Breast Cancer, Peripheral Neuropathy, Secondary to Drugs or Chemicals
Conditions
Keywords
Physical Therapy, Physiotherapy, Breast Cancer, Chemotherapy Induced Peripheral Neuropathy (CIPN), Nerve gliding exercises, Nerve Entrapment
Brief summary
The cause of Chemotherapy-Induced Peripheral Neuropathy (CIPN) is still unknown. An estimated 55-60% of patients will experience lasting symptoms affecting function for years post-treatment. Physical therapy is an established, effective treatment for entrapped nerves and neuropathic pain. This study sought to identify additional risk factors and provide evidence for the role of physical therapy in the treatment of CIPN.
Detailed description
A common side effect is chemotherapy induced peripheral neuropathy (CIPN). CIPN is a small fibre sensory neuropathy that develops in the hands/feet and worsens with increasing dose and duration of treatment. It impacts the Aβ, Aδ, and C-Fiber function involved in light touch and vibration sense, thermal detection and thermal pain. This results in a variety of positive and/or negative sensory symptoms including hypoesthesia, dysesthesias, hyperalgesia, allodynia and neuropathic pain. Quantitative sensory testing (QST) are a variety of non-invasive tests aimed at quantifying sensory perceptions used in research to clinically assess neuropathy. It is used for sensory detection and pain thresholds for both mechanical and thermal stimuli. QST provides information on large myelinated (Aβ), small thinly myelinated (Aδ) and unmyelinated (C-fiber) function or dysfunction. Deep pressure threshold measured by a pressure algometry stimulates intramuscular afferents, and can be used as a measure of central sensitization when used at a distant site from the site of pain. Aδ fibres transmit cool detection threshold, while warm detection threshold is transmitted by C-fibers. Both noxious heat and noxious cold transmit via C-fiber and Aδ fibers. An increased sensitivity to thermal pain thresholds, results in thermal hyperalgesia. Physical therapy treatment for nerve disorders is well established in orthopedics and plastic surgery for entrapment neuropathies, neuropathic pain, post-operative nerve repair and regeneration. Nerve gliding exercises are frequently used exercises in physical therapy to improve neural excursion across joints, improve pain and decrease inflammation. Patient reported symptoms (patient questionnaires NPRS, S-LANSS and DASH) and quantitative sensory testing (QST) specifically pain pressure thresholds and vibration were used for the primary purpose in evaluating the role for an upper extremity nerve mobilization physical therapy home program during chemotherapy for the prevention and management of CIPN. Primary Outcome Measures was the NPRS and reported as those having no vs no pain. Grip strength, Vibration, DASH and S-LANSS were identified outcome measures prior to the trial that would best describe sensory impairment and function for the physical therapy question Additional QST measures collected included warm/cool, Hot/Cold Pain thresholds that were used with the vibration data to compare quantitative data on the right and left side to evaluate possible a possible dual nerve disorder when combined with surgery as well as identifying different sensory profiles of QST data between those reporting neuropathic pain and non-neuropathic pain using the S-LANSS A sub analysis of data was completed dividing participants that remained active throughout compared to less active participants to evaluate the effect of exercise on sensory preservation. This was not an intended analysis at the beginning of the trial and these participants were not randomized.
Interventions
OTHERPhysical Therapy
Physical therapy assessment and treatment for any positive signs of nerve entrapment prior to chemotherapy including nerve gliding exercises, education and splinting. A home program was provided and continued throughout chemotherapy treatment
Sponsors
University of Manitoba
CancerCare Manitoba
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients diagnosed with stage I-III breast cancer undergoing regular docetaxel treatment either docetaxel-cyclophosphamide (TC) or 5FU-epirubicin-cyclophosphamide-docetaxel (FEC-D). * Patients that have not had chemotherapy in the past and do not have identified risk factors (listed below in the
Exclusion criteria
). * All patients must be able to communicate in english or be able to have a translator present at all appointments.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With 'Pain' or 'no Pain' as Measured by the Numeric Pain Rating Scale | Regression models of pain reported over time (mid-docetaxel chemotherapy- 6 months post-chemotherapy). Mid-chemotherapy time frame participants were re-assessed after the 2 round of TC and 4th round of FECD. | Numeric Pain Rating Scale - pain rating scale 0-10 (0= no pain to 10= most pain imaginable). Reported as percentages of participants with pain (1-10) vs no pain (0) |
| Disability of the Arm, Shoulder and Hand (DASH) | administered on each re-assessment (pre-chemotherapy, mid-way through docetaxel chemotherapy, end of chemotherapy, 6 months post-chemotherapy) and mixed models accounted for all time points | A 30 item participant reported questionnaire commonly used to gauge upper limb function. Each item is scored 1-5 with 1 being 'no difficulty' and 5 being 'unable'. Overall score calculated as: \[average response (sum of responses divided by number of responses) -1\] x 25 to give a score out of 100. Minimum score is 30 with a maximum score of 150. The DASH was chosen because of high test-retest reliability and the responsiveness and construct validity in patients with breast cancer over other quality of life measures. A minimal clinical important difference is a change score of 15. Higher score indicates more impairment to the upper limb |
| Percentage of Participants With Neuropathic Pain Defined by the Self Report Version of Leeds Assessment for Neuropathic Symptoms and Signs (S-LANSS). | administered on each re-assessment (Visit 1 - pre-chemotherapy, Visit 2 - half-way through chemotherapy, Visit 3 - end of chemotherapy, Visit 4 - 3 months post-chemotherapy) and mixed models accounted for all time points | a 7 item patient reported questionnaire and was used to confirm the presence of neuropathic pain. The score ranges from 0-19 (no symptoms=0, sever symptoms=19) with a score above 12 indicative of neuropathic pain/symptoms. S-LANSS was chosen because of its' specificity and accuracy in a cancer population. Participants were requested to answer specifically for the hands, not feet. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Vibration Sensory Analysis | administered on each re-assessment (Visit 1 - pre-chemotherapy, Visit 2 - half-way through chemotherapy, Visit 3 - end of chemotherapy, Visit 4 - 6 months post-chemotherapy) and mixed models accounted for all time points | Vibration analysis testing for perception thresholds are specific to Aβ nerve fibres. The TSAII Vibration Sensory Analyzer (VSA): Medoc, Israel, was used. The pulp of the index finger lightly touches the sensor that delivers random and varying vibration amplitudes (µm). The participant responds yes/no to sensing the vibration. Vibration perception was selected for its sensitivity and has been suggested to be the first clinical sign of CIPN symptoms and was tested bilaterally. Low score indicates better perception while a higher score is poorer sensation. Perception score reported in micrometers (up to 4cm) |
| Pain Pressure Thresholds | administered on each re-assessment (Visit 1 - pre-chemotherapy, Visit 2 - half-way through chemotherapy, Visit 3 - end of chemotherapy, Visit 4 - 6 months post-chemotherapy) and mixed models accounted for all time points | Pressure Algometry (Somedic AB, Sweden) measured pressure/pain thresholds. A hand-held device applied perpendicular to the muscles being tested. Increasing pressure is applied until the participant determines that the sensation has changed from a feeling of pressure to a feeling of pain and force (Kpa) is recorded. When tested at a distant site from the source of pain this test measures central sensitization. Lower pressure values (more sensitive to noxious stimuli) suggest impaired central pain and/or diminished descending inhibition pathway. The left quadriceps muscle was tested as a measure of central sensitization. |
| Grip Strength | administered on each re-assessment (Visit 1 - pre-chemotherapy, Visit 2 - half-way through chemotherapy, Visit 3 - end of chemotherapy, Visit 4 - 6 months post-chemotherapy) and mixed models accounted for all time points | Hand Dynamometry records grip strength in kgs and was used as a measure of function (3 trials). The dominant hand was tested using the Jamar dynamometer (Patterson medical, USA) in the 2nd handle position. All 48 participants were right handed. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Physical Therapy 4 Physical therapy treatment sessions provided prior to chemotherapy and a home program to continue throughout the trial.
Physical Therapy: Physical therapy assessment and treatment for any positive signs of nerve entrapment prior to chemotherapy including nerve gliding exercises, education and splinting. A home program will be provided to continue throughout chemotherapy treatment | 22 |
| Control treatment per usual | 26 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 4 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 4 |
Baseline characteristics
| Characteristic | Physical Therapy | Control | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants | 25 Participants | 46 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 22 Participants | 26 Participants | 48 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Disability of the Arm, Shoulder and Hand (DASH)
A 30 item participant reported questionnaire commonly used to gauge upper limb function. Each item is scored 1-5 with 1 being 'no difficulty' and 5 being 'unable'. Overall score calculated as: \[average response (sum of responses divided by number of responses) -1\] x 25 to give a score out of 100. Minimum score is 30 with a maximum score of 150. The DASH was chosen because of high test-retest reliability and the responsiveness and construct validity in patients with breast cancer over other quality of life measures. A minimal clinical important difference is a change score of 15. Higher score indicates more impairment to the upper limb
Time frame: administered on each re-assessment (pre-chemotherapy, mid-way through docetaxel chemotherapy, end of chemotherapy, 6 months post-chemotherapy) and mixed models accounted for all time points
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Physical Therapy | Disability of the Arm, Shoulder and Hand (DASH) | 34 units on a scale |
| Control | Disability of the Arm, Shoulder and Hand (DASH) | 42 units on a scale |
Primary
Percentage of Participants With Neuropathic Pain Defined by the Self Report Version of Leeds Assessment for Neuropathic Symptoms and Signs (S-LANSS).
a 7 item patient reported questionnaire and was used to confirm the presence of neuropathic pain. The score ranges from 0-19 (no symptoms=0, sever symptoms=19) with a score above 12 indicative of neuropathic pain/symptoms. S-LANSS was chosen because of its' specificity and accuracy in a cancer population. Participants were requested to answer specifically for the hands, not feet.
Time frame: administered on each re-assessment (Visit 1 - pre-chemotherapy, Visit 2 - half-way through chemotherapy, Visit 3 - end of chemotherapy, Visit 4 - 3 months post-chemotherapy) and mixed models accounted for all time points
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Physical Therapy | Percentage of Participants With Neuropathic Pain Defined by the Self Report Version of Leeds Assessment for Neuropathic Symptoms and Signs (S-LANSS). | Percentage of patients with non-neuropathic visits | 83.9 percentage of patients |
| Physical Therapy | Percentage of Participants With Neuropathic Pain Defined by the Self Report Version of Leeds Assessment for Neuropathic Symptoms and Signs (S-LANSS). | Percentage of Patients with Neuropathic visits | 16.1 percentage of patients |
| Control | Percentage of Participants With Neuropathic Pain Defined by the Self Report Version of Leeds Assessment for Neuropathic Symptoms and Signs (S-LANSS). | Percentage of patients with non-neuropathic visits | 74 percentage of patients |
| Control | Percentage of Participants With Neuropathic Pain Defined by the Self Report Version of Leeds Assessment for Neuropathic Symptoms and Signs (S-LANSS). | Percentage of Patients with Neuropathic visits | 26 percentage of patients |
Primary
Percentage of Participants With 'Pain' or 'no Pain' as Measured by the Numeric Pain Rating Scale
Numeric Pain Rating Scale - pain rating scale 0-10 (0= no pain to 10= most pain imaginable). Reported as percentages of participants with pain (1-10) vs no pain (0)
Time frame: Regression models of pain reported over time (mid-docetaxel chemotherapy- 6 months post-chemotherapy). Mid-chemotherapy time frame participants were re-assessed after the 2 round of TC and 4th round of FECD.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Physical Therapy | Percentage of Participants With 'Pain' or 'no Pain' as Measured by the Numeric Pain Rating Scale | Percentage of Participants with Pain (1-10) | 30 percentage of participants |
| Physical Therapy | Percentage of Participants With 'Pain' or 'no Pain' as Measured by the Numeric Pain Rating Scale | Percentage of Participants with no pain (0) | 70 percentage of participants |
| Control | Percentage of Participants With 'Pain' or 'no Pain' as Measured by the Numeric Pain Rating Scale | Percentage of Participants with Pain (1-10) | 49 percentage of participants |
| Control | Percentage of Participants With 'Pain' or 'no Pain' as Measured by the Numeric Pain Rating Scale | Percentage of Participants with no pain (0) | 51 percentage of participants |
p-value: 0.05395% CI: [0.17, 1.01]Mixed Models Analysis
Secondary
Grip Strength
Hand Dynamometry records grip strength in kgs and was used as a measure of function (3 trials). The dominant hand was tested using the Jamar dynamometer (Patterson medical, USA) in the 2nd handle position. All 48 participants were right handed.
Time frame: administered on each re-assessment (Visit 1 - pre-chemotherapy, Visit 2 - half-way through chemotherapy, Visit 3 - end of chemotherapy, Visit 4 - 6 months post-chemotherapy) and mixed models accounted for all time points
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Physical Therapy | Grip Strength | 27.2 kgs | Standard Deviation 5.53 |
| Control | Grip Strength | 21.8 kgs | Standard Deviation 4.26 |
Secondary
Pain Pressure Thresholds
Pressure Algometry (Somedic AB, Sweden) measured pressure/pain thresholds. A hand-held device applied perpendicular to the muscles being tested. Increasing pressure is applied until the participant determines that the sensation has changed from a feeling of pressure to a feeling of pain and force (Kpa) is recorded. When tested at a distant site from the source of pain this test measures central sensitization. Lower pressure values (more sensitive to noxious stimuli) suggest impaired central pain and/or diminished descending inhibition pathway. The left quadriceps muscle was tested as a measure of central sensitization.
Time frame: administered on each re-assessment (Visit 1 - pre-chemotherapy, Visit 2 - half-way through chemotherapy, Visit 3 - end of chemotherapy, Visit 4 - 6 months post-chemotherapy) and mixed models accounted for all time points
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Physical Therapy | Pain Pressure Thresholds | 923 kpa | Standard Deviation 383 |
| Control | Pain Pressure Thresholds | 744 kpa | Standard Deviation 285 |
Secondary
Vibration Sensory Analysis
Vibration analysis testing for perception thresholds are specific to Aβ nerve fibres. The TSAII Vibration Sensory Analyzer (VSA): Medoc, Israel, was used. The pulp of the index finger lightly touches the sensor that delivers random and varying vibration amplitudes (µm). The participant responds yes/no to sensing the vibration. Vibration perception was selected for its sensitivity and has been suggested to be the first clinical sign of CIPN symptoms and was tested bilaterally. Low score indicates better perception while a higher score is poorer sensation. Perception score reported in micrometers (up to 4cm)
Time frame: administered on each re-assessment (Visit 1 - pre-chemotherapy, Visit 2 - half-way through chemotherapy, Visit 3 - end of chemotherapy, Visit 4 - 6 months post-chemotherapy) and mixed models accounted for all time points
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Physical Therapy | Vibration Sensory Analysis | Left Hand | 0.23 micrometers (µm) |
| Physical Therapy | Vibration Sensory Analysis | Right Hand | 0.23 micrometers (µm) |
| Control | Vibration Sensory Analysis | Right Hand | 0.23 micrometers (µm) |
| Control | Vibration Sensory Analysis | Left Hand | 0.14 micrometers (µm) |
Post Hoc
Vibration Sensory Outcome Stratified by Patient Activity Level
Measuring Activity Participants were asked about their level of exercise per week at each assessment visit. Participants were considered active if they reported engaging in any form of moderate activity at least 4 times a week (consistent with recommended physical activity guidelines beyond activities of daily living such as walking to the bus or walking the dog around the block) at least 4 times per week on at least 3 out of 4 reassessment visits. Types of reported activities included cycling, running, yoga, swimming, Zumba, dance classes, and tennis. Walking was included if it was at least 30 minutes at a moderate pace. This sub-analysis re-defined the groups as 'active' and 'less active' for the comparison of vibration QST data. This was done to observe the possible impact of exercise on sensory preservation
Time frame: administered on each re-assessment (Visit 1 - pre-chemotherapy, Visit 2 - half-way through chemotherapy, Visit 3 - end of chemotherapy, Visit 4 - 6 months post-chemotherapy) and mixed models accounted for all time points
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Physical Therapy | Vibration Sensory Outcome Stratified by Patient Activity Level | Vibration Left Hand | 0.08 micrometers (µm) |
| Physical Therapy | Vibration Sensory Outcome Stratified by Patient Activity Level | Vibration Right Hand | 0.14 micrometers (µm) |
| Control | Vibration Sensory Outcome Stratified by Patient Activity Level | Vibration Left Hand | 0.23 micrometers (µm) |
| Control | Vibration Sensory Outcome Stratified by Patient Activity Level | Vibration Right Hand | 0.24 micrometers (µm) |