Development of hepatic impairment aggravates chemotherapy-induced peripheral neuropathy following oxaliplatin treatment: Evidence from clinical and preclinical studies

Abstract PurposeChemotherapy-induced peripheral neuropathy (CIPN) is a common adverse events of cancer treatment; however, no drug is recommended for the prevention of CIPN. In Japan, several drugs such as Gosha-Jinki-Gan and duloxetine have been frequently administered for the treatment of CIPN. The aim of this study was to elucidate prescription patterns of drugs administered for the treatment of CIPN caused by oxaliplatin and the association between these drugs and the duration of oxaliplatin treatment.MethodsWe conducted a retrospective nationwide study using the JMDC administrative claims database (January 2005–June 2020). Patients newly treated with oxaliplatin were identified, and prescription patterns of CIPN medication including Gosha-Jinki-Gan, pregabalin, duloxetine, mecobalamin, and mirogabalin were investigated. The primary outcome was the duration of oxaliplatin treatment. Multivariable logistic regression analysis was performed to examine the association between CIPN medication and duration of oxaliplatin treatment.ResultsA total of 4,739 patients who newly received oxaliplatin were identified. Of these, 759 (16.0%) had received CIPN medication. Duloxetine was administered in 99 (2.1%) patients. Multivariable logistic regression analysis revealed that CIPN medication was significantly associated with the prolonged duration of oxaliplatin treatment (odds ratio: 2.35, [95% confidence interval: 1.99-2.77]).ConclusionReal-world data demonstrated that the administration rate of CIPN medication was higher in patients who underwent oxaliplatin treatment for over 6 months. Increasing administration preference of duloxetine and conducting prospective studies to verify the causal relationship between CIPN medication and prolonged duration of oxaliplatin treatment are needed.

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201 HCN Channels Blockade Attenuates Chemotherapy-Induced Pain

Neurosurgery ◽

10.1093/neuros/nyx417.201 ◽

2017 ◽

Vol 64 (CN_suppl_1) ◽

pp. 254-254

Author(s):

Kun Hu ◽

Zerong You ◽

Weihua Ding ◽

Jianren Mao

Keyword(s):

Peripheral Neuropathy ◽

Rat Model ◽

Dorsal Root ◽

Mechanical Hyperalgesia ◽

Hcn Channels ◽

Oxaliplatin Treatment ◽

Gene Transcripts ◽

Pre Treatment ◽

Chemotherapy Agents ◽

Therapeutic Avenue

Abstract INTRODUCTION Painful peripheral neuropathy is a common dose-limiting side effect caused by chemotherapy agents, such as oxaliplatin. Mechanisms underlying this devastating condition are largely unknown. METHODS We established a rat model of chemotherapy induced pain by administering oxaliplatin at 2 mg/Kg for 5 consecutive days. Mechanical hyperalgesia, a typical nociceptive pain behavior, developed after treatment with oxaliplatin. We investigated the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the dorsal root ganglia (DRG) at both gene transcripts level (real-time PCR) and protein level (immunofluorescence). In addition, we examined the functional significance of HCN upregulation after oxaliplatin treatment by using a pan HCN channels blocker-ZD 7288. RESULTS >DRG HCN 1 and HCN 2 were higher in oxaliplatin- treated rats than saline-treated controls, both for gene transcripts and proteins. ZD7288, when administered intrathecally, was able to alleviate, albeit not abrogate, oxaliplatin induced-pain. Interestingly, pre-treatment with ZD7288 prior to oxaliplatin administration did not prevent the development of mechanical hyperalgesia. CONCLUSION Taken together, HCN1 and HCN2 channels are upregulated by oxaliplatin treatment, and that HCN blockade alleviates oxaliplatin-induced pain. Therefore, targeting HCN channels may provide a therapeutic avenue to treat chemotherapy induced-pain.

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Acute changes in nerve excitability following oxaliplatin treatment in mice

Journal of Neurophysiology ◽

10.1152/jn.00260.2020 ◽

2020 ◽

Vol 124 (1) ◽

pp. 232-244

Author(s):

Preet G. S. Makker ◽

Daniel White ◽

Justin G. Lees ◽

Jasneet Parmar ◽

David Goldstein ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Mouse Model ◽

Intramuscular Injection ◽

Motor Nerve ◽

Channel Activity ◽

Peripheral Neurotoxicity ◽

Clinical Observations ◽

Nerve Excitability ◽

Oxaliplatin Treatment ◽

Acute Changes

We present a novel mouse model of acute oxaliplatin-induced peripheral neurotoxicity that is comparable to clinical observations. Intramuscular injection of oxaliplatin produced acute changes in motor nerve excitability that were attributable to alterations in Na+ and K+ channel activity. Conversely, we were unable to show any significant changes in nerve excitability with systemic intraperitoneal injections of oxaliplatin. This study suggests that local intramuscular injection is a valid approach for modelling oxaliplatin-induced peripheral neuropathy in animals.

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Vitamin E for prevention of oxaliplatin-induced peripheral neuropathy: a pilot randomized clinical trial

Sao Paulo Medical Journal ◽

10.1590/s1516-31802013000100006 ◽

2013 ◽

Vol 131 (1) ◽

pp. 35-38 ◽

Cited By ~ 23

Author(s):

Samuel Oliveira de Afonseca ◽

Felipe Melo Cruz ◽

Daniel de Iracema Gomes Cubero ◽

Andrea Thaumaturgo Lera ◽

Fernanda Schindler ◽

...

Keyword(s):

Placebo Group ◽

Vitamin E ◽

Peripheral Neuropathy ◽

Group Versus ◽

University Hospital ◽

Magnesium Supplementation ◽

Oxaliplatin Treatment ◽

Before And After ◽

The Common ◽

To Receive

CONTEXT AND OBJECTIVEOxaliplatin is one of the chemotherapy regimens most used for treating colorectal cancer. One of the main limitations to its use is induction of peripheral neuropathy. Previous studies have shown that vitamin E can reduce the incidence of peripheral neuropathy by 50%. This study aimed to assess the effectiveness of vitamin E for prevention of oxaliplatin-induced peripheral neuropathy.DESIGN AND SETTINGProspective, phase II, randomized pilot study developed at a university hospital in the Greater ABC region.METHODSPatients were randomized five days before starting oxaliplatin treatment, to receive either vitamin E or placebo until the end of the chemotherapy regimen. The outcome was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), version 3, and specific gradation scales for oxaliplatin-induced peripheral neuropathy. Patients with colorectal and gastric cancer who had been scheduled to receive oxaliplatin-based chemotherapy were included. Both groups received calcium and magnesium supplementation before and after oxaliplatin infusions.RESULTSEighteen patients were randomized to the vitamin E group and 16 to the placebo group. Cumulative incidence of 83% with peripheral neuropathy grades 1/2 was observed in the vitamin E group, versus 68% in the placebo group (P = 0.45). A trend towards more diarrhea was observed among patients who received vitamin E (55.6% vs. 18.8%; P = 0.06). There were no other significant differences in toxicity between the groups.CONCLUSIONSNo significant decrease in the incidence of acute oxaliplatin-induced peripheral neuropathy was demonstrated through vitamin E use.CLINICAL TRIAL REGISTRATIONNCT01523574.

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Efficacy of the Motivational Interviewing–Walk Intervention for Chemotherapy-Induced Peripheral Neuropathy and Quality of Life During Oxaliplatin Treatment

Cancer Nursing ◽

10.1097/ncc.0000000000001003 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Grace A. Kanzawa-Lee ◽

Robert J. Ploutz-Snyder ◽

Janet L. Larson ◽

John C. Krauss ◽

Kenneth Resnicow ◽

...

Keyword(s):

Quality Of Life ◽

Peripheral Neuropathy ◽

Motivational Interviewing ◽

Oxaliplatin Treatment

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Neuropathy Severity at the Time of Oxaliplatin Treatment Alteration in Patients with Colon Cancer (Alliance A151912)

10.21203/rs.3.rs-300187/v1 ◽

2021 ◽

Author(s):

Daniel Hertz ◽

Travis J Dockter ◽

Daniel V Satele ◽

Charles L Loprinzi ◽

Jennifer G Le-Rademacher

Keyword(s):

Colon Cancer ◽

Peripheral Neuropathy ◽

Dose Reduction ◽

Clinical Use ◽

Chemotherapy Treatment ◽

Oxaliplatin Treatment ◽

End Of Treatment ◽

Patient Reported ◽

Few Data ◽

Group 1

Abstract Background: Clinical guidelines recommend altering chemotherapy treatment by decreasing, delaying, or discontinuing dosing in patients who are experiencing chemotherapy-induced peripheral neuropathy. There are few data available on the clinical use of treatment alteration including the severity of CIPN at the time of treatment alteration. Methods: This was a retrospective analysis of patients receiving oxaliplatin on the NCCTG N08CB trial. Neuropathy severity was assessed at each cycle by clinicians and patients. Patients were classified as 1) completed treatment without alteration, 2) dose reduction or delay due to neuropathy, 3) discontinuation due to neuropathy, or discontinuation for other toxicity (4), or another reason (5). Comparisons focused primarily on patients with alteration due to neuropathy (groups 2 and/or 3) compared with patients who completed treatment without alteration (group 1). Results: In 350 participants, 135 (39%) completed treatment without alteration, 70 (20%) had a dose reduction or delay due to neuropathy, and 35 (10%) discontinued early due to neuropathy. Clinician-assessed neuropathy severity was greater in patients at the time of dose reduction or delay compared with severity at the end of treatment in patients without alteration (p<0.0001). Patient-reported neuropathy severity at cycle 4 was worse in patients who had an alteration as compared with patients who completed treatment without alteration (p=0.017). Conclusions: Treatment alterations due to neuropathy are common in patients receiving oxaliplatin for colon cancer and are associated with clinician-assessed neuropathy severity. Rapid increases in patient-reported neuropathy severity indicate a potential need for monitoring and intervention.

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Neuropathy severity at the time of oxaliplatin treatment alteration in patients with colon cancer (Alliance A151912).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.12090 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 12090-12090

Author(s):

Daniel Louis Hertz ◽

Travis Dockter ◽

Daniel V. Satele ◽

Charles L. Loprinzi ◽

Jennifer Le-Rademacher

Keyword(s):

Colon Cancer ◽

Peripheral Neuropathy ◽

Dose Reduction ◽

Oxaliplatin Treatment ◽

End Of Treatment ◽

Chi Squared ◽

Few Data ◽

Eortc Qlq ◽

To Receive ◽

Clinical Trial Information

12090 Background: Clinical guidelines recommend altering chemotherapy treatment by decreasing, delaying, or discontinuing dosing in patients (pts) experiencing chemotherapy-induced peripheral neuropathy (CIPN). There are few data available on clinical use of treatment alteration including the severity of CIPN at the time of alteration. Our objective was to investigate the incidence of oxaliplatin treatment alterations and CIPN severity at that time. Methods: This was a retrospective analysis of pts with colon cancer scheduled to receive oxaliplatin-containing combination chemotherapy on the N08CB trial of intravenous calcium and magnesium for prevention of CIPN. Dose alterations were not mandated by the N08CB protocol. Clinicians assessed CIPN using NCI-CTCAE V.4.0; pts used the sensory subscale of the EORTC-QLQ Chemotherapy-Induced Peripheral Neuropathy 20 (CIPN8). Pts were classified as 1) completed oxaliplatin treatment without alteration, 2) dose reduction or delay due to CIPN, 3) discontinuation due to CIPN, 4) discontinuation due to other AE, or 5) discontinuation for another reason. Comparisons focused primarily on pts with alteration due to CIPN (groups 2 and/or 3) compared with pts completing treatment without alteration (group 1) using chi-squared and Kruskal-Wallis tests. Results: In this analysis of 350 N08CB pts, 135 (39%) completed oxaliplatin without treatment alteration, 70 (20%) had a dose reduction (n=66) or delay (n=4) due to CIPN and 35 (10%) discontinued early due to CIPN. Pts who experienced alterations due to CIPN were younger (p=0.0249) and more likely to be female (p=0.008). Clinician-assessed CIPN severity was greater in pts at the time of dose reduction or delay compared with CIPN severity at the end of treatment in pts with no alteration (p<0.0001). Pt-assessed CIPN severity was not different in pts who completed treatment without alteration compared to pts who had a dose reduction or delay (p=0.88) or a discontinuation (p=0.37). CIPN8 scores at cycle 4 were higher (worse) in pts who eventually had any alteration (i.e., reduction, delay, or discontinuation) compared to pts who completed treatment without any alteration (median CIPN8 11.5 vs. 7.7, p=0.023). Conclusions: Treatment alterations due to CIPN are relatively common in pts receiving adjuvant oxaliplatin for colon cancer and are associated with clinician-assessed but not pt-reported CIPN severity. Rapid CIPN8 increases early in treatment are indicative of increased likelihood of a future oxaliplatin treatment alteration, indicating a potential use of early monitoring and intervention. Support: UG1CA189823; https://acknowledgments.alliancefound.org. Clinical trial information: NCT01099449 (NCCTG N08CB).

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Cancer chemotherapy induced peripheral neuropathy (CIPN): preclinical studies

10.14264/uql.2015.831 ◽

2015 ◽

Author(s):

Felicity Yaqin Han

Keyword(s):

Peripheral Neuropathy ◽

Cancer Chemotherapy ◽

Preclinical Studies

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Early Stimulation of TREK Channel Transcription and Activity Induced by Oxaliplatin-Dependent Cytosolic Acidification

International Journal of Molecular Sciences ◽

10.3390/ijms21197164 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7164

Author(s):

Marianna Dionisi ◽

Federico Alessandro Ruffinatti ◽

Beatrice Riva ◽

Dmitry Lim ◽

Annalisa Canta ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Neuronal Excitability ◽

Drg Neurons ◽

Oxaliplatin Treatment ◽

Channel Expression ◽

The Impact ◽

Complex Modulation ◽

Cytosolic Acidification

Oxaliplatin-induced peripheral neuropathy is characterized by an acute hyperexcitability syndrome triggered/exacerbated by cold. The mechanisms underlying oxaliplatin-induced peripheral neuropathy are unclear, but the alteration of ion channel expression and activity plays a well-recognized central role. Recently, we found that oxaliplatin leads to cytosolic acidification in dorsal root ganglion (DRG) neurons. Here, we investigated the early impact of oxaliplatin on the proton-sensitive TREK potassium channels. Following a 6-h oxaliplatin treatment, both channels underwent a transcription upregulation that returned to control levels after 42 h. The overexpression of TREK channels was also observed after in vivo treatment in DRG cells from mice exposed to acute treatment with oxaliplatin. Moreover, both intracellular pH and TREK channel transcription were similarly regulated after incubation with amiloride, an inhibitor of the Na+/H+ exchanger. In addition, we studied the role of oxaliplatin-induced acidification on channel behavior, and, as expected, we observed a robust positive modulation of TREK channel activity. Finally, we focused on the impact of this complex modulation on capsaicin-evoked neuronal activity finding a transient decrease in the average firing rate following 6 h of oxaliplatin treatment. In conclusion, the early activation of TREK genes may represent a mechanism of protection against the oxaliplatin-related perturbation of neuronal excitability.

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