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Introduction: Triple antiemetic therapy with neurokinin-1 receptor antagonist, 5-hydroxytryptamine type 3 receptor antagonist, and dexamethasone has been widely recommended for high emetogenic chemotherapeutic (HEC) agents and regimens, including anthracycline combined with cyclophosphamide (AC). The addition of olanzapine (OLZ) 5 mg or 10 mg to the recommended triple antiemetic therapy has demonstrated superiority in antiemetic efficacy compared with the standard triplet therapy for a cisplatin-based HEC regimen. Although OLZ plus the triple antiemetic treatment may also be effective for patients on an AC-based HEC regimen, no study has investigated its efficacy at a lower dose of 5 mg., Methods and Analysis: To assess whether 5 mg OLZ, as compared with placebo, in combination with triple combination therapy, significantly improves nausea and vomiting, we are conducting a randomised, parallel-group controlled clinical trial with a total of 500 patients at 15 study centres in Japan. The primary outcome is the complete response rate, defined as no emetic episodes and no use of rescue medication during 120 hours after the initiation of chemotherapy. Treatment group comparison for the primary endpoint will be done by using the Cochran-Mantel-Haenszel test., Ethics and Dissemination: The study was approved by the institutional review board of Juntendo University Hospital and relevant approval was obtained from all participating centres. All participants will be required to provide written informed consent. The trial results will be reported at conferences and in peer-reviewed journals., Trial Registration Number: Japan Registry of Clinical Trials (jRCT) jRCT1031200134; protocol date: 30 July 2020, version: 1.3, approval: 25 August 2020., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cardiac dysfunction due to cardiotoxicity from anthracycline chemotherapy is a leading cause of morbidity and mortality in survivors of childhood cancer. The intraventricular pressure gradient (IVPG) of the left ventricle (LV) is the suction force of blood from the left atrium to the LV apex during early diastole and is a sensitive indicator of diastolic function. We assessed IVPG as a new indicator of the cardiac dysfunction in survivors of childhood cancer after anthracycline therapy. We performed a prospective echocardiographic study on 40 survivors of childhood cancer aged 6-26 years who received anthracycline therapy (group A) and 53 similar-age normal controls (group N). The subjects were divided into the younger groups, N1 and A1 (age < 16 years); older groups, N2 and A2 (age ≥ 16 years). IVPG was calculated using color M-mode Doppler imaging of the mitral inflow using Euler's equation. Total IVPG was divided into the basal and mid-to-apical IVPG to demonstrate more clearly the mechanisms of the LV diastolic suction force. The total anthracycline dose was 16.2-600.0 mg/m 2 (median 143.5 mg/m 2 ). Total IVPG significantly decreased in group A2 compared with that in group N2 (0.39 ± 0.07 vs. 0.29 ± 0.11 mmHg/cm; p = 0.010). The mid-to-apical IVPG significantly decreased in groups A1 and A2 compared with that in groups N1 and N2, respectively (N1 vs. A1: 0.20 ± 0.05 vs. 0.16 ± 0.05 mmHg/cm, p = 0.036; N2 vs. A2: 0.21 ± 0.06 vs. 0.14 ± 0.06 mmHg/cm, p = 0.001). Basal IVPG, E wave, and E/e' were not significantly different between patients and normal controls. The total and mid-to-apical IVPG, especially mid-to-apical IVPG, could be sensitive new indicators in survivors of childhood cancer after anthracycline therapy.

Purpose: Streptozocin (STZ) is a key agent for treating advanced pancreatic neuroendocrine tumors (pNET). Most STZ regimens for pNET are daily and also include 5-fluorouracil (5FU), whereas STZ monotherapy and weekly regimens have also been applied in daily practice in Japan. The present study aimed to evaluate responses to weekly regimens and to STZ monotherapy, and to identify a predictive marker of a response to STZ., Methods: Clinical data regarding STZ-based chemotherapy for pNET were collected between 2015 and 2017 at 25 facilities. We analyzed the effects, safety, progression-free survival (PFS), and factors that correlate with responses to STZ., Results: The overall objective response rate (ORR) of 110 patients who underwent STZ-based chemotherapy (monotherapy, 81.8%; weekly regimen 46.4%) was 21.8%, and PFS was 9.8 months. The ORR of weekly vs. daily regimens was 21.6 vs. 22.0% (P = 1.000), and that of monotherapy vs. combination therapy was 21.1 vs. 25.0% (P = 0.766). A Ki67 proliferation index (Ki67) of > 5% was a predictive marker of a response to STZ (P = 0.017), whereas regimen type, mono- or combination therapy, treatment line and liver tumor burden were not associated with responses. The frequencies of Grade ≥ 3 nausea and hematological adverse events were significantly lower for monotherapy than combination therapy (P = 0.032)., Conclusions: The effects of weekly STZ monotherapy on pNET are comparable to those previously reported and the toxicity profile was acceptable. Ki67 > 5% was the sole predictive marker of an objective response.

Objectives . Invasion of differentiated thyroid cancer (DTC) into surrounding structures can lead to morbid procedures such as laryngectomy and tracheal resection. In these patients, there is a potential role for neoadjuvant therapy. Methods . We identified three studies involving the treatment of DTC with neoadjuvant chemotherapy: two from Slovenia and one from Japan. Results . These studies demonstrate that in selected situations, neoadjuvant chemotherapy can have a good response and allow for a more complete surgical resection, the treatment of DTC. Additionally, the SELECT trial shows that the targeted therapy lenvatinib is effective in the treatment of DTC and could be useful as neoadjuvant therapy for this disease due to its short time to response. Pazopanib has also demonstrated promise in phase II data. Conclusions . Thus, chemotherapy in the neoadjuvant setting could possibly be useful for managing advanced DTC. Additionally, some of the new tyrosine kinase inhibitors (TKIs) hold promise for use in the neoadjuvant setting in DTC., Competing Interests: Dr. Brett Miles has received funding within the past 2 years from Advaxis Pharmaceuticals for the investigator-initiated study “Window of Opportunity Trial of Neoadjuvant ADXS 11-001 Vaccination Prior to Robot-Assisted Resection of HPV-Positive Oropharyngeal Squamous Cell Carcinoma.” Otherwise, there are no competing interests to report.

Purpose: To evaluate the safety and efficacy of transcatheter arterial chemoembolization used for the treatment of unresectable hepatocellular carcinoma (HCC) with an Asian cooperative prospective study between Japan and Korea., Materials and Methods: Patients with unresectable HCC unsuitable for curative treatment or with no prior therapy for HCC were enrolled. The patients underwent transcatheter arterial chemoembolization with emulsion of Lipiodol and anthracycline agent, followed by embolization with gelatin sponge particles, which was repeated on an as-needed basis. The primary endpoint was 2-year survival rate, and the secondary endpoints were adverse events and response rate., Results: The 2-year survival rate of 99 patients was 75.0% (95% confidence interval, 65.2%-82.8%). The median time-to-progression was 7.8 months, and the median overall survival period was 3.1 years. Of 99 patients, 42 (42%) achieved a complete response, and 31 (31%) had a partial response. The response rate was 73% using modified Response Evaluation Criteria in Solid Tumors. The grade 3-4 toxicities included increased alanine aminotransferase level in 36%, increased aspartate aminotransferase level in 35%, thrombocytopenia in 12%, and abdominal pain in 4% of patients. All other toxicities were generally transient., Conclusions: Asian transcatheter arterial chemoembolization demonstrated sufficient safety and reasonable efficacy as a standard treatment for unresectable HCC. These results could be useful as reference data for future trials of transcatheter arterial chemoembolization., (Copyright © 2013 SIR. Published by Elsevier Inc. All rights reserved.)

Concurrent chemoradiotherapy with 5-fluorouracil plus mitomycin C has been established as a standard therapy for non-metastatic anal squamous cell carcinoma in the West. However, there have been few reports of chemoradiotherapy for anal squamous cell carcinoma in Japan. We retrospectively investigated seven consecutive anal squamous cell carcinoma patients who were treated with concurrent chemoradiotherapy consisting of 5-fluorouracil plus mitomycin C with a total irradiation of 59.4 Gy. The patients consisted of two males and five females. Clinical stages II/IIIA/IIIB accounted for four, one and two patients, respectively. Full-dose irradiation was completed in all patients. Median relative dose intensities of 5-fluorouracil and mitomycin C were both 99%. All patients achieved complete response. At a median follow-up of 37.5 months, one patient experienced local recurrence. The most common grade 3/4 acute toxicities were dermatitis in 100% and anal pain in 71%. There was no treatment-related death. Concurrent chemoradiotherapy appears to be tolerable and effective in Japanese patients with anal squamous cell carcinoma.

Objectives: Despite long-term clinical experience with epirubicin, unpredictable severe adverse reactions remain an important determinant to limit the drug use. To identify a genetic factor(s) affecting the risk of epirubicin-induced leukopenia/neutropenia, we performed a genome-wide association study., Methods: We studied 270 patients consisting of 67 patients with grade 3 or 4 leukopenia/neutropenia, and 203 patients showing no toxicity (patients with grade 1 or 2 were excluded from the study) for genome-wide association study. We further examined the single nucleotide polymorphisms (SNPs) showing P values of less than 0.0001 using an additional set of 48 patients with grade 3/4 leukopenia/neutropenia., Results: The combined analysis indicated that rs2916733 in microcephalin 1 [combined PFisher min=2.27×10, odds ratio (OR)=2.74 with 95% confidence interval (CI)=1.96-3.83; the nonrisk genotype as reference] was significantly associated with epirubicin-induced leukopenia/neutropenia. A subgroup analysis of patients with only breast cancer showed a similar trend of association for the marker SNP rs2916733 (combined PFisher min=6.76×10, OR=2.80 with 95% CI=1.86-4.21). We subsequently performed haplotype analysis and found that a haplotype constructed from rs2916733 and rs1031309, which was in linkage disequilibrium with rs2916733 (r=0.64), showed stronger association (P=2.20×10, OR=2.88 with 95% CI=2.05-4.03) than a single landmark SNP (rs2916733; P=2.27×10, OR=2.74 with 95% CI=1.96-3.83), suggesting that causative variant(s) that could influence the susceptibility of epirubicin-induced adverse drug reactions (ADRs) might exist in this haplotype., Conclusion: Our findings show that genetic variants in the microcephalin 1 locus are suggestively associated with the risk of epirubicin-induced ADRs and might be applicable in development of diagnostic system for predicting the risk of the ADRs, leading to better prognosis and quality of life for patients with cancer. However, these results should be considered preliminary until replicated in adequately larger powered and controlled samples.

Background: The purpose of the study was to characterize the pharmacokinetics of mycophenolic acid (MPA) in Japanese heart transplant recipients and to find the time point that has the best correlation with the MPA area under the plasma concentration curve (AUC)., Methods and Results: Twenty-two Japanese recipients treated with mycophenolate mofetil were evaluated in the study. Approximately 9 months after transplantation, the area under the MPA serum concentration-time curve from 0 to 12 h (AUC(0-12 h)) was evaluated. The MPA AUC(0-12 h) h values in the cyclosporine (CsA) and tacrolimus (FK) groups ranged from 13.11 to 50.98 mug . h/ml and from 39.19 to 93.18 mug . h/ml, respectively. Fourteen models were developed and analyzed for their ability to estimate the MPA AUC(0-12 h) based on a limited number of samples in the CsA group. Sixteen models were developed in the FK group. The best model for predicting the full MPA AUC(0-12 h) in the CsA group was a 3-time-point model that included C(0 h), C(1 h) and C(2 h) (r(2), 0.96; mean prediction error, 0.15+/-7.85%); a 2-time-point model that included C(0 h), and C(2 h) (r(2), 0.94; mean prediction error, 0.495+/-10.35%) was also reliable. In the FK group, a 3-time-point model that included C(1 h), C(2 h) and C(4h) (r(2), 0.73; mean prediction error, 2.73+/-17.09%) was the best model for predicting the full MPA AUC(0-12 h), but it was not reliable in clinical practice., Conclusion: A 3-(C(0 h), C(1 h) and C(2 h)) and a 2-time-point model (C(0 h) and C(2 h)) are useful for predicting the full MPA AUC(0-12 h) in Japanese heart transplant recipients treated with CsA but not with FK.

To clarify the pharmacokinetic properties of idarubicin (IDA) in Japanese patients and to clarify the relationship between the pharmacokinetic parameters of IDA or idarubicinol (IDAol), an active metabolite of IDA, and leukocytopenia or neutropenia, we examined the pharmacokinetics of IDA in patients with malignant lymphoma. Nine of 21 patients registered in an early phase II study of IDA were enrolled in the pharmacokinetic study. IDA (12 or 15 mg/m2) was administered by intravenous infusion for 5 minutes. The elimination half lives (t 1/2) of IDA were 11.0 hours and 12.5 hours after administration of 12 and 15 mg/m2 IDA, respectively. IDAol appeared rapidly both in plasma and in blood cells, and its concentrations exceeded those of IDA within 4 hours. IDAol had a very long t 1/2 (69.2 hours and 70.0 hours for 12 and 15 mg/m2, respectively). The areas under the concentration curves of IDAol in plasma were 3.4 and 5.8 times higher than those of IDA after administration of 12 and 15 mg/m2 IDA, respectively. The t 1/2 of IDAol in plasma correlated significantly with the nadir of neutrophils, and the steady-state volume of distribution of IDA in plasma and in blood cells correlated significantly with the nadirs of white blood cells and neutrophils. These results suggest that both IDA and IDAol play an important role in leukocytopenia or neutropenia. No substantial differences between Japanese and Caucasian people in the pharmacokinetics of IDA were apparent.

This phase I trial of idarubicin (IDA) was conducted in 32 patients with acute leukemia and chronic myelogenous leukemia (CML) in blastic crisis (CML/BC) who either had failed to achieve a complete remission (CR) after initial induction therapy or had relapsed after CR. IDA was administered at dosages ranging from an initial dose of 5 mg/m2/d for 3 days with an increment of 2.5 mg/m2/d to 15 mg/m2/d for 3 days. The dose-limiting toxicities (DLTs) were thought to be stomatitis and anorexia. The maximum tolerated dose (MTD) was determined to be 15 mg/m2/d for 3 days (45 mg/m2 per course). Bone marrow toxicity was significant when greater than 10 mg/m2/d of IDA was given. When IDA was administered at this dosage or higher, there were three CRs and four partial responses, with an overall response rate of 26.9% in 26 assessable patients. It is recommended that a phase II study be undertaken at an IDA dosage of 10 to 15 mg/m2/d for 3 consecutive days in the treatment of acute leukemia. Twenty-one of 32 patients were also studied for the pharmacokinetics of IDA. The terminal half-life (t1/2) values for IDA were 6.4 to 15.1 hours in plasma and 8.09 to 16.34 hours in blood cells. The t1/2 values for idarubicinol were much longer: 43.46 to 51.01 hours in plasma and 36.61 to 54.70 hours in blood cells. Concentrations of idarubicinol in plasma and blood cells exceeded those of IDA 2 to 4 hours after the start of treatment and remained elevated for a long time. The area under the curve (AUC) of idarubicinol in plasma was 5.16 to 8.36 times higher than that of IDA, and the AUC of idarubicinol in blood cells was 2.05 to 4.57 times higher than that of IDA. The AUCs of both IDA and idarubicinol increased dose-dependently over the dosage range of 5 to 15 mg/m2/d. When two-compartment multiple-dose models were used, plasma t1/2 alpha and t1/2 beta values of IDA were 0.25 +/- 0.13 and 9.4 +/- 3.4 hours, respectively. The steady-state volume of distribution (Vdss) was 934.9 +/- 370.7 L/m2, and the plasma clearance was 82.3 +/- 29.7 L/h/m2. The urinary excretion of IDA and its metabolite was low. The mean cumulative urinary recovery rates were 2.04% for IDA and 11.53% for idarubicinol up to 7 days.

We conducted a randomized controlled study to evaluate the clinical usefulness of (2"R) -4'-O-Tetrahydropyranyladriamycin (THP)-based combination therapy subsequent to induction therapy which was consisted with THP, 5'-DFUR, and CPA in the treatment of advanced or recurrent breast cancer. In maintenance therapy, Arm C received CPA and TAM, and Arm T received these two drugs plus THP. Survival time of 50% for all cases in which maintenance therapy was conducted was 26.9 months in Arm T and 20.9 months in Arm C, showing no significant difference by the log-rank test (p = 0.64). Survival time in all cases in which therapy had been completed was 54.6 months in Arm T and 28.1 months in Arm C, showing a significant difference by the log-rank test (p = 0.03) although the number of cases was few. A few cases showed a decrease in total leukocyte count to below 2,000/mm3 at the time of induction therapy, but this was transient in all cases. No significant difference in count was noted between two arms at the time of maintenance therapy. However, many cases in Arm T showed decreased total leukocyte count and hemoglobin content, and thrombocytopenia. These results suggest that combination therapy including THP conducted as maintenance therapy after induction is useful in the prolongation of survival time in patients with advanced or recurrent breast cancer.