Lipegfilgrastim for prophylaxis of chemotherapy-induced neutropenia in Dutch patients.

BACKGROUND: Chemotherapy (CT)-induced neutropenia and febrile neutropenia (FN) can lead to changes in the treatment plan, potentially worsening the cancer outcome. This study evaluated the effect of the glycopegylated granulocyte-colony stimulating factor lipegfilgrastim, used as primary (PP) or secondary prophylaxis (SP), on treatment modifications in adult patients receiving cytotoxic CT with or without biological/targeted therapy (BT) for solid and haematological tumours. METHODS: This phase 4, prospective, observational study was conducted in eight centres in the Netherlands, in 2015-2017. Other study objectives were to characterise the population of cancer patients receiving lipegfilgrastim, to evaluate the incidence of CT-induced neutropenic events, and to assess safety. RESULTS: Of 142 patients, 73.94% had breast cancer and 55.63% received CT in the adjuvant setting. Most patients received lipegfilgrastim as PP (74.65%) and were at low (34.51%) or high risk (39.44%) of FN. CT dose delays were recorded for 22.64% and 36.11% of patients receiving lipegfilgrastim for PP and SP, respectively. CT dose reductions were recorded for 2.11% of patients; no CT dose omissions and one BT dose omission occurred. FN and grade III/IV neutropenia were reported for 5.63% and 9.86% of patients, respectively; associated hospitalisations were rare. The most frequently lipegfilgrastimrelated adverse events (AE) were myalgia, bone pain, and back pain. Serious AEs (55) were reported for 30 (21.13%) patients. There were two deaths, unrelated to lipegfilgrastim administration. CONCLUSION: Administration of lipegfilgrastim in routine clinical practice in the Netherlands results in limited CT/BT dose modifications and low incidence of neutropenic events, with no new safety concerns.

Preparation and preservation of viable Akkermansia muciniphila cells for therapeutic interventions.

The anaerobic gut bacterium Akkermansia muciniphila is a well-characterised member of the mucosal microbiota and has shown to be a gut symbiont in human. A. muciniphila has been negatively associated with obesity and its associated metabolic disorders in various human cohorts while treatment with A. muciniphila cells reversed highfat diet-induced obesity and its associated metabolic disorders in mouse models. Therefore, administration of A. muciniphila has been suggested as a possible new therapeutic treatment for these omnipresent diseases. Here we describe a potentially scalable workflow for the preparation and preservation of high numbers of viable cells of A. muciniphila obtained from 1 l laboratory scale growth under strict anaerobic conditions for therapeutic interventions. This resulted in viable A. muciniphila cells with high yields and very high stability, with up to 97.9±4.5% survival for a time period of 1 year at -80 °C in glycerol-amended medium. Moreover, various quality assessment and control procedures were developed to ensure the use of viable cells of A. muciniphila. Several microscopic, culturing, and molecular approaches were applied to monitor the presence, abundance and recovery of A. muciniphila before, during, and after its administration to high-fat treated mice. We show that viable A. muciniphila cells can be recovered from caecal and colon content (up to 1×1010 cells/g), testifying for the efficiency of the described workflow.

Recommendations on management of EGFR inhibitor-induced skin toxicity: a systematic review.

Epidermal growth factor receptor (EGFR) inhibitors, such as the monoclonal antibodies cetuximab and panitumumab, have proven efficacy in various types of cancer. However, these agents frequently result in skin toxicity, due to the expression of the EGFR in the skin. A correlation between the occurrence of skin toxicity and anti-tumor activity has been suggested in several phase III studies. However, since skin toxicity may impair the quality of life, and severe skin toxicity requires dose reduction or interruption, adequate and timely management of skin toxicity is important to maximize the anti-tumor efficacy of the EGFR inhibitor, as well as maintaining the patient's quality of life. Due to the small number of randomized controlled trials conducted in the field of EGFR inhibitor-induced skin toxicity so far, it is not possible yet to generate evidence based guidelines on its management. Here, we review and discuss available trials and case studies reporting on the management of EGFR inhibitor-induced skin toxicity.

Classification and management of skin, hair, nail and mucosal side-effects of epidermal growth factor receptor (EGFR) inhibitors.

Inhibitors of epidermal growth factor receptor (EGFR) are commonly used as therapeutic agents in oncology. In contrast to currently used oncological treatments, these inhibitors almost always cause skin- and skin adnex toxicity. About 85% of treated patients develop to a more or lesser extent an acneiform eruption. Xerosis cutis and painful nail disorders occur in, respectively, 35% and 10-15% of all treated patients. Also hair and mucosal changes have been reported, although to a lesser extent. These skin- and skin adnex toxicities are reversible after withdrawal of treatment, but are seldom a reason to stop or interrupt therapy. This review outlines the classification, the pathogenesis and therapy of these skin, hair, nail and mucosal changes due to EGFR inhibition. Informing the patient and management of these side-effects is very important to reduce discomfort and as such to increase compliance to therapy.

Risk factors for catheter-related thrombosis in cancer patients.

We investigated the risk factors for venous thrombosis in cancer patients with implantable ports undergoing chemotherapy. One hundred and seventy one ports were placed in a central ("chest ports") and 84 in a peripheral vein ("arm ports"), 181 received prophylactic nadroparin and 10 coumarin. Clinically overt thrombosis was confirmed by ultrasound or angiography. Catheter-related thrombosis incidence without anticoagulants was 28% in arm and 33% in chest ports, but with anticoagulants this was 32% in arm and only 1% in chest ports (odds ratio (OR) 34.8 95% confidence interval (CI) 7.3-165). Left-sided placement compared with right-sided and catheter tip position in the superior vena cava compared with right atrium were associated with a 3.5 respectively 2.6-fold increased risk. Thrombosis was associated with elevated homocysteine levels (OR=3.8, 95% CI 1.3-11.3), but not with factor V Leiden or prothrombin 20210A gene mutations, or high concentration of factor VIII, IX or XI. Prophylaxis with anticoagulants is recommended for chest, but not for arm ports. Determination of plasma homocysteine levels may identify patients at an increased risk for thrombosis.

Distribution of ifosfamide and metabolites between plasma and erythrocytes.

The distribution of ifosfamide (IF) and its metabolites 2-dechloroethylifosfamide (2DCE), 3-dechloroethylifosfamide (3DCE), 4-hydroxyifosfamide (4OHIF) and ifosforamide mustard (IFM) between plasma and erythrocytes was examined in vitro and in vivo. In vitro distribution was investigated by incubating blood with various concentrations of IF and its metabolites. In vivo distribution of IF, 2DCE, 3DCE and 4OHIF was determined in 7 patients receiving 9 g/m(2)/72 h intravenous continuous IF infusion. In vitro distribution equilibrium between erythrocytes and plasma was obtained quickly after drug addition. Mean (+/-sem) in vitro and in vivo erythrocyte (e)-plasma (p) partition coefficients (P(e/p)) were 0.75+/-0.01 and 0.81+/-0.03, 0.62+/-0.09 and 0.73+/-0.05, 0.76+/-0.10 and 0.93+/-0.05 and 1.38+/-0.04 and 0.98+/-0.09 for IF, 2DCE, 3DCE and 4OHIF, respectively. These ratios were independent of concentration and unaltered with time. The ratios of the area under the erythrocyte and plasma concentration--time curves (AUC(e/p)) were 0.96+/-0.03, 0.87+/-0.07, 0.98+/-0.06 and 1.34+/-0.39, respectively. A time- and concentration-dependent distribution--equilibrium phenomenon was observed with the relative hydrophilic IFM. It is concluded that IF and metabolites rapidly reach distribution equilibrium between erythrocytes and plasma; the process is slower for IFM. Drug distribution to the erythrocyte fraction ranged from about 38% for 2DCE to 58% for 4OHIF, and was stable over a wide range of clinically relevant concentrations. A strong parallelism in the erythrocyte and plasma concentration profiles was observed for all compounds. Thus, pharmacokinetic assessment using only plasma sampling yields direct and accurate insights into the whole blood kinetics of IF and metabolites and may be used for pharmacokinetic-pharmacodynamic studies.

Population pharmacokinetics and exploratory pharmacodynamics of ifosfamide and metabolites after a 72-h continuous infusion in patients with soft tissue sarcoma.

OBJECTIVE: The population pharmacokinetics and pharmacodynamics of the cytostatic agent ifosfamide and its main metabolites 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide were assessed in patients with soft tissue sarcoma. METHODS: Twenty patients received 9 or 12 g/m2 ifosfamide administered as a 72-h continuous intravenous infusion. The population pharmacokinetic model was built in a sequential manner, starting with a covariate-free model and progressing to a covariate model with the aid of generalised additive modelling. RESULTS: The addition of the covariates weight, body surface area, albumin, serum creatinine, serum urea, alkaline phosphatase and lactate dehydrogenase improved the prediction errors of the model. Typical pretreatment (mean +/- SEM) initial clearance of ifosfamide was 3.03 +/- 0.18 l/h with a volume of distribution of 44.0 +/- 1.8 l. Autoinduction, dependent on ifosfamide levels, was characterised by an induction half-life of 11.5 +/- 1.0 h with 50% maximum induction at 33.0 +/- 3.6 microM ifosfamide. Significant pharmacokinetic-pharmacodynamic relationships (P = 0.019) were observed between the exposure to 2- and 3-dechloroethylifosfamide and orientational disorder, a neurotoxic side-effect. No pharmacokinetic-pharmacodynamic relationships between exposure to 4-hydroxyifosfamide and haematological toxicities could be observed in this population.

Evaluation of the autoinduction of ifosfamide metabolism by a population pharmacokinetic approach using NONMEM.

AIMS: This study investigated the population pharmacokinetics of ifosfamide in 15 patients treated for soft tissue sarcoma with 9 or 12 g m-2 ifosfamide by means of a 72 h continuous i.v. infusion. METHODS: A model was developed using nonlinear mixed effects modelling (NONMEM) to describe the nonlinear pharmacokinetics of ifosfamide by linking the ifosfamide plasma concentrations to the extent of the autoinduction. RESULTS: The proposed model revealed the effect of autoinduction on the disposition of ifosfamide. The initial clearance, volume of distribution, rate constant for enzyme degradation, induction half-life of the enzyme and the ifosfamide concentration at 50% of the maximum inhibition of enzyme degradation were estimated at 2.94 +/- 0.27 l h-1, 43.5 +/- 2.9 l, 0.0546 +/- 0. 0078 h-1, 12.7 h and 30.7 +/- 4.8 microM, respectively. Interindividual variabilities of initial clearance, volume of distribution, rate constant for enzyme degradation were 24.5, 23.4 and 22.7%, respectively. Proportional and additive variability not explained by the model were 13.6% and 0.0763 microM, respectively. CONCLUSIONS: The absence of a lag time for the autoinduction of ifosfamide metabolism could be the result of an immediate inhibition of the enzymatic degradation of CYP3A4 by ifosfamide. By application of the autoinduction model individual pharmacokinetic profiles of patients were described with adequate precision. This model may therefore be used in the future development of a model to individualize dose selection in patients.

High-performance liquid chromatographic determination of stabilized 4-hydroxyifosfamide in human plasma and erythrocytes.

A method using reversed-phase high-performance liquid chromatography (RP-HPLC) is described for the measurement of the stabilized activated metabolite of ifosfamide, 4-hydroxyifosfamide (4-OHIF), in human plasma and erythrocytes. Immediately after sample collection and plasma-erythrocyte separation at 4 degrees C, 4-OHIF was stabilized by derivatization with semicarbazide (SCZ). The sample pretreatment involved liquid-liquid extraction with ethyl acetate. RP-HPLC was executed with a C8 column and acetonitrile-0.025 M potassium dihydrogenphosphate buffer (pH 7.40)-triethylamine (13.5:86:0.5, v/v) as mobile phase. The analyte was determined with UV detection at 230 nm. Complete validation, optimisation and stability studies were performed and the method proved to be specific, sensitive and with a stable analyte in the range of clinically relevant concentrations (0.1-10 microg/ml) after conventional dosing. The lower limit of quantitation was 100 ng/ml using 1.00 ml of sample. Accuracy was between 94.1 and 107.0%. Within-day and between-day precisions were less than 6.2% and 7.2%, respectively. 4-OHIF-SCZ was found to be stable in the biological matrix at -20 degrees C for at least 1 month. A pharmacokinetic study conducted in a patient receiving 9 g/m2 over 3 days by means of a continuous infusion, demonstrated the applicability of this method.

Repeated automated versus daytime ambulatory blood pressure measurement in mild, moderate and severe untreated black hypertensive patients.

OBJECTIVE: To examine the extent to which one session of repeated automated (30-45 min) blood pressure measurements in non-treated, hypertensive patients can be used to predict daytime ambulatory blood pressure (ABP). METHODS: Two hundred untreated black hypertensive patients (mean age 50.2+/-11.2) were retrospectively stratified on the basis of the daytime ambulatory diastolic blood pressure (DBP) into mild, moderate and severe hypertensives (90 mmHg

N7-Methylguanine and O(6)-methylguanine levels in DNA of white blood cells from cancer patients treated with dacarbazine.

Abstract Methyl-DNA adducts are induced by a number of lifestyle, environmental and occupational carcinogens, however knowledge about their kinetics is scarce. Here, N7-methylguanine (N7-MeGua) and O(6)-methylguanine (O(6)-MeGua) levels were determined in the DNA of white blood cells from eight cancer patients treated hr with the antitumour drug dacarbazine (DTIC). Five of the patients were treated with the drug as a single agent (a single dose of 800 mg m(-2)) and three on three successive days with dacarbazine (225 mg m(-2) day(-1)) in combination with other drugs. The data indicate that maximum adduct levels are reached at 4-8 h after treatment and that the amount of N7-MeGua is at least 20-fold higher than that of O(6)-MeGua. The half-life of N7-MeGua is 40-96 h and that of O(6)-MeGua 25-27 h. Following treatment on three consecutive days, an accumulation of N7-MeGua was observed but not of O(6)-MeGua. The data show substantial interindividual differences in adduct levels but not in the ratio of N7/O(6)-MeGua. This may reflect differences in the metabolism of dacarbazine or in repair capacities.

Effect of ifosfamide treatment on glutathione and glutathione conjugation activity in patients with advanced cancers.

Several studies have suggested that the glutathione/glutathione S-transferase (GSH/GST) system is involved in resistance of tumors toward ifosfamide and other cytostatic agents. Besides, ifosfamide metabolites (in vitro) as well as ifosfamide treatment (in vivo) have been shown to decrease cellular GSH availability. In the present study, the in vivo effects of three different ifosfamide treatment schedules on the GSH/GST system were studied in patients with advanced cancers (n = 24): continuous i.v. infusions of 1300 mg/m2 daily for 10 days and 5000 mg/m2/day for 24 h, as well as a 4-h infusion of 3000 mg/m2 daily for 3 days. The GSH/GST system was characterized by administering bromisoval, a probe drug to assess GSH conjugation activity in vivo, as well as by daily monitoring of GSH concentrations in blood cells and plasma. Bromisoval pharmacokinetics was assessed before and at the end of the ifosfamide treatment. Blood cell GSH levels decreased significantly (P < 0.05) during the 3- and 10-day ifosfamide treatment schedules; the 24-h treatment had no effect. The ifosfamide treatment schedules had only minimal effects on bromisoval pharmacokinetics. Assuming that the kinetics of the probe drug provide an accurate reflection of enzyme activity, this suggests that GST activity remains unchanged. Because GSH conjugation of bromisoval enantiomers requires both GST activity and GSH availability, these results also indicate that, despite the 35% decrease in GSH in blood cells of two patient groups, the GSH availability of the cancer patients was not rate-limiting for GSH conjugation of bromisoval enantiomers. If GSH levels in blood cells reflect those in tumors/other tissues, the present results indicate that ifosfamide may be used clinically to decrease GSH levels. However, whether a 35% decrease is sufficient to increase tumor sensitivity toward (other) cytostatics remains uncertain.

Ifosfamide treatment as a 10-day continuous intravenous infusion.

Experimental and clinical studies on ifosfamide indicate that fractionated treatment regimens have a higher efficacy compared to a single short-term infusion. In addition, protracted continuous infusion, in general, is often less toxic without loss of antitumour activity. To study the toxicity of a 10-day continuous infusion at increasing dosages of ifosfamide and mesna, 24 patients with a variety of advanced cancers (colon 10, pancreas 5, adenocarcinoma with unknown primary 5, and 4 others) received a total of 60 cycles (range 1-6 cycles, median 2) at 3 to 4 week intervals. The ifosfamide and mesna doses ranged from 654 mg m-2 day-1 to 1562 mg m-2 day-1 for a total of ten doses. Twenty-two patients were chemotherapy-naive. Pharmacia-Deltec CADD-1 pumps and Port-a-Cath implantable venous access devices were used. The dose-limiting toxicity was leucopenia without thrombocytopenia. At a dose of 1300 mg m-2 day-1 in 30% of the cycles in 7 patients leucopenia of WHO grades 3 and 4 was observed, while at higher dosages this percentage increased to 73%. Haemoglobin values usually decreased during the infusion with a mean of 1 mmol/l (range 0.3-2.5 mmol/l), frequently with partial or full recovery by the next cycle. The next most disturbing side-effect was fatigue (50% of patients WHO grades 2 and 3), and nausea and vomiting requiring drug treatment in 75% of patients. Renal failure and haematuria did not occur. There were two catheter-related complications: thrombosis (1 patient) and mechanical obstruction (1 patient). One patient developed severe encephalopathy at day 6 (total dose 18 g ifosfamide) with complete recovery after cessation of the infusion. In summary, a tolerable ifosfamide dose using this regimen in this previously largely untreated patient group appears to be 1200-1300 mg m-2 day-1 for 10 days. Fatigue is a frequent complaint and might be explained as a kind of neurotoxicity. The treatment can be administered to outpatients.

Safe handling of antineoplastic drugs. Results of a survey.

As research continues to highlight the risks involved in handling antineoplastic drugs, the health services are giving increased attention to safety measures. In order to establish what protective measures nursing staff employ and what they know about antineoplastic drugs, a survey was carried out in The Netherlands. The questions were based on the self-study modules by Dunne and the (American) Oncology Nursing Society. A total of 1,373 questionnaires were distributed in 10 hospitals. Of these, 824 were returned, which represents a response rate of 60%. Over two-thirds (68%) of the nursing staff reported that they were involved, on a daily or weekly basis, in caring for patients being treated with antineoplastic drugs. In the view of 94% of the nurses, protective measures are effective. While administering antineoplastic drugs, 91% of the respondents said that they wore gloves, 21% said that they wore a gown, 18% wore a mask, and 3% used goggles. While handling excreta, fewer nurses applied safety measures. Thirty-nine percent of the respondents knew that latex gloves offer a greater degree of protection than PVC gloves. It appeared that there was not one Dutch hospital whose guidelines for the safe handling of antineoplastic material were completely up-to-date and that nurses do not always follow the guidelines established.

Cancer therapy-induced emesis: the nurse's perspective.

There have been significant improvements in the diagnosis and treatment of malignant tumours. However, recent advances in cytostatic therapy are associated with several adverse side-effects which can impair the patient's well-being and may result in refusal or delay of treatment. Nausea and vomiting are perceived to be the most unpleasant of these side-effects. This paper addresses some of the issues involved in the improvement of these two distressing symptoms.

Quantitative analysis of alprazolam and triazolam in hemolysed whole blood and liver digest by GC/MS/NICI with deuterated internal standards.

This report describes sensitive and specific methods for the quantitation of alprazolam and triazolam in hemolysed whole blood and liver tissue. Samples of blood and enzyme-digested liver are extracted without pH adjustment with n-butyl chloride, after addition of deuterated internal standards and urea. The evaporated extracts are reconstituted in acetonitrile for analysis by gas chromatography/mass spectrometry/negative ion chemical ionization (GC/MS/NICI). Fatty extracts may be cleaned up by partitioning between pentane and acetonitrile. Two ion pairs are monitored for each drug. Within-day coefficients of variation in the range 10-50 micrograms/L for blood are approximately 5%. Between-day coefficients of variation are less than 10%. The limit of quantitation (based on analysis of 0.2-mL blood samples) is 0.5 microgram/L for triazolam and 4 micrograms/L for alprazolam.

Solid-phase extraction and gas chromatographic-mass spectrometric determination after hydrolysis of 2-aminofluorene haemoglobin adducts in blood of rats.

2-Nitrofluorene is an environmental pollutant that binds covalently to haemoglobin after nitroreduction and successive N-hydroxylation. these haemoglobin adducts can be cleaved in vitro by mild base-catalysed hydrolysis. For the enrichment of arylamines from the aqueous hydrolysate, an extraction procedure with an organic solvent is widely used. Because of the formation of a thick emulsion layer between the aqueous and organic solvent layers, the extraction is laborious and inefficient. The use of Amberlite XAD2 provides a simple extraction procedure yielding a recovery of ca. 70%. Calibration curves in haemoglobin solution were prepared with a correlation coefficient of 0.998 (n = 12). The inter-day coefficient of variation amounted to 14%.

Determination of N7-methylguanine in DNA of white blood cells from cancer patients treated with dacarbazine.

An ELISA method was used to determine N7-methylguanine (N7-MeGua) adducts in DNA of white blood cells from cancer patients treated with the methylating antitumor drug dacarbazine by i.v. administration. From four patients who received dacarbazine only, at dosages of 250, 400 or 800 mg/m2, the blood samples were collected before and several days after administration, and from one patient also during the first few hours. N7-MeGua levels increased rapidly during the first hour after treatment, hardly changed during the following 7 h and decreased during the next days (half-life of approximately 72 h). The adduct levels appeared to be dose-dependent. Blood cells were also analyzed from three patients who received dacarbazine (225 mg/m2) in combination with other chemotherapeutic drugs during three successive days. One of these patients showed a larger initial level of N7-MeGua and a cumulative increase with the dacarbazine dose compared to the other two patients. For several patients adduct levels were monitored during two chemotherapy cycles, for which quite similar data were obtained.