This is the first study to evaluate the efficacy of mirogabalin for CIPN caused by GnP therapy in PC patients. We found that mirogabalin controlled the progression of CIPN, and sensory neuropathy improved significantly. However, the rate of AEs was relatively high.
Despite the high prevalence of CIPN in association with GnP therapy, there are very few established treatments. It is recommended that, in patients who develop CIPN during chemotherapy, the treatment be delayed or discontinued, or the dose decreased. Effective drugs for CIPN are essential; mirogabalin is one such drug. Nab-PTX is a cytotoxic taxane that frequently causes CIPN. Duloxetine is the only drug recommended by the American Society of Clinical Oncology and Japan Pancreas Society 5,10 for treating established, painful CIPN caused by oxaliplatin or paclitaxel. Randomized controlled trials of duloxetine and pregabalin for taxane-induced CIPN found that pregabalin was more effective 11. Neuropathy caused by nab-PTX usually presents as sensory neuropathy, manifesting as paresthesias, numbness, and tingling in the toes and fingers. These symptoms are similar to those seen in postherpetic neuralgia and diabetic peripheral neuropathy, and mirogabalin has been shown to be effective for treating them 8,9. Pregabalin, which has the same mechanism of action as mirogabalin, can improve taxane-induced peripheral neuropathy 11. We observed no disease progression in CIPN patients after taking mirogabalin compared to baseline, suggesting that it controlled disease progression (which occurs due to cumulative toxicity). Mirogabalin significantly improved sensory neuropathy, including symptoms of CIPN such as tingling and numbness, making it a suitable treatment for these patients.
The CTCAE is generally used to evaluate CIPN, but has several disadvantages. First, the CTCAE was not developed specifically to assess CIPN; moreover, it is not sensitive to changes in disease status and is associated with significant interrater variability 12. The CTCAE also has a grade range of only 0–4, which makes it difficult to perform detailed evaluations; the accuracy and precision of the instrument may be inadequate. The PRO-CTCAE was developed to improve the precision of assessment of AEs. The EORTC-CIPN has a subscale pertaining specifically to symptoms and functional limitations related to CIPN. These instruments provide a more detailed and reliable assessment of CIPN.
Adverse effects were more common in this study compared to the literature, where studies have reported somnolence in 8.1–23.9% of patients receiving mirogabalin, dizziness in 4.9–15.5%, and edema in 2.4–8.5% 8,9,13,14. Most of our patients had somnolence and dizziness. Previous studies on mirogabalin-related AEs focused on diabetic neuropathy and postherpetic neuralgia, in which somnolence and dizziness are less likely compared to CIPN 8,14. CIPN patients tend to receive strong chemotherapy; this increases the likelihood of chemotherapy-related AEs, which may be confused with mirogabalin-related ones 4,15. Studies of AEs associated with mirogabalin reported that the first event tended to occur within 1 month after administration, and that AEs were more frequent in lean women aged over 65 years 8,13,14. In line with this, we observed somnolence in all of our female patients. The frequency of AEs also increases with the mirogabalin dose. In lean elderly women, who are prone to AEs, a low dose (5 mg/day) during the first month may reduce the likelihood of AEs. Four of our patients discontinued mirogabalin due to grade 1 AEs. The proportion of patients who discontinued mirogabalin was in line with the literature. Discontinuing or reducing the dosage of mirogabalin is an important option for patients who do not feel that they are deriving any benefits from the medication.
Our study had some limitations. First, it was a single-center pilot study including a small number of cases. Second, only one questionnaire pertained specifically to nab-PTX, which exhibits cumulative toxicity; prospective studies are therefore necessary. Third, the Japanese version of the EORTC-CIPN is still being validated (currently in “stage 3”).
Despite these limitations, this study had several important strengths; it was the to report the effects of mirogabalin on CIPN in PC patients on GnP therapy and showed that it controlled disease progression. Moreover, using the precise PRO-CTCAE and EORTC-CIPN instruments, we demonstrated that mirogabalin is particularly effective for sensory neuropathy.