Chemotherapy Induced Peripheral Neuropathy. Could Physical Therapy Help Treat Symptoms?

Chemotherapy - Induced Peripheral Neuropathy (CIPN). Could There be a Role for Physical Therapy Treatment?

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Peripheral Neuropathy, Secondary to Drugs or Chemicals
• Intervention / Treatment: Other: Physical Therapy

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.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1M4
      • Rehabilitation Hospital, Health Sciences Centre, 800 Sherbrook St

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Exclusion Criteria:

• Patients diagnosed with stage IV breast cancer or who have co-morbid conditions that are known to cause peripheral neuropathic symptoms, including previous chemotherapy, exposure to toxins (such as lead), Diabetes, Shingles, B12 deficiency, Alcoholism, Lyme disease, Syphilis, HIV, Hereditary disorders such as Charcot-Marie Tooth.
• Patients not planned to receive Docetaxel therapy.
• Patients who cannot communicate in English and unable to bring an interpreter will also be excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Physical Therapy; 4 Physical therapy treatment sessions provided prior to chemotherapy and a home program to continue throughout the trial.	Other: 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 was provided and continued throughout chemotherapy treatment; Other Names: physiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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.
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	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
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.	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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
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.	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
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.	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

Collaborators and Investigators

• Sponsor: CancerCare Manitoba
• Collaborators: University of Manitoba
• Investigators: Study Director: Barbara L Shay, PhD, University of Manitoba; Principal Investigator: Elizabeth R Hammond, PhD, University of Manitoba

Publications and helpful links

General Publications

• Andersen Hammond E, Pitz M, Steinfeld K, Lambert P, Shay B. An Exploratory Randomized Trial of Physical Therapy for the Treatment of Chemotherapy-Induced Peripheral Neuropathy. Neurorehabil Neural Repair. 2020 Mar;34(3):235-246. doi: 10.1177/1545968319899918. Epub 2020 Jan 24.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2014
• Primary Completion (Actual): November 1, 2017
• Study Completion (Actual): November 1, 2017

Study Registration Dates

• First Submitted: September 10, 2014
• First Submitted That Met QC Criteria: September 11, 2014
• First Posted (Estimate): September 15, 2014

Study Record Updates

• Last Update Posted (Actual): October 9, 2019
• Last Update Submitted That Met QC Criteria: September 19, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Breast Cancer; Physical Therapy; Physiotherapy; Chemotherapy Induced Peripheral Neuropathy (CIPN); Nerve gliding exercises; Nerve Entrapment
• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases
• Other Study ID Numbers: H2014:281

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO