Pharmacology Consult

Management of chemotherapy-induced peripheral neuropathy requires personalized approach

Chemotherapy-induced peripheral neuropathy is a frequent and debilitating adverse effect of commonly used chemotherapy agents.

These agents include taxanes (paclitaxel and docetaxel), vinca alkaloids (vincristine), platinums (cisplatin, carboplatin and oxaliplatin), epothilones (ixabepilone [Ixempra, R-Pharm US]) and bortezomib (Velcade, Millennium).

There are no FDA–approved drugs to prevent or treat chemotherapy-induced peripheral neuropathy (CIPN). Given the treatment-limiting nature of the condition and the lack of effective methods to reduce symptom burden, novel and personalized approaches to predict, prevent and treat CIPN are needed.

Clinical course

CIPN involves damage to peripheral nerves caused by exposure to a neurotoxic agent, although the exact mechanisms accounting for differences between offending agents is relatively unknown.

Jai N. Patel, PharmD
Jai N. Patel

It most commonly presents as sensory neuropathy, including numbness, loss of proprioception sense, tingling, pins-and-needles sensation, hyperalgesia or allodynia in the hands or feet.

Although less frequent, damage to motor fibers resulting in motor neuropathy may occur. This is most common with paclitaxel and vincristine.

CIPN typically is dose dependent and can occur at any point after treatment initiation. A randomized trial of oxaliplatin-treated patients with colorectal cancer demonstrated that 89% had at least one symptom of acute neuropathy with the first cycle, including sensitivity to touching or swallowing cold items, throat discomfort and muscle cramps.

Acute symptoms peaked at 3 days, and severity was predictive of chronic neurotoxicity, commonly presenting as tingling, numbness and pain. Notably, sensory symptoms were worse in the upper extremities during chemotherapy, but 6 months after chemotherapy, symptoms reversed and were worse in lower extremities.

Taxane-induced neuropathy usually improves in the months following therapy cessation; however, approximately 80% report long-term persistence to some degree.

Predicting which patients will experience neuropathy has been an ongoing challenge. Proposed clinical risk factors include prior therapy with a neurotoxic agent, diabetes mellitus, folate/vitamin B12 deficiencies, African race and older age. Some of these risk factors also appear to impact recovery from neuropathy.

Lack of treatment options

NCI–supported trials have been unable to identify an effective regimen to manage CIPN.

Randomized phase 3 trials that investigated several options — including alpha lipoic acid, IV calcium and magnesium, vitamin E, Acetyl-L-carnitine, glutathione, nortriptyline, gabapentin, lamotrigine, amifostine, and topical amitriptyline and ketamine — have shown no improvement in CIPN severity or duration, or patient quality of life. In fact, Acetyl-L-carnitine was shown to increase CIPN incidence compared with placebo.

Prior to the results of the North Central Cancer Treatment Group’s (NCCTG) N04C7 trial, up to 40% of oxaliplatin infusions in the United States were administered concurrently with IV calcium and magnesium. This approach was essentially eliminated from practice based on results from randomized trials, saving time, resources, costs and potentially harmful adverse effects.

These examples reiterate the use of evidence-based guidelines to drive medical decision-making as opposed to anecdotal data alone.

The CALGB 170601 trial, however, demonstrated a decrease in pain score at 6 weeks among patients who received duloxetine rather than placebo. Notably, the magnitude of benefit was modest (mean change in pain score, –1.06 vs. –0.34; P = .003) and appeared to be more prominent with oxaliplatin-induced neuropathy than paclitaxel.

Importantly, traditional neuromodulatory agents commonly used in practice — such as nortriptyline and gabapentin — are potentially harmful in vulnerable populations (eg, the elderly, who are at risk for falls).

Taken together with the absence of benefit in randomized studies, caution should be employed with the use of these agents in practice. Study endpoints also should be carefully selected, as earlier trials often relied on clinician assessment of CIPN using criteria such as the Common Toxicity Criteria for Adverse Events, which have been shown to be less sensitive than patient-reported outcomes.

Biomarkers

Candidate biomarker studies of single nucleotide polymorphisms in genes involved in the pharmacology of neurotoxic drugs have been conducted, but no reliable biomarker has been identified for translation into clinical practice.

One study demonstrated an association between CYP2C8*3 and a twofold increase in paclitaxel-induced neuropathy risk, whereas other studies have identified polymorphisms within the therapeutic target of taxanes, beta-tubulin IIa, that increase neuropathy risk.

Samples collected from NCI–supported trials have allowed the discovery and validation of proposed biomarkers to predict CIPN occurrence.

The NCCTG N08C1 study demonstrated an association between genes related to Charcot-Marie-Tooth disease, an inherited neuropathy condition, and occurrence of CIPN.

Baldwin and colleagues performed the first genome-wide association study to investigate paclitaxel-induced neuropathy and identified SNPs in FGD4 — a congenital neuropathy gene associated with Charcot-Marie-Tooth disease — FZD3 and EPHA5 as significantly associated with CIPN occurrence and severity. The set of genes driving heritability of CIPN in this breast cancer cohort was found to be implicated in axonogenesis and regulation of axon outgrowth.

Schneider and colleagues were unable to replicate these findings in another paclitaxel-treated cohort; however, an SNP in the gene GPR177 — also called Wnt — appeared significantly associated with CIPN occurrence, suggesting the importance of the Wnt pathway in paclitaxel-induced neuropathy.

Hertz and colleagues performed the first genome-wide association study to investigate docetaxel-induced neuropathy. They identified a SNP in VAC14 that was significantly associated with CIPN in patients with castrate-resistant prostate cancer. VAC14 has been previously linked to neurodegeneration in animal models and to hereditary conditions in humans, including Charcot-Marie-Tooth disease.

Interestingly, this study also demonstrated that knockdown of VAC14 increased docetaxel sensitivity as measured by decreased neurite processes, and VAC14 heterozygous mice had greater nociceptive sensitivity compared with wild-type controls.

Rieger and colleagues identified that — in the presence of paclitaxel — neuropathy is triggered by increased expression of matrix metallopeptidase 13 (MMP13), which is toxic to nerves and degrades collagen, contributing to paclitaxel-induced nerve damage. In preclinical models, two drugs have been shown to prevent paclitaxel-induced neurotoxicity by decreasing MMP13 activity, but trials in human have not yet started.

Diouf and colleagues identified an SNP in the promoter region of the CEP72 gene, which encodes a centrosomal protein involved in microtubule formation that was significantly associated with occurrence and severity of vincristine-induced neuropathy in children with acute lymphoblastic leukemia. Reducing CEP72 expression in human neurons and leukemia cells increased their sensitivity to vincristine, suggesting a potential basis for safer dosing.

Future directions and practical applications

Given the lack of benefit demonstrated in randomized trials, ASCO guidelines do not recommend any agent for CIPN prevention; however, they do provide a moderate recommendation for treatment with duloxetine for existing CIPN.

Although most neuromodulatory agents tested in randomized trials have been inconclusive, agents such as gabapentin, pregabalin and amitriptyline are commonly used based on data that support their utility in other neuropathic pain conditions.

Dose reductions, alternate chemotherapy or temporary cessation of chemotherapy have been and will continue to be the primary strategies for CIPN management. Until more treatment data are available, a concerted effort should be made to identify signs of CIPN prior to significant deterioration when the condition is more treatable.

Early findings suggest changes in cerebral perfusion and gray matter seen on MRI scans correlated with symptoms of CIPN in patients with breast cancer, which may have potential diagnostic and therapeutic implications.

Another study showed pre-chemotherapy screening with quantitative sensory testing called the Bumps detection test, which measures touch sensation deficits, significantly predicted the development of more severe numbness or tingling. This method may allow for a simple yet personalized approach to CIPN management.

The subjective nature of this phenotype results in a high degree of inter-rater variability. Physician-based clinical assessment tools are less sensitive for identification of chemotherapy-related adverse effects compared with patient-reported outcomes. As such, clinicians should consider the use of patient-reported outcomes, such as the clinically validated EORTC QLQ-CIPN20 questionnaire, to adequately capture treatment effect and further personalize treatment.

Lastly, validation of proposed genes — such as those associated with Charcot-Marie-Tooth disease or those involved in the pharmacologic disposition of offending drugs — may allow for clinicians to better predict which patients are at a higher risk for CIPN. Early identification of the presence of these genes through whole genome sequencing or whole exome sequencing may help clinicians avoid offending agents in patients at elevated baseline neuropathy risk.

A better understanding of the pathophysiology of CIPN and genes associated with predisposition ultimately will prove fruitful in the quest to identify predictive or targetable biomarkers for personalized treatment of this prevalent and debilitating symptom.

References:

Baldwin RM, et al. Clin Cancer Res. 2012;18:5099-5109.

Brewer JR, et al. Gynecol Oncol. 2016;doi:10.1016/j.ygyno.2015.11.011.

Chhibber A, et al. Pharmacogenomics J. 2014;doi:10.1038/tpj.2014.2.

Diouf B, et al. JAMA. 2015; doi:10.1001/jama.2015.0894.

Hershman DL, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.54.0914.

Hershman DL, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2012.44.8738.

Hertz DL, et al. Clin Cancer Res (in review).

Leandro-Garcia LJ, et al. Clin Cancer Res. 2012;18:4441-4448.

Majithia N, et al. Support Care Cancer. 2016;doi:10.1007/s00520-015-3063-4.

MDI Biological Laboratory. Potential new drug therapy for peripheral nerve damage announced by MDI Biological Laboratory. Available at: https://mdibl.org/press-release/potential-new-drug-therapy-for-peripheral-nerve-damage. Accessed on May 2, 2016.

Nudelman KN, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2015.62.1276.

Pachman DR, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.58.8533.

Wang XS, et al. Oncology. 2016;Published online ahead of print Feb. 17.

For more information:

Jai N. Patel, PharmD, is chief of pharmacology research and phase 1 trials at Levine Cancer Institute at Carolinas HealthCare System, as well as adjunct assistant professor at UNC Eshelman School of Pharmacy. He also is a HemOnc Today Editorial Board member. He can be reached at jai.patel@carolinashealthcare.org.

Disclosure: Patel reports no relevant financial disclosures.

Chemotherapy-induced peripheral neuropathy is a frequent and debilitating adverse effect of commonly used chemotherapy agents.

These agents include taxanes (paclitaxel and docetaxel), vinca alkaloids (vincristine), platinums (cisplatin, carboplatin and oxaliplatin), epothilones (ixabepilone [Ixempra, R-Pharm US]) and bortezomib (Velcade, Millennium).

There are no FDA–approved drugs to prevent or treat chemotherapy-induced peripheral neuropathy (CIPN). Given the treatment-limiting nature of the condition and the lack of effective methods to reduce symptom burden, novel and personalized approaches to predict, prevent and treat CIPN are needed.

Clinical course

CIPN involves damage to peripheral nerves caused by exposure to a neurotoxic agent, although the exact mechanisms accounting for differences between offending agents is relatively unknown.

Jai N. Patel, PharmD
Jai N. Patel

It most commonly presents as sensory neuropathy, including numbness, loss of proprioception sense, tingling, pins-and-needles sensation, hyperalgesia or allodynia in the hands or feet.

Although less frequent, damage to motor fibers resulting in motor neuropathy may occur. This is most common with paclitaxel and vincristine.

CIPN typically is dose dependent and can occur at any point after treatment initiation. A randomized trial of oxaliplatin-treated patients with colorectal cancer demonstrated that 89% had at least one symptom of acute neuropathy with the first cycle, including sensitivity to touching or swallowing cold items, throat discomfort and muscle cramps.

Acute symptoms peaked at 3 days, and severity was predictive of chronic neurotoxicity, commonly presenting as tingling, numbness and pain. Notably, sensory symptoms were worse in the upper extremities during chemotherapy, but 6 months after chemotherapy, symptoms reversed and were worse in lower extremities.

Taxane-induced neuropathy usually improves in the months following therapy cessation; however, approximately 80% report long-term persistence to some degree.

Predicting which patients will experience neuropathy has been an ongoing challenge. Proposed clinical risk factors include prior therapy with a neurotoxic agent, diabetes mellitus, folate/vitamin B12 deficiencies, African race and older age. Some of these risk factors also appear to impact recovery from neuropathy.

Lack of treatment options

NCI–supported trials have been unable to identify an effective regimen to manage CIPN.

Randomized phase 3 trials that investigated several options — including alpha lipoic acid, IV calcium and magnesium, vitamin E, Acetyl-L-carnitine, glutathione, nortriptyline, gabapentin, lamotrigine, amifostine, and topical amitriptyline and ketamine — have shown no improvement in CIPN severity or duration, or patient quality of life. In fact, Acetyl-L-carnitine was shown to increase CIPN incidence compared with placebo.

Prior to the results of the North Central Cancer Treatment Group’s (NCCTG) N04C7 trial, up to 40% of oxaliplatin infusions in the United States were administered concurrently with IV calcium and magnesium. This approach was essentially eliminated from practice based on results from randomized trials, saving time, resources, costs and potentially harmful adverse effects.

These examples reiterate the use of evidence-based guidelines to drive medical decision-making as opposed to anecdotal data alone.

The CALGB 170601 trial, however, demonstrated a decrease in pain score at 6 weeks among patients who received duloxetine rather than placebo. Notably, the magnitude of benefit was modest (mean change in pain score, –1.06 vs. –0.34; P = .003) and appeared to be more prominent with oxaliplatin-induced neuropathy than paclitaxel.

Importantly, traditional neuromodulatory agents commonly used in practice — such as nortriptyline and gabapentin — are potentially harmful in vulnerable populations (eg, the elderly, who are at risk for falls).

Taken together with the absence of benefit in randomized studies, caution should be employed with the use of these agents in practice. Study endpoints also should be carefully selected, as earlier trials often relied on clinician assessment of CIPN using criteria such as the Common Toxicity Criteria for Adverse Events, which have been shown to be less sensitive than patient-reported outcomes.

Biomarkers

Candidate biomarker studies of single nucleotide polymorphisms in genes involved in the pharmacology of neurotoxic drugs have been conducted, but no reliable biomarker has been identified for translation into clinical practice.

PAGE BREAK

One study demonstrated an association between CYP2C8*3 and a twofold increase in paclitaxel-induced neuropathy risk, whereas other studies have identified polymorphisms within the therapeutic target of taxanes, beta-tubulin IIa, that increase neuropathy risk.

Samples collected from NCI–supported trials have allowed the discovery and validation of proposed biomarkers to predict CIPN occurrence.

The NCCTG N08C1 study demonstrated an association between genes related to Charcot-Marie-Tooth disease, an inherited neuropathy condition, and occurrence of CIPN.

Baldwin and colleagues performed the first genome-wide association study to investigate paclitaxel-induced neuropathy and identified SNPs in FGD4 — a congenital neuropathy gene associated with Charcot-Marie-Tooth disease — FZD3 and EPHA5 as significantly associated with CIPN occurrence and severity. The set of genes driving heritability of CIPN in this breast cancer cohort was found to be implicated in axonogenesis and regulation of axon outgrowth.

Schneider and colleagues were unable to replicate these findings in another paclitaxel-treated cohort; however, an SNP in the gene GPR177 — also called Wnt — appeared significantly associated with CIPN occurrence, suggesting the importance of the Wnt pathway in paclitaxel-induced neuropathy.

Hertz and colleagues performed the first genome-wide association study to investigate docetaxel-induced neuropathy. They identified a SNP in VAC14 that was significantly associated with CIPN in patients with castrate-resistant prostate cancer. VAC14 has been previously linked to neurodegeneration in animal models and to hereditary conditions in humans, including Charcot-Marie-Tooth disease.

Interestingly, this study also demonstrated that knockdown of VAC14 increased docetaxel sensitivity as measured by decreased neurite processes, and VAC14 heterozygous mice had greater nociceptive sensitivity compared with wild-type controls.

Rieger and colleagues identified that — in the presence of paclitaxel — neuropathy is triggered by increased expression of matrix metallopeptidase 13 (MMP13), which is toxic to nerves and degrades collagen, contributing to paclitaxel-induced nerve damage. In preclinical models, two drugs have been shown to prevent paclitaxel-induced neurotoxicity by decreasing MMP13 activity, but trials in human have not yet started.

Diouf and colleagues identified an SNP in the promoter region of the CEP72 gene, which encodes a centrosomal protein involved in microtubule formation that was significantly associated with occurrence and severity of vincristine-induced neuropathy in children with acute lymphoblastic leukemia. Reducing CEP72 expression in human neurons and leukemia cells increased their sensitivity to vincristine, suggesting a potential basis for safer dosing.

Future directions and practical applications

Given the lack of benefit demonstrated in randomized trials, ASCO guidelines do not recommend any agent for CIPN prevention; however, they do provide a moderate recommendation for treatment with duloxetine for existing CIPN.

Although most neuromodulatory agents tested in randomized trials have been inconclusive, agents such as gabapentin, pregabalin and amitriptyline are commonly used based on data that support their utility in other neuropathic pain conditions.

Dose reductions, alternate chemotherapy or temporary cessation of chemotherapy have been and will continue to be the primary strategies for CIPN management. Until more treatment data are available, a concerted effort should be made to identify signs of CIPN prior to significant deterioration when the condition is more treatable.

Early findings suggest changes in cerebral perfusion and gray matter seen on MRI scans correlated with symptoms of CIPN in patients with breast cancer, which may have potential diagnostic and therapeutic implications.

Another study showed pre-chemotherapy screening with quantitative sensory testing called the Bumps detection test, which measures touch sensation deficits, significantly predicted the development of more severe numbness or tingling. This method may allow for a simple yet personalized approach to CIPN management.

The subjective nature of this phenotype results in a high degree of inter-rater variability. Physician-based clinical assessment tools are less sensitive for identification of chemotherapy-related adverse effects compared with patient-reported outcomes. As such, clinicians should consider the use of patient-reported outcomes, such as the clinically validated EORTC QLQ-CIPN20 questionnaire, to adequately capture treatment effect and further personalize treatment.

PAGE BREAK

Lastly, validation of proposed genes — such as those associated with Charcot-Marie-Tooth disease or those involved in the pharmacologic disposition of offending drugs — may allow for clinicians to better predict which patients are at a higher risk for CIPN. Early identification of the presence of these genes through whole genome sequencing or whole exome sequencing may help clinicians avoid offending agents in patients at elevated baseline neuropathy risk.

A better understanding of the pathophysiology of CIPN and genes associated with predisposition ultimately will prove fruitful in the quest to identify predictive or targetable biomarkers for personalized treatment of this prevalent and debilitating symptom.

References:

Baldwin RM, et al. Clin Cancer Res. 2012;18:5099-5109.

Brewer JR, et al. Gynecol Oncol. 2016;doi:10.1016/j.ygyno.2015.11.011.

Chhibber A, et al. Pharmacogenomics J. 2014;doi:10.1038/tpj.2014.2.

Diouf B, et al. JAMA. 2015; doi:10.1001/jama.2015.0894.

Hershman DL, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.54.0914.

Hershman DL, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2012.44.8738.

Hertz DL, et al. Clin Cancer Res (in review).

Leandro-Garcia LJ, et al. Clin Cancer Res. 2012;18:4441-4448.

Majithia N, et al. Support Care Cancer. 2016;doi:10.1007/s00520-015-3063-4.

MDI Biological Laboratory. Potential new drug therapy for peripheral nerve damage announced by MDI Biological Laboratory. Available at: https://mdibl.org/press-release/potential-new-drug-therapy-for-peripheral-nerve-damage. Accessed on May 2, 2016.

Nudelman KN, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2015.62.1276.

Pachman DR, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.58.8533.

Wang XS, et al. Oncology. 2016;Published online ahead of print Feb. 17.

For more information:

Jai N. Patel, PharmD, is chief of pharmacology research and phase 1 trials at Levine Cancer Institute at Carolinas HealthCare System, as well as adjunct assistant professor at UNC Eshelman School of Pharmacy. He also is a HemOnc Today Editorial Board member. He can be reached at jai.patel@carolinashealthcare.org.

Disclosure: Patel reports no relevant financial disclosures.