Paclitaxel Infusion Research Articles

Paclitaxel Induced Acute ST Elevation Myocardial Infarction: A Rare Case Report

Paclitaxel, is a frequently used anti-neoplastic agent and is included in various chemotherapy regimens. The life threatening cardio toxicity associated with its use and the still unclear pathophysiology, has limited the use of this drug. Acute myocardial infarction is a rare adverse event associated with this drug. We report a case of acute ST-elevation myocardial infarction induced by paclitaxel infusion in a patient of oesophageal carcinoma who was saved by percutaneous primary intervention. The authors emphasize the awareness of this side effect of Paclitaxel among the clinicians.

Effects of Jia-Wei-Xiao-Yao-San on the Peripheral and Lymphatic Pharmacokinetics of Paclitaxel in Rats.

Paclitaxel is effective against breast cancer. The herbal medicine, Jia-Wei-Xiao-Yao-San (JWXYS), is the most frequent prescription used to relieve the symptoms of breast cancer treatments. The aim of the study was to investigate the herb-drug interaction effects of a herbal medicine on the distribution of paclitaxel to lymph. A validated ultraperformance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method was used to determine the paclitaxel levels in rat plasma and lymph after intravenous infusion of paclitaxel alone with or without 7 days of JWXYS pretreatment. The pharmacokinetic results indicate that paclitaxel concentrations in plasma exceeded those in lymph by approximately 3.6-fold. The biodistribution of paclitaxel from plasma to lymph was 39 ± 5%; however, this increased to 45 ± 4% with JWXYS pretreatment. With JWXYS pretreatment, the AUC and C max of paclitaxel in plasma were significantly reduced by approximately 1.5-fold, compared to paclitaxel alone. Additionally, JWXYS decreased the AUC and C max of paclitaxel in lymph. However, the lymph absorption rate of paclitaxel with or without JWXYS pretreatment was not significantly changed (27 ± 3 and 30 ± 2%, resp.). Our findings demonstrate that when paclitaxel is prescribed concurrently with herbal medicine, monitoring of the blood pharmacokinetics of paclitaxel is recommended.

Abstract B95: Is ethanol required for cyst ablation in patients with premalignant type pancreatic cysts?

Abstract Background: Mucinous pancreatic cystic lesions have the propensity to progress into pancreatic cancer. Currently radiographic surveillance or surgical resection is recommended for this premalignant type of cyst, both of which have significant limitations. Recently, endoscopic ultrasound-guided cyst ablation has emerged as an innovative and promising alternative treatment approach. Previous studies have shown that EUS-guided ethanol lavage of pancreatic cysts is safe and results in complete cyst resolution in 1/3 of patients. Subsequent studies demonstrated marked increases in rates of ablation with infusion of paclitaxel following ethanol lavage, which raises the question of whether alcohol is necessary for effective ablation. This is important, since ethanol extravasation is felt to have caused two complications in previous trials, abdominal pain and pancreatitis. This study hypothesizes that the removal of alcohol lavage prior to chemotherapy infusion will not impair ablation rates and will decrease complication rates. A secondary aim of this study is to assess whether a custom chemoablation cocktail tailored to pancreatic neoplasia (paclitaxel+gemcitabine) will improve ablation rates overall. Gemcitabine was chosen because it dilutes paclitaxel for injection and has been the standard in pancreatic cancer chemotherapy. Recently, the combination of paclitaxel and gemcitabine was shown to improve response rates and progression-free survival when compared with gemcitabine alone. Methods: Patients with mucinous or indeterminate type pancreatic cysts of 1-5cm’s without signs of malignancy were randomized to undergo either EUS-guided lavage with 80% alcohol or normal saline followed by infusion of 3 mg/ml paclitaxel + 19mg/ml gemcitabine (both arms). 9 patients were enrolled in this initial pilot study and evaluated post op, at 72 hours, with two week lab tests and by CT scan at 3, 6, and 12 months to assess response rates and for any complications. Results: The initial 9 patients of this trial (expected to have an N of 78 when complete) were randomized for this pilot study with 8 patients then able to be treated. Pancreatic cysts ranged in maximum diameter from 2.2cm to 3.8 cm (mean 2.9 cm). Location included body (n=4), head (n=2), neck (n=1) and tail (n=1). The overall reduction in cyst surface area was 67% at 3 months and 82% at 6 months. At 6 months size reduction was 81% in the alcohol infusion arm and 83% in the alcohol-free arm. Complications were mild abdominal pain (1) in the alcohol free arm (12.5%), moderate abdominal pain (1), and mild pancreatitis (1) in the alcohol arm (25%). Conclusion: The treatment of mucinous type pancreatic cysts with either alcohol or saline lavage followed by gemicitabine-paclitaxel infusion is feasible and safe in this limited pilot study. Initial results indicate that alcohol-free ablation does not impair ablation efficacy and is associated with fewer complications although the full sample size will be required to prove this hypothesis with any certainty. Citation Format: Matthew T. Moyer, Setareh Sharzehi, Charles E. Dye, Wafik El-Deiry, Thomas J. McGarrity, Abraham Mathew, Niraj Gusani, Raquel E. Davila, Brooke Ancrile. Is ethanol required for cyst ablation in patients with premalignant type pancreatic cysts? [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B95.

Pharmacokinetically based dosing of weekly paclitaxel to reduce drug-related neurotoxicity based on a single sample strategy.

The present simulation study was initiated to develop a limited sampling strategy and pharmacokinetically based dosing algorithm of weekly paclitaxel based on pharmacokinetic (PK) and chemotherapy-induced peripheral neuropathy (CIPN) data from a large database. We used paclitaxel plasma concentrations from 200 patients with solid tumors receiving weekly paclitaxel infusions to build a population PK model and a proportional odds model on CIPN. Different limited sampling strategies were tested on their accuracy to estimate the individual paclitaxel time-above-threshold-concentration of 0.05µmol/L (T c>0.05µM), which is a common threshold for paclitaxel. A dosing algorithm was developed based on the population distribution of paclitaxel T c>0.05µM and the correlation between paclitaxel T c>0.05µM and CIPN. A trial simulation based on paclitaxel PK and CIPN was performed using empirical Bayes estimations, applying the proposed dosing algorithm and a single 24-h paclitaxel PK sample. A single paclitaxel plasma concentration taken 18-30h after the start of chemotherapy infusion adequately predicted T c>0.05µM. By using an empirical dosing algorithm to target an average paclitaxel T c>0.05µM between 10 and 14h, Bayesian simulations of repetitive (adapted) dosing suggested a potential reduction of grade 2 CIPN from 9.6 to 4.4%. This simulation study proposes a pharmacokinetically based dosing algorithm for weekly paclitaxel and shows potential improvement of the benefit/risk ratio by using empirical Bayesian models.

Paclitaxel Inhibits Expression of Neuronal Nitric Oxide Synthase and Prevents Mitochondrial Dysfunction in Spinal Ventral Horn in Rats After C7 Spinal Root Avulsion.

This study evaluated the neuroprotective effect of intrathecally infused paclitaxel in the prevention of motoneuron death and mitochondrial dysfunction following brachial plexus avulsion injury. Brachial root avulsion injury was induced in Sprague-Dawley rats. The Paclitaxel treatment group (n = 32) received a 5-d intrathecal infusion of paclitaxel (256 ng/d) via a micro infusion pump, whereas the Control group (n = 32) received normal saline. The cervical cord was harvested at survival times of 1, 2, 4, and 6 wk (n = 8 each). The number of surviving and nNOS-positive motoneurons at the injury level in the ventral horn was determined with NADPH-d histochemistry. Mitochondrial function at this location was measured with CcO histochemistry and densitometry. An independent t-test was applied to detect differences between the study groups at specific survival times. The Paclitaxel treatment group showed a significant relative reduction in nNOS expression at 2, 4, and 6 wk, and significantly improved mitochondrial function at 4 and 6 wk. Motoneuron survival was significantly increased at 2, 4, and 6 wk. Paclitaxel has a significant neuroprotective effect against spinal motoneuron degeneration following brachial plexus avulsion injury, which involves inhibition of nNOS expression and prevention of mitochondrial dysfunction.

Molecular Inclusion Complexes of β-Cyclodextrin Derivatives Enhance Aqueous Solubility and Cellular Internalization of Paclitaxel: Preformulation and In vitro Assessments.

Drugs with low aqueous solubility and permeability possess substantial challenges in designing effective and safe formulations. Synergistic solubility and permeability enhancement in a simple formulation can increase bioavailability and efficacy of such drugs. To overcome limitations of the clinical formulation of Taxol®, Paclitaxel (PTX) was reformulated with various β-cyclodextrin (CD) derivatives suitable for parenteral administration. Results indicated that β-CDs can efficiently form complexes with PTX at lower molar ratios, enhance aqueous solubility up to 500 times and improved cellular internalization of PTX. All β-CD derivatives were found to be safe as excipient since none showed detectable signs of cyto-genotoxicity. As a result, the CD-PTX complexes significantly increased the cytotoxicity of the drug. The study concluded that CD-PTX formulations could substitute the current intravenous infusion of PTX obviating the use of non-inert excipient Cremophor EL.

Stopping paclitaxel premedication after two doses in patients not experiencing a previous infusion hypersensitivity reaction.

Paclitaxel-based chemotherapy continues to be an integral component of breast cancer treatment. Prolonged use of paclitaxel may result in repeated doses of premedications that can have unwanted side effects. Infusion hypersensitivity reactions occurring beyond the second dose of paclitaxel are infrequent and not well characterized. We previously published the results of a small, prospective pilot trial demonstrating the safety and feasibility of discontinuing premedications in patients who received the first two doses of paclitaxel-based chemotherapy without experiencing an infusion hypersensitivity reaction. In this study, we aimed to retrospectively characterize the incidence of rescue medication using this abbreviated premedication regimen in our institution following the publication of the pilot study. Patients with stages I-IV breast cancer who received paclitaxel from January 2011 through June 2013 were screened for eligibility. Patients who did not experience an infusion hypersensitivity reaction with their first or second dose of paclitaxel and discontinued paclitaxel premedication for subsequent doses were included in this analysis. The primary endpoint was to estimate the incidence of rescue medication use for the treatment of paclitaxel infusion hypersensitivity during doses three to six of paclitaxel in the study population. In total, 449 patients received paclitaxel-based chemotherapy for the treatment of breast cancer during the interval time period. After receiving the first two doses of paclitaxel-based chemotherapy without experiencing an infusion hypersensitivity reaction, 234 breast cancer patients had their premedications discontinued for all remaining paclitaxel doses. These patients tolerated future paclitaxel doses without severe or life-threatening complications related to infusion hypersensitivity. The majority of patients did not have any symptoms of an infusion reaction, with only two of these patients requiring rescue medication to treat an infusion hypersensitivity reaction with subsequent paclitaxel doses (0.85; 95% confidence interval (CI), 0.10-3.05%). Discontinuation of paclitaxel premedications in breast cancer patients who have not experienced an infusion hypersensitivity reaction with the first two doses of paclitaxel is not associated with increased rate of rescue medication use for infusion hypersensitivity.

The CHARM Trial (CHemotherapy for Ablation and Resolution of Mucinous Pancreatic Cysts): The Initial Pilot Study for the Prospective, Randomized, Double-Blind, Single-Center Clinical Trial

Introduction: Mucinous pancreatic cystic lesions carry significant potential for progression into pancreatic cancer. Currently radiographic surveillance or surgical resection is generally recommended for these cysts, both of which have significant limitations. Recently, EUS-guided cyst ablation has emerged as promising alternative treatment approach. Previous studies have shown that EUS-guided ethanol lavage of pancreatic cysts is safe and results in complete cyst resolution in roughly one-third of patients without recurrence at a follow-up of 26 months. Subsequent studies demonstrated marked increases in rates of ablation (62-78%) with infusion of paclitaxel following ethanol lavage, which raises the question of whether alcohol is necessary for effective ablation. Importantly, ethanol extravasation is felt to cause the 2 most common complications in previous trials, abdominal pain (12-16%) and pancreatitis (3-5%), and is felt to be the highest risk element of the technique. This study hypothesizes that the removal of alcohol lavage prior to chemotherapy infusion will not impair ablation rates and will decrease complication rates. A secondary aim of this study is to assess whether a custom chemoablation cocktail tailored to pancreatic neoplasia (paclitaxel+gemcitabine) will improve ablation rates overall. Methods: Patients with mucinous or indeterminate type pancreatic cysts of 1-5 cm without signs of malignancy were randomized to undergo either EUS-guided lavage with 80% alcohol or normal saline, followed by infusion of 3 mg/mL paclitaxel + 19 mg/mL gemcitabine (both arms). Patients were evaluated postop, at 72 hours, and by CT scan at 3, 6, and 12 months to assess response and complication rates. Results: The initial 13 patients of this trial (expected to have an N of 78 when complete) were randomized for this pilot study with 11 patients then able to be treated. The overall reduction in cyst surface area was 70% at 3 months and 83% at 6 months. At 3 months, size reduction was 62.5% in the alcohol infusion arm and 74% in the alcohol-free arm. Complications were mild pancreatitis (1/5) in the alcohol arm. Conclusion: The treatment of mucinous pancreatic cysts with either alcohol or saline lavage followed by gemcitabine-paclitaxel infusion is feasible and safe in this limited pilot study. Initial results indicate that alcohol-free ablation does not impair ablation efficacy. Disclosure - Dr. Moyer is a consultant for Boston Scientific Corp. This is unrelated to the current research.

A phase 2 study of fluorouracil/leucovorin in combination with paclitaxel and oxaliplatin as a salvage treatment in patients with refractory or relapsed advanced gastric cancer

The aim of this study was to evaluate the efficacy and safety of paclitaxel plus oxaliplatin plus fluorouracil/leucovorin (POF) as salvage chemotherapy in pretreated advanced gastric cancer. Fifty-two pretreated patients with the advanced gastric cancer were eligible for this study. The POF regimen consisted of a 3-hour infusion of paclitaxel (135 mg/m2) followed by oxaliplatin (85 mg/m2) and leucovorin (400 mg/m2), administered simultaneously over a 2-hour infusion period, followed by an infusion of fluorouracil (2400 mg/m2) over a 46-hour period, every 14 days. From an intention-to-treat analysis, overall response rate and stable disease rate were 28·8 and 38·5%, respectively. The median time to progression and overall survival were 4·1 and 7·9 months, respectively. Grade 3 or 4 neutropaenia, thrombocytopaenia, fatigue, and neuropathy were 38·5, 15·4, 17·3, and 15·4%, respectively. The POF regimen is active in pretreated advanced gastric cancer as salvage chemotherapy, with a favourable toxicity profile.

Systemic toxicity induced by paclitaxel in vivo is associated with the solvent cremophor EL through oxidative stress-driven mechanisms

The toxic effects of paclitaxel (PTX) and its solubilizing agent cremophor EL (CREL) have been well established in vitro; however, the in vivo mechanisms underlying this toxicity remain unclear. Thus, the aim of this study was to analyze the in vivo toxicity induced by infusion of PTX and CREL and to investigate the involvement of oxidative stress as a potential mechanism for this toxicity. We treated male Wistar rats with PTX and/or CREL for 1h using human-equivalent doses (PTX+CREL/ethanol+NaCl 175mg/m2 or CREL+ethanol+NaCl) and sacrificed immediately or 24h after these drug infusions to systemic biochemical evaluations. Hidrosoluble vitamin E (vitE, Trolox) was added as a control in some groups. The oxidative profile was determined by measuring erythrocyte and plasma lipid peroxidation, superoxide dismutase and catalase activities, reduced glutathione (GSH) levels, red blood cell (RBC) counts, hemoglobin profile, plasma total radical-trapping antioxidant parameter (TRAP), plasma lipid peroxidation, nitric oxide levels and malondialdehyde levels. Our findings showed that CREL infusion triggered immediate high plasma lipid peroxidation and augmented TRAP, while PTX caused immediate TRAP consumption and metahemoglobin formation. Pronounced oxidative effects were detected 24h after infusion, when CREL treatment enhanced RBC counts and plasma lipid peroxidation, increased catalase activity, and decreased TRAP levels. On the other hand, after 24h, PTX-infused rats showed reduced catalase activity and reduced metahemoglobin levels. These data indicate the existence of a continuous oxidative stress generation during CREL-PTX treatment and highlight CREL as primarily responsible for the in vivo oxidative damage to RBCs.

Chemoradiation With Paclitaxel and Carboplatin in High-Risk Cervical Cancer Patients After Radical Hysterectomy: A Korean Gynecologic Oncology Group Study

To evaluate the efficacy and toxicity of concurrent chemoradiation with paclitaxel and carboplatin in patients with high-risk cervical cancer. Patients after radical hysterectomy for cervical cancer, with at least 1 high-risk characteristic, were administered paclitaxel 135 mg/m(2), carboplatin area under the curve = 5 every 3 weeks for 3 cycles concomitant with radiation therapy as adjuvant treatment. This prospective study enrolled 71 consecutive patients. Sixty-six patients (93%) completed the planned treatment. The majority of grade 3/4 neutropenia or nonhematologic toxicities were usually self-limited. Diarrhea grades 3/4 were observed in 4 patients (5.6%). One patient developed anaphylactic shock after infusion of paclitaxel. With a median follow-up of 57 months, recurrences occurred in 16 patients. Multivariable analysis indicated that common iliac lymph node involvement is an independent risk factor for disease recurrence (odds ratio 13.48; 95% confidence interval 2.93-62.03). In the intent-to-treat population (n=71), the estimated 5-year disease-free survival and overall survival rates were 77.3% and 80.3% respectively. In the per-protocol population (n=62), disease-free survival was 78.9% and overall survival was 83.9%. Concurrent chemoradiation with paclitaxel/carboplatin is well tolerated and seems to be effective for patients who undergo radical hysterectomy. Therefore, a prospective, randomized controlled study should be designed to evaluate efficacy of this approach for patients with high-risk cervical cancer.

Study on the adverse reactions related to paclitaxel and docetaxel infusion

To determine the incidence of paclitaxel and docetaxel infusion-associated reactions, and the likely causes that may trigger them. Cohort study of the paclitaxel and docetaxel infusions carried out at a tertiary hospital from July of 2010 to December of 2011 (18 months). For each infusion, the clinical data and the drug-related data were recorded. When a reaction occurred during the infusion the following data were specified: type, severity, if treatment withdrawal was needed. The clinical charts and treatment orders were reviewed. The follow-up of the infusions were done by contacting the day-care hospital nurses. A descriptive study was done for the most relevant variables included in the follow-up and we analyzed if any of them could have had an influence on the occurrence of the reactions. During the study period, 357 paclitaxel and docetaxel infusions were administered to 92 patients: mean age 61.4 years (SD 11.1), 50.0% were female. 9 infusion reactions affecting 8 patients occurred, all of them caused by docetaxel (c2 = 8.3, p = 0.004); 14.5% of the patients receiving it, and always during the first or second treatment cycle. The variables significantly associated to the occurrence of the reaction were: lung cancer (p< 0.005), docetaxel-cisplatin regime (p< 0.005), receiving the drug as first line (p=0.021), and non-advanced disease (p = 0.014). At our hospital, docetaxel is the taxane that has provoked the most frequent safety problems during the infusion.

Characteristics and outcomes of patients with advanced hepatocellular carcinoma treated on phase I trials.

281 Background: Patients with advanced hepatocellular carcinoma (HCC) have limited effective therapies. With that purpose, we analyzed the outcomes and prognostic factors of such pts treated on phase I trials w an emphasis on locoregional and targeted agents. Methods: We reviewed the records of 100 consecutive pts referred to the Phase I Clinical Trials Program from March 2004 and assessed characteristics, types of clinical trials, progression-free survival (PFS), overall survival (OS) and oncogenic mutations. Results: Of 100 referred pts, 39 were not treated mainly due to poor performance status (n=22). Of 61 treated pts (49 male, 12 female, median age 60yrs), median # of prior therapies was 3 (range, 0-8). There were no treatment-related mortalities. One pt on a sorafenib regimen had g3 hand foot syndrome unresponsive to dose reduction. A 2nd pt developed a L-sided visual blurriness after 5 days on a sunitinib regimen; CT showed a small R parieto-occipital hemorrhage, possibly related to therapy. Of 61 treated pts, 7 (11%) had stable disease (SD) &gt; 6 months, 4 (7%) partial response (PR), on protocols combining bevacizumab+sorafenib, pazopanib+everolimus, or single-agent novel oral multikinase inhibitor of VEGFR2-TIE2, or hepatic arterial infusion (HAI) of paclitaxel or oxaliplatin w IV bevacizumab. Median PFS on Phase I trials was 2.2 months vs. 4.4 months and 4.1 months for their 1st- and 2nd-line FDA-approved therapy (p 0.019). In univariate analysis, the presence of ascites, portal hypertension, cirrhosis, serum sodium, albumin, and poor Royal Marsden Hospital (RMH) prognostic score were associated with shorter PFS and OS (p &lt; 0.05). On multivariate analysis, independent factors of shorter OS were Caucasian race (p = 0.031), cirrhosis (p = 0.016), serum sodium (p = 0.0013), and poor RMH prognostic score (p = 0.0015). Molecular analysis in progress will be updated. Conclusions: Phase I therapy offer a reasonable therapeutic option for patients with advanced HCC. The RMH prognostic score was validated in this population. The SD &gt; 6 months/PR rate of 18% was observed with regimen of multikinase inhibitors with mTOR inhibitors and HAI therapy.

A Phase II Study on Continuous Infusional Paclitaxel and 5-Fu as First-line Chemotherapy for Patients with Advanced Esophageal Cancer

This study was performed to evaluated the efficacy and safety of continuous infusional paclitaxel and 5-Fu as first-line chemotherapy in patients with advanced esophageal squamous cell cancer (ESCC). A total of 22 patients with advanced esophageal squamous cell cancer with no indications for surgery and radiation therapy, or recurrent patients were enrolled from October 2008 to November 2010. All were treated with PTX 20 mg/m2 was administered through a 16 hours continuous intravenous infusion on days 1 to 3, 8 and 9. DDP 3.75 mg/m2 was given on days 1 to 4 and 8 to 11, continuous infusional 5-FU over 24-hours on days 1 to 5 and 8 to 12 at a dose of 375 mg/m2, and folacin 60 mg orally synchronized with 5-Fu. The treatment was repeated every 21 days for at least two cycles. 22 cases of all enrolled patients could be evaluated for the effect of treatment: 2 cases were CR, 9 cases PR, 5 cases SD and 2 cases PD, giving an overall response rate of 68.2% (15/22). The median time to progression was 7.0 months. The adverse reactions related to chemotherapy were tolerable; the most common toxic effects were marrow depression, alopecia, and fatigue. Low-dose continuous infusional PTX over 16-hours and 5-fu over 24-hours is a promising regimen with good tolerability in treating patients with advanced esophageal squamous cell cancer.

Paclitaxel plus Doxorubicin Chemotherapy as Second-Line Therapy in Patients with Advanced Urothelial Carcinoma Pretreated with Platinum plus Gemcitabine Chemotherapy

Background: We retrospectively evaluated the efficacy and toxicity of paclitaxel plus doxorubicin as a second-line treatment in patients with urothelial carcinoma, who had not responded to a prior platinum plus gemcitabine combination. Patients and Methods: All patients received intravenous infusions of paclitaxel (175 mg/m²/h) and doxorubicin (50 mg/m²/30 min) on day 1. Chemotherapy courses were repeated every 21 days. Results: The median followup duration was 13.5 months (range 2.8–22.4 months). Complete and partial responses were observed in 2 (5.6%) and 10 (27.8%) patients, respectively. Median overall survival was 8.9 months (95% confidence interval (CI): 6.2–11.6). Median time to progression was 3.8 months (95% CI: 2.7–4.8). The most common hematologic toxicities were neutropenia (n = 21, 58.3%), thrombocytopenia (n = 10, 27.8%), and anemia (n = 9, 25%). The most common nonhematologic toxicities consisted of fatigue (n = 15, 41.7%), nausea/vomiting (n = 13, 36.1%), peripheral neuropathy (n = 11, 30.6%), and mucositis (n = 6, 16.7%). Dose reductions by 25–35% were performed in 6 (16.7%) patients because of grade 3/4 toxicity. Anthracycline-related heart failure did not occur. Conclusion: 3-weekly courses of cyclic paclitaxel plus doxorubicin were found to be effective and tolerable in patients with urothelial carcinoma, who had not responded to prior platinum- and gemcitabine-based chemotherapy.

Effect of Ethanol in Paclitaxel Injections on the Ethanol Concentration in Exhaled Breath

BackgroundEthanol is included in certain injectable preparations of anticancer drugs to increase their solubility. Since the volume of ethanol in these preparations is approximately half of the total injection volume, the potential inhibitory effects of ethanol on the central nervous system cannot be disregarded, especially considering that patients may drive immediately after administration of the medication. Therefore, the concentration of ethanol was examined in exhaled breath after administration of paclitaxel, an anticancer medication containing ethanol.MethodsThe ethanol concentration in exhaled breath immediately after an intravenous infusion of paclitaxel was measured in 30 patients, using a balloon-type gas detector tube. Correlations between the concentration of ethanol in exhaled breath and the total amount of ethanol administered or the intravenous infusion speed were calculated.ResultsThe mean ethanol concentration in exhaled breath was 0.028 ± 0.015 mg/L. The correlation between the ethanol concentration in exhaled breath and the total dose of ethanol was weak (R2 = 0.25; p = 0.055), while the intravenous infusion speed showed a stronger positive correlation with the concentration of ethanol in the breath (R2 = 0.49; p = 0.11). The maximum concentration of ethanol measured in exhaled breath (0.06 mg/L) was equivalent to 40% of the threshold for drunk driving, as specified in the Road Traffic Act in Japan.ConclusionIn this study, no patient had a breath ethanol concentration exceeding the legal threshold for drunk driving. However, it is still advisable for patients to avoid driving after receiving paclitaxel injections. When driving cannot be avoided, patients should wait for a sufficient time after receiving the injection before driving.

Effect of Ethanol in Paclitaxel Injections on the Ethanol Concentration in Exhaled Breath

BackgroundEthanol is included in certain injectable preparations of anticancer drugs to increase their solubility. Since the volume of ethanol in these preparations is approximately half of the total injection volume, the potential inhibitory effects of ethanol on the central nervous system cannot be disregarded, especially considering that patients may drive immediately after administration of the medication. Therefore, the concentration of ethanol was examined in exhaled breath after administration of paclitaxel, an anticancer medication containing ethanol.MethodsThe ethanol concentration in exhaled breath immediately after an intravenous infusion of paclitaxel was measured in 30 patients, using a balloon-type gas detector tube. Correlations between the concentration of ethanol in exhaled breath and the total amount of ethanol administered or the intravenous infusion speed were calculated.ResultsThe mean ethanol concentration in exhaled breath was 0.028 ± 0.015 mg/L. The correlation between the ethanol concentration in exhaled breath and the total dose of ethanol was weak (R2 = 0.25; p = 0.055), while the intravenous infusion speed showed a stronger positive correlation with the concentration of ethanol in the breath (R2 = 0.49; p = 0.11). The maximum concentration of ethanol measured in exhaled breath (0.06 mg/L) was equivalent to 40% of the threshold for drunk driving, as specified in the Road Traffic Act in Japan.ConclusionIn this study, no patient had a breath ethanol concentration exceeding the legal threshold for drunk driving. However, it is still advisable for patients to avoid driving after receiving paclitaxel injections. When driving cannot be avoided, patients should wait for a sufficient time after receiving the injection before driving.

Metronomic therapy with 5-FU, weekly nab-paclitaxel, leucovorin, and oxaliplatin, plus bevacizumab for advanced pancreatic cancer: A phase II study.

e14582 Background: The objective of this open label phase 2 study was to evaluate low-dose continuous (metronomic) chemotherapy given in conjunction with conventional anti-VEGF therapy for patients with advanced pancreatic cancer. Continuous infusion of 5FU, calcium leucovorin plus paclitaxel and oxaliplatin has been shown to be active in patients with pancreatic cancer. As a protracted low dose infusion, 5FU is anti-angiogenic and has been demonstrated to be synergistic with bevacizumab. Bevacizumab and nab-paclitaxel are synergistic as seen in the treatment of breast cancer. Methods: Since July 2008, we treated 40 patients with 5FU (180mg/m2/day x 14 days) via an ambulatory pump. Calcium leucovorin (20mg/m2) IVP, nab-paclitaxel (100mg/m2) IV as a 30 minute infusion and oxaliplatin (75mg/m2) IV as a 60 minute infusion were given on days 1, 8, and 15. Bevacizumab (5mg/kg) IV over 30 minutes was given on days 1 and 15. Cycles were repeated every 35 days. There were 24 females and 16 males. The median age was 58. 34 patients had stage IV disease. Results: The median overall survival is greater than 17 months. A partial response was observed in 50% of the patients. There were 22 patients with prior treatment, 11 of whom responded to the protocol. 34 patients began treatment with an elevation of their CA19-9 greater than 40. Of these, 26 patients were subsequently noted to have greater than 50% reduction in their CA 19-9; 17 of whom had an objective CT scan response to therapy. Toxicity (grade 3 and 4) included stomatitis, diarrhea, fatigue, nausea, neuropathy, hypertension and renal failure. Hematologic toxicity included anemia, neutropenia and thrombocytopenia. 19 patients stopped treatment due to disease progression, 18 patients stopped due totoxicity. There were no chemotherapy related deaths. Conclusions: This non-gemcitabine based regimen resulted in response rates and survival benefits greater than that which is ususally observed with gemcitabine based therapy. Low dose continuous (metronomic therapy) cytotoxic chemotherapy when combined with anti-angiogenic therapy is safe and effective for patients with advanced pancreatic cancer.

A Pharmacodynamic Study of the P-glycoprotein Antagonist CBT-1® in Combination With Paclitaxel in Solid Tumors

This pharmacodynamic trial evaluated the effect of CBT-1® on efflux by the ATP binding cassette (ABC) multidrug transporter P-glycoprotein (Pgp/MDR1/ABCB1) in normal human cells and tissues. CBT-1® is an orally administered bisbenzylisoquinoline Pgp inhibitor being evaluated clinically. Laboratory studies showed potent and durable inhibition of Pgp, and in phase I studies CBT-1® did not alter the pharmacokinetics of paclitaxel or doxorubicin. CBT-1® was dosed at 500 mg/m2 for 7 days; a 3-hour infusion of paclitaxel at 135 mg/m2 was administered on day 6. Peripheral blood mononuclear cells (PBMCs) were obtained prior to CBT-1® administration and on day 6 prior to the paclitaxel infusion. (99m)Tc-sestamibi imaging was performed on the same schedule. The area under the concentration-time curve from 0-3 hours (AUC(0-3)) was determined for (99m)Tc-sestamibi. Twelve patients were planned and enrolled. Toxicities were minimal and related to paclitaxel (grade 3 or 4 neutropenia in 18% of cycles). Rhodamine efflux from CD56+ PBMCs was a statistically significant 51%-100% lower (p < .0001) with CBT-1®. Among 10 patients who completed imaging, the (99m)Tc-sestamibi AUC(0-3) for liver (normalized to the AUC(0-3) of the heart) increased from 34.7% to 100.8% (median, 71.9%; p < .0001) after CBT-1® administration. Lung uptake was not changed. CBT-1® is able to inhibit Pgp-mediated efflux from PBMCs and normal liver to a degree observed with Pgp inhibitors studied in earlier clinical trials. Combined with its ease of administration and lack of toxicity, the data showing inhibition of normal tissue Pgp support further studies with CBT-1® to evaluate its ability to modulate drug uptake in tumor tissue. Although overexpression of ABCB1 and other ABC transporters has been linked with poor outcome following chemotherapy efforts to negate that through pharmacologic inhibition have generally failed. This is thought to be a result of several factors, including (a) failure to select patients with tumors in which ABCB1 is a dominant resistance mechanism; (b) inhibitors that were not potent, or that impaired drug clearance; and (c) the existence of other mechanisms of drug resistance, including other ABC transporters. Although an animal model for Pgp has been lacking, recent studies have exploited a Brca1(-/-); p53(-/-) mouse model of hereditary breast cancer that develops sporadic tumors similar to cancers in women harboring BRCA1 mutations. Treatment with doxorubicin, docetaxel, or the poly(ADP-ribose) polymerase inhibitor olaparib brings about shrinkage, but resistance eventually emerges. Overexpression of the Abcb1a gene, the mouse ortholog of human ABCB1, has been shown to be a mechanism of resistance in a subset of these tumors. Treating mice with resistant tumors with olaparib plus the Pgp inhibitor tariquidar resensitized the tumors to olaparib. Although results in this animal model support a new look at Pgp as a target, in this era of "targeted therapies," trial designs that directly assess modulation of drug uptake, including quantitative nuclear imaging, should be pursued before clinical efficacy assessments are undertaken. Such assessment should be performed with compounds that inhibit tissue Pgp without altering the pharmacokinetics of chemotherapeutic agents. This pharmacodynamic study demonstrated that CBT-1®, inhibits Pgp-mediated efflux from PBMCs and normal liver.

Drug-induced hallucinatory syndrome in a patient with breast cancer after paclitaxel infusion

Drug-induced hallucinatory syndrome in a patient with breast cancer after paclitaxel infusion