High level of C-reactive protein as a predictive factor for immune-related adverse events of immune checkpoint inhibitors in non-small cell lung cancer: a retrospective study.

Background: Several risk factors for the immune-related adverse events (irAEs) during treatment with immune checkpoint inhibitors (ICIs) have been reported, of which include high levels of C-reactive protein (CRP). In this study, we aim to evaluate CRP levels before ICIs treatments as potential predictive biomarkers of irAEs incidence rate and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC). Methods: Between December 1, 2015 to December 31, 2019, we retrospectively collected all adult patients with NSCLC who received at least one dose of an ICI targeting the PD-1/PD-L1 axis at the Iwate Medical University Hospital in Japan. In this study the patients were categorized into low and high groups with a cut-off value of 10 mg/L as the baseline level of CRP before the ICI treatment. The primary endpoint was relationship between CRP levels at baseline and incidence of irAEs. The secondary endpoints were the relationship of progression-free survival (PFS) and OS. Results: A total of 101 irAEs, and 25 severe irAEs were observed. The incidence of the most irAEs was higher in the high CRP group compared to the low CRP group (54.4% vs. 34.5%, respectively, P=0.003). The most frequent irAEs were skin rush (28.8%), followed by pneumonitis (19.2%), hypothyroidism (15.4%), and hepatotoxicity (9.6%). The most common grade 3 or 4 irAEs was pneumonitis (7.9%), which tended to be more frequent in the high CRP group. In multivariate analysis, patients with high CRP levels had an adjusted OR of 2.41 and were associated with an increased risk of developing irAEs (95% CI: 1.16-4.43, P=0.020). The high CRP group was related with shorter PFS compared to the low CRP group (2.2 vs. 3.3 months, respectively, P=0.006). The high CRP group were also related with shorter OS compared to the low CRP group (8.9 vs. 39.1 months, respectively, P<0.001). Conclusions: The results suggest that higher level of pretreatment CRP is involved in the development of irAE and poor prognosis. Identification of patients at high risk of irAEs would be of great help. Future multicenter prospective studies are needed to expand on this study.

Plasma endothelin-1 may predict bevacizumab-induced proteinuria in patients with colorectal cancer.

PURPOSE: Proteinuria is one of the most common adverse events leading to the discontinuation of bevacizumab therapy. We analyzed plasma ET-1 levels as an indicator of renal endothelial dysfunction in colorectal cancer patients, to determine the utility of plasma ET-1 for identification of patients at high risk of proteinuria when treated with bevacizumab. METHODS: Patients (n = 40) were recruited from an outpatient chemotherapy center between December 2020 and January 2022. Blood samples for plasma ET-1 levels were collected before treatment with bevacizumab (baseline), and after treatment for 3 and 6 months, and plasma ET-1 was determined by ELISA. Proteinuria was evaluated based on CTCAE v5.0 using urine protein-creatinine ratio instead of 24-h urine protein. RESULTS: Plasma ET-1 levels at baseline were significantly higher in the group with grade ≥ 2 proteinuria than in the non-proteinuria group (p = 0.019). After adjusting for age, systolic and diastolic blood pressure, and hypertension following bevacizumab, plasma ET-1 levels at baseline were found to be an independent predictor of development of grade ≥ 2 proteinuria (OR = 17.8, 95% CI 1.42-223, and p = 0.026). Receiver operating characteristic curve analysis indicated an optimal cut-off value of the plasma ET-1 level of 1.19 pg/mL for predicting grade ≥ 2 proteinuria, with a sensitivity of 80.0% and specificity of 73.3%. CONCLUSION: In conclusion, higher plasma ET-1 levels before treatment might increase the risk of proteinuria in colorectal cancer patients treated with bevacizumab. This might have important implications in the early detection of the risk of proteinuria.

Identifying risk factors for opioid-induced neurotoxicity in cancer patients receiving oxycodone.

PURPOSE: The aim of this study was to determine the frequency of opioid-induced neurotoxicity (OIN) in cancer patients receiving oral controlled-release oxycodone and to define risk factors for OIN. METHODS: This was a single-center, retrospective study of hospitalized adult cancer patients receiving oral controlled-release oxycodone between April 1, 2013, and April, 30, 2020. The onset of OIN within 30 days after oxycodone initiation in the study patients was investigated. OIN was defined as any of the following: delirium, hallucinations (visual or auditory), seizure, myoclonus, hyperesthesia, and excessive somnolence. Multivariate logistic regression analysis was performed to identify risk factors for OIN in patients receiving oxycodone. RESULTS: In total, 520 patients were included in this study. The number of patients with OIN was 65 (12.5%). The median time until onset of OIN after oxycodone initiation was 7.5 days. Multivariate logistic regression analysis revealed that age ≥ 65 years (OR = 2.74, 95% CI [1.30-5.78], p = 0.008), total bilirubin ≥ 1.3 mg/dL (OR = 4.85, 95% CI [2.13-11.0], p < 0.001), and concomitant use of pregabalin or mirogabalin (OR = 3.11, 95% CI [1.47-6.61], p = 0.003) were significant independent risk factors for OIN. CONCLUSION: Age ≥ 65 years, liver dysfunction, and concomitant use of pregabalin or mirogabalin were independent risk factors for OIN in patients receiving oxycodone. Patients with these risk factors who are receiving oxycodone should be monitored for OIN, especially early in the administration of oxycodone.

Effect of risk factors for acneiform rash induced by anti-epidermal growth factor receptor antibody drugs on survival: a retrospective observational study.

BACKGROUND: We previously reported that high body weight was a risk factor affecting the onset of anti-epidermal growth factor receptor (EGFR) antibody drug-induced acneiform rash. The current study investigated the relationship between risk factors for anti-EGFR antibody drug-induced acneiform rash and survival probability in colorectal cancer patients, as well as effects of drug withdrawal, dose reduction, or treatment discontinuation on treatment continuation. METHODS: This retrospective study included 67 patients with unresectable advanced or recurrent colorectal cancer treated with anti-EGFR antibody drugs for the first time. RESULTS: The survival time and acneiform rash grade of patients with high body weight (≥ 67.2 kg) were significantly longer and higher than those of patients with low body weight (< 67.2 kg). Moreover, the treatment continuation time of patients with drug withdrawal or dose reduction was significantly longer than that of patients without drug withdrawal or dose reduction or with/without treatment discontinuation. Meanwhile, the treatment continuation time of patients with treatment discontinuation was significantly shorter than that of patients with drug withdrawal or dose reduction or those without drug withdrawal, dose reduction, or treatment discontinuation. CONCLUSIONS: High body weight is a novel prognostic factor for patients receiving cancer drugs with anti-EGFR antibody drugs. Hence, the results of this study suggest that patients with high body weight should be carefully monitored for the development of acneiform rash when receiving anti-EGFR antibody drugs as cancer drug therapy.

Bevacizumab Increases Endothelin-1 Production via Forkhead Box Protein O1 in Human Glomerular Microvascular Endothelial Cells In Vitro.

Molecular mechanisms underlying the nephrotoxicity associated with bevacizumab are unclear. Endothelin-1 (ET-1) is involved in podocyte injury and proteinuria, and its level increases in most cases of kidney disorders. Forkhead box protein O1 (FoxO1), a transcription factor, is a major determinant of ET-1 promoter activation and is regulated by protein kinase B (Akt) phosphorylation-dependent nuclear exclusion. We evaluated the effect of bevacizumab on ET-1 production in human glomerular microvascular endothelial cells (hGECs). We analyzed the changes in the mRNA and protein levels of ET-1 in hGECs treated with bevacizumab using real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Changes in the protein levels and phosphorylation status of Akt and FoxO1 in hGECs treated with bevacizumab were analyzed by western blotting. After cell lysis, FoxO1 protein was isolated from the cytoplasmic and nuclear fractions. We also investigated the effects of AS1842856 (a FoxO1 inhibitor) on bevacizumab-induced ET-1 production. Bevacizumab significantly and dose-dependently increased the mRNA and protein levels of ET-1 in hGECs (p < 0.05). Bevacizumab treatment also led to a decrease in phosphorylated Akt protein levels. Inhibition of Akt activity by LY294002 promoted ET-1 production. Bevacizumab also induced an increase in FoxO1 protein levels in the nucleus. Inhibition of FoxO1 activity by AS1842856 resulted in decreased ET-1 levels in bevacizumab-treated hGECs. ET-1 axis activation, Akt inactivation, and FoxO1 nuclear localization are the molecular mechanisms underlying bevacizumab-induced nephrotoxicity. Therefore, inhibition of renal ET-1 production could be a promising approach to protect against or treat bevacizumab-induced nephrotoxicity.

Analysis of risk factors for skin disorders caused by anti-epidermal growth factor receptor antibody drugs and examination of methods for their avoidance.

WHAT IS KNOWN AND OBJECTIVE: Cancer drug treatment is often discontinued because of skin disorder aggravation. However, information on risk factors for skin disorders caused by anti-epidermal growth factor receptor (EGFR) antibody drugs is limited. The aim of this study was to analyse the factors associated with skin disorders caused by anti-EGFR antibody drugs and establish a method to minimize such aggravations. METHODS: We retrospectively examined 67 colorectal cancer patients treated with anti-EGFR antibody drugs for the first time. RESULTS AND DISCUSSION: A higher proportion of males than females experienced drug withdrawal, dose reduction or treatment discontinuation. The multiple logistic regression analysis revealed body weight as a risk factor affecting drug withdrawal, dose reduction or treatment discontinuation because of an acneiform rash. An examination of methods to avoid the aggravation of skin disorders revealed the acneiform rash grade in patients who received prophylactic minocycline was significantly lower than that in patients who did not receive prophylactic minocycline. Furthermore, among patients with grade 1 acneiform rash at the initiation of minocycline, the proportion of those who withdrew, required dose reduction or discontinued treatment was lower than that among patients with grade 2 acneiform rash. WHAT IS NEW AND CONCLUSION: High body weight was identified as a novel factor for skin disorder aggravation caused by anti-EGFR antibody drugs. The aggravation of skin disorders during cancer treatment with anti-EGFR antibody drugs can potentially be avoided by carefully observing the onset of acneiform rash in affected patients with high body weight and using minocycline prophylactically or as an early-stage intervention.

Switching from Intravenous to Oral Tacrolimus Reduces its Blood Concentration in Paediatric Cancer Patients.

BACKGROUND/AIM: Tacrolimus is an essential immunosuppressant for successful allogeneic haematopoietic stem cell transplantation (Allo-HSCT). This study aimed to examine the change in the blood concentration of tacrolimus during switching from intravenous to oral administration in allo-HSCT for paediatric cancer to predict the optimal dosage. PATIENTS AND METHODS: We retrospectively examined the medical records of 63 patients who received allo-HSCT and were administered tacrolimus. To compare bioavailability among different dose ranges, the blood concentration was divided by the dose (C/D). RESULTS: Thirty-nine patients (age range=children 1-15 years, adults 17-67 years) were switched to oral administration of tacrolimus. The C/D after switching was significantly lower in children than in adults (p=0.039). There was a strong positive correlation between age and C/D in children, whereas no correlation was observed in adults. CONCLUSION: In paediatric cancer patients, switching tacrolimus administration route may result in reduced blood concentrations. This tendency is more prominent in younger children.

Deterioration of Glycemic Control Contributes to the Prevalence of Proteinuria among Bevacizumab-Treated Cancer Patients with Type 2 Diabetes Mellitus.

The objective of this study was to investigate whether improving glycemic control reduces the prevalence and progression of proteinuria among bevacizumab (BEV)-treated cancer patients with type 2 diabetes mellitus (DM). We retrospectively reviewed the medical records of 55 patients with type 2 DM who were treated with BEV between July 1 2011 and May 31 2018 at Iwate Medical University Hospital. The patients were classified based on changes in glycated hemoglobin (HbA1c) level during the 3 months following BEV administration into the "HbA1c elevated" group (+0.5% or above, n=24) and the "HbA1c non-elevated" group (indicating no change or decrease; n=31). At 3 months following BEV administration, the means of HbA1c and its change rate in the 'HbA1c elevated' group was significantly higher than that in the 'HbA1c non-elevated' group, and the prevalence of proteinuria in the 'HbA1c elevated' group was significantly higher than that in the 'HbA1c non-elevated' group. Additionally, our subjects were classified into the proteinuria group and non-proteinuria group. The mean HbA1c level in the proteinuria group was significantly higher than that in the non-proteinuria group at 3 months following BEV administration. Furthermore, the mean rates of change of HbA1c level in patients experiencing grades 1 and 2 proteinuria were +9.97±2.26 and +14.0±3.82%, respectively. These values were significantly higher than those of patients with no proteinuria (-2.15±1.96%). Our results suggest that deterioration of glycemic control contributes to the prevalence of proteinuria among BEV-treated cancer patients with type 2 DM.

The efficacy of sodium azulene sulfonate L-glutamine for managing chemotherapy-induced oral mucositis in cancer patients: a prospective comparative study.

BACKGROUND: The efficacy of sodium azulene sulfonate L-glutamine (GA) in treating oral mucositis caused by the administration of anticancer agents has not been previously elucidated. Therefore, this prospective comparative study was conducted to evaluate the efficacy of GA in treating oral mucositis caused by chemotherapy regimens involving fluorinated pyrimidine anticancer drugs. METHODS: The subjects of this study were patients with oral mucositis of grade 2 or higher while on outpatient chemotherapy regimens involving fluorinated pyrimidine anticancer drugs for colorectal or breast cancer. The subjects were randomly divided into a group that received GA (the GA group) or a group that did not receive GA (the control group) by using the closed-envelope method. GA was administered three times a day every day from the first day of the regimen until the final day. The primary endpoint was the development of oral mucositis of grade 2 or higher. The secondary endpoint was the severity of oral pain, which was judged using an 11-stage numerical rating scale (NRS) ranging from 0 to 10. RESULTS: The proportion of patients with oral mucositis of grade 2 or higher was 32.4% in the GA group and 57.6% in the control group. The GA group had a significantly lower frequency of occurrence. The changes in the NRS scores before and after the trial began were - 2.9 ± 0.6 in the GA group and - 1.2 ± 0.5 in the control group. The NRS score decreased more significantly in the GA group than in the control group (P = 0.046). One patient stopped GA treatment voluntarily due to nausea; other than nausea, no GA-related side effects were observed. CONCLUSIONS: GA protects against oral mucositis and reduces the severity of prevailing oral mucositis symptoms. Our findings indicate that GA is a highly safe and convenient drug.

Antiproteinuric effects of renin-angiotensin inhibitors in lung cancer patients receiving bevacizumab.

PURPOSE: The objective of this study was to investigate the effect of renin-angiotensin system inhibitors (RASIs) on bevacizumab (BV)-induced proteinuria in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: We retrospectively reviewed the medical records of NSCLC patients receiving BV between 2008 and 2014 at 11 hospitals. The patients were categorized into three groups according to their antihypertensive drug use: RASI user, non-RASI user, and non-user groups. The primary outcome was a proteinuria event of any grade during the first 6 cycles of BV treatment. RESULTS: A total of 211 patients were included, 89 of whom received antihypertensive drugs. Of these 89 patients, 49 were in the RASI user group, and 40 were in the non-RASI user group. The non-user group comprised 122 patients. The occurrence of proteinuria in the RASI user group was significantly lower than that in the non-RASI user group (P = 0.037) but was not significantly lower than that in the non-user group (P = 0.287). Patients using RASIs had a lower rate of proteinuria than those who did not use RASIs according to multivariate analysis (odds ratio 0.32; 95% confidence interval 0.12-0.86; P = 0.024). CONCLUSION: Our study suggests that RASI administration reduces the risk of proteinuria in patients receiving BV.

Objective evaluation of chemotherapy-induced peripheral neuropathy using quantitative pain measurement system (Pain Vision®), a pilot study.

BACKGROUND: In an evaluation of chemotherapy-induced peripheral neuropathy (CIPN), objectivity may be poor because the evaluation is determined by the patient's subjective assessment. In such cases, management of neuropathy may be delayed and CIPN symptoms may become severe. In this pilot study, we attempted an objective evaluation of CIPN using a quantitative pain measurement system (Pain Vision®). METHODS: The subjects were patients with gynecologic cancer who underwent chemotherapy using taxane and platinum drugs. The grade of the peripheral sensory nerve disorder was based on the Common Terminology Criteria for Adverse Events (CTC-AE) ver. 4.0 and was evaluated before the initiation of therapy and up to six chemotherapy cycles. A symptom scale assessed by the patients using a peripheral neuropathy questionnaire (PNQ) was also evaluated. Simultaneously during these evaluations, graded electric current was applied from the probe to a fingertip and measured both the lowest perceptible current and lowest current perceived as pain by Pain Vision®. From these values, the pain degree was calculated from the following formula: (pain perception current value - lowest perceptible current value) ÷ lowest perceptible current value × 100. We compared the pain degrees by Pain Vision® during CIPN development with the value obtained before chemotherapy initiation. RESULTS: Forty-one patients were enrolled. In the evaluation by a medical professional, 28 (64.3%) patients developed CIPN during 2.5 ± 1.1 chemotherapy cycles (mean ± standard deviation). The pain degree by Pain Vision® at grade 1 and 2 CIPN development according to the evaluation (CTC-AE) was significantly decreased compared to that before chemotherapy initiation (126.0 ± 114.5 vs. 69.8 ± 46.8, p = 0.001, and 126.0 ± 114.5 vs. 32.8 ± 32.6, p = 0.004). Changes in the pain degree by Pain Vision® were also found during scale B and C, D CIPN development in the patient evaluation (PNQ) (115.9 ± 112.4 vs. 70.6 ± 56.5, p = 0.005, and 115.9 ± 112.4 vs. 46.3 ± 42.9, p = 0.004). In the 13 patients in whom CIPN did not occur, no significant decrease in the pain degree by Pain Vision® was detected (p = 0.764). There was no discontinuation of the measurements because of adverse events such as discomfort from the electric current. CONCLUSION: The decrease in the pain degree measured by Pain Vision® was associated with the onset of CIPN symptoms. Particularly, detection of CIPN by Pain Vision® was possible, though most of the CIPN that occurred was low grade or mild symptom. Pain Vision® might become a noninvasive and convenient objective CIPN detection tool to supplement subjective CIPN evaluation. TRIAL REGISTRATION: The study approval number in the institution; H25-140. Registered December 17, 2013.

Case series on the association between blood levels and side effects of afatinib maleate.

PURPOSE: Afatinib maleate (AFA) is a second-generation, tyrosine kinase inhibitor (TKI) treatment for specific variants of non-small cell lung cancer exhibiting epidermal growth factor receptor (EGFR) mutations. In this study, we measured the blood AFA levels in six patients with lung cancer and investigated the association between blood levels and side effects of this drug. METHODS: The study subjects were patients who were administered AFA for non-small cell lung cancer. Of these subjects, six patients agreed to participate in the study. The starting dose of AFA was 40 mg/day. We measured trough blood AFA levels on day 1 and 3 after AFA administration, on day 8-12, and every month until AFA administration was discontinued. Side effects were evaluated according to the adverse event codialect standard (CTCAE v.4.0). RESULTS: A temporary discontinuation and/or reduction in AFA dose (within 2 months) because of diarrhea and stomatitis was needed in four patients. Mean blood AFA levels on day 8-12 in these four patients were significantly higher than in other patients (47.0 ± 9.5 vs. 24.4 ± 0.1 ng/mL, P = 0.017). In addition, mean renal function prior to AFA administration in these four patients was significantly lower than that in the other patients (49.0 ± 9.6 mL/min/1.73 m2 vs. 77.2 ± 9.0, P = 0.026). CONCLUSIONS: High blood AFA levels were associated with the early discontinuation and/or dose reduction of AFA because of untoward side effects, which may also be associated with decreased renal function.

The effectiveness of regional cooling for paclitaxel-induced peripheral neuropathy.

BACKGROUND: There are currently no promising therapies available to treat or prevent peripheral neuropathy (PN) induced by anticancer drugs in a cumulative dose-dependent manner. In this study, we investigated the efficacy of regional cooling of hands and feet in preventing paclitaxel (PTX)-induced PN. METHODS: Patients with gynecologic cancer who received a tri-weekly cycle of chemotherapy including PTX at doses of 150-175 mg/m2 were included in this study. Regional cooling was performed by covering patient hands and feet with cold insulators during PTX administration (regional cooling group). The primary end-point was ≥grade 2 PN evaluated by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. The secondary end-points were the frequency of PN therapeutic drug use, PTX dose reduction due to PN, and adverse events due to regional cooling. The efficacy of regional cooling was compared with data retrospectively extracted from the medical records of patients who did not receive regional cooling (control group). All end-points were evaluated for up to six cycles. RESULTS: There were 40 and 142 patients in the regional cooling and control groups, respectively. As a primary end-point, incidences of ≥grade 2 PN in the fourth to sixth cycles were significantly lower than that in the cooling group (5.0-9.1 % vs. 19.8-31.6 %, p < 0.05 after the fourth cycle and p < 0.01 after the fifth cycle). Among secondary end-points, neither the use of PN therapeutic drugs nor the PTX dose reduction due to PN were significantly lower in the cooling group than in the control group (27.5 vs. 36.6 %, p = 0.378 and 5.0 vs. 3.5 %, p = 0.645, respectively). There were no serious regional cooling-associated adverse events such as frostbite. CONCLUSIONS: Regional cooling of hands and feet during PTX administration might have good effectiveness and tolerability, suggesting this approach as a potentially effective supportive care to prevent PTX-induced PN. TRIAL REGISTRATION: The trial approval number in the institution; H25-26. Registered 5 June 2014.

[The Effectiveness of Polaprezinc Preparation for Taste Alteration in Cancer Chemotherapy].

Taste alteration is an adverse effect of cancer chemotherapy that can cause a decrease in the nutritional status owing to appetite suppression. In most cases, taste alteration is attributed to zinc deficiency, which is treated using zinc-containing formulations, such as polaprezinc. Polaprezinc has commonly been administered to protect against taste alteration during the course of cancer chemotherapy, but its efficacy has not been fully evaluated. In addition, the background characteristics of the patients who are likely to experience taste alteration have not been fully investigated. Therefore, the effectiveness of zinccontaining formulations in the prevention of taste alteration was investigated retrospectively in our hospital. The objective of this study was to evaluate the presence of taste alteration and the effectiveness of polaprezinc administration in 136 female breast cancer patients who underwent FEC100 therapy between April 2011 and September 2014. We also investigated the relevance of the patient background factors in the occurrence of taste alteration(age, height, weight, body surface area, and levels of hemoglobin, serum iron, albumin, and total protein). Of 58 patients with taste alteration, 20 received polaprezinc, with the following outcomes: taste alteration improved in 70.0% of the patients, no change was observed in 25.0%, and the condition worsened in 5.0%. In a multiple regression analysis, the body surface area and decreased hemoglobin level were found to be significant independent factors that influence the development of taste alteration(p=0.003 and p=0.021, respectively). These results indicate that for patients who receive high doses of anticancer agents according to their body surface area and likelihood of anemia, such as that due to iron deficiency, early administration of zinc-containing formulations is anticipated to prevent taste alteration.

[Efficacy of Levofloxacin Hydrate in Febrile Neutropenia for Outpatient Chemotherapy].

Management of febrile neutropenia (FN) is important for the safety of patients undergoing outpatient chemotherapy. Oral antimicrobials are usually prescribed as the initial treatment for FN, and outpatients are instructed to begin medication prior to chemotherapy. However, the effectiveness and safety of the use of these oral antibiotics have not yet been established. In this study, we investigated the effectiveness and safety of levofloxacin hydrate (LVFX) for breast cancer patients with FN, and the factors associated with the onset of FN in 134 breast cancer patients who underwent chemotherapy including the anticancer drug anthracycline (total, 513 courses), in an outpatient chemotherapy department. The effectiveness and safety of LVFX were defined respectively as defervescence within 5 days, and the appearance of side effects such as diarrhea and rashes. Fever was observed in 89 (66%) of the 134 patients, and during 164 (32%) of 513 courses. Defervescence was observed with the LVFX medication in 149 (93%) of 160 courses. The primary side effect was the development of rashes, and only 2 (1%) of the 160 courses were discontinued. Onset of stomatitis during chemotherapy was observed as a factor of FN (odds ratio: 1.36, p<0.05). Our results suggest that the use of LVFX according to the patients' discretion might be an effective and safe option for the management of FN during outpatient chemotherapy.

Feasibility study of short hydration using oral rehydration solution in cisplatin including chemotherapy of lung cancer.

BACKGROUND: Cisplatin (CDDP) is used as a key anticancer drug for solid cancers, including lung cancer. However, a large quantity of fluid replacement is required to prevent renal dysfunction. This requirement have made outpatient chemotherapies including CDDP administration less popular among the available therapeutic options. We designed a short-term hydration regimen combined with oral rehydration solution (ORS) that has a supplementary water ability equivalent to intravenous electrolyte maintenance infusion and investigated its safety and feasibility in the CDDP including chemotherapy. METHODS: The subjects received chemotherapy including CDDP administration (60-80 mg/m(2)) for untreated lung cancer were recruited. The intravenous hydration was infused at around 2000 mL on Day 1, and patients drank ORS at a dose of 1000 mL/day for 3 days. Any renal dysfunction, gastrointestinal symptoms or other tolerability variables pertaining to the remaining three cycles of this regimen were analyzed in the patients who were able to continue treatment after the second cycle. RESULTS: The majority (29/35, 82.9 %) of patients completed intake of ORS for 3 days. The mean ± standard deviation of patient body-surface area-adjusted estimated glomerular filtration rate (eGFR), serum creatinine (sCre) and urea nitrogen from the initial therapy to 1 month after the last administration changed from 79.8 ± 11.7-67.0 ± 16.9 mL/min (p = 0.15), 0.70 ± 0.13-0.85 ± 0.27 mg/dL (p = 0.02), and 14.3 ± 3.8-17.1 ± 5.4 mg/dL (p = 0.09), respectively. The CTCAE ver 4.0 grades 1 or 2 adverse events pertaining to renal function after the last administration were 2 (5.7 %)/2 (5.7 %) patients assessed by sCre, and 14 (40.0 %)/12 (34.3 %) patients assessed by eGFR, respectively. There was no patient with ≥3 grade renal dysfunction based on either evaluation. CONCLUSIONS: Based on the results of this study, supplementary use of the ORS as a method of short-term hydration may be a feasible regimen for shortening infusion times and improving safety for those undergoing chemotherapy including CDDP administration.

Effect of olanzapine for breast cancer patients resistant to triplet antiemetic therapy with nausea due to anthracycline-containing adjuvant chemotherapy.

OBJECTIVE: Triplet antiemetic therapy with neurokinin 1 receptor blocker, 5-hydroxytryptamine receptor blocker and steroids is commonly used in patients who are highly emetic after chemotherapy. However, an alternative antiemetic therapy for patients who are resistant to triplet antiemetic therapy is not established. Olanzapine is recommended in the guidelines as an optional antiemetic drug. However, the effectiveness of adding olanzapine to triplet antiemetic therapy is unknown. In this study, the effectiveness and safety of adding olanzapine to triplet antiemetic therapy with aprepitant, palonosetron and dexamethasone as highly emetic anthracycline-containing adjuvant chemotherapy for primary breast cancer patients were prospectively investigated. METHODS: Forty-five patients with breast cancer who experienced >Grade 1 nausea or any vomiting after the first cycle of chemotherapy using both epirubicin and cyclophosphamide were included. Low-dose olanzapine (2.5 mg/day) was administered orally from the first day of chemotherapy for 4 days, and the number of episodes of vomiting, scale of nausea, dietary intake and somnolence were compared with the symptoms after the first cycle. RESULTS: As the primary endpoint, the nausea grade was significantly improved by adding olanzapine (P < 0.05). As the secondary endpoints, mean nausea scale (3.2→1.9, Day 1; 3→1.3-1, Days 2-6) and dietary intake (33.6→53.8%, Day 1; 42.0→60.7-78.1%, Days 2-6) were improved by adding olanzapine. Only four patients withdrew due to somnolence and/or dizziness. CONCLUSIONS: This study demonstrated the effectiveness and tolerability of adding low-dose olanzapine for patients with insufficient nausea relief with triplet antiemetic therapy consisting of palonosetron, steroid and aprepitant.

[Treatment algorithm for oxaliplatin-induced peripheral neuropathy].

Oxaliplatin (L-OHP) is a key drug in the treatment of colorectal cancer; however, L-OHP-induced peripheral neuropathy becomes a dose-limiting factor for which withdrawal is the only effective option. In the present study, we attempted to treat L-OHP-induced peripheral neuropathy using the algorithm consisting of pregabalin, duloxetine, and oxycodone at Iwate Medical University Hospital. The first, second, and third stages of the algorithm consist of pregabalin, duloxetine, and oxycodone, respectively. We examined the usefulness and safety of the treatment algorithm for 27 patients with colorectal cancer by evaluating the side effects and degree of improvement of subjective symptoms. When discontinuation was necessary due to adverse events or invalid treatment during the 4-week study period, the patient was transitioned to the next stage. The response rates of the first, second, and third stages of the algorithm were 33% (9/27), 33% (6/18), and 17% (1/6), respectively, whereas the overall response rate was 59% (16/27). The side effect rates of the first, second, and third stages were 37% (10/27), 33% (6/18), and 83% (5/6), respectively. Somnolence was the most common side effect of these drugs. Thus, our treatment algorithm appears to be useful for L-OHP-induced peripheral neuropathy. However, pregabalin, duloxetine, and oxycodone should be administered with specific attention on the potential side effects.

[Field survey of the anticancer drug contamination in the preparation environment. Usefulness of the 5-FU monitoring by the coupon method].

For medical professionals involved in cancer chemotherapy, occupational exposure of anticancer agents is considered a health risk. Education about the handling of anticancer drugs and proper use of protective equipment are important for reducing occupational exposure of anticancer drugs. Furthermore, monitoring of the contamination level of anticancer drugs is important for determining the propriety of anti-contamination methods. Cyclophosphamide (CPA) has been used as the standard drug of the contamination level; however, it is rarely detected because of the disparity between drug preparation frequency and consumption, and use of a closed system. Therefore, we chose 5-fluorouracil (5-FU) as the standard drug and attempted to monitor its contamination levels by sampling using drug absorption sheets (the coupon method). We measured contamination levels inside a biological safety cabinet (BSC) and at its lower floor, and at a preparation worktable, nurses' station worktable, its lower floor and floor of the hospital room in a chemotherapy room for outpatients of the Iwate Medical University Hospital for 3 time periods. 5-FU was detected in 72% of the coupons (n=108), while CPA was detected in only 7% of the coupons (n=108). Monitoring of 5-FU contamination levels by using the coupon method was considered useful for evaluating anti-contamination method and the contamination process.

[Efficacy and safety of pregabalin for oxaliplatin- and paclitaxel-induced peripheral neuropathy].

This study included patients who were prescribed pregabalin, vitamin B12, amitriptyline, clonazepam, or carbamazepine to improve oxaliplatin(L-OHP)- or paclitaxel(PTX)-induced peripheral neuropathy at Iwate Medical University Hospital between April 2011 and July 2012. The efficacy and safety of pregabalin was evaluated by comparing 27 patients with L-OHP-induced peripheral neuropathy and 28 with PTX-induced peripheral neuropathy prescribed pregabalin(pregabalin group) with 20 patients with L-OHP-induced peripheral neuropathy and 25 with PTX-induced peripheral neuropathy prescribed other drugs(non-pregabalin group). Response was defined as a decrease in neuropathy of at least 1 grade from baseline. The response rates were 40.7% and 10.0% for L-OHP-induced peripheral neuropathy patients and 28.6% and 12.0% for PTX-induced peripheral neuropathy patients in the pregabalin and non-pregabalin groups, respectively. The severity of peripheral neuropathy before and after the administration of pregabalin differed significantly[L-OHP, 1.33±0.48(mean±SD) vs. 1.00±0.78 and PTX, 1.46±0.69 vs. 1.21±0.88]. In 28-37% of patients, pregabalin was associated with adverse events, with drowsiness and dizziness being frequently observed. In conclusion, pregabalin was efficacious in reducing the severity of L-OHP- and PTX-induced peripheral neuropathy.