The Effectiveness of a Modern Educational Intervention for Pain-related Disability After Breast Cancer Surgery: Randomized Controlled Trial
Phase: NA
Conditions: Breast Neoplasm, Pain
Sponsor: Universitaire Ziekenhuizen KU Leuven

 
1
EduCan Trial: Study protocol for a randomized controlled trial on the 
effectiveness of Pain Neuroscience Education after breast cancer surgery on 
pain-, physical-, emotional- and work-related functioning  
 
Trial Registration: ClinicalTrials.gov Identifier: NCT03351075 
Ethical Committee of the University Hospitals Leuven: s60702 
 
Document date: august 2024 
 

 
2
INTRODUCTION 
 
Breast cancer is the most frequent malignancy among women worldwide.(1) Despite the high 
incidence, in Western countries an increase in survival and life expectancy has been observed 
due to the ongoing improvement of detection method accuracy, early diagnosis, and breast 
cancer treatment.(1) Consequently, more attention is warranted towards the debilitating 
problems accompanying this disease and its treatment, which can persist for months or even 
years after diagnosis. In addition to fatigue, pain is the most frequent and persistent symptom 
following cancer and cancer treatment. Between 27 and 79% of women report pain one 
month after surgery, which is often attributed to local pain mechanisms caused by a post-
surgery and/or radiotherapy tissue insult at that time-point. (2-5) One would expect 
prevalence rate to diminish as healing occurs, yet this does not seem to be the case. In fact, 
12-82% of women still report persistent pain one year or later.(4) This may indicate that 
besides local nociceptive and neuropathic pain mechanisms, a third pain mechanism 
characterized by altered nociceptive processing without clear evidence of persistent tissue 
damage causing the activation of peripheral nociceptors (i.e. nociceptive pain) or evidence 
for disease or lesion of the somatosensory system causing the pain (i.e. neuropathic pain). 
(17-19) Moreover, pain interferes with pain-, physical-, emotional- and work-related disability 
and therefore severely prejudices a person’s quality of life (QOL) and participation in 
society.(6-8) Hence, adequate pain management in the early stage of breast cancer treatment 
is necessary to prevent and improve pain and pain-related disability, both at short- and long-
term.  
 
Despite the effectiveness of currently applied physical therapy modalities after breast cancer 
surgery (such as manual techniques, specific exercises and general exercises), up to 72% of 
women still experience pain and the resulting disabilities after finishing breast cancer 
treatment.(9) Over the past decades, awareness on the important role of educational 
interventions in the management of cancer pain has increased.(10-12) These general 
educational interventions have been shown to be effective for improving pain severity, self-
efficacy and knowledge and attitude to pain and analgesia in cancer patients. However, effect 
sizes are only moderate and of limited clinical relevance.(10) This can be explained by the fact 
that these educational interventions mainly focus on tissue and tissue injury as the source of 

 
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pain and are often restricted to biomedical pain management instructions and general advice 
on physical activity and analgesics.(10-12) They focus on explaining treatment side-effects 
and improving patients’ coping strategies. Recently, increased knowledge on pain 
mechanisms has led to a more modern educational approach, also known as Pain 
Neuroscience Education (PNE).(13-16) This explains the neurophysiology of chronic pain and 
the ability of the nervous system to modulate pain experience, as well as the potential 
influences of sleep, thoughts, feelings and culture, among others, on pain. Thereby, it targets 
a reconceptualization from a biomedical or structural model to an actual biopsychosocial 
model of pain. Through the knowledge that pain is often an unreliable indicator of the 
presence or extent of tissue damage and if patients may become open to exploring broader 
contributions to pain, pain-related behavior might change by shifting from passive therapy-
receiving to active self-management. Increased knowledge of the broad contributions to pain 
(4), as well as awareness of different pain mechanisms following breast cancer treatment (17-
19) provides justification for the integration of PNE in this population. Applying PNE could 
enhance the effectiveness of the currently applied physical therapy modalities for prevention 
and treatment of pain and related disabilities after breast cancer treatment, compared to a 
traditional biomedical educational intervention. Indeed, encouraging people to address 
emotional, cognitive and broader health-related factors in the early stage of cancer treatment 
may enhance recovery during and after the treatment. To our knowledge, only one controlled 
trial investigated the effectiveness of PNE in the early stage of breast cancer treatment.(20) 
Although the results were very promising for shoulder function, only short-term effects were 
examined, no randomization was performed and no pain-related or other health-related 
outcomes were evaluated.  
 
Objectives 
The main scientific objective is to examine the effectiveness of PNE, in addition to a standard 
best evidence physical therapy program, on pain-, physical-, emotional-, and work-related 
functioning in the early stage of breast cancer treatment, compared to a traditional 
biomedical educational intervention, up to 1.5 years after surgery (EduCan Trial). This will be 
performed through a double-blinded randomized controlled trial. 
 
 

 
4
METHODS AND ANALYSIS 
Described according to the SPIRIT guidelines (http://www.spirit-statement.org/protocol-
version/). 
 
Trial design and study setting 
A parallel, two-arm randomized controlled trial with blinding of assessors and physical 
therapists providing the standard physical therapy program in both arms and masking of the 
participants. The trial started in November 2017 at the department of Physical Medicine and 
Rehabilitation of the University Hospitals in Leuven (Belgium). A schedule of the EduCan Trial 
is provided in Table 1. 
 
 

 
5
 
Table 1. Schedule of enrolment, interventions, and assessments of the EduCan Trial 
 
 
STUDY PERIOD 
 
Enrolment 
Allocati
on 
Post-allocation 
TIMEPOINT 
-t2 
preop 
consult 
-t1 
postop  
consult 
0 
t1 
4 Mo 
 
t2 
6 Mo 
 
t3 
8 Mo 
 
t4 
12 Mo 
 
t5 
18 Mo 
 
ENROLMENT 
Eligibility screen 
X 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
Allocation 
 
 
X 
 
 
 
 
 
INTERVENTIONS 
 
Intensive 
phase 
Maintenance phase 
 
Standard PT program (All) 
 
n=184 
 
1-2 
sessions
/week 
1 
session 
1 
session 
1 
session 
Pain Neuroscience 
Education (IG)  
 
n=92 
 
3 
sessions 
1 
session 
1 
session 
1 
session 
Biomedical Education (CG) 
 
n=92 
 
3 
sessions 
1 
session 
1 
session 
1 
session 
ASSESSMENTS 
Pain-related functioning 
(primary outcome)* 
X 
X 
 
X 
X 
X 
X 
X 
Pain-related outcomes* 
X 
X 
 
X 
X 
X 
X 
X 
Emotional functioning 
X 
X 
 
X 
X 
X 
X 
X 
Physical functioning* 
 
X 
 
X 
 
 
X 
X 
Work-related functioning* 
 
 
 
X 
X 
X 
X 
X 
*see Table 2 for details on the content of the different assessments at each point in time 
Mo = Months; IG=Intervention Group; CG=Control Group 
 
 
 
 
 

 
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Patient and public involvement in trial design 
One female breast cancer patient and a representative of the National Health Service were 
consulted during the initial grant preparation and trial set up. The patient representative 
provided valuable insight into the worries and concerns experienced during cancer treatment. 
The representative of the National Health service contributed to the design of the study and 
advised on assessment of work-related functioning outcomes.  
 
Eligibility criteria 
Women are eligible to participate in the EduCan Trial if they are scheduled for surgery for 
breast cancer at the Multidisciplinary Breast Center of the University Hospitals of Leuven. 
Patients with increased risk of developing pain after breast cancer surgery are included.(21-
23) Therefore, inclusion criteria are: 1) diagnosed with histologically confirmed invasive or 
non-invasive primary breast cancer, 2) scheduled for surgical excision including either axillary 
lymph node dissection and mastectomy (whether or not in combination with reconstructive 
surgery) or breast-conserving; or either sentinel node biopsy and mastectomy (whether or 
not in combination with reconstructive surgery); 3) aged 18 years or older; 4) can comply with 
the study protocol. Patients with active metastasis are excluded because of the higher risk of 
mortality.  
 
Participant screening, recruitment and consent. 
Participants are identified from scheduled operation lists and screened for eligibility criteria. 
The initial screening process is undertaken by a member of the research team. Potentially 
eligible participants are approached and recruited during the preoperative consult at the 
Multidisciplinary Breast Center of the University Hospitals of Leuven. All eligible patients 
receive an information sheet and the explanation of the study during the preoperative 
consult. Next, they are asked to have a preoperative baseline measurement for which a 
separate informed consent exists. Because of ethical and deontological reason patients will 
not be forced to decide on participation in the complete EduCan Trial at this moment, but 
initially only for the baseline measurements.  
During their postoperative hospital stay, a member of the research team will meet the eligible 
participants again, answer further questions and include them in the further trial if wanted. 

 
7
Then, a second informed consent is signed for participating in the complete EduCan Trial. The 
preoperative baseline measurement of non-participating patients will be stored in the 
medical file of the patient and can be consulted on clinical follow-up appointments to 
evaluate the recovery of the patient but is not used for research purpose. The participants’ 
flow is summarized in Figure 1. 
 
 
 

 
8
Figure 1: Flow diagram of the EduCan Trial 
 
*A separate informed consent is available for the preoperative assessment 
Mo=Months 
 
Allocation and randomization 
Therapists and assessors are blinded to the allocation of the treatment groups. The therapists 
providing the standard physical therapy program will be unaware of the type of education 
received by the patient (PNE in the intervention group and biomedically-focused education 
in the control group). Assessors are blinded to the maximal extent possible. With regard to 
this, patients are asked not to communicate with the assessors about the intervention 
Screening and Recruitment 
Eligible breast cancer patients are identified from operation lists at the Multidisciplinary Breast Center of 
the University Hospitals Leuven (Belgium).  
Informed Consent 
Eligible breast cancer patients willing to participate in the EduCan Trial sign the informed consent 
Informed consent and preoperative assessment* 
Postoperative assessment 
Randomization (n=184) 
Standard physical therapy program 
> intensive phase  
(1-4 Mo: 1-2 sessions/week – 30’) 
> maintenance phase  
(5-12 Mo: sessions at 6, 8 and 12 Mo – 30’)  
 
+ Pain Neuroscience Education 
> intensive phase (1 Mo: 3 sessions – 30’) 
> maintenance phase (5-12 Mo: sessions at 6, 
8 and 12 Mo - 30’)  
 
Standard physical therapy program 
> intensive phase  
(1-4 Mo: 1-2 sessions/week – 30’) 
> maintenance phase  
(5-12 Mo: 3 sessions at 6, 8 and 12 Mo – 30’) 
 
+ Traditional biomedical education 
> intensive phase (1 Mo: 3 sessions – 30’) 
> maintenance phase (5-12 Mo: 3 session at 
6, 8 and 12 Mo – 30’) 
Surgery for treatment of breast cancer 
Follow-up assessments at 4, 6, 8, 12 and 18 
months post-surgery 
Follow-up assessments at 4, 6, 8, 12 and 18 
months post-surgery 

 
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received. Patients are masked for the allocation to the intervention/control group; they do 
not know which one is the experimental intervention and which one is the control 
intervention, however they will of course be aware of the intervention received.  
At the end of the trial, the success of assessor blinding will be examined by asking whether 
the assessor thought the participant had received the experimental or control intervention, 
including the percentage of certainty (i.e. 50% certainty means a pure guess). The same will 
be done for patient masking. The research members performing statistical analysis will be 
blinded as well. 
The randomization is computer-generated and is performed by using permuted blocks 
(size=4). An independent co-worker at the department carries out the randomization to 
ensure blinding of the research team. The sequence of randomization is determined by the 
patient’s identification number, which she receives after signing informed consent. 
Participants are randomized in a 1:1 ratio between intervention and control arms. 
 
Interventions 
Standard physical therapy program 
All participants in the EduCan Trial attend a standard physical therapy program. The standard 
physical therapy program is based on currently available evidence and clinical experience of 
the research team and will include three physical therapy modalities. First, manual 
techniques including (a) passive mobilizations to restore shoulder range of motion, (b) 
stretching of the pectoral muscles to improve muscle flexibility and (c) scar tissue massage to 
improve flexibility of the scar(s) will be implemented.(9, 24, 25) Second, specific exercises to 
improve shoulder range of motion and upper limb strength have been proven to be effective 
for treatment of upper limb problems after breast cancer and will start immediately after 
surgery as well.(9, 26) Specific exercises are instructed during the individual session and 
continued at home. Third, patients are advised on general exercises. General exercises should 
be implemented to increase patient’s physical activity level. In general, these 
recommendations consist of physical activity at a minimum level of moderate intensity over 
an extended period and can include e.g. running, walking, cycling, swimming, etc.(27, 28)  
 
During month 1-4 an intensive physical therapy program is implemented because of the 
postoperative side-effects. Patients will attend 1-2 individual sessions of 30 minutes per week 

 
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during the intensive phase, starting one week post-surgery. All patients start with a frequency 
of two sessions per week, decreasing to once each two weeks. The decrease in frequency of 
the sessions is pragmatically chosen based on the individual progression and need of the 
patient.  
Up to one year after surgery a maintenance physical therapy program is implemented to 
follow-up on the exercises performed at home and to treat possible additional/ new side-
effects of other adjuvant treatment modalities such as radiotherapy, chemotherapy and 
hormone therapy. An individual maintenance session of 30 minutes is scheduled 6, 8 and 12 
months post-surgery. 
 
Additionally, information about prevention of lymphedema is given by a specialized physical 
therapist: about normal use of the upper limb, avoiding pinching off the arm, skin care and 
control of body weight.(29) One group information sessions of 60 minutes on this topic is 
organised each month which should be attended once by every participant (both patients 
from the intervention and control group together) and this as soon as possible after surgery. 
Patients also receive a brochure with this information. If patients develop lymphedema they 
are additionally referred to the Lymfovenous Center of the University Hospitals of Leuven for 
further treatment of the lymphedema. 
 
Educational intervention 
The educational sessions are individual and last for 30 minutes. The first PNE session is given 
within the first postoperative week before the start of the standard physical therapy program 
to prepare the patient for the physical therapy sessions. Information is presented verbally 
(explanation by the therapist) and in multi-media forms (power point presentation with 
summaries, pictures, metaphors and diagrams on computer). After the first session, patients 
also receive an information leaflet on paper and are asked to read it carefully at home. They 
also receive a web-link to an online presentation that summarizes the provided information. 
Additional written information that can be read afterwards is a valuable and essential part of 
the educational intervention. In the following 4 weeks after surgery, 2 additional PNE sessions 
are provided to ensure that the patient understands the pain physiology and principles of 
activity management and can relate this to the physical therapy program and his/her pain 
complaint. However, education is a continuous process initiated at the start and continuing 

 
11
into and followed-up during the longer-term rehabilitation program. Therefore, three 
additional booster sessions are organized at 6, 8 and 12 months post-surgery. During the 
booster sessions, the information given postoperatively will be rehearsed and application of 
the information into future stages of the recovery process will be discussed. Special attention 
is given to return to preoperative activities and return to work (if applicable). Regarding this, 
a second information leaflet on paper will be given to the patient. Patients in the control arm 
and intervention arm will have the same schedule of educational sessions, only the content 
of the education differs from the intervention arm. 
 
Intervention arm: Pain Neuroscience Education (PNE) 
Based on the available literature a modern PNE program has been established to explain pain 
specifically for this population.(10, 12, 20) The content and pictures of the educational 
sessions are based on the book ‘Explain Pain’ (Butler & Moseley, 2003), ‘Pijneducatie een 
praktische handleiding voor (para)medici’ (Van Wilgen & Nijs, 2011) and the ‘The Pain Toolkit’ 
(Peter Moore, 2002), as used in earlier studies.(30, 31) Topics addressed during the PNE 
sessions will include: the characteristics of acute versus chronic pain; specific side effects of 
the different breast cancer treatment modalities in relation to pain; how pain is a product of 
the brain; how pain becomes chronic (plasticity of the nervous system, modulation, 
modification, central sensitization); potential sustaining factors of pain such as emotions, 
stress, pain cognitions, and pain behavior.  
Additionally, this PNE intervention includes advice for activity management, while 
experiencing pain and other symptoms. In addition to the general recommendations for 
general exercise and advice to stay active in the standard physical therapy program, the PNE 
guides patients in performing general exercises and activities according to the graded activity 
principle. Graded activity is applied according to the guidelines reported by the International 
Association for the Study of Pain (IASP).(32) This includes general exercise activities according 
to pacing strategies for ‘persisters’ (i.e. restructuring the activity pattern to avoid peaks of 
over activity and exacerbations of their pain) and graded activity for ‘avoiders’ (i.e. time-
contingent increase of physical activity). PNE is crucial here to help patients interpret pain 
during exercise in the correct context. Finally, advice on returning to work in the context of 
present pain complaints and how to apply the principles described above for activity 
management can be applied in the working situation will be provided. 

 
12
 
Control arm: Traditional biomedical education 
Traditional biomedical educational interventions consist of explaining patient’s pain 
experience in relation to the therapeutic procedures from a tissue and biomechanical 
perspective.(33, 34) Information on the different side effects of surgery, radiotherapy, 
chemotherapy, hormone therapy and target therapy is given. The role of different structures 
and injured versus healthy tissue in acute and persistent pain is discussed. Pain is explained 
from a biomechanical point of view, e.g. deviance from normal expected movement patterns 
and postures. Additionally, during the educational sessions and rehabilitation program, 
patients receive advice on activity management. This advice is to stay active as minimally 
possible during treatment and increase their physical activity level according to current 
recommendations for general exercises after treatment. Based on the American Cancer 
Society Guidelines on Physical Activity at least 150 minutes of moderate intensity (heart rate 
50 to 70% of the maximum heart rate or a score of 12-14 on Borg Rating of Perceived Exertion 
(RPE)) or 75 minutes of vigorous intensity activity (70 to 85% of the maximum heart rate or 
RPE of > 15) each week (or a combination of these), preferably spread throughout the week 
is recommended. Finally, advice on returning to work in the context of the different 
(persistent) side-effects of the treatments will be provided. 
 
Outcomes 
The outcome measures were chosen in accordance with the guideline for core outcome 
domains to be used in clinical trials on multimodal treatment approaches for pain as 
advocated by an international steering committee (VAPAIN recommendations)(35) and the 
IMMPACT recommendations for the outcome measures in pain clinical trials.(36) 
The primary outcome is pain-related functioning at 12 months measured using the Pain 
Disability Index (PDI). Secondary outcomes are other pain symptoms and characteristics, 
physical functioning, emotional functioning and work-related functioning. Assessments are 
performed within one week preoperatively, within one week postoperatively and then at 4 
months, 6, 8, 12 and 18 months after surgery. However, because of feasibility limitations not 
all outcome parameters are assessed at each assessment time point. Table 1 and 2 present 
the study outcome measures by assessment time point. In table 3 the outcome measures are 
described in more detail. 

 
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Table 2. Study outcome measures by assessment time point 
Domain 
Scale/measure 
T-2  
1W 
preop 
T-1  
1W 
postop 
T1  
4 Mo 
T2  
6 Mo 
T3 
8 Mo 
T4 
12 
Mo 
T5 
18 
Mo 
Pain-related 
functioning 
(primary 
outcome) 
Pain Disability Index 
x 
x 
x 
x 
x 
x 
x 
Pain 
symptoms 
and 
characteristics 
Pain intensity (VAS) 
x 
x 
x 
x 
x 
x 
x 
Brief Pain Inventory (BPI) 
x 
x 
x 
x 
x 
x 
x 
Neuropathic Pain 
Questionnaire (DN4) 
x 
x 
x 
x 
x 
x 
x 
Central Sensitisation 
Questionnaire (CSI) 
x 
x 
x 
x 
x 
x 
x 
 
Pain sensitivity testing 
x 
x 
x 
x 
x 
x 
x 
Physical 
functioning 
General physical activity level 
(accelerometry) 
 
x 
x 
 
 
x 
x 
Upper limb performance 
(accelerometry) 
 
x 
x 
 
 
x 
x 
Upper limb function (DASH) 
x 
x 
x 
x 
x 
x 
x 
Emotional 
functioning 
Pain Catastrophizing Scale 
(PCS) 
x 
x 
x 
x 
x 
x 
x 
Depression, Anxiety and Stress 
Scale (DASS-21) 
x 
x 
x 
x 
x 
x 
x 
Health-related quality of life 
(McGill Quality of life 
questionnaire) 
x 
x 
x 
x 
x 
x 
x 
Social 
functioning 
Return to work rate 
 
 
x 
x 
x 
x 
x 
QuickScan 
 
 
x 
x 
x 
x 
x 
Return-to-work self-efficacy 
(RTWSE-19) 
 
 
x 
x 
x 
x 
x 
 
 
 
 

 
14
 
Table 3. Outcome measures of the EduCan Trial 
 
Outcome 
Assessment method 
PAIN-RELATED FUNCTIONING (primary outcome) 
Pain-related functioning 
Pain Disability Index (PDI). The PDI is a short, self-reported 
questionnaire for measuring the degree of interference of pain with 
normal role functioning (family/home responsibilities, recreation, 
social activity, occupation, sexual behavior, self-care, and life-
support activity).(37, 38)  
PAIN SYMPTOMS AND CHARACTERISTICS 
Pain intensity 
Visual Analogue Scale (VAS). Present pain intensity and mean pain 
intensity during the past week for pain at the upper limb region (i.e. 
shoulder-neck region, arm, axilla, trunk side and breast region) 
Brief Pain Inventory 
Medication use, pain quality, pain location, pain severity and 
response to treatment.(39) 
Presence of neuropathic pain 
Douleur Neuropathique en 4 questions (DN4). The DN4 a 
questionnaire generating reliable and valid data for identifying pain 
of predominantly neuropathic origin.(40) 
Presence of hypersensitivity of the 
central nervous system 
Central Sensitisation Inventory (SCI). The CSI is a questionnaire 
generating reliable and valid data to assess symptoms 
related to central sensitization mechanisms.(41) 
Pain sensitivity testing 
 
- Quantitative Sensory testing: 
Mechanical detection and pain 
thresholds*  
Twelve monofilaments (MARSTOCK nerve test - Optihair2, 
Schriesheim, Germany) with a force from 0.25 to 512 mN are used. 
The mechanical detection threshold is defined as the lowest 
mechanical force that the participant can detect. The mechanical 
pain threshold is defined as the lowest mechanical force that the 
participant perceives as painful or unpleasant. Monofilaments are 
applied with a rate of 2 seconds ‘on’ and 2 seconds ‘off’ at the inner 
side of the upper arm and lateral trunk side.  
 
- Quantitative Sensory testing: 
Temperature detection and pain 
thresholds* 
The computerized thermotest device TSA-II-NeuroSensory Analyser 
is used. The method of limits is used. The detection and pain 
thresholds are measured as the first identified stimulus under 
increasing stimulus intensities. The participant has to push the 
button once the stimulus is detected or perceived as painful or 
unpleasant. This is repeated three times for each threshold. The 
mean of three stimuli for each threshold is calculated and used for 
analysis.(42). 
 
- Quantitative Sensory testing: 
Pressure Pain Thresholds* 
Measured by a digital Wagner FPX™ algometer. Points of 
measurement are defined by palpation for most tender muscle 
points (one per muscle) at the major pectoral muscle region, the 
lateral trunk side and upper trapezius muscle region. The participant 
is asked to say ‘stop’ when the sensation of pressure first changes to 
pain. The mean value of the 2 measurements is calculated and used 
for analysis.(43)  
- Presence of widespread 
pain/secondary hyperalgesia 
Quantitative Sensory Testing is performed both at the local painful 
area as at remote body parts (i.e. quadriceps muscle at the non-
affected side) and pain distribution is displayed on a body diagram 
 
- Presence and degree of 
impaired nociceptive inhibitory 
Assessment of conditioned pain modulation will be done using the 
Medoc two thermode Q-Sense CPM system. This system involves a 
‘test’ stimulus and a ‘conditioning’ stimulus applied on the ulnar 

 
15
mechanisms (i.e. conditioned pain 
modulation) 
side of the forearms. The test stimulus (at the affected side) is used 
to assess pain sensitivity to a warmth stimulus pre- and post the 
noxious conditioning stimulus and the difference is calculated 
between pre- and post-measures. When the second pressure pain 
threshold (i.e. test stimulus) is similar or lower than the first, 
dysfunctional inhibitory pain mechanisms are present.(44, 45) 
 
- Presence and degree of 
enhanced facilitation mechanisms 
(i.e. wind-up) 
Wind-up of pain or temporal summation will be assessed by 
applying repetitive nociceptive stimulation with a 26g Nylon 
monofilament at the major pectoral muscle at the affected side. The 
perceived intensity of the stimulus (the first, the last and 
aftersensations) are reported by using a Numeric Rating Scale. The 
temporal summation value is calculated as the difference between 
the first and the last stimuli or the slope of the increase in pain 
intensity. A response for enhanced temporal summation is deemed 
positive if participants perceive the initial stimulus as non-noxious, 
but it becomes noxious, increasing by at least two-points on a 
Numeric Rating Scale, or if baseline pain intensity increases by at 
least two points.(44-46) 
 
 
- Presence and degree of 
hypersensitivity to non-
mechanical stimuli 
The Central Sensitization Inventory, a questionnaire generating 
reliable and valid data to assess symptoms related to central 
sensitization mechanisms (47-49) 
PHYSICAL FUNCTIONING 
 
General physical activity and upper 
limb performance 
Three ActiLife accelerometers, one on the pelvis (7 consecutive 
days) and one on each wrist (3 consecutive days), will be worn 
during waking hours. Outcome parameters are general activity 
level, unimanual/bimanual time and intensity of both 
unimanual/bimanual use. The ActiLife v6.9.5 Firmware v2.2.1 will 
be used to save raw data. Data will be further processed with 
Matlab®, using custom-written routines.(50, 51)  
Upper limb function 
DASH questionnaire. The DASH is a self-reported questionnaire on 
upper limb function.(3) 
EMOTIONAL FUNCTIONING 
 
Pain catastrophizing 
Pain Catastrophizing scale (PCS). The PCS is a self-reported 
questionnaire measuring catastrophic thinking related to pain. (53) 
Depression, anxiety and stress 
Depression Anxiety Stress scales 21 (DASS-21). The DASS-21 is a 
self-reported questionnaire that measures the three related states 
of depression, anxiety and stress. (54) 
Health-related quality of life 
McGill Quality of Life questionnaire (55) 
SOCIAL FUNCTIONING 
 
Return to work rate 
Self-reported questionnaire on return to work, employment status, 
work adjustments 
QuickScan 
Questionnaire on health status and return-to-work obstacles in 
order to assess potential predictive factors for long-term 
absenteeism. 
Patients perceived ability to work 
Return-to-work self-efficacy questionnaire (RTWSE-19). The RTWSE-
19 is a self-reported questionnaire on the patients’ perceived ability 
to work.(56) 
* Testing is performed bilaterally, except preoperatively because of feasibility reasons 
 
 
Sample size 

 
16
A power calculation was performed by the Leuven Biostatistics and statistical bioinformatics 
Centre of KU Leuven for the primary outcome parameter ‘Pain Disability Index (PDI) after 1 
year'’. Sample size calculation was based on data available in literature for the PDI.(37, 38) 
and calculated to detect with 80% power a difference of 20% in Pain Disability Index after 1 
year. Assuming a coefficient of variation (CV) equal to 0.5, 87 participants per group are 
needed based on a two-sample pooled t-test of a mean ratio with lognormal data and setting 
alpha equal to 0.05. The assumed CV is a conservative estimate, derived from the observed 
CV of 0.30 in a sample of normative data for women with chronic pain. To anticipate a dropout 
rate of approximately 5%, 184 participants in total will be recruited. The drop-out rate is 
based on previous similar trials at our institution.(29, 57, 58) To handle the potential missing 
measurements after 1 year, the comparison of the PDI will be based on a multivariate normal 
model for longitudinal measurements fitted on all repeated measures over time (pre-op, 
postop, 4, 6, 8, 12 and 18 months). A log-transformation will be applied if necessary to handle 
the right-skewed distribution of the PDI.  
 
Data analysis 
Statistical analysis will be intention-to-treat and will comply with the Consolidated Standards 
of Reporting Trials (CONSORT) guidelines. Analysis will be conducted in a blinded way. The 
continuous data will be summarized using mean, SD, median and range values. The primary 
outcome will be analyzed using multilevel linear regression models for repeated (longitudinal) 
measures, using an unstructured covariance matrix. The mean change from baseline (i.e. 
preoperative assessment) to 4, 6, 8, 12 and 18 months (with correction for the postoperative 
assessment), will be estimated using contrast statements for each of the treatment arms. The 
difference in mean changes and their 95% CIs between interventions will be plotted 
graphically so that change can be assessed over the course of the study. Continuous 
secondary outcomes will be assessed in a similar way to the primary outcome. Categorical 
data will be analyzed using logistic models. For non-repeated continuous and binary 
measurements, ordinary linear regression and logistic models will be used, respectively.  
 
Data security and management 
Participant data are stored on a secure database in accordance with the General Data 
Protection Regulations (2018). Data is de-identified and a unique trial identification number 

 
17
used on all participant communication. Clinical and patient forms are being checked for 
completeness and congruity before data entry onto the database. Data will undergo 
additional checks to ensure consistency between data submitted and original paper forms. 
Trial documentation and data will be archived for at least 10 years after completion of the 
trial. 
 
Trial monitoring 
The steering committee of the research team will oversee all aspects of design, delivery, 
quality assurance and data analysis. The steering committee will monitor the trial at least 
once per year.  
 
 

 
18
ETHICS AND DISSEMINATION 
 
Ethical considerations 
The EduCan Trial applies the principles established in the Declaration of Helsinki. Participants 
provide written informed consent before data collection. Only de-identified coded and 
interpreted data will be shared between the members of the research team. Ethics approval 
was granted by the local Ethical Committee of the University Hospitals Leuven (s60702). 
 
Dissemination of results 
The research team are committed to full disclosure of the results of the trial. Findings will be 
reported in accordance with CONSORT guidelines and we aim to publish in high impact 
journals. Given the multitude of outcome parameters, results will be divided over several 
papers. Our patient representatives and representative of the National Health Service will 
assist with dissemination of study results. The funder will take no role in the analysis or 
interpretation of trial results. 
 
Acknowledgements 
The authors would like to thank all the trial participants. The authors would also like to thank 
all the physical therapy staff, surgical oncology teams, breast cancer nurses and research 
departments collaborating on this study. 
 
 
 

 
19
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