Efficacy of Mirogabalin for Taxane-associated Chemotherapy-induced Peripheral Neuropathy in Perioperative Chemotherapy for Early Breast Cancer

Abstract

Background/Aim

Treatment with taxanes can result in chemotherapy-induced peripheral neuropathy (CIPN). We investigated the efficacy and safety of mirogabalin for the treatment of CIPN in patients who had been administered perioperative chemotherapy including taxane-based agents for breast cancer.

Patients and Methods

We retrospectively analyzed the case of 43 patients with early breast cancer who received a taxane as perioperative chemotherapy and were administered mirogabalin at the diagnosis of CIPN.

Results

Thirty-six patients (83.7%) had grade 1 CIPN and the other seven patients (16.3%) had grade 2 CIPN. The median mirogabalin dose was 10 mg (5-30 mg). CIPN improved from grade 1 to 0 in 12 patients (27.9%) and from grade 2 to 1 in one patient (2.3%); 13 (30.2%) patients thus had an objective therapeutic response. There were no cases in which chemotherapy was reduced or discontinued due to CIPN. Adverse events were evaluated by Common Terminology Criteria for Adverse Events and included five cases of dizziness (11.7%), three of somnolence (7.0%), and two of nausea (4.7%), all of which were grade ≤2. There were no cases of serious (grade ≥3) adverse effects.

Conclusion

Mirogabalin may be effective and safe for treating CIPN of patients who receive a taxane in a perioperative breast cancer setting.

Breast cancer is becoming extremely common all over the world (1). Breast cancer is considered a systemic disease from a relatively early stage and therefore subject to systemic multidisciplinary treatment, including chemotherapy (2). Perioperative chemotherapy in early-stage breast cancer is effective against micrometastases and is essential to prevent recurrence of breast cancer (3-5). Taxanes are key drugs in the treatment of breast cancer and are also essential in perioperative chemotherapy (3-5), but they are one of the drug types that frequently cause chemotherapy-induced peripheral neuropathy (CIPN) (5-9). CIPN caused by taxanes often results in glove-sock paresthesia, which is an important adverse event that worsens a patient's quality of life (7-9). It is thus important to manage a patient’s CIPN appropriately.

According to the American Society of Clinical Oncology guidelines, duloxetine is the only pharmacological agent that is recommended for treating CIPN, although the recommendation is rather weak (10,11). Gabapentinoid anticonvulsants (12,13) are the standard of care for the treatment of neuropathic pain. The gabapentinoid pregabalin, which was developed after gabapentin, has the advantage of a rapid peak blood concentration and excellent bioavailability (13). Compared to these gabapentinoids, the gabapentinoid mirogabalin has a higher affinity for the α2δ-1 subunit of the dorsal root ganglion and slower dissociation, resulting in more sustained analgesia (14,15). Although there is not sufficient evidence regarding the use of pregabalin for the treatment of CIPN, pregabalin has been reported to be more effective than duloxetine (16,17).

There are few reports concerning the efficacy of mirogabalin against CIPN (15,18) and only a single study confirming its efficacy in CIPN caused by taxanes in patients with cancer, including those with breast cancer (18). We conducted the present retrospective analysis to evaluate the efficacy of mirogabalin for the treatment of CIPN in patients who were administered perioperative chemotherapy that included a taxane-based agent for breast cancer.

Patients and Methods

Patients and mirogabalin treatment. We retrospectively analysed the cases of 43 patients with early breast cancer who received a taxanes as part of their perioperative chemotherapy and were administered mirogabalin at their diagnosis of CIPN at Gunma University Hospital between December 2019 and July 2022. CIPN was diagnosed in patients who newly presented with pain or numbness in the extremities after having received taxanes – which are neurotoxic drugs – as perioperative chemotherapy. The degree of CIPN was evaluated by the Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0 (19). The study’s primary efficacy endpoint was objective improvement in the patients’ CIPN in the mirogabalin-treated population. A response was defined as a decrease in the degree of CIPN by at least one grade according to the CTCAE. We classified the response data into three groups according to the therapeutic effect of mirogabalin: improved, stable, and worsening.

The study’s secondary endpoints were the safety of mirogabalin and the incidence of adverse events associated with mirogabalin treatment. The incidence of adverse events was calculated based on the CTCAE and tabulated in descending order of incidence.

The mirogabalin dose was initiated at 10 mg/day, and the therapeutic effect was assessed at 1-2 weeks of treatment; if a patient’s CIPN did not improve, the mirogabalin dose was increased to a maximum of 30 mg/day. When a severe adverse event was observed, the dose was reduced or discontinued. When a patient’s CIPN improved, the dose was also reduced or discontinued.

All 43 of the patients were female. There were no exclusions based on age or menopausal status. Using the patients’ medical records, we collected the characteristics of the primary tumors including the estrogen receptor and progesterone receptor expression status, the human epidermal growth factor receptor 2 (HER2) score, and the molecular subtypes (luminal, luminal-HER2, HER2-enriched, and triple-negative breast cancer). Written consent for the use of their records and imaging in future studies was obtained from all patients, and the study was approved by our hospital’s Clinical Ethics Committee (approval number: 1297).

Results

A total of 43 patients who received mirogabalin for CIPN due to taxane-based perioperative chemotherapy were included in the analysis. Table I summarizes the patients’ chemotherapy characteristics. The median age of the patients was 58 (range=40-73) years. Twelve of the patients (27.9%) received preoperative chemotherapy, and 31 patients (72.1%) received postoperative chemotherapy, and all of the pre- and postoperative chemotherapy regimens included a taxanes. Thirty-six patients (83.7%) had grade 1 CIPN, and the other seven patients (16.3%) had grade 2 CIPN (Figure 1). The median dose of mirogabalin was 10 mg (range=5-30 mg). CIPN improvement from grade 1 to 0 was achieved by 12 patients (27.9%) and improvement from grade 2 to 1 occurred in one patient (2.3%); thus 13 patients (30.2%) had an objective therapeutic response. There were no cases in which chemotherapy was reduced or discontinued due to CIPN.

Table I. Clinical features of breast cancer patients (n=43) who underwent neoadjuvant or adjuvant chemotherapy.

A: Anthracyclines; DOC: docetaxel; NAC: neoadjuvant chemotherapy; PTX: paclitaxel; TC: docetaxel cyclophosphamide; wPTX: weekly paclitaxel.

Figure 1. Change in the grade of chemotherapy-induced peripheral neuropathy based on the Common Terminology Criteria for Adverse Events during therapy with mirogabalin.

Regarding safety, the adverse events were evaluated based on the CTCAE and included dizziness in five patients (11.7%), somnolence in three (7.0%), and nausea in two (4.7%), all of which were grade ≤2. There were no cases of serious adverse events of grade ≥3, nor death. The median dose of mirogabalin was 10 mg (range=5-30 mg). A total of nine patients (20.9%) had dose reductions due to adverse events: two (4.7%) due to dizziness, three (7.0%) due to somnolence, and one (2.3%) due to nausea; the dose was discontinued at the patient's request due to grade 2 nausea in one case (2.3%). Eleven patients (25.6%) successfully completed mirogabalin treatment, confirming the efficacy of mirogabalin against CIPN.

Discussion

Systemic therapy for early-stage breast cancer is highly effective, and adjuvant chemotherapy has been shown to reduce mortality from breast cancer (2-6). However, adjuvant chemotherapy for breast cancer uses taxanes, which often exert toxic side-effects (especially peripheral neuropathic pain). When chemotherapy is reduced or discontinued based on the intensity of a patient's CIPN-induced pain, this may have a negative impact on patient outcomes (7-9). In the present patient series, mirogabalin was used to treat the CIPN of patients who had received a taxane in the perioperative period of breast cancer, and the results of our analyses demonstrate that the degree of CIPN was reduced in 30% of patients treated with mirogabalin as estimated using the CTCAE, with no cases of dose reduction or withdrawal of chemotherapy with CIPN. Our results thus suggest that mirogabalin may be effective against CIPN among patients who have been treated with taxanes in the perioperative setting of breast cancer.

Mirogabalin is an oral gabapentinoid drug that exerts analgesic effects through its ability to bind to the α2δ subunit of voltage-gated calcium channels (14,15). Mirogabalin has been used for the treatment of neuropathic pain, including diabetic and post-herpetic peripheral neuropathic pain (14,20-22). Phase III clinical trials and meta-analyses have described mirogabalin’s efficacy for neuropathic pain (20-22), but there is only limited clinical evidence on the efficacy and safety of mirogabalin for treating CIPN. Our observation of mirogabalin’s efficacy against CIPN in the perioperative treatment of early-stage breast cancer in this study supports recent reports concerning patients with pancreatic cancer and several other cancer types (15,18).

Our analyses revealed that mirogabalin was well-tolerated by breast cancer patients undergoing chemotherapy. There were no cases of CIPN exacerbation after treatment with mirogabalin. The adverse events in this patient series included somnolence, nausea, and dizziness, all of which were mild, i.e., grade 1 or 2. These adverse events are similar to those described in evaluations of mirogabalin (20-22) and are not considered new safety concerns for mirogabalin.

This study has several limitations. It was a retrospective analysis, a single-center study, and had a relatively small number of cases (n=43). Further analyses from large randomized clinical trials are needed to validate the efficacy of mirogabalin for taxane-induced CIPN. However, the present data reflect real-world clinical experience, and to our knowledge, this is the first study to report the efficacy of mirogabalin against CIPN due to taxanes in the perioperative period of early-stage breast cancer, which is highly significant.

In conclusion, our findings indicate that mirogabalin may be effective and safe for treating patients with taxane-induced CIPN in the perioperative period of breast cancer, and mirogabalin may be a new option for treating other cases of CIPN due to taxanes.

Availability of Data and Material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Conflicts of Interest

TF has received honoraria from Daiichi Sankyo Co. Ltd.

Authors’ Contributions

TF analyzed data and wrote the initial draft of the article. CH, KT, MO, and SO collected data and were involved in the initial study conception and design. TF, CH, KT, MO, and KS were involved in drafting and revising the article. All Authors have read and approved the final article.

Acknowledgements

The Authors would like to thank H. Kanai (Department of General Surgical Science, Gunma University Graduate School of Medicine) for their secretarial assistance.