Home-Based Exercise and Vagus Nerve Stimulation for Chemotherapy-Induced Neuropathy

Background: Studies highlight the potential benefits of home-based exercise for cancer survivors with chemotherapy-induced neuropathy (CIN); however, its effectiveness in alleviating CIN-related sensorimotor impairments and symptoms has been inconsistent and generally modest. Non-invasive vagus nerve stimulation (nVNS) has emerged as a promising adjunct for CIN rehabilitation. Preliminary studies suggest that nVNS can enhance the therapeutic effects of exercise-based rehabilitation, leading to greater improvements in sensorimotor impairments. A recent trial found that nVNS alleviated CIN-related pain and improved mental well-being, but did not significantly enhance physical well-being or clinician-rated CIN severity. Objectives: To evaluate the efficacy, safety, and feasibility of combining home-based exercise with non-invasive vagus nerve stimulation (nVNS) to alleviate chemotherapy-induced neuropathy (CIN) and improve quality of life in cancer survivors. Design and Subjects: This phase II randomized controlled trial will enroll 60 cancer survivors with established CIN following treatment with platinum compounds or taxanes. Participants will be randomly assigned in a 1:1:1 ratio to one of three groups: exercise with real nVNS (ERS), exercise with sham nVNS (ESS), or usual care. Interventions: Participants in the experimental groups will engage in a 12-week home-based exercise program, with the ERS group receiving real nVNS and the ESS group receiving sham stimulation. Study Instruments and Main Outcome Measures: The primary outcome, patient-reported CIN, will be assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20-item (EORTC QLQ-CIPN20). Secondary outcomes will include the Total Neuropathy Score-nurse for clinician-reported CIN, the Symptom Distress Scale for general symptoms, functional performance measures (Timed Up and Go Test and 6-Minute Walk Test), and the EORTC QLQ-Core 30-item for quality of life. Data Analysis and Expected Results: Generalized Estimating Equations will be used for efficacy outcome analysis. It is anticipated that the combined intervention may lead to improvements in CIN, functioning, and quality of life, thereby supporting further research in larger trials.

Inclusion Criteria: 1. Hong Kong residents who can communicate in Cantonese, Mandarin, or English; 2. Aged 18 years or older; 3. Cancer survivors with complete disease remission after radical treatment; 4. Completed a chemotherapy regimen with radical intent that included at least one of the following agents for a minimum of 3 months: * Platinum compounds (e.g., cisplatin, carboplatin, oxaliplatin); * Taxanes (e.g., paclitaxel, docetaxel); 5. Have CIN of at least grade 2 assessed by a clinician based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE 5.0), or self-rate ≥ 2 points on at least one item in the 4-item Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire; 6. Physically capable of engaging in exercise and assessments, as determined by the ability to complete the 6MWT; 7. Able to provide written informed consent. Exclusion Criteria: 1. Known history of peripheral neuropathy or related symptoms prior to chemotherapy; 2. History of heart disease; 3. Bradycardia (heart rate \< 60 beats per minute); 4. Pregnancy; 5. Presence of active implants, such as cardiac pacemakers, cochlear implants, and implanted neurostimulators; 6. Known metastasis to the central or peripheral nervous system; 7. Any physical or mental handicap; 8. History of alcohol or illegal drug abuse; 9. Using a hearing aid device on the left ear; 10. Receiving other non-pharmacological treatments for CIN within the past 2 months; 11. Engaging in over 30 minutes of exercise for 2 or more days per week prior to enrollment; 12. Any wound, infection, skin allergy, or deformity in the left ear; 13. Any other medical contraindication to exercise and/or nVNS as determined by the treating oncologist.