Symptoms: Chemotherapy-Induced Peripheral Neuropathy

Schneider, Bryan P.; Hershman, Dawn L.; Loprinzi, Charles L.

doi:10.1007/978-3-319-16366-6_6

Cited by 43 publications

(25 citation statements)

References 39 publications

(41 reference statements)

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“…The occurrence of CIPN can limit the chemotherapeutic dosage, delay additional treatment cycles, and even lead to early termination of treatment [30; 34]. Moreover, CIPN frequently persists or even worsens after completion of chemotherapy [43], thereby greatly reducing quality of life for cancer survivors. Despite the high prevalence and severity of CIPN, currently there are no effective FDA-approved drugs to prevent or reverse CIPN.…”

Section: Introductionmentioning

confidence: 99%

HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy

Krukowski

Golonzhka

et al. 2017

PAIN

145

152

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Chemotherapy-induced peripheral neuropathy is one of the most common dose-limiting side effects of cancer treatment. Currently, there is no Food and Drug Administration–approved treatment available. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase whose function includes regulation of α-tubulin–dependent intracellular mitochondrial transport. Here, we examined the effect of HDAC6 inhibition on established cisplatin-induced peripheral neuropathy. We used a novel HDAC6 inhibitor ACY-1083, which shows 260-fold selectivity towards HDAC6 vs other HDACs. Our results show that HDAC6 inhibition prevented cisplatin-induced mechanical allodynia, and also completely reversed already existing cisplatin-induced mechanical allodynia, spontaneous pain, and numbness. These findings were confirmed using the established HDAC6 inhibitor ACY-1215 (Ricolinostat), which is currently in clinical trials for cancer treatment. Mechanistically, treatment with the HDAC6 inhibitor increased α-tubulin acetylation in the peripheral nerve. In addition, HDAC6 inhibition restored the cisplatin-induced reduction in mitochondrial bioenergetics and mitochondrial content in the tibial nerve, indicating increased mitochondrial transport. At a later time point, dorsal root ganglion mitochondrial bioenergetics also improved. HDAC6 inhibition restored the loss of intraepidermal nerve fiber density in cisplatin-treated mice. Our results demonstrate that pharmacological inhibition of HDAC6 completely reverses all the hallmarks of established cisplatin-induced peripheral neuropathy by normalization of mitochondrial function in dorsal root ganglia and nerve, and restoration of intraepidermal innervation. These results are especially promising because one of the HDAC6 inhibitors tested here is currently in clinical trials as an add-on cancer therapy, highlighting the potential for a fast clinical translation of our findings.

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Section: Introductionmentioning

confidence: 99%

HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy

Krukowski

Golonzhka

et al. 2017

PAIN

145

152

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“…The predictive strategies have predominantly focused on the search for hereditary biomarkers that could identify patients at increased risk of toxicity through candidate gene or genome-wide association studies (5,11,12). However, the findings from these studies done to date have identified nonoverlapping single or pathway biomarker associations that preclude immediate clinical implementation.…”

Section: Introductionmentioning

confidence: 99%

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

Leblanc¹,

Sprowl²,

Alberti³

et al. 2018

Journal of Clinical Investigation

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“…Clinical trials with taxanes have shown grade 2 to 4 neuropathy rates ranging from 15% to 23%, as graded by the Common Terminology Criteria Adverse Events system, with higher rates related to the specific drug, dose, schedule, and therapy duration. [1][2][3] Patients with grade 2 neuropathy have interference with function (eg, difficulty buttoning a shirt), those with grade 3 have interference with activities of daily living (eg, brushing teeth), and those with grade 4 have permanent and disabling symptoms.…”

Section: Introductionmentioning

confidence: 99%

Comorbidities and Risk of Chemotherapy-Induced Peripheral Neuropathy Among Participants 65 Years or Older in Southwest Oncology Group Clinical Trials

Hershman

Till

Wright

et al. 2016

JCO

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180

129

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Listen to the podcast by Dr Paice at www.jco.org/podcastsNeuropathy is a debilitating toxicity associated with various chemotherapy agents. We evaluated the association between common comorbid conditions and the development of peripheral neuropathy in patients treated with taxane-based chemotherapy. MethodsWe examined the Southwest Oncology Group database to identify phase II and III trials that included taxane therapy from 1999 to 2011. We linked the Southwest Oncology Group clinical records to Medicare claims data according to Social Security number, sex, and date of birth. The following disease conditions potentially associated with peripheral neuropathy were evaluated: diabetes, hypothyroidism, hypercholesterolemia, hypertension, varicella zoster, peripheral vascular disease, and autoimmune diseases. Multivariate logistic regression was used to model the odds of experiencing grade 2 to 4 neuropathy. ResultsA total of 1,401 patients from 23 studies were included in the analysis. Patients receiving paclitaxel were more likely to experience grade 2 to 4 neuropathy compared with docetaxel (25% v 12%, respectively; OR, 2.20; 95% CI, 1.52 to 3.18; P , .001). The inclusion of a platinum agent was also associated with greater neuropathy (OR, 1.68; 95% CI, 1.18 to 2.40; P = .004). For each increase in age of 1 year, the odds of neuropathy increased 4% (P = .006). Patients with complications from diabetes had more than twice the odds of having neuropathy (OR, 2.13; 95% CI, 1.31 to 3.46; P = .002) compared with patients with no diabetes. In contrast, patients with autoimmune disease were half as likely to experience neuropathy (OR, 0.49; 95% CI, 0.24 to 1.02; P = .06). The other conditions were not associated with neuropathy. ConclusionWe found that in addition to drug-related factors, age and history of diabetes were independent predictors of the development of chemotherapy-induced peripheral neuropathy. Interestingly, we also observed that a history of autoimmune disease was associated with reduced odds of neuropathy. Patients with diabetic complications may choose to avoid paclitaxel or taxane plus platinum combination therapies if other efficacious options exist.

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Symptoms: Chemotherapy-Induced Peripheral Neuropathy

Cited by 43 publications

References 39 publications

HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy

HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

Comorbidities and Risk of Chemotherapy-Induced Peripheral Neuropathy Among Participants 65 Years or Older in Southwest Oncology Group Clinical Trials

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