epothilone-a and Peripheral-Nervous-System-Diseases

Taxane-induced peripheral neurotoxicity (TIPN) is the most common non-hematological side effect of taxane-based chemotherapy, and may result in dose reductions and discontinuations, having as such a detrimental effect on patients' overall survival. Epothilones share similar mechanism of action with taxanes. The typical TIPN clinical presentation is mainly comprised of numbness and paresthesia, in a stocking-and-glove distribution and may progress more proximally over time, with paclitaxel being more neurotoxic than docetaxel. Motor and autonomic involvement is less common, whereas an acute taxane-induced acute pain syndrome is frequent. Patient reported outcomes questionnaires, clinical evaluation, and instrumental tools offer complementary information in TIPN. Its electrodiagnostic features include reduced/abolished sensory action potentials, and less prominent motor involvement, in keeping with a length-dependent, axonal dying back predominately sensory neuropathy. TIPN is dose-dependent and may be reversible within months after the end of chemotherapy. The single and cumulative delivered dose of taxanes is considered the main risk factor of TIPN development. Apart from the cumulative dose, other risk factors for TIPN include demographic, clinical, and pharmacogenetic features with several single-nucleotide polymorphisms potentially linked with increased susceptibility of TIPN. There are currently no neuroprotective strategies to reduce the risk of TIPN, and symptomatic treatments are very limited. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of TIPN.

Topics: Antineoplastic Agents; Bridged-Ring Compounds; Clinical Trials as Topic; Duloxetine Hydrochloride; Epothilones; Humans; Neurotoxicity Syndromes; Peripheral Nervous System Diseases; Prospective Studies; Serotonin and Noradrenaline Reuptake Inhibitors; Taxoids; Treatment Outcome; Tubulin Modulators

Chemotherapy-induced peripheral neuropathy (CIPN) is common among cancer patients who undergo chemotherapy with platinum analogues, taxanes, vinca alkaloids, epothilone, bortezomib, and thalidomide. The purpose of this study was to investigate the evidence of using drugs affecting the central nervous system (CNS) to alleviate CIPN in cancer patients.. A systematic literature search was conducted using the CINAHL, EMBASE, and Medline databases to identify randomized controlled clinical trials (RCTs) reported in English up to 2013. We identified ten trials of CNS-acting drugs used to treat CIPN in cancer patients and reviewed efficacy and safety of CNS-acting drugs for CIPN using a standard data collection form. The risk of bias in each RCT was also assessed.. Antidepressants were used in six studies and anticonvulsants in four studies. We found positive results for amitriptyline (topical), venlafaxine, and oxcarbazepine in one study each, but the results were not sufficient to draw definite conclusions. One trial with duloxetine showed a moderate effect (effect size, 0.513, P = .003) on CIPN pain relief. However, none of the results has yet been duplicated in an RCT with a large sample size.. Insufficient RCTs exist to confirm the efficacy of CNS agents to reduce CIPN. This study highlighted the need for and the importance of conducting well-designed RCTs to generate evidence on CIPN symptom management. Additional RCTs are warranted to accelerate the potential use of CNS drugs for CIPN in cancer patients.

Topics: Amitriptyline; Anticonvulsants; Antidepressive Agents; Antineoplastic Agents; Boronic Acids; Bortezomib; Carbamazepine; Central Nervous System; Cyclohexanols; Duloxetine Hydrochloride; Epothilones; Humans; Neoplasms; Neuralgia; Oxcarbazepine; Peripheral Nervous System Diseases; Pyrazines; Taxoids; Thalidomide; Thiophenes; Venlafaxine Hydrochloride; Vinca Alkaloids

Estramustine, an agent with both hormonal and non-hormonal effects in men, is supposed to be effective in treating castration-resistant prostate cancer. However, previous studies have reported conflicting results. We conducted this meta-analysis to evaluate the efficacy and toxicity of additional estramustine to chemotherapy.. Data sources including PubMed, Medline, EMBASE, and Cochrane Controlled Trials Register were searched to identify potentially relevant randomized controlled trials. Prostate specific antigen (PSA) response, overall survival, and grade 3 to 4 toxicity were analyzed.. Seven randomized controlled trials, a total of 839 patients, were enrolled. The pooled odds ratio for PSA response was 3.02 (95% CI=1.69-5.39, P=.0002); the pooled hazard ratio for overall survival was .95 (95% CI=.80-1.14, P=.58); the pooled odds ratio for nausea/vomiting and cardiovascular toxicity were 3.90 (95% CI=1.05-14.45, P=.04) and 2.22 (95% CI=1.15-4.30, P=.02). No significant difference was detected for neutropenia, anemia, thrombocytopenia, diarrhea, fatigue, or neuropathy (P>.05).. According to this meta-analysis, chemotherapy with additional estramustine increased the PSA response rate. However, it increased the risk of grade 3 or 4 adverse effects such as nausea/vomiting and cardiovascular events, and the overall survival was not improved for castration-resistant prostate cancer patients.

Topics: Adenocarcinoma; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cardiovascular Diseases; Combined Modality Therapy; Docetaxel; Epirubicin; Epothilones; Estramustine; Fatigue; Gastrointestinal Diseases; Hematologic Diseases; Humans; Male; Orchiectomy; Paclitaxel; Peripheral Nervous System Diseases; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Salvage Therapy; Survival Analysis; Taxoids; Treatment Outcome; Vinblastine

Epothilones, belonging to the family of microtubule stabilizing agents, have shown prolonged remissions and improved survival in various types of refractory, treatment-resistant cancer. Ixabepilone (BMS-247550) is the main representative of these compounds. Peripheral neuropathy is a significant toxicity of epothilones, eventually resulting in dose modification and changes in the treatment plan.. This review critically looks at the pathogenesis, incidence, risk factors, characteristics, and management of epothilone-induced peripheral neuropathy (EIPN). We also highlight areas of future research to pursue.. References were identified by searches of PubMed from 2000 until December 2010 with related terms.. The mechanism underlying EIPN remains rather unclear. Damage to the ganglion soma cells and peripheral axons through disruption of microtubules of the mitotic spindle and by interference with the axonal transport in the affected neurons may significantly contribute to the pathogenesis of EIPN. As a result, epothilones primarily produce an axonal, dose-dependent, sensory distal peripheral neuropathy, which is reversible in most cases on discontinuation of treatment. The incidence of EIPN is mainly related to risk factors, including cumulative dose and probably pre-existing neuropathy. To date, apart from the use of dose reduction and schedule change algorithm, there is no effective treatment with neuroprotective agents for EIPN.. EIPN remains a very challenging area in the field of toxic neuropathies. As such, there is a need for further preclinical and prospective clinical studies to elucidate the pathogenesis of EIPN and provide further robust evidence on its incidence, course, and reversibility.

Topics: Dose-Response Relationship, Drug; Epothilones; Humans; Peripheral Nervous System Diseases; Risk Factors; Treatment Outcome; Tubulin Modulators

Patterns of breast cancer care continue to be amended because of the more frequent use of anthracyclines and taxanes in earlier lines of therapy (particularly in the adjuvant setting) and the emergence of multidrug resistance. When treating women with recurrent or metastatic breast cancer that is resistant to anthracyclines and taxanes, nurses have a unique opportunity to foster a sense of hope by helping patients understand available treatment options and what to expect during therapy. This article presents information on the use of an epothilone agent, ixabepilone (Ixempra, Bristol-Myers Squibb), a new treatment option for metastatic breast cancer after anthracycline and taxane failure. The information will allow nurses and their patients to collaborate as a team to help prevent or effectively manage side effects. In addition, nurses can take a proactive approach in educating patients about treatment options to enhance their quality of life.

Topics: Anthracyclines; Antimetabolites, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Capecitabine; Deoxycytidine; Drug Therapy, Combination; Epothilones; Female; Fluorouracil; Humans; Peripheral Nervous System Diseases; Taxoids; Tubulin Modulators

The epothilone B analog, ixabepilone, demonstrates low susceptibility to drug resistance mechanisms and has demonstrated clinically meaningful efficacy in patients refractory to other chemotherapeutic options. Ixabepilone is approved by the FDA for treatment of patients with metastatic breast cancer (MBC) progressing after taxanes and anthracyclines, either in combination with capecitabine or as monotherapy if the patient has already progressed on capecitabine. Ixabepilone is generally well tolerated at the approved dose and administration schedule of 40 mg/m(2) every 3 weeks. The most commonly observed dose-limiting adverse events (AEs) associated with ixabepilone are myelosuppression and peripheral neuropathy. Dose modification including dose reduction and dosing schedule modification may be utilized to manage toxicities, but this must be based on careful hematologic, neurologic, and liver function monitoring. Other ixabepilone dose schedules are being evaluated to further improve the risk/benefit profile. Weekly and daily schedules of ixabepilone have shown useful efficacy and reasonable tolerability. A recent phase II trial compared the tolerability of ixabepilone dosed once weekly (16 mg/m(2) on Days 1, 8, and 15 of each 28-day cycle) or every 3 weeks (40 mg/m(2) on Day 1 of each 21-day cycle) in patients with MBC. Preliminary data showed that both dosing schedules had an acceptable safety profile; however, more AEs were reported in patients receiving ixabepilone every 3 weeks. Ixabepilone is also being evaluated in combination with other anticancer agents (e.g., bevacizumab and lapatinib), in earlier breast cancer settings and in other indications.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bone Marrow; Breast Neoplasms; Capecitabine; Clinical Trials, Phase II as Topic; Deoxycytidine; Disease Progression; Drug Administration Schedule; Drug Interactions; Epothilones; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Lapatinib; Lymphatic Metastasis; Peripheral Nervous System Diseases; Quinazolines; Treatment Failure; Treatment Outcome; Tubulin Modulators

The epothilones are a new class of microtubule-stabilizing drugs that exert potent antitumor activity against taxane-resistant and multidrug resistant cell lines. The most clinically advanced member of this class is the semisynthetic epothilone B derivative ixabepilone.. This article reviews the preclinical and clinical data on ixabepilone in patients with locally advanced and metastatic breast cancer (MBC) and provides guidance for pharmacists on its optimal use.. PubMed and conference proceedings through August 2008.. In preclinical studies, ixabepilone has demonstrated potent antitumor activity and low susceptibility to mechanisms that confer tumor resistance. Clinically meaningful benefits have been achieved with ixabepilone monotherapy in phase 2 trials of patients with MBC who have failed previous chemotherapies (anthracyclines, taxanes, or capecitabine). In a randomized, phase 3 trial, the combination of ixabepilone and capecitabine proved more effective than capecitabine alone after the failure of taxane and anthracycline regimens. At the recommended dose and schedule, the therapeutic ratio of ixabepilone is generally favorable, and its adverse effects (notably neutropenia and peripheral neuropathy) are generally manageable and reversible.. Ixabepilone represents an advance in the treatment of anthracycline - and taxane-pretreated MBC. Future studies will define its efficacy in combination with other drugs used in the treatment of MBC, as well as in other types of cancer.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Clinical Trials as Topic; Deoxycytidine; Epothilones; Female; Fluorouracil; Humans; Neoplasm Metastasis; Neutropenia; Peripheral Nervous System Diseases; Premedication; Tubulin Modulators

Ixabepilone (BMS247550) is a semisynthetic derivative of the natural product that optimizes the properties observed with epothilone B. This compound has some similarities with taxanes in targeting and stabilizing microtubules, but it also has major differences. Interestingly, ixabepilone was evaluated in patients with well-characterized resistance to taxanes and was able to overcome the overexpression of multidrug resistance and was unaffected by mutations in the beta-tubulin genes. The interest in ixabepilone was clinically confirmed in Phase II and III clinical studies, which have demonstrated a strong activity in patients with metastatic breast cancer resistant to taxanes and in patients suffering from other types of chemoresistant tumors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Peripheral Nervous System Diseases; Randomized Controlled Trials as Topic; Tubulin Modulators

Ixabepilone is a novel microtubule-stabilizing agent with clinical efficacy in advanced breast cancer, including patients whose disease has progressed on prior anthracyclines and taxanes. The safety profile of single-agent ixabepilone and combination ixabepilone plus capecitabine therapy is reviewed, outlining the steps to effectively manage and prevent common adverse events. Ixabepilone is generally well tolerated, and importantly, its toxicity profile does not overlap with that of capecitabine. Peripheral sensory neuropathy and neutropenia are the most common toxicities associated with ixabepilone; both can be effectively managed by monitoring patients and then, depending on severity, instituting a treatment delay until recovery and reducing the ixabepilone dose for subsequent treatment cycles. Ixabepilone dose reductions are recommended for most grade 3 events, excluding transient fatigue, arthralgia, and myalgia, whereas treatment discontinuation is recommended for persistent grade 3 neuropathy or any grade 4 nonhematological toxicity. Because ixabepilone exposure is greater in patients with hepatic impairment and those receiving concomitant strong cytochrome P-450 CYP3A4 inhibitors, dose adjustments and restrictions are recommended according to the degree of hepatic impairment, whether ixabepilone is administered alone or in combination with capecitabine, and whether a strong CYP3A4 inhibitor is being coadministered. Patients should be premedicated with oral H(1) and H(2) antihistamines to prevent hypersensitivity reactions. Unlike taxanes, corticosteroid premedication is not required unless a hypersensitivity reaction occurred during a previous cycle or during treatment with another Cremophor-containing agent. By effectively managing adverse events and taking steps to minimize them, clinicians can ensure that patients derive the maximum benefit from ixabepilone therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Cells; Breast Neoplasms; Clinical Trials as Topic; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Epothilones; Female; Humans; Liver; Peripheral Nervous System Diseases; Tubulin Modulators

Microtubule-targeted anticancer drugs are effective in treating various cancers but are limited in use due to development of resistance and unacceptable toxicities. The epothilones are a novel class of microtubule-stabilizing anticancer drugs and may have a role in treating taxane-resistant cancers. Revised and updated data from several clinical studies for ixabepilone were recently published and subsequently resulted in ixabepilone becoming the first epothilone approved as monotherapy or in combination for treatment of locally advanced or metastatic breast cancer. BMS-310705, patupilone, KOS-862, KOS-1584 and ZK-EPO are epothilones that have been developed. Although peripheral sensory neuropathy and neutropenia are the dose-limiting toxicities for ixabepilone, these dose-limiting toxicities are ixabepilone specific. This review will discuss the current preclinical, clinical pharmacokinetic and pharmacodynamic, efficacy and toxicity data of the epothilones.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Dogs; Drug Screening Assays, Antitumor; Epothilones; Female; Humans; Male; Mice; Microtubules; Neoplasm Metastasis; Neutropenia; Peripheral Nervous System Diseases; Rats; Structure-Activity Relationship; Tubulin Modulators

The epothilones are a new class of non-taxane tubulin polymerization agents obtained by natural fermentation of the myxobacteria Sorangium cellulosum. The cytotoxic activities of the epothilones, like those of the taxanes, have been linked to stabilization of microtubules, but they also have important differences. Among the epothilone family, ixabepilone (BMS247550) is a semisynthetic derivative of the natural product epothilone B. Ixabepilone was evaluated in vivo in a panel of human and rodent tumour models, the majority of which were chosen because of their known, well-characterized resistance to paclitaxel, and seems able to overcome the over-expression of multidrug resistance and to be unaffected by mutations in the beta tubulin gene. The interest of ixabepilone was clinically confirmed in clinical studies of phase II which demonstrated a strong activity at the patients with metastatic breast cancer resistant to taxanes and in patients suffering of other types of chemoresistant tumors.

Topics: Animals; Bone Marrow; Breast Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Hypersensitivity; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Male; Maximum Tolerated Dose; Neoplasms; Paclitaxel; Peripheral Nervous System Diseases; Taxoids; Tubulin Modulators

Microtubule-stabilizing agents (MTSAs), including the taxanes and epothilones, are effective chemotherapeutic agents for the treatment of many cancers. Neuropathy is a major adverse effect of MTSA-based chemotherapy, with severe peripheral neuropathy (grade 3 or 4) occurring in as many as 30% of patients treated with a MTSA. MTSA-induced neuropathy usually resolves gradually after cessation of the treatment. The most reliable method to accurately assess MTSA-induced neuropathy is by clinical evaluation, although additional techniques are being developed and evaluated. Among MTSA-induced neuropathy, the most extensively studied is that induced by taxanes; such a neuropathy usually presents as sensory neuropathy and is more common with paclitaxel than docetaxel. The incidence of MTSA-induced neuropathy seems to depend on the MTSA dose per treatment cycle, the schedule of treatment, and the duration of the infusion. Although there have been several small clinical trials with neuroprotective agents, early recognition and supportive care are the best approaches for prevention and management of MTSA-induced neuropathy. In the future, research should focus on elucidating the mechanism of MTSA-induced neuropathy, developing reliable in vivo and in vitro preclinical models to study MTSA-induced neuropathy, developing a more reliable grading system for MTSA-induced neuropathy, developing more reliable methods for evaluating MTSA-induced neuropathy, and evaluating the efficacy of potential neuroprotective agents in clinical trials.

Topics: Albumin-Bound Paclitaxel; Albumins; Animals; Antineoplastic Agents; Epothilones; Humans; Microtubules; Neuroprotective Agents; Paclitaxel; Pain Management; Peripheral Nervous System Diseases; Risk Factors; Tubulin Modulators

This paper examines recent research on toxic neuropathy and potential therapeutic developments. It also summarizes reports of new agents reported to cause peripheral neuropathy.. Gene therapy with vasoactive endothelial growth factor, neurotrophic substances such as nerve growth factor and neurotrophin-3 are reported to reverse or protect against neurotoxicity in animal models. The neuroprotective effects of more established therapeutic agents like vitamin E, tacrolimus (FK 506) and erythropoietin hold promise for the immediate future. Cisplatin and high-dose pyridoxine are used more frequently to produce robust models of peripheral neuropathy in animals. Statins do appear to cause peripheral neuropathy. The incidence is low, however, and compared to its benefits in terms of cardiovascular protection, relatively innocuous. The profile of thalidomide neuropathy is becoming clearer as the indications for this drug increases. The incidence of thalidomide neuropathy is high, up to three quarters in some series, and although the information on dose dependency is variable, lower cumulative doses appear to be less toxic. Like thalidomide bortezomib, a novel proteosome inhibitor, is reportedly effective in the treatment of multiple myeloma and is associated with peripheral neuropathy. Oxaliplatin and epothilone are emerging anticancer drugs with neurotoxic potential. Similarly, leflunomide, a new disease modifying-agent approved for the treatment of rheumatoid arthritis, is reported to cause neuropathy.. The study of toxic neuropathy is not only enhancing our knowledge of the mechanisms of neurotoxicity but also the neurobiology of peripheral neuropathy in general; and is likely to reveal avenues for therapeutics.

Topics: Animals; Boronic Acids; Bortezomib; Clinical Trials as Topic; Epothilones; Genetic Therapy; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Isoxazoles; Leflunomide; Neuritis; Neuroprotective Agents; Neurotoxicity Syndromes; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Pyrazines; Pyridoxine; Thalidomide

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major clinical problem because it represents the dose-limiting side effects of a significant number of antineoplastic drugs. The incidence of CIPN varies depending on the drugs and schedules used, and this can be quite high, particularly when neurophysiological methods are used to make a diagnosis. However, even when CIPN is not a dose-limiting side effect, its onset may severely affect the quality of life of cancer patients and cause chronic discomfort. In this review the features of CIPN due to the administration of the most widely used drugs, such as platinum drugs, taxanes and vinca alkaloids, and of two old drugs with new clinical applications, suramin and thalidomide, will be discussed. Moreover, the earliest data regarding the neurotoxicity of some new classes of very promising antineoplastic agents, such as epothilones and proteasome inhibitors, will be discussed. Finally, the data available on neuroprotectants, evaluated in the attempt to prevent CIPN, will be summarised.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Epothilones; Humans; Neoplasms; Neuroprotective Agents; Organoplatinum Compounds; Peripheral Nervous System Diseases; Protease Inhibitors; Suramin; Taxoids; Thalidomide

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity caused by several chemotherapeutic agents. Currently, CIPN is managed by empirical dose modifications at the discretion of the treating physician. The goal of this research is to quantitate the dose-CIPN relationship to inform the optimal strategies for dose modification. Data were obtained from the Cancer and Leukemia Group B (CALGB) 40502 trial, a randomized phase III trial of paclitaxel vs. nab-paclitaxel vs. ixabepilone as first-line chemotherapy for locally recurrent or metastatic breast cancer. CIPN was measured using a subset of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group Neurotoxicity (FACT-GOG-NTX) scale. A kinetic-pharmacodynamic (K-PD) model was utilized to quantitate the dose-CIPN relationship simultaneously for the three drugs. Indirect response models with linear and S

Topics: Albumins; Antineoplastic Agents; Breast Neoplasms; Dose-Response Relationship, Drug; Epothilones; Female; Humans; Models, Biological; Neoplasm Metastasis; Paclitaxel; Peripheral Nervous System Diseases

Peripheral neuropathy is a common toxicity associated with tubulin-targeted chemotherapeutic agents. This Phase II study compares the incidence and severity of neuropathy associated with eribulin mesylate or ixabepilone in metastatic breast cancer (MBC). The primary objective was to assess the incidence of neuropathy; the study was designed to detect a difference in neuropathy rate of 35 % for eribulin versus 63 % for ixabepilone (odds ratio 0.316, 80 % power, 0.05 two-sided significance level). Eligibility criteria included: MBC; prior taxane therapy; at least one chemotherapy for advanced disease; no or minimal pre-existing neuropathy (Grade 0 or 1). The intent-to-treat population comprised 104 patients randomized (1:1) to eribulin mesylate (1.4 mg/m(2), 2-5 min intravenous on days 1 and 8) or ixabepilone (40 mg/m(2), 3 h intravenous on day 1) on a 21-day cycle. 101 patients in the safety population received a median of 5.0 eribulin and 3.5 ixabepilone cycles. Incidence of neuropathy (any grade) was 33.3 and 48.0 %, and peripheral neuropathy was 31.4 and 44.0 % for eribulin and ixabepilone, respectively. After controlling for pre-existing neuropathy and number of prior chemotherapies, these differences were not significant. Compared with ixabepilone, fewer patients receiving eribulin discontinued treatment due to neuropathy (3.9 vs. 18.0 %) or adverse events (AEs) in general (11.8 vs. 32.0 %). Time to onset of neuropathy was 35.9 weeks for eribulin and 11.6 weeks for ixabepilone, and time to resolution was 48 versus 10 weeks, respectively; other AEs were comparable. Objective responses were 15.4 versus 5.8 % and clinical benefit rates were 26.9 versus 19.2 %. In conclusion, after controlling for pre-existing neuropathy and number of prior chemotherapies, the differences in the incidence of neuropathy with eribulin and ixabepilone were not statistically significant. Onset of neuropathy tended to occur later with eribulin and resolve later.

Topics: Adult; Breast Neoplasms; Epothilones; Female; Furans; Humans; Ketones; Middle Aged; Neoplasm Metastasis; Peripheral Nervous System Diseases; Survival Rate

Peripheral neuropathy (PN) is a recognized side effect of microtubule-targeting agents and the most clinically relevant toxicity observed with the epothilone sagopilone (SAG). Studies suggest that acetyl-L-carnitine (ALC) may prevent chemotherapy-induced PN. We conducted a prospective, placebo (PBO)-controlled, double-blind, randomized trial to investigate the safety and efficacy of ALC for the prevention of SAG-induced PN. Methods. Patients with ovarian cancer (OC) or castration-resistant prostate cancer (CRPC) and no evidence of neuropathy received SAG (16 mg/m(2) intravenously over 3 hours every 3 weeks) with ALC (1,000 mg every 3 days) or placebo (PBO). The primary endpoint was incidence of PN within six or fewer cycles in both treatment groups. Results. Overall, 150 patients enrolled (98 OC patients, 52 CRPC patients), with 75 per treatment arm. No significant difference in overall PN incidence was observed between treatment arms. The incidence of grade ≥3 PN was significantly lower in the ALC arm in OC patients. Median duration of neuropathy was similar between treatment arms. The best overall response (according to the modified Response Evaluation Criteria in Solid Tumors), response according to tumor markers, time-to-event variables, and discontinuations because of adverse events (AEs) were comparable between treatment arms. Conclusion. Administration of ALC with SAG did not result in a significant difference in overall PN incidence compared with a PBO. OC patients in the SAG/ALC arm had a significantly lower incidence of grade 3 or 4 PN compared with OC patients in the SAG/PBO arm.

Topics: Acetylcarnitine; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzothiazoles; Double-Blind Method; Epothilones; Female; Humans; Male; Middle Aged; Ovarian Neoplasms; Peripheral Nervous System Diseases; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

This multicenter, open-label, randomized phase II trial compared the efficacy and tolerability of weekly ixabepilone versus the standard 3 weekly dosing regimen. Patients with human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC) were randomly assigned to receive either ixabepilone 16 mg/m(2) as a 1-h intravenous (IV) infusion weekly on days 1, 8, and 15 of a 28-day cycle (1 week off therapy; n = 85), or 40 mg/m(2) as a 3-h IV infusion on day 1 of a 21-day cycle (n = 91), until disease progression or unacceptable toxicity. Randomization was stratified by (i) measurable versus nonmeasurable (evaluable) disease, (ii) ≤two versus >two prior chemotherapy regimens for MBC, and (iii) hormone receptor (HR)-positive versus HR-negative breast cancer. The primary endpoint was rate of progression-free survival (PFS) at 6 months. Of 176 randomized patients, 171 were treated. The 6-month PFS rate was significantly higher in patients treated with ixabepilone every 3 weeks (42.7, 95 % confidence interval [CI] 31.5-53.5) compared with those who received ixabepilone weekly (28.6, 95 % CI 18.9-38.9; log-rank P = 0.03). Every-3-week dosing significantly prolonged median PFS versus weekly dosing (5.3 vs. 2.9 months; log-rank P = 0.05). The every-3-week regimen was associated with higher rates of grade 3/4 toxicities, particularly neutropenia (38.2 vs. 6.1 %) and a higher rate of patient withdrawal due to adverse events. These results suggest that every-3-week ixabepilone is more effective than weekly treatment in MBC, albeit with more toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Drug Administration Schedule; Epothilones; Female; Humans; Middle Aged; Neutropenia; Peripheral Nervous System Diseases; Treatment Outcome

First-in-man study of KOS-1584, a second generation epothilone.. Patients with advanced solid malignancies received KOS-1584 every 3 weeks until disease progression. Using a modified Fibonacci dose escalation scheme, one patient was enrolled at each dose level until the first instance of grade 2 toxicity. Thereafter, a standard 3 + 3 design was utilized.. Sixty-six patients in 14 cohorts were dosed from 0.8 to 48 mg/m(2). Diarrhea, arthralgias, and encephalopathy were dose-limiting toxicities (DLTs) at doses ≥36 mg/m(2). At the recommended phase II dose (RP2D), the most common adverse effects were peripheral neuropathy (low grade), fatigue, arthralgias/myalgias, and diarrhea (31, 6%). The incidence of neutropenia was low. The overall clearance, volume of distribution, and half-life of KOS-1584 were 11 ± 6.17 L/h/m(2), 327 ± 161 L/m(2), and 21.9 ± 8.75 h, respectively. The half-life for the seco-metabolite (KOS-1891) was 29.6 ± 13.8 h. KOS-1584 exhibited linear pharmacokinetics. A dose-dependent increase in microtubulin bundle formation was observed at doses ≥27 mg/m(2). Two patients achieved partial responses and 24 patients had stable disease (SD).. The RP2D of KOS-1584 is 36 mg/m(2). The lack of severe neurologic toxicity, diarrhea, neutropenia, or hypersensitivity reactions; favorable pharmacokinetic profile; and early evidence of activity support further evaluation.

Topics: Adult; Aged; Aged, 80 and over; Area Under Curve; Arthralgia; Diarrhea; Dose-Response Relationship, Drug; Epothilones; Fatigue; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Molecular Structure; Neoplasms; Peripheral Nervous System Diseases; Treatment Outcome; Tubulin Modulators

Effective treatment options for patients with metastatic breast cancer pretreated with or resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed as a prospective clinical trial to evaluate the efficacy and safety of ixabepilone plus capecitabine in both anthracycline-pretreated and resistant and taxane-resistant metastatic breast cancer of Chinese women.. Patients with measurable disease who had anthracycline and taxanes as prior neoadjuvant, adjuvant or metastatic therapy were treated with ixabepilone at 40 mg/m(2) intravenously on day 1 of 21-day cycle plus capecitabine 2,000 mg/m(2) orally on day 1 through 14 of a 21-day cycle. The primary end point was the objective response rate. The secondary end points were time to progression, overall survival, and toxicity profiles.. Twenty-one patients received 146 cycles with a median of 5 cycles (range 1-13 cycles) per patients. Fourteen patients (66.7%) had partial response, 5 patients (23.8%) had stable disease, and 2 patients (9.5%) had progressive disease. Median time to progression and duration of response were 6.2 and 6.0 months, respectively. The median overall survival was 16.7 months. Eight (38.1%) patients required dose reduction and 14 (66.7%) patients discontinued treatment for adverse effect. Grade 3/4 treatment-related events included fatigue (28.6%), peripheral sensory neuropathy (33.3%), neutropenia (61.9%), anemia (4.7%), hypokalemia (4.7%), hand and foot syndrome (19.0%) and infection (9.5%). Resolution of grade 3/4 peripheral neuropathy was reversible after a median period of 6 weeks.. Ixabepilone plus capecitabine demonstrated a clear activity and an acceptable safety profile in Chinese patients with anthracycline-pretreated/resistant and taxane-resistant metastatic breast cancer, and the majority of patients completed 6 cycles of the therapy with manageable neuropathy toxicities.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Asian People; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; China; Deoxycytidine; Disease Progression; Dose-Response Relationship, Drug; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Peripheral Nervous System Diseases; Prospective Studies; Survival Rate; Taxoids; Treatment Outcome

We sought to determine whether the combination of ixabepilone plus capecitabine improved overall survival (OS) compared with capecitabine alone in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes.. A total of 1,221 patients with MBC previously treated with anthracycline and taxanes were randomly assigned to ixabepilone (40 mg/m(2) intravenously on day 1) plus capecitabine (2,000 mg/m(2) orally on days 1 through 14) or capecitabine alone (2,500 mg/m(2) on the same schedule) given every 21 days. The trial was powered to detect a 20% reduction in the hazard ratio (HR) for death.. There was no significant difference in OS between the combination and capecitabine monotherapy arm, the primary end point (median, 16.4 v 15.6 months; HR = 0.9; 95% CI, 078 to 1.03; P = .1162). The arms were well balanced with the exception of a higher prevalence of impaired performance status (Karnofsky performance status 70% to 80%) in the combination arm (32% v 25%). In a secondary Cox regression analysis adjusted for performance status and other prognostic factors, OS was improved for the combination (HR = 0.85; 95% CI, 0.75 to 0.98; P = .0231). In 79% of patients with measurable disease, the combination significantly improved progression-free survival (PFS; median, 6.2 v 4.2 months; HR = 0.79; P = .0005) and response rate (43% v 29%; P < .0001). Grade 3 to 4 neuropathy occurred in 24% treated with the combination, but was reversible.. This study confirmed a previous trial demonstrating improved PFS and response for the ixabepilone-capecitabine combination compared with capecitabine alone, although this did not result in improved survival.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Drug Administration Schedule; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Peripheral Nervous System Diseases; Retreatment; Taxoids

We have previously established the recommended phase II dose (RPTD) of ixabepilone as 40 mg/m(2) administered over 1 h repeated every 3 weeks with neuropathy as a cumulative dose-limiting toxicity. We expanded the cohort at the RPTD to include detailed assessment of nerve damage in these patients. We report our findings on vibration perception threshold (VPT) and neuropathy.. Forty-four patients were treated with a median (range) of three (1-14) cycles of ixabepilone. The VPT (5-min duration) and nerve conduction test (NCT, 10-min duration) were carried out in the office, before ixabepilone dosing, and every two cycles thereafter.. Neuropathy (grade 1 and grades 2-3) was observed in 17 (38.6%) and 11 (25%) patients, respectively. The mean increase in VPT as a function of grade 0-1 versus grades 2-3 neuropathy was 0.235 +/- 0.03 versus 0.869 +/- 0.09 (P = 0.049) vibration units. The F-wave frequency and distal motor latency, as assessed using the NCT, did not correlate with clinical neurotoxicity.. The change in VPT is observed early and likely reflects early vibration perception change. Mean change in VPT correlates with the severity of clinical neuropathy. Whether VPT change predicts onset of severe neuropathy warrants prospective testing and validation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Epothilones; Female; Humans; Male; Middle Aged; Neoplasms; Neural Conduction; Neurologic Examination; Peripheral Nervous System Diseases; Somatosensory Disorders; Vibration

Ixabepilone is a tubulin-polymerizing agent with potential activity in squamous cell carcinoma of the head and neck (SCCHN). Patients were eligible who had incurable, measurable SCCHN and less than two prior regimens for metastatic/recurrent disease. Eastern Cooperative Oncology Group performance status of less than or equal to one and adequate renal/hepatic/hematological function were required. Patients were randomly assigned to receive ixabepilone 6 mg/m(2)/day x 5 days every 21 days (arm A) or 20 mg/m(2) on days 1, 8, and 15 of a 28-day cycle (arm B). Each arm accrued taxane-naive and -exposed strata in a two-stage design. The primary end point was response. Eighty-five eligible patients entered; there was one response in a taxane-exposed patient among 32 patients on arm A. Five of 35 taxane-naive patients on arm B had partial responses (14%). No taxane-exposed patient on arm B responded. Common grades 3 and 4 toxic effects were fatigue, neutropenia, and sensory/motor neuropathy. Median survival for arm A taxane-naive and taxane-exposed patients is 5.6 and 6.5 months; for arm B, taxane-naive and taxane-exposed patients is 7.8 and 6.5 months. Weekly ixabepilone 20 mg/m(2) is active in taxane-naive patients with SCCHN. A high incidence of motor and sensory grade 3 neuropathy resulted at this dose and schedule. Further development of ixabepilone in previously treated head and neck cancer is not warranted on the basis of these data.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Combined Modality Therapy; Disease-Free Survival; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Epothilones; Female; Head and Neck Neoplasms; Hematologic Diseases; Humans; Infusions, Intravenous; Male; Middle Aged; Paclitaxel; Peripheral Nervous System Diseases; Recurrence; Salvage Therapy; Survival Analysis; Taxoids

Twelve patients with metastatic breast cancer previously exposed to taxanes were treated on a Phase II trial with ixabepilone. Eligible patients had histologically confirmed metastatic breast cancer with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), and adequate hematopoietic, renal, and hepatic function. Ixabepilone 8 mg/m(2)/day was given intravenously daily for 3 days for the first 3-week cycle and increased to 10 mg/m(2)/day for subsequent cycles if patients did not have hematologic or other toxicity after the first cycle. Patients continued treatment until progressive disease or unacceptable toxicity. Three, 29, and 33 of 65 cycles administered were at the 7 mg/m(2), 8 mg/m(2) and 10 mg/m(2) dose levels respectively. Grade 4 leukopenia (n=1), grade 3 neutropenia (n=2), grade 2 neuropathy (n=3), and grade 2 transaminase elevation (n=2) were the most notable toxicities. Ten patients had stable disease for at least 6 weeks. No complete or partial responses were observed in 12 evaluable patients treated with ixabepilone daily for 3 days. Although ixabepilone was well-tolerated, the dose of 8-10 mg/m(2) daily for 3 days is not an effective therapy in metastatic breast cancer previously exposed to taxanes.

Topics: Adult; Aspartate Aminotransferases; Breast Neoplasms; Disease Progression; Drug Administration Schedule; Epothilones; Female; Hematologic Diseases; Humans; Injections, Intravenous; Middle Aged; Neoplasm Metastasis; Peripheral Nervous System Diseases; Time Factors; Transaminases; Treatment Outcome; Tubulin Modulators

To establish the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or relapsed/refractory non-Hodgkin's lymphoma. Dosing schedules of 40 mg/m2 and 50 mg/m2 over 3 hours were also evaluated.. Sixty-one patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase, with doses of ixabepilone ranging from 7.4 to 65 mg/m2. The pharmacokinetics of ixabepilone and two of its chemical degradation products were evaluated. Plasma pharmacodynamics were evaluated for both 1- and 3-hour infusions using an assay that measures the amount of endogenous tubulin in peripheral-blood mononuclear cells that exists in the polymerized versus the unpolymerized state. Response evaluation was performed every 6 weeks.. The most common DLTs were neutropenia, stomatitis/pharyngitis, myalgia, and arthralgia. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The maximum plasma concentration and area under the plasma concentration time curve appeared to increase less than proportionally to dose. Durable objective responses were seen in eight patients, including two complete responses. Five of the responders had experienced treatment failure with a taxane.. The recommended dose of ixabepilone for the initiation of phase II studies on the basis of these results is 50 mg/m2 over 1 hour every 3 weeks. The promising efficacy and tolerability results demonstrated by ixabepilone in this study warrant its continued development.

Topics: Adult; Aged; Antineoplastic Agents; Cohort Studies; Drug Administration Schedule; Drug Hypersensitivity; Epothilones; Female; Humans; Infusions, Intravenous; Lymphoma, Non-Hodgkin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Neutropenia; Peripheral Nervous System Diseases; Practice Guidelines as Topic; Survival Analysis; Thrombocytopenia; Time Factors; Treatment Failure; Treatment Outcome; Tubulin Modulators; United States

Ixabepilone is one of the epothilones, a new class of cytotoxics, that function as microtubule-stabilizing agents. With the primary endpoint of assessing ixabepilone's response rate against metastatic gastric cancer previously treated with a taxane, we performed a multi-center phase II trial.. Patients with histologically documented metastatic gastric or gastroesophageal adenocarcinoma, who had previously received a taxane, were eligible. Patients were required to have near normal organ function, > or =18 years of age, ECOG performance status of 0 or 1. A written informed consent was obtained from all patients. Ixabepilone was administered over one hour intravenously at a dose of 50 mg/m2 every 21 days (23 patients; cohort A) and 24 subsequent patients were treated with an amended protocol schedule to receive 6 mg/m2 intravenously on days 1-5 every 21 days (cohort B).. A total of 47 patients were treated. Most patients were men with a median performance status of 1. Two of 23 patients in cohort A achieved a confirmed partial response (9%, 95% CI 1.1-28%) but none of the 24 patients in cohort B achieved a response. A higher proportion of patients in cohort A experienced Grade 3/4 toxicities compared with those in cohort B.. Ixabepilone, on a once every 21-day schedule, is modestly active against metastatic gastric cancer previously treated with a taxane. The days 1-5 every 21 days schedule had a more favorable safety profile but no activity. The results of this study suggest that once every 21-day ixabepilone schedule should be pursued further in untreated gastric or gastroesophageal adenocarcinoma patients.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Bridged-Ring Compounds; Disease Progression; Epothilones; Female; Humans; Male; Middle Aged; Multicenter Studies as Topic; Peripheral Nervous System Diseases; Stomach Neoplasms; Taxoids

To investigate baseline factors and neurologic function tests (NFTs) that may predict the development of grade 2 or higher peripheral neuropathy (PN) after treatment with ixabepilone, an epothilone microtubule-stabilizing agent with antitumor activity.. Advanced breast cancer patients were treated with ixabepilone (6 mg/m2) for 5 consecutive days every 3 weeks in a phase II clinical trial. Physical examinations, questionnaires, nerve conduction studies, and NFTs, including the Jebsen Test of Hand Function (JTH) and the Grooved Pegboard Test (GPT), were performed at baseline and during subsequent cycles.. Forty-seven patients assessable for PN received a median of five cycles of therapy (range, one to 22 cycles). Nine of these patients developed grade 2 PN, and two developed grade 3 PN, with a median time to onset of 144 days (range, 6 to 189 days). Among these 11 patients, PN resolved in eight patients, with a median of 15 days (range, 6 to 346 days) after onset, but PN did not resolve in three patients during follow-ups at 76, 361, and 746 days after onset. GPT and changes of JTH scores at onset of PN were significantly different between patients with and without PN at comparable follow-up times (P = .006 and P = .002, respectively). Changes in GPT and JTH scores over the first two cycles were often associated with the development of PN by exploratory actuarial analysis.. Serious ixabepilone-induced neuropathy was relatively rare on the treatment schedule used. NFTs, such as JTH and GPT, may have utility for predicting PN, but further testing is needed.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Epothilones; Female; Humans; Middle Aged; Peripheral Nervous System Diseases; Prospective Studies

To evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer.. Patients were randomly assigned to receive ixabepilone (35 mg/m(2)) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5.. Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of > or = 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm.. Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Castration; Epothilones; Estramustine; Fatigue; Humans; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Peripheral Nervous System Diseases; Prostatic Neoplasms; Thrombosis

Chemotherapy-induced peripheral neuropathy (henceforth, neuropathy) is often dose limiting and is generally managed by empirical dose modifications. We aimed to (1) identify an early time point that is predictive of future neuropathy using a patient-reported outcome and (2) propose a dose-adjustment algorithm based on simulated data to manage neuropathy. In previous work, a dose-neuropathy model was developed using dosing and patient-reported outcome data from Cancer and Leukemia Group B 40502 (Alliance), a randomized phase III trial of paclitaxel, nanoparticle albumin-bound paclitaxel or ixabepilone as first-line chemotherapy for locally recurrent or metastatic breast cancer. In the current work, an early time point that is predictive of the future severity of neuropathy was identified based on predictive accuracy of the model. Using the early data and model parameters, simulations were conducted to propose a dose-adjustment algorithm for the prospective management of neuropathy in individual patients. The end of the first 3 cycles (12 weeks) was identified as the early time point based on a predictive accuracy of 75% for the neuropathy score after 6 cycles. For paclitaxel, nanoparticle albumin-bound paclitaxel, and ixabepilone, simulations with the proposed dose-adjustment algorithm resulted in 61%, 48%, and 35% fewer patients, respectively, with neuropathy score ≥8 after 6 cycles compared to no dose adjustment. We conclude that early patient-reported outcome data on neuropathy can be used to guide dose adjustments in individual patients that reduce the severity of future neuropathy. Prospective validation of this approach should be undertaken in future studies.

Topics: Albumins; Algorithms; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Computer Simulation; Drug Administration Schedule; Drug Tapering; Epothilones; Female; Humans; Models, Biological; Paclitaxel; Patient Reported Outcome Measures; Peripheral Nervous System Diseases; Precision Medicine

Chemotherapy-induced peripheral neuropathy is a common adverse reaction in a variety of medications frequently used for a great number of cancer treatments. This condition consists of mainly sensory-type symptoms, motor components and autonomic changes. Reported prevalence ranges from 30-68%, after the completion of chemotherapy in non-Latin American people with different populations and socioeconomic levels.. To determine the prevalence of chemotherapy-induced peripheral neuropathy in a Colombian population.. A real-world evidence cross-sectional retrospective study was performed in all patients from oncological clinical centers in Colombia, which received pharmacological therapy for any cancer between January 2015 and December 2016, with taxanes (paclitaxel, docetaxel), alkylators (oxaliplatin), proteasome inhibitors (bortezomib), and epothilone B analogs (ixabepilone).. A total of 1,551 patients in four cities were included, and 11,280 doses were applied; predominantly females (n = 1,094; 70.5%), with a mean age of 57 ± 13 years old. Paclitaxel was the most commonly prescribed drug (n = 788; 50.8%). Chemotherapy-induced peripheral neuropathy was developed in 48.9% of paclitaxel, 58.5% of oxaliplatin, 50.5% of docetaxel, 43.7% of bortezomib and 95.2% of ixabepilone patients. Thirty-three patients were treated with two of these medications simultaneously.. Chemotherapy-induced peripheral neuropathy is a frequent adverse reaction to daily cancer therapy in Colombian patients managed with taxanes, alkylators, proteasome inhibitors, and epothilone B analogs. Hence, it is necessary to establish more successful diagnostic methods and incorporate validated scales in the routine evaluation of all patients receiving these medications in our environment.. Prevalencia de neuropatia periferica asociada a quimioterapia en cuatro centros oncologicos de Colombia.. Introduccion. La neuropatia periferica inducida por quimioterapia es una reaccion comun a una variedad de medicamentos usados en el tratamiento del cancer, que consiste principalmente en sintomas sensitivos, con componentes motores y cambios autonomicos. La prevalencia es del 30-68% despues de terminar la quimioterapia en paises no latinoamericanos. Objetivo. Determinar la prevalencia de la neuropatia periferica inducida por quimioterapia en la poblacion colombiana. Pacientes y metodos. Estudio retrospectivo con evidencia del mundo real en la totalidad de pacientes atendidos en cuatro centros oncologicos de Colombia, quienes recibieron terapia farmacologica para algun tipo de cancer entre enero de 2015 y diciembre de 2016 con taxanos (paclitaxel, docetaxel), agentes alquilantes (oxaliplatino), inhibidores de proteasoma (bortezomib) y analogos de epotilona B (ixabepilona). Resultados. Se siguio a un total de 1.551 pacientes en cuatro ciudades a quienes se les aplicaron 11.280 dosis, con predominio femenino (n = 1.094; 70,5%) y una edad media de 57 ± 13 años. El paclitaxel fue el farmaco mas prescrito (n = 788; 50,8%). La neuropatia inducida por quimioterapia se presento en el 48,9% de los pacientes con paclitaxel, el 58,5% de los pacientes con oxaliplatino, el 50,5% de los pacientes con docetaxel, el 43,7% de los pacientes con bortezomib y el 95,2% de los pacientes con ixabepilona. Se trato a 33 pacientes con dos de estos medicamentos simultaneamente. Conclusiones. La neuropatia periferica inducida por quimioterapia es una reaccion adversa frecuente en pacientes con cancer en Colombia tratados con taxanos, alquilantes, inhibidores de proteasoma e ixabepilona. Es necesario establecer metodos diagnosticos efectivos e incorporar escalas validadas en la evaluacion rutinaria de los pacientes que reciben estas medicaciones.

Topics: Adult; Aged; Antineoplastic Agents; Bortezomib; Cancer Care Facilities; Colombia; Cross-Sectional Studies; Epothilones; Female; Humans; Male; Middle Aged; Oxaliplatin; Peripheral Nervous System Diseases; Prevalence; Protease Inhibitors; Retrospective Studies; Taxoids

Peripheral neuropathy is a dose-limiting side effect of anticancer treatment with the microtubule-targeted agents (MTAs), paclitaxel and epothilone B (EpoB); however, the mechanisms by which the MTAs alter neuronal function and morphology are unknown. We previously demonstrated that paclitaxel alters neuronal sensitivity, in vitro, in the presence of nerve growth factor (NGF). Evidence in the literature suggests that NGF may modulate the neurotoxic effects of paclitaxel. Here, we examine whether NGF modulates changes in neuronal sensitivity and morphology induced by paclitaxel and EpoB. Neuronal sensitivity was assessed using the stimulated release of calcitonin gene-related peptide (CGRP), whereas morphology of established neurites was evaluated using a high content screening system. Dorsal root ganglion cultures, maintained in the absence or presence of NGF, were treated from day 7 to day 12 in culture with paclitaxel (300nM) or EpoB (30nM). Following treatment, the release of CGRP was stimulated using capsaicin or high extracellular potassium. In the presence of NGF, EpoB mimicked the effects of paclitaxel: capsaicin-stimulated release was attenuated, potassium-stimulated release was slightly enhanced and the total peptide content was unchanged. In the absence of NGF, both paclitaxel and EpoB decreased capsaicin- and potassium-stimulated release and the total peptide content, suggesting that NGF may reverse MTA-induced hyposensitivity. Paclitaxel and EpoB both decreased neurite length and branching, and this attenuation was unaffected by NGF in the growth media. These differential effects of NGF on neuronal sensitivity and morphology suggest that neurite retraction is not a causative factor to alter neuronal sensitivity.

Topics: Animals; Antineoplastic Agents; Calcitonin Gene-Related Peptide; Capsaicin; Epothilones; Ganglia, Spinal; Male; Microtubules; Nerve Growth Factor; Neurites; Neuropeptides; Neurotransmitter Agents; Paclitaxel; Peripheral Nervous System Diseases; Potassium; Rats; Rats, Sprague-Dawley; Sensory Receptor Cells

Chemotherapy-induced peripheral neuropathy is a dose-limiting side effect of many antineoplastic agents, but the mechanisms underlying the toxicities are unclear. At their MTDs, the microtubule-binding drugs paclitaxel and ixabepilone induce more severe neuropathy in mice relative to eribulin mesylate, paralleling their toxicity profiles in clinic. We hypothesized that the severity of their neurotoxic effects might be explained by the levels at which they accumulate in the peripheral nervous system. To test this hypothesis, we compared their pharmacokinetics and distribution in peripheral nerve tissue. After administration of a single intravenous dose, each drug was rapidly cleared from plasma but all persisted in the dorsal root ganglia (DRG) and sciatic nerve (SN) for up to 72 hours. Focusing on paclitaxel and eribulin, we performed a 2-week MTD-dosing regimen, followed by a determination of drug pharmacokinetics, tissue distribution, and multiple functional measures of peripheral nerve toxicity for 4 weeks. Consistent with the acute dosing study, both drugs persisted in peripheral nervous tissues for weeks, in contrast to their rapid clearance from plasma. Notably, although eribulin exhibited greater DRG and SN penetration than paclitaxel, the neurotoxicity observed functionally was consistently more severe with paclitaxel. Overall, our results argue that sustained exposure of microtubule-binding chemotherapeutic agents in peripheral nerve tissues cannot by itself account for their associated neurotoxicity. Cancer Res; 76(11); 3332-9. ©2016 AACR.

Topics: Animals; Apoptosis; Blotting, Western; Cell Proliferation; Dose-Response Relationship, Drug; Electrophysiology; Epothilones; Female; Furans; Ganglia, Spinal; Ketones; Mice; Mice, Inbred BALB C; Microtubules; Paclitaxel; Peripheral Nervous System Diseases; Sciatic Nerve; Time Factors; Tissue Distribution; Tubulin Modulators

Peripheral neuropathy is a serious, dose-limiting side effect of cancer treatment with microtubule-targeting drugs. Symptoms present in a "stocking-glove" distribution, with longest nerves affected most acutely, suggesting a length-dependent component to the toxicity. Axonal transport of ATP-producing mitochondria along neuronal microtubules from cell body to synapse is crucial to neuronal function. We compared the effects of the drugs paclitaxel and ixabepilone that bind along the lengths of microtubules and the drugs eribulin and vincristine that bind at microtubule ends, on mitochondrial trafficking in cultured human neuronal SK-N-SH cells and on axonal transport in mouse sciatic nerves. Antiproliferative concentrations of paclitaxel and ixabepilone significantly inhibited the anterograde transport velocity of mitochondria in neuronal cells, whereas eribulin and vincristine inhibited transport only at significantly higher concentrations. Confirming these observations, anterogradely transported amyloid precursor protein accumulated in ligated sciatic nerves of control and eribulin-treated mice, but not in paclitaxel-treated mice, indicating that paclitaxel inhibited anterograde axonal transport, whereas eribulin did not. Electron microscopy of sciatic nerves of paclitaxel-treated mice showed reduced organelle accumulation proximal to the ligation consistent with inhibition of anterograde (kinesin based) transport by paclitaxel. In contrast, none of the drugs significantly affected retrograde (dynein based) transport in neuronal cells or mouse nerves. Collectively, these results suggest that paclitaxel and ixabepilone, which bind along the lengths and stabilize microtubules, inhibit kinesin-based axonal transport, but not dynein-based transport, whereas the microtubule-destabilizing drugs, eribulin and vincristine, which bind preferentially to microtubule ends, have significantly less effect on all microtubule-based axonal transport. Cancer Res; 76(17); 5115-23. ©2016 AACR.

Topics: Animals; Antineoplastic Agents; Axonal Transport; Epothilones; Furans; Humans; Ketones; Mice; Microtubules; Mitochondria; Neurons; Paclitaxel; Peripheral Nervous System Diseases; Sciatic Nerve; Tubulin Modulators; Vincristine

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious, painful and dose-limiting side effect of cancer drugs that target microtubules. The mechanisms underlying the neuronal damage are unknown, but may include disruption of fast axonal transport, an essential microtubule-based process that moves cellular components over long distances between neuronal cell bodies and nerve terminals. This idea is supported by the "dying back" pattern of degeneration observed in CIPN, and by the selective vulnerability of sensory neurons bearing the longest axonal projections. In this study, we test the hypothesis that microtubule-targeting drugs disrupt fast axonal transport using vesicle motility assays in isolated squid axoplasm and a cell-free microtubule gliding assay with defined components. We compare four clinically-used drugs, eribulin, vincristine, paclitaxel and ixabepilone. Of these, eribulin is associated with a relatively low incidence of severe neuropathy, while vincristine has a relatively high incidence. In vesicle motility assays, we found that all four drugs inhibited anterograde (conventional kinesin-dependent) fast axonal transport, with the potency being vincristine=ixabepilone>paclitaxel=eribulin. Interestingly, eribulin and paclitaxel did not inhibit retrograde (cytoplasmic dynein-dependent) fast axonal transport, in contrast to vincristine and ixabepilone. Similarly, vincristine and ixabepilone both exerted significant inhibitory effects in an in vitro microtubule gliding assay consisting of recombinant kinesin (kinesin-1) and microtubules composed of purified bovine brain tubulin, whereas paclitaxel and eribulin had negligible effects. Our results suggest that (i) inhibition of microtubule-based fast axonal transport may be a significant contributor to neurotoxicity induced by microtubule-targeting drugs, and (ii) that individual microtubule-targeting drugs affect fast axonal transport through different mechanisms.

Topics: Animals; Antineoplastic Agents; Axonal Transport; Axons; Dose-Response Relationship, Drug; Epothilones; Furans; Ketones; Kinesins; Loligo; Microtubules; Paclitaxel; Peripheral Nervous System Diseases; Time Factors; Tubulin; Tubulin Modulators; Vincristine

Topics: Acetylcarnitine; Benzothiazoles; Epothilones; Female; Humans; Male; Peripheral Nervous System Diseases

Since peripheral sensory neuropathy is the major, clinically relevant side effect of sagopilone we investigated the general and peripheral neurotoxicity of sagopilone administered intravenously with different doses (1.2 and 2.4 mg/kg) and schedules in 48 Wistar rats and we performed in parallel a pharmacokinetic/pharmacodynamic (PK/PD) study. A trend toward a different peripheral neurotoxicity could be assessed after 2 weeks of treatment (bolus > 30-min infusion > 3-h infusion) with both doses of sagopilone. Although sagopilone concentrations in peripheral nerve tissue above 100 ng/g were associated with a reduction in nerve conduction velocity (NCV), a clear dose-dependence of this reduction on the level of systemic exposure to sagopilone was not observed. The PK/PD evaluation revealed no consistent effect of the infusion duration on serum PK parameters or the PD read-out NCV. Sagopilone concentrations in brain, sciatic nerve, liver, and kidney were higher after bolus compared to infusion, but there were no influence of infusion duration on these concentrations. No correlation between sagopilone concentrations in any organ/tissue with NCV changes was detected. This study evidences that the PD of sagopilone is not the main determinant of the onset and severity of sagopilone-induced peripheral neurotoxicity in the investigated clinically-relevant dose range, thus indicating that further investigation might identify neuronal-specific mechanisms of action able to drive a focused strategy to prevent peripheral neurotoxicity without reducing the anticancer effectiveness of the epothilones.

Topics: Animals; Area Under Curve; Benzothiazoles; Blood Cell Count; Blood Chemical Analysis; Body Weight; Data Interpretation, Statistical; Epothilones; Female; Infusions, Intravenous; Kidney; Liver; Neural Conduction; Neurotoxicity Syndromes; Peripheral Nervous System Diseases; Rats; Rats, Wistar; Sciatic Nerve

Dose-limiting neuropathy is a major adverse event associated with most of the microtubule-stabilizing agent-based chemotherapy regimens. Ixabepilone, a semisynthetic analogue of the natural epothilone B, has activity against a wide range of tumor types. Peripheral neuropathy (PN), associated with ixabepilone treatment, is usually mild to moderate, predominantly sensory and cumulative. Preclinical studies demonstrate that ixabepilone and taxanes produce a similar neurotoxicity profile.. We searched databases of phase II/III clinical trials involving patients receiving ixabepilone as a monotherapy or in combination with capecitabine for incidences of neuropathy. Potential risk factors for grade 3/4 PN were identified by a Cox regression analysis on a dataset of 1,540 patients with different tumor types across multiple studies.. Rates for incidence of ixabepilone-induced severe PN (Common Terminology Criteria for Adverse Events grade 3/4) ranged from 1% in early untreated breast cancer up to 24% in heavily pretreated metastatic breast cancer; grade 4 PN was rare (≤ 1%). Common symptoms included numbness, paresthesias, and sometimes dysesthesias. Cox regression analysis identified only preexisting neuropathy as a risk factor for increased ixabepilone-associated PN. The management of PN has been primarily through dose adjustments (dose delays and/or dose reduction). Patients had resolution of their neuropathy within a median time of 5 to 6 weeks.. PN is a dose-limiting toxicity associated with ixabepilone treatment, is reversible in most patients, and can be managed with dose reduction and delays.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Databases, Factual; Deoxycytidine; Dose-Response Relationship, Drug; Epothilones; Female; Fluorouracil; Humans; Male; Middle Aged; Neoplasms; Peripheral Nervous System Diseases; Proportional Hazards Models; Risk Factors; Severity of Illness Index; Time Factors; Tubulin Modulators; Young Adult

Ixabepilone is a novel microtubule-stabilising agent used as monotherapy or in combination with capecitabine to treat taxane- and anthracycline-refractory breast cancer. We report the case of a patient who experienced an unusual motor neuropathy after the first cycle. This is a very uncommon secondary effect, but it must be taken into account as a possible complication of treatment with ixabepilone.

Topics: Axons; Breast Neoplasms; Epothilones; Fatal Outcome; Female; Humans; Microtubules; Middle Aged; Neurons, Afferent; Peripheral Nervous System Diseases; Treatment Outcome; Tubulin Modulators