"The Effect of Memantine on the Prevention and Amelioration of Paclitaxel-induced Toxicity in Breast Cancer Patients"

Cancer is currently a leading cause of morbidity and mortality worldwide. Chemotherapeutic agents, despite being effective in arresting the progression of cancer by targeting and eliminating rapidly dividing cancer cells, are associated with various adverse effects. Chemotherapy-induced peripheral neuropathy (CIPN) is a serious clinical adverse effect of certain chemotherapeutic agents. For many patients, CIPN symptoms could be severe, disabling, and significantly impairing the activities of daily living (ADL) and diminishing the quality of life (QoL). Paclitaxel-induced peripheral neuropathy may affect up to 97% of paclitaxel-treated patients and become chronic in more than 60% of cases. The initial symptoms of paclitaxel-induced peripheral neuropathy (PIPN) include numbness, tingling, and allodynia (painful sensations in response to normally non-painful stimuli) that can be manifested in the patient's fingers and toes within 24-72 h post-injection. These symptoms may later progress to affect the patient's lower leg and wrists in a "glove and stocking" pattern. Symptoms typically begin distally and continue proximally as the situation worsens. Memantine is a non-competitive NMDA receptor antagonist that inhibits the prolonged influx of Ca2+, responsible for neuronal excitotoxicity while maintaining the physiological NMDA receptor's function and avoiding psychotropic adverse events. Although memantine has been the main treatment option for moderate and severe Alzheimer's disease in the last two decades, numerous studies have investigated its other potential uses. Some studies showed that memantine diminished chronic pain in complex regional pain syndrome, phantom limb pain, and fibromyalgia. Most in vivo and in vitro studies attributed the neuroprotective effects of memantine to the blockade of NMDA receptors on neurons as well as inhibition of microglia activation with subsequent reduction of pro-inflammatory mediators' production such as extracellular superoxide anion, intracellular ROS, nitric oxide, prostaglandin E2, and TNF-α, and stimulation of neurotrophic factor release from astroglia.

Up till now, no treatment options are available for prevention of PIPN. Several options have been investigated for treatment of CIPN with only duloxetine had proven benefits. Additional investigations are needed to develop preventive and ameliorative therapy of PIPN.

Eligibility Criteria:
Inclusion Criteria:

* Adult patients (\>18 years old).
* Patients with confirmed diagnosis of non-metastatic breast cancer planned to receive weekly adjuvant/neo-adjuvant paclitaxel.
* Patients with Eastern Cooperative Oncology Group (ECOG) performance (Oken et al., 1982) status of 0-2.

Exclusion Criteria:

* Patients with pre-existing neuropathic conditions.
* Patients with diabetes mellitus.
* Patients with a history of seizure disorder.
* Patients with renal impairment (creatinine clearance less than 60 ml/min), or hepatic impairment (defined as ALT an AST \> 3 times upper limits of normal)
* Patients with inadequate bone marrow functions (defined as absolute neutrophilic count less than 1,500/mm3 or platelets count less than 100,000/mm3).
* Concomitant use of vitamin B1, B6, B9, or B12.
* Patients receiving medications that possibly induce peripheral neuropathy including amiodarone, colchicine, metronidazole, antimycobacterials, and nucleoside reverse transcriptase inhibitors, and phenytoin (Jones et al., 2020).
* Patients receiving gabapentinoids, antidepressants, or opioids.
* Pregnancy or lactation.
* History of hypersensitivity to memantine.