SOX trials.

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.

Prospective evaluation and refinement of an S-1 dosage formula based on renal function for clinical application.

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 m2 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.

Optimizing antiemetic treatment for chemotherapy-induced nausea and vomiting in Japan: Update summary of the 2015 Japan Society of Clinical Oncology Clinical Practice Guidelines for Antiemesis.

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).

Weekly paclitaxel plus ramucirumab versus weekly nab-paclitaxel plus ramucirumab for unresectable advanced or recurrent gastric cancer with peritoneal dissemination refractory to first-line therapy-the P-SELECT trial (WJOG10617G)-a randomised phase II trial by the West Japan Oncology Group.

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/m2; 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/m2; 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).

Clinical impact of baseline renal function on safety and early discontinuation of adjuvant capecitabine plus oxaliplatin in elderly patients with resected colon cancer: a multicenter post-marketing surveillance study.

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 Japanese Lung Cancer Society Guideline for non-small cell lung cancer, stage IV.

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.

Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer.

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.

The effects of advanced age and serum α1 -acid glycoprotein on docetaxel unbound exposure and dose-limiting toxicity in cancer patients.

AIM: α1 -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.

Dose-escalation study for the targeting of CD44v+ cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205).

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.

Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study.

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.

[Dose optimization of anticancer drugs in the elderly].

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.

A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese.

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.

Sunitinib-induced severe toxicities in a Japanese patient with the ABCG2 421 AA genotype.

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.

Significance of the comprehensive geriatric assessment in the administration of chemotherapy to older adults with cancer: Recommendations by the Japanese Geriatric Oncology Guideline Committee.

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.

Multicentre, randomised, double-blind, placebo-controlled phase II study of prophylactic olanzapine for patients with metastatic breast cancer receiving T-DXd treatment: protocol for the ERICA study (WJOG14320B).

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-HT3)-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.

Efficacy, safety, and biomarker analysis of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR-positive HER2-negative metastatic breast cancer: a phase II study (WJOG11418B NEWFLAME trial).

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.

Dose-adjustment study of tamoxifen based on CYP2D6 genotypes in Japanese breast cancer patients.

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.