Breast Cancer, Chemotherapy-Induced Peripheral Neuropathy
Conditions
Keywords
nursing, breast cancer, electrostimülation, compression therapy, cryotherapy
Brief summary
This single-center, four-arm, parallel-group randomized controlled trial evaluates transcutaneous electrical nerve stimulation (TENS), compression, and cryotherapy for the management of chemotherapy-induced peripheral neuropathy (CIPN) in women with breast cancer receiving weekly adjuvant paclitaxel. A total of 140 participants with NCI-CTCAE Version 5.0 Grade 2 peripheral sensory neuropathy before the third weekly paclitaxel infusion were randomized in a 1:1:1:1 ratio to TENS, compression, cryotherapy, or routine care. The interventions were administered during weekly paclitaxel sessions from weeks 3 through 12. Outcomes were assessed at baseline before the third weekly infusion and before the sixth, ninth, and twelfth weekly infusions. The primary outcome is the EORTC QLQ-CIPN20 total score during the treatment period.
Detailed description
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.
Interventions
DEVICETranscutaneous Electrical Nerve Stimulation
Conventional high-frequency transcutaneous electrical nerve stimulation (TENS) was administered once weekly from the third through the twelfth weekly paclitaxel infusion, for a total of 10 planned sessions. TENS was delivered using a dual-channel, battery-powered portable digital Bosch TENS device and four self-adhesive hypoallergenic surface electrodes. Electrodes were placed bilaterally over the PC6 region on the inner wrists and on the soles of the feet. The device was set to a frequency of 80 Hz and a pulse duration of 200-250 microseconds. Current intensity was increased gradually to produce a strong but comfortable tingling sensation without pain or visible muscle contraction, typically 10-30 mA and up to 60 mA according to participant tolerance. Each session lasted 120 minutes: 30 minutes before, 60 minutes during, and 30 minutes after the paclitaxel infusion.
OTHERCryotherapy
Bilateral local cryotherapy was administered once weekly from the third through the twelfth weekly paclitaxel infusion, for a total of 10 planned sessions. Cryotherapy was applied to both hands and feet using glycerin-containing DETAMED Coolcare Chemotherapy Neuropathy Set cooling gel gloves and socks that completely covered the distal extremities and remained flexible when frozen. The gel gloves and socks were stored for at least 3 hours before each application in a freezer maintained at -20°C to -30°C. Cotton liners were worn under the gloves and socks, and the cooling sets were replaced at standardized intervals. Each session lasted 120 minutes: 30 minutes before, 60 minutes during, and 30 minutes after the paclitaxel infusion. Skin condition, peripheral circulation, and participant tolerance were monitored throughout each session.
OTHERCompression Therapy
Compression therapy was administered once weekly from the third through the twelfth weekly paclitaxel infusion, for a total of 10 planned sessions. For the lower extremities, bilateral Varimed CCL II knee-high graduated compression stockings were selected according to each participant's ankle and calf measurements. The stockings provided 23-32 mmHg pressure at the ankle, with pressure decreasing gradually toward the calf. For the upper extremities, each participant's standard glove size was determined by hand measurement, and two layers of Beybi Gloves surgical gloves one size smaller were applied bilaterally. Hand pressure was not measured directly; application was standardized using the same sizing procedure and double-glove technique. Each session lasted 120 minutes: 30 minutes before, 60 minutes during, and 30 minutes after the paclitaxel infusion. Fit, skin condition, peripheral circulation, and participant tolerance were monitored throughout each session.
Sponsors
Cumhuriyet University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Masking description
Participants, the intervention provider, the outcome assessor, and the analyst were not masked to group assignments. Because TENS, compression, and cryotherapy were visible and physically perceptible, masking of participants and the intervention provider was not feasible. Patient-reported outcomes were completed by participants who were aware of 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. Therefore, the study was conducted as an open-label trial.
Intervention model description
Participants were randomized in a 1:1:1:1 ratio to four parallel groups: transcutaneous electrical nerve stimulation, compression, cryotherapy, or routine care.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 Total Score | Baseline before the third weekly paclitaxel infusion and first study intervention, and before the sixth, ninth, and twelfth weekly infusions, approximately 3, 6, and 9 weeks after baseline | The EORTC QLQ-CIPN20 is a patient-reported questionnaire assessing chemotherapy-induced peripheral neuropathy symptoms experienced during the previous week. Item responses are used to calculate a total score that is linearly transformed to a 0-to-100 scale. Higher scores indicate greater peripheral neuropathy symptom burden. Follow-up scores at T1, T2, and T3 are evaluated jointly in a baseline-adjusted longitudinal model, with the T0 score included as the baseline covariate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Douleur Neuropathique 4 Questions (DN4) Total Score | Baseline before the third weekly paclitaxel infusion and first study intervention, and before the sixth, ninth, and twelfth weekly infusions, approximately 3, 6, and 9 weeks after baseline | Neuropathic pain characteristics are assessed using the Douleur Neuropathique 4 Questions (DN4). The instrument includes seven participant-reported symptom items and three clinical examination items. Each item is scored as 0 when absent and 1 when present, producing a total score ranging from 0 to 10. Higher scores indicate a greater neuropathic pain burden. Follow-up scores at T1, T2, and T3 are evaluated using a baseline-adjusted longitudinal model, with the corresponding T0 DN4 total score included as the baseline covariate. |
| European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Global Health Status/Quality of Life Score | Baseline before the third weekly paclitaxel infusion and first study intervention, and before the sixth, ninth, and twelfth weekly infusions, approximately 3, 6, and 9 weeks after baseline | Health-related quality of life is assessed using the Global Health Status/Quality of Life scale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Version 3.0. The scale score is linearly transformed to a 0-to-100 scale. Higher scores indicate better global health status and quality of life. Follow-up scores at T1, T2, and T3 are evaluated using a baseline-adjusted longitudinal model, with the corresponding T0 score included as the baseline covariate. |
| Peripheral Sensory Neuropathy Grade Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 | Baseline before the third weekly paclitaxel infusion and first study intervention, and before the sixth, ninth, and twelfth weekly infusions, approximately 3, 6, and 9 weeks after baseline | Peripheral sensory neuropathy severity is rated by an outcome assessor using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. The outcome assessor was not involved in randomization or intervention delivery but was aware of group assignments. Grade 1 indicates asymptomatic neuropathy, loss of deep tendon reflexes, or paresthesia; Grade 2 indicates moderate symptoms limiting instrumental activities of daily living; Grade 3 indicates severe symptoms limiting self-care activities of daily living; and Grade 4 indicates life-threatening consequences requiring urgent intervention. Higher grades indicate greater neuropathy severity. Grade 2 peripheral sensory neuropathy at baseline was an eligibility criterion. |
Countries
Turkey (Türkiye)
Outcome results
None listed