Chemotherapy - Induced Peripheral Neuropathy (CIPN). Could There be a Role for Physical Therapy Treatment?
Phase: NA
Conditions: Breast Cancer, Peripheral Neuropathy, Secondary to Drugs or Chemicals
Sponsor: CancerCare Manitoba

June 1st, 2018 
Physical Therapy and Nerve Gliding Exercises for the Treatment of 
Chemotherapy Induced Peripheral Neuropathy 
Clinical trials number NCT02239601 
 
PROTOCOL 
METHODS 
Participants and eligibility 
 
Stage I-III patients with breast cancer that attended oncology clinics at 
CancerCare Manitoba were eligible for enrolment if they were receiving standard taxane 
chemotherapy. Two different chemotherapy regimens were included 1) docetaxel 
75mg/m2 and cyclophosphamide x 4 (TC) or 2) 5-fluorouracil, epirubicin, 
cyclophosphamide x3, followed by Docetaxel 100mg/m2 x 3 (FECD)(Jones et al., 2009; 
Roche et al., 2006; Swain et al., 2013). Participants were approached by a member of 
the team at their initial oncology visit to advise them of the physical therapy study taking 
place. If interested, patients signed a consent to contact form. Participants were 
excluded if they had co-morbid conditions causing peripheral neuropathic symptoms 
(including previous chemotherapy) or patients not scheduled for regular Taxane 
therapy. In total, 80 patients were contacted to participate between November 2014 and 
January 2017. Sixty-one participants were enrolled and 7 withdrew over the course of 
the study. Reasons for withdrawal included too ill to continue, too busy to continue, or 
re-diagnosed as stage IV. Data collection was complete by October of 2017 and 
consisted of 54 participants. Six participants had received neo-adjuvant chemotherapy 
or chemotherapy that differed from the TC or FECD regimes and were excluded from 

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analysis because these regimes substantially affected the timing for surgery, and in 
some cases, the overall dose of taxane chemotherapy. Forty-eight participants were 
then included for analysis. Figure 1. Provides a consort diagram of the enrolment 
process.  
 
Protocol 
This was a single blind (blinded assessor) randomized controlled pilot study 
testing the potential for nerve specific home exercises to improve pain and function 
post-surgery during and after chemotherapy. Random numbers were drawn to assign 
either treatment or control. Envelopes containing the assigned group were sealed and 
the blinded assessor needed only to provide the envelope to the participant after initial 
consent and assessment. Ethics approval was obtained from both the Health Research 
Ethics Board (H:2014:281) at the University of Manitoba and the Research Resource 
Impact Committee (RRIC 2014-031) at CancerCare Manitoba. 
Nerve assessments using quantitative sensory testing were administered at the 
Pain Research Laboratory (PRL), College of Rehabilitation Sciences, University of 
Manitoba. Quantitative sensory testing (QST) are a variety of non-invasive tests aimed 
at quantifying sensory perceptions commonly used in research (Boyette-Davis et al., 
2013; Hershman et al., 2011; Park et al., 2011; Walk et al., 2009). It is used for sensory 
detection and pain thresholds for both mechanical and thermal stimuli. The advantages 
of using QST are that, ‘the experimental stimulus, intensity, duration, and modality are 
controlled; the responses are quantifiable; and, can be compared over time’ (Arendt-
Nielsen & Yarnitsky, 2009).  

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Outcome Measures 
Primary Outcome Measures for Physical Therapy Intervention 
The primary outcome measures related to function and quality of life and included the 
Numeric Pain Rating Scale (NPRS), the Disability of the Arm, Shoulder and Hand 
(DASH), and the Self report version of the Leeds Assessment for Neuropathic 
Symptoms and Signs (S-LANSS).  
 
1) Numeric Pain Rating Scale (NPRS) rated CIPN pain. The NPRS is an 11 point scale 
(0-10) ranking pain from 0 indicating no pain at all to 10 indicating worst pain imaginable 
on each assessment visit of the finger tips. This was to specifically identify pain from 
CIPN. A change score of 2 is reported to be a clinically relevant change. 
2) Disability of the Arm, Shoulder and Hand (DASH) is a 30 item participant reported 
questionnaire commonly used to gauge upper limb function (attached in appendix E). 
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 
(Beaton et al., 2001; Harrington, Michener, Kendig, Miale, & George, 2014). A minimal 
clinical important difference is a change score of 15.  
3) Self report version of Leeds Assessment for Neuropathic Symptoms and Signs (S-
LANSS) is a 7 item patient reported questionnaire and was used to confirm the 
presence of neuropathic pain (Bennett, Smith, Torrance, & Potter, 2005). The score 
ranges from 0-19 with a score above 12 indicative of neuropathic pain/symptoms. S-
LANSS was chosen because of its’ specificity and accuracy in a cancer population 

June 1st, 2018 
(Hardy, Quinn, Fazekas, Agar, & Currow, 2013; Perez et al., 2015). Participants were 
requested to answer specifically for the hands, not feet (attached in appendix E). 
 
Secondary Outcome Measures for Physical Therapy Intervention 
Secondary outcomes included vibration sensation assessment as a measure of Aβ 
function, pain pressure thresholds as a measure of central sensitization, and grip 
strength as a general measure of function.  
 
1) Vibration analysis testing for perception thresholds are specific to Aβ nerve fibres. 
The TSAII Vibration Sensory Analyzer module for the Medoc was used. The pulp of the 
index finger lightly touches the sensor. The sensor delivers different vibration 
amplitudes (µm). Random, varying vibration thresholds are delivered with the participant 
responding “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 (Gutierrez-Gutierrez, Sereno, Miralles, Casado-Saenz, & 
Gutierrez-Rivas, 2010). 
2) Pressure Algometry measured pressure/pain thresholds. It is a hand-held device 
(Somedic AB, Sweden) and 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. The test stops when the 
participant presses a button, and the force (Kpa) was recorded. The left quadriceps 
muscle was tested as a measure of central sensitization.  

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3) Hand Dynamometry records grip strength in kgs and was used as a measure of 
function (3 trials). The dominant hand was tested. For our participants, all 48 in analysis 
were right handed.  
 
Outcome Measures Assessing Dual Nerve Disorder 
QST using the neurosensory analyzer (TSA II, Medoc) for thermal and vibration 
sensation quantified the differences between surgical and non-surgical side.  
 
1) Thermal detection threshold (warm and cool) and thermal pain thresholds (hot and 
cold) measured Aδ and C-fibre function. The Neurosensory Analyzer (TSA ll, Medoc, 
Israel) thermode was attached to the volar surface of the index and middle distal 
phalanx. Temperature was increased or decreased by 0.1-degree Celsius increments 
until the patient pressed a button indicating temperature detection or thermal pain. The 
patient is always in control and is never at risk for tissue damage (temperature limits are 
set to vary only from 0-50 degrees Celsius). Hands were tested bilaterally. 
 
2) Vibration analysis testing from the physical therapy data was used for Aβ nerve fibre 
function (Vibration Sensory Analyzer module, TSA II). 
 
Assessment Visits 
 
Five visits in total with the research coordinator were required over an average of 
8 months at the Pain Research Laboratory (PRL), College of Rehabilitation Sciences, 
University of Manitoba. The first visit proceeded after the initial oncology visit confirmed 

June 1st, 2018 
chemotherapy was required. This primary assessment (visit 1) consisted of completing 
the informed consent and baseline nerve evaluation including the subjective 
questionnaires and QST data. Pre-randomized envelopes were sent home with 
participants that contained which experimental group they were assigned to either 
physical therapy treatment or standard care. Participants were advised not to disclose 
their assigned group to the research coordinator in order to maintain blinding. If 
participants had questions, they were to contact the oncologist or co-investigator 
involved in the study. Standard care for the control group was to attend nerve re-
assessments at the pain research laboratory, but no exercises or appointments with a 
physical therapist were provided. Instructions only in the treatment group envelope 
directed participants to arrange 3 sessions at their convenience with the physical 
therapist prior to the start of chemotherapy.  
An estimated nerve re-assessment date for Visit 2 was scheduled for all 
participants based on their treatment cycles and start date. Visit 3 was post-
chemotherapy. Visit 4 was 3 months post-chemotherapy and Visit 5 was the final 
assessment at 6 months post-chemotherapy. After final evaluation participants could 
disclose whether they were treatment or control, and they signed a form to receive a 
$70 honorarium to cover transportation costs. Patients with residual symptoms allocated 
to the control group were then offered a physical therapy assessment and tailored home 
program.   
 
Physical Therapy treatment 

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Four visits with a certified hand physical therapist to develop a home exercise 
and education program were provided to each of the participants in the treatment group 
prior to their first round of chemotherapy. The three appointments provided upper 
extremity nerve gliding exercises that were the focus of the daily home program and 
upper extremity range of motion exercises to restore pre-operative range, if required. 
Nerve gliding exercises are frequently used exercises to improve neural excursion 
across joints, improve pain and decrease inflammation (Coppieters & Butler, 2008; Nee, 
Vicenzino, Jull, Cleland, & Coppieters, 2012; Schmid et al., 2012).  Nerve gliding 
exercises were completed several times daily and required approximately 5-10 minutes 
of time to complete. Participants were advised to complete these exercises during 
chemotherapy and after until the symptoms of neuropathy subsided.  
Education was provided on how to manage symptoms of neuropathic pain, cold 
intolerance and hyperalgesia. This included the possibility of using compression gloves, 
heated mittens, resting splints and desensitization exercises. Education was also 
provided for hypoesthesia symptoms including safety and protection. Stretching 
exercises for the neck and upper limb and axillary webbing exercises were provided if 
appropriate. All the information was contained in an education package. Only one follow 
up phone call, 6 weeks after the last treatment appointment, was provided by the 
physical therapist. The purpose of the call was to ask if they had questions about the 
exercises and encourage compliance. Therefore, both the treatment and control group 
received no active intervention during or after chemotherapy in order to avoid a possible 
treatment effect.  
Data and Statistical Analysis 

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Outcomes for the effect of the treatment and control groups were analyzed with a 
mixed models analysis, which accounts for repeated measurements, unequal time 
intervals and data missing at random. Comparisons were made during follow up. Linear 
mixed models were used to predict continuous outcomes when the assumption of 
normality was met. Quantile mixed models were used to predict ordinal outcomes or 
continuous outcomes where the assumption of normality was not met. More than half of 
the NPRS pain scores were 0 indicating ‘no pain’. Due to this floor effect the pain scale 
score was dichotomized into 0 and 1+ (no pain or pain) for analysis. Logistic mixed 
models were used for predicting binary outcomes, and the results were marginalized 
using the approach by Hedeker et al. 27 that converts the ‘subject-specific’ estimates to 
‘population-averaged’ estimates. Residual plots were used to evaluate the assumption 
of normality and to detect outliers. The assumption of linearity for continuous predictors 
was evaluated using restricted cubic splines. The predictors for all models were 
treatment variable and follow up time. Analyses were run using the R project for 
statistical computing software version 3.4.1. (R Development team, 2017) and SAS 9.4. 
Specific programs for the models included; nmle package (linear mixed), lqmm (quantile 
mixed) and NLMixed (logistic mixed).28,29