Cryotherapy to Prevent Taxane-Induced Sensory Neuropathy of the Hands and Feet
Phase: NA
Conditions: Breast Carcinoma
Sponsor: Mayo Clinic

 
 
 
 
 
19-008929 
 
 
Cryotherapy to Prevent Taxane-induced Sensory Neuropathy 
of the Hands and Feet 
 
 
NCT04256512 
 
 
Document Date: 04/15/2022 

Please check the Focus Research Team funding source:
Cancer
Comprehensive
Digestive Diseases
Heart-Lung
Neuroscience
Transplant–Regenerative Med.
Title of the study: Cryotherapy to prevent taxane-induced sensory neuropathy of the hands and 
feet 
Date: version 6, 15Apr2022  
Principal investigator: Pooja Advani, MD 
Statistician: David Hodge
Funding Requested: $30,000
FORMAT: Please limit Sections I-VI to 10 single-spaced pages using one-inch (1") margins, 
Times New Roman, 12 pt. font size. Protocols not adhering to these guidelines are subject to 
being returned without review. 
DESCRIPTION:
Taxane based chemotherapy forms an integral component of breast cancer treatment in the 
adjuvant and neoadjuvant settings. Unfortunately, taxane based agents are associated with 
peripheral neuropathy of the hands and feet, which can result in significant decline in quality of 
life and also has the potential to affect survival by limiting the dose of paclitaxel received. Several 
attempts have been made to prevent or limit taxane induced peripheral neuropathy but 
unfortunately have been unsuccessful. Recently, studies have examined the use of cryotherapy to 
prevent the development of taxane induced side effects such as skin and fingernail toxicity. 
Furthermore, there is preliminary evidence to suggest benefit of cryotherapy in minimizing the 
incidence and severity of peripheral neuropathy. Given the high incidence and severity of taxane-
based chemotherapy, this study was designed to assess the efficacy and tolerability of cryotherapy 
in the form of frozen mittens and foot wraps. Both subjective and objective outcome measures will 
be assessed. If cryotherapy in our study is found to be effective in reducing the incidence of 
peripheral neuropathy, it has the potential to transform supportive care in oncology allowing 
patients to complete the desired dose intensity of chemotherapy improving the survival outcomes 
as well as minimizing the risk of debilitating side effects that can compromise quality of life. 
Abstract 
Protocol Submission Template
 
 

Advani et al, Cryotherapy to prevent taxane-induced sensory neuropathy of the hands and feet
I. Specific Aims
We plan to investigate the efficacy and tolerability of cryotherapy (Elasto Gel® frozen mittens and 
foot wraps) and to evaluate whether they can prevent or ameliorate taxane-induced sensory 
peripheral neuropathy. The hypothesis of our pilot study is that patients receiving cryotherapy 
during infusion of taxane therapy will have lower incidence of peripheral neuropathy, better 
physical function, and higher quality of life as compared to patients previously reported in 
literature. 
II. Background and Significance
Chemotherapy induced peripheral neuropathy (CIPN) occurs in approximately 25-35% of patients 
treated with chemotherapy, most notably with taxanes.(1) Taxanes are a standard chemotherapy 
option for treatment of breast cancer (NCCN, 2018). Peripheral neuropathy (PN) is a dose limiting 
toxicity of taxane-based chemotherapy. While mild neuropathy tends to improve after completion 
of chemotherapy, many patients, especially those with moderate to severe CIPN, can have
prolonged symptoms causing pain and limiting function including vocation. This can last months 
to years or even become a permanent long-term consequence of the chemotherapy significantly 
affecting their QOL. Additionally, the presence of CIPN can lead to chemotherapy interruptions, 
delays or dose reductions that may negatively affect the outcome of their cancer. 
At this time there are no effective preventative strategies for taxane induced PN(2,3). Several 
measures including amifostine, minocycline, and recombinant human leukemia inhibitory factor 
and acetyl-l-carnitine(4-6) have been evaluated to prevent or limit taxane induced PN without 
much success. 
It is well known that the therapeutic regional hypothermia (cryotherapy) is helpful to prevent or 
decrease chemotherapy induced (Doxorubicin and taxane based) alopecia(7,8), chemotherapy 
induced (5-FU based) mucositis(9), and chemotherapy induced onycholysis(10,11). Hypothermia 
to the peripheral nerves is thought to inhibit uptake of the chemotherapy into the neurons, thereby 
preventing neuropathy(12). A recent study from Japan reported in the Journal of the National 
Cancer Institute(12) prospectively evaluated the use of cryotherapy to prevent CIPN from weekly 
paclitaxel regimen. Among the 36 evaluable patients who wore frozen gloves and socks on the 
dominant side (non-dominant side serving as control), the incidence of objective and subjective 
CIPN was clinically and statistically significantly lower on the intervention side than on the control
side. 
Elasto Gel® frozen mittens and footwraps are a commercially available form of cryotherapy that 
can be purchased at online retailers at low cost. In the last year we have started to routinely 
recommend the use of prophylactic cryotherapy to our patients during taxane administration and 
we have observed that our patients who use the gloves and slippers seem to experience significantly 
less neuropathy than previous patients. If the frozen gloves and slippers are indeed effective at 
preventing taxane induced PN, it would completely transform oncology practice 
2
Research Plan 
 
 

Advani et al, Cryotherapy to prevent taxane-induced sensory neuropathy of the hands and feet
from the current model of treating pain and efforts to minimize functional decline, to one of 
prevention, allowing patients to resume their usual activities and level of function much quicker 
than is possible with the limited treatment options for taxane induced PN that are currently 
available. 
III. Progress Report and Preliminary Studies
The potential utility for frozen gloves/socks worn during paclitaxel infusion to prevent 
neurotoxicity was recently reported. This study suggested that continuous limb hypothermia at a 
coolant temperature of 22 degrees Celsius may reduce paclitaxel induced peripheral neuropathy 
and was noted to be safe and well tolerated in 20 evaluable patients(13). 
In a recently reported self-controlled clinical trial, 36 evaluable patients wore frozen flexible 
gloves and socks on the dominant hand and foot from 15 minutes before paclitaxel administration 
to 15 minutes after the infusion was completed (12). The non-dominant side acted as the untreated 
control. The primary end point was the incidence of CIPN (any grade), defined as a decline in 
tactile sensation from the pretreatment baseline as assessed by the Semmes-Weinstein 
monofilament test. Secondary outcome measures included physician-rated thermosensory deficits 
using a thermal stimulator at 3 and 48°C, vibration perception using a 128 Hz tuning fork, 
performance speed as assessed by a grooved pegboard test, abnormal electrophysiologic signs as 
assessed by electrophysiologic testing of the median nerve, and current perception thresholds using 
a neurometer. Subjective symptoms were also assessed using a patient neuropathy questionnaire 
in which individual items were scored as A (no neuropathy), B (mild neuropathy), C (moderate 
neuropathy not interfering with activities of daily living [ADL]), D (moderate neuropathy that 
interferes with ADL), or E (severe neuropathy). Grades D and E were scored as severe neuropathy.
The investigators noted a clinically and statistically significant reduction in patient-reported 
subjective symptoms, diminished objective signs (tactile and thermosensory-see figure A and B 
below) and prevention of manipulative dexterity. Significant differences were reported for both 
objective and subjective signs of CIPN. On the control (nondominant) side, 81 and 64 percent of 
patients had a decrease in tactile sensation in their hands and feet, respectively, while on the 
intervention (dominant) side, only 28 and 25 percent were reported to have had a decrease in tactile 
sensation in their hands and feet, respectively. Subjects reported less severe neuropathy on the 
intervention side (for the hand, 3 versus 42 percent; for the foot, 3 versus 36 percent), and there 
were differences in perception of warmth and reaction speed but no differences in vibration 
threshold or electrophysiological testing between the intervention and control sides. 
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Advani et al, Cryotherapy to prevent taxane-induced sensory neuropathy of the hands and feet
In further support of the concept that cryotherapy may be helpful, Tsuyuki et al evaluated the effect 
of wearing 1 size too small surgical gloves (two gloves per hand) on only one hand for 90 mins in 
42 patients receiving nanoparticle albumin bound paclitaxel (nabpaclitaxel).(14) The goal was to 
reduce the flow of blood to the hand during chemotherapy. The investigators reported that surgical 
glove compression therapy significantly decreased the temperature of each fingertip (measured by 
thermography) by 1.6 – 2.2°C as compared with the temperature before chemotherapy (p < 
0.0001). The occurrence of grade 2 or higher sensory and motor peripheral neuropathy was 
significantly lower for surgical glove protected hands then for control hands (sensory neuropathy 
21.4 vs. 76.1 %; motor neuropathy 26.2 vs. 57.1 %) (14) 
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Advani et al, Cryotherapy to prevent taxane-induced sensory neuropathy of the hands and feet
IV. Research Design and Methods
a. Study Design or Overview – This is a longitudinal quasi-experimental pilot study. Patients will 
be identified for this study during a standard of care visit with a physician in the Breast Center 
(medical oncologist) to discuss the patient’s treatment plan. This visit could take place pre- surgery 
to discuss neoadjuvant treatment or post-surgery to discuss adjuvant treatment. If the patient 
decides to proceed with taxane-based treatment, the physician or study coordinator will discuss 
this study with the patient and review the consent form. If the patient would like to participate, 
inclusion criteria will be confirmed and the study consent will be obtained either by the physician 
or study coordinator. 
Prior to the patient’s first chemotherapy infusion (this can include the planned chemotherapy 
education visit which occurs prior to chemotherapy initiation), the study coordinator will complete 
questionnaires with the patient including the FACT-G Version 4, FACT/GOG-NTX Version 4 and 
the Chemotherapy Induced Peripheral Neuropathy Rasch-Built Overall Disability Scale (CIPN-R-
ODS). Dr. Cindy Tofthagen, a nurse-scientist at Mayo Clinic, Florida, with expertise in 
understanding both the immediate and long-term effects of CIPN on function and quality of life 
will conduct sensory testing using Quantitative Sensory Testing (QST) Computer Aided Sensory 
Evaluation (CASE IV), Von Frey Monofilament Kit, and Testworks Neurological Testing 
Management Software Version 3.2 (WR Medical Electronics). The study coordinator will conduct 
the Timed Up and Go test to measure physical function, balance, and fall risk. All data collected 
will be recorded into the REDCap database by the study coordinator, along with demographics 
and pre-specified medical history information retrieved from the patient’s medical record. 
One set each of Elasto Gel® Therapy Mittens and Foot Wraps will be provided to each patient and 
are expected to be worn on both hands and feet at each chemotherapy infusion during their three 
months of treatment. Patients will start wearing the mittens and foot wraps 15 minutes prior to 
each infusion, during the entire infusion, and for 15 minutes after the completion of each infusion. 
We will have extra frozen mittens and foot-wraps on site to replace the mittens/foot-wraps after 
the first 30-45 minutes as needed. These extra pairs will be appropriately sterilized after patient 
use and stored.  A research coordinator will record the time that the mittens and foot wraps were 
Upon completion of the three months of treatment, patients will return to the Breast Center for an 
end of intervention visit with their providers. During this standard of care visit, the study 
coordinator will meet with the patient to complete the study-related questionnaires including the 
FACT-G Version 4, FACT/GOG-NTX Version 4, and the Chemotherapy Induced Peripheral 
Neuropathy Rasch-Built Overall Disability Scale (CIPN-R-ODS). Repeat objective testing using 
Quantitative Sensory Testing (QST) Computer Aided Sensory Evaluation (CASE IV), Von Frey 
Monofilament Kit, and Testworks Neurological Testing Management Software Version 3.2 (WR 
Medical Electronics) will be conducted at this point. The study coordinator will conduct the Timed 
Up and Go test to measure physical function, balance, and fall risk. All data collected will be 
recorded into the REDCap database by the study coordinator. 
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Advani et al, Cryotherapy to prevent taxane-induced sensory neuropathy of the hands and feet
The end of study visit will occur approximately three months (+/- one month) after the last 
chemotherapy infusion during a standard of care appointment in the Breast Center. During this 
standard of care visit, the study coordinator will meet with the patient to complete the study- related 
questionnaires including the FACT-G Version 4, FACT/GOG-NTX Version 4, and the 
Chemotherapy Induced Peripheral Neuropathy Rasch-Built Overall Disability Scale (CIPN-R-
ODS). Repeat objective testing using Quantitative Sensory Testing (QST) Computer Aided 
Sensory Evaluation (CASE IV), Von Frey Monofilament Kit, and Testworks Neurological Testing 
Management Software Version 3.2 (WR Medical Electronics) will be conducted at this point. The 
study coordinator will conduct the Timed Up and Go test to measure physical function, balance, 
and fall risk. All data collected will be recorded into the REDCap database by the study 
coordinator, along with pre-specified medical history information retrieved from the patient’s 
medical record. 
The clinical data and outcome measures data entered in the database will then be analyzed by the 
biostatistician. 
*If not collected during pre-chemo visit with MD
b. Study Subjects – Adults ages 18 and older with diagnosis of breast cancer undergoing 3 months 
of taxane based chemotherapy (4 cycles of weekly paclitaxel (1 cycle = 3 week) or docetaxel every 
3 weeks x 4-6 cycles) 
Inclusion Criteria:


Patients ≥18 years of age with a diagnosis of breast cancer 
Patients receiving 12-18 weeks of chemotherapy with a taxane-based regimen (4 
cycles of weekly x3 paclitaxel or 4-6 cycles of docetaxel every 3 weeks) 
Absence of sensory peripheral neuropathy, skin or nail disorders at the start of 
treatment 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 
Ability to complete questionnaires by themselves or with assistance. 
Ability to give signed informed consent 




Exclusion Criteria:

History of prior sensory/motor peripheral neuropathy from any cause
6
 
Pre-chemo 
MD visit 
Chemotherapy 
Education 
Appointment 
End of 
Chemo 
MD visit 
3 months 
post-chemo 
MD visit 
Consent 
x 
x* 
 
 
FACT-G questionnaire 
 
x 
x 
x 
FACT/GOG-NTX 
questionnaire 
 
x 
x 
x 
CIPN-R-ODS 
 
x 
x 
x 
Timed Up and Go Test 
 
x 
x 
x 
Data entry 
 
x 
x 
x 
 

Advani et al, Cryotherapy to prevent taxane-induced sensory neuropathy of the hands and feet
History of prior Raynaud's phenomenon  
History of cryoglobulinemia 
Active peripheral vascular disease  
Cold intolerance 
Prior exposure to neurotoxic chemotherapy in the last 10 years  
Hand-foot syndrome 
Tumor metastasis in bone, soft tissue, or skin of the hands or feet  
Absence of one or more fingers or toes 
Prior exposure to taxane chemotherapy 









c. Sample Size – We will seek to recruit 100 breast cancer patients (with at least 30% being African 
American/Black, Native American, Asian, and/or Hispanic/Latino patients) to receive cryotherapy 
with the Elasto-Gel® Therapy Mittens and Foot Wraps as they receive taxane based chemotherapy.
One of our exploratory analysis goals is to compare safety and efficacy of cryotherapy between 
white and non-white patients.  
d. Data Collection – We will assess for PN, physical functioning, and quality of life prior to 
initiation of taxane based therapy (T1), immediately after completion of taxane based 
chemotherapy (T2), and again at 3 months following completion of therapy (T3). 
PN has both subjective and objective components that are equally important outcomes. 
Monofilament testing will be performed at three time points by a specially trained research 
coordinator using 
(CASE  IV),  Von
Software Version
Quantitative Sensory Testing (QST) Computer Aided Sensory Evaluation  
Frey Monofilament  Kit,  and  Testworks  Neurological  Testing Management
3.2 (WR   Medical   Electronics).   Monofilament   testing for touch pressure 
sensation will be performed using previously established procedures established by Dr. Peter Dyck 
and colleagues.(15) Monofilament testing will be performed on the dorsal terminal phalanges of the 
5 toes and fingers on one side of the body using 9 monofilaments ranging from 0.05 gm (A) to 
148.4gm (I). Participants will close their eyes during testing. Two or three practice sessions will be 
done on the hand or forearm with monofilament E to familiarize the patient with the procedure and
appropriate responses. Testing will begin with monofilament E and use a forced choice 2:1 
algorithm to assess touch pressure threshold. Ten pairs of computer selected stimulus events (a 
stimulus and a null stimulus) are given at each level of stimulus required, based upon patient 
response. During both the stimulus and non-stimulus, the technician will identify periods 1 and 2 
verbally without giving any verbal or non-verbal indication of which period contained the stimulus. 
During the stimulus, the technician will slowly make contact with the skin on the selected site, 
increasing pressure so that the monofilament bends about 5/6 of its length before withdrawing the 
monofilament. Null stimulus is done without skin contact. After each pair of stimuli, the participant 
will be asked to identify whether they felt the touch during 1 or 2 (WR Medical Electronics 
Testworks 3 user guide). Reliability and validity of this approach, using the CASE IV equipment 
was demonstrated in a multi-site study that demonstrated significantly different results in healthy 
age matched controls (n=6) to those of individuals with diabetic polyneuropathy (n=6). High 
correlations between quantitative sensory testing results and clinician assessment of neuropathy 
signs and symptoms, as well as nerve conduction provide evidence of validity. Intra and inter-rater 
reliability were also demonstrated. Testing will be performed on the left hand/foot only unless there 
are physical problems that necessitate use of the right side instead. Testing will not be performed 
on broken or exfoliating skin. Testing will not be performed on any patient who is not attentive,
sedated, or too ill to cooperate. Vibratory and thermal sensation will not be 
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Advani et al, Cryotherapy to prevent taxane-induced sensory neuropathy of the hands and feet
evaluated in this study as we are primarily interested in touch pressure sensation as an outcome 
variable. 
We will assess patient reported symptoms of peripheral neuropathy using the FACT-GOG 
neurotoxicity –scale (FACT-GOG-NTX), plus an 11-item measure neurotoxicity subscale. Scores 
on the neurotoxicity subscale range from 0-44 with higher scores indicating more severe 
neuropathy. Evidence of validity was provided by Calhoun and colleagues, who found significant 
correlations between the FACT/GOG-Ntx and neurological examination evaluating sensory 
symptoms, pin sensibility, strength, deep tendon reflexes, vibration sensibility, and nerve 
conduction.(16) Significant differences in scores from chemotherapy naïve individuals and those 
with known 
CIPN demonstrated construct validity. Cronbach’s ranged from .78 to .88. Reliability and validity 
were also demonstrated in 240 patients receiving paclitaxel and carboplatin. Consistent with 
previous studies, we will define a 3.3–4.4 point change in score as a clinically important change in 
the 11-item NTX subscale. 
Chemotherapy-Induced Peripheral Neuropathy Rasch-built Overall Disability Scale (CIPN-R-
ODS) will be used to measure physical functioning related to chemotherapy-induced peripheral 
neuropathy.(17) It is a 28-item scale that assesses participant’s ability to perform specific physical 
tasks. Possible responses for each task are 0=unable to perform; 1=perform with some difficulty 
and 2=no difficulty performing. Higher scores indicate better physical functioning. Correlations with 
the National Cancer Center- Common Toxicity Criteria for sensory neuropathy demonstrate 
construct validity. Internal consistency reliability was high (0.92) and the test-retest reliability also 
demonstrated reliability in individuals receiving neurotoxic chemotherapy, including patients with 
colorectal cancer. 
The Timed Up and Go is a well validated measure of physical function, balance, and fall risk that 
will be used as an objective measure of physical functioning.(18,19) To perform the procedure, a 
piece of tape is placed on the floor 3 meters away from the chair so that it is easily seen. Participants 
are prompted to stand up, walk to the line on the floor, turn around and walk back to the chair and 
sit back down, walking at their regular pace. Participants wear their regular footwear, may use any 
gait aid that they normally use during ambulation, but may not be assisted by another person. There 
is no time limit. They may stop and rest (but not sit down) if they need to. Scores under 10 seconds 
indicate good balance and physical function and low fall risk. A score of greater than 14 seconds 
indicated a high risk of falls. 
The 27 item FACT-G(20) will be used to assess quality of life. It is measure to be used in people 
with any type of cancer, contains 4 quality of life subscales; physical, emotional, social/family, and 
functional. Each item is scored from 0 (not at all) to 4 (very much). Higher scores on the FACT-G 
correspond with better quality of life. The FACT-G was developed for and has been used 
extensively in cancer research and demonstrates excellent reliability and validity. 
Clinical data will be collected from the patient’s medical record and this will include age, race, sex, 
age at diagnosis, breast cancer stage, neoadjuvant/adjuvant setting of chemotherapy administration, 
baseline medical conditions, karnofsky performance status, patient hand dominance, history of 
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Advani et al, Cryotherapy to prevent taxane-induced sensory neuropathy of the hands and feet
smoking, history of alcohol use, type of chemotherapy received, dose intensity of chemotherapy, 
chemotherapy dose reductions/modifications (if any), use of prescription medications at baseline, 
use of supplements including multivitamins at baseline. 
e. Data Handling – All clinical data and outcome data which includes subjective and objective 
outcome of peripheral neuropathy (as outlined in section IV, part d) will be collected by the data 
coordinator and inputted into a password secured REDCap database in a de-identified manner. 
Only research staff designated by the PI will have access to the data. Hardcopy data will be kept 
in locked filing cabinets within secured department areas. All study data will be entered by a staff 
member designated by the PI. In order to maintain patient confidentiality and to de-identify study 
data, patients will be given a study code which will be used on all data collected and entered in the
database. 
After this data is entered into the REDCap database, the biostatistician will then perform the 
statistics. 
f. Data Analysis – The overall estimate of PN in the group will be estimated with a simple 
percentage, and 95% confidence intervals will be calculated for that estimate. In additional other 
measures of symptoms or other parameters will be summarized in the group. Categorical
parameters will be estimated using percentages, and continuous measures will be summarized 
using means, or medians. The decision about which measure to use for the continuous measures 
will depend on the distribution of the data of interest. Overall the primary aim of the study is to 
provide preliminary data for a potential larger trial. These measures will be used to estimate the 
sample size and power for that future trial. 
g. Feasibility and Time Frame – We anticipate to recruit 100 patients amongst the four medical 
oncologists-Dr. Advani, Dr. Chumsri, Dr. Moreno and Dr. Sideras. We see a large volume of patients 
each year in the breast clinic. In the year 2018, we treated 1,359 breast cancer patients with 
chemotherapy (in 2019 YTD-617 patients), and majority of these patients receive a taxane based 
chemotherapy regimen. 
h. Strengths – This project helps address a very important side effect of chemotherapy in patients 
with breast cancer. As survival outcomes of patients improve with advances in (neo)adjuvant 
therapies, oncologists need to strive towards mitigating chemotherapy related side effects, some of 
which can be debilitating and impact quality of life. 
In this regard, we have partnered with Dr. Cindy Tofthagen who is a nurse-scientist at Mayo Clinic, 
Florida. Her work has focused on understanding both the immediate and long-term effects of CIPN
on function and quality of life, as well as on development and evaluation of non- 
pharmacologic interventions to alleviate symptoms of CIPN. 
She also has expertise in 
development and psychometric evaluation of patient-reported outcomes in CIPN. 
She secured
funding to purchase smart sensation quantitative testing (SQST) equipment to enhance objective 
measurement of sensory deficits in research conducted at MCF. The monofilament testing we 
propose will be conducted using some of this equipment. Dr. Tofthagen is also a clinical expert in 
CIPN.
As a faculty member at the University of South Florida, she founded a free 
multidisciplinary clinic for individuals with CIPN and other forms of neuropathy. She served as 
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Advani et al, Cryotherapy to prevent taxane-induced sensory neuropathy of the hands and feet
director of that clinic, prior to coming to Mayo Clinic. She has served as an advisor for several 
neuropathy related organizations including the Neuropathy Association, Foundation for Peripheral
Neuropathy, and Neuropathy Support Network. 
She also serves as the Oncology Nursing 
Society’s lead faculty on their committee to develop evidence-based guidelines for CIPN and has 
served on that committee since 2009. 
The intervention proposed in this study (frozen gloves and mittens) is relatively inexpensive and is 
easily available for purchase on the internet. If the results of this study are promising, this 
intervention has the potential for a large impact across several patient population groups including 
that from lower socio-economic strata. 
At the Robert and Monica Jacoby Center for Breast Health in Mayo Clinic Florida, we see a large 
volume of breast cancer patients each year and the smaller number of patients proposed in this study 
due to its pilot nature allows for this recruitment in a relatively short period of time. 
Taxane-based chemotherapy is also used in several other cancers such as ovarian, lung, bladder, 
melanoma, prostate, pancreatic and esophageal cancer thereby expanding the use of cryotherapy to 
prevent neuropathy in these patient population groups as well. 
i. Limitations – The relatively small number of patients may limit the statistical significance of 
the study results. 
Additionally, this is a non-randomized study and this can affect the 
interpretation of results in terms of cause and effect relationship establishment and impact 
internal validity. 
Due to the preliminary data reporting the benefit of cryotherapy and more recently frozen mittens 
and foot wraps, my colleagues and I as medical oncologists have been sharing this empiric 
information with patients and many of them have opted to proceed with wearing frozen mittens 
and foot wraps at the time of chemotherapy infusion and reported benefit in protection from 
neuropathy. Hence, we wanted to perform a non-randomized pilot study first to assess the benefit 
of this intervention prior to conducting a larger randomized clinical trial which is the overarching 
goal of our team. Additionally, there is pre-existing data in the literature on incidence of CIPN 
from taxanes and although not ideal, for this initial pilot study, we can use this data to compare the 
incidence of CIPN from that reported in literature to patients enrolled in our study. 
V. Human Subjects
a. Population – Adults ages 18 and older with diagnosis of breast cancer undergoing 3 months of 
taxane based chemotherapy (4 cycles of weekly paclitaxel (1 cycle = 3 week); or docetaxel every 
3 weeks x 4-6 cycles) will be included in the study. 
Special classes of subject, such as fetuses, pregnant women, children, prisoners, institutionalized 
individuals, or others who are likely to be vulnerable will not be included in the study. 
b. Research Materials – Clinical data and subjective and objective outcome measures data (as 
outlined in section IV, part d) will be collected from each patient. This data will be used specifically 
for research purposes and stored in a custom-made REDcap database. 
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Advani et al, Cryotherapy to prevent taxane-induced sensory neuropathy of the hands and feet
c. Recruitment of Subjects – Participants meeting Inclusion/Exclusion criteria will meet with a 
clinical coordinator to review the study consent form. They will be given ample opportunity to ask 
any questions they may have and to discuss their potential participation with friends or family 
members if they so desire. 
d. Potential Risks – We do not anticipate any significant physical risk to the patient with 
cryotherapy intervention as patients will be carefully selected after a thorough review of the 
inclusion and exclusion criteria. Those with pre-existing conditions that may predispose harm to 
digits of the hands and feet such as frostbite will be excluded from the study. Additionally, patients 
will be closely monitored for any side effects from cryotherapy such as painful digits, cold 
intolerance, frostbite and ulceration of the digits. Those patients that report any of these side effects 
will be evaluated by the PI with consideration to discontinue the study and initiation of immediate 
therapy for stated side effect. 
e. Benefits – CIPN can be disabling and negatively affect quality of life and survivorship of 
patients. This study has the potential to directly impact patient care by improving patient outcomes 
and quality of life during chemotherapy as well in the survivorship phase. Reducing the incidence 
and severity of CIPN allows avoiding dose reduction, delay or interruption in the chemotherapy 
schedule that may also negatively affect the oncologic outcome. This pilot study is relatively low 
risk to the patient and utilizes an inexpensive intervention to help ameliorate the risk of 
chemotherapy induced neuropathy. We eventually plan on conducting a larger prospective 
randomized study based on the data generated from this preliminary study. Based on 
the results of these studies, if cryotherapy is found effective, it will have a huge impact 
prevention and improvement in quality of life in patients receiving taxane chemotherapy. 
on
VI. Gender/Minority Mix
All eligible patients will be encouraged to enroll regardless of ethnicity, gender, or race.
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Advani et al, Cryotherapy to prevent taxane-induced sensory neuropathy of the hands and feet
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1.
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survivors of adult cancers: American Society of Clinical Oncology clinical practice 
guideline. J Clin Oncol 2014;32(18):1941-67 doi 10.1200/JCO.2013.54.0914. 
Tofthagen CI, M. Tofthagen, C & Irwin, M. (2014). Peripheral Neuropathy in Irwin, M 
and Johnson, LA (Eds.) Putting Evidence into Practice: A Pocket Guide to Cancer 
Symptom Management (p. 201-205). Pittsburgh, PA. Oncology Nursing Society. 
ISBN:9781935864547. 
Openshaw H, Beamon K, Synold TW, Longmate J, Slatkin NE, Doroshow JH, et al. 
Neurophysiological study of peripheral neuropathy after high-dose Paclitaxel: lack of 
neuroprotective effect of amifostine. Clin Cancer Res 2004;10(2):461-7. 
Pachman DR, Dockter T, Zekan PJ, Fruth B, Ruddy KJ, Ta LE, et al. A pilot study of 
minocycline for the prevention of paclitaxel-associated neuropathy: ACCRU study 
RU221408I. Support Care Cancer 2017;25(11):3407-16 doi 10.1007/s00520-017-3760-2.
Davis ID, Kiers L, MacGregor L, Quinn M, Arezzo J, Green M, et al. A randomized, 
double-blinded, placebo-controlled phase II trial of recombinant human leukemia 
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peripheral neuropathy. Clin Cancer Res 2005;11(5):1890-8 doi 10.1158/1078-0432.CCR-
04-1655. 
Nangia J, Wang T, Osborne C, Niravath P, Otte K, Papish S, et al. Effect of a Scalp 
Cooling Device on Alopecia in Women Undergoing Chemotherapy for Breast Cancer: 
The SCALP Randomized Clinical Trial. JAMA 2017;317(6):596-605 doi 
10.1001/jama.2016.20939. 
Rugo HS, Klein P, Melin SA, Hurvitz SA, Melisko ME, Moore A, et al. Association 
Between Use of a Scalp Cooling Device and Alopecia After Chemotherapy for Breast 
Cancer. JAMA 2017;317(6):606-14 doi 10.1001/jama.2016.21038. 
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