Peripheral Neuropathy In Cancer Patients Research Articles

1695P - Acupuncture for peripheral neuropathy in cancer patients: TCM diagnosis as a predictor of treatment response

1695P - Acupuncture for peripheral neuropathy in cancer patients: TCM diagnosis as a predictor of treatment response

Indibulin dampens microtubule dynamics and produces synergistic antiproliferative effect with vinblastine in MCF-7 cells: Implications in cancer chemotherapy

Indibulin, a synthetic inhibitor of tubulin assembly, has shown promising anticancer activity with a minimal neurotoxicity in preclinical animal studies and in Phase I clinical trials for cancer chemotherapy. Using time-lapse confocal microscopy, we show that indibulin dampens the dynamic instability of individual microtubules in live breast cancer cells. Indibulin treatment also perturbed the localization of end-binding proteins at the growing microtubule ends in MCF-7 cells. Indibulin reduced inter-kinetochoric tension, produced aberrant spindles, activated mitotic checkpoint proteins Mad2 and BubR1, and induced mitotic arrest in MCF-7 cells. Indibulin-treated MCF-7 cells underwent apoptosis-mediated cell death. Further, the combination of indibulin with an anticancer drug vinblastine was found to exert synergistic cytotoxic effects on MCF-7 cells. Interestingly, indibulin displayed a stronger effect on the undifferentiated neuroblastoma (SH-SY5Y) cells than the differentiated neuronal cells. Unlike indibulin, vinblastine and colchicine produced similar depolymerizing effects on microtubules in both differentiated and undifferentiated SH-SY5Y cells. The data indicated a possibility that indibulin may reduce chemotherapy-induced peripheral neuropathy in cancer patients.

The Influence of Nicotine on Lung Tumor Growth, Cancer Chemotherapy, and Chemotherapy-Induced Peripheral Neuropathy.

Studies in animal models have suggested that nicotine, an agonist of nicotinic acetylcholine receptors, may have the potential to prevent and/or reverse the peripheral neuropathy induced by cancer chemotherapeutic drugs, such as paclitaxel and oxaliplatin. However, a large body of evidence suggests that nicotine may also stimulate lung tumor growth and/or interfere with the effectiveness of cancer chemotherapy. Whereas the reported proliferative effects of nicotine are highly variable, the antagonism of antitumor drug efficacy is more consistent, although this latter effect has been demonstrated primarily in cell culture studies. In contrast, in vitro and in vivo studies from our own laboratory indicate that nicotine fails to enhance the growth of nonsmall cell lung cancer cells or attenuate the effects of chemotherapy (paclitaxel). Given the inconsistencies in the literature, coupled with our own findings, the weight of evidence suggests that caution may be warranted in proposing to use nicotine to mitigate chemotherapy-induced peripheral neuropathy in cancer patients receiving chemotherapy. Conversely, clinical trials could be performed in patients who have completed therapy and are considered to be disease-free to determine whether nicotine, in the form of commercially available patches or gum, is effective in alleviating peripheral neuropathy symptoms.

Effect of Oral Glutamine on Chemotherapy-Induced Peripheral Neuropathy in Cancer Patients: An Evidence-Based Appraisal

Chemotherapy may induce peripheral neuropathy, which often results in the chemotherapy dose being reduced or the chemotherapy regimen being stopped. At present, there are no treatment guidelines for chemotherapy-induced peripheral neuropathy. Glutamine is one of the treatment strategies currently applied in practice. This strategy is expensive and lacks clear evidence as to its efficacy. To evaluate the effect of oral glutamine on CIPN in cancer patients. PICO (population- intervention- comparison- outcome) was used to focus the problem: P: cancer patient; I: glutamine, L-glutamine; C: usual care; O: alleviate, reduce, improve, and prevent. Databases searched included Airiti Library, Cochrane Library, CINAHL, and PubMed. Three randomized clinical trials and two quasi-experimental designs were evaluated using evidence-based appraisal. Four studies used 30 g/day of glutamine either at the beginning of chemotherapy or at 24 hours after the beginning of chemotherapy. The shortest duration for taking glutamine was four days and longest duration was two months. The incidences of CIPN-induced pain were significantly different (risk ratio = 0.26; 95% CI [0.09, 0.70], Z = 2.65, p = .008) between the intervention and control groups. The incidences of CIPN grading, numbness, and muscle weakness were not significantly different between the intervention and control groups. From an economic point of view, the clinical efficacy of taking glutamine does not justify the additional daily cost to the patient of NT¤500 (about US¤17). Because of the small sample size, minimal effects of glutamine, and no significant decrease in risk, we do not suggest routinely using oral glutamine to prevent or reduce CIPN symptoms in cancer patients.

Incidence and relative risk of peripheral neuropathy in cancer patients treated with eribulin: a meta-analysis.

BackgroundEribulin is a microtubule inhibitor, which is approved for the treatment of breast cancer. Peripheral neuropathy has been reported in the studies of eribulin, but the incidence and relative risk (RR) of eribulin-associated peripheral neuropathy varied greatly in cancer patients. The purpose of this meta-analysis was to determine the overall incidence and RR of eribulin-associated peripheral neuropathy in cancer patients.Materials and MethodsPubmed database and Embase and abstracts presented at the American Society of Clinical Oncology (ASCO) meetings were systematically reviewed for primary studies. Eligible studies included prospective clinical trials and expanded access programs of cancer patients treated with eribulin. Statistical analyses were performed to calculate the incidences, RRs, and 95% confidence intervals (CIs).ResultsAltogether, 4,849 patients from 19 clinical trials were selected for this meta-analysis. The incidences of all-grade and high-grade peripheral neuropathy were 27.5% (95% CI: 23.3–32.4%) and 4.7% (95% CI: 3.6–6.2%), respectively. The relative risks of peripheral neuropathy of eribulin compared to control were increased for all-grade (RR = 1.89, 95% CI: 1.10–3.25) but not statistically significant for high-grade (RR = 2.98, 95% CI: 0.71–12.42).ConclusionsThe use of eribulin is associated with an increased incidence of peripheral neuropathy. The RR is increased for all-grade peripheral neuropathy.

Correlation Analysis of Organic Acid Comprehensive Profile Markers with Chemotherapy Induced Peripheral Neuropathy in Cancer Patients

Correlation Analysis of Organic Acid Comprehensive Profile Markers with Chemotherapy Induced Peripheral Neuropathy in Cancer Patients

Effects of transcutaneous electrical nerve stimulation on chemotherapy-induced peripheral neuropathy symptoms (CIPN): a preliminary case-control study.

[Purpose] The aim of this double-blind, randomized and placebo-controlled study is to investigate the effects of Transcutaneous Electrical Nerve Stimulation for reducing the side effects of Chemotherapy-induced Peripheral Neuropathy in cancer patients undergoing chemotherapy with oxaloplatin or paclitaxel. [Subjects and Methods] Twenty-four patients were randomly allocated into two groups: active or placebo stimulation. All patients were assessed for pain, numbness/tingiling, frequency of symptoms, and quality of life. The transcutaneous Electrical Nerve Stimulation device was applied daily with modulating frequencies ranging between 7 Hz and 65 Hz in distal limb regions during three cycles of chemotherapy (45 days). The other stimulation parameters were: pulse duration of 200 μsec, intensity at the highest tolerable level, and increases in intensity when it diminished. [Results] The data showed no difference between active or placebo groups in terms of pain, numbness/tingling, frequency of symptoms or impact on daily life activities. [Conclusion] These results suggest that Transcutaneous Electrical Nerve Stimulation applied in the frequency variation mode was not proven to be effective to improve the symptoms of Chemotherapy-induced Peripheral Neuropathy during chemotherapy cycles. There was no worsening of symptoms in subsequent cycles of the onset of symptoms of the disease.

Occurrence of chemotherapy-induced peripheral neuropathy in cancer patients at Belagavi city: An observational study

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a progressive condition, often irreversible. The chances of peripheral nervous system getting affected by the antineoplastic drugs are very high as compared to that of the central nervous system. Hence, this study is planned to assess the occurrence among cancer patients.Purpose: The objective of the present study was to screen patients undergoing cancer treatment for CIPN.Design: This was an observational study.Setting: The study was conducted at a tertiary care cancer hospital.Patients: Twenty-six individuals with CIPN, 30 years and above, were assessed using the modified total neuropathy score (mTNS) of >5.Measurements: Patients were assessed using mTNS.Results: Statistical analysis was done and it was found that 20% who received the drug cisplatin and 32% who received paclitaxel had CIPN. Forty-eight percent (48%) of the participants with CIPN received a combination of drugs.Conclusion: The drug paclitaxel was a major source for causing neuropathy. Neuropathy was seen when paclitaxel was given as the soul drug and also when given in combination with carboplatin.

Cisplatin induces mitochondrial deficits in Drosophila larval segmental nerve

Cisplatin is an effective chemotherapy drug that induces peripheral neuropathy in cancer patients. In rodent dorsal root ganglion neurons, cisplatin binds nuclear and mitochondrial DNA (mtDNA) inducing DNA damage and apoptosis. Platinum-mtDNA adducts inhibit mtDNA replication and transcription leading to mitochondrial degradation. Cisplatin also induces climbing deficiencies associated with neuronal apoptosis in adult Drosophila melanogaster. Here we used Drosophila larvae that express green fluorescent protein in the mitochondria of motor neurons to observe the effects of cisplatin on mitochondrial dynamics and function. Larvae treated with 10μg/ml cisplatin had normal survival with deficiencies in righting and heat sensing behavior. Behavior was abrogated by, the pan caspase inhibitor, p35. However, active caspase 3 was not detected by immunostaining. There was a 27% decrease in mitochondrial membrane potential and a 42% increase in reactive oxygen species (ROS) in mitochondria along the axon. Examination of mitochondrial axonal trafficking showed no changes in velocity, flux or mitochondrial length. However, cisplatin treatment resulted in a greater number of stationary organelles caused by extended pausing during axonal motility. These results demonstrate that cisplatin induces behavior deficiencies in Drosophila larvae, decreased mitochondrial activity, increased ROS production and mitochondrial pausing without killing the larvae. Thus, we identified particular aspects of mitochondrial dynamics and function that are affected in cisplatin-induced peripheral neuropathy and may represent key therapeutic targets.

Palmitoylethanolamide Reverses Paclitaxel-Induced Allodynia in Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) represents a serious complication associated with antineoplastic drugs. Although there are no medications available that effectively prevent CIPN, many classes of drugs have been used to treat this condition, including anticonvulsants, serotonin and noradrenaline reuptake inhibitors, and opioids. However, these therapeutic options yielded inconclusive results in CIPN clinical trials and produced assorted side effects with their prolonged use. Thus, there is an urgent need to develop efficacious and safe treatments for CIPN. In this report, we tested whether the endogenous lipid palmitoylethanolamide (PEA) alone or in combination with the anticonvulsant gabapentin would reduce allodynia in a mouse paclitaxel model of CIPN. Gabapentin and PEA reversed paclitaxel-induced allodynia with respective ED50 doses (95% confidence interval) of 67.4 (61.52-73.94) and 9.2 (8.39-10.16) mg/kg. Isobolographic analysis of these drugs in combination revealed synergistic antiallodynic effects. The PPAR-α antagonist receptor antagonist GW6471 [N-((2S)-2-(((1Z)-1-methyl-3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-enyl)amino)-3-(4-(2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy)phenyl)propyl)propanamide] completely blocked the antinociceptive effects of PEA. In addition, PEA administered via intraplantar injection into a paw, intrathecal injection, and intracerebroventricular injection reversed paclitaxel-induced allodynia, suggesting that it may act at multiple sites in the neuroaxis and periphery. Finally, repeated administration of PEA (30 mg/kg, 7 days) preserved the antiallodynic effects with no evidence of tolerance. These findings taken together suggest that PEA possesses potential to treat peripheral neuropathy in cancer patients undergoing chemotherapy.

Incidence and risk of peripheral neuropathy with nab-paclitaxel in patients with cancer: a meta-analysis.

Nab-paclitaxel, a Cremophor EL-free formulation of paclitaxel, is used to treat various malignancies. Peripheral neuropathy is one of its major toxicities, although the overall incidence remains unclear. We performed a meta-analysis to calculate the incidence of peripheral neuropathy in cancer patients treated with nab-paclitaxel and to compare the relative risk (RR) with conventional taxanes. The electronic databases were searched for relevant clinical trials. Eligible studies included phase II and III prospective clinical trials of cancer patients treated with nab-paclitaxel with toxicity profile on peripheral neuropathy. Statistical analyses were done to calculate summary incidences, RRs and 95% confidence intervals (CI), using fixed-effects or random-effects models based on the heterogeneity of the included studies. Nineteen trials were selected for the meta-analysis, yielding a total of 2878 cancer patients. The overall incidences of peripheral neuropathy (all-grade) was 51.0% (95% CI: 45.1-57.6%), and that of high-grade peripheral neuropathy was 12.4% (9.8-15.7%). The RRs of peripheral neuropathy of nab-paclitaxel compared to taxanes were not increased for all-grade and high-grade peripheral neuropathy. Nab-paclitaxel is associated with an increased risk of developing peripheral neuropathy. Future clinical studies are still needed to investigate the risk reduction and possible use of nab-paclitaxel.

Current use of drugs affecting the central nervous system for chemotherapy-induced peripheral neuropathy in cancer patients: a systematic review.

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.

No clear evidence on electroacupuncture for chemotherapy-induced peripheral neuropathy in cancer patients

No clear evidence on electroacupuncture for chemotherapy-induced peripheral neuropathy in cancer patients

Identification of pharmacogenetic target genes associated with chemotherapy-induced peripheral neuropathy.

e13541 Background: Chemotherapy-induced Peripheral Neuropathy (CIPN) is a dose-limiting toxicity of many anticancer drugs, including taxanes, vinca alkaloids and platinating agents. There are no effective means to predict which patients are at risk for CIPN nor are there effective treatments. Therefore, we have used a whole genome approach in lymphoblastoid cell lines (LCLs) alone or combined with clinical study data to identify target genes associated with CIPN that we tested further in Neuroscreen-1 (NS-1: rat pheochromocytoma) cells and human neurons derived from induced pluripotent stem cells (iCell neurons). Methods: For selecting candidate target genes, we compared published genome-wide association studies (GWAS) results of sensory peripheral neuropathy in cancer patients receiving paclitaxel with GWAS results of pharmacologic phenotypes in LCLs after paclitaxel treatment. We evaluated neurotoxic drug-induced cell growth inhibition using Cell Titer Glo and neurite parameters of outgrowth, processes and branching through imaging following transient knockdown of target genes in NS-1 cells and iCell neurons. Results: After treatment of paclitaxel, vincristine and cisplatin, iCell neurons showed decrease of neurite outgrowth, processes and branching. Whereas, these parameters did not decrease for hydroxyurea, which is not reported to induce neuropathy. Through transient knockdown in NS-1 cells of RFX2, a gene identified through clinical and preclinical studies to be associated with paclitaxel-induced neuropathy, sensitivity to paclitaxel increased as measured by a decrease of neurite outgrowth. Conclusions: These findings imply our model system could identify pharmacogenetic target genes associated with CIPN. These genes have potential for biomarkers or therapeutic targets and enable future personalized treatments for cancer patients at risk for CIPN.

Chemotherapy-induced peripheral neuropathy in cancer patients: a four-arm randomized trial on the effectiveness of electroacupuncture.

Purpose. Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting side effect of cytostatic drugs. Since there are no proven therapeutic procedures against CIPN, we were interested to define the role of electroacupuncture (EA) from which preliminary data showed promising results. Methods. In a randomized trial with a group sequential adaptive design in patients with CIPN, we compared EA (LV3, SP9, GB41, GB34, LI4, LI11, SI3, and HT3; n = 14) with hydroelectric baths (HB, n = 14), vitamin B1/B6 capsules (300/300 mg daily; VitB, n = 15), and placebo capsules (n = 17). The statistical power in this trial was primarily calculated for proving EA only, so results of HB and VitB are pilot data. Results. CIPN complaints improved by 0.8 ± 1.2 (EA), 1.7 ± 1.7 (HB), 1.6 ± 2.0 (VitB), and 1.3 ± 1.3 points (placebo) on a 10-point numeric rating scale without significant difference between treatment groups or placebo. In addition no significant differences in sensory nerve conduction studies or quality of life (EORTC QLQ-C30) were found. Conclusions. The used EA concept, HB, and VitB were not superior to placebo. Since, contrary to our results, studies with different acupuncture concepts showed a positive effect on CIPN, the effect of acupuncture on CIPN remains unclear. Further randomized, placebo controlled studies seem necessary. This trial is registered with DRKS00004448.

Neurological complications of medical anti-cancer therapies

This review describes the features of central and peripheral neurological disorders caused by anti-cancer chemotherapy and supportive medications, such as antiepileptic drugs, glucocorticosteroids and opioids, frequently used in cancer patients. Diffuse encephalopathy with or without epileptic seizures, cerebellar disorders and aseptic meningitis may occur after systemic administration of conventional drug doses, but their incidence is much higher when either high-dose chemotherapy, or intrathecal or intracarotid administration is used. Spinal cord and/or spinal root lesions have been reported after intrathecal administration of methotrexate or cytosinearabinoside. Anti-cancer chemotherapy is the leading cause of peripheral neuropathy in cancer patients. The main culprits are vinca alkaloids, platinum derivatives and taxanes. Anti-cancer chemotherapy has no significant toxic effect on muscle tissue, but heavy administration of glucocorticosteroids is a common cause of disabling, predominantly pelvic, muscle atrophy.

Neurological complications of medical anti-cancer therapies

This review describes the features of central and peripheral neurological disorders caused by anti-cancer chemotherapy and supportive medications, such as antiepileptic drugs, glucocorticosteroids and opioids, frequently used in cancer patients. Diffuse encephalopathy with or without epileptic seizures, cerebellar disorders and aseptic meningitis may occur after systemic administration of conventional drug doses, but their incidence is much higher when either high-dose chemotherapy, or intrathecal or intracarotid administration is used. Spinal cord and/or spinal root lesions have been reported after intrathecal administration of methotrexate or cytosinearabinoside. Anti-cancer chemotherapy is the leading cause of peripheral neuropathy in cancer patients. The main culprits are vinca alkaloids, platinum derivatives and taxanes. Anti-cancer chemotherapy has no significant toxic effect on muscle tissue, but heavy administration of glucocorticosteroids is a common cause of disabling, predominantly pelvic, muscle atrophy.

Pathophysiology and Animal Models of Cancer-Related Painful Peripheral Neuropathy

There are undoubtedly several causes of painful peripheral neuropathy in cancer patients. Some mechanisms are directly attributable to the tumor; others lie with the therapy, be it surgery, radiation, or chemotherapy. Several animal models have been developed to study the pathophysiological mechanisms that contribute to neuropathic pain. These include inflammation-based models, nerve trauma-induced models, and chemotherapy-induced models of neuropathic pain. My colleagues and I recently identified abnormalities in mitochondrial structure and function in peripheral sensory fibers that are associated with neuropathic pain induced by common chemotherapeutic agents and that can be reversed by agents that enhance mitochondrial function. Our hope is that further identification and clarification of the pathophysiological mechanisms involved at the periphery will help us to develop new classes of medicines and treatment options.

Discrete proteolysis of neuronal calcium sensor-1 (NCS-1) by μ-calpain disrupts calcium binding

Neuronal calcium sensor-1 (NCS-1) is a high-affinity, low-capacity Ca(2+)-binding protein expressed in many cell types. We previously showed that NCS-1 interacts with inositol 1,4,5-trisphosphate receptor (InsP(3)R) and modulates Ca(2+)-signaling by enhancing InsP3-dependent InsP(3)R channel activity and intracellular Ca(2+) transients. Recently we reported that the chemotherapeutic agent, paclitaxel (taxol) triggers mu-calpain dependent proteolysis of NCS-1, leading to reduced Ca(2+)-signaling within the cell. Degradation of NCS-1 may be critical in the induction of peripheral neuropathy associated with taxol treatment for breast and ovarian cancer. To begin to design strategies to protect NCS-1, we treated NCS-1 with mu-calpain in vitro and identified the cleavage site by N-terminal sequencing and MALDI mass spectroscopy. mu-Calpain cleavage of NCS-1 occurs within an N-terminal pseudoEF-hand domain, which by sequence analysis appears to be unable to bind Ca(2+). Our results suggest a role for this pseudoEF-hand in stabilizing the three functional EF-hands within NCS-1. Using isothermal titration calorimetry (ITC) we found that loss of the pseudoEF-hand markedly decreased NCS-1's affinity for Ca(2+). Physiologically, this significant decrease in Ca(2+) affinity may render NCS-1 incapable of responding to changes in Ca(2+) levels in vivo. The reduced ability of mu-calpain treated NCS-1 to bind Ca(2+) may explain the altered Ca(2+) signaling in the presence of taxol and suggests a strategy for therapeutic intervention of peripheral neuropathy in cancer patients undergoing taxol treatment.

Neurological complications of medical anti-cancer therapies

This review describes the features of central and peripheral neurological disorders caused by anti-cancer chemotherapy and supportive medications, such as antiepileptic drugs, glucocorticosteroids and opioids, frequently used in cancer patients. Diffuse encephalopathy with or without epileptic seizures, cerebellar disorders and aseptic meningitis may occur after systemic administration of conventional drug doses, but their incidence is much higher when either high-dose chemotherapy, or intrathecal or intracarotid administration is used. Spinal cord and/or spinal root lesions have been reported after intrathecal administration of methotrexate or cytosinearabinoside. Anti-cancer chemotherapy is the leading cause of peripheral neuropathy in cancer patients. The main culprits are vinca alkaloids, platinum derivatives and taxanes. Anti-cancer chemotherapy has no significant toxic effect on muscle tissue, but heavy administration of glucocorticosteroids is a common cause of disabling, predominantly pelvic, muscle atrophy.