Mirtazapine plus granisetron and dexamethasone for carboplatin-induced nausea and vomiting in patients with thoracic cancers: A prospective multicenter phase II trial.

BACKGROUND: Mirtazapine blocks 5-hydroxytryptamine type (5-HT)2A, 5-HT2C, 5-HT3 and histamine H1 receptors, similarly to olanzapine. This study aimed to investigate the efficacy and safety of mirtazapine plus granisetron and dexamethasone for carboplatin (CBDCA)-induced nausea and vomiting in patients with thoracic cancers. METHODS: We conducted a prospective, open-label, single-arm, multicenter, phase II trial in four institutions in Japan. Registered patients were moderately to highly emetogenic chemotherapy-naïve, and were scheduled to receive CBDCA at area under the curve (AUC) ≥ 4 mg/mL per minute. Patients received mirtazapine 15 mg/day orally at bedtime for four consecutive days, in combination with granisetron and dexamethasone. Primary endpoint was complete response (CR; no emesis and no use of rescue medication) rate during the delayed period (24-120 h). RESULTS: Between July 2022 and July 2023, 52 patients were enrolled, and 48 patients were evaluated. CR rates in the delayed (24-120 h), overall (0-120 h), and acute periods (0-24 h) were 83.3%, 83.3%, and 100%, respectively. No grade 3 or higher treatment-related adverse events were observed except for one patient who had grade 3 dry mouth as evaluated by Common Terminology Criteria for Adverse Events version 5.0. CONCLUSIONS: Prophylactic antiemetic therapy with mirtazapine plus granisetron and dexamethasone shows promising efficacy and an acceptable safety profile. This three-drug combination appears to be a reasonable treatment approach in patients with thoracic cancers receiving a CBDCA-based regimen at AUC ≥ 4 mg/mL per minute.

Prognostic impact of severe neutropenia in colorectal cancer patients treated with TAS-102 and bevacizumab, addressing immortal-time bias.

BACKGROUND: Several studies have reported an association between severe neutropenia and long-term survival in patients treated with trifluridine-tipiracil (TAS-102). Because some of these studies failed to address immortality time bias, however, their findings should be interpreted with caution. Additionally, the association between severe neutropenia and survival in patients receiving TAS-102 in combination with bevacizumab (Bmab) remains unclear. PATIENTS AND METHODS: We conducted a single-center retrospective cohort study in patients with colorectal cancer who received Bmab + TAS-102. We compared overall survival (OS) between patients who developed grade ≥ 3 neutropenia during the treatment period and those who did not. To account for immortal time bias, we used two approaches, time-varying Cox regression and landmark analysis. RESULTS: Median OS was 15.3 months [95% CI: 14.1-NA] in patients with grade ≥ 3 neutropenia and 10.0 months [95% CI: 8.1-NA] in those without. In time-varying Cox regression, onset grade ≥ 3 neutropenia was significantly related to longer survival after adjustment for age and modified Glasgow Prognostic Score. Additionally, 30-, 60-, 90-, and 120-day landmark analysis showed that grade ≥ 3 neutropenia was associated with longer survival after adjustment for age and modified Glasgow Prognostic Score, with respective HRs of 0.30 [0.10-0.90], 0.65 [0.30-1.42], 0.39 [0.17-0.90], and 0.41 [0.18-0.95]. CONCLUSION: We identified an association between long-term survival and the development of severe neutropenia during the early cycle of Bmab + TAS-102 using an approach that addressed immortality time bias.

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.

Emetogenicity and Risk Factors of Nausea and Vomiting in Patients With Metastatic Colorectal Cancer Receiving Trifluridine/Tipiracil and Bevacizumab Chemotherapy.

BACKGROUND/AIM: Although combination chemotherapy with trifluridine/tipiracil (TAS-102) and bevacizumab (BEV) is highly effective for metastatic unresectable colorectal cancer (mCRC), this combination chemotherapy often induces nausea and vomiting. To identify risk factors for nausea and vomiting, we investigated the occurrence of nausea and vomiting in mCRC patients treated with TAS-102 and BEV. PATIENTS AND METHODS: Study patients with mCRC received TAS-102 and BEV between March 2016 and December 2021. The status of nausea, vomiting, and antiemetic measures in each course were investigated, and factors involved in the occurrence of nausea and vomiting were analysed by logistic regression analysis. RESULTS: Data from 57 patients were analysed. The incidence rates of nausea and vomiting during the overall period were 57.9% and 17.5%, respectively. Nausea and vomiting were frequent not only in the early courses but also after the sixth course. Multivariate logistic regression analysis showed that the experience of nausea and vomiting in previous treatment with other agents was significantly associated with nausea and vomiting with TAS-102 and BEV. CONCLUSION: The experience of nausea and vomiting in previous treatment was associated with increased risk for nausea and vomiting in mCRC patients treated with TAS-102 and BEV.

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.

Pharmaceutical intervention for adverse events improves quality of life in patients with cancer undergoing outpatient chemotherapy.

BACKGROUND: The effect of pharmaceutical intervention to treat adverse events on quality of life (QOL) in outpatients receiving cancer chemotherapy is unclear. We investigated whether pharmaceutical intervention provided by pharmacists in collaboration with physicians improves QOL with outpatient cancer chemotherapy. METHODS: We conducted a single-center retrospective descriptive study of pharmaceutical intervention for patients receiving outpatient cancer chemotherapy at Gifu University Hospital between September 2017 and July 2020. We assessed patient QOL using the Japanese version of the EuroQol 5 Dimension5 Level (EQ-5D-5L). Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. We compared the EQ-5D-5L utility value and incidence of grade 2 or higher adverse events before and after pharmaceutical intervention. RESULTS: Our analysis included 151 patients who underwent 210 chemotherapy cycles. Pharmaceutical intervention significantly improved patients' EQ-5D-5L utility values from 0.8197 to 0.8603 (P < 0.01). EQ-5D-5L utility values were significantly improved after pharmaceutical intervention for nausea and vomiting (pre-intervention 0.8145, post-intervention 0.8603, P = 0.016), peripheral neuropathy (pre-intervention 0.7798, post-intervention 0.7988, P = 0.032) and pain (pre-intervention 0.7625, post-intervention 0.8197, P = 0.035). Although not statistically significant, the incidence of grade 2 or higher adverse events, including nausea and vomiting, dermopathy, pain, oral mucositis, diarrhea and dysgeusia, tended to be lower post-intervention than pre-intervention. CONCLUSIONS: Pharmaceutical intervention by pharmacists in collaboration with physicians may improve QOL in patients undergoing outpatient cancer chemotherapy.

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.

Real-world data of the association between quality of life using the EuroQol 5 Dimension 5 Level utility value and adverse events for outpatient cancer chemotherapy.

BACKGROUND: Outpatient cancer chemotherapy may lead to improved quality of life (QOL) by allowing treatment to continue without impairing the social lives of patients compared with hospitalization. However, the occurrence of serious adverse events may cause a decline in QOL. We investigated the relationship between outpatient chemotherapy-induced adverse events and QOL. METHODS: A single-center retrospective descriptive study was conducted in patients who received outpatient chemotherapy at Gifu University Hospital (Gifu, Japan) between September 2017 and December 2018. The utility values of QOL, type and severity of adverse events, type of cancer, chemotherapy regimen, and other patient demographics were analyzed. Adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. QOL was evaluated using the Japanese version of the EuroQol 5 Dimension 5 Level (EQ-5D-5L). Associations between the EQ-5D-5L utility value and serious adverse events were assessed using adjusted (age and sex) odds ratios obtained with a proportional odds logistic regression model. RESULTS: Data from 1008 patients who received 4695 chemotherapy cycles were analyzed. According to proportional odds logistic regression, the adverse events that significantly correlated with a decreased EQ-5D-5L utility value were malaise, edema of the limbs, peripheral neuropathy, pruritus, and dry skin. Based on the proportional odds logistic analysis, neither cancer type nor anticancer drugs were significantly correlated with the EQ-5D-5L utility value in patients who received chemotherapy. Pharmaceutical care for peripheral neuropathy significantly improved patients' EQ-5D-5L utility value from 0.747 to 0.776 (P < 0.01). CONCLUSIONS: Adverse events (i.e., peripheral neuropathy, malaise, and edema of the limbs) are significantly correlated with a decrease in QOL, regardless of the type of cancer or anticancer drugs used. Pharmaceutical care provided by pharmacists in collaboration with physicians may improve QOL.

Bevacizumab in Combination with TAS-102 Improves Clinical Outcomes in Patients with Refractory Metastatic Colorectal Cancer: A Retrospective Study.

OBJECTIVE: TAS-102 is effective for treating patients with metastatic colorectal cancer (mCRC). This study determined whether combining bevacizumab (Bmab) with TAS-102 improves clinical outcomes in refractory mCRC. PATIENTS AND METHODS: We retrospectively analyzed data from Japanese patients with refractory mCRC who received TAS-102 (35 mg/m2 , twice a day) with (T-B group) or without Bmab (TAS-102 monotherapy; T group) between July 2014 and December 2018. The primary endpoint was median overall survival (OS), and secondary endpoints were median time to treatment failure, overall response rate, and the incidence of adverse events. Clinical outcomes were compared using propensity score matched analysis. RESULTS: Data from 57 patients were analyzed (T-B group: 21 patients, T group: 36 patients). Median OS was significantly longer in the T-B group than the T group (14.4 months vs. 4.5 months, p < .001). Cox proportional hazard analysis showed that combination therapy with Bmab was significantly correlated with OS. Propensity score matched analysis confirmed that the median OS was significantly longer in the T-B group than the T group (14.4 months vs. 6.1 months, p = .006) and that there was a significant correlation between Bmab and OS. The incidence of hypertension (grade ≥2) as an adverse event was significantly higher in the T-B group than the T group (23.8% vs. 0.0%, p = .005), whereas other adverse events were comparable between the two groups. CONCLUSION: Treatment with Bmab in combination with TAS-102 is significantly associated with improved clinical outcomes in patients with mCRC refractory to standard therapies. IMPLICATIONS FOR PRACTICE: Combining bevacizumab (Bmab) with TAS-102 significantly improved overall survival and several prognostic indicators in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, with manageable toxicities. Treatment with Bmab in combination with TAS-102 is significantly associated with improved clinical outcomes in patients with mCRC.

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.

Improvement of Dysgeusia by Polaprezinc, a Zinc-L-carnosine, in Outpatients Receiving Cancer Chemotherapy.

BACKGROUND/AIM: Dysgeusia is one of the adverse events frequently affecting patients undergoing cancer chemotherapy. Dysgeusia-induced anorexia could decrease patient's quality of life. The present study was designed to determine whether the zinc-containing compound polaprezinc improves chemotherapy-induced dysgeusia. PATIENTS AND METHODS: The incidence of grade 2 dysgeusia was assessed in 634 patients receiving cancer chemotherapy in outpatient settings during January 2013 and June 2017. Polaprezinc was administered to patients showing grade 2 dysgeusia and the effect was compared with that in patients subjected to follow-up observation. RESULTS: Grade 2 dysgeusia appeared in 80 patients (12.6%), in whom pancreatic cancer and treatment with fluoropyrimidines were significant risks for dysgeusia. Polaprezinc, when administered to patients with grade 2 dysgeusia, significantly shortened the duration of dysgeusia compared with that in the follow-up observation group. Subgroup analysis indicated that polaprezinc was less effective in patients with pancreatic cancer, those receiving gemcitabine, or those whose age was 65 year-old and over. CONCLUSION: Chemotherapy-induced dysgeusia occurred with high frequency in patients with pancreatic cancer or in those receiving fluoropyrimidines. Polaprezinc was highly effective in improving the symptom of dysgeusia, except for patients with pancreatic cancer, those receiving gemcitabine and the elderly.

Control of Nausea and Vomiting in Patients Receiving Anthracycline/Cyclophosphamide Chemotherapy for Breast Cancer.

BACKGROUND/AIM: Chemotherapy-induced nausea and vomiting (CINV) is one of most distressing adverse events during cancer chemotherapy. In breast cancer patients receiving anthracycline and cyclophosphamide (AC) chemotherapy, CINV is poorly controlled. PATIENTS AND METHODS: The prevalence of guideline-consistent antiemetic medication and control of CINV were investigated retrospectively in breast cancer patients receiving the first cycle of AC chemotherapy. Risks for CINV were analyzed by the multivariate logistic regression analysis. The effect of olanzapine added to the standard antiemetic medication on the incidence of CINV was subsequently evaluated in separate patients who received the first cycle of AC chemotherapy. RESULTS: Although the guideline-consistent antiemetic medication was performed in all subjects, the control rate of nausea (32%), but not vomiting (78%) was low. Risk analysis indicated that age younger than 55-year-old was a significant factor that reduces the control of both nausea and vomiting. Olanzapine (5 mg/day for 5 days), when added to the standard three-drug antiemetic medication, significantly improved the control of nausea and complete response. CONCLUSION: CINV was poorly controlled in breast cancer patients receiving AC chemotherapy, in which age younger than 55-year-old was a significant risk for both nausea and vomiting. Olanzapine was effective for improvement of the control of CINV associated with AC chemotherapy. Therefore, care should be taken to prevent CINV in young patients receiving AC chemotherapy by adding olanzapine to the standard three-drug antiemetic medication.