CIPN - Chemotherapy-Induced Peripheral Neuropathy, Gastrointestinal Cancers
Conditions
Keywords
Chemotherapy ınduced peripheral neuropathy, Nursing, compression, Oxaliplatin, Transcutaneous electrical nerve stimulation, Randomized controlled trial
Brief summary
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.
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. TENS was delivered using Program 4 of the F. Bosch FB2405 TENS+EMS device. Program 4 provided frequency- and pulse-width-modulated stimulation, with pulse rates ranging from 2 to 60 Hz and pulse widths ranging from 156 to 260 microseconds. The 40-Hz value informed the original intervention rationale; however, the actual stimulation was not a fixed 40-Hz, 100-microsecond output. Intensity was individually titrated to produce a strong but comfortable and non-painful 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. TENS began 30 minutes before the oxaliplatin infusion and continued during the first 60 minutes of the 120-minute infusion. After TENS was discontinued and the electrodes were removed, compression was initiated and maintained during the remaining 60 minutes of the infusion and for 30 minutes after its completion. 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-by-Time interaction represented the primary treatment effect. The set of baseline-adjusted planned between-group contrasts at T4 represented the primary endpoint pairwise comparisons. 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.
Interventions
DEVICETENS
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 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.
DEVICECompression Garments
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.
DEVICESequential TENS Plus Compression
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.
Sponsors
Cumhuriyet University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Masking description
Because of the physical nature of the interventions, participants and intervention providers could not be blinded; therefore, the study was open-label. Group allocation was concealed from the enrolling researcher until assignment by the independent nurse. Coded group identities were concealed from the independent statistician until the statistical analyses were completed.
Intervention model description
Participants were randomized in a 1:1:1:1 ratio to four parallel groups: usual care, compression, TENS, and sequential TENS followed by compression. Randomization was stratified by prespecified age categories (\<65 and \>=65 years) and sex. Within each stratum, a computer-generated fixed-block randomization sequence with a fixed block size of four was used. Each block contained one allocation to each of the four study groups, and the order of allocations was randomly permuted within each block. The allocation sequence was prepared and maintained by an independent oncology nurse. Participants remained in their originally assigned groups throughout the study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline-Adjusted EORTC QLQ-CIPN20 Total Score Trajectory Across T1-T4 | Before Cycles 3, 4, 5, and 6 (T1-T4), corresponding to 2, 4, 6, and 8 weeks after the T0 assessment before Cycle 2; each chemotherapy cycle lasted 14 days. | The EORTC QLQ-CIPN20 is a 20-item patient-reported questionnaire assessing sensory, motor, and autonomic symptoms associated with chemotherapy-induced peripheral neuropathy. Scores are linearly transformed to a 0-100 scale, with higher scores indicating greater CIPN-related symptom burden. The primary outcome was the baseline-adjusted post-baseline trajectory of the EORTC QLQ-CIPN20 total score across T1-T4. The assessments before Cycles 3-6 (T1-T4) were modelled jointly, with the score obtained before Cycle 2 (T0) included as the baseline covariate. The overall Group-by-Time interaction constituted the primary treatment-effect test. Baseline-adjusted between-group contrasts at T4 constituted the primary endpoint pairwise comparisons. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline-Adjusted EORTC QLQ-C30 Scale Score Trajectories Across T1-T4 | Before Cycles 3, 4, 5, and 6 (T1-T4), corresponding to 2, 4, 6, and 8 weeks after the T0 assessment before Cycle 2; each chemotherapy cycle lasted 14 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. For each EORTC QLQ-C30 scale, the assessments before Cycles 3-6 (T1-T4) were modelled jointly, with the corresponding score obtained before Cycle 2 (T0) included as the baseline covariate. The Group-by-Time interaction was evaluated as a secondary treatment-period effect. |
| NCI-CTCAE v5.0 Peripheral Sensory Neuropathy Grade Across T1-T4 | Before Cycles 3, 4, 5, and 6 (T1-T4), corresponding to 2, 4, 6, and 8 weeks after the T0 assessment before Cycle 2; each chemotherapy cycle lasted 14 days. | Chemotherapy-induced peripheral sensory neuropathy severity was assessed by a medical oncologist using the clinician-rated National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI-CTCAE v5.0). Peripheral sensory neuropathy was graded from 0 to 4, with higher grades indicating greater severity and functional impairment. Because all participants were classified as Grade 2 at T0 and sparse or zero cells prevented stable repeated-measures categorical modelling, grade distributions were compared among the randomized groups separately at each post-baseline treatment-period assessment from T1 to T4. |
| DN4 Total Score Trajectory and DN4-Defined Neuropathic Pain Positivity Across T1-T4 | Before Cycles 3, 4, 5, and 6 (T1-T4), corresponding to 2, 4, 6, and 8 weeks after the T0 assessment before Cycle 2; each chemotherapy cycle lasted 14 days. | Neuropathic pain was assessed using the Douleur Neuropathique en 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 a greater number of neuropathic pain features. A score of 4 or higher was classified as DN4-defined neuropathic pain positivity. The DN4 total scores obtained before Cycles 3-6 (T1-T4) were modelled jointly, with the DN4 total score obtained before Cycle 2 (T0) included as the baseline covariate. The Group-by-Time interaction was evaluated as a continuous secondary treatment-period effect. DN4-defined neuropathic pain positivity was compared among the randomized groups separately at each T1-T4 assessment. |
Countries
Turkey (Türkiye)
Contacts
STUDY_DIRECTORŞerife KARAGÖZOĞLU, Proff.
Cumhuriyet University
Outcome results
None listed