Sensory Neurotoxicity Research Articles

Cisplatin-induced DNA crosslinks trigger neurotoxicity in C. elegans

The anticancer drug cisplatin (CisPt) injures post-mitotic neuronal cells, leading to neuropathy. Furthermore, CisPt triggers cell death in replicating cells. Here, we aim to unravel the relevance of different types of CisPt-induced DNA lesions for evoking neurotoxicity. To this end, we comparatively analyzed wild-type and loss of function mutants of C. elegans lacking key players of specific DNA repair pathways. Deficiency in ercc-1, which is essential for nucleotide excision repair (NER) and interstrand crosslink (ICL) repair, revealed the most pronounced enhancement in CisPt-induced neurotoxicity with respect to the functionality of post-mitotic chemosensory AWA neurons, without inducing neuronal cell death. Potentiation of CisPt-triggered neurotoxicity in ercc-1 mutants was accompanied by complex alterations in both basal and CisPt-stimulated mRNA expression of genes involved in the regulation of neurotransmission, including cat-4, tph-1, mod-1, glr-1, unc-30 and eat-18. Moreover, xpf-1, csb-1, csb-1;xpc-1 and msh-6 mutants were significantly more sensitive to CisPt-induced neurotoxicity than the wild-type, whereas xpc-1, msh-2, brc-1 and dog-1 mutants did not distinguish from the wild-type. The majority of DNA repair mutants also revealed increased basal germline apoptosis, which was analyzed for control. Yet, only xpc-1, xpc-1;csb-1 and dog-1 mutants showed elevated apoptosis in the germline following CisPt treatment. To conclude, we provide evidence that neurotoxicity, including sensory neurotoxicity, is triggered by CisPt-induced DNA intra- and interstrand crosslinks that are subject of repair by NER and ICL repair. We hypothesize that especially ERCC1/XPF, CSB and MSH6-related DNA repair protects from chemotherapy-induced neuropathy in the context of CisPt-based anticancer therapy.

Targeting a xenobiotic transporter to ameliorate vincristine-induced sensory neuropathy.

Vincristine is a widely used chemotherapeutic drug for the treatment of multiple malignant diseases that causes a dose-limiting peripheral neurotoxicity. There is no clinically effective preventative treatment for vincristine-induced sensory peripheral neurotoxicity (VIPN), and mechanistic details of this side effect remain poorly understood. We hypothesized that VIPN is dependent on transporter-mediated vincristine accumulation in dorsal root ganglion neurons. Using a xenobiotic transporter screen, we identified OATP1B3 as a neuronal transporter regulating the uptake of vincristine. In addition, genetic or pharmacological inhibition of the murine orthologue transporter OATP1B2 protected mice from various hallmarks of VIPN - including mechanical allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes and neuronal morphology - without negatively affecting plasma levels or antitumor effects of vincristine. Finally, we identified α-tocopherol from an untargeted metabolomics analysis as a circulating endogenous biomarker of neuronal OATP1B2 function, and it could serve as a companion diagnostic to guide dose selection of OATP1B-type transport modulators given in combination with vincristine to prevent VIPN. Collectively, our findings shed light on the fundamental basis of VIPN and provide a rationale for the clinical development of transporter inhibitors to prevent this debilitating side effect.

Prevention of taxane-associated acute pain syndrome with etoricoxib for patients with breast cancer: A phase II randomised trial

BackgroundFor patients with breast cancer who receive docetaxel chemotherapy, taxane-associated acute pain syndrome (T-APS), considered a form of neural pathology, is a significant clinical problem. We evaluated the effect of prophylactic etoricoxib on T-APS in patients with breast cancer. Materials and methodsWe conducted a phase II randomised trial including 144 patients with breast cancer receiving four cycles of docetaxel-based chemotherapy. Patients were randomised in the ratio 1:1 to receive prophylactic etoricoxib (60 mg, Day 1 to Day 8) or no prophylactic treatment. The primary end-point was the overall incidence of T-APS across all cycles. Secondary end-points included the incidence of severe pain (greater than 5 on a scale 0–10); severity and duration of T-APS; Functional Assessment of Cancer Therapy-Breast subscale; chronic sensory and motor neurotoxicity and adverse events. ResultsThe overall incidence of T-APS across all cycles of chemotherapy in the etoricoxib group was 57.1%, while that in the control group was 91.5% (P < 0.001). The incidences of severe T-APS were 11.4% and 54.9% for the etoricoxib and control groups, respectively (P < 0.001). The mean Functional Assessment of Cancer Therapy-Breast subscale score of the etoricoxib group (103.79–107.24) was significantly higher than that of the control group (93.88–96.71) (P = 0.001 at cycle 1 and P < 0.001 at cycles 2–4). After four cycles of docetaxel chemotherapy, the etoricoxib group demonstrated a significantly higher mean Functional Assessment of Cancer Treatment Neurotoxicity subscale score than the control group (38.46, 95% CI: 37.63–39.29; 34.59, 95% CI: 33.73–35.45, respectively; P < 0.001). Electromyography showed that most peripheral sensory nerves in the etoricoxib group had significantly improved action potential amplitudes and conduction velocities compared with those in the control group. ConclusionProphylactic use of etoricoxib could significantly reduce the incidence and severity of docetaxel-induced acute pain syndrome and potentially decrease docetaxel-induced peripheral neuropathy. Trial registrationClinicalTrials.gov, NCT04565600.

The effectiveness and safety of acupuncture/electroacupuncture for chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse effect of anticancer agents with virtually no effective treatment. Safe and effective therapies are needed urgently. Acupuncture shows therapeutic possibilities in this regard but needs to be further evaluated. A systematic search was conducted in seven databases from their inception to April 2020. Randomized controlled trials (RCTs) focused on acupuncture/electroacupuncture (EA) for the treatment of CIPN were included. Revman 5.3 software was used for meta-analysis if there was no significant heterogeneity. Otherwise, qualitative analysis was utilized. Nine studies involving 582 patients were included in this review. Most of the studies exhibited unclear risk of bias because some details were not mentioned. As the clinical heterogeneity was significant, qualitative analysis was performed to describe nerve conduction velocity, effective rate for motor neuropathy, pain scores, quality of life and adverse events. Meta-analysis was performed on four studies to analyze the effective rate for sensory neuropathy due to inconspicuous heterogeneity. The results indicated that acupuncture may generate a better effect on sensory neuropathy than vitamin B (risk ratio = 1.60, 95% confidence interval = 1.31-1.95, I2 = 0%, p < 0.00001). The efficacy of EA plus glutathione (GSH) appeared to be better than that of GSH alone in alleviating sensory neurotoxicity and in improving nerve conduction velocity. Acupuncture plus methylcobalamin showed more favorable effects than methylcobalamin alone in relieving neuralgia, restoring nerve conduction velocity and improving quality of life. In terms of pain relief and improved CIPN-specific quality of life, acupuncture plus standard care was better than standard care alone. In terms of pain relief, EA was more effective than usual care. Acupuncture may be effective and safe in the treatment of CIPN according to the analyzed studies. However, more studies with higher methodological quality are warranted in order to be able to draw firmer conclusions. Future rigorous RCTs will be necessary to confirm the effectiveness and safety of acupuncture for CIPN.

Time-dependent discrepancies between physician-assessed and patient-reported oxaliplatin-induced peripheral neuropathy in patients with metastatic colorectal cancer who received mFOLFOX6 plus bevacizumab: a post hoc analysis (WJOG4407GSS2).

Cumulative sensory neurotoxicity induced by oxaliplatin impairs patients' quality of life and treatment continuation. This study investigated the relationship between physician-assessed and patient-reported oxaliplatin-induced peripheral neuropathy (OIPN) during treatment of metastatic colorectal cancer (mCRC) over time. A post hoc analysis was conducted for 191 patients with mCRC who received mFOLFOX6 plus bevacizumab in the WJOG4407G trial. Physician-assessed OIPN was graded by CTCAE every 2weeks. Patient-reported OIPN was assessed with the FACT/GOG-Ntx (11 items, best score 44) at baseline and at 3, 6, and 9months. Physician underestimation was defined as when the highest scores of the NTX1-4 sensory subscale/CTCAE grade were 2/0, 3/0-1, or 4/0-1, and overestimation as 0/2-3, 1/2-3, or 2/3. The median total dose (range) of oxaliplatin was 762 (85-5950) mg/m2. Overall, the least squares mean of FACT/GOG-Ntx scores (standard error), estimated by a linear mixed model, were 36 (0.8), 34 (0.9), 29 (1.0), and 27 (1.1) for CTCAE grades 0, 1, 2, and 3, respectively. FACT/GOG-Ntx scores were weakly-to-moderately correlated with CTCAE grade (Spearman's r = - 0.24 [p = 0.0026], - 0.46 [p < 0.0001], and - 0.56 [p < 0.0001] at 3, 6, and 9months, respectively). OIPN was underestimated in 85/159 (54%), 43/109 (39%), and 18/69 (26%) patients at 3, 6, and 9months, respectively. In contrast, OIPN was overestimated in less than 5% of the patients at any time. During early treatment, physician underestimation of OIPN in patients with mCRC is likely.

Phase I Study of Ixazomib with Conventional Chemotherapy in the Treatment of Acute Myeloid Leukemia in Older Adults

Phase I Study of Ixazomib with Conventional Chemotherapy in the Treatment of Acute Myeloid Leukemia in Older Adults

The Optimal Duration of Adjuvant Chemotherapy in Colon Cancer.

Simple SummaryThis review provides an overview of adjuvant chemotherapy in colon cancer over the last 30 years. Key questions address choice of regimen, treatment duration, treatment-dependent toxicity and possible prognostic/predictive factors. Thus, main focus is on the International Duration Evaluation of Adjuvant therapy (IDEA) collaboration which was founded to investigate whether a shortened (3 months) of adjuvant therapy containing a fluoropyrimidine and oxaliplatin is comparable to the current/former standard of care (duration of 6 months). Results of this collaboration will be discussed and evaluated in the context of achieving the best efficacy possible while reducing severe toxicities, and future prognostic/predictive factors.Adjuvant chemotherapy for colon cancer (UICC stage II and III) has been under investigation over the last 30 years, regarding treatment duration and regimens. In this review, choice of regimen, its duration, possible limitations and future perspectives are discussed. Monotherapy with 5-fluorouracil was followed by addition of oxaliplatin, resulting in improved 3-yr disease free survival (DFS) and overall survival (OS) rates, but also increased peripheral sensory neurotoxicity (PSN). The International Duration Evaluation of Adjuvant therapy (IDEA) collaboration demonstrated less toxicity, especially PSN, when shortening treatment duration to 3 months. However, formally, the anticipated non-inferiority of 3 months with fluoropyrimidine (FP)/oxaliplatin over 6 months (at 3-yr DFS) was not met for all patients groups, although subgroup analyses showed non-inferiority with capecitabine/oxaliplatin (CAPOX) rather than with FOLFOX, and also in relation to the prognostic information (e.g., clinical low-risk group, pT1-3 N0). In addition, first data of newer parameters like Immunoscore® and ctDNA show promising results as stratification parameters. Further investigations to better define clinical risk groups and prognostic factors are mandatory. Besides this, individual decision-making of treatment intensity (FP or FP/oxaliplatin) and duration should always consider patient characteristics and preferences, also given the absolute relatively small differences and their clinical relevance.

The efficacy and adverse reactions of DCF and FOLFOXs regimens for patients with advanced gastric cancer in China: a meta-analysis

BackgroundGastric cancer is a malignant tumor originating from the gastric mucosal epithelium, ranking fourth in the incidence of male malignant tumors and third in mortality rate. The aim of this study is to investigate the efficacy and adverse reactions of DCF and FOLFOXs regimens in the treatment of advanced gastric cancer.MethodsRelevant prospective clinical controlled studies were retrieved from WanFang Data, CBM, CNKI, PubMed, The Cochrane Library and Embase databases and meta-analysis was performed using RevMan 5.3 software.ResultsThe effective rates of DCF group and FOLFOXs group were basically the same (RR 1.06, 95% CI: 0.92–1.23, P=0.41). The incidence of nausea and vomiting (RR 1.36, 95% CI: 1.15–1.60), anemia (RR 2.04, 95% CI: 1.55–2.68), thrombocytopenia (RR 1.52, 95% CI: 1.15–2.01) and leukopenia (RR 1.70, 95% CI: 1.44–2.01) with FOLFOXs regimen were significantly lower than DCF regimen, while the incidence of sensory neurotoxicity was significantly higher than DCF regimen (RR 0.53, 95% CI: 0.38–0.74). There were no significant differences in efficacy, ORR and DCR between different doses in the FOLFOXs group (P=0.233).ConclusionsThe efficacy of FOLFOXs regimen was comparable to that of DCF regimen in the treatment of advanced gastric cancer, but the incidence of adverse reactions was significantly lower, and there were no significant differences between different therapeutic doses.

Coral Snake Envenomations in Central and South America

Snakebites are increasingly recognized as a neglected tropical disease. The purposes of this review were to determine the significance of coral snakebites in Central and South America and how best to treat these envenomations. Questions that needed to be answered included: What is the incidence of coral snake envenomation? What are the features of coral snake envenomation? What are the pharmacological and nonpharmacological ways to treat these bites? Multiple case reports and series describe the clinical features of coral snake envenomations, which account for fewer than 5% of all snakebites in Central and South America. Coral snake venom is a complex mixture of neurotoxins and other biologically active substances. There are multiple coral snake antivenoms available, but no single antivenom can be used for all species. Coral snake envenomations are characterized by motor and sensory neurotoxicity. However, muscle damage, renal injury, hematologic toxicity, electrocardiographic abnormalities, and nonspecific signs and symptoms are also possible consequences. Supportive care and antivenom are the mainstays of therapy. Pressure immobilization may prevent systemic absorption, and neostigmine may protect against paralysis. Death is uncommon if treatment is initiated promptly. Nonspecific inhibitors of various venom components may serve as a bridge to definitive therapy.

Acute Peripheral Motor Neuropathy Induced by Oxaliplatin-Correlated Hypokalaemia.

Neurotoxicity is one of the most common side effects of oxaliplatin-based therapy. Most patients who receive at least 3–4 months of treatment suffer from peripheral sensory neurotoxicity (PSN), characterised by the loss or impairment of tactile and proprioceptive sensory function. Motor impairment, such as muscle weakness or palsy, has been rarely described, and the physiopathology of PSN, as well as the motor symptoms due to oxaliplatin-based treatment, are not adequately understood. Here we report the case of a patient who experienced severe acute peripheral motor neuropathy as a side effect of oxaliplatin-based treatment. We also review other cases of PSN published in the literature and suggest a novel hypothesis on the physiopathology of this particular event. Take-away lessons: Not all of the neurological symptoms observed during oxaliplatin-based treatment can be traced back directly to the oxaliplatin itself, and other factors, such as electrolyte imbalances, may contribute to the symptoms. Patients with gastro-intestinal malignancies are the patients most affected by neurotoxicity due to the side effects of chemotherapy and the disease itself.Electronic Supplementary MaterialThe online version of this article (10.1007/s40487-019-00102-3) contains supplementary material, which is available to authorized users.

A RARE CASE OF CHEMOTHERAPY-INDUCED PHRENIC NEUROPATHY

SESSION TITLE: Tuesday Fellows Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Chemotherapy induced peripheral neuropathy is a well described sequela of several chemotherapeutic agents, which can lead to permanent symptoms and disability in up to 40% of cancer survivors1. Large sensory nerve fibers are most commonly affected; however, motor neuropathy can also develop. Up to 20 to 40% of patients receiving platinum compounds have been reported to experience sensory neurotoxicity, however motor neuropathy is uncommon. Furthermore, motor impairment of the phrenic nerve has rarely been encountered with only four prior case reports being found in the literature2,3,4,5. Only one possible case of platinum associated phrenic neuropathy has been described4. CASE PRESENTATION: A 34 year old male with a metastatic right testicular cancer presented with a three month history of progressive dyspnea on exertion. He had undergone right orchiectomy & had received 4 cycles of chemotherapy with bleomycin, cisplatin and etoposide. Symptoms were first noted during the final cycle of chemotherapy, which continued to progress over the next two months. Physical exam was notable for clear lungs on auscultation with no evidence of diaphragmatic paradox. Pulmonary function tests showed a restrictive pattern, with low maximal inspiratory and expiratory pressures (Figure 1). Repeat CT showed bibasilar atelectasis with low lung volumes on scout film when compared to prior chest x-ray (Figure 2). Fluoroscopic sniff evaluation demonstrated evidence of right greater than left diaphragmatic weakness, and phrenic nerve EMG, while within normal limits, was notable for asymmetric right side predominant nerve conduction discrepancies consistent with possible fascicular phrenic neuropathy. Constellation of findings was most concerning for drug induced phrenic neuropathy leading to diaphragmatic weakness. DISCUSSION: Chemotherapy induced phrenic motor neuropathy leading to diaphragmatic weakness or paralysis is a rarely described phenomenon. Of the four prior case reports, two were associated with vincristine, which is more associated with motor neuropathies2,3. Only one these case reports described a phrenic neuropathy associated with a regimen that included a platinum based agent4. However, this case also involved radiation therapy, which has been associated with phrenic neuropathy in prior case reports. Here we describe a clear case of platinum associated phrenic neuropathy leading to symptomatic diaphragmatic weakness. CONCLUSIONS: Platinum based chemotherapy is a possible cause of phrenic neuropathy leading to diaphragmatic impairment. Reference #1: Park SB, Goldstein D, Krishnan AV, Lin CSY, Friedlander ML, Cassidy J, Koltzenburg M, Kiernan MC. Chemotherapy-induced peripheral neurotoxicity: A critical analysis. Ca Cancer J Clin. 2013;63: 419-437 Reference #2: Stevens WW, Sporn PHS. Bilateral diaphragm weakness after chemotherapy for lymphoma. Am J Respir Crit Care Med. 2014;189(7):12 Reference #3: Gilliland P, Holguin M. Phrenic nerve paralysis due to vincristine. Leuk Lymphoma. 2007;48(12): 2452-2453 DISCLOSURES: No relevant relationships by Vivek Iyer, source=Web Response No relevant relationships by Mark Norton, source=Web Response

The Correlation of the Grading of Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) Using the Total Neuropathy Score-Reduced and Various Electrophysiological Parameters in Breast Cancer Patients

Background The accurate grading of chemotherapy-induced peripheral neuropathy (CIPN) represents an unsolved issue. This study evaluated usefulness of the reduced version of Total Neuropathy Score TNS (TNSr) and the correlation of this scale with various electrophysiological parameters. Methods Neuropathic symptoms and quality of life were assessed using the neuropathy symptom scale and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-NTX) scale. A detailed neurologic examination, nerve conduction study (NCS), and the current perception threshold (CPT) were also performed.The TNSr score was calculated by a single examiner. We divided the patients with small fiber neuropathy and large fiber neuropathy and compared each variable between groups. Also, we analyzed correlations of the TNSr score with various parameters (NCS data, CPT score, and neuropathy symptom scales). Results Of 30 recruited patients, 16 (53%) had large fiber neuropathy, and the other 14 (47%) had small fiber neuropathy. Patients with large fiber neuropathy had a lower sural sensory nerve action potential (SNAP) (p=0.000), lower peroneal compound muscle action potential (CMAP) (p=0.002), higher National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, NTC) sensory grade (p=0.029) and higher TNSr score (p=0.000). There were no differences in any domain of the FACT/G, neuropathy symptom scale, or FACT/GOG-NTX between the two groups. The TNSr score was most significantly correlated with the sural SNAP (p=0.000), NTC-sensory grade (p=0.000), neuropathy symptom scale (p=0.001), FACT/GOG-NTX score (p=0.009), and pin score (p=0.002). Conclusions The TNSr score is correlated with sensory peripheral neurotoxicity and also present the symptom severity in CIPN. Key Words: Breast neoplasms, Polyneuropathies, Neurologic manifestations

Mir-pharmacogenetics of Vincristine and peripheral neurotoxicity in childhood B-cell acute lymphoblastic leukemia.

Vincristine (VCR), an important component of childhood acute lymphoblastic leukemia (ALL) therapy, can cause sensory and motor neurotoxicity. This neurotoxicity could lead to dose reduction or treatment discontinuation, which could in turn reduce survival. In this line, several studies associated peripheral neurotoxicity and polymorphisms in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) of VCR. Nowadays, it is well known that these genes are regulated by microRNAs (miRNAs) and SNPs in miRNAs could modify their levels or function. Therefore, the aim of this study was to determine whether SNPs in miRNAs could be associated with VCR-induced neurotoxicity. To achieve this aim, we analyzed all the SNPs in miRNAs (minor allele frequency (MAF) ≥ 0.01) which could regulate VCR-related genes in a large cohort of Spanish children with B-cell precursor ALL (B-ALL) homogeneously treated with LAL/SHOP protocols. We identified the A allele of rs12402181 in the seed region of miR-3117-3p, that could affect the binding with ABCC1 and RALBP1 gene, and C allele of rs7896283 in pre-mature sequence of miR-4481, which could be involved in peripheral nerve regeneration, significantly associated with VCR-induced neurotoxicity. These findings point out the possible involvement of two SNPs in miRNA associated with VCR-related neurotoxicity.

Abstract PD4-08: Efficacy of compression therapy using surgical gloves for nanoparticle albumin-bound-paclitaxel-induced peripheral neuropathy: A phase II multicenter study by the Kamigata breast cancer study group

Abstract PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse effect of many commonly used chemotherapeutic agents, including taxanes. However, there is currently no established effective prophylactic management for CIPN. Thus, we investigated the efficacy of using surgical glove (SG) compression therapy to prevent nanoparticle albumin-bound-paclitaxel (nab-PTX)-induced peripheral neuropathy. PATIENTS AND METHODS: Patients with primary and recurrent breast cancer who received 260 mg/m2 of nab-PTX were eligible for this case-control study. The patients wore two SGs of the same size, that is, one size smaller than the size that fit, on their dominant hand for 90 minutes. They did not wear SGs on the non-dominant hand, which served as the control hand. Peripheral neuropathy was evaluated at each treatment cycle using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and the Patient Neurotoxicity Questionnaire (PNQ). The temperatures of each fingertip of the compression SG-protected and control hands were measured by using thermography. RESULTS: Between August 2013 and January 2016, 43 patients were enrolled, and 42 were evaluated. As shown in Table 1, the overall occurrence of ≥grade 2 sensory and motor peripheral neuropathy according to the CTCAE was significantly lower in the SG-protected hands than in the control hands (76.1% vs. 21.4% and 57.1% vs. 26.2%, respectively, p &amp;lt; 0.0001). The PNQ results showed that the incidence of ≥grade 4 neuropathy was significantly higher in the control hands than in the SG-protected hands in terms of both sensory and motor neurotoxicity (p &amp;lt; 0.0001, Table 2). As the treatment cycles of nab-PTX increased, the mean CTCAE and PNQ grades of the control hands gradually increased. However, the SG-protected hands maintained significantly lower mean grades than the control hands over time (p &amp;lt; 0.0001). No patients withdrew from this study because they could not tolerate the compression from the SGs. The mean temperature of each fingertip significantly decreased (1.42–2.60 °C) in the SG-protected hands compared to in the control hands. CONCLUSIONS: SG compression therapy appears effective for reducing nab-PTX-induced peripheral neuropathy. The nab-PTX exposure to the peripheral nerve may be decreased because the SG decreases microvascular flow to the fingertip. Table 1: Comparison of the overall occurrences of the different grades of peripheral neuropathy according to CTCAE version 4.0 between the compression surgical glove-protected hands and control handsCTCAE v.4.0SensoryMotorGradeSurgical GloveControlSurgical GloveControl012418712161311292411163080840000 Table 2: Changes in the overall occurrence of the Patient Neurotoxicity Questionnaire (PNQ) grade with surgical glove compression therapyPNQSensoryMotorGradeSurgical gloveControlSurgical gloveControl194209223512113717912431611050000 Citation Format: Tsuyuki S, Senda N, Kanng Y, Yamaguchi A, Yoshibayashi H, Kikawa Y, Katakami N, Kato H, Hashimoto T, Okuno T, Yamauchi A, Inamoto T. Efficacy of compression therapy using surgical gloves for nanoparticle albumin-bound-paclitaxel-induced peripheral neuropathy: A phase II multicenter study by the Kamigata breast cancer study group [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD4-08.

Preventive Effects of Bee Venom Derived Phospholipase A₂ on Oxaliplatin-Induced Neuropathic Pain in Mice.

Oxaliplatin, a chemotherapy drug used to treat colorectal cancer, induces specific sensory neurotoxicity signs that are aggravated by cold and mechanical stimuli. Here we examined the preventive effects of Bee Venom (BV) derived phospholipase A2 (bvPLA2) on oxaliplatin-induced neuropathic pain in mice and its immunological mechanism. The cold and mechanical allodynia signs were evaluated by acetone and von Frey hair test on the hind paw, respectively. The most significant allodynia signs were observed at three days after an injection of oxaliplatin (6 mg/kg, i.p.) and then decreased gradually to a normal level on days 7–9. The oxaliplatin injection also induced infiltration of macrophages and upregulated levels of the pro-inflammatory cytokine interleukin (IL)-1β in the lumbar dorsal root ganglia (DRG). Daily treatment with bvPLA2 (0.2 mg/kg, i.p.) for five consecutive days prior to the oxaliplatin injection markedly inhibited the development of cold and mechanical allodynia, and suppressed infiltration of macrophages and the increase of IL-1β level in the DRG. Such preventive effects of bvPLA2 were completely blocked by depleting regulatory T cells (Tregs) with CD25 antibody pre-treatments. These results suggest that bvPLA2 may prevent oxaliplatin-induced neuropathic pain by suppressing immune responses in the DRG by Tregs.

Efficacy of venlafaxine for the relief of taxane and oxaliplatin-induced acute neurotoxicity: a single-center retrospective case-control study.

Oxaliplatin and taxane-induced neurosensory toxicity is dose-limiting and mostly presents with acute symptoms that affect the activities of daily living and overall quality of life. The objective of the present study is to assess the relief of acute neuropathy with venlafaxine treatment during the chemotherapy period. In this retrospective case-control study, from January 2010 to February 2015, patients who experienced treatment with oxaliplatin and taxane-induced acute neurotoxicity were evaluated according to the NCI-CTCAE v. 4.03 grading scale. Neurotoxicity was evaluated using a numeric rating scale (NRS) for pain intensity and experienced relief under the treatment of venlafaxine and using a neuropathic pain symptom inventory scale (NPSI) for the style of complaints. Patients who were diagnosed as mildly depressed according to the HOST anxiety and depression scale and who had grade 1 to 3 sensory neurotoxicity based on the NCI-CTCAE v. 4.03 grading scale, and who also reported ≥ 4/10 on a NRS were eligible. The primary end point was the rate of more than 75 % symptomatic relief under venlafaxine treatment. Two hundred six patients were included (82 % female, median age: 52.7 years). Most patients had breast, gynecologic, and colon cancer (93.4 %). Ninety-one patients who received venlafaxine and 115 patients as the control group were assessed for neurotoxicity every 3 weeks. Based on the NRS, a rate of more than 75 % symptomatic relief was 53.5, 58.3, and 45.2 % in venlafaxine arm versus 0, 0, and 0 % in the control arm in the first, second, and third visits, respectively. Side-effects of venlafaxine (n = 7) were grade 1-2 nausea/vomiting (3.2 %) and asthenia/somnolence (3.2 %) without grade 3-4 events. Venlafaxine has a significant clinical activity against taxane-oxaliplatin-induced acute neurosensory toxicity.

Analgesic Effects of Bee Venom Derived Phospholipase A(2) in a Mouse Model of Oxaliplatin-Induced Neuropathic Pain.

A single infusion of oxaliplatin, which is widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs that are triggered or aggravated when exposed to cold or mechanical stimuli. Bee Venom (BV) has been traditionally used in Korea to treat various pain symptoms. Our recent study demonstrated that BV alleviates oxaliplatin-induced cold allodynia in rats, via noradrenergic and serotonergic analgesic pathways. In this study, we have further investigated whether BV derived phospholipase A2 (bvPLA2) attenuates oxaliplatin-induced cold and mechanical allodynia in mice and its mechanism. The behavioral signs of cold and mechanical allodynia were evaluated by acetone and a von Frey hair test on the hind paw, respectively. The significant allodynia signs were observed from one day after an oxaliplatin injection (6 mg/kg, i.p.). Daily administration of bvPLA2 (0.2 mg/kg, i.p.) for five consecutive days markedly attenuated cold and mechanical allodynia, which was more potent than the effect of BV (1 mg/kg, i.p.). The depletion of noradrenaline by an injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4, 50 mg/kg, i.p.) blocked the analgesic effect of bvPLA2, whereas the depletion of serotonin by injecting DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for three successive days did not. Furthermore, idazoxan (α2-adrenegic receptor antagonist, 1 mg/kg, i.p.) completely blocked bvPLA2-induced anti-allodynic action, whereas prazosin (α1-adrenegic antagonist, 10 mg/kg, i.p.) did not. These results suggest that bvPLA2 treatment strongly alleviates oxaliplatin-induced acute cold and mechanical allodynia in mice through the activation of the noradrenergic system, via α2-adrenegic receptors, but not via the serotonergic system.

Effects of Analgecine on Oxaliplatin-Induced Neurotoxicity in Patients with Gastrointestinal Cancer

As the third generation of platinum-based antineoplastic agent aginst gastrointestinal cancer, oxaliplatin is considered to be associated with severe sensory neurotoxicity. Acorrding to previous studies, vitaminE, intravenous Ca/Mg and glutamine may partly reduce the incidence and severity of oxaliplatin-induced neurotoxicity. The aim of this study was to investigate the safety and efficacy of analgecine for preventing oxaliplatin-induced neurotoxicity in the patients with gastrointestinal tumors. In this study, patients undergoing oxaliplatin-based chemotherapy were assigned to analgecine (experimental) group or control group. Analgecine 6ml was administered once a day for seven days from the day of oxaliplatin treatment. The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3) was used to evaluate oxaliplatin-induced neurotoxicity. The incidence rates and grade of neurotoxicity of patients were assessed before and during (after four and eight cycles) treatment. Totally, 82 patients were enrolled in this study, 42 in experimental group and 40 in control group. The occurrence of each grade neurotoxicity in the experimental group was significantly lower than that in control group. The overall occurrence rate was 31% vs 55% (P=0.043) after 4 cycles and 52% vs 75% (P=0.050) after 8 cycles. Analgecine appears could be effective in reducing oxaliplatin-induced neurotoxicity and be applicated for patients with gastrointestinal tumors who would be treated with oxaliplatin-based chemotherapy.

P-280 Reduction effect of Oxaliplatin-Related sensory neurotoxicity by Goshajinkigan (TJ-107) plus Powdered processed aconite root (TJ-3023)

Introduction: FOLFOX and CapeOX is one of standard therapies for advanced-stage colorectal cancer. Sensory neurotoxicity (SN) with oxaliplatin is its dose-limiting toxicity. We decided to use goshajinkigan (TJ-107) for prevention of oxaliplatin-related SN. We think that the main action is the one with powdered processed aconite root (TJ-3023).

Platinum-induced neurotoxicity and preventive strategies: past, present, and future.

Neurotoxicity is a burdensome side effect of platinum-based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. Peripheral sensory neurotoxicity varies from paresthesia in fingers to ataxic gait, which might be transient or irreversible. Because the number of patients being treated with these neurotoxic agents is still increasing, the need for understanding the pathogenesis of this dramatic side effect is critical. Platinum derivatives, such as cisplatin and carboplatin, harm mainly peripheral nerves and dorsal root ganglia neurons, possibly because of progressive DNA-adduct accumulation and inhibition of DNA repair pathways (e.g., extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase/stress-activated protein kinase, and p38 mitogen-activated protein kinass), which finally mediate apoptosis. Oxaliplatin, with a completely different pharmacokinetic profile, may also alter calcium-sensitive voltage-gated sodium channel kinetics through a calcium ion immobilization by oxalate residue as a calcium chelator and cause acute neurotoxicity. Polymorphisms in several genes, such as voltage-gated sodium channel genes or genes affecting the activity of pivotal metal transporters (e.g., organic cation transporters, organic cation/carnitine transporters, and some metal transporters, such as the copper transporters, and multidrug resistance-associated proteins), can also influence drug neurotoxicity and treatment response. However, most pharmacogenetics studies need to be elucidated by robust evidence. There are supportive reports about the effectiveness of several neuroprotective agents (e.g., vitamin E, glutathione, amifostine, xaliproden, and venlafaxine), but dose adjustment and/or drug withdrawal seem to be the most frequently used methods in the management of platinum-induced peripheral neurotoxicity. To develop alternative options in the treatment of platinum-induced neuropathy, studies on in vitro models and appropriate trials planning should be integrated into the future design of neuroprotective strategies to find the best patient-oriented solution.