Dexamethasone-sparing on days 2-4 with combined palonosetron, neurokinin-1 receptor antagonist, and olanzapine in cisplatin: a randomized phase III trial (SPARED Trial).

BACKGROUND: This study evaluated the non-inferiority of dexamethasone (DEX) on day 1, with sparing on days 2-4 in cisplatin-based chemotherapy. METHODS: Patients with malignant solid tumors who were treated with cisplatin (≥50 mg/m²) were randomly assigned (1:1) to receive either DEX on days 1-4 (Arm D4) or DEX on day 1 (Arm D1) plus palonosetron, NK-1 RA, and olanzapine (5 mg). The primary endpoint was complete response (CR) during the delayed (24-120 h) phase. The non-inferiority margin was set at -15%. RESULTS: A total of 281 patients were enrolled, 278 of whom were randomly assigned to Arm D4 (n = 139) or Arm D1 (n = 139). In 274 patients were included in the efficacy analysis, the rates of delayed CR in Arms D4 and D1 were 79.7% and 75.0%, respectively (risk difference -4.1%; 95% CI -14.1%-6.0%, P = 0.023). However, patients in Arm D1 had significantly lower total control rates during the delayed and overall phases, and more frequent nausea and appetite loss. There were no significant between-arm differences in the quality of life. CONCLUSION: DEX-sparing is an alternative option for patients receiving cisplatin; however, this revised administration schedule should be applied on an individual basis after a comprehensive evaluation. CLINICAL TRIALS REGISTRY NUMBER: UMIN000032269.

Prognostic Model of Baseline Medications plus Neutrophil-to-lymphocyte Ratio in Patients with Advanced Non-small-cell Lung Cancer Receiving Immune Checkpoint Inhibitor plus Platinum Doublet: A Multicenter Retrospective Study.

Background: Association between baseline medications plus neutrophil-to-lymphocyte ratio (NLR) and the effectiveness of immune checkpoint inhibitor (ICI) plus platinum doublet remains unknown, despite several reported prognostic models. We used real-world data to investigate whether baseline medications plus NLR predict survival outcomes in patients with advanced non-small-cell lung cancer (NSCLC) receiving ICI plus platinum doublet. Methods: This multicenter, retrospective, observational study conducted in Japan between December 2018 and March 2021 used real-world data of consecutive patients with advanced NSCLC who received ICI (pembrolizumab or atezolizumab) plus platinum doublet as first-line treatment. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The prognostic score for baseline medications plus NLR was weighted by regression ß coefficients and used to categorize patients into good, intermediate, and poor prognoses groups. In addition, time-dependent receiver operating characteristic curve analyses and univariable and multivariable Cox proportional hazards models were constructed. Results: Overall, 241 patients were included. Poor prognosis was significantly associated with worse PFS (hazard ratio [HR]: 1.78; 95% confidence interval [CI]: 1.08-2.94; P = 0.025) and OS (HR: 3.59; 95% CI: 2.05-6.28; P < 0.001) than good prognosis. Harrell's C-index for this prognostic model was 0.648. Conclusions: Baseline medication plus NLR could predict progressively worse survival outcomes in patients with advanced NSCLC receiving ICI plus platinum doublet and could be used as a prognostic index for poor outcomes.

Effect of Mirtazapine for the Prevention of Nausea and Vomiting in Patients With Thoracic Cancer Receiving Platinum-based Chemotherapy.

BACKGROUND/AIM: Mirtazapine, which exerts an antagonistic effect on 5-hydroxytryptamine type 5-HT2A, 5-HT2C, 5-HT3 and H1 receptors, is considered useful for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV). This study investigated the efficacy and safety of mirtazapine for the prevention of CINV in patients with thoracic cancer receiving platinum-based chemotherapy. PATIENTS AND METHODS: A retrospective cohort study was conducted in patients with thoracic cancer receiving platinum-based chemotherapy with 15 mg mirtazapine once daily as a prophylactic antiemetic drug between January 2014 and December 2021. The effects of mirtazapine added to the standard antiemetic regimen for the prevention of CINV were evaluated in patients who had poor control of CINV in a preceding cycle and in patients who received the standard antiemetic therapy plus mirtazapine from their first cycle. RESULTS: A total of 35 patients were evaluated. Of these, 14 had poor control of CINV in a preceding cycle and received the standard antiemetic therapy plus mirtazapine in the next cycle. The rate of complete response in the delayed period in these patients was significantly improved from the preceding cycle to the next cycle (35.7% vs. 85.7%, p=0.018). In contrast, the other 21 patients had received the standard antiemetic regimen plus mirtazapine from the first cycle. The rate of complete response in the delayed period in these patients receiving the triplet antiemetic regimen plus mirtazapine as part of a cisplatin-based or carboplatin-based regimen and in patients receiving a doublet antiemetic regimen plus mirtazapine in a carboplatin-based regimen was 100%, 85.7% and 100%, respectively. No severe adverse events, including somnolence, were observed with the addition of mirtazapine. CONCLUSION: The addition of mirtazapine to the standard antiemetic regimen for CINV may be beneficial with acceptable safety when administered in association with platinum-based regimens to patients with thoracic cancer.

Relationship Between Osimertinib Concentration and Clinical Response in Japanese Patients With Non-small Cell Lung Cancer.

BACKGROUND/AIM: Osimertinib is the first-line treatment for patients with advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). The present study aimed to determine the previously unclarified association of osimertinib plasma trough concentrations with efficacy, adverse events, and genetic polymorphisms in Japanese patients with NSCLC harboring EGFR mutations. PATIENTS AND METHODS: In this prospective study, blood samples of 25 patients who received osimertinib were collected to measure plasma osimertinib concentrations and to genotypically characterize ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2 polymorphisms. Plasma osimertinib concentrations were analyzed using validated multiple reaction monitoring mode-based liquid chromatography-tandem mass spectrometry. Osimertinib concentration necessary to achieve optimal median progression-free survival (PFS) was determined using receiver operating characteristic curve analysis. PFS and overall survival were analyzed using the Kaplan-Meier method, and between-group differences were compared using the log-rank test. Plasma osimertinib concentrations between different patient groups were compared using the Mann-Whitney U-test. RESULTS: Patients were divided into high and low concentration groups based on a plasma osimertinib cut-off concentration of 211 ng/ml. Median PFS was longer in the high trough concentration group than that in the low trough concentration group (46.3 vs. 16.8 months, p=0.029). Plasma osimertinib concentrations adjusted for dose and body weight did not differ between the patients with and without variant polymorphisms. CONCLUSION: Monitoring plasma trough concentrations during maintenance might improve osimertinib treatment efficacy in patients with NSCLC harboring EGFR mutations.

Efficacy of cisplatin plus vinorelbine adjuvant chemotherapy with split-dose administration of cisplatin after complete resection of stage II-IIIA non-small cell lung cancer.

Although co-administration of cisplatin (CDDP) and vinorelbine (VNR) has been established as a standard of care adjuvant chemotherapy for non-small cell lung cancer (NSCLC), there is a lack of clinical data on its safety and efficacy in Japanese patients receiving split-dose administration of CDDP. The present study analyzed patients who received CDDP + VNR with split-dose administration of CDDP after undergoing complete resection of NSCLC. Patients received four courses of CDDP (40 mg/m2) and VNR (25 mg/m2) on days 1 and 8, every 3 weeks. There were 27 male and 13 female patients; the mean age was 65 years (range 38-78 years), the postoperative disease staging distribution was IIA/IIB/IIIA: 14/8/18 patients, and histological distribution was adenocarcinoma/squamous cell carcinoma/others: 24/12/4 patients, respectively. Of the 40 patients, 28 (70%) completed the four courses of treatment. The mean total dose administered was 279 mg/m2 CDDP (87.2%) and 172 mg/m2 VNR (86%). The major adverse events included Grade (G) 3 or higher neutropenia (80%), G3 phlebitis (5%) and vomiting (2.5%). There was no G2 or higher serum creatinine level elevation, G3 or higher anorexia and nausea, or any treatment-related deaths. The overall completion rate of four courses was 70 and 62.5% for patients aged 70 years and older, whereas the overall percentage of patients that could complete three or more courses was 85 and 87.5% for patients aged 70 years and older. The relapse-free survival rate was 60% at 3 years and 57.5% at 5 years. Overall survival rate was 80% at 3 years and 60% at 5 years. The present study demonstrated the sufficient tolerability, safety and efficacy of combined CDDP + VNR adjuvant chemotherapy with split-dose administration of CDDP, with a low risk of gastrointestinal toxicities or nephrotoxicity.

Cancer cachexia as a determinant of efficacy of first-line pembrolizumab in patients with advanced non-small cell lung cancer.

Pembrolizumab, either as a type of monotherapy or in combination with cytotoxic anticancer agents, is effective in the treatment of advanced non-small cell lung cancer (NSCLC). However, the development of cancer cachexia may adversely affect anticancer drug therapy. The present study investigated the effect of cancer cachexia on clinical outcomes in patients with advanced NSCLC who received first-line pembrolizumab. The data of patients with advanced NSCLC receiving first-line monotherapy or combination therapy with pembrolizumab were retrospectively analyzed. The primary endpoint was time to treatment failure (TTF), and the secondary endpoints were overall survival (OS) and incidence of adverse events (AEs). Clinical outcome was compared between patients with and without cancer cachexia. A total of 53 patients were analyzed. Among all patients, median TTF and OS were significantly shorter in patients with cancer cachexia than in those without [TTF: 5.8 vs. 10 months; hazard ratio (HR): 2.13; 95% confidence interval (CI): 1.07-4.24; P=0.016; OS: 12.1 months vs. not reached; HR: 5.85; 95% CI: 2.0-17.1; P=0.001]. In addition, TTF in the pembrolizumab monotherapy group was significantly shorter in patients with cancer cachexia than in those without, but no significant difference was detected in patients receiving pembrolizumab combination therapy. The incidence of AEs did not significantly differ between patients with and without cancer cachexia, except with regard to hypothyroidism. In conclusion, although cancer cachexia is prognostic of a poor outcome in patients with advanced NSCLC who receive first-line pembrolizumab, cancer cachexia might not affect therapeutic efficacy in combination therapy with pembrolizumab and cytotoxic anticancer agents.

Effects of adding a neurokinin-1 receptor antagonist to 5 mg olanzapine, a 5-hydroxytryptamine-3 receptor antagonist, and dexamethasone for preventing carboplatin-induced nausea and vomiting: a propensity score-matched analysis.

BACKGROUND: Olanzapine has been reported to be an effective antiemetic in patients receiving carboplatin-based chemotherapy. However, the efficacy of a neurokinin-1 receptor antagonist (NK1RA) added to olanzapine, a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA), and dexamethasone (DEX) has not been proven. This study aimed to assess the efficacy and safety of NK1RA, in combination with three-drug antiemetic regimens containing olanzapine, in preventing nausea and vomiting induced by carboplatin-based chemotherapy. METHODS: Data were pooled for 140 patients receiving carboplatin-based chemotherapy from three multicenter, prospective, single-arm, open-label phase II studies that evaluated the efficacy and safety of olanzapine for chemotherapy-induced nausea and vomiting. The propensity score of the co-administration of NK1RA was estimated for each patient using a logistic regression model that included age, sex, and carboplatin dose. We analyzed a total of 62 patients, who were treated without NK1RA (non-NK1RA group: 31 patients) and with NK1RA (NK1RA group: 31 patients). The patients were selected using propensity score matching. RESULTS: The complete response rate (without emetic episodes or with no administration of rescue medication) in the overall period (0-120 h post carboplatin administration) was 93.5% in the non-NK1RA group and 96.8% in the NK1RA group, with a difference of -3.2% (95% confidence interval, -18.7% to 10.9%; P = 1.000). In terms of safety, there was no significant difference between the groups in daytime sleepiness and concentration impairment, which are the most worrisome adverse events induced by olanzapine. CONCLUSIONS: The findings suggest that antiemetic regimens consisting of olanzapine, 5HT3RA, and DEX without NK1RA may be a treatment option for patients receiving carboplatin-based chemotherapy.

COVID-19 and acute exacerbation of interstitial lung disease.

We conducted a study to examine the effect of COVID-19 on the acute exacerbation of interstitial lung disease (AE-ILD) early in the COVID-19 epidemic (January 1-April 30, 2020). An online questionnaire survey was conducted, which was completed by 134 hospitals. During this period, 854 patients with AE-ILD (including 12 cases of COVID-AE-idiopathic pulmonary fibrosis were hospitalized at 128 hospitals. In comparison, the total number of AE-ILD hospitalizations during the same period in 2019 was 894. The number of hospitalizations increased at 17 hospitals, decreased at 27, and remained the same at 88 hospitals in 2020 compared to the same period in 2019. In 2020, COVID-19-related acute exacerbations had a significantly worse prognosis than non-COVID-19-related acute exacerbations in both 30-day and 90-day mortality. Because the prognosis of AE-ILD associated with COVID-19 is extremely poor, prevention of COVID-19 is especially important for patients with ILD.

Efficacy and safety of 5 mg olanzapine for nausea and vomiting management in cancer patients receiving carboplatin: integrated study of three prospective multicenter phase II trials.

BACKGROUND: The efficacy of olanzapine as an antiemetic agent in cancer chemotherapy has been demonstrated. However, few high-quality reports are available on the evaluation of olanzapine's efficacy and safety at a low dose of 5 mg among patients treated with carboplatin regimens. Therefore, in this study, we investigated the efficacy and safety of 5 mg olanzapine for managing nausea and vomiting in cancer patients receiving carboplatin regimens and identified patient-related risk factors for carboplatin regimen-induced nausea and vomiting treated with 5 mg olanzapine. METHODS: Data were pooled for 140 patients from three multicenter, prospective, single-arm, open-label phase II studies evaluating the efficacy and safety of olanzapine for managing nausea and vomiting induced by carboplatin-based chemotherapy. Multivariable logistic regression analyses were performed to determine the patient-related risk factors. RESULTS: Regarding the endpoints of carboplatin regimen-induced nausea and vomiting control, the complete response, complete control, and total control rates during the overall study period were 87.9, 86.4, and 72.9%, respectively. No treatment-related adverse events of grade 3 or higher were observed. The multivariable logistic regression models revealed that only younger age was significantly associated with an increased risk of non-total control. Surprisingly, there was no significant difference in CINV control between the patients treated with or without neurokinin-1 receptor antagonist. CONCLUSIONS: The findings suggest that antiemetic regimens containing low-dose (5 mg) olanzapine could be effective and safe for patients receiving carboplatin-based chemotherapy.

Evaluation of clinical pharmacist interventions for adverse events in hospitalized patients with thoracic cancer receiving cancer chemotherapy.

Due to the increasing complexity of cancer chemotherapy and its associated supportive care, the role of clinical pharmacists in cancer chemotherapy is becoming increasingly more important. The present study evaluated the clinical interventions of a single pharmacist on the adverse events in hospitalized patients with thoracic cancer receiving cancer chemotherapy. A single-center, retrospective study was conducted at the 614-bed, tertiary care Gifu University Hospital. Hospitalized patients with thoracic cancer who received cancer chemotherapy in the respiratory medicine ward between April 2013 and May 2014 were enrolled. One of the two clinical pharmacists in charge was based in the respiratory medicine ward and implemented pharmaceutical care for the patients, including management of adverse events. Patient data were recorded in the electronic medical chart and retrospectively analyzed. A total of 445 patients with thoracic cancer received cancer chemotherapy in the respiratory medicine ward. A total of 152 interventions (101 patients) were performed by the clinical pharmacist prior to the administration of cancer chemotherapy, half of which comprised the addition of drugs to prevent adverse events. A total of 190 patients (39.4%) experienced grade ≥2 non-hematological or grade ≥3 hematological adverse events associated with cancer chemotherapy, and 223 medical interventions for relief of adverse events lowered the incidence of grade ≥2 non-hematological or grade ≥3 hematological adverse events to 17.8%. Of these, 45.3 and 7.5% of medical interventions for non-hematological and hematological adverse events, respectively, were implemented based on the pharmacist's recommendations. These findings revealed the marked contribution of a single clinical pharmacist in the respiratory medicine ward to the prevention and relief of adverse events in hospitalized patients with thoracic cancer receiving cancer chemotherapy.

Low-Dose Olanzapine Plus Granisetron and Dexamethasone for Carboplatin-Induced Nausea and Vomiting in Patients with Thoracic Malignancies: A Prospective Multicenter Phase II Trial.

BACKGROUND: Olanzapine is an inexpensive and durable agent for the treatment of chemotherapy-induced nausea and vomiting and is also superior to neurokinin-1 receptor antagonists in the control of nausea. This study aimed to investigate the efficacy and safety of a low dose of 5 mg olanzapine plus granisetron and dexamethasone for treatment of carboplatin (CBDCA)-induced nausea and vomiting in patients with thoracic malignancies. MATERIALS AND METHODS: We conducted a prospective, open-label, single-arm, multicenter, phase II trial in four centers in Japan. Registered patients were scheduled to receive area under the curve (AUC) ≥5 mg/mL per minute of CBDCA and had never received moderately to highly emetogenic chemotherapy. Patients received olanzapine 5 mg/day orally after supper for 4 days, in combination with granisetron and dexamethasone. Primary endpoint was complete response (CR; no emesis and no use of rescue medication) rate during the overall phase (0-120 hours). RESULTS: Between February 2018 and June 2020, 51 patients were enrolled, and 50 patients were evaluated. The CR rates in the overall (0-120 hours), acute (0-24 hours), and delayed phases (24-120 hours) were 94.0%, 100%, and 94.0%, respectively. No grade 3 or higher adverse effects of olanzapine were observed. CONCLUSION: Prophylactic antiemetic therapy with a low dose of 5 mg olanzapine plus granisetron and dexamethasone showed durable efficacy with an acceptable safety profile. This three-drug combination appears to be a reasonable treatment approach in patients with thoracic malignancies receiving an AUC ≥5 mg/mL per minute of CBDCA-based regimen. Clinical trial identification number: UMIN000031267. IMPLICATIONS FOR PRACTICE: The results of this phase II trial indicated that the prophylactic administration of low-dose of 5 mg olanzapine combined with granisetron and dexamethasone has promising activity with acceptable safety profile in patients with thoracic malignancy receiving high-dose carboplatin chemotherapy.

Primary Prophylaxis of Febrile Neutropenia With Pegfilgrastim in Small-cell Lung Cancer Patients Receiving Amrubicin as Second-line Therapy.

BACKGROUND/AIM: We evaluated the efficacy of primary prophylaxis with pegfilgrastim (PEG) for febrile neutropenia (FN) in small cell lung cancer (SCLC) patients receiving amrubicin (AMR). PATIENTS AND METHODS: A retrospective cohort study was conducted in patients with SCLC receiving AMR as second-line therapy. RESULTS: A total of 33 patients were treated with AMR (no PEG group), while 13 patients were treated with AMR plus prophylactic administration of PEG (PEG group). The severity of neutropenia was significantly reduced in the PEG group compared to the no PEG group (p=0.02). The incidence of FN in the no PEG and PEG groups was 27.3% and 7.7%, respectively. The time to development of FN tended to be longer in the PEG group compared to the no PEG group (p=0.132). CONCLUSION: Primary prophylaxis with PEG may be beneficial in reducing the risk of FN in patients with SCLC receiving AMR.

Evaluation of covalent binding of flutamide and its risk assessment using 19F-NMR.

The formation of reactive metabolites (RMs) is a problem in drug development that sometimes results in severe hepatotoxicity. As detecting RMs themselves is difficult, a covalent binding assay using expensive radiolabelled tracers is usually performed for candidate selection. This study aimed to provide a practical approach toward the risk assessment of hepatotoxicity induced by covalent binding before candidate selection. We focused on flutamide because it contains a trifluoromethyl group that shows a strong singlet peak by 19F nuclear magnetic resonance (NMR) spectrometry. The covalent binding of flutamide was evaluated using quantitative NMR and its risk for hepatotoxicity was assessed by estimating the RM burden, an index that reflects the body burden associated with RM exposure by determining the extent of covalent binding, clinical dose and in vivo clearance. The extent of covalent binding and RM burden was 296 pmol/mg/h and 37.9 mg/day, respectively. Flutamide was categorised as high risk with an RM burden >10 mg/day consistent with its clinical hepatotoxicity. These results indicate that a combination of covalent binding assay using 19F-NMR and RM burden is useful for the risk assessment of RMs without using radiolabelled compounds.

Study protocol for SPARED trial: randomised non-inferiority phase III trial comparing dexamethasone on day 1 with dexamethasone on days 1-4, combined with neurokinin-1 receptor antagonist, palonosetron and olanzapine (5 mg) in patients receiving cisplatin-based chemotherapy.

INTRODUCTION: Dexamethasone (DEX) is administered for multiple days to prevent chemotherapy-induced nausea and vomiting for patients receiving highly emetogenic chemotherapy (HEC); however, its notorious side effects have been widely reported. Although our multicentre randomised double-blind comparative study verified non-inferiority of sparing DEX after day 2 of chemotherapy when combined with neurokinin-1 receptor antagonist (NK1-RA) and palonosetron (Palo) for patients receiving HEC regimen, DEX sparing was not non-inferior in patients receiving cisplatin (CDDP)-based HEC regimens in subgroup analysis. Recently, the efficacy of the addition of olanzapine (OLZ) to standard triple antiemetic therapy on HEC has been demonstrated by several phase III trials. This study aims to confirm non-inferiority of DEX sparing when it is combined with NK-1RA, Palo and OLZ in patients receiving CDDP-based HEC regimens. METHODS AND ANALYSIS: This is a randomised, double-blind, phase III trial. Patients who are scheduled to receive CDDP ≥50 mg/m2 as initial chemotherapy are eligible. Patients are randomly assigned to receive either DEX on days 1-4 or DEX on day 1 combined with NK1-RA, Palo and OLZ (5 mg). The primary endpoint is complete response (CR) rate, defined as no emesis and no rescue medications during the delayed phase (24-120 hours post-CDDP administration). The non-inferiority margin is set at -15.0%. We assume that CR rates would be 75% in both arms. Two hundred and sixty-two patients are required for at least 80% power to confirm non-inferiority at a one-sided significance level of 2.5%. After considering the possibility of attrition, we set our final required sample size of 280. ETHICS AND DISSEMINATION: The institutional review board approved the study protocol at each of the participating centres. The trial result will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: UMIN000032269.

Localized solitary left renal vein thrombus complicating nutcracker syndrome: a case report and review of the literature.

Nutcracker syndrome (NCS) refers to compression of the left renal vein (LRV) between the abdominal aorta and the superior mesenteric artery (SMA). The clinical presentation of NCS includes hematuria, abdominal and left flank pain, gonadal varices, and varicocele formation. Theoretically, thrombosis can occur in the LRV in patients with NCS. However, an isolated solitary left renal vein thrombus (LRVT) complicating NCS is rare. In addition, the clinical features of an LRVT complicating NCS remain unclear. We describe a 43-year-old woman presenting with an asymptomatic LRVT complicating NCS. She was referred to our hospital for investigation of dysfunctional uterine bleeding, and detailed examination revealed endometrial cancer. Computed tomography angiography (CTA) and Doppler ultrasonography revealed compression of the LRV between the aorta and the SMA, as well as an LRVT. CTA performed 4 months after the administration of an anticoagulant showed complete disappearance of the LRVT. We have also included a review of published reports describing LRVT complicating NCS and discussed the clinical features of such a presentation.

Effects of pharmacokinetics-related genetic polymorphisms on the side effect profile of afatinib in patients with non-small cell lung cancer.

OBJECTIVES: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) represent the first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer. Afatinib is a second-generation EGFR-TKI with excellent therapeutic effects. However, severe diarrhea and skin disorders are observed at high frequencies, often leading to treatment interruption because of low quality of life (QOL). The relationship between individual variations and the onset of these side effects remains to be elucidated. This study aimed to reveal the association among these side effects, pharmacokinetics, and related genetic polymorphisms. MATERIALS AND METHODS: In total, 33 patients were recruited between July 2014 and June 2017. Afatinib plasma concentrations were measured at day 9 when the concentrations reached a steady state (early phase) and when the prescription dose was stable for more than 1 month (stable phase). We analyzed single nucleotide polymorphisms in the genes ATP-binding cassette sub-family B member 1 (ABCB1), ABCG2, and flavin-containing monooxygenase 3. RESULTS: The incidences of both diarrhea and acneiform eruption were greater than 80%. Afatinib plasma concentration and the severity of diarrhea in the early phase were correlated. Pharmacokinetics-related genetic polymorphisms influenced the severity of diarrhea. Particularly, the afatinib plasma concentration was higher and diarrhea was more severe in patients carrying the A allele of ABCG2 C421A. Onset of side effects, genetic polymorphisms, and diarrhea in the maintenance phase or acneiform eruption in the early or maintenance phases were not correlated. The severity of diarrhea is influenced by drug plasma concentrations in the early phase and genetic polymorphisms related to afatinib pharmacokinetics. CONCLUSION: Particular genetic polymorphisms can be screened before afatinib administration and the dose adapted to individual patients can be controlled, leading to reduced side effects, improved QOL, and better patient compliance to maintain the therapeutic effects.

Clinical trial protocol of doublet therapy and olanzapine for carboplatin-induced nausea and vomiting in patients with thoracic cancer: a multicentre phase II trial.

INTRODUCTION: Adding neurokinin-1 receptor antagonist (NK1RA) to 5-hydroxytryptamine-3 receptor antagonist and dexamethasone (DEX) improved carboplatin (CBDCA)-induced chemotherapy-induced nausea and vomiting (CINV) in patients with thoracic cancer. NK1RAs with high-drug cost are raising medical expenses. Olanzapine (OLZ) is less expensive and can be expected to have an excellent effect on CINV. This phase II trial aimed at evaluating the efficacy and safety of 5 mg OLZ plus granisetron (GRN) and DEX in CBDCA combination therapy with area under curve (AUC) ≥5 mg/mL/min for the prevention of nausea and vomiting in patients with thoracic cancer. METHODS AND ANALYSIS: This is an open-label, single-arm, multicentre, phase II trial. Patients who receive CBDCA-based therapies (AUC ≥5) and have never been administered moderate to high emetogenic chemotherapy will be enrolled. All patients will receive a combination of GRN, DEX and OLZ. The primary endpoint is complete response (CR) rate, defined as the absence of emetic episodes and no use of rescue medication for 120 hours after the initiation of CBDCA. Forty-eight patients are required based on our hypothesis that this regimen can improve CR rate from 65% (null hypothesis) to 80% (alternative hypothesis) with a one-sided type I error of 0.1 and a power of 0.8. We set the target sample size at 50 considering dropouts. ETHICS AND DISSEMINATION: The study protocol was approved by the institutional review board at each of the participating centres. Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: UMIN000031267.

Immune thrombocytopenia induced by nivolumab in a patient with non-small cell lung cancer.

Antibodies targeting the receptor programmed death 1 on T cells have been approved for the treatment of lung cancer. Immune checkpoint inhibitors (ICIs) induce various immune-related adverse events. Life-threatening hematotoxicity can be provoked by ICI therapy. Although ICI-related endocrinopathy and interstitial lung disease have been well documented, hematotoxicity requiring intensive treatment is relatively rare. We describe a case of nivolumab induced thrombocytopenia after transient mild fever. A 77-year-old man with non-small cell lung cancer was administered nivolumab (240 mg/body, every 2 weeks) as second line therapy. On the day 2 after the first nivolumab infusion, he had a fever and his C-reactive protein level was elevated. Thoracic computed tomography revealed no interstitial lung disease or pneumonia. The fever resolved on day 9 and was not seen thereafter. On day 15 after the first nivolumab infusion, severe thrombocytopenia suddenly emerged. A bone marrow examination revealed no dysplasia or invasion. Based on the presence of high platelet-associated IgG titer, normal bone marrow plasticity and a lack of effectiveness of platelet infusion, we diagnosed nivolumab-induced immune thrombocytopenia. Daily administration of 60 mg of prednisolone restored the patient's platelet count and platelet-associated IgG. We also found that there was significant shrinkage of the primary lesion and that stable disease was achieved. One must be aware of this relatively rare side effect and the unusual clinical findings that could be associated with immunoreaction.

Identification of molecular-interaction sites between lowly hydrolyzed polyvinyl alcohols and indomethacin by NMR spectroscopy.

To evaluate the potency of hydrolyzed polyvinyl alcohols (PVAs) as matrices for solid dispersion (SD) formulations, we examined their inhibitory effects on precipitation of a poorly water-soluble drug, indomethacin (IND). Additionally, to clarify their mechanism, we investigated the intermolecular interaction of IND with PVAs in the supersaturated aqueous solution of IND. In the present study, we used five kinds of PVAs, i.e. JR-05 (70.0-74.0% hydrolyzed), JL-05E (80.0-84.0% hydrolyzed), JP-05 (87.0-89.0% hydrolyzed), JT-05 (93.5-94.5% hydrolyzed) and JF-05 (98.0-99.0% hydrolyzed). Of various PVAs, the lowly hydrolyzed PVAs such as JR-05 and JL-05E dramatically inhibited the precipitate formation of IND. Interestingly, the lowly hydrolyzed PVAs possessed micelle-forming ability, and inhibited the nucleation and crystal growth of IND. Moreover, strong hydrophobic interactions between vinyl acetate unit of lowly hydrolyzed PVA and hydrophobic moiety of IND were suggested based on the results of nuclear magnetic resonance (1H NMR) and nuclear overhauser effect spectroscopy (NOESY) in deuterium oxide. To the best of our knowledge, this is the first report describing the inhibitory effects of the hydrolyzed degree of PVAs on the precipitation of a drug, and demonstrating the intermolecular interaction between PVAs and a drug using NOESY in water.

Efficacy of Single-dose First-generation 5-HT3 Receptor Antagonist and Dexamethasone for Preventing Nausea and Vomiting Induced by Low-dose Carboplatin-based Chemotherapy.

BACKGROUND: Carboplatin (CBDCA) is known to exhibit a high emetic risk among moderate-emetic risk anticancer drugs, and the dose of CBDCA varies in different therapies. In concurrent chemoradiotherapy (CCRT) for non-small cell lung cancer (NSCLC), the weekly administration of CBDCA (area under the curve (AUC) 2 mg/ml/min) and paclitaxel (PTX: 40 mg/m2) is frequently applied as standard therapy. However, the optimal antiemetic measures in the use of such low-dose CBDCA remain unclear. In this study, we retrospectively assessed the antiemetic effect of a single-dose of a first-generation 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA) and dexamethasone in the weekly CBDCA+PTX therapy in CCRT. PATIENTS AND METHODS: The subjects were patients with NSCLC who were administered weekly CBDCA+PTX therapy in CCRT between January 2011 and December 2016 at our Department. As an antiemetic measure, a first-generation 5-HT3RA, azasetron (10 mg, orally) or granisetron (3 mg, intravenously), and dexamethasone (9.9 mg, intravenously) were administered on day 1. The patients were evaluated for the following efficacy end-points for the first cycle: Complete response (CR; defined as no vomiting or retching episodes with no rescue medication) in the acute phase (0-24 hours), delayed phase (>24-120 hours), and overall phase (0-120 hours). Other efficacy endpoints evaluated were no vomiting or retching, and no nausea in all phases. RESULTS: The subjects we assessed in this study were 46 patients who were administered weekly CBDCA+PTX therapy in CCRT. For the overall, acute, and delayed phases, the complete response rates were 89.1%, 100%, and 89.1%, respectively. The rate of no nausea in the overall, acute, and delayed phases was 78.3%, 100%, and 78.3%, respectively. The rate of no vomiting in the overall, acute, and delayed phases was 95.7%, 100%, and 95.7%, respectively. CONCLUSION: A single dose of a first-generation 5-HT3RA and dexamethasone had a favorable suppressive effect on nausea and vomiting in weekly CBDCA+PTX therapy for NSCLC.