Chemotherapy-induced peripheral neuropathy: limitations in current prophylactic strategies and directions for future research

Introduction

Different types of neurologic complications, including central neurotoxicity conditions ranging from minor cognitive deficits to encephalopathy with dementia or even coma, and peripheral neurotoxicity, may be associated with antineoplastic drug therapy. Peripheral neuropathy is the most common neurological complication of cancer treatment, representing a set of symptoms ranging from minor, and temporary symptoms, to severe and permanent forms of polyneuropathy. Because this kind of neurotoxicity is due to the administration of anticancer drugs it is commonly indicated as chemotherapy-induced peripheral neuropathy (CIPN).

Epidemiology

CIPN is a common treatment-related adverse effect, affecting up to 48% of cancer patients who received chemotherapy¹, and this serious complication can negatively impact the long-term quality of life (QoL) of cancer survivors, because up to 40% of these individuals may experience permanent symptoms, mainly as paresthesia, but also as pain and other types of disability, after the end of the therapeutic course^2,3.

Anticancer drugs involved

Many anticancer drugs, mostly platinum compounds, antitubulins (taxanes, vinca alkaloids, eribulin), and proteasome inhibitors (bortezomib), but also immunomodulatory agents (thalidomide, lenalidomide, pomalidomide), are known to cause peripheral neuropathy⁴. Other drugs, such as etoposide, methotrexate, 5-fluorouracile (5-FU), and gemcitabine are less commonly or not associated with CIPN, whereas the use of biological agents has also been occasionally associated with CIPN. For instance, about 50% of patients with relapsed or refractory Hodgkin’s lymphoma treated with brentuximab vedotin developed mild sensory neuropathy, although mostly not clinically relevant⁵. The role of synergistic neurotoxicity caused by previously given chemotherapies and concomitant chemotherapies is not clear, indeed approximately 6% of patients treated with the biologic agent alemtuzumab, combined with fludarabine and melphalan, developed a progressive sensorimotor radiculoneuropathy and/or a myelitis⁶, and up to 40% of patients who received cisplatin and taxol developed CIPN⁷. Again, 92% of patients underwent the drug combination FOLFOX (folinic acid, 5-FU and oxaliplatin) suffered by sensory CIPN⁸.

Clinical features

Although CIPN is generally a temporary manifestation, it may represent a permanent side effect from the chemotherapy treatment employed, and painful CIPN can also persist from months to years after the chemotherapy conclusion, leading to significant challenges for cancer survivors because of its negative influence on functional activity and QoL⁹. A frequent question asked by patients regards the time course of symptom resolution. We can respond using data from the most important trials published on the topic, assuming that clinical features depend on several conditions, including chemotherapy regimens, duration of exposure, and assessment methods. Thus, the APEX trial showed that of patients with grade 2, or higher, bortezomib-induced peripheral neuropathy, 64% experienced improvement or resolution to baseline at a median of 110 days¹⁰, whereas cumulative oxaliplatin-induced peripheral neuropathy is reported to be partially reversible in approximately 80% of patients and completely resolves in approximately 40%, at 6 to 8 months after cessation of treatment¹¹.

Prophylactic agents proposed

American Society of Clinical Oncology (ASCO) on the topic, based on a systematic review of 42 randomized controlled trials (RCTs) investigating 18 agents, found that there are no agents that have shown consistent clinically meaningful benefits for CIPN prevention¹². Moreover, a Cochrane review states that chemoprotective agents do not seem to prevent CIPN caused by cisplatin and related compounds¹³.

Furthermore, several preclinical and clinical investigations have been conducted to verify the neuroprotective effects of a wide range of agents, such as glutathione¹⁴, amifostine¹⁵, N-acetylcysteine¹⁶, the calcium-channel antagonist nimodipine¹⁷, nutraceuticals, such as glutamine¹⁸, acetyl-L-carnitine¹⁹, vitamin E²⁰, omega-3 fatty acids²¹, all-trans retinoic acid²², calcium and magnesium²³, curcumin²⁴, quercetin²⁵, matricaria chamomilla²⁵, ginkgo biloba extract²⁶, green tea²⁷, the aromatic plant in the family Lamiaceae ocimum sanctum²⁸, acorus calamus²⁹ and salvia officinalis³⁰, as well as the Kampo medicine Goshajinkigan³¹ and other herbal combinations³². In addition, anti-seizure drugs, such as carbamazepine and pregabalin³³ and antidepressants, such as venlafaxine, are ineffective or seem to have more results in the treatment of CIPN rather than in its prevention³⁴. In Argyriou et al.’s analysis oxcarbazepine has been shown to be modestly effective in prophylaxis against cumulative oxaliplatin-induced neuropathy³⁵. Briefly, there are no effective agents, or protocol, with strong evidence of effectiveness to prevent this serious treatment-related toxicity.

Drug regimen strategies

CIPN prevention mainly consists of several proposed strategies, including the application of a stop-and-go regimen, consisting in chemotherapy (e.g. oxiplatinum) free intervals to reduce advanced sensory neuropathy³⁶, cumulative dose reduction, or the use of lower dose intensities, especially in patients which are at higher risk to develop neurotoxic side effects, or in patients which already have neuropathic symptoms due to diabetes mellitus, hereditary neuropathies, or earlier treatment with neurotoxic chemotherapy.

This background is particularly important as it introduces two questions. Why does CIPN represent such a paramount side effect, so difficult to prevent and/or to treat? And, what are promising future directions for research in this field?

The response to the first question must be addressed through the explanation of CIPN mechanisms. While much research has been conducted on the topic, the precise pathophysiology of CIPN has not yet been defined. Probably, the key factor lies within the clinical observation that any group of anticancer drugs exhibits a different mechanism of damage to the peripheral nervous system³⁷. Thus, the pathogenetic chain of CIPN could comprehend initial steps that differ between different chemotherapies – which would explain the differences in clinical manifestations – and ending stages with many points in common.

Usually, CIPN manifests itself after a typical cumulative dose (dose-dependent mechanism) but, in some cases, such as those following the use of oxaliplatin, or taxanes, immediate toxic effects may occur (acute neurotoxicity). Thus, several drug-dependent pathogenetic mechanisms exist, whereas different mechanisms may be involved in the development of the clinical manifestations (acute/chronic) due to the same agent. For instance, the proposed mechanism of action of acute oxaliplatin-induced CIPN includes alteration in the current of voltage-gated sodium channels in response to oxalate, a metabolic by-product of oxaliplatin, as well as the indirect interaction of oxalate with voltage-gated sodium channels through chelation of calcium and magnesium³⁸. On the other hand, it seems that chronic oxaliplatin-induced CIPN could be caused by a dose-dependent accumulation of platinum compounds in the dorsal root ganglia (DRG) causing neuronal atrophy and apoptosis, indeed studies have demonstrated a strong affinity of platinum compounds to the deoxyribonucleic acid (DNA) of spinal ganglion cells³⁹.

With respect to taxanes, the so-called paclitaxel acute pain syndrome, which is an expression of acute neurotoxicity, has been linked with a sensitization of nociceptors and their fibers by proinflammatory cytokines (IL-6, IL-8, IL1β, TNF-α), whereas the promotion of microtubule polymerization and inhibition of depolymerization, leading to inhibition of axonal transport within neurons, are involved in dose-dependent taxane neurotoxicity⁴⁰.

Furthermore, preclinical studies suggest that peripheral neuropathy due to proteasome inhibitors (e.g. bortezomib) is probably the result of different pathogenetic mechanisms, including pathological changes in Schwann cells and myelin – affecting the flow of information related to proprioception, touch, pain and temperature through myelinated (Aα, Aβ, Aδ) fibers – combined with axonal degeneration in all major primary afferent myelinated and unmyelinated (C) fibers⁴¹, and DRG neuron changes, manifested as nuclear and nucleolar atrophy and/or loss of neurons⁴².

But explaining the CIPN pathogenesis is a very complex matter, because other variables, such as other cancer treatments, like surgery or radiation, neural compression or invasion by the tumor, diabetes, alcohol abuse, low vitamin B levels, and peripheral vascular disease come into play. Moreover, the results of Schneider’s and co-authors’ study⁴³ showed a significant association between neuropathy and African-American race, and some genetic studies suggested that certain genes were related to CIPN. A very interesting review on the topic focused on several potential genes associated with CIPN⁴⁴. These genes are involved in different functions, including regulation of the intracellular drug concentrations (GSTP1, GSTM1 and ABCB1), response to DNA damage (ERCC1, FANCD2, BCL2, and SOX10), cellular stress response (BCL2), inflammation processes (ABCC1, ABCC2, ABCG2, ITGA1, ITGB3, TAC1, ABCB1, ABCC2, EPHA4, EPHA6, SLCO1B1, TUBB2A, ABCA1, BCL2, OPRM1 and TRPV1), and neuronal plasticity (ERCC1 and TAC1)⁴⁴. However, until now, no conclusive data has been found, and the precise gene–phenotype association is not fully understood.

Whatever the precise mechanism(s), neurotoxic chemotherapy agents usually induce mitochondrial dysfunction – as suggested by the loss of mitochondrial mobility in bortezomib, paclitaxel, and vinca alkaloid – with progressive axonal neuropathy and combined DRG neuronal cell body changes, which are the last steps of the pathogenetic chain.

On these bases, research should be finalized: 1) to better understand all the steps of the pathogenetic mechanisms of CIPN; 2) to identify patients who are at high risk for CIPN; 3) to explore more about molecule or combinations, already tested; 4) to develop novel strategies in order to offer more effectiveness drug molecules for the future; 5) to design more effectiveness protocols.

Research on CIPN mechanisms is a flourishing field of study. For instance, several lines of evidence support the notion that DNA damage may be a causative factor in CIPN induced by a number of cancer therapies. Thus, specific targeted molecules, such as APX2009 and APX3330, which improve the activity of apurinic/apyrimidinic endonuclease APE-1, involved in base excision repair, could be effective in preventing or reversing CIPN^45,46. The results of clinical trials (APX3330 has been approved for phase 1 clinical investigations), and further in vitro and in vivo studies, could represent a significant step forward in the battle against CIPN.

Moreover, further extensive preclinical and clinical studies need to be conducted with the aim of completing the safety and the effectiveness profiles of certain substances, such as nutraceuticals, already tested. In case of complex herbal medicines more controlled investigations should better elucidate the pharmacokinetics and pharmacodynamics of the single compounds, also studying potential interactions of these agents with chemotherapies and adjuvants, as well as evaluating long term results.

On the other hand, research is currently aimed at testing new molecules. For instance, the endogenous lipid palmitoylethanolamide, alone or in combination with the anticonvulsant gabapentin, could be effective for this purpose, as a preclinical investigation showed that this strategy was able to reduce allodynia in a mouse paclitaxel model of CIPN⁴⁷, whereas several antioxidants, such as ethoxyquin⁴⁸ have been also tested.

At the moment very few options are available for CIPN prevention, which mainly consists of several proposed strategies, including the application of a stop-and-go regimen, cumulative dose reduction, or the use of lower dose intensities. The dearth of effective prevention strategies for CIPN represents a big lack in oncology as this side effect can lead to dose reduction of the chemotherapy agent, or possible cessation of treatment, which may have an adverse impact on cancer treatment and disease outcomes. On the other hand, although CIPN prevalence decreases with time, at 6 months 30% of patients continue to suffer from CIPN¹. Thus, the elevated incidence of CIPN and the conspicuous number of cancer survivors calls for a rapid resolution of the phenomenon through the search for more effective prophylactic approaches.

Marco Cascella

Division of Anesthesia, Department of Anesthesia, Endoscopy and Cardiology Istituto Nazionale Tumori “Fondazione G. Pascale” – IRCCS, Naples, Italy

[email protected]

Transparency

Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

M.C. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this article.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

I would like to express my sincere gratitude to Dr. Maria Rosaria Muzio for the immeasurable amount of support and guidance she has provided throughout this paper.