Mechanisms, Characteristics, and Treatment of Neuropathic Pain and Peripheral Neuropathy Associated with Dinutuximab in Neuroblastoma Patients

Abstract

Prognosis of metastatic neuroblastoma is very poor. Its treatment includes induction chemotherapy, surgery, high-dose chemotherapy, radiotherapy, and maintenance with retinoic acid, associated with the anti-GD2 monoclonal antibody (ch14.18) dinutuximab. Immunotherapy determined a significant improvement in survival rate and is also utilized in relapsed and resistant neuroblastoma patients. Five courses of dinutuximab 100 mg/m² are usually administered as a 10-day continuous infusion or over 5 consecutive days every 5 weeks. Dinutuximab targets the disialoganglioside GD2, which is highly expressed on neuroblastoma cells and minimally present on the surface of normal human neurons, peripheral pain fibers, and skin melanocytes. Anti GD2 antibodies bind to surface GD2 and determine the lysis of neuroblastoma cells induced by immune response via the antibody-dependent cellular cytotoxicity and the complement-dependent cytotoxicity. Dinutuximab has significant side effects, including neuropathic pain, peripheral neuropathy, hypersensitivity reactions, capillary leak syndrome, photophobia, and hypotension. The most important side effect is neuropathic pain, which is triggered by the same antibody-antigen immune response, but generates ectopic activity in axons, which results in hyperalgesia and spontaneous pain. Pain can be severe especially in the first courses of dinutuximab infusion, and requires the administration of gabapentin and continuous morphine infusion. This paper will focus on the incidence, mechanisms, characteristics, and treatment of neuropathic pain and peripheral neuropathy due to dinutuximab administration in neuroblastoma patients.

Keywords: dinutuximab; molecular mechanisms; neuroblastoma; neuropathic pain; pediatric cancer; peripheral neuropathy; treatment.

Figure 1

GD2 is a disialoganglioside obtained from ceramides via glycosylations. Ceramides are synthetized from serine and palmitoyl-CoA after various steps. The first glycosylation produces glycosylceramide, which is glycosylated in lactosylceramide. This is converted to GM3 by GM3 synthase, GM3 to GD3, and GD3 to GD2 by GM2/GD2 synthase.

Figure 2

Mechanisms of action of dinutuximab beta. GD2 is expressed on (a) nociceptive fiber, (d) motor and sensory fibers, and (g) neuroblastoma cell membrane. The complex antigen–anti-GD2-antibody is formed on the surface of (b) nociceptive fiber, (e) motor and sensory fibers, and (h) neuroblastoma cell membrane. The complex antigen GD2-antibody activates the antibody-dependent cellular cytotoxicity and the complement-dependent cyto-toxicity, which cause (c) neuropathic pain on nociceptive fiber, (f) peripheral neuropathy on motor and sensory fibers, and (i) apoptosis of neuroblastoma cell. IL-2 acts on Natural Killer (NK) cells and granulocyte-macrophage colony-stimulating factor (GM-CSF) on monocytes and granulocytes to enhance the immunological response.

Figure 3

Neuropathic pain management during continuous dinutuximab beta infusion. Gabapentin administration is started three days prior to dinutuximab beta infusion and increased up to 10 mg/kg for three daily administrations. After a bolus, morphine is commenced just before dinutuximab beta infusion and continued as a 24 h intravenous infusion (0.03 mg/kg/h). Following reduction of its infusion rate, morphine is stopped 4 h after the end of dinutuximab beta infusion. If neuropathic pain persist after the intravenous morphine weaning off, oral morphine sulphate or tramadol can be administered on demand.