Effect of Liver Dysfunction on S-1 Therapy Induced Adverse Effects: A Retrospective Cohort Study.

BACKGROUND/AIM: Renal dysfunction necessitates S-1 dose reduction. However, decreased dihydropyrimidine dehydrogenase (DPD) activity may lead to adverse events due to 5-FU. The guidelines provided by pharmaceutical companies state that total bilirubin (T-Bil) should be ≤upper limit of normal (ULN)×1.5 as a reference value for safely taking S-1. Nevertheless, the relationship between the degree of liver dysfunction and S-1 dose reduction has not been clearly established. PATIENTS AND METHODS: This study focused on patients who received S-1 monotherapy for various types of cancer. The primary outcome was defined as the variation between blood sampling results on the test day and the subsequent test. The variation data were categorized based on the difference in T-Bil: Low T-Bil group (≤2.25) and High T-Bil group (>2.25). RESULTS: The number of patients that underwent S-1 monotherapy was 883 and the running number was 7,511; Low T-Bil group included 7,245 and High T-Bil group included 266. Examination of the effect of the T-Bil Group on clinical outcomes revealed a correlation with red blood cell (RBC) count, platelet (PLT) count, and T-Bil level. When the impact of the interaction between the T-Bil Group and any of the clinical outcomes, such as the RBC count, PLT count, and T-Bil level, was determined, each outcome showed a significant decrease in the High T-Bil group compared with the Low T-Bil group. CONCLUSION: S-1 administration in patients with liver dysfunction accompanied by elevated T-Bil levels may cause thrombocytopenia.

Factors associated with early discontinuation of anamorelin in patients with cancer-associated cachexia.

PURPOSE: Cancer-associated cachexia, a multifactorial syndrome involving loss of muscle mass and anorexia, is an unremitting problem for cancer patients. Anamorelin has become available for cancer-associated cachexia, but early discontinuation is common in clinical practice. This study aimed to explore factors related to the early discontinuation of anamorelin and its relationship to survival. PATIENTS AND METHODS: This prospective, observational study of multimodal clinical practice involved patients who took anamorelin (100 mg) for cancer-associated cachexia at Aichi Medical University Hospital between 14 May 2021 and 31 March 2022. In July 2022, clinical data were extracted from electronic clinical records. Patients who discontinued anamorelin less than 4 weeks after initiation were defined as the early discontinuation group, and their clinical data and survival time were compared with those of the continuation group. This study was approved by the Ethics Committee of the university (approval no. 2021-124). RESULTS: Of the 42 patients treated with anamorelin, 40 (median age 72.5 years, median BMI 18.7 kg/m2) were analyzed, including 13 with non-small cell lung cancer, and 12 with pancreatic, 8 with colorectal, and 7 with gastric cancers. On univariate analysis, the early discontinuation group included more patients with worse performance status (PS) (p=0.028), low prognostic nutritional index (PNI) (p=0.001), and no concomitant anticancer drugs (p=0.003). On multivariate analysis, PS and PNI were related to anamorelin continuation. Survival time was significantly shorter in the early discontinuation group (p=0.039). CONCLUSION: Worse PS and low PNI were associated with early discontinuation of anamorelin. Longer survival time was observed in the continuation group.

[Predicting the Incidence of Venous Thromboembolism Using the Khorana Score: A Literature Review].

Venous thromboembolism (VTE) is the second most common cause of cancer-related deaths globally. The Khorana score, a VTE prediction model, is calculated using the site of cancer, white blood cell count, hemoglobin level, platelet count, and body mass index. This study aimed to investigate the usefulness of the Khorana score, using data available in the literature. On July 28, 2020, we collected papers using the following keywords: "cancer", "venous thromboembolism", "deep vein thrombosis", "pulmonary embolism", and "Khorana score" on PubMed. Papers published after 2016 were eligible. The selection criteria were as follows: "English or Japanese", "original paper", "abstract and full text", and "comply with the clinical question". There were 131 papers that matched the keywords, and 15 of them complied with the selection criteria. In 15 papers, Khorana score was calculated in 8047 patients. In the low- and intermediate-risk groups, 532 of 6812 patients developed VTE [7.8%, 95%confidence intervals (CI) 7.2-8.5], whereas in the high-risk group, 127 of 1235 patients developed VTE (10.3%, 95% CI 8.7-12.1) [odds ratio (OR) 1.3, 95% CI 1.0-1.6] (I2=0%, τ2=0, p=0.50). Venous thromboembolism prediction using the Khorana score might be useful. However, most of the number of VTE patients are in the low- and intermediate-risk groups. Therefore, a comprehensive evaluation according to clinical conditions is required, regardless of the risk classification using the Khorana score.

Effect of Obesity on Hematotoxicity Induced by Carboplatin and Paclitaxel Combination Therapy in Patients with Gynecological Cancer.

Despite in vivo studies suggesting that obesity increases carboplatin (CBDCA) bone marrow toxicity, the American Society of Clinical Oncology recommends that full weight-based cytotoxic chemotherapy doses be used to treat obese patients with cancer. Accordingly, the present study retrospectively investigated the effect of body mass index (BMI) on bone marrow toxicity in patients with gynecological cancer who underwent paclitaxel and carboplatin (TC) therapy after eliminating the effect of the target area under the curve (AUC). Risk factors for CBDCA bone marrow toxicity were also identified. A total of 110 patients with primary gynecological cancer or gynecological cancer of unknown primary origin who underwent TC therapy with a target AUC of 5-6 were included herein. Patients with a BMI of ≥25 and <25 kg/m2 were assigned to the obesity and control groups, respectively, and evaluated according to changes in hematological test values (platelet, white blood cell, and hemoglobin counts) starting from initial TC therapy administration until 21 d after the second treatment course. The obesity group had a significantly higher thrombocytopenia rate than the control group. Risk factors for thrombocytopenia ≥ grade 2 included BMI ≥25 kg/m2. Among patients with primary gynecological cancer or gynecological cancer of unknown primary origin who had a BMI of ≥25 kg/m2, those receiving CBDCA may be at increased risk for thrombocytopenia ≥ grade 2 when the dosage is calculated using the Calvert formula with the creatinine clearance level.

Risk factors for cancer-associated thrombosis in patients undergoing treatment with immune checkpoint inhibitors.

Purpose Anticancer agents are known to increase cancer-associated thrombosis (CAT) onset. CAT onset rate is reported to be 1.92% in cisplatin-based therapy, 6.1% in paclitaxel plus ramucirumab combination therapy, and 11.9% in bevacizumab monotherapy. Because immune checkpoint inhibitors (ICIs) cause a sudden increase in T cell number, an association between administration of these drugs and increase in CAT incidence is likely. However, the extent to which ICI administration affects CAT incidence remains unclear. Further, risk factors for CAT incidence have not yet been identified. The present study investigated CAT incidence and associated risk factors in patients receiving ICI. Methods Patients administered nivolumab or pembrolizumab at Fujita Health University Hospital from April 2017 to March 2018 were enrolled. We collected retrospective data regarding age, sex, cancer type, BMI, medical history, laboratory data at treatment initiation, medications, and computed tomography (CT) interpretations from electronic medical records. Results We identified 122 eligible participants from 135 patients receiving nivolumab or pembrolizumab. Ten patients (8.2%) developed CAT. A history of venous thromboembolism (VTE) or arterial thromboembolism (ATE) was a risk factor for CAT incidence (odds ratio: 6.36, P = 0.039). A history of heart disease may be a risk factor for CAT incidence (odds ratio 6.56, P = 0.052). Significantly higher usage of antiplatelet and anticoagulant therapy was noted in patients who developed CAT (60%) than in those who did not (13.4%, p < 0.01). Conclusion High (8.2%) CAT incidence during ICI administration suggested that ICI is not associated with a lower blood clot risk than other anticancer agents investigated in previous studies. For patients with VTE, ATE, or heart disease history, it is crucial to consider the possibility of CAT even with antiplatelet therapy.

Tradescantia pallida extract inhibits biofilm formation in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is capable of biofilm formation. In this study, we investigated the effects of aqueous Tradescantia pallida extract on Pseudomonas aeruginosa growth and biofilm formation. Aqueous Tradescantia pallida extracts significantly inhibited both bacterial growth and biofilm formation. However, methanolic Tradescantia pallida extracts inhibited neither. Aqueous Tradescantia pallida extracts were deactivated by heating but were not deactivated by light exposure. The ingredients retained the inhibitory effect on the bacterial growth and biofilm formation after ultrafiltration of aqueous Tradescantia pallida extract. Furthermore, polyphenol-rich Tradescantia pallida extracts inhibited bacterial growth, thus, polyphenols are possible to be an active ingredient. We observed the biofilm by scanning electron microscopy, and quantitative and qualitative differences in the biofilm and cells morphology. Interestingly, the biofilm treated aqueous Tradescantia pallida extracts remained premature. We postulated that premature biofilm formation was due to the inhibition of swarming motility. Indeed, aqueous Tradescantia pallida extracts inhibited swarming motility. These results demonstrate that Peudomonas aeruginosa growth and biofilm formation are inhibited by aqueous Tradescantia pallida extracts.

Oxidative DNA Damage and Apoptosis Induced by Aclarubicin, an Anthracycline: Role of Hydrogen Peroxide and Copper.

BACKGROUND/AIM: This study aimed to investigate aclarubicin (ACR)-induced oxidative DNA damage and apoptosis. MATERIALS AND METHODS: ACR-induced apoptosis was analyzed using HL-60 leukemia cells and HP100 cells, hydrogen peroxide (H2O2)-resistant cells derived from HL-60 cells. ACR-induced DNA damage was analyzed using plasmid DNA. RESULTS: HL-60 cells were more sensitive to ACR than HP100 cells. In HP100 cells, DNA ladder formation and caspase-3/7 activity induced by ACR were suppressed or delayed in comparison to those in HL-60 cells. ACR-induced DNA damage occurred in the presence of Cu(II), and scavenger experiments showed that the reactive species causing DNA damage appeared to be generated from H2O2 and Cu(I). Moreover, we detected intracellular Cu(I) induced by ACR in HL-60 cells, using CopperGREEN™, a fluorescent probe for detection of Cu(I) ion specifically. CONCLUSION: ACR-induced DNA damage and apoptosis can be accounted for by the involvement of H2O2 and Cu(I).

[A Survey of Health Food Use and Patient Satisfaction among Patients Undergoing Cancer Pharmacotherapy].

This study aimed to clarify the situation of use of health foods by patients and the level of satisfaction of patients in order to make use of information on cases where patients undergoing cancer medication therapy use health foods. Between May 7, 2018 and June 29, 2018, we conducted a questionnaire survey of patients with progressive cancer who were undergoing cancer chemotherapy at Ogaki Municipal Hospital. In addition, we conducted a multivariate analysis of patients who were using health foods and those who were not. The questionnaire items included the objectives of use, product effectiveness and satisfaction, and QOL. The rate of health food use was 81/281 (29.5%). The primary objectives of use were, "to maintain health" (29.8%) and "to alleviate symptoms" (24.0%). The primary sources of information about health foods were "a friend" (50.6%) and "TV" (13.5%). The satisfaction level was 0-3 points in 8.3% of patients, 4-6 points in 38.1% of patients, and 7-10 points in 53.6% of patients. For "stage of illness (recurrence)," the odds ratio was 1.810 (95% CI, 1.040-3.150; p=0.035), and for "QOL value," the odds ratio was 2.210 (95% CI, 1.220-4.020; p=0.009), indicating that these factors had a significant influence on health food use. Health foods tended to be used in patients who had recurring cancer with low QOL and various symptoms, and friends and other people close to the patient had a large influence on the patient's decision. It was clear that the patients' satisfaction level was high.

Repeat hepatectomy with systemic chemotherapy might improve survival of recurrent liver metastasis from colorectal cancer-a retrospective observational study.

BACKGROUND: Although hepatectomy for metastatic colorectal cancer (mCRC) prolongs survival in up to 40% of people, recurrence rates approach 70%. We used a multidisciplinary approach to treat recurrent liver metastases, including chemotherapy, surgery, and palliative care. On the other hand, development of chemotherapeutic agents is remarkable and improves long-term survival. However, whether chemotherapy and repeat hepatectomy combination therapy improve survival or not is still unclear. The aim of this study was to analyze the outcomes of repeat hepatectomy with systemic chemotherapy for mCRC. METHODS: Following Institutional Review Board approval, we reviewed the records of all patients who underwent hepatectomy for mCRC between 1974 and 2015 at Fujita Health University Hospital. We used the Kaplan-Meier method to estimate overall survival from the first and last hepatectomy in multi hepatectomy cases after 2005 and compared outcomes between groups using the log-rank test. RESULTS: A total of 426 liver resections were performed for mCRC; of these, 236 cases were performed after 2005 (late group). In 118 (50%) cases, the site of recurrence was the liver, 59 (50%) underwent repeat hepatectomy, and 14 cases had ≥ 2 repeat hepatectomies. Overall survival (OS) before and after 2005 was 42.2 and 64.1 months, respectively, with the late group having better OS compared to the early (1974-2004) group. OS for single hepatectomy cases was 83.2 months, for two hepatectomies was 42.9 months, and for three hepatectomies was 35.3 months. In total, 59 patients did not undergo surgery after recurrence with an OS of 28.7 months. Mortality of the second and third repeat hepatectomy was 1.7% and 15.3%, respectively. CONCLUSION: Repeat hepatectomy with systemic chemotherapy for mCRC is feasible and might achieve improved survival in carefully selected patients.

Cost-effectiveness of aprepitant in Japanese patients treated with cisplatin-containing highly emetogenic chemotherapy.

Chemotherapy-induced nausea and vomiting (CINV) remains a major adverse event in cancer chemotherapy. Although aprepitant is effective in preventing CINV, an increment in financial burden for uniform use of aprepitant is a concern. The aim of the present study was to define the cost-effectiveness of aprepitant from the perspective of the Japanese National Health Insurance system. Based on the results of a randomized phase II trial comparing an aprepitant-containing regimen versus a nonaprepitant regimen in Japanese patients who received cisplatin-containing highly emetogenic chemotherapy, a decision analytic model was developed. The incremental cost-effectiveness ratio (ICER) was calculated both in the outpatient care setting (OCS) and in the inpatient care setting (ICS). The use of the aprepitant-containing regimen was associated with improved quality of life compared with the nonaprepitant regimen, with an increment in quality-adjusted life years (QALY) of 0.0016. The incremental total medical costs associated with the use of the aprepitant regimen were lower in the OCS than in the ICS, 6192 JPY (56.92 USD) and 9820 JPY (90.27 USD), respectively. The ICER was calculated as 3 906 698 JPY (35 910 USD) per QALY gained in the OCS and 6 195 781 JPY (56 952 USD) per QALY gained in the ICS. Cost-effectiveness of the aprepitant-containing antiemetic therapy was limited to the OCS, considering the threshold of willingness-to-pay commonly accepted (5 million JPY [45 960 USD] in Japan and 50 000 USD in the USA). The efficacy of aprepitant offsets the costs for revisiting clinics or rehospitalization added with rescue medications in the OCS.

Oxidative DNA Damage Induced by Pirarubicin, an Anthracycline Anticancer Agent, in the Presence of Copper(II).

BACKGROUND/AIM: One mechanism of the anticancer action of anthracyclines is believed to be oxidative DNA damage. Previously, we reported that doxorubicin induced oxidative DNA damage in the presence of Cu(II). However, the mechanism of pirarubicin-induced oxidative DNA damage has not been well clarified. MATERIALS AND METHODS: DNA damage by pirarubicin in the presence of Cu(II) was analyzed using pBR322 plasmid DNA. O2•- derived from pirarubicin in the presence of Cu(II) was detected by cytochrome c reduction. RESULTS: Pirarubicin induced DNA damage in the presence of Cu(II). Scavenger experiments suggest that reactive species are generated from H2O2 and Cu(I). Pirarubicin induced O2•- production in the presence of Cu(II). CONCLUSION: These findings suggest that pirarubicin plus Cu(II) induces oxidative DNA damage in a similar manner to doxorubicin, and Cu(II)-mediated oxidative DNA damage may serve as a common mechanism for antitumor effects of anthracyclines.

Pirarubicin, an Anthracycline Anticancer Agent, Induces Apoptosis Through Generation of Hydrogen Peroxide.

BACKGROUND/AIM: Pirarubicin (THP) has shown equal or superior cytotoxicity compared to doxorubicin. One of the main anticancer actions of doxorubicin is believed to be involved in ROS (reactive oxygen species) generation. Therefore, the anticancer mechanisms of THP may involve ROS generation. The aim of this study was to clarify the mechanisms of THP-induced apoptosis through ROS generation. MATERIALS AND METHODS: We analyzed the apoptotic events induced by THP in HL-60 cells and HP100 cells, hydrogen peroxide (H2O2)-resistant cells derived from HL-60. RESULTS: The apparent cytotoxicity could be detected at above 0.1 µM in HL-60 cells after 24-h incubation, whereas it was suppressed under these conditions in HP100 cells. In HP100 cells, THP-induced apoptosis, evaluated by DNA ladder formation, H2O2 generation, mitochondrial membrane potential decrease and caspase-3/7 activity, was suppressed or delayed compared to those of HL-60 cells. CONCLUSION: These findings can be explained by the involvement of H2O2 generation in the THP apoptotic pathway. This is the first report on THP-induced apoptosis through the H2O2 generation.

Comparison between hypersensitivity reactions to cycles of modified FOLFOX6 and XELOX therapies in patients with colorectal cancer.

PURPOSE: Although hypersensitivity reactions (HSRs) to oxaliplatin (L-OHP) therapy are well-documented, few reports have compared different therapies in terms of HSR occurrence. In this study, we compared the frequency and pattern of HSRs to modified FOLFOX6 (mFOLFOX6; 5-fluorouracil, levofolinate calcium and L-OHP infusions) and XELOX (capecitabine and L-OHP) therapies, and sought to identify risk factors associated with HSRs. METHODS: Patients who had received mFOLFOX6 or XELOX chemotherapeutic regimens for unresectable colon or rectal cancer or as adjuvant chemotherapy following colon cancer surgery between April 2012 and August 2015 were included. Potential correlation between treatment modalities (regimen, dosage and route of administration of L-OHP, and injection timing for dexamethasone administration) and HSRs was assessed. RESULTS: Among the 240 patients included in the study, 136 had received mFOLFOX6 therapy and 104 had received XELOX therapy. Although the frequency of HSRs did not differ between the two groups, incidence of HSRs in the first cycle was higher in the XELOX therapy group. Treatment method or cumulative dosage was not identified as a risk factor for HSR; however, the incidence of ≥grade-2 HSR was higher in cases where the cumulative L-OHP dosage was ≥600 mg/m2 and in patients in whom dexamethasone was not co-infused with L-OHP. CONCLUSION: Although HSR rates were comparable among patients treated with mFOLFOX6 and XELOX, HSRs tended to occur more frequently during the first cycle of XELOX therapy as compared to that with mFOLFOX6 therapy. Our findings warrant careful assessment of ≥grade-2 HSRs in patients who are prescribed cumulative L-OHP dosages of ≥600 mg/m2.

Effect of renal function on pemetrexed-induced haematotoxicity.

PURPOSE: Pemetrexed (PEM) is an anticancer agent used for the treatment of non-small cell lung cancer, malignant pleural mesothelioma and thymoma. Reportedly, PEM has higher efficacy and safety when used in combination with platinum-based agents. However, there are only few reports on the safety of PEM in patients with an eGFR of ≤45 mL/min. We examined the effect of renal function on the safety of regimens containing PEM. METHODS: We retrospectively reviewed 221 patients with lung cancer, malignant pleural mesothelioma or thymoma who received treatment with a PEM-containing regimen between 2009 and 2014. Subgroup analyses were performed on the basis of pre-treatment renal function: group A [creatinine clearance (CLcr), <45 mL/min]; group B (CLcr, 45-80 mL/min); and group C (CLcr, ≥80 mL/min). For the purpose of this analysis, the lowest documented blood cell counts and haemoglobin levels, the highest levels of serum creatinine, aspartate aminotransferase, alanine aminotransferase and CLcr from the time of initial administration up to prior to the start of second administration were considered. RESULTS: Groups A, B and C had 8, 123 and 90 patients, respectively. The incidence of grade 2 thrombocytopaenia was significantly higher in group A as compared to that in groups B (P < 0.01) and C (P < 0.05). On multivariate analysis, only a CLcr of <45 mL/min was an independent risk factor for thrombocytopaenia of ≥grade 2. CONCLUSION: When administering a PEM-containing regimen, thrombocytopaenia of ≥grade 2 is more likely to develop in patients with a CLcr of <45 mL/min.

[A case of rectal gastrointestinal stromal tumor in an elderly patient who was successfully treated with imatinib mesylate with no significant adverse events].

An 89-year-old male patient was found to have a mass with a diameter of 54 mm in the pelvic cavity, connected to the rectum, and was diagnosed with a gastrointestinal stromal tumor (GIST)of the rectum by transrectal biopsy. The patient was treated continuously with 400mg/day of imatinib mesylate with no significant adverse events, and the tumor gradually reduced in size. The tumor reduced in size to a diameter of 24 mm at 57 months post-treatment, and a partial response has been maintained for 60 months. Colorectal GIST is rare, comprising 5% of all GIST cases, and surgical resection is the first choice of treatment. In this case, due to a lack of consent, we chose imatinib mesylate as the treatment. However, imatinib mesylate has been reported to induce adverse events more frequently in older patients, and thus we took care to reduce the treatment dosage. We report this case to highlight that a normal quantity of imatinib mesylate can be administered, with no significant adverse events.

[A project of the 6th chapter of the Oncology Research Group, Aichi Prefectural Society of Hospital Pharmacists: an attempt to make a pamphlet for patients undergoing LEED therapy, based on analysis of complications].

To date, medical guidance for patients undergoing cancer chemotherapy has mainly been with regard to individual medicines. Only a few reports have been available dealing with information on side effects by a regimen unit. Therefore, we accumulated information on side effects and made a pamphlet for patients with malignant lymphoma undergoing peripheral blood stem cell transplantation after Melphalan (L-PAM), Cyclophosphamide (Endoxan), VP-16 (etoposide) and Dexamethasone (LEED)therapy, for the purpose of explanation for patients on pharmacist's rounds. This pamphlet consists of time schedule of anticancer therapy, harmful phenomena due to cancer chemotherapy and counterplans for such side effects. Easy-to-understand graphics are used to explain the appearance and duration of side effects by anticancer agents. This pamphlet will serve to improve comprehension and the attitude of patients toward cancer chemotherapy. The pamphlets will also be a useful tool to reassure patients on pharmacist's rounds.