Voltage‐gated sodium channel dysfunction and the search for other satellite channels in relation to acute oxaliplatin‐induced peripheral neurotoxicity

Dear Editor, We would like to thank Drs. Modoni and Basso for their comments in relation to our recently published paper on the role of the KCNN3 (SK3) gene in the development of acute oxaliplatin-induced peripheral neurotoxicity (OXAIPN). An extensive discussion of their previously published findings but also on the content of their current critical letter already forms a major component in the discussion of our paper. Nonetheless, we are happy to further elaborate this scientific debate on the topic. The main message of the Modoni and Basso letter is that their previously published study, which showed a positive association between KCNN3 CAG repeat polymorphisms and increased risk of acute OXAIPN is not comparable to our study, which failed to reproduce these results. Identification of robust genetic risk factors that influence susceptibility to OXAIPN is critical in order to identify patients at risk prior to chemotherapy administration and enable tailored treatment approaches to minimize toxicity. To date, there have been difficulties in identifying genetic variants consistently associated with neurotoxicity risk across different patient cohorts. Variability in assessment tools is one factor which may influence results, while low sample size and insufficient statistical power, as particularly evident in the Basso et al study, are also potent contributors. Particularly, small sized pharmacogenetic studies can be easily biased from uncontrolled or unexpected variables and as such their results warrant reproduction in further larger studies. For example, diabetic status emerged in the Basso et al study as a significant variable in the multivariate analysis, despite the baseline electrophysiological assessment, which may introduce potential bias to their findings, and remained undiscussed. Noteworthy, they have estimated their sample size with a power of 80%; assuming surprisingly the incidence of acute OXAIPN to be 10%, although it is known that the acute OXAIPN can occur in up to 90% of oxaliplatin-treated patients. On the contrary, our study represents a well characterized patient sample and the largest oxaliplatin-treated cohort assessed for KCNN3 polymorphisms to date. Our patients were chemotherapy naïve, had no comorbidities likely to impose bias, and the analysis framework and breakdown of allele lengths was based on prior work. While we acknowledge methodological differences that may account for some of the discrepancies in results between studies, we definitely cannot concur with the suggestion by Modoni and Basso that findings are not able to be compared between our studies. A key area of difference between the studies is in the selection of outcome measures. There is no gold standard clinical assessment for CIPN or specifically for acute OXAIPN. In our study, we utilized clinical symptom based methods of ascertaining acute OXAIPN severity, while the prior study by Basso et al used neurophysiological evaluations to determine OXAIPN incidence without a focus on severity. Tellingly, it is clinical symptom assessment that is utilized in clinical practice to make decisions regarding dose modification and toxicity. Further, Basso et al utilized neurophysiological evaluation of oxaliplatin-treated patients only at the first treatment cycle. This approach may also be problematic due to the extremely high incidence of patients who demonstrate neurophysiological abnormalities following oxaliplatin treatment, leading to ceiling effects. Spontaneous high frequency motor fiber action potentials on electromyography are often identified in 100% of patients with evidence of repetitive compound muscle action potentials in 71-92%. Identification of neurophysiological evidence of acute neurotoxicity relies heavily on the method used and the number of muscles sampled. Furthermore, large scale clinical studies have suggested that 99% of oxaliplatin-treated patients report symptoms of acute neurotoxicity at some point during treatment. Accordingly, it is likely that severity-based rather than incidence-based assessment metrics will be more useful in determining the risk of significant acute neurotoxicity. Surprisingly, Modoni and Basso also claim that their results have been strongly confirmed by the in vitro experiments of Anon et al, although this effect was not eventually translated into the clinical setting of chronic OXAIPN patients. However, it would seem speculative to suggest that in vitro results alone confirm their claims in the absence of large-scale confirmatory clinical studies. Our genetic data support the data presented by Anon et al in chronic OXAIPN. As such, we remain confident in our negative results because the clinical analysis we applied is applicable to both acute OXAIPN as in the Basso et al study and also to chronic OXAIPN as in the Anon et al study. Thus far, existing evidence suggests that there is no lost channel to be found in the pathogenesis of acute OXAIPN but rather satellite Received: 22 October 2019 Accepted: 23 October 2019