A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy
Phase: NA
Conditions: Peripheral Neuropathy, Stage 0 Breast Cancer, Stage I Breast Cancer, Stage IA Breast Cancer, Stage IB Breast Cancer, Stage II Breast Cancer, Stage IIA Breast Cancer, Stage IIB Breast Cancer, Stage III Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer
Sponsor: Wake Forest University Health Sciences

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral 
Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 05/09/18 
Page i of 39 
Study Chairs: 
Co-Chair: 
Roy Strowd, MD, Assistant Professor 
Neurology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
Glenn J. Lesser, MD, Professor 
Section on Hematology and 
Oncology Wake Forest School of 
Medicine Medical Center Boulevard 
Winston-Salem, NC 27157 
Thomas Lycan, DO 
Hematology & Oncology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
Co-Investigators (alphabetical) Christine Ahn, MD 
Dermatology, WFBMC 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
Vanessa Baute, MD Neurology, 
WFBMC 
Wake Forest School of 
Medicine Medical Center 
Boulevard Winston-Salem, NC 
27157 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral 
Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 05/09/18 
Page ii of 39 
James B. Caress, MD, Professor 
Neurology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
Michael Cartwright, MD, Associate Professor 
Neurology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
James Crisp, MD 
Neurology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
Omar P. Sangueza, MD, Professor 
Pathology, WFBMC 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
Yusuke Shiozawa, MD, PhD, Assistant 
Professor Cancer Biology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral 
Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 05/09/18 
Page iii of 39 
Biostatistician: 
Research Nurse: 
Study Coordinator: 
Regulatory Contact: 
Alexandra Thomas, MD, Professor 
Hematology & Oncology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
Francis O. Walker, MD, Professor 
Neurology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
Fang-Chi Hsu,PhD, Professor 
Department of Biostatistical Sciences 
Wake Forest Baptist Comprehensive Cancer 
Center Medical Center Blvd 
Winston-Salem, NC 27157 
Charity Patton 
Wake Forest Baptist Comprehensive Cancer 
Center Medical Center Blvd 
Winston-Salem, NC 27157 
Summer Harris 
Wake Forest Baptist Comprehensive Cancer Center 
Medical Center Blvd 
Winston-Salem, NC 27157 
Cindy Miller 
Wake Forest Baptist Comprehensive Cancer 
Center Medical Center Blvd 
Winston-Salem, NC 27157 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral 
Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 05/09/18 
Page iv of 39 
Protocol Editor: 
Participating Institution(s): 
Version Date: 
Amended: 
 
Mac Robinson, PhD 
Wake Forest Baptist Comprehensive Cancer Center 
Winston-Salem, NC 27157 
Wake Forest Baptist Medical Center 
05-22-17
05-09-18
Confidential

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 05/09/18 
Page 5 of 39 
Table of Contents 
1.0 
Introduction and Background ................................................................................................................. 7 
2.0 
Objectives ............................................................................................................................................ 10 
2.1 
Primary Objectives ........................................................................................................................... 10 
2.2 
Secondary Objective ........................................................................................................................ 10 
2.3 
Exploratory Objectives ..................................................................................................................... 10 
3.0 
Study Population .................................................................................................................................. 11 
3.1 
Inclusion Criteria .............................................................................................................................. 11 
3.2 
Exclusion Criteria ............................................................................................................................. 11 
3.3 
Inclusion of women and minorities ................................................................................................... 11 
4.0 
Methods ............................................................................................................................................... 12 
4.1 
Registration Procedures ................................................................................................................... 12 
4.2 
Study Activities ................................................................................................................................. 13 
4.3 
Study setting .................................................................................................................................... 13 
4.4 
Enrollment (Encounter 1) ................................................................................................................. 13 
4.5 
Clinical assessment (Encounter 2) ................................................................................................... 13 
4.6 
Diagnostic testing (Encounter 3) ...................................................................................................... 14 
4.7 
Follow-up ......................................................................................................................................... 16 
4.8 
Data entry/storage ............................................................................................................................ 16 
5.0 
Outcome Measures .............................................................................................................................. 16 
5.1 
Primary Outcome ............................................................................................................................. 16 
5.2 
Secondary Outcomes ....................................................................................................................... 16 
5.3 
Exploratory Outcome ....................................................................................................................... 16 
6.0 
Analytic Plan ........................................................................................................................................ 17 
6.1 
Sample Size and Power ................................................................................................................... 17 
6.1.1 
Primary outcome: ............................................................................................................................. 17 
6.1.2 
Secondary outcome: ........................................................................................................................ 17 
6.2 
Analysis of Primary Outcome ........................................................................................................... 18 
6.3 
Analysis of Secondary Outcome ...................................................................................................... 18 
6.4 
Analyses of Exploratory Outcomes................................................................................................... 18 
6.5 
Accrual Rate .................................................................................................................................... 18 
6.6 
Length of Study ................................................................................................................................ 18 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 05/09/18 
Page 6 of 39 
7.0 
Data Management ............................................................................................................................... 18 
8.0 
Confidentiality and Privacy ................................................................................................................... 19 
9.0 
Data Safety and Monitoring .................................................................................................................. 19 
10.0 
Reporting of Unanticipated Problems, Adverse Events or Deviations ................................................... 19 
References ...................................................................................................................................................... 20 
Appendix A: Subject Eligibility Checklist .......................................................................................................... 22 
Appendix B: Protocol Registration Form .......................................................................................................... 23 
Appendix C - Race & Ethnicity Verification Form ............................................................................................. 24 
Appendix D: Clinical Evaluation from History/Exam ......................................................................................... 25 
Appendix E: Exploratory Outcomes Data Collection Form ............................................................................... 28 
Appendix F QLQ-CIPN20 ................................................................................................................................ 29 
Appendix G: Nerve Fiber Density Data Collection Form .................................................................................. 30 
Appendix H: Ultrasound Nerve Diameter Data Form ....................................................................................... 31 
Appendix I: Nerve Conduction Study Data Collection Form ............................................................................. 32 
Appendix J: Adverse Events Log ..................................................................................................................... 33 
Appendix K: Follow-up Form for Skin Biopsy ................................................................................................... 34 
Appendix L: Mandatory STRC SAE Reporting Requirements .......................................................................... 35 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 05/09/18 
Page 7 of 39 
1.0 
Introduction and Background 
Taxane chemotherapies such as paclitaxel and docetaxel have had an increasing role in the 
treatment of breast cancer and are now used in the majority of patients receiving perioperative 
chemotherapy.1 Taxanes exert their effect by excess stabilization of microtubules which 
disrupts the mitotic spindle of dividing cancer cells. However, healthy neuronal cells also rely 
on functional mitrotubules in their axons and dendrites for both structural support and transport 
of intracellular products. Disruption of these neuronal microtubules leads to a dose-dependent 
peripheral neuropathy that is the dose-limiting toxicity of taxanes.2 Taxane-induced peripheral 
neuropathy (TIPN) initially tends to manifest as a progressively worsening sensory impairment 
which is often felt as painful paresthesias with decreased deep tendon reflexes; this may be 
followed by a delayed motor deficit causing distal weakness.3 TIPN is often reversible if it is 
intervened upon early enough with dose reduction or discontinuation of taxane treatments; if 
treatment is continued there is higher risk of irreversible symptoms.4 A retrospective clinical 
practice study of early-stage taxane-treated breast cancer patients found that 10% of them had 
dose-limiting TIPN; roughly half of whom had early discontinuation of treatment with an 
average 28% lower cumulative taxane dose than planned.5 When chemotherapy cannot be 
given as intended due to dose reductions it is generally associated with worse outcomes,6 
suggesting that TIPN may have an indirect effect upon overall survival in some breast cancer 
patients. 
TIPN manifests via several different pathophysiological mechanisms that can be assessed by 
current modalities; none of which have yet emerged as a widely-adopted standardized 
approach. Taxane disruption of microtubules impairs the normal self-maintenance of neurons 
which is evident structurally as the degeneration of distal axons and nerve terminals. 
Inflammatory changes occur as the innate immune system responds to these damaged and 
leaking organelles. Genetic polymorphisms in neuronal and inflammatory cells contribute to 
individual variability in TIPN vulnerability. Functionally, as a neuronal myelin sheath 
deteriorates it increases the membrane surface area through which current must flow, slowing 
electrical conduction velocity and weakening its signal amplitude. Finally, as a result of the 
above mechanisms, degradation and inflammation can alter large peripheral nerves to the 
point that gross anatomic changes are evident on imaging. 
Ultrasound (US) is a non-invasive, non-irradiating, emerging imaging modality which can be 
used to assess peripheral nerves. Nerve fiber cross-sectional area (CSA), echogenicity, and 
vascularity are assessed and provide an indication of nerve health and potential pathology. 
The majority of US data have been published on detection of entrapment syndromes such as 
carpal tunnel syndrome. In these cases the most common US findings include nerve 
enlargement, decreased echogenicity proximal to the entrapment, and an increase in nerve 
vascularity.7 Other studies have found that US can detect other peripheral nerve lesions or 
neuropathies, with the most reliable finding a change in nerve CSA. Ultrasound measurements 
of the sensory sural nerve at the distal calf in healthy participants without neuropathy had an 
average CSA of 5.3 mm2 with standard deviation 1.8 mm2 for a normal reference range of 1.7-
8.9 mm2.8 Another ultrasound study assessed the sural nerve more distally at the ankle and 
found a smaller CSA which was significantly enlarged (p <0.001) in patients with diabetic 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 05/09/18 
Page 8 of 39 
polyneuropathy as compared to healthy controls (mean/standard deviation 2.59 / 0.96 mm2 as 
compared to 1.40 / 0.59 mm2).9 
To date, there has only been one small study assessing US detection of chemotherapy-
induced peripheral neuropathy; this was done among colorectal cancer patients who had 
received oxaliplatin. Similar to several other etiologies of nerve lesions/neuropathies, this study 
also found an increased peripheral nerve CSA compared to reference values. Interestingly, 
although the patients had denied symptoms of neuropathies at time of recruitment, this study 
found areas of increased peripheral nerve CSA at upper extremity sites of entrapment such as 
the carpal tunnel and ulnar groove; it did not find US abnormalities in terms of CSA or 
echogenicity at the sural nerve or other sites.10 Oxaliplatin has a much different mechanism of 
action from the taxanes; as a platinum-based agent it causes DNA cross-linking which inhibits 
cancer cell growth. Oxaliplatin-induced neuropathy is also a distinct entity that is characterized 
by cold sensitivity and mediated by prolonged opening of sodium ion channels along neuronal 
axons.11 On a review of publications in the MEDLINE database as well as abstracts from the 
American Society of Clinical Oncology, we did not find any other prior studies that focused on 
the use of US to detect chemotherapy-induced peripheral neuropathy, and none for TIPN. 
As noted above, there are currently several different diagnostic modalities that can assess 
TIPN, including self-reported symptoms, physical examination, nerve conduction study, 
sudometer testing, and skin biopsies. But each have limitations so that none have emerged as 
a widely-adopted standardized approach. 
In routine practice, most clinicians rely on patients’ self-reported symptoms alone for TIPN 
detection. These symptoms can be measured on one of several clinician-administered grading 
scales, although these have inter-scale and inter-observer variability.12 The European 
Organization for Research and Treatment of Cancer (EORTC) QLQ-CIPN20 Questionnaire is 
a 20-item self-reported survey that is easy to administer and was validated across participants 
in four large cooperative group trials.13 Furthermore, although in many patients the 
development of acute TIPN symptoms is predictive of eventual chronic TIPN,14 some patients 
develop a disproportionately delayed TIPN that is not able to be self-reported early enough to 
allow for intervention. 
The European Organization for Research and Treatment of Cancer (EORTC) QLQ-CIPN20 
Questionnaire is a 20-item self-reported survey that is easy to administer and was validated 
across participants in four large cooperative group trials.13 The QLQ-CIPN20 sensory scale 
has been studied specifically with TIPN among breast cancer patients and was shown to be 
correlated with patient-reported symptoms from the Common Toxicity Criteria (0.79, p < 
0.00001). Since taxanes are not associated with hearing loss, that corresponding item was 
excluded from analysis in that study.15 For normative comparison, non-cancer patients tend to 
have very low scores on the QLQ-CIPN20 with a sum score average of 3.6 (standard deviation 
7.2) and subtotals of 3.2 (7.3) for sensory measures, 3.8 (9.2) for motor, and 4.4 (10.7) for 
autonomic. The vast majority of non-cancer patients (90.1%) had a sum score of 0-10%; older 
age and self-reported comorbidities were associated with higher QLQ-CIPN20 scores. Based 
on the results from that study, age-matched normative data has been generated for the QLQ-
CIPN20.16 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 05/09/18 
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Physical examination with quantitative sensory testing (QST) uses tuning forks or 
monofilaments to objectively measure the sensory threshold for proprioception. QST may be a 
useful addition to self-reported symptoms as it is non-invasive, easily implemented, and well-
correlated with self-reported TIPN symptoms. Although promising, it has not been shown to 
provide early detection of subclinical TIPN.17,18 
Nerve conduction studies (NCS) measure impairment of electrical function in large peripheral 
nerves and are thought to be a sensitive and specific measure of TIPN. NCS measures 
amplitude and latency of neuronal signaling. Reduction in the conduction velocity within a 
peripheral nerve indicates damage to the myelin, while reduction in the amplitude indicates 
axonal damage. Typical NCS findings suggestive of TIPN include slowed conduction velocity 
at common sites of entrapment (such as the carpal tunnel) and an earlier reduction of sural 
sensory amplitude relative to the radial nerve.19 A prospective study of patients receiving 
paclitaxel and carboplatin found a reduction in sural nerve conduction from baseline in terms of 
the sensory action potential amplitude (14.5 +/- 9.0 uV to 9.7 +/- 7.1) and the sensory 
conduction velocity (54.6 +/- 7.7 m/s to 46.3 +/- 8.8).20 A series of patients who received 
paclitaxel and cisplatin had a reduction in the sural nerve amplitude of sensory action potential 
from average 13.7 uV (standard deviation 6.5) to 6.5 (standard deviation 4.1).21 However, NCS 
are invasive; can be mildly painful for the patient; require expertise and time to administer; and 
can only detect TIPN once it has progressed to the point that there is functional impairment of 
large peripheral nerves; these problems make it less preferable for the routine clinical 
evaluation for TIPN-like symptoms.22 Other functional assays besides NCS have been 
investigated. Sudomotor testing is a novel technique that uses the topical administration of 
acetylcholine to measure the sweat response that is mediated by the small fibers of peripheral 
nerves. Although non-invasive, sudomotor testing tends to have wide variability which can 
make interpretation difficult and it has not yet been tested in chemotherapy-induced peripheral 
neuropathy.  A nerve excitability study is a novel non-invasive functional assay that detects the 
threshold of current that is needed to elicit an action potential. Similar to US, this experimental 
technique has been shown that it can detect oxaliplatin-induced peripheral neuropathy;23 but 
has not yet been studied for TIPN. 
Skin biopsies are able to detect TIPN with good diagnostic sensitivity that may be superior to 
NCS in chronic TIPN.24 Measurement of the intraepidermal nerve fiber (IENF) density is a 
standard clinical assessment used in the evaluation of peripheral neuropathies. Healthy control 
participants have an average IENF density of 21.1 (standard deviation 10.4) at the thigh and 
13.8 (standard deviation 6.7) in the distal leg.25,26 Typical IENF density findings in TIPN include 
reduced nerve fiber density that is typically more pronounced distally at the lower leg (mean 
3.0, range 0.5-6.3) as compared to the thigh (mean 5.5, range 0.7-13.2).27 As expected, the 
IENF density likely continues to decrease with continued exposure to chemotherapy and 
worsening neuropathy, as a small longitudinal study of patients receiving oxaliplatin found that 
the distal leg IENF density progressively decreased from baseline 15.39 (6.75) to 12.89 (4.73) 
at 6 months to 9.45 (3.92) at 12 months.28 However, IENF density has not been shown to be 
predictive of chemotherapy-induced peripheral neuropathy and, similar to NCS, skin biopsies 
are invasive and may be mildly painful. 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 05/09/18 
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The inflammatory mechanism by which TIPN causes neurotoxicity is poorly understood. Mast 
cells may have a role in the pathophysiology of some other types of chemotherapy-induced 
peripheral neuropathy. A mouse study found that prevention of mast cell degranulation by a 
congenital mast cell deficiency or administration of a mast cell stabilizer could prevent 
oxaliplatin neuropathy.29 Mast cell markers can be detected in serum and increased number or 
atypia of mast cells can be detected on skin biopsy. 
Given the lack of a consensus approach to the diagnosis of TIPN, further research is needed 
to better characterize TIPN that ideally uses non-invasive methods to facilitate serial 
measurements if they are needed. The accurate assessment of TIPN allows for appropriate 
adjustment of taxane chemotherapy dosing and potential improvement of clinical outcomes in 
breast cancer patients. This pilot study will assess the utility of ultrasound as a novel technique 
to assess TIPN. 
2.0 
Objectives 
2.1 
Primary Objectives 
2.1.1 To compare tibial motor nerve ultrasound CSA between TIPN patients and 
historical data among healthy adults. 
2.2 
Secondary Objective 
2.2.1 To compare sural sensory nerve ultrasound CSA between TIPN patients and 
historical data among healthy adults. 
2.2.2 To determine if the above changes in nerve CSA correlate with NCS changes in 
the same TIPN patients. 
2.2.3 To determine if the above changes in nerve CSA correlate with changes on a 
self-reported neuropathy scale (QLQ-CIPN20) in the same TIPN patients. 
2.2.4 To determine if the above changes in nerve CSA correlate with IENF density 
changes on skin biopsy in the same TIPN patients. 
2.3 
Exploratory Objectives 
2.3.1 To assess activated mast cells in skin biopsies in TIPN patients in relation to 
severity of symptoms and above findings. 
2.3.2 To assess serum inflammatory markers in TIPN patients in relation to severity of 
symptoms and above findings. 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 05/09/18 
Page 11 of 39 
3.0 
Study Population 
This study is designed to enroll breast cancer patients with clinically documented symptoms 
consistent with TIPN. 
3.1 
Inclusion Criteria 
o
Breast cancer (any stage).
o
Previously or currently receiving taxane-based chemotherapy.
o
Clinical symptoms of peripheral neuropathy noted in medical record and suspected to
be secondary to taxane-based therapy.
o
Ability and willingness to understand and sign an informed consent.
3.2 
Exclusion Criteria 
o
Self-reported or documented history of pre-existing peripheral neuropathy prior to
initiation of taxane chemotherapy.
o
Male patients.
o
Unable to provide history.
3.3 
Inclusion of women and minorities 
3.3.1 Women of all races and ethnicity who meet the above-described eligibility criteria 
are eligible for this trial. 
3.3.2 The study consent form will also be provided in Spanish for Spanish-speaking 
participants. Male patients will be excluded as the frequency of breast cancer 
among males is low and the frequencies needed to treat men for male breast 
cancer are currently unknown; therefore, 100% of participants to be women. We 
plan to enroll at least 20% Black or African American (N=4). Because of the low 
incidence among American Indian/Alaska Native, Asian, and Hispanic/Latino 
women in our catchment area, we do not expect accruals of individuals of those 
ancestries; however, no ancestry background is being excluded. Should we not 
meet or exceed these estimates, the PI will engage the Cancer Center Health 
Equity Advisory Group to discuss strategies to enhance recruitment in these 
target populations. 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 05/09/18 
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4.0 
Methods 
4.1 
Registration Procedures 
All patients entered on any WFBCCC trial, whether treatment, companion, or cancer 
control trial, must be linked to a study protocol in EPIC within 24 hours of Informed 
Consent. Patients must be registered prior to the initiation of treatment. 
You must perform the following steps in order to ensure prompt registration of your 
patient: 
1. Complete the Eligibility Checklist (Appendix A)
2. Complete the Protocol Registration Form (Appendix B)
3. Complete the Ethnicity Verification Form (Appendix C)
4. Alert the Cancer Center registrar by phone, and then send the signed Informed
Consent Form, Eligibility Checklist and Protocol Registration Form to the registrar,
either by fax or e-mail.
Contact Information: 
Protocol Registrar PHONE (336) 713-6767 
Protocol Registrar FAX (336) 713-6772 
Protocol Registrar E-MAIL (registra@wakehealth.edu) 
*Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday.
5. Fax/e-mail ALL eligibility source documents with registration. Patients will not be
registered without all required supporting documents.
Note: If labs were performed at an outside institution, provide a printout of the results. 
Ensure that the most recent lab values are sent. 
To complete the registration process, the Registrar will: 
•
assign a patient study number
•
register the patient on the study

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 05/09/18 
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4.2 
Study Activities 
Study Calendar* 
Encounter 
1 
Encounter 
2 
Encounter 
3 
Follow-up: 30 days to 
confirm adequate 
healing of biopsy 
Informed Consent 
X 
Medical history (Appendix C) 
X 
Physical exam 
X 
QLQ-CIPN20f 
X 
Blood drawc,f 
X 
Abbreviated Neurologic Exama 
X 
Nerve Conduction Studyb 
X 
Ultrasoundd 
X 
Skin Biopsiese 
X 
Follow-up skin assessment 
X 
* The Study Calendar represents an ideal schedule for the completion of study related activities; however, depending on patient and
physician availability, the completion of these clinical tasks may occur at any clinical encounter. ***The exceptions to this rule are
following: the informed consent should be signed before any research activity occurs, and the blood draw and the QLQ-CPIN20 should
be performed on the same day. While all study related tasks may be completed at a single visit, it is anticipated that due to scheduling,
at least 2 study visits will be required.
a: exam to include strength assessment of the tibialis anterior and gastrocnemius and deep tendon reflex exam of the Achilles on the
limb to be examined with NCV and US.
b: Sural and Tibial nerve assessments
c: Green top heparin tube: 12 ml blood sample
d: Sural and Tibial nerve assessments
e: Two skin biopsies will be obtained as 4mm punch biopsies at distal end of leg in sural nerve territory (10cm above lateral malleolus)
and from the thigh
f: The blood draw and the QLQ-CIPN20 should be performed on the same day.
4.3 
Study setting 
Enrollment of participants will be take place at WFBMC Comprehensive Cancer Center 
(CCC) outpatient clinics.
4.4 
Enrollment (Encounter 1) 
Recruitment information will be posted in the CCC outpatient clinics in the rooms where 
breast cancer patients are treated. Study investigators will also review medical records 
and work with WFBMC clinicians to identify patients who would potentially meet 
inclusion criteria. If a breast cancer patient expresses interest in enrollment on the 
study, a study investigator or research employee will meet the patient in clinic to ensure 
that they are eligible and to obtain consent for enrollment on the study. We anticipate an 
accrual rate of 1-2 participants per month. This is feasible because 242 breast cancer 
patients received taxanes (52% paclitaxel, 45% docetaxel) in 2016 at the WFBCCC 
alone and with additional breast cancer patients treated at the Clemmons satellite office. 
4.5 
Clinical assessment (Encounter 2) 
Clinical assessment will take place in the CCC outpatient clinic and will include a 
focused history by one of the study investigators or research employees. The medical 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 05/09/18 
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record will also be reviewed to confirm details of the medical history. The focused 
history will assess age, body-mass index (BMI), breast cancer staging, types and 
dosages of chemotherapy received, corticosteroid and analgesic use, and presence of 
comorbidities (diabetes, B12 deficiency, thyroid disorders, alcoholism, depression, 
carpal tunnel syndrome, sciatica). . A physical examination will occur to document 
strength and reflexes. The QLQ-CIPN20 questionnaire will also be administered at this 
encounter. 
In most cases, blood testing will be added on to regularly scheduled phlebotomy for 
clinical labs which are drawn as part of routine oncology care. Some participants may 
require an additional blood draw if insufficient blood samples were collected. For the 
purposes of our study, 12mL of venous blood will be collected in a sodium heparin 
(green-top) collection tube and then transferred directly to Dr. Shiozawa’s lab for 
processing. 
Blood Sample Preparation 
1. Email notification will be sent to Matt Eber (meber@wakehealth.edu), Sun Park
(shpark@wakehealth.edu) and Yusuke Shiozawa (yshiozaw@wakehealth.edu) the day
before the blood collection.
2. Blood will be collected in two green-top vacutainer tubes containing heparin (60 USP Units of
Lithium Heparin/6ml tube), and immediately inverted 8-10 times to prevent coagulation.
Attention: Protocol #: CCCWFU # (97217) and the ORIS PID in addition to the other
standard information should be on the tube.
3. Samples will then be transported from the Cancer Center to the Shiozawa lab (Lab: 3-6624,
3-5119, Office: 6-8743).
4.6 
Diagnostic testing (Encounter 3) 
Participants will be referred to Diagnostic Neurology clinic for and abbreviate 
neurological exam to assess strength of the tibialis anterior and gastrocnemius and 
deep tendon reflex exam of the Achilles tendon on the limb to be examined in nerve 
conduction studies and ultrasound evaluation during this encounter. Further, a skin 
biopsy will be obtained.  These tests will be completed at a single visit and no further 
follow-up with neurology is required as part of the study protocol. All of these studies are 
considered standard clinical tests for the evaluation of peripheral neuropathy and 
sensory neuropathy. Patients will receive a Visa gift card upon completion of the 
neuropathy assessment. 
Peripheral nerve US technique and reference values for the sural sensory (measured at 
the ankle) and tibial motor nerves are based on institutional data and standard 
institutional practice. These reference values were de-identified historical data which 
have also been published by Cartwright et al.(2008) 8 as noted in the Introduction and 
Background section. Peripheral nerves will be assessed at non-compressive sites with a 
routine 15Hz linear probe. If available, a higher resolution 70Hz linear probe may be 
used – this would allow for descriptive characterization of nerve changes and would not 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 05/09/18 
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be anticipated to cause variability in terms of CSA measurement as compared to the 
standard 15Hz US. 
NCS technique and reference values for the sural and tibial nerves among healthy 
adults are based on data from Chen et al. (2016) and standard institutional practice 30. 
NCS assessment of the sural sensory nerve involves electrode placement at the ankle 
(posteroinferior to the lateral malleolus) and more distally with a 3cm bar for a distance 
of approximately 14cm; the nerve is stimulated at the calf midline with a display 
sensitivity 2-5 uV/div and sweep of 1 ms/div. The sural sensory nerve reference values 
for amplitude is a lower limit (3rd percentile) of 4 uV (onset-to-peak) and 4 uV (peak-to-
peak); and for latency is an upper limit (97th percentile) of 3.6 ms (onset) and 4.5 ms 
(peak). NCS assessment of the tibial motor nerve involves electrode placement at the 
medial foot (slightly anterior/inferior to the navicular tubercle) and more distally at the 
first metatarsophalangeal (MTP) joint for a distance of approximately 8cm; the nerve is 
stimulated at the ankle (posterior to the medial malleolus) and knee (at the midpopliteal 
fossa) with a display sensitivity 5 mV/div and sweep of 5 ms/div. The tibial motor nerve 
reference values for distal amplitude is a lower limit (3rd percentile) of 4.4 mV across all 
ages; and for distal latency is an upper limit (97th percentile) of 6.1 ms. 
Two skin biopsies will be obtained as 4-5mm punch biopsies at distal end of leg in sural 
nerve territory (10cm above lateral malleolus) and in the upper thigh. As described in a 
review by Lauria and Devigili (2007),31 biopsied tissue will be cut into 50 uM sections 
which will be hematoxylin and eosin stained and also immunostained with an antibody 
to PGP (protein gene product) 9.5, a neuron- and neuroendocrine cell-specific ubiquitin 
carboxy-terminal hydrolase expressed throughout the peripheral nervous system. Slides 
will be reviewed by Dermatopathology (Dr. Ahn and/or Dr. Sangueza) in order to count 
PGP9.5-positive fibers as they cross the dermal-epidermal junction to calculate linear 
density of IENF (IENF/mm). Additional staining will be done as indicated. Routine 
processing of specimens and comparison to standardized values (similar to those 
described by McArthur et al.(1998))25 will be done by Dermatopathology as per their 
institutional guidelines. These methods are standard clinical procedures for the routine 
assessment of IENF density. Dermatopathology will also obtain descriptive measures of 
morphologic changes that will be analyzed as an exploratory outcome. Additional 
unstained slides or blocks will be stored and transferred to Dr. Shiozawa’s lab for 
staining and testing of mast cell concentration, tryptase, chymase and histamine. The 
results will be recorded on Appendix E for transfer into REDCap. 
Storage of Serum and Skin Biopsy Material 
Venous blood will be stored in lab refrigerator prior to transfer (in oncology lab) and after 
transfer (in Dr. Shiozawa’s lab). Serum and left over skin biopsy material from patients 
will be stored in Dr. Shiozawa’s laboratory in the Department of Cancer Biology until 
use. 
Tests Using Serum 
Serum testing for inflammatory markers will be performed using commercially available 
kit that may include but not be limited to ELISA and will be performed according to the 

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manufacturers’ instructions and modified accordingly if needed given the type of sample 
and/or target of interest to be detected. Data resulting from these experiments may be 
kept in laboratory notebooks or in on the data sheets provided in Appendix C. 
4.7 
Follow-up 
Results of diagnostic testing will be made available in the participant's medical record. If 
unexpected abnormalities are detected, the primary oncologist will be contacted and a 
Neurology referral can be placed as part of the patient’s routine clinical care. The 
patient will also be followed for 30 days to ensure the biopsy site is healing adequately. 
This follow up may be by telephone or in person. 
4.8 
Data entry/storage 
Paperwork with identifying patient information will be stored at the investigator’s 
workspace in the locked workroom of the Hem/Onc 1st floor Watlington office or in the 
lab notebook of Dr. Shiozawa in his locked lab; both are located on the WFBMC 
campus. Electronic data will be stored on the secure personal computers of the 
investigators on the medical center campus prior to transfer into the secure RedCap 
online database. 
5.0 
Outcome Measures 
Listed below are the primary, secondary and exploratory outcomes. However, given this is a pilot 
study, other parameters associated with nerve conduction and ultrasound studies will be captured 
and may be used for exploratory analyses and will include, but will not be limited to latency for nerve 
conduction studies and for ultrasound, echogenicity, vascularity, fascicle concentration, and other 
qualitative descriptions of nerve changes. 
5.1 
Primary Outcome 
5.1.1 Tibial nerve CSA as determined by ultrasound in the tibial nerve in TIPN patients 
and derived from historical controls. 
5.2 
Secondary Outcomes 
5.2.1 Sural nerve CSA as determined by ultrasound of the sural nerve in TIPN patients 
and derived from historical controls. 
5.2.2 Amplitude, distal latency, and conduction velocity of nerve response derived from 
NCS in TIPN patients. 
5.2.3 Self-reported neuropathy score as assessed by the EORTC QLQ-CIPN20. 
5.2.4 Nerve fiber density in the skin (IENF/mm) in TIPN patients. 
5.3 
Exploratory Outcome 
5.3.1 The number of activated mast cells (per mm) in TIPN patients 

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5.3.2 Serum levels of inflammatory molecules  in TIPN patients chosen at the 
investigators discretion 
5.4 
Covariates 
5.4.1 BMI 
5.4.2 Age 
5.4.3 Breast cancer staging 
5.4.4 Types/dosages of chemotherapy and corticosteroids received 
5.4.5 Presence of previously documented comorbidities (diabetes, B12 deficiency, 
thyroid disorders, alcoholism, depression, carpal tunnel syndrome, sciatica) 
5.4.6 Use of analgesics or treatments for neuropathy 
5.4.7 History of clinically documented compressive neuropathy (carpal tunnel 
syndrome) 
6.0 
Analytic Plan 
6.1 
Sample Size and Power 
6.1.1 Primary outcome: 
This current study will enroll a sample size of 22 in TIPN patients to compare to 
historical data that was previously collected from 60 healthy patients. Using a 
two-sided test and significance level of 0.05, we will have an 80% power to 
detect an effect size of 0.73 (unit: standard deviation [SD]) when comparing TIPN 
patients to that historical data. We have permission to utilize historical data 
(primary data) collected from healthy patients which found that the mean and SD 
of the tibial nerve CSA were 14.2 and 4.4 mm2, respectively (published by 
Cartwright et al., 2008). Assuming the same SD in TIPN patients, we will have 
more than 80% power to detect a difference of 3.2 mm2 for the tibial nerve.  
Based on Riazi et al. (2012),32 the mean increase in size of tibial nerve was 5.3 
when comparing subjects with diabetic sensorimotor polyneuropathy and control 
subjects. Even though the study sample is not exactly the same, with the minimal 
detectable difference equal to 3.2, we should have sufficient power for this 
analysis. 
6.1.2 Secondary outcome: 
In historical data collected from healthy patients (Cartwright et al., 2008),8 the 
mean and standard deviation (SD) of the sural nerve CSA were 5.3 and 1.8 mm2, 
respectively. Assuming the same SDs in TIPN patients, we will have more than 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
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80% power to detect a detectable difference of 1.3 mm2 for the sural nerve 
between TIPN patients and healthy patients. 
6.2 
Analysis of Primary Outcome 
The distribution of the primary outcome, nerve CSA, will be transformed to satisfy 
conditional normality assumption if necessary.  It will be compared to the historical data 
from healthy patients using two-sample t-test (two-sample t-test selected as primary 
data from the historical control patients is available and will be used for analysis).  We 
will also compare the nerve CSA in our study sample to that in the historical diabetic 
neuropathy patients and historical oxaliplatin neuropathy patients using one-sample t-
test.  The general linear model will be used to evaluate any factors (e.g., age) that may 
be associated with the nerve CSA. Due to the limited sample size, no more than two 
covariates will be included in the model. 
6.3 
Analysis of Secondary Outcome 
The analysis of sural sensory nerve CSA will be the same as that specified for primary 
outcome. To examine the associations between nerve CSA and NCS measures, the 
self-reported neuropathy scale, and intraepidermal nerve fiber density, Spearman’s rank 
correlation coefficient will be used.  The general linear model will be also used to 
evaluate the association after adjusting for one or two risk factors (e.g., age). Nerve 
CSA will be treated as the dependent variable. NCS measures, the self-reported 
neuropathy scale, and intraepidermal nerve fiber density are the covariates of interest.  
They will be fitted in the model one at a time. 
6.4 
Analyses of Exploratory Outcomes 
Spearman’s rank correlation coefficient will be used to assess the associations between 
activated mast cells in skin biopsies, serum inflammatory markers, severity of 
symptoms, and primary outcome and secondary outcomes in TIPN patients. 
6.5 
Accrual Rate 
1-2 participants per month
6.6 
Length of Study 
16-20 months
7.0 
Data Management 
Informed consent document 
EPIC 
Protocol Eligibility Form 
Protocol Registration Form (Appendix B) 
ORIS 
Race and Ethnicity Verification Form 
Clinical Evaluation from History/Exam (Appendix D) 
REDCap 
Exploratory Outcome Data Collection Form (Appendix E) 
REDCap 
EORTC QLQ-CIPN20 (neuropathy scale) (Appendix F) 
REDCap 
Nerve Fiber Density Data Collection Form (Appendix G) 
REDCap 
Ultrasound Nerve Diameter Data Form (Appendix H) 
REDCap 

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Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
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Nerve Conduction Study Data Collection Form (Appendix I) 
REDCap 
Adverse Events Log (Appendix J) 
ORIS 
8.0 
Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly identify 
subjects, and maintaining all study information in a secure manner. To help ensure subject privacy 
and confidentiality, only a unique study identifier will appear on the data collection form. Any collected 
patient identifying information corresponding to the unique study identifier will be maintained on a 
linkage file, store separately from the data. The linkage file will be kept secure, with access limited to 
designated study personnel. Following data collection subject identifying information will be destroyed 
(state the anticipated time the data will be destroyed, e.g. three years after closure of the study, and 
the method of destruction), consistent with data validation and study design, producing an 
anonymous analytical data set. Data access will be limited to study staff. Data and records will be 
kept locked and secured, with any computer data password protected. No reference to any individual 
participant will appear in reports, presentations, or publications that may arise from the study. 
9.0 
Data Safety and Monitoring 
The principal investigator will be responsible for the overall monitoring of the data and safety of study 
participants. The principal investigator will be assisted by other members of the study staff. 
10.0 Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol changes 
will be promptly reported by the principal investigator or designated member of the research team to 
the IRB and sponsor or appropriate government agency if appropriate. 
Adverse events will be tracked for 30 days following skin biopsy. This time is adequate to evaluate for 
potential adverse events from this and all study procedures. Adverse events will not be tracked beyond 30 
days following the neurodiagnostic and skin biopsy procedures unless a delayed event is felt to be related to 
the study intervention.  

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Giordano SH, Lin YL, Kuo YF, Hortobagyi GN, Goodwin JS. Decline in the use of
anthracyclines for breast cancer. Journal of clinical oncology : official journal of the American
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2.
Baas PW, Ahmad FJ. Beyond taxol: microtubule-based treatment of disease and injury of the
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3.
Augusto C, Pietro M, Cinzia M, et al. Peripheral neuropathy due to paclitaxel: study of the
temporal relationships between the therapeutic schedule and the clinical quantitative score
(QST) and comparison with neurophysiological findings. Journal of neuro-oncology.
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Pace A, Nistico C, Cuppone F, et al. Peripheral neurotoxicity of weekly paclitaxel
chemotherapy: a schedule or a dose issue? Clin Breast Cancer. 2007;7(7):550-554.
5.
Speck RM, Sammel MD, Farrar JT, et al. Impact of chemotherapy-induced peripheral
neuropathy on treatment delivery in nonmetastatic breast cancer. Journal of oncology practice
/ American Society of Clinical Oncology. 2013;9(5):e234-240.
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Budman DR, Berry DA, Cirrincione CT, et al. Dose and dose intensity as determinants of
outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B.
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Walker FO, Cartwright MS, Wiesler ER, Caress J. Ultrasound of nerve and muscle. Clin
Neurophysiol. 2004;115(3):495-507.
8.
Cartwright MS, Passmore LV, Yoon JS, Brown ME, Caress JB, Walker FO. Cross-sectional
area reference values for nerve ultrasonography. Muscle Nerve. 2008;37(5):566-571.
9.
Arumugam T, Razali SN, Vethakkan SR, Rozalli FI, Shahrizaila N. Relationship between
ultrasonographic nerve morphology and severity of diabetic sensorimotor polyneuropathy. Eur
J Neurol. 2016;23(2):354-360.
10.
Briani C, Campagnolo M, Lucchetta M, et al. Ultrasound assessment of oxaliplatin-induced
neuropathy and correlations with neurophysiologic findings. Eur J Neurol. 2013;20(1):188-192.
11.
Sittl R, Lampert A, Huth T, et al. Anticancer drug oxaliplatin induces acute cooling-aggravated
neuropathy via sodium channel subtype Na(V)1.6-resurgent and persistent current.
Proceedings of the National Academy of Sciences of the United States of America.
2012;109(17):6704-6709.
12.
Park SB, Goldstein D, Krishnan AV, et al. Chemotherapy-induced peripheral neurotoxicity: a
critical analysis. CA: a cancer journal for clinicians. 2013;63(6):419-437.
13.
Lavoie Smith EM, Barton DL, Qin R, Steen PD, Aaronson NK, Loprinzi CL. Assessing patient-
reported peripheral neuropathy: the reliability and validity of the European Organization for
Research and Treatment of Cancer QLQ-CIPN20 Questionnaire. Qual Life Res.
2013;22(10):2787-2799.
14.
Reeves BN, Dakhil SR, Sloan JA, et al. Further data supporting that paclitaxel-associated
acute pain syndrome is associated with development of peripheral neuropathy: North Central
Cancer Treatment Group trial N08C1. Cancer. 2012;118(20):5171-5178.
15.
Eckhoff L, Knoop A, Jensen MB, Ewertz M. Persistence of docetaxel-induced neuropathy and
impact on quality of life among breast cancer survivors. European journal of cancer.
2015;51(3):292-300.

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Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 05/09/18 
Page 21 of 39 
16.
Mols F, van de Poll-Franse LV, Vreugdenhil G, et al. Reference data of the European
Organisation for Research and Treatment of Cancer (EORTC) QLQ-CIPN20 Questionnaire in
the general Dutch population. European journal of cancer. 2016;69:28-38.
17.
Forsyth PA, Balmaceda C, Peterson K, Seidman AD, Brasher P, DeAngelis LM. Prospective
study of paclitaxel-induced peripheral neuropathy with quantitative sensory testing. Journal of
neuro-oncology. 1997;35(1):47-53.
18.
Hershman DL, Weimer LH, Wang A, et al. Association between patient reported outcomes and
quantitative sensory tests for measuring long-term neurotoxicity in breast cancer survivors
treated with adjuvant paclitaxel chemotherapy. Breast Cancer Res Treat. 2011;125(3):767-
774.
19.
Chen X, Stubblefield MD, Custodio CM, Hudis CA, Seidman AD, DeAngelis LM.
Electrophysiological features of taxane-induced polyneuropathy in patients with breast cancer.
J Clin Neurophysiol. 2013;30(2):199-203.
20.
Argyriou AA, Polychronopoulos P, Iconomou G, Koutras A, Kalofonos HP, Chroni E. Paclitaxel
plus carboplatin-induced peripheral neuropathy. A prospective clinical and electrophysiological
study in patients suffering from solid malignancies. J Neurol. 2005;252(12):1459-1464.
21.
Argyriou AA, Polychronopoulos P, Koutras A, et al. Clinical and electrophysiological features of
peripheral neuropathy induced by administration of cisplatin plus paclitaxel-based
chemotherapy. European journal of cancer care. 2007;16(3):231-237.
22.
Cavaletti G, Bogliun G, Marzorati L, et al. Grading of chemotherapy-induced peripheral
neurotoxicity using the Total Neuropathy Scale. Neurology. 2003;61(9):1297-1300.
23.
Park SB, Goldstein D, Lin CS, Krishnan AV, Friedlander ML, Kiernan MC. Acute abnormalities
of sensory nerve function associated with oxaliplatin-induced neurotoxicity. Journal of clinical
oncology : official journal of the American Society of Clinical Oncology. 2009;27(8):1243-1249.
24.
Osmani K, Vignes S, Aissi M, et al. Taxane-induced peripheral neuropathy has good long-term
prognosis: a 1- to 13-year evaluation. J Neurol. 2012;259(9):1936-1943.
25.
McArthur JC, Stocks EA, Hauer P, Cornblath DR, Griffin JW. Epidermal nerve fiber density:
normative reference range and diagnostic efficiency. Archives of neurology. 1998;55(12):1513-
1520.
26.
Han Y, Smith MT. Pathobiology of cancer chemotherapy-induced peripheral neuropathy
(CIPN). Frontiers in pharmacology. 2013;4:156.
27.
Kroigard T, Schroder HD, Qvortrup C, et al. Characterization and diagnostic evaluation of
chronic polyneuropathies induced by oxaliplatin and docetaxel comparing skin biopsy to
quantitative sensory testing and nerve conduction studies. Eur J Neurol. 2014;21(4):623-629.
28.
Burakgazi AZ, Messersmith W, Vaidya D, Hauer P, Hoke A, Polydefkis M. Longitudinal
assessment of oxaliplatin-induced neuropathy. Neurology. 2011;77(10):980-986.
29.
Sakamoto A, Andoh T, Kuraishi Y. Involvement of mast cells and proteinase-activated receptor
2 in oxaliplatin-induced mechanical allodynia in mice. Pharmacol Res. 2016;105:84-92.
30.
Chen S, Andary M, Buschbacher R, et al. Electrodiagnostic reference values for upper and
lower limb nerve conduction studies in adult populations. Muscle Nerve. 2016;54(3):371-377.
31.
Lauria G, Devigili G. Skin biopsy as a diagnostic tool in peripheral neuropathy. Nature clinical
practice Neurology. 2007;3(10):546-557.
32.
Riazi S, Bril V, Perkins BA, et al. Can ultrasound of the tibial nerve detect diabetic peripheral
neuropathy? A cross-sectional study. Diabetes care. 2012;35(12):2575-2579.

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
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Appendix A: Subject Eligibility Checklist 
IRB Protocol No. 00043631 
CCCWFU Protocol No. 97217 
Study Title: A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Principal Investigators:  Roy Strowd, M.D., Glenn Lesser, M.D 
Inclusion Criteria 
(as outlined in study protocol) 
Criteria 
is met 
Criteria is 
NOT met 
Source Used to Confirm * 
(Please document dates and lab results) 
Breast cancer (any stage). 
□ 
□ 
Previously or currently receiving taxane-
based chemotherapy 
□ 
□ 
Clinical symptoms of peripheral 
neuropathy noted in medical record 
□ 
□ 
Ability and willingness to understand and 
sign an informed consent 
□ 
□ 
Exclusion Criteria 
(as outlined in study protocol) 
Criteria 
NOT 
present 
Criteria is 
present 
Source Used to Confirm * 
(Please document dates and lab results) 
Self-reported or documented history of 
pre-existing peripheral neuropathy prior 
to initiation of taxane chemotherapy 
□ 
□ 
Unable to provide history 
□ 
□ 
Male patients 
□ 
□ 
This subject is      
 eligible / 
ineligible     for participation in this study. 
ORIS Assigned PID: __ __ __ __ __ __ __ __ 
Signature of research professional confirming eligibility:_______________________ 
Date: __ __/__ __/__ __ 
Signature of Treating Physician:  ____________________________Date:  __ __/__ __/__ __ 
Signature of Principal Investigator**:  ________________________  Date:  __ __/__ __/__ __ 
* Examples of source documents include clinic note, pathology report, laboratory results, etc. When listing the source,
specifically state which document in the medical record was used to assess eligibility. Also include the date on the
document. Example: “Pathology report, 01/01/14” or “Clinic note, 01/01/14”
**Principal Investigator signature can be obtained following registration if needed 

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Protocol version date 05/09/18 
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Appendix B: Protocol Registration Form 
DEMOGRAPHICS 
Patient: Last Name: _____________________ First Name: ___________________________ 
MRN:          ___ ___ ___ ___ ___ ___ ___ ___ DOB (mm/dd/yy): ___ ___ / ___ ___ / ___ ___ 
ZIPCODE: ___ ___ ___ ___ ___ 
SEX: 
 Male      Female 
Ethnicity (choose one):  Hispanic 
Non-Hispanic
Race (choose all that 
apply): 
 WHITE           BLACK            ASIAN 
 PACIFIC ISLANDER                 NATIVE AMERICAN 
Height:   ___ ___.___ inches 
Weight: ___ ___ ___.___lbs.(actual) 
Surface Area: ___ ___.___m2 
         BMI: ___ ___.___kg/m2 
Primary Diagnosis: ____________________________________________________________ 
Date of Diagnosis: ___ ___ /___ ___/___ ___ 
 
Performance Status: ___ ___ ___    ECOG   Karnofsky 
Protocol Registrar can be contact by calling 336-713-6767 between 8:30 AM and 4:00 PM, Monday – Friday. 
Completed Eligibility Checklist and Protocol Registration Form must be hand delivered, faxed or e-mailed to the registrar at 
336-7136772 or registra@wakehealth.edu.
PROTOCOL INFORMATION 
Date of Registration: 
___ ___ / ___ ___ / ___ ___ 
MD Name (last) : 
______________________ 
Date protocol treatment started: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to registration) 
YES  NO
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
PID # (to be assigned by ORIS): 
___ ___ ___ ___ ___ ___ ___ ___ 

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Appendix C - Race & Ethnicity Verification Form 
Thank you so much for helping us to verify your race and ethnicity to ensure the quality of our 
information. As a brief reminder, the information you provide today will be kept confidential. 
1. Are you:
Hispanic or Latino/a 
Not Hispanic or Latino/a 
2. What is your race? One or more categories may be selected.
White or Caucasian 
Black or African American 
American Indian or Alaskan Native 
Asian 
Native Hawaiian or Other Pacific Islander 
Other, Please Specify: ___________________________ 
Internal use only: 
Name: ____________________ MRN#: ___ ___ ___ ___ ___ ___ ___ ___ 
Was the self-reported race and ethnicity of the participant verified at the time of consent? 
Yes        No 
Was a discrepancy found?       Yes   
 No 
If yes, please provide what is currently indicated in the EMR: 
Ethnicity: ____________________ 
Race: ____________________ 
Additional comments: __________________________________________________________________ 
_____________________________________________________________________________________ 
_____________________________________________________________________________________

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Appendix D: Clinical Evaluation from History/Exam 
ORIS PID: __ __ __ __ __ __ __ __ 
Date Completed: __ __ / __ __ / __ __ 
PI: Roy Strowd, M.D., Glenn Lesser, M.D.  Study Number: CCCWFU 97217 
Instructions: To be filled out by medical staff. 
1. Oncologic history
Diagnosis and stage: ________________________________
a. Most immediate prior cancer therapy (select one):
 chemotherapy  
 radiation 
 surgery  
 hormone  
 other: 
___________________________ 
b. Specify most immediate prior taxane chemotherapy:
______________________________________________
Dates of administration:  Started: __ __ / __ __ / __ __  Stopped: __ __ / __ __ / __ __ 
Dose ___________ & total # of treatments ________ 
c. Other prior cancer therapies (excluding 1b.) for most recent cancer. Mark all that apply:
 None  
 Chemotherapy  
 Radiation  
 Surgery  
 Hormone therapy  
 Other: 
_____________ 
Regimen Name 
Total # of Treatments 
Date of Last Treatment, or 
‘ongoing’ for certain HT 
1. 
__ __ / __ __ / __ __ 
2. 
__ __ / __ __ / __ __ 
3. 
__ __ / __ __ / __ __ 
4. 
__ __ / __ __ / __ __ 
5. 
__ __ / __ __ / __ __ 
6. 
__ __ / __ __ / __ __ 
7. 
__ __ / __ __ / __ __ 
8. 
__ __ / __ __ / __ __ 
9. 
__ __ / __ __ / __ __ 
10. 
__ __ / __ __ / __ __ 
Site of RT 
Total Dose in Gy 
Date of Last Treatment 
1. 
__ __ / __ __ / __ __ 
2. 
__ __ / __ __ / __ __ 
3. 
__ __ / __ __ / __ __ 
4. 
__ __ / __ __ / __ __ 
5. 
__ __ / __ __ / __ __ 
Type of surgery 
Date of surgery 
1. 
__ __ / __ __ / __ __ 
2. 
__ __ / __ __ / __ __ 

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Hormone Therapy Name 
Dose 
Date of Last Treatment 
1. 
__ __ / __ __ / __ __ 
2. 
__ __ / __ __ / __ __ 
Other 
Dose 
Date of Last Treatment 
1. 
__ __ / __ __ / __ __ 
2. 
__ __ / __ __ / __ __ 
2. Medical history (check all that apply):
 Thyroid Disorder 
 Hyperthyroidism 
Hypothyroidism 
 Vitamin B12 deficiency 
 Peripheral vascular disease (claudication, arterial bypass, untreated aneurysm 
(≥6cm) 
 Cerebrovascular disease (history of TIA or CVA) 
 Alcoholism 
 Carpal tunnel syndrome 
 Sciatica 
 Diabetes 
end organ damage? Yes 
 
No 
 AIDS 
 Depression 
 Other major medical condition; specify 
___________________________________________________________________
___________________________________________________________________
___________________________________________________________________ 
4.
Concurrent medications and supplements
a. List all prescription and over-the-counter medications (includes prescription supplements)
Medication Name 
Is it PRN? 
Medication Name 
Is it PRN? 
1. 
yes    
no 
11. 
yes    
no 
2. 
yes    
no 
12. 
yes    
no 
3. 
yes    
no 
13. 
yes    
no 
4. 
yes    
no 
14. 
yes    
no 
5. 
yes    
no 
15. 
yes    
no 
6. 
yes    
no 
16. 
yes    
no 
7. 
yes    
no 
17. 
yes    
no 
8. 
yes    
no 
18. 
yes    
no 

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Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
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9. 
yes    
no 
19. 
yes    
no 
10. 
yes    
no 
20. 
yes    
no 
b. List all supplements (excludes prescription supplements)
Supplement Name 
Is it PRN? 
Supplement Name 
Is it PRN? 
1. 
yes    
no 
11. 
yes    
no 
2. 
yes    
no 
12. 
yes    
no 
3. 
yes    
no 
13. 
yes    
no 
4. 
yes    
no 
14. 
yes    
no 
5. 
yes    
no 
15. 
yes    
no 
6. 
yes    
no 
16. 
yes    
no 
7. 
yes    
no 
17. 
yes    
no 
8. 
yes    
no 
18. 
yes    
no 
9. 
yes    
no 
19. 
yes    
no 
10. 
yes    
no 
20. 
yes    
no 
5.
Physical exam:
Derm – 
 WNL 
 Abnormal, specify ______________________________ 
HEENT – 
 WNL 
 Abnormal, specify ______________________________ 
CV – 
 WNL 
 Abnormal, specify ______________________________ 
Pulm – 
 WNL 
 Abnormal, specify ______________________________ 
GI – 
 WNL 
 Abnormal, specify ______________________________ 
Other – 
 Abnormal, specify ____________________________ 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 03/02/18 
Page 28 of 39 
Appendix E: Exploratory Outcomes Data Collection Form 
ORIS PID: __ __ __ __ __ __ __ __ 
Date Completed: __ __ / __ __ / __ __ 
PI: Roy Strowd, M.D., Glenn Lesser, M.D.  Study Number: CCCWFU 97217 
Instructions 
•
Use the ORIS PID to Identify the Sample
•
Date is the date of experimentation
•
Target Name (Serum Outcomes): Name of the target of the assay
•
Record amounts to 3 decimal places (serum outcomes)
•
Initials of person performing the assay.
*Do not erase entries. If an entry is incorrect, cross the entry out, initial, and write in the correct entry. Please write neatly.
Exploratory Outcomes Data Form
Date of blood 
sample collection 
Serum Outcomes 
IHC and Positive Cell Count 
Target Name 
Amount 
(ng/ml) 
Initials 
Mast Cell 
Number 
Tryptase 
Chymase 
Histamine 
__ __/__ __/__ __ 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral 
Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 03/02/18 
Page 29 of 39 
Appendix F QLQ-CIPN20 
ORIS PID: __ __ __ __ __ __ __ __ Date Completed: __ __ / __ __ / __ __ 
PI: Roy Strowd, M.D., Glenn Lesser, M.D.      Study Number: CCCWFU 97217 
EORTC QLQ-CIPN20 
Patients sometimes report that they have these following symptoms or problems. Please indicate 
the extent to which you have experienced these symptoms or problems during the past week. 
Please answer by circling the number that best applies to you. 
DURING THE PAST WEEK 
Not at 
all 
A 
little 
Quite 
a bit 
Very 
much 
1) Did you have tingling fingers or hands
1 
2 
3 
4 
2) Did you have tingling toes or feet?
1 
2 
3 
4 
3) Did you have numbness in your fingers or hands?
1 
2 
3 
4 
4) Did you have numbness in your toes or feet?
1 
2 
3 
4 
5) Did you have shooting or burning pain in your fingers or hands?
1 
2 
3 
4 
6) Did you have shooting or burning pain in your toes or feet?
1 
2 
3 
4 
7) Did you have cramp in your hands?
1 
2 
3 
4 
8) Did you have cramp in your feet?
1 
2 
3 
4 
9) Did you have problems standing or walking because of a
difficulty in feeling the ground under your feet?
1 
2 
3 
4 
10) Did you have difficulty in distinguishing between hot and cold
water?
1 
2 
3 
4 
11) Did you have a problem holding a pen, which made writing
difficult?
1 
2 
3 
4 
12) Did you have difficulty in manipulating small objects with
your fingers (for example, fastening small buttons)?
1 
2 
3 
4 
13) Did you have difficulty in opening a jar or bottle because of
weakness in your hand?
1 
2 
3 
4 
14) Did you have difficulty because your feet dropped
downwards?
1 
2 
3 
4 
15) Did you have difficulty in climbing stairs or getting up out of a
chair because of weakness in your legs?
1 
2 
3 
4 
16) Were you dizzy when standing up from a sitting or lying
position?
1 
2 
3 
4 
17) Did you have blurred vision?
1 
2 
3 
4 
Please, answer the following question, only if you drive a car
18) Did you have difficulty using pedals?
1 
2 
3 
4 
Please, answer the following question, only if you are a man 
19) Did you have difficulty in having or maintaining an erection?
1 
2 
3 
4 
Adapted from Postma et al. 2005 and Cavaletti et al. 2009 
Excludes the question: “Did you have difficulty in hearing?” 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral 
Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 03/02/18 
Page 30 of 39 
Appendix G: Nerve Fiber Density Data Collection Form 
ORIS PID: __ __ __ __ __ __ __ __ 
Date Completed: __ __ / __ __ / __ __ 
PI: Roy Strowd, M.D., Glenn Lesser, M.D.  Study Number: CCCWFU 97217 
Instructions 
•
Use the ORIS PID to Identify the Sample
•
Date is the date of experimentation and listed before the technique. Use the following
format: __ __/__ __/__ __
•
Initials of person performing the assay.
*Do not erase entries. If an entry is incorrect, cross the entry out, initial, and write in the
correct entry. Please write neatly.
Date of Biopsy: __ __/__ __/__ __ 
Nerve Fiber Density Form 
Location of Biopsy (Distal/Leg 
or Proximal/Thigh) 
Nerve Fiber Density 
(IENF/mm) 
Initials of 
Dermatologist/ 
Pathologist 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral 
Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 03/02/18 
Page 31 of 39 
Appendix H: Ultrasound Nerve Diameter Data Form 
ORIS PID: __ __ __ __ __ __ __ __ 
Date Completed: __ __ / __ __ / __ __ 
PI: Roy Strowd, M.D., Glenn Lesser, M.D.  Study Number: CCCWFU 97217 
To be used for determination of tibial and sural nerve diameters. 
Date of Procedure:  __ __/__ __/__ __ 
Person recording information: ________________________________ 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 03/02/18 
Page 32 of 39 
Appendix I: Nerve Conduction Study Data Collection Form 
ORIS PID: __ __ __ __ __ __ __ __ 
Date Completed: __ __ / __ __ / __ __ 
PI: Roy Strowd, M.D., Glenn Lesser, M.D.  Study Number: CCCWFU 97217 
Instructions 
•
Use the ORIS PID to Identify the Sample
•
Date is the date of experimentation and listed before the technique. Use the following format: __ __/__ __/__ __
•
Initials of person collecting the data.
*Do not erase entries. If an entry is incorrect, cross the entry out, initial, and write in the correct entry. Please write neatly.
Nerve Conduction Worksheet
Date of Nerve 
Conduction Study 
Conduction studies 
Initials of 
Neurologist 
Tibial 
Sural 
Amplitude 
Latency 
Conduction 
Velocity 
Amplitude 
Latency 
Conduction 
Velocity 
__ __/__ __/__ __ 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 03/02/18 
Page 33 of 39 
Appendix J: Adverse Events Log 
CCCWFU 97217 Adverse Event (AE) Log 
PI: Roy Strowd, M.D., 
Glenn Lesser, M.D 
PID: __ __ __ __ __ __ __ __ 
MRN: __ __ __ __ __ __ __ __ 
Adverse Event CTC 
Term 
Value 
(-5 if non-
numeric) 
Grade 
(0-5) per 
CTC 
Start 
Date 
Attribution 
1=Related 
2=Probably 
3=Possible 
4=Unlikely 
5=Unrelated 
Treating MD 
Initials/Date 
End Date 
Expected 
1=Yes       
0=No 
*Serious
Adverse
Event (SAE)  
1=Yes 0=No 
Dose 
Limiting 
Toxicity 
(DLT) 
1=Yes 
0=No 
Action 
Taken 
1=None     
2=Tx 
withheld 
3=Tx D/C   
4=Tx 
adjusted 
5=Other 
Reportable?  
1=IRB 
2=STRC 
3=FDA 
4=Sponsor 
Injection site 
reaction 
Skin infection 
Infections and 
infestations - other 
Bruising 
Dizziness 
Syncope 
*Serious Adverse Event: Hospitalization; Disability; Birth Defect; Life-threatening; Death.
CTCAE Version 4 - http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 03/02/18 
Page 34 of 39 
Appendix K: Follow-up Form for Skin Biopsy 
ORIS PID: __ __ __ __ __ __ __ __ 
Date Completed: __ __ / __ __ / __ __ 
PI: Roy Strowd, M.D., Glenn Lesser, M.D.  Study Number: CCCWFU 97217 
Date of Skin Biopsy 
Phone / In-person 
assessment completed 
within 30 days 
(circle one) 
Any skin biopsy 
problems reported 
by participant? 
__ __/__ __/__ __ 
__ __/__ __/__ __ 
Yes     /     No 
Yes     /     No 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral 
Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 03/02/18 
Page 35 of 39 
Appendix L: Mandatory STRC SAE Reporting Requirements 
Safety and Toxicity Review Committee 
(STRC; previously known as CROC)  Serious 
Adverse Event (SAE) Notification SOP 
  Date: 11/17/2016 
Mandatory STRC SAE Reporting Requirements 
This document describes STRC reporting and use of the electronic submission form that is 
submitted for unexpected grade 4 and any grade 5 (death during protocol intervention) SAEs 
on CCCWFU Institutional interventional trial patients. There are multiple entities that require 
reporting of SAEs. Each entity has different rules for what is reported, and how it is reported.  
Rules used by other entities (Institutional Review Board (IRB), AdEERS, MedWatch, etc.) should 
NOT be used to evaluate whether an event should be reported to STRC. Only the rules for 
reporting described in this document should be considered. 
As defined in the NCI Data Table 4 reporting guidelines, CCCWFU Institutional Interventional 
studies covered by these reporting requirements are defined as: In-house, internally reviewed 
trials, including those collaborative studies conducted with industry sponsorship in which the 
center is a primary contributor to the design, implementation, and monitoring of the trial, or 
participation in a multi-site trial initiated by an institutional investigator at another center.  
Institutional trials are almost always authored by a researcher here at CCCWFU. Institutional 
protocols are labeled NCI Code=”I” for Institutional on the protocol screen in ORIS. Cooperative 
group protocols are not considered Institutional, but Research Base trials are classified as 
Institutional. 
The STRC is responsible for reviewing SAEs for CCCWFU Institutional Interventional studies, as 
defined above. STRC currently requires that unexpected grade 4 and all grade 5 SAEs on these 
trials be reported to the STRC for review. All Clinical Protocol and Data Management (CPDM) 
staff members assisting a PI in documenting and reporting an SAE that qualifies for STRC 
reporting are responsible for informing a clinical member of the STRC by phone (or in-person), 
followed by informing the entire committee via the required email notification. 
THESE REPORTING REQUIREMENTS APPLY TO any faculty or staff member on the study team 
for a CCCWFU Institutional Interventional trial. Once an event is observed, it is the 
responsibility of the person who observed the event to be sure that it is reported. 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral 
Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 03/02/18 
Page 36 of 39 
What is considered an SAE under this mandatory procedure? 
Any unexpected grade 4 event and all grade 5 events (death during protocol intervention) 
should be reported. These events should be reported if they occur while a patient is on study 
treatment or if they occur within 30 days of last study treatment (even if patient begins a new 
treatment during the 30 days). This window of 30 days should be the standard window to be 
used in all protocols unless a specific scientific rationale is presented to suggest that a shorter 
window can be used to identify events.  In addition, if it is not clear whether the Grade 4 is 
unexpected it should be reported. 
Table 1: Summary of STRC Reporting Requirements for Institutional Pilot, Phase 1, Phase 2  
and Phase 3 Interventional Trials  
STRC reporting may not be appropriate for specific expected adverse events for protocols. In 
those situations the adverse events that will not require STRC reporting must be specified in 
the text of the approved protocol. 
STRC notification responsibilities of the person handling the reporting/documenting of the 
SAE: 
1. Make a phone call (or speak in person) to the appropriate clinical member of the STRC as
listed below (page if necessary)—see note 2 below
2. Submit the STRC Notification Form WITHIN 24 HOURS of first knowledge of the event. This
form is found at either the ORIS main menu page or by going to
http://ccc.wfubmc.edu/oris/strc.aspx.
This will ensure that all persons that need to be made aware of the event (i.e., study team
members and STRC members) will be notified; remember to file a copy of your
ADVERSE EVENT 
Grade 1, Grade 2, 
Grade 3 
Grade 4 
Grade 5 
Unexpected Expected 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated Not 
Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Unlikely 
Not 
Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Possible 
Not 
Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Probable 
Not 
Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Definite 
Not 
Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral 
Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 03/02/18 
Page 37 of 39 
confirmation. (Form instructions will walk you through the required fields, consult the help 
page for further instructions.) 
3. Ensure that you document that the appropriate person(s) on the STRC has been contacted.
This documentation is placed on the STRC Notification form described above.
4. Follow up with/update the clinical member(s) of STRC regarding any new developments or
information obtained during the course of the SAE investigation and reporting process.
Elements to complete the electronic STRC form:
Please use ‘reply to All’ when responding with one of these terms:  Definite, Probable,
Possible, Unlikely, or Unrelated
1. Patient ID (ORIS PID)
2. Patient Name
3. Patient MR#
4. CCCWFU(ORIS) Study Number
5. Title
6. PI Name
7. PI Contact Number
8. PI Comments
9. STRC Clinician notified by Phone
10. Notified Date
11. Notified Time
12. STRC Clinician Comments
13. Category [This is the Grade – Either Unexpected Grade 4 or Grade 5 should be entered]
14. Additional Information (IRB Reporting)(after discussion with PI or STRC Clinician
i. Is This Event Related to Protocol Treatment?
ii. Is Suspension of the Protocol Needed?
iii. Any Changes to Consent or Protocol Needed?
iv. Was Nature or Severity of Event Unexpected?
15. Date of the event.
16. Brief description (include brief clinical history relevant to this event, including therapies
believed related to event).
17. Date of Last Dose before event
18. Relevant tests/labs.
19. Other Relevant Treatment Information
20. Other Comments/Notes (include regimen of chemo and dates the patient received them
if known).
21. Cc (email) (include treating Physician; separate email list with comma”,”)
22. Your Name
23. Your Email
24. Confirm Your Email

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A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral 
Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
The Clinical Members of STRC to Notify by Phone or Page: 
Bayard Powell, MD – Director-at-Large, CCCWFU; Section Head, Hematology/Oncology 
Glenn Lesser, MD – Hematology Oncology 
Stefan Grant, MD, JD-Hematology Oncology 
Jimmy Ruiz, MD-Hematology Oncology 
Kathryn Greven, MD – Vice Chair – Radiation Oncology
Marissa Howard-McNatt, MD – General Surgery 
Mercedes Porosnicu, MD- Hematology Oncology 
Definition of Unavailable:  
As a general guideline if the first clinician that is contacted does not respond to the phone call 
or page within a reasonable amount of time, then initiate contact with their backup.  Give the 
back-up a reasonable amount of time to respond to a phone call or page before contacting 
another member. This is a general guideline.  You must use your best judgment as a clinical 
research professional given the time of day, severity of the SAE, and other circumstances as to 
when it is appropriate to contact backup clinicians.  If the event occurs near the end of day, 
then leave messages (voice or email) as appropriate and proceed with submitting your STRC 
notification form.  The important criteria is that you have taken reasonable steps to notify and 
document that you have initiated some type of contact to one or more of the clinical members 
of STRC. 
STRC CLINICAN RESPONSIBILITY: 
It is the responsibility of the STRC clinician to review all reported events, evaluate the events as 
they are reported; and communicate a response to the Investigator, event reporter and the 
members of STRC. The review will include but not be limited to the information reported; there 
may be times when additional information is needed in order for an assessment to be made 
and further communication directly with the investigator may be warranted. STRC reserves the 
right to agree with the investigator’s assessment if STRC does not agree with the investigator. 
STRC reserves the right to suspend the trial pending further investigation. 
Is there any immediate danger or harm that could be present for a future patient based on the 
information provided in the STRC report – and if so an immediate suspension of enrollment 
should take place. 
AMENDMENTS TO PREVIOUS REPORTS 
If you are not able to supply all pertinent information with the initial submission, once the 
additional information is available do not submit a new report. Go to the original email that 
was received by STRC and others “reply to all” and entitle your email “Amendment for (list date 
of event and patient ID) this will avoid duplications of the same event. List the additional 
information which you are reporting. 

A Pilot Study Using Ultrasound for the Detection of Taxane-Induced Peripheral 
Neuropathy 
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
CCCWFU # 97217 
Protocol version date 03/02/18 
Page 39 of 39 
Acronyms and Definitions 
STRC-Safety and Toxicity Review Committee 
SAE-Serious Adverse Event 
IRB-Institutional Review Board 
CCCWFU-Comprehensive Cancer Center Wake Forest University 
ORIS-Oncology Research Information System 
NCI-National Cancer Institute 
CPDM-Clinical Protocol and Data Management 
Interventional Trials-Therapeutic Level 1 and Level 2 trials 
Therapeutic Level 1-A cancer treatment protocol aimed at directly treating/curing the patient’s 
cancer. 
Therapeutic Level 2-A therapeutic protocol not cancer treatment involves clinical activity to 
treat symptoms, improve the patient’s quality of life, or prevent cancer.