Dose-limiting Toxicity Of Paclitaxel Research Articles

Vitamin D insufficiency and risk of paclitaxel-induced peripheral neuropathy.

e12027 Background: Peripheral neuropathy (PN) is a severe, dose-limiting toxicity of paclitaxel that occurs in up to 25% of patients and can lead to permanent loss of balance and manual dexterity. Due to the lack of effective strategies for PN prevention or treatment, there is a critical need to identify predictive risk factors for paclitaxel-induced PN. Vitamin insufficiencies are known risk factors for PN in other disease states. However, the effect of vitamin insufficiency on paclitaxel-induced PN has not been adequately investigated. Methods: Baseline levels of vitamin D and other nutrients (vitamin B, homocysteine, folate) were measured, and PN was assessed weekly in an observational trial of patients receiving paclitaxel 80 mg/m2 for 12 weeks for non-metastatic breast cancer (NCT0233811). Nutrient levels were measured by Michigan Medicine and insufficiency defined by institutional standards (vitamin D insufficiency < 20 ng/mL). In the primary analysis, the maximum increase from baseline in the 8-item sensory subscale (ΔCIPN8) of the EORTC CIPN20, a validated patient-reported PN assessment tool, was compared in nutrient insufficient and sufficient patients. The effect of vitamin insufficiencies on PN-induced treatment disruptions (dose decrease, delay, or discontinuation) was conducted as a secondary analysis. Results: Only vitamin D insufficiency was identified in enough patients for analysis (15/37 = 41%). Vitamin D insufficient patients reported a greater mean (+/- SD) ΔCIPN8 (36.39 ±22.8) than vitamin D sufficient patients (16.29 ±16.3) (p = 0.003). However, the increase in treatment disruption for vitamin D insufficient patients was not significant (OR = 2.98, 95% CI [0.72, 12.34], p = 0.16). Conclusions: Paclitaxel-treated patients who were vitamin D insufficient at baseline had greater increases in patient-reported PN. If validated in larger studies, vitamin D insufficiency may be a clinically translatable, modifiable risk factor that can be used to prevent paclitaxel-induced PN in patients with non-metastatic breast cancer.

Clinical and genetic predictors of paclitaxel neurotoxicity based on patient- versus clinician-reported incidence and severity of neurotoxicity in the ICON7 trial

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of paclitaxel, with no reliable method to identify at-risk patients. We investigated the incidence and risk factors including genetic polymorphisms associated with the development of CIPN based on clinician and patient reporting of neuropathic symptoms. Patients and methodsRisk factors for the development of CIPN were examined in 454 patients treated with paclitaxel/carboplatin from the International Collaboration on Ovarian Neoplasms 7 (ICON7) trial. Neuropathy was graded by clinicians by standard adverse event reporting and by patients utilising OV28 questionnaire. Genetic risk factors were examined by selecting six single nucleotide polymorphisms in genes associated with microtubule function. Risk factors were assessed via dose-to-event cox regression models. ResultsGrade>2 neuropathy was reported by clinicians in 28% of patients, while 67% of patients reported ‘quite a bit’ or ‘very much’ tingling or numbness. Agreement between clinicians and patients was poor (κ=0.236, 95% confidence interval, 0.177–0.296, P < 0.001). Older age, bevacizumab treatment and bowel resection were associated with clinician reported CIPN, while older age and volume of residual disease were associated with patient-reported neuropathy. There were no significant associations between clinician-reported neuropathy or patient-reported neuropathy and TUBB2, CEP72 or individual MAPT or GSK3B SNPs, however MAPT additive polymorphisms were associated with patient-reported neuropathy and GSK3B additive polymorphisms were associated with clinician reported CIPN. ConclusionsThere was significant discordance between patient- and clinician-reported neurotoxicity. The lack of consensus regarding optimal outcome measures and whose opinion with regard to CIPN takes precedence is a limitation in the investigation of risk factors for CIPN. Care must be taken to select and include patient-reported outcome measures in CIPN assessment to enable accurate identification of genetic and other risk factors for neuropathy.

Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy.

Purpose: Neuropathy is the dose-limiting toxicity of paclitaxel and a major cause for decreased quality of life. Genetic factors have been shown to contribute to paclitaxel neuropathy susceptibility; however, the major causes for interindividual differences remain unexplained. In this study, we identified genetic markers associated with paclitaxel-induced neuropathy through massive sequencing of candidate genes.Experimental Design: We sequenced the coding region of 4 EPHA genes, 5 genes involved in paclitaxel pharmacokinetics, and 30 Charcot-Marie-Tooth genes, in 228 cancer patients with no/low neuropathy or high-grade neuropathy during paclitaxel treatment. An independent validation series included 202 paclitaxel-treated patients. Variation-/gene-based analyses were used to compare variant frequencies among neuropathy groups, and Cox regression models were used to analyze neuropathy along treatment.Results: Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced neuropathy. Low-frequency nonsynonymous variants in EPHA6 were present exclusively in patients with high neuropathy, and all affected the ligand-binding domain of the protein. Accumulated dose analysis in the discovery series showed a significantly higher neuropathy risk for EPHA5/6/8 low-frequency nonsynonymous variant carriers [HR, 14.60; 95% confidence interval (CI), 2.33-91.62; P = 0.0042], and an independent cohort confirmed an increased neuropathy risk (HR, 2.07; 95% CI, 1.14-3.77; P = 0.017). Combining the series gave an estimated 2.5-fold higher risk of neuropathy (95% CI, 1.46-4.31; P = 9.1 × 10-4).Conclusions: This first study sequencing EPHA genes revealed that low-frequency variants in EPHA6, EPHA5, and EPHA8 contribute to the susceptibility to paclitaxel-induced neuropathy. Furthermore, EPHA's neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs. Clin Cancer Res; 23(5); 1227-35. ©2016 AACR.

Clinical features of taxane neuropathy

Sensory neuropathy is the dose-limiting toxicity of paclitaxel and also impacts on the use of docetaxel and other taxanes. The cause of this adverse effect has to do with their mechanism of action against microtubules and its interaction with neuronal cytoskeletal components. The variability of this toxicity is defined by several factors including disease type, taxane class, schedule and dose of the specific drug, patient demographics, and use of taxanes in combination regimens (especially with the platinums that are also neurotoxic). Prevention of life-long neuropathy is only produced if the causative drug is halted--treatments to reverse toxicity have shown only minimal improvement. This review investigates trials defining the clinical factors that determine the therapeutic window of taxanes and the enhanced susceptibility to this toxicity. In addition, case vignettes illustrate the range of clinical manifestations of this toxicity during taxane administration.

An Open-Label Safety Study of Lapatinib Plus Trastuzumab Plus Paclitaxel in First-Line HER2-Positive Metastatic Breast Cancer

Recent data support the hypothesis that combining lapatinib and trastuzumab with taxane chemotherapy may offer added clinical benefit to patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). This study examined the safety of the triplet combination in first-line HER2-positive MBC. Patients were enrolled into three sequential cohorts; the last two cohorts were added by protocol amendment following review of safety data from cohort 1. Patients in cohort 1 received lapatinib (1000 mg/day) plus paclitaxel (80 mg/m(2) per week, 3 of every 4 weeks); cohort 2 received lapatinib (1000 mg/day) plus paclitaxel (70 mg/m(2) per week, 3 of every 4 weeks); and cohort 3 received lapatinib (750 mg/day) plus paclitaxel (80 mg/m(2) per week, 3 of every 4 weeks). All received standard trastuzumab dosing. The primary objective was assessment of dose-limiting toxicities, safety, and tolerability of this combination. The most frequent adverse events (AEs) for all cohorts were diarrhea (89%), rash (79%), fatigue (73%), alopecia (63%), nausea (63%), and vomiting (40%). In cohorts 1 and 2, the incidence of grade 3 diarrhea was 62% and 50%, respectively; in cohort 3, the incidence was 25% (with prophylactic loperamide). Dehydration was the most frequent serious AE (10%). Across cohorts, overall response rate was 75%. The dose-limiting toxicity of paclitaxel, trastuzumab, and lapatinib in first-line HER2-positive MBC was diarrhea. Of the triplet combinations tested, the cohort receiving 750 mg/day dose of lapatinib had the lowest incidence of diarrhea; therefore, this dose should be used in further studies on the treatment of MBC.

Regulatory Polymorphisms in β-Tubulin IIa Are Associated with Paclitaxel-Induced Peripheral Neuropathy

Peripheral neuropathy is the dose-limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat several solid tumors such as breast, lung, and ovary. The cytotoxic effect of paclitaxel is mediated through β-tubulin binding in the cellular microtubules. In this study, we investigated the association between paclitaxel neurotoxicity risk and regulatory genetic variants in β-tubulin genes. We measured variation in gene expression of three β-tubulin isotypes (I, IVb, and IIa) in lymphocytes from 100 healthy volunteers, sequenced the promoter region to identify polymorphisms putatively influencing gene expression and assessed the transcription rate of the identified variants using luciferase assays. To determine whether the identified regulatory polymorphisms were associated with paclitaxel neurotoxicity, we genotyped them in 214 patients treated with paclitaxel. In addition, paclitaxel-induced cytotoxicity in lymphoblastoid cell lines was compared with β-tubulin expression as measured by Affymetrix exon array. We found a 63-fold variation in β-tubulin IIa gene (TUBB2A) mRNA content and three polymorphisms located at -101, -112, and -157 in TUBB2A promoter correlated with increased mRNA levels. The -101 and -112 variants, in total linkage disequilibrium, conferred TUBB2A increased transcription rate. Furthermore, these variants protected from paclitaxel-induced peripheral neuropathy [HR, 0.62; 95% confidence interval (CI), 0.42-0.93; P = 0.021, multivariable analysis]. In addition, an inverse correlation between TUBB2A and paclitaxel-induced apoptosis (P = 0.001) in lymphoblastoid cell lines further supported that higher TUBB2A gene expression conferred lower paclitaxel sensitivity. This is the first study showing that paclitaxel neuropathy risk is influenced by polymorphisms regulating the expression of a β-tubulin gene.

Paclitaxel for non-small cell lung cancer

Paclitaxel, a tubulin-binding agent, is widely used for the treatment of non-small cell lung cancer (NSCLC). The combination of paclitaxel and a platinum compound is an approved regimen for the treatment of advanced NSCLC. The dose-limiting toxicity of paclitaxel is myelosuppression when administered on a prolonged infusion schedule, whereas neuropathy is more common with short infusions. Although the 3-weekly schedule of paclitaxel is the commonly utilised regimen for the treatment of advanced NSCLC, the weekly regimens appear to be associated with lesser myelosuppression and neuropathy. A randomised clinical trial is currently underway to compare the efficacy of the weekly versus 3-weekly regimen of paclitaxel, in combination with carboplatin for the treatment of advanced NSCLC. The radiosensitising effect of paclitaxel has led to its incorporation into multi-modality treatment of NSCLC patients in combination with thoracic radiation. Paclitaxel has also demonstrated synergistic interaction with several molecularly-targeted agents and is at present being evaluated in the neoadjuvant and adjuvant treatment settings for early stage NSCLC.

Hypersensitivity to paclitaxel manifested as a bullous fixed drugeruption

Paclitaxel is the first of a new class of microtubule-stabilizing antitumor agents, with demonstrated activity against advanced and refractory ovarian, breast, lung, and head and neck cancers. It was first isolated from the bark of the endangered Pacific yew Taxus brevifolia. 1 Neutropenia is the dose-limiting toxicity of paclitaxel. A high incidence of major hypersensitivity reactions (HSRs) (including those with cutaneous manifestations) occurred in phase I studies, but they were minimized by premedication schemes and prolonged administration times. 2 We describe a previously unrecognized hypersensitivity to paclitaxel that we classified as a bullous fixed drug eruption.