Chemotherapy-induced peripheral neuropathy in children and adolescent cancer patients

Abstract

Brain cancer and leukemia are the most common cancers diagnosed in the pediatric population and are often treated with lifesaving chemotherapy. However, chemotherapy causes severe adverse effects and chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting and debilitating side effect. CIPN can greatly impair quality of life and increases morbidity of pediatric patients with cancer, with the accompanying symptoms frequently remaining underdiagnosed. Little is known about the incidence of CIPN, its impact on the pediatric population, and the underlying pathophysiological mechanisms, as most existing information stems from studies in animal models or adult cancer patients. Herein, we aim to provide an understanding of CIPN in the pediatric population and focus on the 6 main substance groups that frequently cause CIPN, namely the vinca alkaloids (vincristine), platinum-based antineoplastics (cisplatin, carboplatin and oxaliplatin), taxanes (paclitaxel and docetaxel), epothilones (ixabepilone), proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide). We discuss the clinical manifestations, assessments and diagnostic tools, as well as risk factors, pathophysiological processes and current pharmacological and non-pharmacological approaches for the prevention and treatment of CIPN.

Keywords: CIPN mechanisms; chemotherapy-induced peripheral neuropathy; neuroinflammation; pediatric cancer patients and survivors; pharmacological and non-pharmacological treatment strategies.

FIGURE 1

Mode of action of chemotherapeutic agents in cancer cells. (A) Thalidomide inhibits angiogenesis, prevents the production of interleukin-6 and activates apoptotic pathways via caspase 8-mediated cell death. (B) Chemotherapy affects the tumor immune microenvironment. (C) Vincristine binds to the β-tubulin subunit of microtubule in the S phase of the cell cycle, which leads to the inhibition of microtubule assembly. The disruption of mitotic spindle formation results in the mitotic arrest of cancer cells at metaphase and subsequent cell death. (D) Paclitaxel, docetaxel and ixabepilone bind to the β-tubulin subunit of microtubule and inhibit microtubule disassembly, which causes G2/M cell cycle arrest and cell death. (E) Bortezomib reversibly inhibits the 26S proteasome, which disrupts proteasome-mediated proteolysis. This disruption causes the accumulation of ubiquitinated proteins and subsequent cell death. (F) Oxaliplatin, cisplatin and carboplatin bind to DNA to form cross-links that prevent DNA replication and transcription, leading to cell cycle arrest and apoptosis. (G) Vincristine, paclitaxel and docetaxel alter the mitochondrial electron transport chain while cisplatin results in the increased production of reactive oxygen species.

FIGURE 2

The effects of chemotherapy on various components of the nervous and immune system: (A) nerve terminal, (B) dorsal root ganglia (DRG), (C) spinal cord, (D) immune cells and (E) neuronal axons. Ca_V, voltage-gated calcium channel; K⁺, potassium channel; Na_V, voltage-gated sodium channel; TRPA1, transient receptor potential (TRP) ankyrin 1; TRPM8, transient receptor potential cation channel subfamily melastatin member 8; TRPV1, transient receptor potential vanilloid-type 1; TRPV4, transient receptor potential vanilloid-type 4; ROS, reactive oxygen species; TLR4, toll-like receptor 4; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; IL-1B, interleukin-1 beta; IL-1R, interleukin-1 receptor; CX3CR, CX3C chemokine receptor 1.