TENS, Compression, and Cryotherapy for Paclitaxel-Induced Peripheral Neuropathy in Women With Breast Cancer

Chemotherapy-induced peripheral neuropathy is a clinically important and potentially dose-limiting adverse effect of paclitaxel. Most previous studies of cryotherapy and compression initiated these interventions before neuropathy developed and primarily evaluated prevention. This study evaluated transcutaneous electrical nerve stimulation (TENS), compression therapy, and cryotherapy when initiated after Grade 2 peripheral sensory neuropathy had developed during ongoing weekly paclitaxel treatment.

Women aged 18 years or older with early-stage or locally advanced breast cancer receiving 12 weeks of weekly adjuvant paclitaxel were assessed for eligibility before the third weekly infusion. Participants with NCI-CTCAE Version 5.0 Grade 2 peripheral sensory neuropathy who met all other eligibility criteria and provided written informed consent were randomized in a 1:1:1:1 ratio to four parallel groups: TENS, compression therapy, cryotherapy, or routine care. Randomization was stratified by age and implemented using computer-generated blocks of four with allocation concealment.

The active interventions were initiated during the third weekly paclitaxel session and administered once weekly through week 12, for a total of 10 planned sessions. Each active intervention was administered for 120 minutes, beginning 30 minutes before the paclitaxel infusion, continuing throughout the 60-minute infusion, and ending 30 minutes after infusion completion. The control group received routine oncological care and monitoring.

Because TENS, compression therapy, and cryotherapy were visible and physically perceptible, the study was conducted as an open-label trial. Participants, the intervention provider, the outcome assessor, and the analyst were aware of group assignments. Patient-reported outcomes were completed by participants who knew their assigned groups. NCI-CTCAE peripheral sensory neuropathy grading and the clinical examination components of the DN4 were performed before the weekly paclitaxel infusion and study intervention using standardized assessment procedures.

Assessments were performed at baseline before randomization, the third weekly paclitaxel infusion, and the first study intervention; before the sixth and ninth weekly infusions; and before the twelfth weekly infusion. The primary outcome was the baseline-adjusted treatment-period trajectory of the EORTC QLQ-CIPN20 total score. Secondary outcomes included the DN4 total score, EORTC QLQ-C30 Global Health Status/Quality of Life score, and NCI-CTCAE peripheral sensory neuropathy grade. The EORTC QLQ-CIPN20 sensory, motor, and autonomic subscale scores were evaluated as other pre-specified supportive outcomes.

Inclusion criteria

• Female and 18 years of age or older.
• Diagnosed with early-stage or locally advanced breast cancer.
• Receiving 12 weeks of weekly paclitaxel as adjuvant treatment.
• Clinically confirmed National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 Grade 2 peripheral sensory neuropathy during the third week of paclitaxel treatment, before the third weekly infusion and randomization.
• Eastern Cooperative Oncology Group performance status of 0-2 and Karnofsky Performance Status greater than 70.
• Able to communicate and complete the study procedures.
• Provided written informed consent to participate.

Exclusion criteria

• Peripheral neuropathy present before initiation of paclitaxel treatment.
• Diabetic neuropathy or another neurological disorder that could affect the assessment of peripheral neuropathy.
• Receiving paclitaxel as neoadjuvant, metastatic, or palliative treatment.
• Cardiac pacemaker or another implanted electronic device contraindicating transcutaneous electrical nerve stimulation.
• Active infection, open wound, serious skin lesion, or clinically significant peripheral circulatory impairment in the upper or lower extremities where the interventions would be applied.
• Raynaud phenomenon, cryoglobulinemia, cold urticaria, or another clinical condition contraindicating cryotherapy.
• Regularly receiving another physical intervention for chemotherapy-induced peripheral neuropathy outside the study at enrollment or planning to receive such an intervention during the study.