Application Potential of Plant-Derived Medicines in Prevention and Treatment of Platinum-Induced Peripheral Neurotoxicity

As observed with other chemotherapeutic agents, the clinical application of platinum agents is a double-edged sword. Platinum-induced peripheral neuropathy (PIPN) is a common adverse event that negatively affects clinical outcomes and patients’ quality of life. Considering the unavailability of effective established agents for preventing or treating PIPN and the increasing population of cancer survivors, the identification and development of novel, effective interventions are the need of the hour. Plant-derived medicines, recognized as ideal agents, can not only help improve PIPN without affecting chemotherapy efficacy, but may also produce synergy. In this review, we present a brief summary of the mechanisms of platinum agents and PIPN and then focus on exploring the preventive or curative effects and underlying mechanisms of plant-derived medicines, which have been evaluated under platinum-induced neurotoxicity conditions. We identified 11 plant extracts as well as 17 plant secondary metabolites, and four polyherbal preparations. Their effects against PIPN are focused on oxidative stress and mitochondrial dysfunction, glial activation and inflammation response, and ion channel dysfunction. Also, ten clinical trials have assessed the effect of herbal products in patients with PIPN. The understanding of the molecular mechanism is still limited, the quality of clinical trials need to be further improved, and in terms of their efficacy, safety, and cost effectiveness studies have not provided sufficient evidence to establish a standard practice. But plant-derived medicines have been found to be invaluable sources for the development of natural agents with beneficial effects in the prevention and treatment of PIPN.

Nutraceuticals for Prevention of Chemotherapy-Induced Peripheral Neuropathy

A wide range of neurologic complications, including central neurotoxicity conditions and peripheral neurotoxicity, are associated with antineoplastic drug regimens. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common and severe cancer treatment-related adverse effect, as well as the most diffuse type of neurotoxicity, because about one third of all patients who undergo chemotherapy may experience this side effect. CIPN can negatively impact the long-term quality of life of cancer survivors, and can lead to dose reduction of the chemotherapy agent, or possible cessation of treatment. Unfortunately, although several agents and protocols have been proposed, no prophylactic strategies have proven useful yet. Therefore, new alternative therapies have been considered for CIPN prevention. In this chapter, the authors analyze the potential applications of nutrients, dietary supplements and herbal products, such as single herbs, the Kampo medicine goshajinkigan and other herbal combinations, for CIPN prevention.

Brentuximab-Induced Peripheral Neurotoxicity: A Multidisciplinary Approach to Manage an Emerging Challenge in Hodgkin Lymphoma Therapy

Brentuximab vedotin (BV) is an anti-CD30 antibody–drug conjugate approved to treat classical Hodgkin lymphoma (HL). BV-induced peripheral neurotoxicity (BVIN) is one of the greatest concerns for haematologists treating HL for several reasons. First, BVIN is highly frequent. Most patients receiving BV will experience some degree of BVIN, resulting in the primary reason for dose modification or discontinuation of HL therapy. Second, BV produces sensory, motor, and/or autonomic peripheral nerve dysfunction, which can present as severe, disabling forms of BVIN—predominantly motor—in some patients. Third, although largely reversible, BVIN may persist months or years after treatment and thereby become a major issue in HL survivorship. BVIN may, therefore, negatively affect the quality of life and work-life of often young patients with HL, in whom long-term survival is expected. Currently, the only strategy for BVIN includes dose adjustments and treatment discontinuation; however, this could interfere with LH therapy efficacy. In this setting, early recognition and adequate management of BVIN are critical in improving clinical outcomes. Careful neurologic monitoring may allow accurate diagnoses and gradation of ongoing forms of BVIN presentation. This review analysed current, available data on epidemiology, pathophysiology, patient- and treatment-related risk factors, clinical and neurophysiologic phenotypes, and management in patients with HL. Furthermore, this review specifically addresses limitations posed by BVIN assessments in clinical practice and provides skills and tools to improve neurologic assessments in these patients. Integrating this neurotoxic drug in clinical practice requires a multidisciplinary approach to avoid or minimise neurotoxicity burden in survivors of HL.

Targeting strategies for oxaliplatin-induced peripheral neuropathy: clinical syndrome, molecular basis, and drug development

Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN) is a severe clinical problem and potentially permanent side effect of cancer treatment. For the management of OIPN, accurate diagnosis and understanding of significant risk factors including genetic vulnerability are essential to improve knowledge regarding the prevalence and incidence of OIPN as well as enhance strategies for the prevention and treatment of OIPN. The molecular mechanisms underlying OIPN are complex, with multi-targets and various cells causing neuropathy. Furthermore, mechanisms of OIPN can reinforce each other, and combination therapies may be required for effective management. However, despite intense investigation in preclinical and clinical studies, no preventive therapies have shown significant clinical efficacy, and the established treatment for painful OIPN is limited. Duloxetine is the only agent currently recommended by the American Society of Clinical Oncology. The present article summarizes the most recent advances in the field of studies on OIPN, the overview of the clinical syndrome, molecular basis, therapy development, and outlook of future drug candidates. Importantly, closer links between clinical pain management teams and oncology will advance the effectiveness of OIPN treatment, and the continued close collaboration between preclinical and clinical research will facilitate the development of novel prevention and treatments for OIPN.

Cannabinoids: an Effective Treatment for Chemotherapy-Induced Peripheral Neurotoxicity?

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most frequent side effects of antineoplastic treatment, particularly of lung, breast, prostate, gastrointestinal, and germinal cancers, as well as of different forms of leukemia, lymphoma, and multiple myeloma. Currently, no effective therapies are available for CIPN prevention, and symptomatic treatment is frequently ineffective; thus, several clinical trials are addressing this unmet clinical need. Among possible pharmacological treatments of CIPN, modulation of the endocannabinoid system might be particularly promising, especially in those CIPN types where analgesia and neuroinflammation modulation might be beneficial. In fact, several clinical trials are ongoing with the specific aim to better investigate the changes in endocannabinoid levels induced by systemic chemotherapy and the possible role of endocannabinoid system modulation to provide relief from CIPN symptoms, a hypothesis supported by preclinical evidence but never consistently demonstrated in patients. Interestingly, endocannabinoid system modulation might be one of the mechanisms at the basis of the reported efficacy of exercise and physical therapy in CIPN patients. This possible virtuous interplay will be discussed in this review.

Intravenous Immunoglobulin Suppresses Chemotherapy-induced Peripheral Neurotoxicity via Macrophage Modulation in Rats and Mice

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a serious adverse effect that leads to treatment discontinuation by patients receiving anticancer therapy. Treatment discontinuation is a serious and life-threatening problem for patients with cancer; hence, there is a need for drugs that suppress the induction of CIPN by anticancer drugs. Intravenous immunoglobulin (IVIg) reportedly suppresses bortezomib-induced CIPN in a rat model. Here, using rodent models, we showed that IVIg can also suppress peripheral neurotoxicity induced by anticancer drugs other than bortezomib. Furthermore, the suppressive effect of IVIg disappeared when macrophages were depleted. These findings indicate two novel independent possibilities of alleviating CIPN using IVIg. First, CIPN can be controlled by macrophage modulation. Second, IVIg directly combined with anti-cancer drugs can avoid restrictions on the use of anti-cancer drugs due to CIPN inductions. However, further research is necessary for the bench-to-bedside translation of these novel applications of IVIg. Our findings lay a strong foundation for research on IVIg therapeutics.