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Optimization of G-CSF dosing schedule in patients treated with eribulin: a modeling approach.
Reda, M, Macaire, P, Bellio, H, Uwer, L, Ilie, S, Lorgis, V, Hennequin, A, Ladoire, S, Rederstorff, E, Fumoleau, P, et al
Cancer chemotherapy and pharmacology. 2022;(2):197-208
Abstract
BACKGROUND Granulocyte colony-stimulating factors (G-CSF) are commonly given to limit chemotherapy-induced neutropenia, but, in case of weekly chemotherapy such as eribulin, their administration schedules remain empirical. OBJECTIVES This pharmacokinetic/pharmacodynamic (PK/PD) study was conducted to establish the effect of different G-CSF regimens on neutropenia's incidence for patients treated by eribulin, to propose an optimal G-CSF dosing schedule. METHODS A population PK/PD model was developed to describe absolute neutrophil counts' (ANC) time course in 87 cancer patients receiving eribulin. The structural model considered ANC dynamics, neutropenic effect of eribulin and stimulating effect of G-CSF. Final model estimates were used to calculate neutropenia's incidence following different G-CSF dosing schedules for 1000 virtual subjects. RESULTS The final model successfully described most of the ANC time course for all patients. Simulations showed that a single G-CSF administration 48 h after each eribulin injection reduced the risk of severe neutropenia from 29.7 to 5.2%. Five days of G-CSF only after the second eribulin injection or no G-CSF administration induces similar incidence of neutropenia. CONCLUSION Simulations showed a single G-CSF administration 48 h after the end of each eribulin injection seems to be the optimal schedule to reduce eribulin-induced neutropenia. However, the new administration scheme should be tested in real life to evaluate its pertinence. TRIAL REGISTRATION Eudract 2015-001753-32, 2015/01/26.
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Feasibility of pharmacometabolomics to identify potential predictors of paclitaxel pharmacokinetic variability.
Chen, L, Chen, CS, Sun, Y, Henry, NL, Stringer, KA, Hertz, DL
Cancer chemotherapy and pharmacology. 2021;(3):475-483
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Abstract
PURPOSE Paclitaxel is a commonly used chemotherapy drug with substantial variability in pharmacokinetics (PK) that affects treatment efficacy and toxicity. Pharmacometabolomic signatures that explain PK variability could be used to individualize dosing to improve therapeutic outcomes. The objective of this study was to identify pretreatment metabolites or metabolomic signatures that explain variability in paclitaxel PK. METHODS This analysis was conducted using data previously collected on a prospective observational study of 48 patients with breast cancer receiving weekly 80 mg/m2 paclitaxel infusions. Paclitaxel plasma concentrations were measured during the first infusion to estimate paclitaxel time above threshold (Tc>0.05) and maximum concentration (Cmax). Metabolites measured in pretreatment whole blood by nuclear magnetic resonance spectrometry were analyzed for an association with Tc>0.05 and Cmax using Pearson correlation followed by stepwise linear regression. RESULTS Pretreatment creatinine, glucose, and lysine concentrations were positively correlated with Tc>0.05, while pretreatment betaine was negatively correlated and lactate was positively correlated with Cmax (all uncorrected p < 0.05). After stepwise elimination, creatinine was associated with Tc>0.05, while betaine and lactate were associated with Cmax (all p < 0.05). CONCLUSION This study identified pretreatment metabolites that may be associated with paclitaxel PK variability demonstrating feasibility of a pharmacometabolomics approach for understanding paclitaxel PK. However, identification of more robust pharmacometabolomic predictors will be required for broad and routine application for the clinical dosing of paclitaxel.
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A preliminary study on the association of tamoxifen, endoxifen, and 4-hydroxytamoxifen with blood lipids in patients with breast cancer.
Siqueira, MLS, Andrade, SMV, Vieira, JLF, Monteiro, MC
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;:111972
Abstract
The long-term treatment with tamoxifen can alter the lipid profile of patients with breast cancer. Only a few studies associated the plasma concentrations of tamoxifen, endoxifen, and 4-hydroxytamoxifen with blood lipids, which is relevant as the distribution of these compounds for the tissues can be changed, negatively affecting the treatment. The variations in lipids also can account for the high interindividual variation in plasma concentrations of these compounds. The aim of this preliminary study was to associate the plasma levels of tamoxifen and the active metabolites with the lipid levels. An observational study of cases was conducted in patients with breast cancer using tamoxifen in a daily dose of 20 mg. The lipids were measured by spectrophotometric methods and the plasma concentrations of tamoxifen, endoxifen, and 4-hydroxytamoxifen by high-performance liquid chromatography. A total of 20 patients were included in the study. The median plasma concentrations of tamoxifen, 4-hydroxytamoxifen and endoxifen were 62 ng/mL, 1.04 ng/mL and 8.79 ng/mL. Triglycerides levels ranged from 59 to 352 mg/dL, total cholesterol from 157 to 321 mg/dL, LDL-c from 72 mg/dL to 176 mg/dL and HDL-C from 25.1 mg/dL to 62.8 mg/dL. There were no significant associations between the plasma concentrations of tamoxifen, 4-hydroxytamoxifen, and endoxifen with the levels of triglycerides and total cholesterol. The multivariate analysis revealed a weak association between plasma concentrations of tamoxifen and the active metabolites with HDL-c, LDL-c and VLDL-c. This finding provides preliminary evidence of the low impact of lipoproteins levels in the exposure to tamoxifen, 4-hydroxytamoxifen and endoxifen.
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Carbohydrate antigen 125, carbohydrate antigen 15-3 and low-density lipoprotein as risk factors for intraocular metastases in postmenopausal breast cancer.
Tang, J, Yan, B, Li, GF, Li, QY, Liu, WF, Liang, RB, Ge, QM, Shao, Y
Medicine. 2021;(43):e27693
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Abstract
The prognosis of patients with postmenopausal breast cancer (PBC) could be improved by the early detection of intraocular metastases (IOMs). However, serum biomarkers for IOMs in PBC remain elusive. In the current study, we investigated patients with PBC, and compared serum parameters in an IOM and a non-IOM group, and then differentiated the risk factors related to IOMs. A comparison between an IOM and a non-IOM (NIOM) group was performed using Student t-test and a Chi-Squared test. After constructing a Poisson regression model to identify risk factors, we plotted receiver operating characteristic curves to evaluate the predictive value of significant risk factors in detecting IOMs. The incidence of IOMs in PBC was 1.16%. The histopathology results were not significantly different between the 2 groups. The levels of serum carbohydrate antigen 125 (CA-125), carbohydrate antigen 15-3 (CA15-3) and alkaline phosphatase were significantly elevated in IOMs compared with NIOMs (P = .082, P < .001, and P < .001, respectively). Compared with NIOMs, age, carbohydrate antigen 19 to 9, hemoglobin, calcium, total cholesterol, low-density lipoprotein (LDL) and apolipoprotein A1 were remarkably lower in IOMs (P = .038, P < .001, P < .001, P = .032, P = .041, P < .001, and P = .001, respectively). Poisson regression suggested that CA-125, CA15-3 and LDL were contributing to IOMs in PBC as risk factors (OR = 1.003, 95% CI: 1.001-1.005; OR = 1.025, 95% CI: 1.019-1.033; OR = 0.238, 95% CI: 0.112-0.505, respectively). A receiver operating characteristic curve revealed that the cut-off values for CA-125, CA15-3 and LDL were 16.78 0 U/mL, 63.175 U/mL, and 2.415 mmol/L, respectively. The combination of CA-125 and CA15-3 showed significant diagnostic value (area under the curve [AUC] = 0.982, P < .001). Our investigation suggests that CA-125, CA15-3 and LDL remarkably predict IOMs in PBC as risk factors, and the combination of CA-125 and CA15-3 shows considerable diagnostic value.
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Omega 6 polyunsaturated fatty acids in red blood cell membrane are associated with xerostomia and taste loss in patients with breast cancer.
Amézaga, J, Ugartemendia, G, Larraioz, A, Bretaña, N, Iruretagoyena, A, Camba, J, Urruticoechea, A, Ferreri, C, Tueros, I
Prostaglandins, leukotrienes, and essential fatty acids. 2021;:102336
Abstract
Chemosensory and physical complaints are common disorders in cancer patients under chemotherapy treatments that may affect the food intake, leading to a decreased quality of life. Lipid metabolism is a major pathway of cancer proliferation, where erythrocyte membrane phospholipids and their fatty acid composition are promising tools for monitoring metabolic pathways. Relationship between lipid profile in erythrocyte membrane phospholipids and chemosensory alterations in 44 newly diagnosed patients with breast cancer was here investigated. Smell changes and xerostomia were the most common complaints, with xerostomia as the main influencing factor on the development of other taste disorders. Lipid profiles revealed significant negative correlation between diminution of linoleic acid levels and xerostomia as well as positive correlation between increased arachidonic acid and salty taste. The involvement of these polyunsaturated lipids suggests the importance of oxidative and nutritional conditions of cancer patients, which can affect the molecular status for taste signals.
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Effectiveness of Combined Treatment with Traditional Chinese Medicine and Western Medicine on the Prognosis of Patients with Breast Cancer.
Lee, YC, Chen, YH, Huang, YC, Lee, YF, Tsai, MY
Journal of alternative and complementary medicine (New York, N.Y.). 2020;(9):833-840
Abstract
Objective: Traditional Chinese Medicine (TCM) can be used to balance the body's immunity and tumor development during different stages of cancer treatment. Recently, TCM has been an important part of the health care system for breast cancer in Taiwan. This study was conducted as a prospective observation of the prognosis of Western medicine and combined treatment of TCM and Western medicine. Methods: Between April 2014 and March 2015, eligible participants were treated with Western medicine (n = 16) or TCM plus Western medicine (n = 29). The TCM treatment for patients followed the principles of a breast cancer protocol that had been developed in the Integrative Cancer Center. The outcome measures included quality of life, frequency of symptom distress, and clinical safety, and were measured with the Functional Assessment of Cancer Therapy-General (FACT-G), the Common Terminology Criteria for Adverse Events (CTCAE) Scale, and laboratory examinations, respectively. Data on these measures were collected at baseline and at 3 months after treatment initiation. Survival was estimated by Kaplan-Meier curves. Results: The two treatment groups did not differ significantly at baseline in terms of demographic information, FACT-G score, or frequency of symptom distress, except for fatigue, sleep disturbance, and mucositis. Most laboratory examinations did not differ significantly between the two groups, but higher red blood cell counts and lower liver function were found with the combined treatment than with Western medicine alone (p < 0.05). The mean overall survival rates were 25.5 months for the combined group and 22.7 months for the Western medicine group (p = 0.037). Conclusion: The results of this study suggest that combining Western and TCM therapy may have a favorable effect on the prognosis of breast cancer patients. Chinese herbal medicine is worth studying in a future larger cohort with a control group. It also warrants verification as a preventive intervention.
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Association Between Physical Activity and Use of Complementary Medicine by Female Oncology Patients in an Integrative Palliative Care Setting.
Gressel Raz, O, Samuels, N, Levy, M, Leviov, M, Lavie, O, Ben-Arye, E
Journal of alternative and complementary medicine (New York, N.Y.). 2020;(8):721-728
Abstract
Objective: To examine the association between physical activity and the reported use of complementary medicine by patients with breast and gynecological cancer referred or self-referred to a complementary/integrative medicine (CIM) consultation within a palliative care context. Methods: Retrospective observational study analyzing the medical files of patients referred to a CIM consultation provided within a specialized integrative oncology clinic for demographic and cancer-related parameters; participation in physical exercise and activities; and current use of nonconventional medical practices. Quality of life (QoL) outcomes were assessed during the initial CIM consultation by using the Edmonton Symptom Assessment Scale (ESAS) tool. Results: Among the 162 patient files examined, participation in physical activities was reported in 152, of whom 83 were identified as active and 69 inactive according to the American Cancer Society guidelines. A logistic multivariate regression model showed that physical activity was associated with higher rates of herbal/dietary supplement use for noncancer-related outcomes (odds ratio = 7.21, 95% confidence interval [CI] 1.6-32.46, p = 0.01); more frequently reported use of acupuncture for cancer-related outcomes (odds ratio = 7.79, 95% CI 1.93-31.5, p = 0.004); and lower ESAS scores for well-being (odds ratio = 0.77, 95% CI 1.0.65-0.92, p = 0.004), indicating better QoL. Conclusion: Physical activity was found to be associated with a greater use of CIM (specifically herbal/dietary supplement use and acupuncture) in patients with breast and gynecological cancer during oncology treatment. Further research is needed to explore whether CIM use and physical activity are influenced by patients' health-belief models of care, and whether the CIM consultation can promote physical activity among these patients.
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Chemotherapy-induced peripheral neuropathy in breast cancer patients treated with eribulin: interim data from a post-marketing observational study.
Tsurutani, J, Sakata, Y, Matsuoka, T
Breast cancer (Tokyo, Japan). 2019;(2):235-243
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Abstract
BACKGROUND Few studies have examined chemotherapy-induced peripheral neuropathy (CIPN) following the administration of eribulin as first- or second-line therapy in patients with breast cancer. We therefore assessed CIPN incidence by severity and risk factors for CIPN in patients treated with eribulin for HER2-negative inoperable or recurrent breast cancer, regardless of line therapy status. METHODS This multicenter, prospective, post-marketing observational study enrolled patients from September 2014 in Japan and followed them for 2 years. For this interim analysis, the data cut-off point was in November 2017. CIPN severity was assessed based on the Japanese version of the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS Among 634 patients included in the safety analysis, 374 patients did not have existing CIPN at baseline. CIPN was observed in 105 patients (28.1%), including 67 (17.9%), 34 (9.1%), and 4 (1.1%) patients with grade 1, 2, and 3 severity, respectively. Of the 105 patients, 85.7% patients continued, 7.6% reduced, interrupted or postponed, and 6.7% discontinued eribulin. The median time (min‒max) from baseline to CIPN onset was 60 (3‒337) days. Multivariate logistic regression identified a significant association between CIPN and hemoglobin level at baseline, starting dose of eribulin, and history of radiotherapy. CONCLUSIONS Our findings indicate that, with respect to CIPN, eribulin is well-tolerated, as approximately one-quarter of patients developed CIPN, most cases were grade 1 or 2, and the majority of patients continued eribulin after CIPN onset.
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Assessment of left ventricular function by CMR versus MUGA scans in breast cancer patients receiving trastuzumab: a prospective observational study.
Dhir, V, Yan, AT, Nisenbaum, R, Sloninko, J, Connelly, KA, Barfett, J, Haq, R, Kirpalani, A, Chan, KKW, Petrella, TM, et al
The international journal of cardiovascular imaging. 2019;(11):2085-2093
Abstract
Little is known about the comparison of multiple-gated acquisition (MUGA) scanning with cardiovascular magnetic resonance (CMR) for serial monitoring of HER2+ breast cancer patients receiving trastuzumab. The association of cardiac biomarkers with CMR left ventricular (LV) function and volume is also not well studied. Our objectives were to compare CMR and MUGA for left ventricular ejection fraction (LVEF) assessment, and to examine the association between changes in brain natriuretic peptide (NT-BNP) and troponin-I and changes in CMR LV function and volume. This prospective longitudinal two-centre cohort study recruited HER2+ breast cancer patients between January 2010 and December 2013. MUGA, CMR, NT-BNP and troponin-I were performed at baseline, 6, 12, and 18 months after trastuzumab initiation. In total, 41 patients (age 51.7 ± 10.8 years) were enrolled. LVEF comparison between MUGA and CMR demonstrated weak agreement (Lin's correlation coefficient r = 0.46, baseline; r = 0.29, 6 months; r = 0.42, 12 months; r = 0.39, 18 months; all p < 0.05). Bland-Altman plots demonstrated wide LVEF agreement limits (pooled agreement limits 3.0 ± 6.2). Both modalities demonstrated significant LVEF decline at 6 and 12 months from baseline, concomitant with increased LV volumes on CMR. Changes in NT-BNP correlated with changes in LV diastolic volume at 12 and 18 months (p < 0.05), and LV systolic volume at 18 months (p < 0.05). Changes in troponin-I did not correlate with changes in LV function or volume at any timepoint. In conclusion, CMR and MUGA LVEF are not interchangeable, warranting selection and utility of one modality for serial monitoring. CMR is useful due to less radiation exposure and accuracy of LV volume measurements. Changes in NT-BNP correlated with changes in LV volumes.
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Feasibility of Eribulin Mesylate in older patients with locally advanced or metastatic breast cancer: A post-hoc analysis of the ESEMPiO study.
Barni, S, Livraghi, L, Gravina, A, Martella, F, D'Onofrio, L, Morritti, M, Michelotti, A, Vici, P, Mentuccia, L, Porcu, L, et al
Journal of geriatric oncology. 2019;(6):990-993