Voltage‐gated sodium channel polymorphisms play a pivotal role in the development of oxaliplatin‐induced peripheral neurotoxicity: Results from a prospective multicenter study

Abstract

BACKGROUND:The current prospective, multicenter study sought to identify single nucleotide polymorphisms of voltage-gated sodium channels (SCNAs) genes that might confer susceptibility to an increased incidence and severity of oxaliplatin-induced peripheral neuropathy (OXAIPN) in patients treated with either leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX) or oxaliplatin plus capecitabine (XELOX) for colorectal cancer (CRC). METHODS: A total of 200 patients with CRC were genotyped with real-time polymerase chain reaction using locked nucleic acid hydrolysis probes or allele-specific primers. All patients had received oxaliplatin-based chemotherapy, either in the adjuvant or metastatic setting. The incidence and severity of cumulative OXAIPN was graded using the clinical version of the Total Neuropathy Score and the neurosensory National Cancer Institute Common Toxicity Criteria (version 3.0). The incidence of acute OXAIPN was assessed using a descriptive questionnaire (yes=no response format) at each clinical evaluation. Acute OXAIPN was present in 169 of 200 patients (84.5%), whereas after treatment discontinuation, the cumulative=chronic form of neurotoxicity occurred in 145 of 200 patients (72.5%). RESULTS: In the logistic regression analysis adjusted for confounding factors, the overdominant model (CT vs CC 1 TT) of 2 single nucleotide polymorphisms (ie, SCN4A-rs2302237 and SCN10A-rs1263292) emerged as being significantly associated with an increased incidence of acute OXAIPN (rs2302237: odds ratio of 2.62 [95% confidence interval (95% CI), 1.15-6.00]; P 5.019; and rs12632942: OR of 0.39 [95% CI, 0.17-0.88]; P 5.023). However, only SCN4A-rs2302237 emerged as also being predictive of the clinical severity of acute OXAIPN (OR, 2.50 [95% CI, 1.35-4.63]; P 5.0029) and the occurrence of cumulative=chronic OXAIPN (OR, 2.47 [95% CI, 1.04-5.85]; P 5.037). CONCLUSIONS: The results of the current study provide evidence to support a causal relationship between SCNA polymorphisms and OXAIPN. However, further studies from independent groups are warranted to confirm these results. Cancer 2013;119:3570-7.

Oxaliplatin-Induced Peripheral Neuropathy and Identification of Unique Severity Groups in Colorectal Cancer

“…The details of the original study have been previously reported 24 . In brief, 200 CRC patients scheduled to receive oxaliplatin plus leucovorin and 5-fluorouracil (FOLFOX) or oxaliplatin plus capecitabine (XELOX), either in the adjuvant or metastatic setting, were enrolled in a multisite study.…”

Chemotherapy-induced peripheral neuropathy in the adult

“…For historical reasons, in most clinical trials the occurrence and severity of CIPN are assessed by the United States National Cancer Institute common toxicity criteria (NCI-CTC) scales despite notable interobserver disagreement in clinical studies of anticancer treatments [18] or neuroprotective strategies [19][20][21][22][23][24][25] …”

Are chemotherapy-associated symptoms underestimated? A view beyond common toxicity criteria

“…Identifying patients at risk of developing toxicities is of major importance. The findings of recent studies demonstrate that certain patients, who are treated with oxaliplatin, might be more at risk of developing CIPN due to variants in encoding genes of ion channels in the central nervous system [20][21][22]. Therefore a clinician might decide to restrain oxaliplatin for that patient.…”