DOLORISK: Understanding Risk Factors and Determinants for Neuropathic Pain - Chronic Neuropathy Following Chemotherapy
Conditions: Peripheral Nervous System Diseases, Chronic Pain
Sponsor: Danish Pain Research Center

Cover page 
 
 
 
Official title: Chronic neuropathy following chemotherapy (DOLORISKCIPN) 
 
Unique Protocol ID: CIPN-2015 
 
NCT number: NCT02654691    
 
Date: 23 March 2016 
 
 

Chronic neuropathy following chemotherapy 
Background 
Peripheral neuropathy is a well-known side effect of chemotherapy(1). With an increasing number 
of cancer survivors receiving adjuvant chemotherapy, this complication represents a significant 
problem since chemotherapy-induced peripheral neuropathy (CIPN) affects physical, emotional, 
and cognitive functioning in cancer survivors, and thus their quality of life, and may be associated 
with pain(2, 3).  
Most previous studies on CIPN have graded neuropathy using the National Cancer Institute, 
Common Toxicity Criteria (NCI-CTC v3.0) with a range of grades from 0 (no problem at all) to 4 
(extensive problems interfering with activities of daily living). This rough grading scale has well-
known limitations(4). Despite the introduction of different scales, only a few studies have 
described various types of pain and distinguished CIPN-related pain from other pain types(5, 6).  
Several studies have explored the incidence, predictors, and impact of CIPN, but less is 
known about CIPN-related pain(7, 8). Most studies have pooled patients with different types of 
cancer treated with different neurotoxic agents(9, 10), which complicates the interpretation of the 
results, since the incidence and type of CIPN are dependent on the specific chemotherapeutic 
agent used(11). Additional therapies such as surgery, radiation therapy, and endocrine therapy 
can cause other types of neuropathy and pain(12) and are used to varying degrees, but this has 
rarely been discussed.  
Neuropathic pain/painful polyneuropathy: The most common disabling condition of 
chemotherapy-induced peripheral neuropathy is neuropathic pain(13). Neuropathic pain is not a 
term applied to a single underlying mechanism or disease, but describes a syndrome of various 
sensory symptoms and signs (e.g. spontaneous ongoing pain, allodynia and painful attacks). 
Patients treated with the chemotherapeutic drug oxaliplatin for colorectal cancer experience 
acute onset of perioral and distal paresthesia and a very characteristic and disabling cold 
allodynia. These symptoms are most severe immediately and in the first days after the 
chemotherapy and then gradually subside, and are usually reversed at the time of the next 
treatment. Later on, the patients may develop a cumulative sensory axonal polyneuropathy with 
vibration deficits, numbness and distal paresthesia or pain. Docetaxel a chemotherapeutic drug 
used in the adjuvant treatment of high-risk breast cancer, also has dose limiting side-effects 

including hematologic depression occurring around the first 2 weeks after a cycle and chronic 
peripheral neuropathy.  
Ion channels and pain: The transmission and processing of pain signals rely critically on the 
activities of ion channels that are expressed in afferent pain fibers(14). Abnormal ion channel 
expression following nerve injury results in enhanced neuronal excitability that underlies ongoing 
and evoked neuropathic pain, and sodium, calcium, potassium and chloride channels are emerging 
as attractive targets for the treatment of pain(14). It is likely that certain pain phenotypes are 
related to specific changes in ion channels. 
 
Threshold tracking: Axonal excitability testing using the threshold tracking technique provides 
complementary information to conventional nerve conduction studies and may be used to infer 
the activity of a variety of ion channels, energy-dependent pumps and ion exchange processes 
activated during the process of impulse conduction(15, 16)  
 
This protocol describes a clinical study, which we wish to add to an ongoing prospective 
questionnaire study. The study enrolled 174 patients aged ≥ 18 years who were treated with 
standard adjuvant capecitabine and oxaliplatin (Xelox) after high-risk colorectal cancer or standard 
docetaxel for high-risk breast cancer in the period of 2011 and 2012. Patients completed a 
questionnaire before, during and after treatment. The first part of the study is published (17).  We 
found that chronic CIPN symptoms (tingling and/or numbness) in the feet at 1-year follow-up were 
present in 63.6% of patients without pre-existing neuropathy in the oxaliplatin group and in 44.8% 
in the docetaxel group, while pain in hands and feet was found in 31.3% and 35.1%, respectively. 
While the symptoms were very different between the two types of chemotherapy in the acute 
phase, neuropathy symptoms were more similar in the chronic phase. The CIPN affected the 
quality of life, but the general health was high (17).  
The questionnaire study includes an additional follow-up postal questionnaire to surviving 
patients, which we will send out early 2016. In addition, and hence this protocol, we would like to 
conduct a clinical study to be able to diagnose neuropathy using clinical examination, corneal 
confocal microscopy, and neurophysiology, and to describe the sensory phenotypes and 
excitability changes in more detail using quantitative sensory testing and threshold tracking. The 

present follow-up is part of the DOLORisk project: Understanding risk factors and determinants for 
neuropathic pain funded by the European Commission Horizon 2020 (ID633491), a collaboration 
between several European Universities. 
 
Hypotheses for the clinical study 
1. Chronic neuropathy following treatment with oxaliplatin and docetaxel is a length-dependent, 
sensory, axonal neuropathy characterized mainly by sensory loss. 2. There is a positive correlation 
between greater neuropathy severity and the presence and severity of neuropathic pain 
 
Methodology and Research Plan 
Patients and controls and inclusion and exclusion criteria 
This is a follow-up study of a prospective questionnaire study(17) approved by Datatilsynet (J.nr. 
2011-41-5725) and Sundhedsstyrelsen (videregivelse af oplysninger fra patientjournal) (Sagsnr. 3-
3013-605/1). The study enrolled 174 patients aged ≥ 18 years who where treated with standard 
adjuvant Capecitabine and oxaliplatin (Xelox) after high-risk colorectal cancer or standard 
docetaxel for high-risk breast cancer in the period of 2011 and 2012. 
The exclusion criteria were: 
• Known metastatic cancer,  
• Previous treatment with chemotherapy,  
• Patients who do not speak, read or understand Danish  
 
The patients received a specially designed questionnaire at baseline, after the 1st cycle of 
neurotoxic chemotherapy, midway in the adjuvant treatment, after one year. 93% (67 of 74 who 
received oxaliplatin and 94/100 who received docetaxel) responded after one year.  
 
 
This study is a 5-year follow-up study, where we will send the questionnaire to all surviving 
patients who participated in the study. The questionnaire study(17) included 44 men and 30 
females with an average age of 62.5 years (SD 8.4 years) in the group of colon cancer and 100 
females with an average age  of 51.6 years (SD 7.7 years) in the group of breast cancer. These will 
be asked if we may contact them with information on the clinical study.  We expect that 60% in 

the oxaliplatin group and 75% in the docetaxel group are alive and willing to participate, i.e. 
around 30 patients in each treatment group in the clinical study. 
. 
These patients will participate in a one-session clinical study, which will include questionnaires and 
examinations to determine the presence of neuropathy by clinical examination, 
neurophysiological assessment, Quantitative Sensory Testing (QST), Nerve Conduction Studies 
(NCSs), Treshold Tracking, and Corneal Confocal Microscopy (CCM). The exclusion criteria for the 
5-year follow-up questionarieis: if they are dead. The exclusion criteria for the clinical examination 
is: if they are not able to visit the Danish Pain Research Center or dead. 
 
Methods 
A follow-up questionnaire containing questions on pain, sensory abnormalities, mood, sleep, and 
quality of life, similar to previous questionnaires sent out to this population (Appendix 1), will be 
send out early 2016, with one reminder to non-responders.  
At the end of the questionnaire, the two patient groups that have received chemotherapy 
(oxaliplatin or docetaxel), will be asked if we may contact them with information on a clinical 
study and if so, we ask them to provide their preferred contact details and preferred way of 
contact (mail, email or telephone) (see document “rekrutteringsmateriale”). After accepting 
contact regarding information about the clinical study, we will contact them via their preferred 
way of contact with short information. If they are interested in more information, we will send 
them the written patient information. If they are still interested, they will be invited to a visit at 
the Danish Pain Research Center, where they will receive the oral information as described under 
“Enlistment of the participants and guidelines for oral participation information”. 
 
Procedures 
A medical and pain history will be taken and a neurological examination including mapping of 
sensory abnormalities will be performed. In addition, patients will be asked about alcohol and 
smoking consumption, medication use, family history of pain and neuropathy, trauma, physical 
activity, anxiety and depression symptoms and sleep disturbance. For case definition of 
neuropathy, we will use Tesfaye et al. 2010(18)  

 
Questionnaires 
Patients will fill out following questionnaires: 
The Douleur Neuropathique 4 Questions (DN4) (19), which includes various pain descriptors and a 
small clinical examination, which will be performed by the investigator (see appendix 2).  
The Neuropathic Pain Symptom Inventory (NPSI) (20), where patients rate the intensity of various 
pain descriptors (see appendix 3). 
The Pain Catastrophizing Scale (PCS)(21). The questionnaire includes 3 dimensions: rumination, 
magnification, and helplessness. In addition, a total score indicates the level of pain 
catastrophizing (see appendix 4). 
The PainDETECT (22). PainDETECT comprises questions on specific neuropathic pain symptoms, 
(see appendix 5).  
The Michigan Neuropathy Screening Instrument (MNSI) (23) consist of 15 questions on foot 
sensation (pain, numbness, and sensitivity to temperature)  (see appendix 6). 
 
Quantitative sensory testing (QST): By using standardized QST, which assesses functional 
characteristics of both small and large afferent fibers by examining mechanical detection and pain 
thresholds, thermal detection and pain thresholds, and dynamic mechanical allodynia, the profile 
of sensory symptoms can be elucidated in each patient on the foot.  
QST examinations will take approximately 3/4 hours.  
 
Corneal Confocal Microscopy (CCM) is a new promising non-invasive tool to assess fiber loss at an 
early stage of polyneuropathy. The main CCM parameters to be analyzed are (a) corneal nerve 
fiber length (NFL), defined as the absolute length of nerves and branches per mm2, (b) nerve fiber 
density (NFD), defined as the total number of major nerves per mm2 and (c) nerve fiber branching 
(NFB), defined as the number of branch points per mm2 (24, 25).  CCM examinations will take 
approximately ½ hour. 
 
 
 

Neurophysiological Examinations:  
Nerve conduction studies (NCSs): Motor NCSs in peroneal, tibial and median nerves and sensory 
NCSs in sural and median nerves using conventional procedures with surface electrodes and a 
standard electromyography machine will be performed. NCSs will be used for diagnosis and 
staging of chronic neuropathy(26).   
 
Threshold tracking 
Motor and sensory excitability tests (threshold tracking) will be performed on the median nerve at 
the wrist using a computerized program (TRONDNF, Institute of Neurology, London, UK) as 
described previously(15). Multiple excitability parameters will be assessed included 1) Stimulus 
response curve to define the amplitude of the target response, 2) strength–duration time 
constant, a measure of passive membrane properties and nodal persistent Na+ conductance; 3) 
threshold electrotonus, a measure of internodal conductances and membrane potential and 4) 
recovery cycle of excitability, an assessment of the recovery of excitability following an action 
potential marking the function of nodal Na+ channels. Additionally, using a more detailed stimulus 
response curve called MScan, the number of motor units will be estimated.  
Neurophysiological examinations will take approximately 1½ hours.  
 
Screening tools 
We will use following screening tools for neuropathy, and the assessments described in these are 
all part of the standard clinical neurological examination: 
• The Toronto Clinical Scoring System (TCSS)(Bril & Perkins, 2002) (Appendix 7). 
• Total Neuropathy Score (Appendix 8). 
• NCI-CTC _ National Cancer Institute–Common Toxicity Criteria (Appendix 8). 
• The Michigan Neuropathy Screening Instrument (Appendix 6). 
 
Blood samples and biobank 
We will collect blood (10ml) from each subject, which will be stored at -800C in a locked freezer. 
All samples will eventually be transported to the research lab led by Prof Mark McCarthy based at 
the University of Oxford, UK for storage in compliance with The Human Tissues Act and EU. DNA 

will be taken for studies in genetics polymorphisms or mutations within genes that may modify 
the risk of a person developing a neuropathic pain and/or the severity of neuropathic pain, if and 
only if the patient agrees. Genetic analysis will be strictly restricted to the neuropathy and 
neuropathic pain field.   
 
Character of planned bioinformatic analyses:  
A genome wide association study will be performed. This will look at variants that are common in 
the general population.  
Candidate gene analysis: This will be to look at genes previously implicated in pain such as voltage 
gated sodium channels and potassium channels. These genes have a role in pain only and not in 
other diseases such as e.g. inherited risk of cancer development. 
Whole Genome and Whole Exome Sequencing. This will investigate at cohort level and look at 
variants enriched in those patients at the extreme of pain sensibility either high or low. Thus, since 
our cohort share pain perception as part of their phenotype, the risk of detecting variations in 
genes predisposing to e.g. cancer would be extremely low. We will use standardized analysis 
software to investigate variants e.g. common platforms such as ingenuity variant analysis. 
 
The genes expected for sequencing is coding for ion channels (e.g. SCN9A, SCN10A,  SCN11A, 
KCNS1), and enzymes (GCH1, COMT, FAAH), and trafficking proteins (CACNA2D1, NK1R). The 
biobank is a research biobank and all material will be destroyed at completion of the study. The 
analyses will be restricted to the neuropathy and neuropathic pain field. When the project and 
research biobank ends, all material will be destroyed. Patient who accepts biobank also accepts to 
be informed of incidental genetic findings with health impact unless they specifically declines (See 
the informed content). 
Patients can participate in the clinical study independent of whether they accept to have a blood 
sample taken and stored in a research biobank or not. If they do not wish to have their blood 
stored in a biobank, they sign the informed consent S21. If they accept to have their blood taken 
and stored in a research biobank, they sign the informed consent S42.  
 
                                                          
1 Standardsamtykkeerklæring udarbejdet af Det Videnskabsetiske Komitésystem, december 2011. 
2 Standardsamtykkeerklæring udarbejdet af Det Videnskabsetiske Komitésystem, december 2011 (Biologisk materiale) 

Data analysis, statistics, and number of patients. 
This is a follow-up of an on going study and thus a new sample size calculation is not performed. 
We expect that around 30 patients in each treatment group will participate in the clinical study. 
Analysis will be mainly descriptive. In relation to performing single nucleotide polymorphism 
analysis to study the risk of developing pain, previous studies would predict a requirement of 200 
patients per group as an estimate (however this depends on the strength of the genetic influence). 
For genome wide association studies very large group sizes (at least a thousand) are needed and 
data will be combined within the DOLORisk consortium. 
Analysis of Quantitative Sensory Testing data will be in accordance with the DFNS protocol using Z-
transferred data. Normality is tested using qq-plots. Data are analysed depending on the 
distribution using either unpaired t-test or Mann Whitney U test.  The results will be presented as 
means ±SD if normal distributed and medians with 10 and 90 percentiles or range if not. Estimates 
are given with exact 95% confidence intervals. P- values < 0.05 will be considered statistically 
significant.  
 
 
Data storing and transfer 
The acquired data is stored on a personal computer that is password protected. The patient data is 
held in the local database at Aarhus University. Pseudonymized patient data will be transferred to 
participating centres in the DOLORisk consortium with the patient’s consent, maintaining patient 
confidentiality at all times. Data transferred is answers of questionnaires and results of 
examinations. Anonymized data may also be made available to researchers outside the DOLORisk 
consortium as part of the ICMJE, International Committee of Medical Journal Editors, 
recommendations on data sharing. Thus, this informed consent also includes consent to a further 
use of the anonymous date for scientific use.  A unique patient identification number is used for 
export of the data which is generated in the local center, so that export can be conducted without 
any personal data like the name, date of birth, residence. 
 
 
The research group and practical framework 

This study has been planned as a PhD project for MD Kristine Jepsen Bennedsgaard. Associate 
Professor Nanna Brix Finnerup, Danish Pain Research Center will be the main supervisor.  Lise 
Ventzel, MD, PhD, Department of Oncology and Hatice Tankisi, MD, PhD, Department of Clinical 
Neurophysiology, will be co-supervisors. Head of Department, MD, PhD Anni Ravnsbæk Jensen, 
Department of Oncology, will be another collaborator. Lise Ventzel has conducted a prospective 
PhD study titled “Neuropathy and Pain after Chemotheraphy” with the same research group, from 
which the patients can be recruited for the PhD project. Other participants from the DOLORisk 
consortium are collaborators on parts of the study, including David Bennett, UK, Jordi Serra, Spain, 
and Geert Crombez, Belgium. 
 
Feasibility, research education and time schedule 
All examinations including QSTs, NCSs and threshold tracking are used for clinical and research 
purposes at the Danish Pain Research Center and the Department of Clinical Neurophysiology, 
Aarhus University Hospital. Kristine Jepsen Bennedsgaard will under supervision and after 
complete training, perform the neurological examination, Treshold Tracking, QST, and NCSs and 
be responsible for the examination of patients and control subjects. A trained research nurse at 
the Danish Pain Research Center will perform the CCM. 
Time schedule: The first patients will receive the questionnaire in January 2016, and if there is no 
response a notification will be send 14 days later. The clinical examinations will take place from 
February 2016 until December 2019.  
 
Publication and Dissemination 
We expect to publish at least 1 scientific peer-reviewed paper in an international journal. Both 
negative, inconclusive and positive results will be tried to be published. Kristine Jepsen 
Bennedsgaard will be first author of the main publication. Relevant collaborators will be co-
authors. DOLORisk (EU Horizon 2020) and Aarhus University will be acknowledged for their 
support. Further publications from this material, including the genetic results, will be published 
with relevant researchers in the DOLORisk consortium. Details regarding this issue have already 
been settled in the contracts with the DOLORisk  participants 
 
Economical Aspects  

The study is mainly supported by the EU, grant number 633491 (Ph.D. scholarship, equipment 
purchase, etc. about 250.000 DDK) and Aarhus University (Ph.D.  scholarship, about 100.000 DDK). 
The initiative to the study was taken by the sponsor in collaboration with the collaborators. The 
project participants do not have any connection to those supporting the study. There are no 
current plans of applying for more financial support to the project. 
The project patients will not be paid. The transport will be paid according to the usual rules by the 
department.  
Ethical Aspects 
Risks, side effects and benefits:  
The project requires participation in a series of examinations, which are mostly standard 
procedures at the involved departments and are conducted by experienced staff. In general the 
examinations are without risks. The electrophysiological procedures may cause slight discomfort 
due to the use of electrical stimulation. During thermal stimulation the minimal stimulation 
temperature is 0 °C and maximum stimulation temperature 50 °C. All thresholds during 
stimulation are reached with temperature changes of 1 °C/s. This technique does not provide 
tissue damage, and patients switch of stimulation themselves when pain threshold is reached. No 
known risks or side effects are observed in relation to the examinations. Patients with 
hypersensitivity can experience some of the stimulations as discomfort or painful. Patients can 
themselves at any time switch of the stimulation. Unknown side effects can occur.  
Project participation will not influence the patient’s possible medical treatment and the research 
subjects will be informed that they will not have direct personal benefits from the project 
participation.  If the patient agrees to participant with a blood sample there are a small risk of very 
mild transitory pain, local hematoma, local irritation and minor local bleeding. 
Subjects are covered by the public patient insurance, if any damage contrary to expectations is 
occurring during the examinations. Subjects will in case of damage or death not related to the 
project be covered by the hospital insurance.  
Enlistment of the participants and guidelines for oral participation information 
Patients who are participants in the on-going questionnaire survey are eligible. In the 
questionnaire, we ask if we may contact them with information on a clinical study and if so, we ask 

them to provide their preferred contact details and preferred way of contact (mail, email or 
telephone) (see document “rekrutteringsmateriale”). After accepting contact regarding 
information about the clinical study, we will contact them via their preferred way of contact with a 
short information. If they are interested in more information, we will send them the written 
patient information and “Forsøgspersoners rettigheder i et sundhedsvidenskabeligt 
forskningsprojekt”. 
If they are still interested, they will be invited to a visit at the Danish Pain Research Center, where 
they will receive the oral information. The oral information meeting will take place in a closed 
office and there will be enough time to give information and discuss the possible questions. After 
the verbal information the patients will be offered at least 24 hours to decide, whether they want 
to attend to the project or not. The participants will also be informed that they can withdraw from 
the project at any time.  
The participants’ physical and mental integrity and private life’s peace will be respected.  
The project will be conducted in accordance with the Helsinki declaration II.  The project is 
approved by the data protection agency (J.nr. 2011-41-5725), but we have sent in a new 
application to get approval to send pseudonymized data to other researchers, to send blood 
samples to the UK, and to register Kristine Jepsen Bennedsgaard as a the main investigator. The 
law on processing the personal information will be followed using REDCap 
An informed written consent will be obtained from all patients before examinations. There are 
two different written consents one with acceptance of the study with blood sample(S4), and one 
with acceptance to participate in the study, without the blood sample (S2).  
 
Handling of expected and unexpected/incidental findings: 
It is not expected that we will find variants in genes that are linked to carcinogenesis or risk of 
disease. The study is performed in collaboration with Prof. Uffe Birk Jensen, Dept of Clinical 
Genetics, Aarhus University Hospital. He will appoint an independent committee in case of 
unexpected/incidental findings. This committee will evaluate whether there should be feedback to 
the patient and in this case provide counseling to the patient. This committee will also consider if 
report to relatives is recommended in case the patients is dead or do not want information on 

own health. In addition, there will be possibility for the patient to receive genetic counseling 
before accepting to give blood to the biobank.  
 
Overall it is judged that the expected gain of the project will exceed the disadvantages 
experienced by the research subjects, and that the project therefore is ethically justifiable. The 
conduction of the project will be of large importance regarding knowledge about chemotherapy 
induced neuropathy and pain Moreover, this project is expected to contribute to better 
understanding of pathophysiology of pain and eventually better treatment possibilities.  
 
 
 
 
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