Oxaliplatin-induced peripheral neuropathy risk factors and management in Tunisian population

The most important limits of oxaliplatin treatment is its peripheral neurotoxicity. The aim of our study was to evaluate the oxaliplatin-induced peripheral neuropathy, its impact on treatment and its management. One hundred chemo-naive patients treated with oxaliplatin-based regimen in the medical oncology department of the military hospital of Tunis between 2012 and 2017 were recruited retrospectively. Evaluation of neuropathy was done according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE V4). Fifty-six patients were aged more than 60 years. The sex-ratio was 1.56. Twenty-seven patients were overweight, 17 were obese and 56 had a BMI inferior to 25 kg/m2. Two patients were consuming alcohol. Twenty-three patients had diabetes. Sixty-four patients developed chronic peripheral neuropathy because of oxaliplatin (grade 1-2 in 58 cases and grade 3 in 6 cases). Sex, BMI, diabetes and alcohol consumption were not associated with the development of peripheral neuropathy. No association was found between grades of neuropathy and sex, alcohol consumption and diabetes. The median cumulative dose of oxaliplatin that induced neuropathy was 432.4 mg/m2. The most prescribed treatment was gabapentin (81%) and carbamazepine (16.8%). The treatment was not sufficient to stop neuropathy in 82.6% of cases. Dose reduction was done in 64.2% of cases, treatment delay in 10.7% of cases and treatment interruption in 10.7% of cases. We didn't find any association between known risk factors and peripheral neuropathy. The cumulative dose is interesting to define or to predict the timing of neurotoxicity.


Introduction
Oxaliplatin is a third generation platinum-based agent largely used in oncology. It's effective in the treatment of localized and metastatic gastrointestinal cancers and has improved survival with a 5 year disease free survival of 78% [1][2][3][4]. One of the most important limits of oxaliplatin treatment is its peripheral neurotoxicity. Acute and chronic neuropathy differ in their timing, duration and symptomatology. Acute oxaliplatin neurotoxicity is induced by cold and is characterized by distal sensory symptoms such as paresthesia and dysesthesia occurring in days following oxaliplatin infusion [5]. It occurs rapidly in nearly all patients treated and is typically transient [6,7]. The chronic form occurs because of the repetition of chemotherapy (CT) cycles. Neuropathy is cumulative dose-dependent and can persist for months leading to quality of life deterioration [8][9][10]. Currently, there is no effective strategy for preventing oxaliplatin-induced peripheral neuropathy (OIPN) and pharmacologic management is limited [11]. The aim of our study was to evaluate the OIPN, its impact on treatment and to discuss its management. Data collection: we collected parameters that might be associated with neuropathy according to literature: diabetes, alcohol consumption, body mass index (BMI) and neuropathy treatment.

Methods
Statistical analysis: statistical analysis was performed with SPSS software version 20. The comparison between the different variables was made using the khi-2 test for qualitative variables and the T-student test or Anova for quantitative variables. A p-value equal or less than 0.05 was considered statistically significant.

Discussion
In our population, 64% of patients developed chronic peripheral neuropathy. Berg C et al. reported a rate of 71% of neuropathy [12].
According to our study, neither age, sex, alcohol consumption nor BMI were associated to neuropathy. We didn't find any association between known risk factors and OIPN probably because the study was retrospective with a limited number of patients. A study done by Shahriari A et al. [13] on patients with colorectal cancer in Iran reported no association between age, sex, alcohol consumption and incidence of neuropathy. Patients with neuropathy had a higher BMI (p=0.003). Incidence of neuropathy was higher if alcohol consumption was ≥5 glasses in a single occasion for men and ≥4 glasses in a single occasion for women, usually within 2 h (p=0.003) [7] and grade 2/3 neurotoxicity occurred more often if there was high alcohol intake [14]. Diabetes wasn't associated with neuropathy in our study. Uwah AN et al. [15] evaluated the relationship between preexisting diabetes and OIPN and found a mean cumulative dose at onset of oxaliplatin regimen of 554 mg/m 2 for all patients with neuropathy, 388 mg/m 2 for patients with diabetes and 610 mg/m 2 for patients without diabetes. Although patients with diabetes developed OIPN at a lower cumulative dose of oxaliplatin, diabetes did not appear to affect the severity of OIPN. Other troubles such as hypomagnesaemia and anemia must be considered as they seem to be associated with peripheral neuropathy. These biological disorders are easily measurable before the initiation of treatment and could predict toxicity.
There is an association between the incidence of neuropathy and hypomagnesaemia and anemia [13]. The cumulative dose is interesting to know to prevent the risk of treatment discontinuation.

Conclusion
In our study, we didn't find any association between known risk factors and OIPN. The cumulative dose is interesting to define or to predict the timing of neurotoxicity. We may then consider protocol continuation, doses re-estimation or therapeutic alternative, benefit/risk ratio evaluation. Few ways to prevent and limit neurotoxicity are yet available.
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