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Dexamethasone is an antiemetic drug widely used to prevent nausea and vomiting caused by anticancer drugs. However, dexamethasone can cause several side effects even after short-term administration. Therefore, the development of dexamethasone-free antiemetic therapies has been recognized as an important challenge. The objective of this study was to investigate the efficacy and safety of palonosetron, aprepitant, and olanzapine. Patients who were chemotherapy-naïve and scheduled to receive highly emetogenic chemotherapy for breast cancer were enrolled and assessed for nausea and vomiting occurring within 120 h after the start of chemotherapy. The primary endpoint was the total control (TC) rate of overall phases. Secondary endpoints included the complete response (CR) rate, which was evaluated during the acute, delayed, and overall phases. A total of 88 patients were enrolled from eight centers in Japan, of whom 84 were included in the analysis. The proportion of patients achieving TC throughout the overall period was 17.1%. Similarly, CR and CC rates for the overall period were 43.4% and 39.5%, respectively. Frequently reported adverse events were loss of appetite and constipation, with rates of 52.4% and 50.0%, respectively. The primary endpoint was not achieved. Therefore, antiemetic therapy without dexamethasone shows an inadequate effect on nausea, and it is generally advisable to avoid omitting dexamethasone. However, in the overall period, both CR and CC were comparable to conventional three-drug combination therapy. Thus, in patients unable to use dexamethasone, replacing it with olanzapine could be an option. Trial registration number: UMIN 000038644, November 20, 2019. The date of first trial registration: 13/03/2020. [ABSTRACT FROM AUTHOR]

Proton pump inhibitor (PPI) use may be associated with renal dysfunction. Renal dysfunction in PPI users requires evaluation of development and progression risks simultaneously, using estimated glomerular filtration rate (eGFR) slope, which indicates changes in eGFR per year. To the best of our knowledge, no studies have evaluated eGFR slope in PPI users. This study investigated the association between PPI use and renal dysfunction using eGFR slope. A single-center cohort study was conducted using the health records data at Hamamatsu University Hospital in Japan. Participants were defined as first users of acid-suppressing drugs (PPIs or Histamine H2 receptor antagonists (H2RAs)) from 2010 to 2021 and continuously prescribed for ≥ 90 days. The H2RA group was used for the propensity-score matching (PSM) to the PPI group to minimize the effects of confounders. The eGFR slope was estimated using a linear mixed effects model. Participants were stratified by baseline eGFR and age, respectively, as subgroup analyses. A total of 4,649 acid-suppressing drug users met the inclusion criteria, including 950 taking H2RAs and 3,699 PPIs. After PSM, 911 patients were assigned to each group. The eGFR slopes of the PPI and H2RA users were -4.75 (95% CI: -6.29, -3.20) and -3.40 (-4.38, -2.42), respectively. The difference between the groups was not significant. Significant declines in eGFR were observed with PPIs with baseline eGFR ≥ 90 and age < 65. PPI use for ≥ 90 days may hasten eGFR decline compared to H2RA use, especially in patients with eGFR ≥ 90 or age < 65. [ABSTRACT FROM AUTHOR]

Summary: Dexamethasone is one of the key antiemetic agents and is widely used even now. However, dexamethasone has been associated with several adverse reactions even after short-term administration. Therefore, developing a steroid-free antiemetic regimen is an important issue to consider. Thus, the purpose of this study was to investigate the efficacy and safety of palonosetron, aprepitant, and olanzapine in a multi-institutional phase II study. Chemotherapy-naive patients scheduled to receive cisplatin were enrolled and evaluated for the occurrence of chemotherapy-induced nausea and vomiting during 120 h after chemotherapy. The primary endpoint of the study was total control (TC) in the overall phase. The key secondary endpoint was complete response (CR), which was assessed in the acute, delayed, and overall phase, respectively. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events. Eighty-five patients were enrolled from 8 centers in Japan, of which 83 were evaluable for analyses. The percentage of patients who achieved TC during the overall phase was 31.3%. CR was achieved in 61.4%, 84.3%, and 65.1% of patients during the overall, acute, and delayed phases, respectively. The most frequently reported adverse event was anorexia. The primary endpoint was below the threshold and we could not find benefit in the dexamethasone-free regimen, but CR during the overall phase was similar to that of the conventional three-drug regimen. This antiemetic regimen without dexamethasone might be an option for patients for whom corticosteroids should not be an active application. [ABSTRACT FROM AUTHOR]

Purpose: Chemotherapy-induced neutropenia (CIN) is a dose-limiting factor for cytotoxic chemotherapy, but recently, it was suggested that CIN contributes to prolonged survival. In this study, we examined the association between severe CIN and survival and determined whether CIN affected survival in patients with extensive-stage small cell lung cancer (ES-SCLC). Methods: The medical records from 214 patients with ES-SCLC treated with etoposide or irinotecan in combination with cisplatin (EP/IP) between 2012 and 2016 were collected and retrospectively analyzed. Landmark analysis was performed at the end of cycle 4, and the relationship between severe CIN and survival was determined by a log-rank test. In addition, a multivariate analysis using the COX proportional hazard model was performed to identify independent predictive factors. The Landmark analysis included 102 patients in the IP group and 47 patients in the EP group. Results: No significant difference was found between grades 0–3 and grade 4 neutropenia and overall survival (OS) in the EP group (P = 0.57). Contrariwise, for the IP patients, the median OS was 444 days for grades 0–3 and 633 days for grade 4 neutropenia, which was significantly longer for patients who developed grade 4 neutropenia (P = 0.03). Multivariate analysis adjusted for potential factors revealed that the development of grade 4 CIN was identified as a significant predictor of longer OS (hazard ratio [HR], 0.50; 95% confidence interval (CI), 0.28–0.87, P = 0.015). Conclusion: The results indicated that the development of severe CIN with IP therapy is associated with prolonged OS. [ABSTRACT FROM AUTHOR]

Summary: Purpose. Docetaxel, cisplatin, and 5-fluorouracil (DCF) have high response rates, but severe neutropenia is frequently observed. The occurrence of neutropenia is associated with high histological response in solid tumors, and it might be associated with tumor shrinkage after DCF therapy. This study aimed to determine the genetic polymorphisms involved in the clinical response to preoperative DCF therapy in esophageal cancer patients. Methods. We included 56 patients with measurable lesions who received preoperative DCF therapy for esophageal cancer. Twenty-one genetic polymorphisms were analyzed, and univariate logistic regression analysis was used to evaluate the association between genetic polymorphisms and tumor shrinkage. A multivariate logistic regression analysis adjusted for T category and tumor location and a univariate analysis for potential genetic factors with P values < 0.05 were performed to explore the predictive factors and to estimate odds ratios and their 95% confidence intervals. Results. No patient achieved a complete response, whereas 20 patients achieved a partial response, 31 patients had stable disease, and 5 patients had progressive disease. Although no association was found between pharmacokinetic-related gene polymorphisms, XRCC3 rs17997944 was extracted as the only genetic factor that affected tumor shrinkage (P = 0.033) by univariate analysis. The multivariate analysis adjusted for T category and tumor site also showed that XRCC3 rs1799794: AA was a predictive factor that affected tumor shrinkage (odds ratio, 0.243; 95% confidence interval, 0.065–0.914; P = 0.036). Conlusions. XRCC3 rs1799794, which is involved in homologous recombination, is a genetic factor that affects clinical responses to DCF therapy. [ABSTRACT FROM AUTHOR]

Purpose: Chemotherapy-induced nausea and vomiting (CINV) can lead to a significant deterioration in the quality of life of cancer patients receiving chemotherapy. This study aimed to determine whether ABCB1 2677G > T/A was associated with complete response (CR; defined as no vomiting and no rescue medication) in acute phase (CR0–24), as well as to explore the genetic factors affecting delayed phase (CR24–120) CINV in cancer patients treated with a standard triple antiemetic regimen that included aprepitant. Methods: This prospective single-center study included a total of 166 chemotherapy-naïve patients with breast cancer who received a standard dose of doxorubicin and cyclophosphamide combination chemotherapy; granisetron, dexamethasone, and aprepitant were administered prior to chemotherapy. CR0–24 was compared between minor allele homozygous (TT, AA, and TA) and major allele homozygous plus heterozygous (GG, GA, and GT) groups of ABCB1 2677G > T/A. In addition, 14 genetic polymorphisms were genotyped and their associations with CRs were investigated. Results: The proportion of patients who achieved CR0–24, which was the primary endpoint of this study, was 59% in the minor allele homozygous and 61% in the major allele homozygous plus heterozygous groups of ABCB1 2677G > T/A. Although this difference was not statistically significant, multivariate logistic regression analysis adjusted for potential risk factors showed that TACR1 1323TT (OR, 2.57; P = 0.014) was a significant determinant of CR24–120. Conclusion: No significant association was found between ABCB1 2677G > T/A and CR0–24. However, it was observed that the polymorphism of TACR1, which encodes the neurokinin 1 receptor, might be a potential genetic risk factor for the development of delayed phase CINV. [ABSTRACT FROM AUTHOR]

Purpose: The combination of docetaxel, cisplatin and 5-fluorouracil (DCF) is a newly developed chemotherapy regimen for esophageal cancer. Severe neutropenia is dose-limiting toxicity of docetaxel and it is well known to be frequently occurred during DCF chemotherapy. This study aimed to investigate the relationship between severe neutropenia and genetic polymorphisms in patients treated with preoperative DCF chemotherapy. Methods: A total of 158 patients were investigated for their absolute neutrophil count (ANC) within the first cycle of DCF chemotherapy at the National Cancer Center (NCC) Hospital East. DNA samples obtained from the NCC Biobank Registry were used for the analysis of nine genetic polymorphisms related to docetaxel pharmacokinetics. These genotypes were evaluated for their association with severe neutropenia, and further their risk factors were examined using a multivariate logistic regression. Results: A total 81 (51.3%) patients developed severe neutropenia. Multivariate analysis revealed that age (OR 1.054; CI 1.008–1.102, P = 0.022), baseline ANC (OR 1.019; CI 1.002–1.037, P = 0.030), ABCB1 3435C>T (OR 2.191; CI 1.087–4.417, P = 0.028) and ABCC2 *+9383C>G (OR 2.342; CI 1.108–4.948, P = 0.026) were significant risk factors for severe neutropenia development. The results from this study showed that age, ANC, ABCB1 3435C>T, and ABCC2 *+9383 G>C increased the incidence of severe neutropenia with the number of identified risk factors. Conclusions: In addition to age and baseline ANC, ABCB1 3435C>T and ABCC2 *+9383C>G were identified as independent predictors for severe neutropenia in esophageal cancer patients treated with DCF chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: The triplet antiemetic regimen is recommended for cisplatin-based highly emetogenic chemotherapy, in the current guidelines for antiemetic prophylaxis. Although risk factors related to chemotherapy-induced nausea and vomiting (CINV) have been identified by several prior studies, there are only few studies evaluating risk factors associated with the prophylactic triplet antiemetic therapy, particularly in palonosetron use. The present study aimed to reveal the risk factors related to CINV development in patients receiving cisplatin and to compare CINV risk factors between palonosetron and granisetron use.Methods: In total, 825 patients in a phase III trial receiving palonosetron with graniestron were evaluated. Multivariate logistic regression models were used to predict risk factors associated with CINV development. Additionally, risk factors associated with CINV development were separately evaluated in each treatment group.Results: Multivariate analysis of the entire study group revealed that sex, age, cisplatin dose, and granisetron use were significant and independent factors affecting CINV development in the overall phase. Similarly, sex and age were risk factors for CINV in both treatment groups. Kaplan-Meier curves classified by each treatment group showed no significant difference between the groups among patients without any risk factors for CINV (P = 0.353). Conversely, complete response rates for patients with at least one risk factor were higher in patients receiving palonosetron (P = 0.049).Conclusions: This analysis revealed the importance of previously reported CINV risk factors when using triplet antiemetics. Palonosetron might be preferred for patients with at least one risk factor. [ABSTRACT FROM AUTHOR]

Purpose: Younger age and female sex have already been well-known risk factors for chemotherapy-induced nausea and vomiting (CINV), and 30-50% of cancer patients still suffer from CINV. Genetic polymorphisms are suggested to influence antiemetic treatment response.Methods: This study included a subset of patients previously enrolled in a randomised controlled trial; 156 patients were evaluated. This study aimed to evaluate the role of pharmacogenomic polymorphisms relevant to antiemetic response in patients with cancer receiving cisplatin-based chemotherapy. The study's efficacy endpoint was the proportion of patients with complete response (CR). The study endpoint was evaluated separately in the acute (CR0-24) and delayed (CR24-120) phases. Thirteen polymorphisms were genotyped, and the association of these genotypes with the efficacy of prophylactic antiemetics was then investigated. Confounding variables for the CR were identified using stepwise multivariate logistic regression analysis. Age and sex were included as independent variables by the forced-entry method, and the stepwise method was used to select the pharmacogenomic factors for inclusion as independent variables.Results: Multivariate logistic regression analysis revealed that the ERCC1 8092AA (odds ratio [OR] = 11.25; 95% confidence interval [CI] 1.74-72.71; p = 0.011) and female sex (OR = 3.63; 95% CI 1.14-11.58; p = 0.029) were significant predictors of CR0-24. No significant association of CR24-120 with pharmacogenomic polymorphisms was found via multivariate logistic regression analysis.Conclusions: ERCC1 polymorphism influenced the extent of CINV control in patients receiving cisplatin-based chemotherapy.Trial Registration: Clinical trial information: UMIN 000009335. [ABSTRACT FROM AUTHOR]

Purpose: Chemotherapy-induced neutropenia (CIN) is a common side effect of chemotherapy and an important dose-limiting factor. However, an association between CIN development and longer survival was recently reported in several solid cancers. In the present study, we aimed to assess whether CIN could be a prognostic factor and clarify other prognostic factors for patients with metastatic pancreatic cancer. Methods: We retrospectively analyzed the medical records of 84 patients who received gemcitabine monotherapy as first-line chemotherapy for metastatic pancreatic cancer to assess whether CIN could be a prognostic factor. Potential prognostic factors of survival were examined by univariate and multivariate analyses using the log-rank test and Cox proportional hazard model, respectively. Results: Median survival time was 170 days [95% confidence interval (CI), 147-193] in patients without CIN (grade 0), 301 days (95% CI, 152-450) in patients with grade 1-2 CIN, and 406 days (95% CI, 271-541) in patients with grade 3 CIN. The multivariate analysis revealed that a pretreatment C-reactive protein level of <0.50 mg/dL [hazard ratio (HR), 0.534; 95% CI, 0.323-0.758, P = 0.015] and grade 3 CIN (HR, 0.447; 95% CI, 0.228-0.875, P = 0.019) were independent favorable prognostic factors in patients with metastatic pancreatic cancer treated with gemcitabine. Conclusions: Neutropenia during chemotherapy was associated with increased survival of patients with metastatic pancreatic cancer. Monitoring of CIN could be used to predict treatment responsiveness. [ABSTRACT FROM AUTHOR]

Purpose: The long-term efficacy of tolvaptan, a vasopressin V2 receptor antagonist, has been reported. However, the safety of long-term treatment remains to be fully elucidated. We assessed the safety profile of tolvaptan with respect to hypernatremia. Methods: This retrospective study included 371 patients treated with tolvaptan. Risk factors for hypernatremia (serum sodium concentration ≥147 mEq/L) were determined. Results: Hypernatremia occurred in 95 patients (25.6 %), of whom 71 (19.1 %) developed hypernatremia within 7 days of tolvaptan treatment (early onset). Stepwise logistic regression analysis demonstrated that baseline serum sodium ≥140 mEq/L, an initial tolvaptan dosage >7.5 mg, and a BUN/serum creatinine ratio ≥20 were independent risk factors for early onset of hypernatremia. Tolvaptan was prescribed for more than 7 days to 233 patients, of whom 123 were administrated tolvaptan for more than 1 month. Hypernatremia occurred in 24 of these patients (10.3 %) (late onset). Predictive factors for late onset of hypernatremia were an average daily dosage of tolvaptan >7.5 mg and age ≥75 years. Conclusions: A daily dosage of 7.5 mg or less was recommended to prevent hypernatremia in short- as well as long-term tolvaptan treatment, and mainly elderly patients were at risk for hypernatremia. [ABSTRACT FROM AUTHOR]

Purpose: Lamotrigine (LTG) is used to treat epilepsy. The variability of LTG pharmacokinetics among individuals may be attributed to polymorphisms in the genes of uridine diphosphate glucuronosyltransferases (UGTs) 1A4 and UGT2B7 and/or combination with other drugs. In this study, we evaluated the association between LTG concentrations and patient characteristics such as genetic polymorphisms and the co-administration of antiepileptic drugs. Methods: We recruited 122 patients with epilepsy. LTG concentrations were measured in blood samples from each patient under steady-state condition. We assessed the influence of multiple factors on LTG concentrations and derived a formula for predicting LTG concentrations using multiple linear regression analysis. Results: We derived a formula to predict LTG concentrations that considers the daily dose of LTG, body weight, valproic acid concentration, phenytoin co-administration, and the co-administration of phenobarbital and/or carbamazepine as well as UGT1A4 142T>G and UGT2B7 -161C>T polymorphisms (adjusted coefficients of determination R = 0.734). Furthermore, we used this formula to reveal a strong positive correlation between measured and predicted LTG concentrations ( r = 0.76, p < 0.001). Conclusion: We derived a formula that will be useful in clinical practice for predicting LTG concentrations in patients with epilepsy. [ABSTRACT FROM AUTHOR]

Purpose: A single 3 mg or 40 μg/kg intravenous dose of granisetron combined with dexamethasone is routinely used in several countries, although the antiemetic guidelines have recommended granisetron at the dose of 1 mg or 10 μg/kg. A randomized, multicenter trial was conducted to determine the optimal intravenous granisetron dose, 1 or 3 mg, in cancer patients receiving emetogenic chemotherapy. Methods: We enrolled 365 patients and randomly assigned them to receive intravenous granisetron 3 mg (3-mg group) or 1 mg (1-mg group), combined with dexamethasone at an adequate dose fixed as per the emetic risk category. The primary end point was the proportion of patients with a complete response during the first 24 h after chemotherapy. Results: The study demonstrated that 1 mg of granisetron was not inferior in effect to 3 mg. For the primary end point, 359 patients were evaluable according to the modified intention-to-treat (ITT) analysis. Complete protection was achieved in the modified ITT population, 90.6% and 88.8% for the 3- and 1-mg groups, respectively ( p < 0.01 for non-inferiority). Conclusions: This study showed that 1 mg granisetron is not inferior to 3 mg when both doses are combined with dexamethasone. Therefore, 1-mg dose of intravenous granisetron should be the recommended prophylactic regimen for the prevention of acute emesis. [ABSTRACT FROM AUTHOR]