TENS and Compression for Established Oxaliplatin-Induced Peripheral Neuropathy
Comparative Effects of Transcutaneous Electrical Nerve Stimulation, Compression, and Sequential TENS Plus Compression on Established Oxaliplatin-Induced Peripheral Neuropathy in Patients With Metastatic Gastrointestinal Cancer: A Four-Arm Randomized Controlled Trial
Chemotherapy-induced peripheral neuropathy is a clinically important adverse effect of oxaliplatin-based chemotherapy that may cause sensory symptoms, neuropathic pain, functional limitations, and reduced quality of life. This randomized, open-label, four-arm parallel-group study evaluated the comparative effects of transcutaneous electrical nerve stimulation (TENS), compression, sequential TENS followed by compression, and usual care in 140 adults with metastatic gastrointestinal cancer who developed Grade 2 or higher chemotherapy-induced peripheral neuropathy after the first cycle of oxaliplatin-based chemotherapy. Participants were allocated in a 1:1:1:1 ratio.
The primary outcome was the EORTC QLQ-CIPN20 total score evaluated longitudinally across the post-baseline treatment-period assessments before Cycles 3-6, with the score obtained before Cycle 2 included as the baseline covariate. The overall Group×Time interaction represented the primary treatment effect, and the baseline-adjusted between-group comparison before Cycle 6 represented the primary endpoint comparison.
Secondary outcomes included the EORTC QLQ-CIPN20 sensory, motor, and autonomic domain scores; EORTC QLQ-C30 scale scores; DN4 total score and DN4-defined neuropathic pain positivity; and clinician-rated NCI-CTCAE v5.0 peripheral sensory neuropathy grade. A separate exploratory follow-up assessment was conducted 6 months after Cycle 6.
Study Overview
Status
Intervention / Treatment
Detailed Description
This randomized, open-label, four-arm parallel-group study evaluated supportive interventions for the management of established chemotherapy-induced peripheral neuropathy in patients receiving oxaliplatin-based chemotherapy. Eligible participants were adults with metastatic gastrointestinal cancer who had received one cycle of FOLFOX or FOLFIRINOX and had Grade 2 or higher peripheral sensory neuropathy according to NCI-CTCAE v5.0 before the Cycle 2 intervention.
A total of 140 participants were randomly allocated in a 1:1:1:1 ratio to TENS, compression, sequential TENS followed by compression, or usual care, with 35 participants in each group. Participants remained in their assigned parallel groups throughout the study. Intervention sessions were administered at 14-day intervals from Cycle 2 through Cycle 6, resulting in five sessions per participant.
The prespecified peri-infusion intervention window lasted 180 minutes, comprising 30 minutes before, 120 minutes during, and 30 minutes after the oxaliplatin infusion. In the TENS group, transcutaneous electrical nerve stimulation was administered throughout this 180-minute window. Stimulation was delivered at a nominal pulse rate of 40 Hz and a pulse width of 100 microseconds. The intensity was adjusted individually to produce a strong but comfortable sensory sensation without visible muscle contraction.
In the compression group, bilateral compression of the hands and feet was applied throughout the same 180-minute peri-infusion window. Surgical gloves one size smaller than each participant's individually determined size and Class II graduated compression stockings providing 23-32 mmHg were used.
Because no established combined TENS-plus-compression dosing protocol was available, participants in the sequential intervention group received 90 minutes of TENS followed by 90 minutes of compression within the same 180-minute peri-infusion window. The usual care control group received routine clinical care without a study-specific TENS or compression intervention.
Outcomes were assessed before Cycle 2 (T0), before Cycles 3-6 (T1-T4), and 6 months after completion of Cycle 6 (T5). The primary outcome was the EORTC QLQ-CIPN20 total score evaluated longitudinally across the post-baseline treatment-period assessments from T1 to T4, with the T0 score included as the baseline covariate. The overall Group×Time interaction represented the primary treatment effect, and the baseline-adjusted between-group contrast at T4 represented the primary endpoint comparison.
Secondary treatment-period outcomes included the EORTC QLQ-CIPN20 sensory, motor, and autonomic domain scores; EORTC QLQ-C30 scale scores; clinician-rated NCI-CTCAE v5.0 peripheral sensory neuropathy grade; DN4 total score; and DN4-defined neuropathic pain positivity. The T5 assessments were treated as separate exploratory follow-up outcomes.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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Sivas
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Sivas, Sivas, Turkey (Türkiye), 58010
- Sivas Cumhuriyet University Health Services Application and Research Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Aged 18 years or older
- Diagnosed with metastatic gastrointestinal cancer, including gastric, pancreatic, colon, or rectal cancer
- Scheduled to receive six cycles of oxaliplatin-based chemotherapy with FOLFOX or FOLFIRINOX
- Having received one cycle of oxaliplatin-based chemotherapy
- Having Grade 2 or higher chemotherapy-induced peripheral neuropathy according to NCI-CTCAE v5.0 before the Cycle 2 intervention
- Eastern Cooperative Oncology Group performance status of 0-2
- Having provided written informed consent to participate
Exclusion Criteria:
- Having a diagnosed psychiatric disorder that could interfere with informed consent, communication, or adherence to the study procedures
- Having a cardiac pacemaker or another implanted electronic device contraindicating TENS
- Having pre-existing peripheral neuropathy before the initiation of oxaliplatin-based chemotherapy or neuropathy attributable to another cause
- Having diabetes mellitus
- Having peripheral vascular disease or another clinically significant circulatory disorder affecting the hands or feet
- Having a skin lesion or other skin condition at the sites where TENS electrodes or compression garments would be applied
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Supportive Care
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: TENS Group
Participants received the TENS intervention at each scheduled session from Cycle 2 through Cycle 6 during oxaliplatin-based chemotherapy, in addition to usual care.
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TENS was delivered using the F. Bosch FB2405 TENS+EMS dual-channel device with four 5 × 5-cm surface electrodes placed bilaterally over PC6 and KI1.
Program 4 provided a modulated pulse rate of 2-60 Hz and a pulse width of 156-260 microseconds; the nominal pulse rate was set to 40 Hz.
The device output was adjustable from 0-80 mA per channel into a 500-Ω load, but no fixed mA value was used.
Intensity was individually titrated to a strong, comfortable, non-painful sensory level without visible muscle contraction.
Each session lasted 180 minutes: 30 minutes before, throughout the 120-minute oxaliplatin infusion, and 30 minutes after the infusion.
Sessions were administered every 14 days from Cycle 2 through Cycle 6, for five sessions.
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|
Experimental: Compression group
Participants received the compression intervention at each scheduled session from Cycle 2 through Cycle 6 during oxaliplatin-based chemotherapy, in addition to usual care.
|
Bilateral compression of the hands and feet was applied using Beybi Sensitive surgical gloves one size smaller than the participant's measured glove size and knee-high Varimed CCL II graduated compression stockings providing 23-32 mmHg.
Each session lasted 180 minutes: 30 minutes before, throughout the 120-minute oxaliplatin infusion, and 30 minutes after the infusion.
Sessions were administered every 14 days from Cycle 2 through Cycle 6, for five sessions.
All applications were individually fitted and directly supervised by the same research nurse.
|
|
Experimental: Sequential TENS Plus Compression Group
Participants received TENS followed by compression at each scheduled intervention session from Cycle 2 through Cycle 6 during oxaliplatin-based chemotherapy, in addition to usual care.
|
Participants received 90 minutes of TENS followed immediately by 90 minutes of bilateral hand-and-foot compression, using the same devices, parameters, electrode placement, gloves, and stockings as in the monotherapy groups.
TENS began 30 minutes before the oxaliplatin infusion and continued during the first 60 minutes of the 120-minute infusion.
After TENS was stopped and the electrodes were removed, compression was applied during the remaining 60 minutes of the infusion and for 30 minutes afterward.
The total sequential intervention lasted 180 minutes.
Sessions were administered every 14 days from Cycle 2 through Cycle 6, for five sessions.
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|
No Intervention: Usual Care Control Group
Participants received usual care from Cycle 2 through Cycle 6 and received no study-specific TENS or compression intervention.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Change in EORTC QLQ-CIPN20 Total Score From Before Cycle 2 to Before Cycle 6
Time Frame: From baseline before Cycle 2 to before Cycle 6, with assessments every 14 days (five assessments over approximately 8 weeks [56 days]).
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The EORTC QLQ-CIPN20 is a 20-item patient-reported questionnaire assessing sensory, motor, and autonomic symptoms and functional limitations associated with chemotherapy-induced peripheral neuropathy.
Scores were linearly transformed to a 0-100 scale, with higher scores indicating greater CIPN-related symptom burden.
The primary outcome was the between-group difference in change in the total score from baseline before Cycle 2 to Cycle 6.
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From baseline before Cycle 2 to before Cycle 6, with assessments every 14 days (five assessments over approximately 8 weeks [56 days]).
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Change in EORTC QLQ-C30 Scale Scores From Before Cycle 2 to Before Cycle 6
Time Frame: From baseline before Cycle 2 to before Cycle 6, with assessments every 14 days (five assessments over approximately 8 weeks [56 days]).
|
The EORTC QLQ-C30 is a 30-item patient-reported questionnaire assessing health-related quality of life in patients with cancer.
It includes five functional scales, three symptom scales, a global health status/quality-of-life scale, and six single-item symptom measures.
Scores are linearly transformed to a 0-100 scale.
Higher functional and global health status scores indicate better functioning and quality of life, whereas higher symptom scores indicate greater symptom burden.
Changes in scale scores were compared between groups over time.
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From baseline before Cycle 2 to before Cycle 6, with assessments every 14 days (five assessments over approximately 8 weeks [56 days]).
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NCI-CTCAE v5.0 Peripheral Sensory Neuropathy Grade From Before Cycle 2 to Before Cycle 6
Time Frame: From baseline before Cycle 2 to before Cycle 6, with assessments every 14 days (five assessments over approximately 8 weeks [56 days]).
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Chemotherapy-induced peripheral sensory neuropathy severity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI-CTCAE v5.0).
Peripheral sensory neuropathy is graded from 0 to 5, with higher grades indicating greater severity and functional impairment.
Changes in grade distributions were compared between groups over the treatment period.
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From baseline before Cycle 2 to before Cycle 6, with assessments every 14 days (five assessments over approximately 8 weeks [56 days]).
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Change in DN4 Total Score From Before Cycle 2 to Before Cycle 6
Time Frame: From baseline before Cycle 2 to before Cycle 6, with assessments every 14 days (five assessments over approximately 8 weeks [56 days]).
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Neuropathic pain was assessed using the Douleur Neuropathique 4 Questions (DN4), a 10-item clinician-administered instrument comprising seven symptom-interview items and three clinical examination items.
The total score ranges from 0 to 10, with higher scores indicating more neuropathic pain features.
A score of 4 or higher was classified as positive for neuropathic pain.
Changes in total scores and DN4 positivity were compared between groups over the treatment period.
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From baseline before Cycle 2 to before Cycle 6, with assessments every 14 days (five assessments over approximately 8 weeks [56 days]).
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Exploratory QLQ-CIPN20 Total Scores at 6-Month Follow-up
Time Frame: At 6 months after Cycle 6 (exploratory follow-up assessment).
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The EORTC QLQ-CIPN20 total score was assessed at the prespecified 6-month follow-up.
Scores range from 0 to 100, with higher scores indicating greater CIPN-related symptom burden.
This assessment was analyzed separately as an exploratory follow-up outcome and was not included in the primary T0-T4 treatment-period analysis.
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At 6 months after Cycle 6 (exploratory follow-up assessment).
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Exploratory EORTC QLQ-C30 Scale Scores at 6-Month Follow-up
Time Frame: At 6 months after Cycle 6 (exploratory follow-up assessment).
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EORTC QLQ-C30 scale scores were assessed exploratorily at the prespecified long-term follow-up.
Scores range from 0 to 100.
Higher functional and global health status scores indicate better functioning and quality of life, whereas higher symptom scores indicate greater symptom burden.
This assessment was conducted to examine participants' health-related quality-of-life status after the extended follow-up interval.
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At 6 months after Cycle 6 (exploratory follow-up assessment).
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Exploratory NCI-CTCAE v5.0 Peripheral Sensory Neuropathy Grade at 6-Month Follow-up
Time Frame: At 6 months after Cycle 6 (exploratory follow-up assessment).
|
Peripheral sensory neuropathy severity was assessed exploratorily at the prespecified long-term follow-up using NCI-CTCAE v5.0.
Neuropathy is graded from 0 to 5, with higher grades indicating greater severity and functional impairment.
This assessment was conducted to examine participants' neuropathy status after the extended follow-up interval.
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At 6 months after Cycle 6 (exploratory follow-up assessment).
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Exploratory DN4 Total Score and Neuropathic Pain Positivity at 6-Month Follow-up
Time Frame: At 6 months after Cycle 6 (exploratory follow-up assessment).
|
Neuropathic pain was assessed exploratorily at the prespecified long-term follow-up using the DN4.
Total scores range from 0 to 10, with higher scores indicating more neuropathic pain features.
A score of 4 or higher was classified as positive for neuropathic pain.
This assessment was conducted to examine participants' neuropathic pain status after the extended follow-up interval.
|
At 6 months after Cycle 6 (exploratory follow-up assessment).
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Collaborators and Investigators
Sponsor
Investigators
- Study Director: Şerife KARAGÖZOĞLU, Proff., Cumhuriyet University
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- CumhuriyetU-SBE-SÖ-1
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
- ANALYTIC_CODE
- CSR
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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