A Prospective Observational Cohort Study to Develop a Predictive Model of Taxane-Induced Peripheral Neuropathy in Cancer Patients
Conditions: Anatomic Stage I Breast Cancer AJCC v8, Anatomic Stage IA Breast Cancer AJCC v8, Anatomic Stage IB Breast Cancer AJCC v8, Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage IIA Breast Cancer AJCC v8, Anatomic Stage IIB Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8, Anatomic Stage IIIB Breast Cancer AJCC v8, Anatomic Stage IIIC Breast Cancer AJCC v8, Lung Non-Small Cell Carcinoma, Prognostic Stage I Breast Cancer AJCC v8, Prognostic Stage IA Breast Cancer AJCC v8, Prognostic Stage IB Breast Cancer AJCC v8, Prognostic Stage II Breast Cancer AJCC v8, Prognostic Stage IIA Breast Cancer AJCC v8, Prognostic Stage IIB Breast Cancer AJCC v8, Prognostic Stage III Breast Cancer AJCC v8, Prognostic Stage IIIA Breast Cancer AJCC v8, Prognostic Stage IIIB Breast Cancer AJCC v8, Prognostic Stage IIIC Breast Cancer AJCC v8, Stage I Lung Cancer AJCC v8, Stage I Ovarian Cancer AJCC v8, Stage IA Ovarian Cancer AJCC v8, Stage IA1 Lung Cancer AJCC v8, Stage IA2 Lung Cancer AJCC v8, Stage IA3 Lung Cancer AJCC v8, Stage IB Lung Cancer AJCC v8, Stage IB Ovarian Cancer AJCC v8, Stage IC Ovarian Cancer AJCC v8, Stage II Lung Cancer AJCC v8, Stage II Ovarian Cancer AJCC v8, Stage IIA Lung Cancer AJCC v8, Stage IIA Ovarian Cancer AJCC v8, Stage IIB Lung Cancer AJCC v8, Stage IIB Ovarian Cancer AJCC v8, Stage III Lung Cancer AJCC v8, Stage III Ovarian Cancer AJCC v8, Stage IIIA Lung Cancer AJCC v8, Stage IIIA Ovarian Cancer AJCC v8, Stage IIIA1 Ovarian Cancer AJCC v8, Stage IIIA2 Ovarian Cancer AJCC v8, Stage IIIB Lung Cancer AJCC v8, Stage IIIB Ovarian Cancer AJCC v8, Stage IIIC Lung Cancer AJCC v8, Stage IIIC Ovarian Cancer AJCC v8
Sponsor: SWOG Cancer Research Network

 
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PRIVILEGED COMMUNICATION 
FOR INVESTIGATIONAL USE ONLY 
 
SWOG CANCER RESEARCH NETWORK 
TITLE 
S1714, A PROSPECTIVE OBSERVATIONAL COHORT STUDY TO DEVELOP A PREDICTIVE MODEL 
OF TAXANE-INDUCED PERIPHERAL NEUROPATHY IN CANCER PATIENTS 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by 
the National Cancer Institute (NCI). The trial will be led by SWOG with the participation of the 
network of NCTN organizations: Alliance for Clinical Trials in Oncology; ECOG-ACRIN Medical 
Group; and NRG. 
 
NCT# 03939481 
 
STUDY CHAIRS: 
TRANSLATIONAL MEDICINE STUDY CHAIR: 
 
Meghna S. Trivedi, M.D., M.S. 
Daniel L. Hertz, PharmD, Ph.D. 
(Medical Oncology) 
(Translational Medicine) 
Columbia University 
University of Michigan 
Herbert Irving Comprehensive Cancer Center 
Department of Clinical Pharmacy 
Herbert Irving Pavilion 
College of Pharmacy 
161 Fort Washington Avenue, HIP 9-907 
428 Church Street 
New York, NY 10032 
Ann Arbor, MI 48109 
Phone: 212/305-1945 
Phone: 734/763-0015 
FAX: 212/305-0178 
E-mail: dlhertz@med.umich.edu  
E-mail: S1714@swog.org  
 
Dawn L. Hershman, M.D., M.S. 
CLINICAL NURSE COORDINATOR: 
(Medical Oncology) 
Columbia University 
Stephanie J. Reyes, R.N., M.S.N, O.C.N 
Herbert Irving Comprehensive Cancer Center 
Nancy N. and J.C. Lewis Cancer and  
Herbert Irving Pavilion 
Research Pavilion at St. Joseph’s/Candler 
161 Fort Washington Avenue, HIP 10 
225 Candler Drive, Suite 204 
New York, NY 10032 
Savannah, GA  31405 
Phone: 212/305-1945 
Phone:  912/819-5723 
FAX: 212/305-0178 
FAX:  912/691-9299 
E-mail: S1714@swog.org  
E-mail: smiths1@sjchs.org  
 
 
Thomas H. Brannagan, M.D. 
BIOSTATISTICIANS: 
(Neurology) 
 
Columbia University 
Joseph M. Unger, Ph.D. 
Department of Neurology 
Amy Darke, M.S. 
710 W. 168th Street 
SWOG Statistics and Data Management Center 
New York, NY 10032 
Fred Hutchinson Cancer Research Center 
Phone: 212/305-0405 
1100 Fairview Avenue N, M3-C102 
FAX: 212/305-5396 
P.O. Box 19024 
E-mail: S1714@swog.org  
Seattle, WA 98109 
 
Phone: 206/667-4623 
 
FAX: 206/667-4408 
  
E-mail: junger@fredhutch.org  
 
E-mail: adarke@fredhutch.org  
ECOG-ACRIN CHAMPION: 
 
 
Bryan P. Schneider, M.D. 
 
Indiana University  
 
535 Barnhill Dr. RT 473 
Indianapolis, IN 46202 
Phone: 317/948-3855 
FAX: 371/948-3646 
E-Mail: bpschnei@iu.edu  
 

 
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PARTICIPANTS 
 
U.S. and International Participants: 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG Cancer Research Network 
 
 
 

 
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TABLE OF CONTENTS 
 
TITLE  ......................................................................................................................................................... 1 
PARTICIPANTS ............................................................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................................................... 3 
PROTOCOL CONTACT INFORMATION ..................................................................................................... 5 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 6 
SCHEMA ....................................................................................................................................................... 7 
1.0 
OBJECTIVES .................................................................................................................................. 8 
1.1 
Primary Objective ............................................................................................................................. 8 
1.2 
Secondary Objectives ...................................................................................................................... 8 
1.3 
Other Objectives .............................................................................................................................. 8 
1.4 
Imaging Objectives ........................................................................................................................... 8 
2.0 
BACKGROUND ............................................................................................................................... 8 
2.1 
Chemotherapy-Induced Peripheral Neuropathy (CIPN) .................................................................. 8 
2.2 
Drug Pharmacokinetics and CIPN ................................................................................................... 9 
2.3 
CIPN Risk Factors .......................................................................................................................... 10 
2.4 
CIPN Clinical Implications .............................................................................................................. 10 
2.5 
Inclusion of Women and Minorities and Planned Enrollment Report ............................................ 11 
3.0 
DRUG INFORMATION .................................................................................................................. 12 
4.0 
STAGING CRITERIA ..................................................................................................................... 12 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 12 
5.1 
Disease Related Criteria ................................................................................................................ 12 
5.2 
Prior/Concurrent Therapy Criteria .................................................................................................. 12 
5.3 
Clinical/Laboratory Criteria ............................................................................................................. 13 
5.4 
Specimen Submission Criteria ....................................................................................................... 13 
5.5 
Regulatory Criteria ......................................................................................................................... 13 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 14 
7.0 
STUDY ASSESSMENTS ............................................................................................................... 14 
7.1 
Pre-Treatment Laboratory Assessment ......................................................................................... 14 
7.2 
Medical History ............................................................................................................................... 14 
7.3 
Chemotherapy Treatment Schedule .............................................................................................. 14 
7.4 
Active Topical Agents/Medications/Supplements/Interventions .................................................... 15 
7.5 
Patient and Physician-Reported Outcomes ................................................................................... 15 
7.6 
Neuropen (provided to each participating site) .............................................................................. 16 
7.7 
128 Hertz Tuning Fork (,) (provided to each participating site)...................................................... 18 
7.8 
Timed Get Up and Go ()................................................................................................................. 22 
7.9 
Research Biospecimens ................................................................................................................ 23 
7.10 
Criteria for Removal from Protocol Participation ............................................................................ 23 
7.11 
Discontinuation of Protocol Participation ....................................................................................... 24 
7.12 
Follow-Up Period ............................................................................................................................ 24 
7.13 
COVID-19 Guidance ...................................................................................................................... 24 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 24 
9.0 
STUDY CALENDAR ...................................................................................................................... 25 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS ................................................. 27 
10.1 
Primary Endpoint ............................................................................................................................ 27 
10.2 
Secondary Endpoints ..................................................................................................................... 27 
10.3 
Performance Status ....................................................................................................................... 28 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 28 
11.1 
CIPN Predictors and Risk Factors ................................................................................................. 28 
11.2 
Sample Size and Analysis Plan ..................................................................................................... 29 
11.3 
Data and Safety Monitoring Committee ......................................................................................... 32 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 32 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 33 
13.1 
Registration Timing ........................................................................................................................ 33 
13.2 
Investigator/Site Registration ......................................................................................................... 33 
13.3 
OPEN Registration Requirements ................................................................................................. 37 

 
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13.4 
Exceptions to SWOG registration policies will not be permitted. ................................................... 37 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 37 
14.1 
Data Submission Requirement ...................................................................................................... 37 
14.2 
Master Forms ................................................................................................................................. 38 
14.3 
Data Submission / Data Reporting Procedures ............................................................................. 38 
14.4 
Data Submission Overview and Timepoints .................................................................................. 39 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 42 
15.1 
Translational Medicine (REQUIRED) and Banking (OPTIONAL FOR PATIENT) ......................... 42 
15.2 
Imaging Ancillary Study (OPTIONAL FOR PARTICIPANT / REQUIRED IF PARTICIPANT 
CONSENTS) .................................................................................................................................. 48 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 49 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 50 
18.0 
APPENDIX ..................................................................................................................................... 56 
18.1 
Protocol-Specified Chemotherapy Regimens for Breast, Lung, and Ovarian/Fallopian tube Cancer
 ....................................................................................................................................................... 57 
18.2 
Staging Criteria:  Definitions and Staging ...................................................................................... 58 
18.3 
Instructions for the SWOG Biospecimen Bank .............................................................................. 75 
18.4 
CTCAE Version 5.0 Nervous System Disorders Category  ........................................................... 76 
18.5 
Patient and Physician-Reported Outcomes Instruments ............................................................... 84 
18.6 
Causes of Neuropathy ................................................................................................................... 88 
18.7 
Foot Diagram ................................................................................................................................. 90 
18.8 
Translational Medicine - Pharmacokinetic Prediction of Taxane-Induced Peripheral Neuropathy 91 
18.9 
Translational Medicine – Genome-wide Pharmacogenetic Prediction of Taxane-Induced Peripheral 
Neuropathy (TIPN) (Funded R01) .................................................................................................. 96 
18.10 
Translational Medicine – Nutrient Prediction of Taxane-Induced Peripheral Neuropathy (TIPN) 
(Funded R01) ............................................................................................................................... 102 
18.11 
Imaging Study – Personalized Taxane Infusion Rate Recommendations to Reduce Neuropathy 
Risk in Patients with Low Skeletal Muscle Area .......................................................................... 106 
 

 
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PROTOCOL CONTACT INFORMATION 
 
 
Eligibility, RAVE, Data Submission: 
 
SWOG Statistics and Data Management Center  
E-mail: cancercontrolquestion@crab.org or  
Phone: 206/652-2267 
 
Regulatory, Protocol, Informed Consent: 
 
SWOG Operations Office 
E-mail: protocols@swog.org or Phone: 210/614-8808 
 
 
Study Assessment-Related questions: 
 
Email: S1714@swog.org 
 
Protocol Specific Training: 
• NeuroPen 
• 128 Hertz Tuning Fork 
• Timed Get Up and Go 
 
 
Email: S1714@swog.org 
• Section 7.6 
• Section 7.7 
• Section 7.8 
https://www.swog.org/required-s1714-training  
Patient Advocate 
Amy R. Geschwender, PhD 
ageschwender@gmail.com  
 
Specimen 
Tracking 
System 
(STS) 
Amendments, Errors, Connectivity Issues 
and Technical issues with the SWOG CRA 
Workbench: 
 
technicalquestion@crab.org 
 
Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-
IAM) 
 
To review CTEP-IAM account (new requests, reset 
passwords): 
 
 https://ctepcore.nci.nih.gov/iam/index.jsp 
 
Access to iMedidata Rave or Delegation of 
Task Log (DTL) 
 
See Protocol Section 14 or contact  
CTSU Help Desk:  
Phone: 
1-888-823-5923 
or 
Email: 
ctsucontact@westat.com 
 
Questions related to: 
Oncology Patient Enrollment Network 
(OPEN) 
 
See Protocol Section 13.3 or contact  
CTSU Help Desk:  
Phone: 
1-888-823-5923 
or 
Email: 
ctsucontact@westat.com 
Patient Transfers: 
patienttransfer@crab.org 
 
 

 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
For 
regulatory 
requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation 
must be submitted to the 
Cancer Trials Support Unit 
(CTSU) via the Regulatory 
Submission Portal. 
 
 (Sign 
in 
at 
https://www.ctsu.org, 
and 
select the Regulatory > 
Regulatory Submission.)  
 
Institutions with patients 
waiting that are unable to 
use the Portal should alert 
the 
CTSU 
Regulatory 
Office 
immediately 
by 
phone or email: 1-866-651-
CTSU 
(2878), 
or 
CTSURegHelp@coccg.org 
to 
receive 
further 
instruction and support. 
 
Contact 
the 
CTSU 
Regulatory Help Desk at 1-
866-651-CTSU (2878), or 
CTSURegHelp@coccg.org 
for regulatory assistance. 
Refer to the patient enrollment 
section 
of 
the 
protocol 
for 
instructions on using the Oncology 
Patient 
Enrollment 
Network 
(OPEN). OPEN can be accessed 
at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with 
any OPEN related questions by 
phone or email: 1-888-823-5923, 
or ctsucontact@westat.com. 
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave. Refer to the 
data submission section of the 
protocol for further instructions.  
 
Other 
Tools 
and 
Reports: 
Institutions participating through 
the CTSU continue to have 
access to other tools and 
reports available on the SWOG 
CRA Workbench via the SWOG 
website (www.swog.org).   
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website (https://www.ctsu.org).  
 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the Roster Maintenance application and in 
most cases viewable and manageable via the Roster Update Management System (RUMS) on the 
CTSU members’ website. 
For patient eligibility or data submission questions contact the SWOG Statistics and Data 
Management Center (SDMC) in Seattle, Washington by phone or email: 
206/652-2267 
cancercontrolquestion@crab.org   
 
For study assessment-related questions contact the Study Chairs by e-mail at 
S1714@swog.org.   
 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 

 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* 
Can be administered with a non-neurotoxic chemotherapy, such as cyclophosphamide, and/or 
biologic agents, such as trastuzumab, and/or carboplatin. 
 
 
REGISTRATION 
BASELINE EVALUATION 
Taxane-based  
chemotherapy regimen* 
Study Assessment:  4 weeks after registration (± 14 days) 
Study Assessment:  8 weeks after registration (± 14 days) 
Study Assessment:  12 weeks after registration (± 14 days) 
Study Assessment:  24 weeks after registration (± 28 days) 
Study Assessment:  52 weeks after registration (± 28 days) 
PROTOCOL PARTICIPATION COMPLETE 
Study Assessment: 104 weeks (2 years) after registration (± 90 days) 
Study Assessment:  156 weeks (3 years) after registration (± 90 days) 

 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
a. 
To develop and validate a clinical risk prediction model using clinical factors for the 
development of peripheral neuropathy in patients receiving taxane-based 
chemotherapy regimens. 
 
1.2 
Secondary Objectives 
 
a. 
To examine patient-reported outcomes (PROs) and objective measures of 
chemotherapy induced peripheral neuropathy (CIPN) to better define the 
phenotype of peripheral neuropathy in this patient population. 
 
b. 
To assess the incidence of CIPN within one year in this patient population. 
 
c. 
To identify predictors of treatment dose reductions, delays, and discontinuations 
associated with CIPN symptoms in this patient population. 
 
1.3 
Other Objectives 
 
a. 
To collect serum and plasma samples for future testing for biomarker and 
mechanistic studies of CIPN. 
 
1.4 
Imaging Objectives 
 
To estimate SMA-based taxane infusion rates for 1-hour paclitaxel (Pac1h) and docetaxel 
(Doc1h) to prevent supratherapeutic Cmax and reduce TIPN risk in female patients with 
breast cancer. 
2.0 
BACKGROUND 
 
2.1 
Chemotherapy-Induced Peripheral Neuropathy (CIPN) 
 
Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of many 
anti-cancer drugs, including platinum analogs, antitubulins such as taxanes and vinca 
alkaloids, and bortezomib. It can present as sensory symptoms in the hands and/or feet, 
typically in a “stocking-glove” pattern manifested as pain, numbness, or tingling, or as 
motor symptoms, manifested as weakness or cranial nerve deficits, or as autonomic 
neuropathy. In a meta-analysis of 31 CIPN studies involving 4179 patients, the aggregate 
prevalence of CIPN was 48%; however, the methods used to assess for the presence of 
CIPN varied widely among the studies included. (1) Within the first month of finishing 
chemotherapy, the prevalence of CIPN was 68.1%. After 6 or more months of completing 
chemotherapy, the prevalence of CIPN decreased to 30.0%. (2) In SWOG S0715, a 
randomized, double-blind, multi-center trial comparing acetyl-L-carnitine versus placebo 
for prevention of CIPN in women with stage I-III breast cancer undergoing taxane-based 
chemotherapy, symptoms of neuropathy were persistent 2 years following treatment. (3) 
The course of CIPN can be unpredictable. Although some symptoms may improve with 
time, other symptoms may persist or worsen as a result of permanent nerve damage. The 
incidence of CIPN varies not only with the chemotherapeutic agent used but also the dose 
or frequency with which an agent is given, and the cumulative dose received (Table 2.1). 
(4,5) 
 
Studies of CIPN have been limited by the absence of a clearly defined phenotype for CIPN. 
There are several methods available to assess CIPN; however, there is no consensus on 
the best method to evaluate CIPN. Postma et al. developed a CIPN subscale as part of the 
European Organization for Research and Treatment of Cancer (EORTC) Quality of Life 

 
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Questionnaire 30 (QLQ-30), called the QLQ-CIPN-20 module. (6) The instrument contains 
20 questions evaluating sensory, motor, and autonomic symptoms and has been validated 
as an assessment tool for CIPN. (7) There are several therapeutic and observational trials 
that have used the CIPN-20 as the primary outcome. (8,9,10,11) The challenge is how to 
incorporate CIPN measures into clinical practice and standardize this approach across 
multiple centers. 
 
A further challenge in managing and preventing CIPN is that the exact pathophysiology is 
not well understood and is likely multifactorial with both genetic and non-genetic risk 
factors. (12) Additionally, the pathophysiology appears to vary depending upon the 
chemotherapeutic agent. The hypothesized mechanisms of taxane-induced peripheral 
neuropathy include the disruption of the axonal microtubule structure and a deficit in axonal 
energy supply through the toxic effect of chemotherapy on mitochondria in primary afferent 
neurons. (13,14) Platinum agents are thought to cause CIPN by exerting damage in the 
dorsal root ganglion through neuronal apoptosis, either by DNA crosslinking or oxidative 
stress, and mitochondrial dysfunction. (15,16) 
 
Table 2.1. Incidence of CIPN based on chemotherapeutic agent 
Chemotherapy 
regimen 
Disease 
Incidence of CIPN 
Motor 
neuropathy 
(all grades) 
Sensory 
neuropathy 
(all grades) 
Grade 3-4 
sensory 
neuropathy  
Docetaxel and 
Carboplatin 
(17,18,19) 
Ovarian/Fallopian 
tube/ Peritoneal 
cancer tube, 
breast, and lung 
cancer 
5- 9% 
45-46% 
1-2% 
FOLFOX 
(20,21,22) 
Colorectal cancer 
- 
59-92% 
7-12% 
Bortezomib 
(23,24) 
Multiple myeloma 
6% 
44% 
13% 
Paclitaxel 
(25,26) 
Breast cancer 
9-17% 
33-45% 
12-24% 
 
2.2 
Drug Pharmacokinetics and CIPN 
 
The association of drug pharmacokinetics with the development of CIPN has also been 
studied. In a study of patients with advanced cancer receiving weekly paclitaxel (N=24), 
having exposure to a concentration of total paclitaxel above 0.05 mcmol/L (Tc>0.05) for 
greater than or equal to 10.6 hours was the most important pharmacokinetic factor 
influencing the development of CIPN. (27) In this study, 12-14 serum samples were 
obtained from each patient during and until 48 hours after the end of paclitaxel 
administration. Confirmation that paclitaxel exposure, not dose, is the critical determinant 
of paclitaxel-induced peripheral neuropathy (PIPN) was provided by a prospective, 
randomized, phase III trial of 3-weekly paclitaxel (200 mg/m2)/carboplatin in lung cancer 
patients. Patients who received individualized dosing to maintain a therapeutic paclitaxel 
exposure target had significantly lower PIPN occurrence (38% vs. 23%, p<0.001) than 
patients receiving standard maximum tolerated dosing, with similar efficacy. (28) 
Preliminary data from an observational clinical study by one of the Co-Is (NCT02338115, 
PI: Daniel Hertz) further supports the importance of paclitaxel exposure in determining 
neuropathy. The observational clinical trial enrolled 60 women with early stage breast 
cancer scheduled to receive weekly paclitaxel (80 mg/m2 x 12 cycles) who had no existing 
neuropathy, family history of hereditary neuropathy, or prior neurotoxic chemotherapy 
treatment. (29,30) Paclitaxel concentration (exposure) was measured in plasma collected 
just prior to the end of the first infusion and 16-24 hours later via liquid chromatography-

 
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mass spectroscopy. The end of infusion sample provides an estimate of the maximum 
concentration (Cmax), and the 16–24-hour sample was used to estimate the patient’s time 
above threshold (Tc>0.05) using a previously published population-pharmacokinetic model. 
(31) PIPN data were collected at baseline (prior to paclitaxel) and weekly throughout 
treatment using the sensory subscale of the CIPN-20. (32,33) The change in the sensory 
subscale from baseline was calculated for each patient at each weekly cycle to estimate 
neuropathy progression. All patients with neuropathy and exposure data were included in 
a logistic regression model to predict treatment-limiting neuropathy (i.e. paclitaxel dose 
decrease, delay, or discontinuation). Each exposure parameter significantly contributed to 
this prediction model; a one standard deviation increase in Cmax (664.8 ng/mL) and Tc>0.05 
(2.7 hours) were associated with 174% (OR=2.74, 95% CI: 1.45-5.20, p=0.0020) and 76% 
(OR =1.76, 95% CI: 1.45-2.14, p=0.0294) higher risk of treatment-limiting PIPN, confirming 
the contribution of exposure to neuropathy development. 
 
2.3 
CIPN Risk Factors 
 
Several studies have attempted to identify risk factors for the development of CIPN, which 
also vary with chemotherapeutic agent. Some of the clinical factors implicated in the 
development of CIPN include increasing age, (34) baseline neuropathy, (35,36) presence 
of diabetes, (37,38) smoking history, (39) and decreased creatinine clearance. (40) One 
study found that the presence of autoimmune disease reduced the risk of CIPN 
development. (41) Additionally, there is interest in pharmacogenomics and identifying 
genes that may play a role in the development of CIPN.  Although numerous genes have 
been investigated (Table 2.2), there have been no conclusive findings. (42) The lack of a 
well-defined phenotype of CIPN has limited the identification of CIPN risk factors and 
genetic predictors. Despite investigations leading to hypotheses of several mechanisms of 
CIPN, none of these have resulted in clinically relevant therapeutic interventions. Given the 
many variables that seem to affect the development of CIPN, particularly the differences 
among each neurotoxic chemotherapeutic agent, it is likely that CIPN cannot be defined 
as a single entity. 
 
Table 2.2. Putative genetic predictors of CIPN 
Chemotherapy agent 
Predictive genes 
Oxaliplatin 
CCNH(43), ABCG2(44), 
TAC1(45), FOXC1(46) 
GMDS(47), ITGA1(48), 
PELO(49), ACYP2(50), 
TSPYL6(51), DLEU7(52) 
Bortezomib 
RDM1(53), CASP9(54), 
ALOX12(55), LSM1(56), 
CTLA4(57), PSMB1(58)1 
Taxane 
FDG4(59), EPHA5(60), 
FZD3(61), ABCB1(62), 
TUBB2A(63), 
FANCD2(64), CYP2C8*3(65),  
EPHA4(66) 
 
2.4 
CIPN Clinical Implications 
 
One of the clinical implications of CIPN is that the symptoms can lead to treatment dose 
reduction or discontinuation, which may ultimately affect overall survival. (67) In addition, 
for cancer survivors, CIPN symptoms can significantly impact quality of life and functional 
status. (68,69) The primary objective of this study is to develop a risk prediction model for 
CIPN due to taxanes that can be utilized in the clinic. By focusing on identifying the 
predictors of peripheral neuropathy caused by a single class of chemotherapy agents, the 
investigators will be able to develop a clinically meaningful prediction model. Although it is 

 
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anticipated that age, pre-existing neuropathy, and paclitaxel exposure will be strong 
predictors of taxane induced peripheral neuropathy, our goal is to examine a broad range 
of factors from an agnostic perspective, with no a priori design specification favoring any 
particular factor. In addition, this study will aim to characterize the clinical phenotype of 
CIPN due to taxanes and describe the trajectory of CIPN. This will be accomplished by 
collecting patient reported outcome measures and objective measures of CIPN over the 
course of 12 months. Through this prospective cohort study, the investigators will build an 
associated repository of biospecimens that can be used for future biomarker and 
mechanistic studies. It is anticipated that over the course of the study, new proteomic, 
metabolomic, or genomic biomarkers will be identified. The biospecimen repository 
developed from this study will allow us to investigate such biomarkers and potentially 
incorporate these new findings into our risk prediction model in the future.  
 
Taxanes are commonly used in the treatment of cancer and given the clinical implications 
of this frequently occurring adverse effect, it is important to understand the risk factors for 
development of CIPN and its clinical course.  This study will also include a broader 
population of patients than is generally enrolled in clinical trials, including patients with co-
morbidities such as diabetes and pre-existing peripheral neuropathy.  By better 
characterizing CIPN due to taxanes, the investigators may be able to select cancer 
treatment regimens more appropriately for patients at higher risk of CIPN.  Furthermore, 
these data would inform future clinical trial designs for therapeutic trials and symptom 
research intended to prevent or relieve CIPN. 
 
2.5 
Inclusion of Women and Minorities and Planned Enrollment Report 
 
This study was designed to include women and minorities, but was not designed to 
measure differences of intervention effects.  The anticipated accrual in the ethnicity/race 
and sex categories is shown in the table below.  
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American 
Indian/ 
Alaska 
Native 
2 
0 
1 
0 
3 
Asian 
40 
6 
3 
0 
49 
Native 
Hawaiian or 
Other 
Pacific 
Islander 
8 
2 
0 
0 
10 
Black 
or 
African 
American 
68 
10 
5 
0 
83 
White 
692 
105 
51 
3 
851 
More Than 
One Race 
2 
0 
0 
0 
2 
Total 
812 
123 
60 
3 
998 
 
 
 

 
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INTERNATIONAL (including Canadian participants) PLANNED ENROLLMENT 
REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American 
Indian/ 
Alaska 
Native 
0 
0 
27 
4 
31 
Asian 
0 
0 
0 
0 
0 
Native 
Hawaiian or 
Other 
Pacific 
Islander 
0 
0 
0 
0 
0 
Black 
or 
African 
American 
0 
0 
0 
0 
0 
White 
0 
0 
245 
36 
281 
More Than 
One Race 
0 
0 
0 
0 
0 
Total 
0 
0 
272 
40 
312 
 
3.0 
DRUG INFORMATION 
 
Drug information is not applicable to this protocol. 
 
 
4.0 
STAGING CRITERIA 
 
This protocol will use the American Joint Committee on Cancer (AJCC) 8th Edition. (70)  See 
Appendix 18.2 for complete definitions and staging. 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered 
eligible for registration.  For each criterion requiring test results and dates, please record this 
information on the Onstudy Form and submit via Medidata Rave® (see Section 14.0).  Any potential 
eligibility issues should be addressed to the SWOG Statistics and Data Management Center at 
206/652-2267 or cancercontrolquestion@crab.org prior to registration. NCI policy does not allow 
for waiver of or deviation within any eligibility criterion  
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
 
In calculating days of tests and measurements, the day of registration is Day 0.  Therefore, if the 
day of registration is on a Monday, the Monday 4 weeks later would be considered Day 28.   
 
5.1 
Disease Related Criteria 
 
a. 
Patients must have Stage I, II, or III primary non-small cell lung, primary breast, or 
primary ovarian/fallopian tube/ peritoneal cancer based on clinical or pathologic 
evaluation.  Patients with Stage IV disease are not eligible.   
 
5.2 
Prior/Concurrent Therapy Criteria 
 
a. 
Patients must be planning to start treatment with a taxane-based chemotherapy 
as part of one of the study-approved taxane regimens (docetaxel chemotherapy 

 
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regimens for treatment of breast or ovarian/fallopian tube/ peritoneal cancer, or 
paclitaxel chemotherapy regimens for treatment of breast, non-small cell lung, or 
ovarian/fallopian tube/ peritoneal cancer) within 14 days after registration.  (Note 
that carboplatin is allowed only as described in Appendix 18.1. However, any of 
the regimens in Appendix 18.1 may be combined with a non-neurotoxic 
chemotherapy, such as cyclophosphamide, and/or a biologic agent, such as 
trastuzumab.  Permitted biologic agents include, but are not limited to, 
pembrolizumab, bevacizumab, trastuzumab, and/or pertuzumab. Nab-
paclitaxel may not be substituted for paclitaxel for purposes of this study.)  See 
Appendix 18.1 for the study-approved docetaxel and paclitaxel-based regimens. 
 
b. 
Patients who will receive treatment in the setting of any other clinical trial are 
eligible as long as it is one of the study-approved regimens listed in Appendix 18.1. 
Patients may receive additional treatments (i.e., experimental therapy, 
immunotherapy, biologics, etc.) as part of another clinical trial in addition to any 
regimen approved in this study. 
 
c. 
Patients must not have received a taxane (paclitaxel, docetaxel, or protein-bound 
paclitaxel), platinum (cisplatin, carboplatin, or oxaliplatin), vinca alkaloid 
(vinblastine, vincristine, or vinorelbine), or bortezomib-based chemotherapy 
regimen prior to registration. (Note that while patients must not have received 
carboplatin in the past, patients may receive a carboplatin-containing regimen after 
registration as part of the docetaxel or paclitaxel regimen.)   
5.3 
Clinical/Laboratory Criteria 
 
a. 
Patients must be ≥ 18 years of age. 
 
b. 
Patients must be able to complete Patient-Reported Outcome (PRO) instruments 
in English or Spanish. Patients must:  
1) agree to complete PROs at all scheduled assessments; and  
2) complete the baseline PRO forms prior to registration as outlined in 
Section 7.5.  
 
c. 
Patients with pre-existing neuropathy are eligible, including those with diabetes 
and neurological conditions such as multiple sclerosis or Parkinson’s disease. 
 
5.4 
Specimen Submission Criteria 
 
a. 
Patients must agree to submit required specimens for defined translational 
medicine as outlined in Section 15.1. 
 
b. 
Patients must be offered the opportunity to submit additional optional specimens 
for future, unspecified translational medicine and banking.  With patient’s consent, 
specimens must be submitted as outlined in Section 15.1. 
 
5.5 
Regulatory Criteria 
 
a. 
Patients must be informed of the investigational nature of this study and must sign 
and give informed consent in accordance with institutional and federal guidelines. 
 
b. 
As a part of the OPEN registration process (see Section 13.3 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that the 
current (within 365 days) date of institutional review board approval for this study 
has been entered in the system. 
 
 

 
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6.0 
STRATIFICATION FACTORS 
 
Patients will be classified by primary cancer (lung vs breast vs ovarian/fallopian tube/ peritoneal) 
and planned taxane (paclitaxel vs docetaxel) in order to ensure a representative balance of 
registrations by cancer and treatment type.  When 250 lung cancer patients have been accrued, 
the lung cancer category will be closed to further accrual. 
 
 
7.0 
STUDY ASSESSMENTS 
 
See Section 14.0 for forms submission requirements. 
 
7.1 
Pre-Treatment Laboratory Assessment 
 
Patients must have creatinine clearance or serum creatinine (for calculation of creatinine 
clearance) collected either:  
 
1) within 30 days prior to registration, OR  
2) after registration but prior to beginning their taxane-based chemotherapy regimen. 
 
Estimated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 
72 x creatinine (mg/dl) 
 
7.2 
Medical History  
 
Active medical problems, past medical history, smoking history, and concomitant 
medications will be documented at baseline for this study and reported on the appropriate 
baseline form.  Oncologic history, including primary tumor size and grade, lymph node 
status, stage, hormone receptor status (for breast cancer), Her2/neu status (for breast 
cancer), and treatment history (including prior regimens) will be collected.  Data will also 
be collected on other comorbidities, including but not limited to diabetes, thyroid disease, 
vitamin B12 deficiency, vitamin D deficiency, autoimmune disease, and neurological 
conditions, as well as Zubrod performance status and history of falls. Data regarding the 
causes of pre-existing neuropathy will also be collected. A comprehensive list of 
neuropathies is included in Appendix 18.6. 
 
7.3 
Chemotherapy Treatment Schedule  
 
This protocol will not dictate which treatment is given or any dose reductions, dose delays, 
or discontinuation of therapy; however, a list of protocol-specified allowable treatment 
regimens at the time of patient registration per eligibility requirements in  Section 5.0 is in 
Appendix 18.1. Radiation may be administered concurrently with chemotherapy and will 
be documented and reported. Document and report chemotherapy drugs, doses, and 
schedules. Any chemotherapy dose reductions, delays, or discontinuations will be 
determined by the treating physician and will also be documented and reported. A 
treatment will be considered dose reduced if the dose administered is ≥ 20% less than the 
standard taxane dose listed for the regimen in Appendix 18.1. A treatment will be 
considered delayed if the dose is administered ≥ 7 days later than the standard taxane 
interval for the regimen in Appendix 18.1.  A treatment discontinuation is defined as 
stopping the taxane-based chemotherapy prior to the standard number of doses listed for 
the regimen in Appendix 18.1. The reason for change in treatment will also be noted (i.e., 
CIPN symptoms, neutropenia, patient preference, progression of disease, etc.). 
Assessment of treatment schedule will occur at baseline prior to chemotherapy, then at 4 
weeks, 8 weeks, and 12 weeks (± 14 days), at 24 weeks,  52 weeks, (± 28 days), and 104 
weeks (2 years), and 156 weeks (3 years) (± 90 days) after registration as outlined in 
Section 9.0. Efforts should be made to perform the 4-week, 8-week, and 12-week 
assessments on a day of taxane treatment that falls within the study window period and 
prior to taxane administration. 

 
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If additional adjuvant therapies are administered following the completion of the taxane-
based regimen, this will be documented and reported in the follow up treatment forms. 
Adjuvant therapies may include, but are not limited to, chemotherapy (i.e. capecitabine), 
biologic therapy (i.e. trastuzumab), immunotherapy (i.e. pembrolizumab), or targeted 
therapy (i.e. PARP inhibitor). This protocol will not dictate which treatment is given or any 
dose reductions, dose delays, or discontinuation of therapy. 
 
7.4 
Active Topical Agents/Medications/Supplements/Interventions 
 
Sites will collect information regarding the patient’s use of all topical agents, medications, 
vitamins and multivitamins, supplements, or acupuncture and will document and report 
the information via the S1714 Supplements, Topical Agents, and Other Treatments Form.  
The use of cooling gloves or socks (or other means of cooling hands and feet) and 
compression gloves or socks as a means of CIPN prevention will also be collected. If any 
of the above are used specifically for CIPN symptoms, this will also be reported.  
Assessment will occur at baseline prior to chemotherapy, then at 4 weeks, 8 weeks, and 
12 weeks (± 14 days), and at 24 weeks and 52 weeks (± 28 days) after registration as 
outlined in Section 9.0.  Efforts should be made to perform the 4-week, 8-week, and 12-
week assessments on a day of taxane treatment that falls within the study window period 
and prior to taxane administration. 
 
7.5 
Patient and Physician-Reported Outcomes 
 
Patients are to complete the instruments in English or Spanish and physicians will complete 
questionnaires at baseline prior to registration and chemotherapy and as outlined in 
Section 9.0, throughout the patient’s participation in the study. The instruments that will be 
used and assessments to be performed are: 
• 
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CIPN20 
(CIPN-20) 
• 
Patient-Reported Outcomes Measurement Information System 29 (PROMIS-29) 
• 
Godin-Shephard Leisure-Time Physical Activity Questionnaire (GSLTPAQ) 
• 
Patient Reported Symptom (and Side Effect) Burden  
• 
Visual Analog Toxicity Score 
• 
PRO-CTCAE 
• 
NCI-CTCAE 
• 
FACT-GOG-NTX-4  
 
Complete details regarding each instrument, the associated grading scales and time points 
for administration are in Appendix 18.5. 
 
NOTE: Patients should continue to complete questionnaires at study time points even if 
patient discontinues taxane-based chemotherapy, disease progression or relapse prior to 
52 weeks after registration per Section 7.10 and 7.12. 
 
NOTE: For all patient reported outcome questionnaire timepoints, participating sites may 
follow-up with patients via telemedicine (phone or virtual visit) to conduct the 
questionnaires and patient follow-up provided that the Responsible Investigator determines 
that the phone/virtual visit is adequate to achieve the central purpose of the visit and assure 
the safety of the patient. Patient must be provided with a copy of the questionnaire via mail 
or email. 
 
 

 
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7.6 
Neuropen (provided to each participating site)  
 
Sites must have a Neuropen prior to the first patient registration.  Neuropen ordering 
instructions are in Section 7.6a. Additionally, at least one clinician (physician, nurse 
practitioner, registered nurse, licensed practical nurse, or physician assistant) at each site 
must be certified to use the Neuropen (see Section 7.6b for details on obtaining 
certification) prior to first patient registration. Neuropen assessments must be performed 
by a certified clinician. Local site authority logs should be updated to include this task. Note: 
CRA may not conduct the testing.  
 
a. 
Neuropen Ordering 
 
Sites may order Neuropen at the time that IRB approval has been submitted to the 
CTSU Regulatory Office (see Section 13.2b).  Requests should be submitted via 
e-mail to S1714@swog.org.  The subject of the e-mail should be “S1714 Neuropen 
Order.”  (Note that this order may be combined with the 128 Hertz tuning fork order 
(see Section 7.7) by specifying “S1714 Neuropen and Tuning Fork Order.”)  The 
e-mail must include the following information: 
• 
site name  
• 
site NCI code 
• 
mailing address to which the Neuropen should be shipped 
• 
contact information (phone number and e-mail address) for a staff contact at 
the site in the event there are questions about the order 
• 
verification that the site’s IRB approval has been submitted to Regulatory 
Office 
• 
name of the clinician(s) who will complete the Neuropen training and 
certification 
 
NOTE: Only 150 tools are available (first come, first serve basis) for this study.  A 
notification will be circulated to sites via the SWOG and CTSU mailout once this 
number has been met.  
 
b. 
General Neuropen Information 
 
The Neuropen has a 10-g monofilament on one end and Neurotip on the other 
end.  Instructions on how to replace the monofilament and Neurotip are in the user 
manual. The Neuropen may be reused and is not patient-specific.   
 
• 
The monofilament should be replaced after 100 uses. A single use is defined 
as a single 10-point examination on the dominant foot of a subject.  
• 
The Neurotip should be replaced with each 10-point examination on the 
dominant foot of a subject. 
 
Neuropathy evaluation is to be performed by a clinician certified to perform the 
testing.  A clinician can be certified to perform Neuropen testing by completing the 
steps below.  
 
First, the clinician must review the user manual and instructional video for the 
Neuropen, which are available on the protocol abstract pages of the SWOG 
website (www.swog.org) and the CTSU website (www.ctsu.org).  Note that the 
user manual outlines the basic instructions for use of the Neuropen, but more 
detailed, study-specific instructions are included in Sections 7.6c and 7.6d below.  
For purposes of this study, sites should use the more detailed instructions outlined 
below. Once the clinician has reviewed the instructions below, the instructional 
video, and user manual, the clinician must complete a training verification available 

 
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on the protocol abstract page of the SWOG website (www.swog.org) and the 
verification must be submitted via CTSU (see Section 13.2b.3).   
 
Second, the clinician must be observed demonstrating proficiency in using the 
Neuropen.  This can be done in one of 2 ways: 1) in-person observation at a bi-
annual SWOG meeting, or 2) observation via video-conference. One of the Study 
Chairs or the Clinical Nurse Coordinator will be responsible for assessing the 
proficiency demonstration. Observation via video-conference may be arranged by 
e-mailing S1714@swog.org. Once the clinician has been observed performing 
Neuropen testing, he/she will obtain a certificate of training via email from the 
SWOG Operations Office which must be submitted via CTSU Regulatory Portal 
(see Section 13.2b.3).   
 
All clinicians who will perform Neuropen assessments must submit certification of 
training. Any questions regarding the use of the Neuropen can be directed to the 
Clinical Nurse Coordinator for the study. 
 
Assessments will occur at baseline prior to start of taxane treatment, then at 4 
weeks, 8 weeks, and 12 weeks (± 14 days), and at 24 weeks and 52 weeks (± 28 
days) as outlined in Section 9.0.  Efforts should be made to perform the 4-week, 
8-week, and 12-week assessments on a day of taxane-based treatment that falls 
within the study window period and prior to taxane administration.  Results of this 
assessment will be submitted via the S1714 Neuropathy Assessment Form.  The 
Neuropen assessment will take approximately 5-10 minutes to complete. 
 
 
c. 
Instructions for Assessing Touch and Pressure Perception 
 
Touch and Pressure Perception: Touch and pressure sensation is assessed using 
the 10-g monofilament in the Neuropen on the subject’s dominant foot. The 
dominant foot can be identified by asking the subject with which foot they would 
kick a ball.  The clinician will follow the subsequent steps using the subject’s 
dominant foot:  
 
1. 
Ask the subject to remove sock and/or shoe on the dominant foot and lay 
flat or sit up on an examination table.    
2. 
Fully extend the monofilament by sliding the button to the end of the 
device until a click is heard. 
3. 
Wipe the end of the monofilament with an alcohol wipe or antiseptic 
solution. 
4. 
The 10 sites in the below figure (Figure 7.1) are to be tested at random 
on the dominant foot. Press the monofilament at a 90-degree angle to the 
skin surface and increase the pressure until it bows. The subject should 
not be able to see which site is being tested. 
5. 
Hold in position for 1-2 seconds. 
6. 
For each of the 10 sites tested, ask the subject if he/she can detect 
pressure applied from monofilament and name the location of sensation. 
Subjects may use the unmarked picture of the feet (similar to Figure 7.1) 
which is included in Appendix 18.7 to point to the location of sensation if 
they are unable to adequately name the location. Record subject 
response for each site tested. The sensation must be detected in the 
accurate location to be marked as correct.  
 
 

 
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d. 
Instructions for Assessing Protective Pain and Sharpness Sensation 
 
Protective Pain and Sharpness Sensation: This is a calibrated and sterile 
pain/sharpness test on the subject’s dominant foot. The spring mechanism is 
calibrated to exert a force of 40 grams to help identify subjects with a loss of pain 
sensation.  The dominant foot can be identified by asking the subject with which 
foot they would kick a ball. The clinician will follow the subsequent steps using the 
subject’s dominant foot: 
 
1. 
Ask the subject to remove sock and/or shoe on the dominant foot and lay 
flat or sit up on an examination table.   
 
2. 
Take an unused Neurotip and hold by the cap. Do not use if Neurotip cap 
has previously been removed.  
3. 
Press Neurotip firmly down into the Neurotip carrier of the Neuropen as far 
as it will go and clicks into position. The Neurotip is correctly positioned 
when only one chevron can be seen on the Neurotip. 
4. 
To expose the sterile semi-sharp tip, place thumb gently over the Neurotip 
pressure gauge and remove Neurotip cap by twisting and pulling 
outwards. 
5. 
The 10 sites in the below figure (Figure 7.1) are to be tested at random. 
Press the Neurotip against the skin surface at a 90-degree angle. The 
subject should not be able to see which site is being tested. 
6. 
Hold in position for 1-2 seconds before removing, taking care to depress 
within the 40-gram marked white area. 
7. 
For each of the sites tested, ask the subject if they detect a sharp 
sensation and name the location of sharp sensation. Subjects may use the 
unmarked picture of the feet (similar to Figure 7.1) which is included in 
Appendix 18.7 to point to the location of sensation if they are unable to 
adequately name the location. Record subject response for each site 
tested. The sensation must be detected in the accurate location to be 
marked as correct. 
8. 
Remove and discard the used Neurotip in an appropriate sharps container 
after completing the 10 site examinations. 
 
Figure 7.1 Sites on the feet to be evaluated with Neuropen 
monofilament and Neurotip 
 
7.7 
128 Hertz Tuning Fork (71,72) (provided to each participating site) 
 
Sites must have a 128 Hertz tuning fork prior to the first patient registration.   
 
128 Hertz Tuning Form ordering instructions are in Section 7.7a.  Additionally, at least one 
clinician (physician, nurse practitioner, registered nurse, licensed practical nurse, or 
physician assistant) at each site must be certified to use the tuning fork (see Section 7.7b 
for details on obtaining certification) prior to first patient registration. 128 Hertz tuning fork 
assessments must be performed by a certified clinician. Local site authority logs should be 
updated to include this task. Note: CRA may not conduct the testing. 
 

 
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a. 
128 Hertz Tuning Fork Ordering 
 
Sites may order the 128 Hertz tuning fork at the time that IRB approval has been 
submitted to the CTSU Regulatory Office (see Section 13.2b).  Orders should be 
submitted via email to S1714@swog.org.  The subject of the e-mail should state 
“S1714 Tuning Fork Order.”  (Note that this order may be combined with the 
Neuropen order (see Section 7.6) by specifying “S1714 Neuropen and Tuning Fork 
Order.”)  The e-mail must include the following information: 
• 
site name  
• 
site NCI code 
• 
mailing address to which the 128 Hz tuning fork should be shipped 
• 
contact information (phone number and e-mail address) for a staff contact at 
the site in the event there are questions about the order 
• 
verification that the site’s IRB approval has been submitted to the CTSU 
Regulatory Office   
• 
name of the clinician(s) who will complete the tuning fork training and 
certification 
 
NOTE: Only 150 tools are available (first come, first serve basis) for this study.  A 
notification will be circulated to sites via the SWOG and CTSU mailout once this 
number has been met.  
 
b. 
128 Hertz Tuning Fork Information 
 
Neuropathy evaluation is to be performed by a clinician certified to perform the 
testing.  A clinician can be certified to perform 128 Hz tuning fork testing by 
completing the following steps below.  
 
First, the clinician must review the detailed instructions on how to perform the 
testing included below and the instructional video for the 128 Hz tuning fork, which 
is available on the protocol abstract page of the SWOG website (www.swog.org) 
and the CTSU website (www.ctsu.org). Once the clinician has reviewed the 
instructions below and the instructional video, the clinician must complete a 
training verification available on the protocol abstract page of the SWOG website 
(www.swog.org) and the verification must be submitted via CTSU (see Section 
13.2b.3).  
 
Second, the clinician must be observed demonstrating proficiency in using the 128 
Hz tuning fork.  This can be done in one of 2 ways: 1) in-person observation at a 
bi-annual SWOG meeting, or 2) observation via video-conference. One of the 
study chairs or the clinical nurse coordinator will be responsible for assessing the 
proficiency demonstration. Observation via video-conference may be arranged by 
e-mailing S1714@swog.org. Once the clinician has been observed performing 128 
Hz tuning fork testing, he/she will obtain a certificate of training via email from the 
SWOG Operations Office which must be submitted via CTSU Regulatory Portal 
(see Section 13.2b.3).   
 
All clinicians who will perform 128 Hz tuning fork assessments must submit 
certification of training. Any questions regarding the use of the 128 Hz tuning fork 
can be directed to the Clinical Nurse Coordinator for the study.   
 
The 128 Hz tuning fork will be used to assess vibration sensation in the dominant 
upper extremity and dominant lower extremity.  Results of this assessment will be 
submitted via the S1714 Neuropathy Assessment Form.  Assessment will occur at 

 
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baseline prior to start of chemotherapy, then at 4 weeks, 8 weeks, and 12 weeks 
(± 14 days), and at 24 weeks and 52 weeks (± 28 days) as outlined in Section 9.0.  
Efforts should be made to perform the 4-week, 8-week, and 12-week assessments 
on a day of taxane-treatment that falls within the study window period and prior to 
taxane administration. The 128 Hertz tuning fork assessment will take about 5 
minutes to complete. 
 
c. 
Instructions for Dominant Lower Extremity Vibration Sensation Testing 
 
1. 
The tuning fork should be firmly tapped on the palm of the hand of the 
clinician to initiate vibration.  
 
2. 
The vibrating tuning fork is first placed on the interphalangeal joint of the 
great toe of the dominant foot (Figure 7.2 [2a] below). The dominant foot 
can be identified by asking the subject with which foot they would kick a 
ball. A timer is started once the vibrating tuning fork is placed on the 
interphalangeal joint of the great toe of the dominant foot.  
 
3. 
The patient is instructed to report when vibration is no longer detected. 
The time at which the vibration is no longer detected should be noted. 
 
4. 
If the patient feels the vibration for 15 seconds or longer, this is defined as 
normal and should be recorded as such. If vibration sensation is normal at 
the great toe, additional assessments of the lower extremity are not 
needed.  
 
5. 
If vibration sensation in the great toe of the dominant foot is less than 15 
seconds, this is defined as absent or decreased vibration sensation and 
should be recorded as such. If vibration sensation is absent or decreased 
in the interphalangeal joint of the great toe of the dominant foot, the 
clinician then conducts the testing at all additional sites listed below on the 
dominant side.  For each site tested, the tuning fork should be firmly 
tapped on the palm of the hand of the clinician to initiate vibration and the 
vibrating tuning fork is placed on the site. Once the vibrating tuning fork is 
placed on the testing site, a timer is started to measure the time at which 
the vibration is no longer detected.  This time should be noted for each 
site. 
 
a. 
The middorsal foot (Figure 7.2 [2b]): If the patient feels the 
vibration for 15 seconds or longer, this is defined as normal. If the 
patient feels the vibration less than 15 seconds, this is defined as 
absent or decreased vibration sensation. 
 
b. 
The medial malleolus (ankle) (Figure 7.2 [2c]): If the patient feels 
the vibration for 15 seconds or longer, this is defined as normal. If 
the patient feels the vibration less than 15 seconds, this is defined 
as abnormal.  
 
c. 
The midfibular region of the dominant lower extremity (Figure 7.2 
[2d]): If the patient feels the vibration for 15 seconds or longer, this 
is defined as normal. If the patient feels the vibration less than 15 
seconds, this is defined as absent or decreased vibration 
sensation. 
 
d. 
The patellar region of the dominant lower extremity (Figure 7.2 
[2e]): If the patient feels the vibration for 10 seconds or longer, this 
is defined as normal. If the patient feels the vibration less than 10 
seconds, this is defined as absent or decreased vibration 
sensation.   
 
 

 
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Figure 7.2:  Sites of lower extremity vibration sensation testing (73)  
 
Note:  The tuning fork is firmly tapped on the palm and then placed on the 
interphalangeal joint of the great toe (2a).  If vibration sensation is diminished or 
absent in the great toe, testing should be performed at the middorsal foot (2b) and 
the medial malleolus (2c), followed by the midfibular (2d) and patellar (2e) regions. 
  
d. 
Dominant upper extremity vibration sensation testing 
 
1. 
The clinician will conduct the testing at all three sites below on the 
dominant upper extremity. The dominant upper extremity can be identified 
by asking the subject with which hand they write.  
 
2. 
For each site tested, the tuning fork should be firmly tapped on the palm 
of the hand of the clinician to initiate vibration and the vibrating tuning fork 
is placed on the site. Once the vibrating tuning fork is placed on the testing 
site, a timer is started to measure the time at which the vibration is no 
longer detected.  This time should be noted for each site. The three sites 
to be tested on the dominant upper extremity vibrating tuning fork are:   
 
a. 
The distal interphalangeal joint of the index finger (Figure 7.3 [3a]): 
If the patient feels the vibration for 25 seconds or longer, this is 
defined as normal. If the patient feels the vibration less than 25 
seconds, this is defined as absent or decreased vibration 
sensation. Regardless of sensation at site (a), all three upper 
extremity sites will be tested. 
 

 
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b. 
The ulnar styloid (wrist) (Figure 7.3 [3b]): If the patient feels the 
vibration for 15 seconds or longer, this is defined as normal. If the 
patient feels the vibration less than 15 seconds, this is defined as 
absent or decreased vibration sensation.  
 
c. 
The lateral epicondyle (elbow) (Figure 7.3 [3c]): If the patient feels 
the vibration for 15 seconds or longer, this is defined as normal. If 
the patient feels the vibration less than 15 seconds, this is defined 
as absent or decreased vibration sensation. 
 
Figure 7.3 Sites of upper extremity vibration sensation testing (74)  
 
Note:  The tuning fork is firmly tapped on the palm and then placed at the 
distal interphalangeal joint of the index finger (3a), the ulnar styloid (3b), and 
the lateral epicondyle (3c). 
 
7.8 
Timed Get Up and Go (75) 
 
The ‘Timed Get Up and Go’ test is a simple, quick, and widely used clinical performance-
based measure of lower extremity function, mobility, and fall risk. Subjects are asked to 
stand up from a standard chair (seat height between 44 and 47 cm), walk a distance of 3 
meters (marked on the floor) at a comfortable pace, turn, walk back and sit down. Subjects 
are permitted to use routine walking aids and are instructed not to use their arms to stand 
up. No physical assistance is given. The time to complete the task is measured with a 
stopwatch to the tenth of a second. Timing commences on the command ‘go’ and stops 
when the subject's back is positioned against the back of the chair after sitting down. 
Shorter times indicate better performance. Patients who are wheelchair-bound will not be 
required to complete this assessment.  Training on this test is available online 
(https://www.youtube.com/watch?v=grrYoBucNPE) and any questions can be directed to 
the Clinical Nurse Coordinator of the study. Once the CRA has viewed the online training 
video, the CRA must also complete a training verification available on the protocol abstract 
page of the SWOG website (www.swog.org) and the verification must be submitted via 
CTSU (see Section 13.2b.3).  All CRAs who will be performing this assessment must 
submit verification of training. The training certificate may be obtained from the S1714 
protocol abstract page on the SWOG website.  Click “Required S1714 Training,” complete 
the required information certifying that you have successfully completed the training and 
click “Submit.”  The website will generate a confirmation.  At the end of the confirmation 

 
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page, click “Print Confirmation.”  The printed confirmation serves as the certificate of 
completion which must be submitted via CTSU Regulatory Portal (see Section 13.2b.3). 
 
Results of this assessment will be reported on the S1714 Neuropathy Assessment form.  
Assessments will occur at baseline, 24 weeks, and 52 weeks as outlined in Section 9.0.  
The Timed Get Up and Go assessment will take about 5-10 minutes to complete. 
 
At the time of Timed Get Up and Go assessments at 24 weeks and 52 weeks, a history of 
falls within the past 6 months will also be collected on the S1714 Neuropathy Assessment 
Form. 
 
7.9 
Research Biospecimens 
 
Study assessments will include mandatory specimen submission of translational research 
biospecimens and optional specimen submission for banking for future research as 
outlined in Section 15.1. 
 
7.10 
Criteria for Removal from Protocol Participation 
 
a. 
Patient completes 156 weeks (3 years) of protocol participation.* 
 
b. 
Patient does not receive at least one cycle of taxane-containing chemotherapy 
within 30 days after registration.  
 
c. 
Patient receives another chemotherapy regimen and does not receive at least one 
cycle of one of the study-approved taxane regimens included in Appendix 18.1.  
 
d. 
The patient may withdraw from the study at any time for any reason. (Research 
staff should only submit the S1714 Off Protocol Notice if the patient refuses both 
direct and indirect follow-up (e.g., follow-up for vital status via medical records or 
contact with the patient’s physician) on the study. If the patient allows for indirect 
follow-up or is refusing to complete any further patient forms but will allow the site 
to follow them indirectly, do not submit the S1714 Off Protocol Notice and continue 
to submit the site-completed forms (S1714 Treatment Form or S1714 Off 
Treatment Follow-up Form, as appropriate, and S1714 Solicited Neuropathy 
Events Form at the time points required as outlined in Section 14.4c.   
 
e. 
Patient has disease progression or relapse after the 52-week assessment. A 
patient’s disease progression or relapse prior to 52-week assessment does not 
necessitate removal from protocol participation. 
 
f. 
Patient death 
 
* 
NOTE:  A patient’s completion or discontinuation of taxane-based 
chemotherapy does not necessitate removal from protocol participation, if prior 
to completion of 156 weeks (3 years) of protocol participation.  Patients should 
continue to have their protocol-scheduled assessments and submit their 
protocol-scheduled Patient Reported Outcomes (see Section 7.5) until one of 
the outlined criteria for removal listed in Section 7.10 has been met. 
 
 

 
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7.11 
Discontinuation of Protocol Participation 
 
All reasons for discontinuation of protocol participation as defined in Section 7.10, including 
patient death, must be documented in the S1714 Off Protocol Notice and submitted per 
Section 14.4d.   
 
7.12 
Follow-Up Period 
 
No further follow-up will be required once the patient completes 156 weeks (3 years) of 
protocol participation, or if the patient meets one of the criteria for removal from protocol 
participation outlined in Section 7.10 prior to completion of 156 weeks (3 years) of 
participation and the S1714 Off Protocol Notice is submitted. 
 
NOTE: Sites must continue to follow all patients per study requirements even if the patient 
completed or discontinued taxane-based chemotherapy prior to completion of  156 weeks 
(3 years) of protocol participation (see Section 7.10a).  Patients should continue to have 
their protocol-scheduled assessments until one of the outlined criteria for removal listed in 
Section 7.10 has been met. 
 
7.13 
COVID-19 Guidance 
 
Patient-Reported Outcome Questionnaires via Telemedicine (Phone or Virtual Visit). 
 
Follow-up Visits via Telemedicine (Phone or Virtual Visit):  
• 
Follow-up visits at timepoints indicated in Section 9.0, may be conducted via 
telemedicine (Phone or Virtual Visit) to provide continuity of care and patient follow-up 
provided that the Responsible Investigator determines that the phone/virtual visit is 
adequate to achieve the central purpose of the visit and assure the safety of the patient. 
• 
Study visits may also be delayed or missed if in the judgment of the Responsible 
Investigator the benefit of delay/omission of a visit outweighs the risks of exposure of 
the patient to the virus by coming in for an in-person visit and an alternative method 
(phone or virtual visit) is not possible.  
• 
The above alterations would need to be thoroughly documented in the medical record 
by the Responsible Investigator with the reason for the deviation and brief justification 
for why the deviation was considered to be minor (e.g., routine follow-up on patient no 
longer on active therapy). 
 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
Toxicity monitoring and dose modifications are not relevant to this study, (but will be collected per 
Section 7.3) and occurrence of neuropathy-related events will be collected using CTCAE v. 5.0. 
 
 

 
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9.0 
STUDY CALENDAR 
 
REQUIRED 
Registration 
1st Taxane Cycle C 
WK 
4 A 
WK 
8 A 
WK 
12 A 
WK 
24 A 
WK 
52 A 
WK 
104A 
WK 
156 A 
TESTS/ASSESSMENTS 
 
 
 
 
 
 
 
 
 
History 
X 
 
 
 
 
 
 
 
 
Chemotherapy Treatment Schedule 
X 
 
X 
X 
X 
X 
X 
X 
X 
Active Topical Agents, Medications, Supplements, 
and Interventions 
X 
 
X 
X 
X 
X 
X 
 
 
Visual Analog Toxicity Score G 
X 
 
X 
X 
X 
X 
X 
 
 
NCI-CTCAE H  
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum Creatinine or Creatinine Clearance E 
X 
 
 
 
 
 
 
 
 
History of Falls Assessment 
X 
 
 
 
 
X 
X 
 
 
SENSORY TESTS 
 
 
 
 
 
 
 
 
 
Neuropen (Monofilament and Neurotip) F 
X 
 
X 
X 
X 
X 
X 
 
 
128 Hertz Tuning Fork F 
X 
 
X 
X 
X 
X 
X 
 
 
FUNCTIONAL TEST 
 
 
 
 
 
 
 
 
 
Timed Get Up and Go 
X 
 
 
 
 
X 
X 
 
 
PATIENT REPORTED OUTCOMES (PROs) G,H 
 
 
 
 
 
 
 
 
 
CIPN-20 
X 
 
X 
X 
X 
X 
X 
X 
X 
PROMIS-29 
X 
 
X 
X 
X 
X 
X 
 
 
Symptom (and Side Effect) Burden Score 
X 
 
X 
X 
X 
X 
X 
 
 
Godin-Shephard Leisure-Time Physical Activity 
Questionnaire (GSLTPAQ) 
X 
 
X 
X 
X 
X 
X 
 
 
PRO-CTCAE 
X 
 
X 
X 
X 
X 
X 
X 
X 
FACT-GOG-NTX-4 
X 
 
 
 
X 
X 
X 
X 
X 
SPECIMEN SUBMISSION 
 
 
 
 
 
 
 
 
 
Blood (Lavender Top EDTA – Whole Blood for DNA) 
D 
X 
 
 
 
 
 
 
 
 
Blood (Lavender Top EDTA– Plasma for Taxane 
Maximum Concentration [Cmax]) D 
 
X C 
 
 
 
 
 
 
 
Blood (Red Top no additive – Serum for Proteomics) 
B 
X 
X C 
X 
X 
X 
X 
X 
 
 
Blood (Green Top sodium heparin – Plasma for 
Metabolomics) B 
X 
X C 
X 
X 
X 
X 
X 
 
 
Click here for footnotes. 
 
 
 

 
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NOTE: the study calendar is a good tool for a general snapshot of study requirements but does not replace details provided in the relevant sections 
of the protocol. Use the study calendar in conjunction with the detailed procedures and information in the protocol but not as the sole or primary 
source for managing this trial. 
 
NOTE: Forms are found on the protocol abstract page on the SWOG website (www.swog.org) and on the CTSU website (www.ctsu.org).  Forms 
submission guidelines are found in Section 14.0. 
 
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined 
in https://www.swog.org/protocol-workbench. 
 
Footnotes for Calendar 9.1 
 
A 
Study assessments, sensory tests, functional test, PROs, physician assessments, and specimen submissions should be attempted to be 
obtained on the same day as a taxane-based chemotherapy treatment that falls within ± 14 days of Weeks 4, 8, and 12, within ± 28 days of 
Weeks 24 and 52, and within ± 90 days 104 (2 years) and 156 (3 years) and prior to taxane administration.  
B 
Optional research biospecimen:  The optional research biospecimens should be attempted to be obtained during a clinical blood drawn that 
occurs within the allowed visit window for each timepoint.  See Section 15.1. 
C Draw specimen during the last 10 minutes of infusion of the cycle of taxane-based chemotherapy (see Section 15.1c.2). NOTE: Blood (Lavender 
Top EDTA– Plasma for Taxane Maximum Concentration [Cmax]) can be collected in the last 10 minutes of any cycle if it is missed with the first 
cycle.  
D The lavender top for DNA and lavender top for Cmax submissions are mandatory (see Section 15.0). 
E 
To be collected either 1) within 30 days prior to registration, OR 2) after registration but prior to start of taxane-based chemotherapy per Section 
7.1. 
F 
Sensory tests may only be performed by the site’s certified clinician(s). Refer to Sections 7.6b and 7.7b for instructions on obtaining certification 
G See Section 7.5. 
H See Appendix 18.5. 
 

 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
10.1 
Primary Endpoint 
 
Development of peripheral neuropathy: an absolute increase of ≥ 8 points over the baseline 
CIPN-20 sensory neuropathy subscale score (Appendix 18.4; scale 0-100) before or at 24-
week assessment (occurring during the 24 weeks +/- 28 days window). 
 
The primary endpoint will be collected before or at the 24-week assessment as the taxane-
based chemotherapy regimens in this study are expected to be completed within 8 to 18 
weeks. Thus, it is anticipated that those participants who are going to develop clinically 
significant CIPN would develop symptoms while receiving treatment. The presence of 
CIPN will be captured at 104 and 156 weeks (3 years) to evaluate the duration of 
neuropathy which is anticipated to wane after treatment discontinuation. 
 
Multiple studies in the literature indicate that patients with CIPN experience approximately 
a 7 to 10-point increase in the CIPN-20 sensory neuropathy subscale score. For instance, 
Smith et al. showed that those not receiving neurotoxic therapy had a CIPN-20 sensory 
subscale score of around 10, whereas those who did had a score of around 20, (76) while 
Floortje Mols et al. showed an increase from 8 to 15. (77)  Finally, Cavaletti et al. reinforce 
the idea that a mean score of about 20 on the 0-100 sensory subscale is reasonable for 
those with CIPN. (78) Thus, a reasonable indication of a meaningful increase in the CIPN-
20 would be an absolute increase of ≥ 8 points. Based on these considerations, patients 
having an absolute increase of ≥ 8 points over the baseline sensory neuropathy subscale 
score (scale 0-100) at the 4, 8, 12, or 24-week assessment will be defined as having 
experienced CIPN for the purposes of this study.  The 24-week assessment cannot be 
measured later than 28 weeks (24 weeks +/- 28 day window) 
 
10.2 
Secondary Endpoints 
 
Patients experiencing a treatment change attributed to CIPN symptoms will be considered 
to have reached the corresponding secondary endpoint. 
 
Dose reductions, delays, and discontinuations of treatment (prior to completing the original 
treatment plan) will be collected during follow-up visits.  Definitions of these treatment 
changes can be found in Section 7.3. Study sites will be asked to classify the reasons for 
these changes (i.e., CIPN symptoms, neutropenia, patient preference, progression of 
disease). 
 
Other patient and physician reported outcomes including the Patient-Reported Outcomes 
Measurement Information System 29 (PROMIS-29; Section 18.5b), the Godin-Shephard 
Leisure-Time Physical Activity Questionnaire (GSLTPAQ; Section 18.5c), Visual Analog 
Toxicity Score and Symptom Burden Score (Section 18.5d), PRO-CTCAE items for severity 
of numbness and tingling and interference caused by numbness and tingling (Section 
18.5e), and the National Cancer Institute-Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) Grading Scale (Section 18.5f). 
 
 

 
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10.3 
Performance Status 
 
Patients will be graded according to the Zubrod performance status scale. 
 
POINT  
DESCRIPTION 
 
0  
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1  
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light housework, office work. 
 
2  
Ambulatory and capable of self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours. 
 
3  
Capable of limited self-care, confined to bed or chair more than 50% of 
waking hours. 
 
4  
Completely disabled; cannot carry on any self-care; totally confined to bed 
or chair. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
CIPN Predictors and Risk Factors 
 
Previous studies have described a variety of clinical, biologic, and treatment-related factors 
implicated in the development of CIPN. In this study, clinical and treatment-related factors 
potentially predictive of CIPN will be investigated in order to identify the strongest 
predictors. The primary objective is to develop and validate a clinical risk prediction model 
for CIPN. This model will enable rapid identification of patient risk of developing CIPN for 
individuals treated with taxane-based therapy using common factors obtained during clinical 
exams, aiding in timely care decision-making. The clinical factors (including treatment 
factors) to be considered in the risk prediction model are shown in Table 11.1. 
 
 

 
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Table 11.1. Clinical factors to be incorporated in the risk prediction model 
Clinical factor 
Scale 
Demographics 
Age in years (continuous) 
Sex: Male/Female (dichotomous) 
Race: White/Black/Asian/Other (categorical) 
Ethnicity: Hispanic/Non-Hispanic (categorical) 
Baseline co-morbid 
conditions 
Diabetes: yes/no (dichotomous) 
Thyroid disease: yes/no (dichotomous) 
Vitamin B12 deficiency*: yes/no (dichotomous) 
Autoimmune disease: yes/no (dichotomous) 
Vitamin D deficiency ***: yes/no (dichotomous) 
Neurological condition: yes/no (dichotomous) 
Pre-existing neuropathy as evaluated by baseline CIPN20 
sensory subscale score (continuous) 
Creatinine clearance < 30 mL/min: yes/no (dichotomous) 
Zubrod performance status: 0-4 (categorical) 
 
Falls history 
History of falls** within past 6 months: yes/no (dichotomous), 
assessed at baseline 
Smoking history 
Never smoker/Former smoker/Active smoker (categorical) 
Number of pack years (continuous) 
Oncologic history 
Malignancy: Breast/Lung/Ovary/Fallopian tube/ peritoneal 
(categorical) 
Prognostic stage at diagnosis: I/II/III (categorical) 
Treatment factors 
Taxane: paclitaxel/docetaxel (dichotomous) 
Planned Frequency: weekly/biweekly/triweekly (categorical) 
Planned taxane dosing: full dose/reduced dose (dichotomous) 
Planned use of platinum agent: yes/no (dichotomous); if yes: 
full dose/reduced dose (dichotomous) 
Concurrent radiation: yes/no 
* 
Defined as requiring B12 repletion (patient reported) 
** Defined as unintentionally coming to rest on the ground or at some other lower level, 
not as a result of a major intrinsic event (e.g., stroke or syncope) or an overwhelming 
hazard. The patient will be asked if he/she has had been any falls in the past 6 months 
*** Defined as requiring vitamin D supplements ≥ 50,000 IU per week (patient-reported). 
 
A two-step approach will be used. In Step 1, factors that are independently predictive of 
CIPN will be identified, from which a candidate model will be built. In Step 2, the investigators 
will undertake independent validation of the model. Each step will be considered a separate 
experiment and independently powered. Multiplicity will be handled by the validation set.  As 
secondary analysis, the investigators will consider the joint distribution of the different 
endpoints to adjust the alpha.   
 
11.2 
Sample Size and Analysis Plan 
 
Assuming 5% ineligibility rate, the sample size will be N = 1,310 to accrue 1,245 eligible 
patients.  The goal is to establish accurate prediction of CIPN among important and 
commonly used taxane treatments. The goal is to enroll at least 500 docetaxel and paclitaxel 
patients to each group; based on a feasibility/enrollment assessment conducted in April, 
2021, this goal is expected to be met with the total sample size. This design will ensure a 
large enough population of docetaxel and paclitaxel users to model CIPN in those groups. 
Further, the investigators plan to cap accrual of lung cancer patients at 250 to ensure 
variability in dose and frequency among paclitaxel users. Accrual of 35-50 patients per 
month is estimated for a total accrual time of 35 months.  Data from 60% of eligible patients, 
or n=745 (stratified by primary cancer type and taxane regimen) will be randomly used to 
develop the model in Step 1. Potential risk factors (Table 11.1) using the prospectively 

 
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collected baseline data will be evaluated in univariate fashion, and rank ordered according 
to their chi-square statistic under logistic regression. As an illustration of power to identify a 
statistically significant univariate predictor of CIPN with 600 patients and using 2-sided 
alpha=.05 tests under a two-arm binomial design (without continuity correction), there will 
be sufficient power (>=85%) to identify an absolute 10% difference in CIPN rates between 
equal numbers of low and high-risk patients for each factor, for CIPN rates up to 30% (i.e., 
25% vs. 35% if the overall CIPN rate is 30%). (Low risk patients are defined as those having 
a risk score below the median [based on individual values on the predictors chosen in the 
model]; high risk patients are defined as those having a risk score above the median.)  
 
Best subset selection will be used to identify a best k-variable model from among the factors 
most predictive of CIPN in univariate examinations. (79) Model building will be based on 
logistic regression to simplify identification and interpretation of adverse risk within each 
individual factor. The goal is to minimize the predictive error (i.e., logistic model deviance) 
across a range of k-variable models. K-fold cross validation of the entire model building 
approach, including the identification of univariate predictors for inclusion in best-subset 
selection analysis, will be used to limit overfitting and provide insight into how the model will 
generalize in Step 2. (80) This will allow identification of optimal models when choosing 
between models with different numbers of factors, for instance a 4-variable vs. 5-variable 
model, as well as for choosing between models which are not nested. Once a best model 
is identified, a risk model will be built, by summing the number of adverse risk factors from 
among the k-variables in the best model to create a score, split at the median to identify 
high vs. low risk patients. The use of K-fold cross validation of the model building process 
also enables evaluation of different modeling techniques to assess sensitivity to the chosen 
analytic approach, for instance Lasso. (81)  
 
Before a risk-prediction model can be used in clinical practice it is essential to validate it in 
an independent study. Risk models that have not been validated but implemented into 
clinical care can lead to potential harm if the model is over- or under-predicting risk.  Thus, 
in Step 2 the investigators would test the k-variable risk model identified in Step 1. The risk 
model from Step 1 will be tested in the remaining 500 patients. This sample size is sufficient 
to identify an absolute difference of 12% in CIPN rates for high vs. low risk patients for CIPN 
rates up to 30%, with > 90% power using a one-sided binomial test with alpha=.05.  
 
If a difference of this magnitude is not achieved in the validation step, this will indicate that 
this experiment failed to differentiate risk under the protocol design, and will suggest the 
difficulty of predicting CIPN based on clinical factors alone. In this scenario, future analyses 
using biological factors to characterize CIPN risk will gain added importance.  
 
To avoid dropping variables or samples in risk modeling, in which all variables are 
considered simultaneously, each variable needs to be available for all samples and in all 
studies. Although completeness of data submission is encouraged by prospective data 
collection, in combination with SWOG SDMC’s data Expectation system and the Rave Data 
Quality Portal (DQP) both of which identify data delinquencies, even small numbers of 
missing can lead to sizable loss of data when multiple variables are modeled together. 
Therefore, missing data will be imputed in Step 2. Resampling will be used to acknowledge 
the sampling error on the test sample, and cross validation will be used in the model building 
process to select model complexity. 
 
The investigators will examine whether the clinical risk model can predict the other 
outcomes collected in the study (Table 11.2), to assess whether the experience of CIPN 
reflects a more comprehensive patient symptom experience that includes both subjective 
measures of outcome – based on PRO data – and objective measures of neuropathy 
symptoms. To accomplish this, we will consider the derived clinical risk model as the main 
independent variable in a multivariable regression model that also incorporates the 
baseline score for the respective outcome as a covariate. Linear (Timed Get Up and Go 
and PROMIS 29 and its subscales) and logistic (diminished touch and pressure sensation 

 
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according to the Neuropen, GSLTPAQ, and PRO-CTCAE [moderate or worse, yes vs. no]) 
regressions will be used as appropriate to assess whether the model predicts outcomes at 
individual timepoints (i.e. 4 weeks, 8 weeks, etc.). We will also conduct linear mixed models 
with continuous and binary outcomes, as appropriate, to examine trajectories of outcomes 
over time, with patient as the random effect. Vibration sensibility according to the tuning 
fork will be examined both as a continuous variable and as a binary categorical variable 
based on an optimal splitpoint to maximize power (i.e. splitpoint closest to the median) 
using observed distributions. 
 
The correlation between the secondary outcome measures and neuropathy as measured 
by the CIPN20 will also be described to aid in the interpretation of the neuropathy 
phenotype. This analysis will allow better characterization and definition of the taxane-
induced peripheral neuropathy phenotype.  
 
Table 11.2. Outcome measures 
Outcome 
Scale 
Follow-Up  
Assessment Times 
(in weeks) 
Neuropen 
Diminished touch and pressure sensation 
(yes/no) 
Diminished pain and sharpness sensation 
(yes/no) 
4, 8, 12, 24, 52 
128 Hertz tuning 
fork  
Vibration sensibility (categorical, 0-4) 
4, 8, 12, 24, 52 
Timed Get Up 
and Go 
Continuous scale (seconds) 
24, 52 
PROMIS-29 
Physical function (continuous, 4-20) 
Anxiety (continuous, 4-20) 
Depression (continuous, 4-20) 
Fatigue (continuous, 4-20) 
Sleep disturbance (continuous, 4-20) 
Ability to participate in social roles and 
activities (continuous, 4-20) 
Pain interference (continuous, 4-20) 
Pain intensity (continuous, 0-10) 
4, 8, 12, 24, 52 
GSLTPAQ 
Active (yes/no) 
4, 8, 12, 24, 52 
PRO-CTCAE 
Numbness and tingling, severity (none, 
mild, moderate, severe, very severe) 
Numbness and tingling, interference (not at 
all, a little bit, somewhat, quite a bit, very 
much) 
General pain, frequency (never, rarely, 
occasionally, frequently, almost constantly) 
General 
pain, 
severity 
(none, 
mild, 
moderate, severe, very severe) 
General pain, interference (not at all, a little 
bit, somewhat, quite a bit, very much) 
4, 8, 12, 24, 52, 104, 
156 
FACT-GOG-
NTX-4 
Neurotoxicity (continuous, 0-16) 
12, 24, 52, 104,156 
* 
All measures are collected at baseline. 
 

 
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The investigators will further examine whether the clinical risk model predict treatment dose 
reductions, delays, discontinuations, and treatment changes associated with CIPN 
symptoms.  
 
The incidence of CIPN within one year as measured by the CIPN-20 will be assessed in 
all 1245 eligible enrolled patients. Using a test of proportions without continuity correction, 
a sample size of 1245 will allow us to estimate the confidence interval to within ± 3.1%, or 
in proportion to the assumed incidence, to within ± 6.2% (based on the upper bound of 
95% confidence interval – the "relative accuracy"), if the incidence of CIPN is 50% and the 
dropout rate at year 1 is 20%. The relative accuracy will improve with higher incidence, as 
shown in Table 11.3 below.  These estimates are conservative as they are based on the 
assumption of no information from the 20% of patients estimated to drop out. The 
cumulative incidence of CIPN at 1, 2, and 3 years will also be estimated to account for 
censoring and the competing risk of death. Conservative estimates of the confidence 
interval (as calculated from the exact binomial in patients with complete follow-up) are 
shown in Table 11.3 for different rates of assumed incidence of CIPN. 
 
Table 11.3. Table of relative accuracy 
Assumed incidence 
95% confidence interval 
about p 
Relative accuracy [(95% CI 
upper bound – p)/p] 
20% 
17.6%-22.6% 
13.0% 
30% 
27.2%-32.9% 
9.7% 
40% 
37.0%-43.1% 
7.7% 
50% 
46.9%-53.1% 
6.2% 
 
To examine the applicability of the derived clinical risk prediction model in important 
patient groups, rather than build separate models for each meaningful marginal subset, 
our plan is to build the model using the entire data set.  The investigators will then examine 
the extent to which the model meaningfully predicts development of CIPN within 
subgroups to see if the risk prediction model will hold. Important potential subsets of 
patients are defined by pre-existing CIPN (yes vs. no), age (< 65 vs. ≥ 65), sex, race (black 
vs. other), and treatment groups (i.e., paclitaxel versus docetaxel). For each factor, the 
investigators will examine whether the relationship between the clinical risk model and 
CIPN20 differs by levels of the factor (i.e., blacks vs. non-blacks) using interaction tests. 
The absence of any interactions will suggest no statistical evidence that the clinical risk 
model performance differed substantially based on these factors. If a statistically 
significant interaction is evident (p< 0.05), examinations separately within subgroups will 
be conducted to enable interpretation of the observed differences by subgroup. 
 
11.3 
Data and Safety Monitoring Committee 
 
There is no formal data and safety monitoring committee for this study.  Monitoring of study 
conduct and accrual for feasibility will be performed routinely by the Study Chair, Study 
Statistician, and the Disease Committee Chair.  Accrual reports will be generated monthly. 
 
 
12.0 
DISCIPLINE REVIEW 
 
There is no discipline review for this study. 
 
 
 

 
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13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Patients must be registered no more than 14 calendar days prior to planned start of 
treatment with a taxane-containing regimen. 
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a Cooperative Group.  Each investigator must have an NCI investigator number and 
must maintain an “active” investigator registration status through the annual submission of 
a complete investigator registration packet to CTEP. 
 
a. 
CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations require sponsors to select 
qualified investigators. National Cancer Institute (NCI) policy requires all 
individuals contributing to NCI-sponsored trials to register with their qualifications 
and credentials and to renew their registration annually. To register, all individuals 
must obtain Cancer Therapy Evaluation Program (CTEP) credentials necessary to 
access secure NCI Clinical Oncology Research Enterprise (CORE) systems. 
Investigators and clinical site staff who are significant contributors to research must 
register in the Registration and Credential Repository (RCR). The RCR is a self-
service online person registration application with electronic signature and 
document submission capability. 
 
RCR utilizes four person registration types that are applicable to this study. 
 
• 
Investigator (IVR) — MD, DO, or international equivalent;  
• 
Non Physician Investigator (NPIVR) — advanced practice providers (e.g., NP 
or PA) or graduate level researchers (e.g., PhD);  
• 
Associate Plus (AP) — clinical site staff (e.g., RN or CRA) with data entry 
access to CTSU applications such as the Roster Update Management System 
[RUMS], OPEN, Rave, acting as a primary site contact, or with consenting 
privileges;  
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-
sponsored trials. 
 
RCR requires the following registration documents: 
 
 
 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
✔ 
✔ 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
✔ 
✔ 
✔ 
 
GCP training 
✔ 
✔ 
✔ 
 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 

 
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Page 34 
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IVRs and NPIVRs must list all clinical practice sites and Institutional Review 
Boards (IRBs) covering their practice sites in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Selection as the treating, credit, or consenting person in OPEN;  
• 
Ability to be named as the site-protocol Principal Investigator (PI) on the IRB 
approval; and  
• 
Assignment of the Clinical Investigator (CI) task on the Delegation of Tasks 
Log (DTL).  
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on 
the IRB approval), consenting or treating investigator in OPEN, or as the CI on the 
DTL must be rostered at the enrolling site with a participating organization.  
 
Refer to the NCI RCR page on the CTEP website for additional information. For 
questions, 
please 
contact 
the 
RCR 
Help 
Desk 
by 
email 
at 
RCRHelpDesk@nih.gov. 
 
b. 
CTSU Registration Procedures 
 
Permission to view and download this protocol and its supporting documents is 
restricted and is based on the person and site roster assignment housed in the 
Roster Maintenance application and in most cases viewable and manageable via 
the Roster Update Management System (RUMS) on the Cancer Trials Support 
Unit (CTSU) members’ website. 
 
This study is supported by the NCI CTSU. 
 
1. 
IRB Approval:   
 
As of March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB) in order to participate in 
Cancer Therapy Evaluation Program (CTEP) and Division of Cancer 
Prevention (DCP) studies open to the National Clinical Trials Network 
(NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases. In addition, U.S.-based sites must accept the NCI CIRB 
review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the 
CIRB, or if the study was previously open at the site under the local IRB. 
International sites should continue to submit Research Ethics Board (REB) 
approval to the CTSU Regulatory Office following country-specific 
regulations. 
 
Sites participating through the NCI CIRB must submit the Study Specific 
Worksheet (SSW) for Local Context to the CIRB using IRBManager to 
indicate their intent to open the study locally. The NCI CIRB’s approval of 
the SSW is automatically communicated to the CTSU Regulatory Office, 
but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network. Site preferences can 
be set at the network or protocol level. Questions about establishing site 
preferences can be addressed to the CTSU Regulatory Office by email 
(CTSURegPref@ctsu.coccg.org) or by calling 1-888-651-CTSU (2878). 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the 
investigator on the IRB/REB approval) must meet the following criteria for 

 
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the site to be able to have an Approved status following processing of the 
IRB/REB approval record: 
 
• 
Have an active CTEP status; 
• 
Have an active status at the site(s) on the IRB/REB approval 
(applies to US and Canadian sites only) on at least one 
participating organization’s roster; 
• 
If using NCI CIRB, be active on the NCI CIRB roster under the 
applicable CIRB Signatory Institution(s) record; 
• 
Include the IRB number of the IRB providing approval in the Form 
FDA 1572 in the RCR profile; 
• 
List all sites on the IRB/REB approval as Practice Sites in the 
Form FDA 1572 in the RCR profile; and 
• 
Have the appropriate CTEP registration type for the protocol. 
 
2. 
Additional Requirements 
 
Additional site requirements to obtain an approved site registration status 
include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) 
or a Participating Organization (PO);  
• 
An active roster affiliation with the NCI CIRB roster under at least one 
CIRB Signatory Institution (US sites only); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
 
3. 
Downloading Site Registration Documents:   
 
Download the site registration forms from the protocol-specific page 
located on the CTSU members’ website. Permission to view and download 
this protocol and its supporting documents is restricted to institutions and 
their associated investigators and staff on a participating roster. To 
view/download site registration forms: 
• 
Log in to the CTSU members’ website (https://www.ctsu.org);  
• 
Click on Protocols in the upper left of the screen 
o 
Enter the protocol number in the search field at the top of the 
protocol tree; or 
o 
Click on the By Lead Organization folder to expand, then select 
SWOG, and protocol number S1714. 
• 
Click on Documents, Protocol Related Documents, and use the 
Document Type filter and select Site Registration to download and 
complete the forms provided. (Note: For sites under the CIRB, IRB 
data will load automatically to the CTSU.)  
 
4. 
Requirements for S1714 Site Registration: 
 
• 
CTSU Transmittal Sheet (optional)  
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol 
of Human Subjects Assurance Identification/IRB Certification/ 
Declaration of Exemption Form, or combination is accepted) 
 
 
 
Sites must complete the following Protocol Specific Requirements (PSRs) 
prior to patient registration and submit the certificates and verifications to 

 
S1714 
 
 
Page 36 
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CTSU Regulatory Office via the Regulatory Submission Portal on the 
CTSU website.  
 
• 
Certificate that at least one clinician at the site has completed the 
Neuropen training outlined in Section 7.6.  
• 
Certificate that at least one clinician at the site has completed the 128 
Hertz tuning fork training outlined in Section 7.7. 
• 
Verification that at least one CRA at the site has completed the ‘Timed 
Get Up and Go’ training outlined in Section 7.8 
 
In addition, sites must also have ordered and received both the Neuropen 
and 128 Hertz tuning fork prior to consenting a patient to the study. 
 
5. 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office 
using the Regulatory Submission Portal on the CTSU members’ website.  
 
To access the Regulatory Submission Portal log in to the CTSU members’ 
website, go to the Regulatory section and select Regulatory Submission.  
 
Institutions with patients waiting that are unable to use the Regulatory 
Submission Portal should alert the CTSU Regulatory Office immediately 
by 
phone 
or 
email: 
1-866-651-CTSU 
(2878), 
or 
CTSURegHelp@coccg.org to receive further instruction and support. 
 
6. 
Checking Your Site’s Registration Status: 
 
Site registration status may be verified on the CTSU members’ website.   
 
• 
 
• 
Click on Regulatory at the top of your screen; 
• 
Click on Site Registration; and 
• 
Enter the sites 5-character CTEP Institution Code and click on Go: 
o 
Additional filters are available to sort by Protocol, 
Registration Status, Protocol Status, and/or IRB Type.  
 
Note: The status shown only reflects institutional compliance with site 
registration requirements as outlined within the protocol. It does not reflect 
compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated 
networks. 
 
 

 
S1714 
 
 
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13.3 
OPEN Registration Requirements 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs’ registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management system, 
Medidata Rave. 
 
Requirements for OPEN access:   
• 
; 
• 
Active CTEP registration with the credentials necessary to access secure NCI/CTSU 
IT systems; 
• 
To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, or receiving investigator for a patient transfer in OPEN, the IVR or 
NPIVR must list the Institutional Review Board (IRB) number used on the site’s IRB 
approval on their Form Food and Drug Administration (FDA) 1572 in the Registration and 
Credential Repository (RCR). If a DTL is required for the study, the IVR or NPIVR must be 
assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. You may print this confirmation for your records. 
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
13.4 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 

 
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Data must be submitted according to the protocol requirements for ALL patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible. 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and the CTSU website (www.ctsu.org) and (with the exception of the 
sample consent form and the Registration Worksheet) must be submitted on-line via the 
Web; see below for details. 
 
14.3 
Data Submission / Data Reporting Procedures 
 
a. 
Medidata Rave is the clinical data management system being used for data 
collection for this trial/study. Access to the trial in Rave is controlled through the 
CTEP-IAM system and role assignments. 
 
Requirements to access Rave via IMedidata: 
• 
Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems;  
and 
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: 
Rave CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or 
Rave Investigator. 
 
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type; 
• 
Rave Investigator role must be registered as a Non-Physician 
Investigator (NPIVR) or Investigator (IVR); and 
• 
Rave Read Only or Rave SLA role must have at a minimum an 
Associate (A) registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration 
types and documentation required. 
 
Upon initial site registration approval for the study in the Regulatory application, 
all persons with Rave roles assigned on the appropriate roster will be sent a 
study invitation email from iMedidata. No action will be required; each study 
invitation will be automatically accepted and study access in Rave will be 
automatically granted. Site staff will not be able to access the study in Rave until 
all required Medidata and study-specific trainings are completed. Trainings will 
be in the form of electronic learnings (eLearnings) and can be accessed by 
clicking on the eLearning link in the Tasks pane located in the upper right corner 
of the iMedidata screen. If an eLearning is required for a study and has not yet 
been taken, the link to the eLearning will appear under the study name in the 
Studies pane located in the center of the iMedidata screen; once the successful 
completion of the eLearning has been recorded, access to the study in Rave will 
be granted, and a Rave EDC link will replace the eLearning link under the study 
name. 
Action will be required by site staff (to activate their account) who have not 
previously activated their iMedidata/Rave account at the time of initial site 

 
S1714 
 
 
Page 39 
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registration approval for the study in the Regulatory application. Account 
activation instructions are located on the CTSU website in the Data Management 
section under the Data Management Help Topics > Rave Resources > Medidata 
Account Activation and Study Invitation (to activate your iMedidata account).  
Additional information on iMedidata/Rave is available on the CTSU members’ 
website in the Data Management Rave Resources section or by contacting the 
CTSU Help Desk at 1-888-823-5923 or by email at ctsucontact@westat.com. 
   
b. 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management. The 
Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms, DQP 
Form Status and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, forms with current status, and 
timeliness reports. Site staff should review the DQP modules on a regular basis to 
manage specified queries and delinquent forms.. 
 
The DQP is accessible by site staff who are rostered to a site and have access to 
the CTSU website. Staff who have Rave study access can access the Rave study 
data via direct links available in the DQP modules. 
 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice 
a month. These notifications serve as alerts that queries and/or delinquent forms 
require site review, providing a summary count of queries and delinquent forms for 
each Rave study that a site is participating in. Additional site staff can subscribe 
and unsubscribe to these notifications using the CTSU Report and Information 
Subscription Portal on the CTSU members’ website. 
 
To learn more about DQP use and access, click on the Help Topics button 
displayed on the Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form 
Status, and DQP Reports modules. 
 
14.4 
Data Submission Overview and Timepoints  
 
a. 
WITHIN 15 DAYS OF REGISTRATION: 
 
Collect baseline specimens as outlined in Section 15.0. 
 
Submit the following: 
 
S1714 Onstudy Form 
 
S1714 Baseline Tumor Description (Breast, Lung, or Ovarian/Fallopian/Peritoneal 
tube, as applicable) 
 
S1714 Supplements, Topical Agents, and Other Treatments 
 
S1714 Baseline Physician CTCAE Assessment 
 
S1714 Neuropathy Assessment 
 

 
S1714 
 
 
Page 40 
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S1714 Cover Sheet for Patient-Completed Questionnaires 
 
S1714 EORTC QLQ-CIPN20 
 
S1714 Patient-Reported Outcomes Measurement Information System 29 
(PROMIS-29) 
 
S1714 Baseline Patient Reported Symptom Burden  
 
S1714 Godin-Shephard Leisure-Time Physical Activity Questionnaire 
 
S1714 PRO-CTCAE 
 
S1714 FACT-GOG-NTX-4 
 
Upload source documentation in Rave necessary to support diagnosis of primary 
Breast, Lung, or Ovarian/Fallopian tube/ Peritoneal cancer and establish stage (I, 
II, or III) (e.g., pathology report, radiology reports), if available. 
 
b. 
DURING THE LAST 10 MINUTES OF THE FIRST TAXANE INFUSION: 
 
Collect specimens as outlined in Section 15.0. 
 
c. 
WITHIN 15 DAYS OF ASSESSMENTS AT 4 WEEKS (± 14 DAYS), 8 WEEKS (± 
14 DAYS), 12 WEEKS (± 14 DAYS), 24 WEEKS (± 28 DAYS) AND 52 WEEKS (± 
28 DAYS): 
 
NOTE: Assessments should be scheduled so that patient-completed forms can be 
completed on the same day (and prior to) taxane-containing chemotherapy 
treatment (if applicable).    
 
Collect follow-up specimens as outlined in Section 15.0. 
 
Submit the following: 
 
S1714 Treatment Form (if patient’s taxane treatment was not previously indicated 
complete). 
 
S1714 Off Treatment Follow-up Form (if patient’s taxane treatment was previously 
indicated complete). 
 
S1714 Supplements, Topical Agents, and Other Treatments 
 
S1714 Solicited Neuropathy Events Form 
 
S1714 Follow-Up Physician Assessment 
 
S1714 Neuropathy Assessment  
 
S1714 Cover Sheet for Patient-Completed Forms 
 
S1714 EORTC QLQ-CIPN20 
 
S1714 Patient-Reported Outcomes Measurement Information System 29 
(PROMIS-29) 
 

 
S1714 
 
 
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S1714 Follow-up Patient Reported Symptom and Side Effect Burden 
Questionnaire 
 
S1714 Godin-Shephard Leisure-Time Physical Activity Questionnaire (GSLTPAQ) 
 
S1714 PRO-CTCAE 
 
S1714 FACT-GOG-NTX-4 (12, 24, and 52 weeks only) 
 
d. 
WITHIN 15 DAYS OF ASSESSMENTS AT 104 WEEKS (2 YEARS, ± 90 DAYS), 
AND 156 WEEKS (3 YEARS, ± 90 DAYS) : 
 
S1714  Solicited Neuropathy Event 
 
S1714 EORTC QLQ-CIPN20 
 
S1714 PRO-CTCAE 
 
S1714 FACT-GOG-NTX-4 
 
S1714 Off Treatment Follow-up Form (if patient’s taxane treatment was previously 
indicated complete). 
 
e. 
WITHIN 
15 
DAYS 
AFTER 
DISCONTINUATION 
OF 
PROTOCOL 
PARTICIPATION: 
 
Submit the following: 
 
S1714 Off Protocol Notice 
 
f. 
WITHIN 30 DAYS OF KNOWLEDGE OF DEATH: 
 
Submit the Notice of Death and S1714 Off Protocol Notice documenting death 
information. 
 
 
 

 
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Page 42 
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15.0 
SPECIAL INSTRUCTIONS 
 
M = Mandatory; Opt = Optional 
 
Specimen 
Baseline End 
of 
1st 
Taxane Cycle 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
24 
Wk 
52 
Blood (Lavender Top EDTA – 
Whole Blood for DNA) * 
M 
 
N/A 
N/A 
N/A 
N/A 
N/A 
Blood (Lavender Top EDTA– 
Plasma for Taxane Maximum 
Concentration [Cmax]) * 
 
M 
N/A 
N/A 
N/A 
N/A 
N/A 
Blood (Red Top no additive – 
Serum for Proteomics) 
Opt 
Opt 
Opt 
Opt 
Opt 
Opt 
Opt 
Blood (Green Top sodium 
heparin 
– 
Plasma 
for 
Metabolomics) 
Opt 
Opt 
Opt 
Opt 
Opt 
Opt 
Opt 
*International site please follow EDTA blood processing instruction in Section 15.1h. 
 
15.1 
Translational Medicine (REQUIRED) and Banking (OPTIONAL FOR PATIENT) 
 
Specimens for translational medicine and banking (submitted to the SWOG Biospecimen 
Bank – Solid Tissue, Myeloma and Lymphoma Division, Lab #201). 
 
a. 
Collection instructions are outlined in Section 15.1c and submission instructions 
are outlined in Section 15.1e. 
 
b. 
With patient’s consent, specimens must be collected at the time points listed 
below.  It is recommended that the optional banking specimens be collected at the 
time of a clinical blood draw in order to minimize blood draws in the subject. 
 
1. 
Baseline (within 14 days after registration), prior to taxane treatment 
 
2. 
First Taxane Cycle During Last 10 minutes of infusion  
 
3. 
Follow Up (Prior to infusion or pre-medication at 4 Weeks (± 14 days), 8 
Weeks (± 14 days), 12 Weeks (± 14 days), 24 Weeks (± 28 days), and 52 
Weeks (± 28 days) after beginning taxane-based chemotherapy.) 
 
c. 
Specimen Collection and Processing Instructions 
 
Note that specimen processing outlined below is to be performed at the site prior 
to storage and shipping.   
 
1. 
Baseline: 
 
Tubes for Collection 
 
Three (3) 10-mL tubes of whole blood will be collected: 
 
o 
Collect 10 mL of whole blood into a 10-mL lavender top 
EDTA tube* (MANDATORY) 
o 
Collect 10 mL of whole blood into a 10-mL green top sodium 
heparin tube (preferably BD catalog # 367874)* (OPTIONAL) 
o 
Collect 10 mL of whole blood into a 10-mL red top no-additive 
tube (preferably BD catalog # 367820)* (OPTIONAL) 
 
* 
If 10 mL tubes are not available, two 5 mL tubes may be used. 

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Site Sample Handling Instructions for the LAVENDER TOP Tube (for 
Collecting DNA): 
2. 
Immediately following collection, invert blood in lavender tube by hand 10 
times to ensure the blood and EDTA are thoroughly mixed.  
 
Do not process – send to the SWOG Biospecimen Bank 
at ambient temperature. 
Site Sample Processing for RED TOP Tube for Serum (for Serum 
Proteomics): 
 
Following blood collection, the red top tube should be left 
upright and undisturbed at room temperature for at least 
30 minutes but no more than 2 hours to allow a clot to 
form. 
Place a conical vial (or two 2-mL microcentrifuge tubes) 
in an ice-water bath to pre-chill (for step 5).  
After clot formation, centrifuge the red top tube at 1,300 x 
g for 10 minutes (at 4°C if a refrigerated centrifuge is 
available) separate serum from the blood cells. 
Immediately after centrifugation, place the red top tube in 
an ice-water bath. 
Using a pipette, transfer serum into the pre-chilled, 
labeled conical vial (or microcentrifuge tubes). Avoid 
disturbing the red blood cell layer.   
From these samples, generate a total of six (6) 600 mcL 
(0.6 mL) serum aliquots into 2-mL, pre-labeled, screw-top 
cryovials. Discard any remaining plasma and blood cells. 
Store specimens in a -80°C freezer until shipment to the 
SWOG Bank. If a -80°C freezer is not available, then 
specimens may be stored in a -20°C freezer before 
shipment.   
If samples are stored at > -70°C until shipment, make a 
note of the actual storage temperature and duration of 
storage in the instructions field when the specimen is 
logged into the SWOG Specimen Tracking System. 
Site Sample Processing for the GREEN TOP Tube for Plasma (for Plasma 
Metabolomics): 
 
Immediately after collection, invert the green top tube by 
hand 10 times to ensure the blood and sodium heparin 
are thoroughly mixed, and then immediately place in an 
ice-water bath. Place a conical vial (or two 2-mL 
microcentrifuge tubes) in the ice-water bath to pre-chill 
(for step 4).  
Centrifuge the green top tube at 1,300 x g for 10 minutes 
at 4°C to separate plasma from red and white blood cells.  
Immediately after centrifugation, return the green top tube 
to the ice-water bath.  
Using a pipette, transfer the plasma into the pre-chilled, 
labeled conical vial (or microcentrifuge tubes).  
From these samples, generate a total of six (6) 600 mcL 
(0.6 mL) plasma aliquots into 2-mL, pre-labeled, screw-

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top cryovials. Discard any remaining plasma and blood 
cells.  
Store specimens upright in a -80°C freezer until shipment 
to the SWOG Bank. If a -80°C freezer is not available, 
then specimens may be stored in a -20°C freezer before 
shipment. 
If samples are stored at > -70°C until shipment, make a 
note of the actual storage temperature and duration of 
storage in the instructions field when the specimen is 
logged into the SWOG Specimen Tracking System. 
3. 
First Cycle of Taxane-Based Chemotherapy 
 
Three (3) 10-mL tubes of whole blood will be collected before the taxane 
infusion ends, but no more than 10 minutes prior to the end of infusion. 
Sample must be collected by venipuncture or through a peripheral IV line 
to avoid contamination by the infusing drug. DO NOT collect the blood 
sample from the infusion IV port or peripheral IV port used to 
administer the taxane chemotherapy. The site of collection must not 
be near the site of concurrent taxane administration and the supplies 
used to collect the sample must not have previously been or 
currently be administering the taxane. Any of these will lead to 
sample contamination and incorrectly elevated measurements. 
 
The sample should be collected from the arm contralateral to the 
infusion, if possible.  If a contralateral arm collection is not possible 
(i.e. due to axillary lymph node dissection), then the sample may be 
collected on the ipsilateral arm distal to the site of infusion. If the 
sample is collected from an IV saline lock using a syringe, then draw 
a waste before collecting the sample to avoid risk of the sample being 
diluted with saline. 
 
The end of infusion plasma sample provides an estimate of the maximum 
concentration (Cmax). This sample must be collected before infusion ends, 
but no more than 10 minutes prior to the end of infusion. NOTE: The 
plasma for Taxane Maximum Concentration [Cmax]) can be collected 
in the last 10 minutes of any cycle if it is missed with the first cycle. 
 
Please note that the start time of infusion, stop time of infusion, and the 
time of the specimen collection must be entered into the Specimen 
Tracking System. 
Tubes for Collection 
o 
Collect 10 mL of whole blood into a lavender top EDTA 
tube* (MANDATORY) 
o 
Collect 10 mL of whole blood into a green top sodium heparin 
tube (preferably BD catalog # 367874) (OPTIONAL) 
o 
Collect 10 mL of whole blood into a red top no-additive tube 
(preferably BD catalog # 367820) (OPTIONAL) 
 
* 
If 10 mL tubes are not available, two 5 mL tubes may be used. 
 
 

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Site Sample Processing for the LAVENDER TOP Tube for Plasma (for 
Plasma Cmax): 
 
Immediately after collection, invert the lavender tube by 
hand 10 times to ensure the blood and EDTA are 
thoroughly mixed and immediately placed on ice. 
Process the sample within 30 minutes of collection. 
Maintain the sample on ice until processing.   
Note: For sites that must transport samples prior to 
processing, processing can occur up to 2 hours from time 
of collection as long as the samples remain on ice until 
that time. 
Centrifuge the lavender top tube at 1,300 x g for 10 
minutes (at 4°C if a refrigerated centrifuge is available) to 
separate plasma from red and white blood cells.    
Using a pipette, transfer the entire volume of plasma (top 
layer) into a labeled conical vial (or 2-mL microcentrifuge 
tubes).  
From this sample, generate at least two (2) 1-mL plasma 
aliquots in 2-mL, pre-labeled cryovials. 
Place the remaining plasma (up to 2 mL) in a third pre-
labeled cryovial. Discard remaining blood cells.  
Store specimens in a -80°C freezer until shipment to the 
SWOG Bank. If a -80°C freezer is not available, then 
specimens may be stored in a -20°C freezer before 
shipment. 
If samples are stored at > -70°C until shipment, make a 
note of the actual storage temperature and duration of 
storage in the instructions field when the specimen is 
logged into the SWOG Specimen Tracking System. 
Sample processing for the RED TOP and GREEN TOP tubes for serum 
proteomics and plasma metabolomics: 
 
Process the red top tube for serum (serum proteomics) and green 
top tube for plasma (plasma metabolomics) as described above 
in Sections 15.1c.1c and 15.1c.1d, respectively.  
4. 
Follow Up 
 
For the follow up blood collections (4 Weeks [± 14 days], 8 Weeks [± 14 
days], 12 Weeks [± 14 days], 24 Weeks [± 28 days], and 52 Weeks [± 28 
days] after beginning taxane-based chemotherapy), two (2) 10-mL tubes 
of whole blood will be collected prior to infusion and administration of pre-
medications.  
 
Tubes for Collection 
 
o 
Collect 10 mL of whole blood into a green top sodium heparin 
tube(s) (preferably BD catalog #367874) (OPTIONAL) 
o 
Collect 10 mL of whole blood into a red top no-additive tube(s) 
(preferably BD catalog # 67820)* (OPTIONAL) 
 
* 
If 10 mL tubes are not available, two 5 mL tubes may be used. 
 
Site Sample Processing for the RED TOP and GREEN TOP Tubes for 
Serum Proteomics and Plasma Metabolomics:
 
x 
Process the red top tube for serum (serum proteomics) and process 
the green top tube for plasma (plasma metabolomics) as described 
above in Sections 15.1c.1c and 15.1c.1d, respectively.  

 
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d. 
Specimen Kits 
 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
e. 
Specimen Labeling Instructions 
 
Specimens must be labeled with the following:  
• 
SWOG patient number 
• 
Patient initials (L, FM) 
• 
Date of specimen collection (month/day/year) 
• 
Specimen type (ex: whole blood, serum, plasma, etc.) 
 
f. 
Specimen Submission Instructions 
 
Frozen serum and plasma specimens should be stored in a -70 to -80°C freezer 
after processing and prior to packaging/shipping.  Specimens should be shipped 
completely covered in dry ice to ensure that they remain frozen during shipment.   
 
For specimens stored at -70 to -80°C:  Specimens may be batched and shipped 
at least quarterly, or after specimens from 5 patients are ready to be shipped, 
whichever is sooner.  
 
For specimens stored at -20°C to -70°C:  Specimens may not be batched; they 
should be shipped following collection and processing. Refer to the SWOG 
Specimen Submission webpage for shipping instructions.  Note:  The site must 
make a note of the actual storage temperature and duration of storage in the 
instructions field when the specimen is logged into the SWOG Specimen Tracking 
System. 
 
For specimens to be shipped at ambient temperature:  Refer to the SWOG 
Specimen Submission webpage for shipping instructions for ambient whole blood 
specimens. 
 
All specimen submissions for this study must be entered and tracked using the 
SWOG online Specimen Tracking system. Complete specimen collection and 
submission instructions can be accessed on the SWOG Specimen Submission 
webpage  
(https://www.swog.org/member-resources/biospecimen-resources/solid-tissue-
specimen-submission).  If collection/submission instructions differ from those in 
the protocol, the protocol instructions should be followed; otherwise, the website 
instructions should be followed. 
 
g. 
Genetic Data Sharing Plan 
 
The investigators will share anonymized, large-scale germ-line data in accordance 
with NIH Genomic Data Sharing (GDS) policy. The Data Sharing Policy requires 
controlled access to the genomic data based on the informed consent document. 
Access to de-identified, individual-level participant data will be controlled, unless 
participants explicitly consent to allow unrestricted access to and use of their data 
for any purpose.  
 
 

 
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h. 
International Specimen Processing Instructions 
 
LAVENDER TOP EDTA Tube: 
 
Note that specimen processing of blood plasma is outline below and done at site 
prior to storage. 
 
Please do NOT use LAVENDER TOP EDTA tubes that have a separation 
gel. The laboratory is unable to extract remaining cells from these tubes. 
The specimens should be collected in plastic EDTA tubes. 
 
1. 
Centrifuge the lavender top tube(s) at 1,200 x g for 10 minutes at room 
temperature. 
 
Distinct layers should be present after centrifugation. 
• 
The plasma layer will be clear and yellowish and comprise the top 
layer. 
• 
A thin, white, and cloudy buffy coat layer will be visible just below the 
plasma layer. 
• 
The bottom layer will be red and contain other cell types and debris. 
 
2. 
Using a pipette, remove only the plasma (top layer) place into a labeled 
15-mL conical tube. (Avoid pulling up the buffy coat layer by leaving about 
0.25-0.5 mL of plasma in the collection tube.) 
3. 
From this sample, generate at least two (2) 1 mL plasma aliquots in 2-mL, 
pre-labeled cryovials.  
4. 
After the plasma has been drawn off the specimen, use a sterile transfer 
pipette to gently mix the buffy coat layer and red blood cells together. 
Ensure the mixture is homogenous before freezing. The remnant blood 
can be frozen in the EDTA collection tube.   
5. 
Store both specimens in at -70 to -80C freezer until shipment to the 
SWOG Bank. If a -80°C freezer is not available, then specimens may be 
stored in a -20°C freezer before shipment.  
6. 
If samples are stored at > -70°C until shipment, make a note of the actual 
storage temperature and duration of storage in the instructions field when 
the specimen is logged into the SWOG Specimen Tracking System. 
 

 
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15.2 
Imaging Ancillary Study (OPTIONAL FOR PARTICIPANT / REQUIRED IF PARTICIPANT 
CONSENTS) 
 
The study team has developed an ancillary study aimed at identifying ways to prevent or 
reduce peripheral neuropathy from taxane treatment. As part of this study, the team is 
requesting access to imaging that has already been collected as part of standard of care. 
No additional or new scans will be required from patients. 
 
a. Digital Clinical CT Scan of the chest, abdomen, or thorax must be submitted to IROC 
Ohio for review at the following timepoint: 
• 
Baseline: performed within 6 months prior or 1 month after S1714 registration  
 
If a patient consents, sites must submit the images to the Imaging and Radiation 
Oncology Core (IROC) at Ohio via TRIAD Imaging Submission within 30 days.  
 
b. TRIAD Digital Image Submission 
 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s (ACR) 
image exchange application. TRIAD provides sites participating in clinical trials a 
secure method to transmit images. TRIAD anonymizes and validates the images as 
they are transferred. 
 
TRIAD Access Requirements: 
 
• 
Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems; 
 
• 
Registration type of: Associate (A), Associate Plus (AP), Non-Physician 
Investigator (NPIVR), or Investigator (IVR). Refer to the CTEP Registration 
Procedures section for instructions on how to request a CTEP-IAM account and 
complete registration in RCR; and 
 
• 
TRIAD Site User role on an NCTN, ETCTN, or other relevant roster. 
 
TRIAD Access Requirements: 
 
• 
Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems; 
 
• 
Registration type of: Associate (A), Associate Plus (AP), Non-Investigational New 
Drug (IND)/Non-Treatment (NINT), Non-Physician Investigator (NPIVR), or 
Investigator (IVR). Refer to the CTEP Registration Procedures section for 
instructions on how to request a CTEP-IAM account and complete registration in 
RCR; and 
 
• 
TRIAD Site User role on an NCTN, ETCTN, or other relevant roster. 
 
All individuals on the Imaging and Radiation Oncology Core provider roster have 
access to TRIAD and may submit images for credentialing purposes, or for enrollments 
to which the provider is linked in OPEN. 
 
TRIAD Installation: 
 

 
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To submit images, the individual holding the TRIAD Site User role will need to install 
the TRIAD application on their workstation. TRIAD installation documentation is 
available at https://triadinstall.acr.org/triadclient/. 
 
This process can be done in parallel to obtaining your CTEP-IAM account and RCR 
registration. 
 
For questions, contact TRIAD Technical Support staff via email TRIAD-
Support@acr.org or 1-703-390-9858. 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice:  
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). They must 
be followed to comply with FDA regulations for the conduct and monitoring of clinical investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the 
Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46). 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due January 31, 
April 30, July 31 and October 31. 
 
Adverse Experiences 
 
There is no SAE Reporting for this study. 
 
 

 
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17.0 
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13  
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14  
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24  
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26  
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24(10):1633-1642, 2006. 
 
27  
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28  
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29  
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30 
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33  
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34  
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35  
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36  
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37  
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38  
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39 
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40  
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41  
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44  
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46  
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47  
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48  
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49  
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50  
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51  
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chronic peripheral neuropathy in colon cancer patients. Cancer. 118(11):2828-2836, 2012. 
 
52  
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chronic peripheral neuropathy in colon cancer patients. Cancer. 118(11):2828-2836, 2012. 
 
53  
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54  
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55  
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56  
Broyl A, Corthals SL, Jongen JL, et al. Mechanisms of peripheral neuropathy associated with 
bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective 
 

 
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58  
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63  
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65  
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Smith EM. “Current methods for the Assessment and Management of Taxane-Related 
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75  
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76  
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. Quality of life research : an 
international journal of quality of life aspects of treatment, care and rehabilitation. 22(10):2787-
2799, 2013. 
 
77 
Mols F, Beijers T, Lemmens V, van den Hurk CJ, Vreugdenhil G, van de Poll-Franse LV. 
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colorectal cancer survivors: results from the population-based PROFILES registry. J Clin Oncol. 
31(21):2699-2707, 2013. 
 
78  
Cavaletti G, Cornblath DR, Merkies IS, et al. The chemotherapy-induced peripheral neuropathy 
outcome measures standardization study: from consensus to the first validity and reliability findings. 
Annals of oncology: official journal of the European Society for Medical Oncology / 
ESMO.;24(2):454-462, 2013. 
 
79  
Furnival GM, Wilson RW. Regressions by Leaps and Bounds. Technometrics.16(4):499-511, 1974. 
 
80  
Kohavi R. A study of cross-validation and bootstrap for accuracy estimation and model selection. 
Paper presented at: International Joint Conference on Artificial Intelligence; Montreal, Quebec, 
Canada, 1995. 
 
81  
Tibshirani R. Regression shrinkage and selection via the Lasso. J Roy Stat Soc B Met. 58(1):267-
288, 1996. 
 
 
 

 
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18.0 
APPENDIX 
 
18.1 
Protocol - Specified Chemotherapy Regimens for Breast, Lung, and Ovarian/Fallopian 
tube/Peritoneal Cancer 
 
18.2 
Staging Criteria:  Definitions and Staging 
 
18.3 
Instructions for the SWOG Biospecimen Bank 
 
18.4 
CTCAE Version 5.0 Nervous System Disorders Category 
 
18.5 
Patient and Physician-Reported Outcomes Instruments 
 
18.6 
Causes of Neuropathy  
 
18.7 
Foot Diagram 
 
18.8 
Translational Medicine - Pharmacokinetic Prediction of Taxane-Induced Peripheral 
Neuropathy 
 
18.9 
Translational Medicine – Genome-wide Pharmacogenetic Prediction of Taxane-Induced 
Peripheral Neuropathy (Funded R01) 
 
18.10 
Translational Medicine – Nutrient Prediction of Taxane-Induced Peripheral Neuropathy 
(Funded R01)  
 
18.11 
Imaging Study – Personalized Taxane Infusion Rate Recommendations to Reduce 
Neuropathy Risk in Patients with Low Skeletal Muscle Area 
 
  
 
 

 
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18.1 
Protocol-Specified Chemotherapy Regimens for Breast, Lung, and Ovarian/Fallopian tube 
Cancer 
 
 
Breast cancer 
Regimen 
Standard Taxane Dose 
Frequency 
*P x 4 
Paclitaxel 175 mg/m2 
Every 2 weeks for 4 cycles 
*P x 12 +/- Carboplatin (AUC 2 
for weekly or AUC 5-6 for every 
3 weeks) 
Paclitaxel 80 mg/m2 
Every week for 12 weeks (1 week 
= 1 cycle) 
TC x 4 or TC x 6 
Docetaxel 75 mg/m2 
Every 3 weeks for 4 or 6 cycles 
TAC x 6 
Docetaxel 75 mg/m2 
Every 3 weeks for 6 cycles 
*T x 4 
Docetaxel 100 mg/m2 
Every 3 weeks for 4 cycles 
T/Carboplatin  (AUC 6)  
Docetaxel 75 mg/m2 
Every 3 weeks for 6 cycles 
Lung cancer 
Regimen 
Standard Taxane Dose 
Frequency 
Carboplatin  (AUC 6) + P x 4 
Paclitaxel 200 mg/m2 
Every 3 weeks for 4 cycles 
Ovarian/Fallopian tube/ Peritoneal cancer 
Regimen 
Standard Taxane Dose 
Frequency 
Carboplatin (AUC 5-6) + P x 6 
Paclitaxel 175 mg/m2 
Every 3 weeks for 6 cycles 
Carboplatin (AUC 5-6) + ddP x 
6 
Paclitaxel 80 mg/m2 
Carboplatin every 3 weeks and 
paclitaxel weekly for 18 weeks 
Carboplatin (AUC 2) + P x 18 
Paclitaxel 60 mg/m2 
Weekly for 18 weeks 
Carboplatin (AUC 5-6) + T x 6 
Docetaxel 60-75 mg/m2 
Every 3 weeks for 6 cycles 
Abbreviations: dd, dose-dense; A, doxorubicin; C, cyclophosphamide; P, paclitaxel; T, docetaxel  
Biologic agents, including but not limited to trastuzumab and/or pertuzumab, may be added to any 
of the regimens. 
* Can be preceded or followed by AC. 
 
See Section 5.2 for additional information regarding allowable prior/concurrent therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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18.2 
Staging Criteria:  Definitions and Staging 
 
a. 
Breast Definitions (1) 
 
1. 
Definitions 
 
Primary Tumor (T) 
 
T0  
No evidence of primary tumor  
 
Tis (DCIS)* 
Ductal carcinoma in situ 
 
* 
Note:  Lobular carcinoma in situ (LCIS) is a benign entity and is 
removed from TNM staging in the AJCC Cancer Staging Manual, 
8th Edition. 
 
Tis (Paget) 
Paget disease of the nipple NOT associated with invasive 
carcinoma and/or carcinoma in situ (DCIS) in the 
underlying breast parenchyma.  Carcinomas in the breast 
parenchyma 
associated 
with 
Paget 
disease 
are 
categorized based on the size and characteristics of the 
parenchymal disease, although the presence of Paget 
disease should still be noted. 
 
T1 
Tumor ≤ 20 mm in greatest dimension  
 
T1mi  
Tumor ≤ 1 mm in greatest dimension  
 
T1a  
Tumor > 1 mm but ≤ 5 mm in greatest dimension (round 
any measurement > 1.0–1.9 mm to 2 mm) 
 
T1b  
Tumor > 5 mm but ≤ 10 mm in greatest dimension  
 
T1c  
Tumor > 10 mm but ≤ 20 mm in greatest dimension  
 
T2 
Tumor > 20 mm but ≤ 50 mm in greatest dimension  
 
T3 
Tumor > 50 mm in greatest dimension  
 
T4 
Tumor of any size with direct extension to the chest wall and/or to 
the skin (ulceration or macroscopic nodules); invasion of the 
dermis alone does not qualify as T4  
 
T4a  
Extension to the chest wall; invasion or adherence to 
pectoralis muscle in the absence of invasion of chest wall 
structures does not qualify as T4  
 
T4b  
Ulceration and/or ipsilateral macroscopic satellite nodules 
and/or edema (including peau d’orange) of the skin that 
does not meet the criteria for inflammatory carcinoma  
 
T4c  
Both T4a and T4b are present 
 
T4d  
Inflammatory carcinoma (see “Rules for Classification”) 
 
T Suffix (m) 
Select if synchronous primary tumors are found in a single 
organ 

 
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2. 
Regional Lymph Node (N) 
 
cNX* 
Regional lymph nodes cannot be assessed (e.g., previously 
removed) 
 
cN0 
No regional lymph node metastases (by imagining or clinical 
examination) 
 
cN1 
Metastases to movable ipsilateral Level I, II axillary lymph node(s) 
 
cN1mi** Micrometastases (approximately 200 cells, larger than 
0.2 mm, but none larger than 2.0 mm 
 
cN2 
Metastases in ipsilateral Level I, II axillary lymph nodes that are 
clinically fixed or matted; or in ipsilateral internal mammary nodes 
in the absence of axillary lymph node metastases 
 
cN2a 
Metastases in ipsilateral Level I, II axillary lymph nodes 
fixed to one another (matted) or to other structures 
 
cN2b 
Metastases only in ipsilateral internal mammary nodes in 
the absence of axillary lymph node metastases 
 
cN3 
Metastases in ipsilateral infraclavicular (Level III axillary) lymph 
node(s) with or without Level I, II axillary lymph node involvement; 
or in ipsilateral internal mammary lymph node(s) with Level I, II 
axillary lymph node metastases; or metastases in ipsilateral 
supraclavicular lymph node(s) with or without axillary or internal 
mammary lymph node involvement 
 
cN3a 
Metastases in ipsilateral infraclavicular lymph node(s) 
 
cN3b 
Metastases in ipsilateral internal mammary lymph node(s) and 
axillary lymph node(s) 
 
cN3c 
Metastases in ipsilateral supraclavicular lymph node(s) 
 
Note:  (sn) and (f) suffixes should be added to the N category to denote 
confirmation of metastasis by sentinel node biopsy or fine needle 
aspiration/core needle biopsy, respectively. 
 
* 
The cNX category is used sparingly in cases where regional lymph 
nodes have previously been surgically removed or where there is 
no documentation of physical examination of the axilla. 
 
** 
cN1mi is rarely used but may be appropriate in cases where 
sentinel node biopsy is performed before tumor resection, most 
likely to occur in cases treated with neoadjuvant therapy 
 
N Suffix (sn) 
Select if regional lymph node metastasis identified by SLN 
biopsy only 
 
N Suffix (f) 
Select if regional lymph node metastasis identified by 
FNA or core needle biopsy only 
 

 
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3. 
Distant Metastasis (M) 
 
The terms pM0 and MX are NOT valid categories in the TNM system. 
 
Assignment of the M category for clinical classification may be cM0, cM1, 
or pM1.  Any of the M categories (cM0, cM1, or pM1) may be used with 
pathological stage grouping. 
 
cM0  
No clinical or radiographic evidence of distant metastases* 
 
cM0(i+) No clinical or radiographic evidence of distant metastases in the 
presence of tumor cells or deposits no larger than 0.2 mm 
detected microscopically or by molecular techniques in circulating 
blood, bone marrow, or other nonregional nodal tissue in a patient 
without symptoms or signs of metastases. 
 
cM1  
Distant metastases detected by clinical and radiographic means  
 
pM1 
Any histologically proven metastases in distant organs; or if non-
regional nodes, metastases greater than 0.2 mm 
 
* 
Note that imaging studies are not required to assign the cM0 
category. 
 
4. 
Histologic Grade (G) 
 
Invasive Carcinoma 
 
GX 
Grade cannot be assessed 
 
G1 
Low combined histologic grade (favorable), SBR score of 3-5 
points 
 
G2 
Intermediate combined histologic grade (moderately favorable); 
SBR score 6-7 points 
 
G3 
High combined histologic grade (unfavorable); SBR score of 8-9 
points 
 
Carcinoma in situ 
 
GX 
Grade cannot be assessed 
 
G1 
Low nuclear grade 
 
G2 
Intermediate nuclear grade 
 
G3 
High nuclear grade 
 
 

 
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5. 
HER2 Status 
 
Positive  
 
Negative 
 
When TNM is… 
And 
Grade 
is… 
And HER2 
Status is… 
And ER 
Status 
is… 
And PR 
Status 
is… 
Then the 
Clinical 
Prognostic 
Stage 
Group 
is… 
T1* N0 M0 
T0 N1mi M0 
T1* N1mi M0 
G1 
Positive 
Positive 
Positive 
IA 
Negative 
IA 
Negative 
 
Positive 
IA 
Negative 
IA 
Negative 
 
Positive 
Positive 
IA 
Negative 
IA 
Negative 
Positive 
IA 
Negative 
IB 
G2 
Positive 
Positive 
Positive 
IA 
Negative 
IA 
Negative 
 
Positive 
IA 
Negative 
IA 
Negative 
 
Positive 
Positive 
IA 
Negative 
IA 
Negative 
Positive 
IA 
Negative 
IB 
G3 
Positive 
Positive 
Positive 
IA 
Negative 
IA 
Negative 
 
Positive 
IA 
Negative 
IA 
Negative 
 
Positive 
Positive 
IA 
Negative 
IB 
Negative 
Positive 
IB 
Negative 
IB 
T0 N1** M0 
T1* N1** M0 
T2 N0 M0 
G1 
Positive 
Positive 
Positive 
IB 
Negative 
IIA 
Negative 
 
Positive 
IIA 
Negative 
IIA 
Negative 
 
Positive 
Positive 
IB 
Negative 
IIA 
Negative 
Positive 
IIA 
Negative 
IIA 
G2 
Positive 
Positive 
Positive 
IB 
Negative 
IIA 
Negative 
 
Positive 
IIA 
Negative 
IIA 
Negative 
 
Positive 
Positive 
IB 
Negative 
IIA 
Negative 
Positive 
IIA 
Negative 
IIB 
G3 
Positive 
Positive 
Positive 
IB 
Negative 
IIA 

 
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When TNM is… 
And 
Grade 
is… 
And HER2 
Status is… 
And ER 
Status 
is… 
And PR 
Status 
is… 
Then the 
Clinical 
Prognostic 
Stage 
Group 
is… 
Negative 
 
Positive 
IIA 
Negative 
IIA 
Negative 
 
Positive 
Positive 
IIA 
Negative 
IIB 
Negative 
Positive 
IIB 
Negative 
IIB 
T2 N1*** M0 
T3 N0 M0 
G1 
Positive 
Positive 
Positive 
IB 
Negative 
IIA 
Negative 
 
Positive 
IIA 
Negative 
IIB 
Negative 
 
Positive 
Positive 
IIA 
Negative 
IIB 
Negative 
Positive 
IIB 
Negative 
IIB 
G2 
Positive 
Positive 
Positive 
IB 
Negative 
IIA 
Negative 
 
Positive 
IIA 
Negative 
IIB 
Negative 
 
Positive 
Positive 
IIA 
Negative 
IIB 
Negative 
Positive 
IIB 
Negative 
IIIB 
G3 
Positive 
Positive 
Positive 
IB 
Negative 
IIB 
Negative 
 
Positive 
IIB 
Negative 
IIB 
Negative 
 
Positive 
Positive 
IIB 
Negative 
IIIA 
Negative 
Positive 
IIIA 
Negative 
IIIB 
T0 N2 M0 
T1* N2 M0 
T2 N2 M0 
T3 N1*** M0 
T3 N2 M0 
G1 
Positive 
Positive 
Positive 
IIA 
Negative 
IIIA 
Negative 
 
Positive 
IIIA 
Negative 
IIIA 
Negative 
 
Positive 
Positive 
IIA 
Negative 
IIIA 
Negative 
Positive 
IIIA 
Negative 
IIIB 
G2 
Positive 
Positive 
Positive 
IIA 
Negative 
IIIA 
Negative 
 
Positive 
IIIA 
Negative 
IIIA 
Negative 
 
Positive 
Positive 
IIA 
Negative 
IIIA 
Negative 
Positive 
IIIA 
Negative 
IIIB 
G3 
Positive 
Positive 
Positive 
IIB 
Negative 
IIIA 
Negative 
Positive 
IIIA 

 
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When TNM is… 
And 
Grade 
is… 
And HER2 
Status is… 
And ER 
Status 
is… 
And PR 
Status 
is… 
Then the 
Clinical 
Prognostic 
Stage 
Group 
is… 
 
Negative 
IIIA 
Negative 
 
Positive 
Positive 
IIIA 
Negative 
IIIB 
Negative 
Positive 
IIIB 
Negative 
IIIC 
T4 N0 M0 
T4 N1*** M0 
T4 N2 M0 
Any T N3 M0 
G1 
Positive 
Positive 
Positive 
IIIA 
 
Negative 
IIIB 
Negative 
 
Positive 
IIIB 
 
Negative 
IIIB 
Negative 
 
Positive 
Positive 
IIIB 
 
Negative 
IIIB 
Negative 
Positive 
IIIB 
 
Negative 
IIIC 
G2 
Positive 
Positive 
Positive 
IIIB 
Negative 
IIIB 
Negative 
 
Positive 
IIIB 
Negative 
IIIB 
Negative 
 
Positive 
Positive 
IIIB 
Negative 
IIIB 
Negative 
Positive 
IIIB 
Negative 
IIIC 
G3 
Positive 
Positive 
Positive 
IIIB 
Negative 
IIIB 
Negative 
 
Positive 
IIIB 
Negative 
IIIB 
Negative 
 
Positive 
Positive 
IIIB 
Negative 
IIIC 
Negative 
Positive 
IIIC 
Negative 
IIIC 
*T1 includes T1mi 
**N1 does not include N1mi.  T1 N1mi M0 cancers are included for prognostic 
staging with T1 N0 M0 cancers of the same prognostic factor status. 
***N1 includes n1mi.  T2, T3, and T4 cancers are included for prognostic 
staging with T2 N1, T3 N1, and T4 N1, respectively. 
 
Notes: 
1. Because N1mi categorization requires evaluation of the entire node, 
and cannot be assigned on the basis of an FNA or core biopsy, N1mi 
can only be used with Clinical Prognostic Staging when clinical staging 
is based on a resected lymph node in the absence of resection of the 
primary cancer, such as the situation where sentinel node biopsy is 
performed prior to receipt of neoadjuvant chemotherapy or endocrine 
therapy. 
2. For cases where HER2 is determined to be “equivocal” by ISH (FISH 
or CISH) testing under the 2013 ASCO/CAP HER2 testing guidelines, 
the HER2 “negative” category should be used for staging in the 
Clinical Prognostic Stage Group table. 
3. The prognostic value of these Prognostic Stage Group is based on 
populations of persons with breast cancer that have been offered and 

 
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When TNM is… 
And 
Grade 
is… 
And HER2 
Status is… 
And ER 
Status 
is… 
And PR 
Status 
is… 
Then the 
Clinical 
Prognostic 
Stage 
Group 
is… 
mostly treated with appropriate endocrine and/or systemic 
chemotherapy (including anti-HER2 therapy). 
 
Equivocal (use negative category for prognostic stage group assignment) 
 
6. 
ER Status 
 
Positive  
 
Negative 
 
7. 
PR Status  
 
Positive 
 
Negative 
 
8. 
Oncotype Dx® Recurrence Score 
 
Less than 11 
 
11 or greater 
 
Not performed 
 
Not available 
 
9. 
Clinical Prognostic Stage 
 
 

 
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10. 
Pathological Prognostic Stage 
 
When TNM is… 
And 
Grade 
is… 
And HER2 
Status is… 
And ER 
Status 
is… 
And PR 
Status 
is… 
Then the 
Clinical 
Prognostic 
Stage 
Group 
is… 
T1* N0 M0 
T0 N1mi M0 
T1* N1mi M0 
G1 
Positive 
Positive 
Positive 
IA 
Negative 
IA 
Negative 
 
Positive 
IA 
Negative 
IA 
Negative 
 
Positive 
Positive 
IA 
Negative 
IA 
Negative 
Positive 
IA 
Negative 
IA 
G2 
Positive 
Positive 
Positive 
IA 
Negative 
IA 
Negative 
 
Positive 
IA 
Negative 
IA 
Negative 
 
Positive 
Positive 
IA 
Negative 
IA 
Negative 
Positive 
IA 
Negative 
IB 
G3 
Positive 
Positive 
Positive 
IA 
Negative 
IA 
Negative 
 
Positive 
IA 
Negative 
IA 
Negative 
 
Positive 
Positive 
IA 
Negative 
IA 
Negative 
Positive 
IA 
Negative 
IB 
T0 N1** M0 
T1* N1** M0 
T2 N0 M0 
G1 
Positive 
Positive 
Positive 
IA 
Negative 
IB 
Negative 
 
Positive 
IB 
Negative 
IIA 
Negative 
 
Positive 
Positive 
IA 
Negative 
IB 
Negative 
Positive 
IB 
Negative 
IIA 
G2 
Positive 
Positive 
Positive 
IA 
Negative 
IB 
Negative 
 
Positive 
IB 
Negative 
IIA 
Negative 
 
Positive 
Positive 
IA 
Negative 
IIA 
Negative 
Positive 
IIA 
Negative 
IIA 
G3 
Positive 
Positive 
Positive 
IA 
Negative 
IIA 
Negative 
 
Positive 
IIA 
Negative 
IIA 
Negative 
 
Positive 
Positive 
IB 
Negative 
IIA 

 
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When TNM is… 
And 
Grade 
is… 
And HER2 
Status is… 
And ER 
Status 
is… 
And PR 
Status 
is… 
Then the 
Clinical 
Prognostic 
Stage 
Group 
is… 
Negative 
Positive 
IIA 
Negative 
IIA 
T2 N1*** M0 
T3 N0 M0 
G1 
Positive 
Positive 
Positive 
IA 
Negative 
IIB 
Negative 
 
Positive 
IIB 
Negative 
IIB 
Negative 
 
Positive 
Positive 
IA 
Negative 
IIB 
Negative 
Positive 
IIB 
Negative 
IIB 
G2 
Positive 
Positive 
Positive 
IB 
Negative 
IIB 
Negative 
 
Positive 
IIB 
Negative 
IIB 
Negative 
 
Positive 
Positive 
IB 
Negative 
IIB 
Negative 
Positive 
IIB 
Negative 
IIB 
G3 
Positive 
Positive 
Positive 
IB 
Negative 
IIB 
Negative 
 
Positive 
IIB 
Negative 
IIB 
Negative 
 
Positive 
Positive 
IIA 
Negative 
IIB 
Negative 
Positive 
IIB 
Negative 
IIIA 
T0 N2 M0 
T1* N2 M0 
T2 N2 M0 
T3 N1*** M0 
T3 N2 M0 
G1 
Positive 
Positive 
Positive 
IB 
Negative 
IIIA 
Negative 
 
Positive 
IIIA 
Negative 
IIIA 
Negative 
 
Positive 
Positive 
IB 
Negative 
IIIA 
Negative 
Positive 
IIIA 
Negative 
IIIA 
G2 
Positive 
Positive 
Positive 
IB 
Negative 
IIIA 
Negative 
 
Positive 
IIIA 
Negative 
IIIA 
Negative 
 
Positive 
Positive 
IB 
Negative 
IIIA 
Negative 
Positive 
IIIA 
Negative 
IIIB 
G3 
Positive 
Positive 
Positive 
IIA 
Negative 
IIIA 
Negative 
 
Positive 
IIIA 
Negative 
IIIA 
Negative 
 
Positive 
Positive 
IIB 
Negative 
IIIA 
Negative 
Positive 
IIIA 

 
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When TNM is… 
And 
Grade 
is… 
And HER2 
Status is… 
And ER 
Status 
is… 
And PR 
Status 
is… 
Then the 
Clinical 
Prognostic 
Stage 
Group 
is… 
Negative 
IIIC 
T4 N0 M0 
T4 N1*** M0 
T4 N2 M0 
Any T N3 M0 
G1 
Positive 
Positive 
Positive 
IIIA 
 
Negative 
IIIB 
Negative 
 
Positive 
IIIB 
 
Negative 
IIIB 
Negative 
 
Positive 
Positive 
IIIA 
 
Negative 
IIIB 
Negative 
Positive 
IIIB 
 
Negative 
IIIB 
G2 
Positive 
Positive 
Positive 
IIIA 
Negative 
IIIB 
Negative 
 
Positive 
IIIB 
Negative 
IIIB 
Negative 
 
Positive 
Positive 
IIIA 
Negative 
IIIB 
Negative 
Positive 
IIIB 
Negative 
IIIC 
G3 
Positive 
Positive 
Positive 
IIIB 
Negative 
IIIB 
Negative 
 
Positive 
IIIB 
Negative 
IIIB 
Negative 
 
Positive 
Positive 
IIIB 
Negative 
IIIC 
Negative 
Positive 
IIIC 
Negative 
IIIC 
*T1 includes T1mi 
**N1 does not include N1mi.  T1 N1mi M0 cancers are included for prognostic 
staging with T1 N0 M0 cancers of the same prognostic factor status. 
***N1 includes n1mi.  T2, T3, and T4 cancers are included for prognostic 
staging with T2 N1, T3 N1, and T4 N1, respectively. 
 
Notes: 
1. For cases where HER2 is determined to be “equivocal” by ISH (FISH 
or CISH) testing under the 2013 ASCO/CAP HER2 testing guidelines, 
the HER2 “negative” category should be used for staging in the 
Pathological Prognostic Stage Group table. 
2. The prognostic value of these Prognostic Stage Group is based on 
populations of persons with breast cancer that have been offered and 
mostly treated with appropriate endocrine and/or systemic 
chemotherapy (including anti-HER2 therapy). 
 
b. 
Non-Small Cell Lung (2) 
 
1. 
Definitions 
 
Primary Tumor (T) 
 
T1 
Tumor ≤ 3 cm in greatest dimension, surrounded by lung or 
visceral pleura, without bronchoscopic evidence of invasion more 

 
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proximal than the lobar bronchus (for example, not in the main 
bronchus)* 
 
T1mi 
Minimally invasive adenocarcinoma:  adenocarcinoma (≤ 
3 cm in greatest dimension) with a predominantly lepidic 
pattern and ≤ 5 mm invasion in greatest dimension 
 
T1a 
Tumor ≤ 1 cm in greatest dimension.  A superficial, 
spreading tumor of any size whose invasive component 
is limited to the bronchial wall and may extend proximal to 
the main bronchus also is classified as T1a, but these 
tumors are uncommon. 
 
T1b 
Tumor > 1 cm but ≤ 2 cm in greatest dimension 
 
T1c 
Tumor > 2 cm but ≤ 3 cm in greatest dimension 
 
T2 
Tumor > 3 cm ≤ 5 cm or having any of the following features  
• 
involves main bronchus regardless of distance to the carina, 
but without involvement of the carina 
• 
invades visceral pleura (PL1 or PL2) 
• 
associated with atelectasis or obstructive pneumonitis that 
extends to the hilar region, involving part or all of the lung  
 
T2a 
Tumor > 3 cm but ≤ 4 cm in greatest dimension  
 
T2b 
Tumor > 4 cm but ≤ 5 cm in greatest dimension  
 
T3 
Tumor > 5 cm but ≤ 7 cm in greatest dimension or directly invading 
any of the following:   
• 
parietal pleural (PL3) 
• 
chest wall (including superior sulcus tumors) 
• 
phrenic nerve 
• 
parietal pericardium 
• 
separate tumor nodule(s) in the same lobe as the primary 
 
T4 
Tumor > 7 cm or tumor of any size invading one or more of the 
following:  
• 
diaphragm 
• 
mediastinum 
• 
heart 
• 
great vessels 
• 
trachea 
• 
recurrent laryngeal nerve 
• 
esophagus 
• 
vertebral body 
• 
carina 
• 
separate tumor nodule(s) in a different ipsilateral lobe  
 
T Suffix (m) 
Select if synchronous primary tumors are found in a single 
organ 
 
 

 
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2. 
Regional Lymph Node (N) 
 
N0 
No regional lymph node metastasis 
 
N1 
Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph 
nodes and intrapulmonary nodes, including involvement by direct 
extension 
 
N2 
Metastasis in ipsilateral mediastinal and/or subcarinal lymph 
node(s) 
 
N3 
Metastasis in contralateral mediastinal, contralateral hilar, 
ipsilateral or contralateral scalene, or supraclavicular lymph 
node(s) 
 
N Suffix (sn) 
Select if regional lymph node metastasis identified by SLN 
biopsy only 
 
N suffix (f) 
Select if regional lymph node metastasis identified by 
FNA or core needle biopsy only 
 
3. 
Distant Metastasis (M) 
 
M0  
No distant metastasis  
 
cM1  
Distant metastasis  
 
cM1a  Separate tumor nodule(s) in a contralateral lobe, tumor 
with pleural or pericardial nodules or malignant pleural or 
pericardial effusion.  Most pleural (pericardial) effusions 
with lung cancer are a result of the tumor.  In a few 
patients, however, multiple microscopic examinations of 
pleural (pericardial) fluid are negative for tumor, and the 
fluid is nonbloody and not an exudate.  If these elements 
and clinical judgment dictate that the effusion is not 
related to the tumor, the effusion should be excluded as a 
staging descriptor. 
 
cM1b  Single extrathoracic metastasis in a single organ 
(including involvement of a single nonregional node) 
 
cM2c 
Multiple extrathoracic metastases in a single organ or in 
multiple organs 
 
pM1 
Distant metastasis, microscopically confirmed 
 
pM1a 
Separate tumor nodule(s) in a contralateral lobe; tumor 
with pleural or pericardial nodules or malignant pleural or 
pericardial effusion, microscopically confirmed.  Most 
pleural (pericardial) effusions with lung cancer are a result 
of the tumor.  In a few patients, however, multiple 
microscopic examinations of pleural (pericardial) fluid are 
negative for tumor, and the fluid is non-bloody and not an 
exudate.  If these elements and clinical judgment dictate 
that the effusion is not related to the tumor, the effusion 
should be excluded as a staging descriptor. 

 
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pM1b 
Single extrathoracic metastasis in a single organ 
(including involvement of a single nonregional node), 
microscopically confirmed 
 
pM1c 
Multiple extrathoracic metastases in a single organ or in 
multiple organs, microscopically confirmed 
 
* 
The uncommon superficial spreading tumor of any size with its 
invasive component limited to the bronchial wall, which may extend 
proximally to the main bronchus, is also classified as T1a. 
 
** Most pleural (and pericardial) effusions with lung cancer are due to 
tumor. In a few patients, however, multiple cytopathologic 
examinations of pleural (pericardial) fluid are negative for tumor, and 
the fluid is nonbloody and is not an exudate. Where these elements 
and clinical judgment dictate that the effusion is not related to the 
tumor, the effusion should be excluded as a staging element and the 
patient should be classified as M0. 
 
4. 
Prognostic Stage Groups 
 
When T is… 
And N is… 
And M is… 
Then the stage group is… 
T1mi 
N0 
M0 
IA1 
T1a 
N0 
M0 
IA1 
T1a 
N1 
M0 
IIB 
T1a 
N2 
M0 
IIIA 
T1a 
N3 
M0 
IIIB 
T1b 
N0 
M0 
IA2 
T1b 
N1 
M0 
IIB 
T1b 
N2 
M0 
IIIA 
T1b 
N3 
M0 
IIIB 
T1c 
N0 
M0 
IA3 
T1c 
N1 
M0 
IIB 
T1c 
N2 
M0 
IIIA 
T1c 
N3 
M0 
IIIB 
T2a 
N0 
M0 
IB 
T2a 
N1 
M0 
IIB 
T2a 
N2 
M0 
IIIA 
T2a 
N3 
M0 
IIIB 
T2b 
N0 
M0 
IIA 
T2b 
N1 
M0 
IIB 
T2b 
N2 
M0 
IIIA 
T2b 
N3 
M0 
IIIB 
T3 
N0 
M0 
IIB 
T3 
N1 
M0 
IIIA 
T3 
N2 
M0 
IIIB 
T3 
N3 
M0 
IIIC 
T4 
N0 
M0 
IIIA 
T4 
N1 
M0 
IIIA 
T4 
N2 
M0 
IIIB 
T4 
N3 
M0 
IIIC 
 
 
 

 
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c. 
Ovarian/Fallopian tube/ Peritoneal (3) 
 
1. 
Definitions 
 
Primary Tumor (T) and FIGO Stages in () 
 
T1(I)  
Tumor limited to ovaries (one or both) or fallopian tube(s) 
 
T1a(IA)  
Tumor limited to one ovary (capsule intact) or 
fallopian tube, no tumor on ovarian or fallopian 
tube surface; no malignant cells in ascites or 
peritoneal washings  
 
T1b(IB) 
Tumor limited to one or both ovaries (capsules 
intact) or fallopian tubes; no tumor on ovarian or 
fallopian tube surface, no malignant cells in 
ascites or peritoneal washings  
 
T1c(IC) 
Tumor limited to one or both ovaries or fallopian 
tubes with any of following:  
 
T1c1(IC1) Surgical spill  
 
T1c2(IC2) Capsule ruptured before surgery or 
tumor on ovarian or fallopian tube 
surface  
 
T1c3(IC3) Malignant 
cells 
in 
ascites 
or 
peritoneal washings  
 
T2(II) 
Tumor involves one or both ovaries or fallopian tubes with 
pelvic extension below pelvic brim or primary peritoneal 
cancer 
 
T2a(IIA) 
Extension and/or implants on uterus and/or 
fallopian tube(s) and/or ovaries  
 
T2b(IIB) 
Extension to and/or implants on other pelvic 
tissue 
 
T3(III) 
Tumor involves one or both ovaries or fallopian tubes, or 
primary peritoneal cancer, with microscopically confirmed 
peritoneal metastasis outside the pelvis and/or metastasis to 
the retroperitoneal (pelvic and/or para-aortic) lymph nodes 
 
T3a(IIIA2) Microscopic extrapelvic (above the pelvic brim) 
peritoneal involvement with or without positive 
retroperitoneal lymph nodes  
 
T3b(IIIB) 
Macroscopic peritoneal metastasis beyond pelvis 
2 cm or less in greatest dimension with or without 
metastasis to the retroperitoneal lymph nodes 
 
T3c(IIIC) 
Macroscopic peritoneal metastasis beyond pelvis 
more than 2 cm in greatest dimension with or 
without metastasis to the retroperitoneal lymph 

 
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nodes (includes extension of tumor to capsule of 
liver 
and 
spleen 
without 
parenchymal 
involvement of either organ) 
 
T Suffix (m) 
Select if synchronous primary tumors are found in single 
organ 
 
2. 
Regional Lymph Node (N) and FIGO Stage in () 
 
N0  
Regional lymph nodes cannot be assessed 
 
N0(i+) 
Isolated tumor cells in regional lymph node(s) no greater than 
0.2 mm 
 
N1(IIIA1) 
Positive retroperitoneal lymph nodes only (histologically 
confirmed)  
 
N1a(IIIA1i) Metastasis up to and including 10 mm in greatest 
dimension  
 
N1b(IIIA1ii) Metastasis more than 10 mm in greatest 
dimension 
 
N Suffix (sn) 
Select if regional lymph node metastasis identified by SLN 
biopsy only 
 
N Suffix (f) 
Select if regional lymph node metastasis identified by 
FNA or core needle biopsy only 
 
M1(IV) 
Distant metastasis excluding peritoneal metastases  
 
M1a(IVA) 
Pleural effusion with positive cytology  
 
M1b(IVB) 
Parenchymal metastases and metastases to 
extra-abdominal organs (including inguinal lymph 
nodes and lymph node s outside the abdominal 
cavity)  
 
 

 
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3. 
Distant Metastasis (M) and FIGO Stage in () 
 
M0 
No distant metastasis  
 
cM1 (IV) 
Distant metastasis, including pleural effusion with positive 
cytology; liver or splenic parenchymal metastasis; metastasis 
to extra-abdominal organs (including inguinal lymph nodes 
and lymph nodes outside the abdominal cavity); and 
transmural involvement of intestine 
 
cM1a (IVA) Pleural effusion with positive cytology  
 
cM1b (IVB) Liver 
or 
splenic 
parenchymal 
metastasis; 
metastasis to extra-abdominal organs (including 
inguinal lymph nodes and lymph nodes outside 
the 
abdominal 
cavity); 
and 
transmural 
involvement of intestine 
 
pM1 (IV) 
Distant metastasis, including pleural effusion with positive 
cytology; liver or splenic parenchymal metastasis; metastasis 
to extra-abdominal organs (including inguinal lymph nodes 
and lymph nodes outside the abdominal cavity); and 
transmural 
involvement 
of 
intestine, 
microscopically 
confirmed 
 
pM1a (IVA) Pleural 
effusion 
with 
positive 
cytology, 
microscopically confirmed 
 
pM1b (IVB) Liver 
or 
splenic 
parenchymal 
metastasis; 
metastasis to extra-abdominal organs (including 
inguinal lymph nodes and lymph nodes outside 
the 
abdominal 
cavity); 
and 
transmural 
involvement 
of 
intestine, 
microscopically 
confirmed 
 
4. 
Prognostic Stage Groups 
 
When T is… 
And N is… 
And M is… 
Then the stage group is… 
T1 
N0 
M0 
I 
T1a 
N0 
M0 
IA 
T1b 
N0 
M0 
IB 
T1c 
N0 
M0 
IC 
T2 
N0 
M0 
II 
T2a 
N0 
M0 
IIA 
T2b 
N0 
M0 
IIB 
T1/T2 
N1 
M0 
IIIA1 
T3a 
NX, N0, N1 
M0 
IIIA2 
T3b 
NX, N0, N1 
M0 
IIIB 
T3c 
NX, N0, N1 
M0 
IIIC 
 
 
 

 
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Appendix 18.2 References
 
1  
AJCC 8 Breast 
 
2  
AJCC 8 Lung  
 
3  
AJCC 8 Ovarian/Fallopian tube/Peritoneal 
 
 
 

 
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18.3 
Instructions for the SWOG Biospecimen Bank 
 
Frozen Serum and Plasma Aliquots 
The SWOG Biospecimen Bank will receive frozen vial of serum and plasma (from sodium 
heparin) at seven time points, and plasma (from EDTA) at one time point. Upon receipt, 
serum and plasma vials will be accessioned, barcoded, and banked in a -80°C freezer until 
distribution for testing and/or future studies.  
 
Whole Blood 
The SWOG Biospecimen Bank will receive ambient whole blood at one time point.  Upon 
receipt, whole blood in EDTA will be accessioned and barcoded. Blood will be processed 
for plasma and then DNA will be extracted and stored in a -80°C freezer for future studies 
(including for DNA for pharmacogenetic analyses).  
 
Distribution of Specimens from SWOG Biospecimen Bank 
 
 
 
Assay 
Specimen 
Type 
Collection 
Tube 
Timepoint 
Amount 
Lab 
Shipping 
Kinetics 
Plasma 
EDTA 
w/in 10 min 
prior to end 
of 1st infusion 
1 x 0.6ml  
UM 
Pharmacokinetics 
Core 
Room 3400 of Building 520, North 
Campus 
Research 
Complex (1600 
Huron Parkway, Ann Arbor, MI 48109) 
Genetics 
DNA 
EDTA 
Baseline 
250 uL at 20 
ng/uL (5 ug 
total DNA) 
UM 
Advanced 
Genomics 
UM Advanced Genomics Core, NCRC 
Building 14, Room 122, University of 
Michigan, 2800 Plymouth Rd, Ann 
Arbor, MI 48109-2800 
Vitamin D 
Plasma 
NaHep 
Baseline 
1 x 0.6ml 
Heartland Assays  
Iowa State University Research Park, 
2711 S. Loop Dr., Ste 4400, Ames, IA 
50010 
Amino 
Acids  
Plasma 
NaHep 
Baseline 
1 x 0.6ml 
Metabolon, Inc 
617 Davis Dr. Suite 100  
Morrisville, NC 27560  
Lipidomics 
Plasma 
NaHep 
Baseline 
1 x 0.6ml 
Metabolon, Inc 
617 Davis Dr. Suite 100  
Morrisville, NC 27560 
Proteomics 
Serum 
Red Top 
Baseline 
2 x 0.6ml 
University 
of 
Michigan 
College of Pharmacy, Room 4065, 428 
Church Street, Ann Arbor, MI 48104,  

 
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18.4 
CTCAE Version 5.0 Nervous System Disorders Category (1) 
 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Abducens 
nerve 
disorder 
Asymptomatic; 
clinical 
or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care ADL 
 - 
 - 
Accessory 
nerve 
disorder 
Asymptomatic; 
clinical 
or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care ADL 
 - 
 - 
Acoustic 
nerve 
disorder NOS 
Asymptomatic; 
clinical 
or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care ADL 
 - 
 - 
Akathisia 
Mild 
restlessness 
or 
increased motor activity 
Moderate restlessness 
or 
increased 
motor 
activity; 
limiting 
instrumental ADL 
Severe restlessness or 
increased motor activity; 
limiting self care ADL 
 - 
 - 
Amnesia 
Mild; transient memory 
loss 
Moderate; short term 
memory loss; limiting 
instrumental ADL 
Severe; 
long 
term 
memory loss; limiting 
self care ADL 
 - 
 - 
Anosmia 
Present 
 - 
 - 
 - 
 - 
Aphonia 
 - 
 - 
Voicelessness; unable 
to speak 
 - 
 - 
Arachnoiditis 
Mild symptoms 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care ADL 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Ataxia 
Asymptomatic; 
clinical 
or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care ADL; 
mechanical assistance 
indicated 
 - 
 - 
Brachial plexopathy 
Asymptomatic; 
clinical 
or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care ADL 
 - 
 - 

 
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CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Central 
nervous 
system necrosis 
Asymptomatic; 
clinical 
or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
corticosteroids indicated 
Severe 
symptoms; 
medical 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Cerebrospinal 
fluid 
leakage 
Post-craniotomy: 
asymptomatic; 
Post-
lumbar 
puncture: 
transient 
headache; 
postural care indicated 
Post-craniotomy: 
moderate 
symptoms; 
medical 
intervention 
indicated; Post-lumbar 
puncture: 
persistent 
moderate 
symptoms; 
blood patch indicated 
Severe 
symptoms; 
medical 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Cognitive disturbance 
Mild cognitive disability; 
not 
interfering 
with 
work/school/life 
performance; 
specialized educational 
services/devices 
not 
indicated 
Moderate 
cognitive 
disability; 
interfering 
with 
work/school/life 
performance 
but 
capable of independent 
living; 
specialized 
resources on part time 
basis indicated 
Severe 
cognitive 
disability; 
significant 
impairment 
of 
work/school/life 
performance 
 - 
 - 
Concentration 
impairment 
Mild 
inattention 
or 
decreased 
level 
of 
concentration 
Moderate impairment in 
attention or decreased 
level of concentration; 
limiting 
instrumental 
ADL 
Severe impairment in 
attention or decreased 
level of concentration; 
limiting self care ADL 
 - 
 - 
Depressed level of 
consciousness 
Decreased 
level 
of 
alertness 
Sedation; 
slow 
response 
to 
stimuli; 
limiting 
instrumental 
ADL 
Difficult to arouse 
Life-threatening 
consequences; 
coma; 
urgent 
intervention 
indicated 
Death 
Dizziness 
Mild unsteadiness or 
sensation of movement 
Moderate unsteadiness 
or 
sensation 
of 
movement; 
limiting 
instrumental ADL 
Severe unsteadiness or 
sensation of movement; 
limiting self care ADL 
 - 
 - 
Dysarthria 
Mild slurred speech 
Moderate impairment of 
articulation or slurred 
speech 
Severe impairment of 
articulation or slurred 
speech 
 - 
 - 
Dysesthesia 
Mild sensory alteration 
Moderate 
sensory 
alteration; 
limiting 
instrumental ADL 
Severe 
sensory 
alteration; limiting self 
care ADL 
 - 
 - 

 
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CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Dysgeusia 
Altered taste but no 
change in diet 
Altered 
taste 
with 
change in diet (e.g., oral 
supplements); noxious 
or unpleasant taste; loss 
of taste 
 - 
 - 
 - 
Dysphasia 
Awareness of receptive 
or 
expressive 
characteristics; 
not 
impairing 
ability 
to 
communicate 
Moderate receptive or 
expressive 
characteristics; 
impairing 
ability 
to 
communicate 
spontaneously 
Severe 
receptive 
or 
expressive 
characteristics; 
impairing ability to read, 
write or communicate 
intelligibly 
 - 
 - 
Edema cerebral 
 - 
 - 
New onset; worsening 
from baseline 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Encephalopathy 
Mild symptoms 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care ADL 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Extrapyramidal 
disorder 
Mild 
involuntary 
movements 
Moderate 
involuntary 
movements; 
limiting 
instrumental ADL 
Severe 
involuntary 
movements or torticollis; 
limiting self care ADL 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Facial 
muscle 
weakness 
Asymptomatic; 
clinical 
or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care ADL 
 - 
 - 
Facial nerve disorder 
Asymptomatic; 
clinical 
or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care ADL 
 - 
 - 
Glossopharyngeal 
nerve disorder 
Asymptomatic; 
clinical 
or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care ADL 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Guillain-Barre 
syndrome 
Mild symptoms 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care ADL 
Life-threatening 
consequences; 
urgent 
intervention 
indicated; 
intubation 
Death 
Headache 
Mild pain 
Moderate pain; limiting 
instrumental ADL 
Severe pain; limiting self 
care ADL 
 - 
 - 

 
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CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hydrocephalus 
Asymptomatic; 
clinical 
or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
intervention 
not 
indicated 
Severe symptoms or 
neurological 
deficit; 
intervention indicated 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Hypersomnia 
Mild increased need for 
sleep 
Moderate 
increased 
need for sleep 
Severe increased need 
for sleep 
 - 
 - 
Hypoglossal 
nerve 
disorder 
Asymptomatic; 
clinical 
or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care ADL 
 - 
 - 
Intracranial 
hemorrhage 
Asymptomatic; 
clinical 
or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
intervention indicated 
Ventriculostomy, 
ICP 
monitoring, 
intraventricular 
thrombolysis, 
or 
invasive 
intervention 
indicated; 
hospitalization 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Ischemia 
cerebrovascular 
Asymptomatic; 
clinical 
or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate symptoms 
 - 
 - 
 - 
Lethargy 
Mild symptoms; reduced 
alertness 
and 
awareness 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
 - 
 - 
 - 
Leukoencephalopathy 
Asymptomatic; 
small 
focal 
T2/FLAIR 
hyperintensities; 
involving periventricular 
white matter or <1/3 of 
susceptible 
areas 
of 
cerebrum 
+/- 
mild 
increase 
in 
subarachnoid 
space 
(SAS) 
and/or 
mild 
ventriculomegaly 
Moderate 
symptoms; 
focal 
T2/FLAIR 
hyperintensities, 
involving periventricular 
white matter extending 
into centrum semiovale 
or involving 1/3 to 2/3 of 
susceptible 
areas 
of 
cerebrum +/- moderate 
increase in SAS and/or 
moderate 
ventriculomegaly 
Severe 
symptoms; 
extensive 
T2/FLAIR 
hyperintensities, 
involving periventricular 
white matter involving 
2/3 
or 
more 
of 
susceptible 
areas 
of 
cerebrum +/- moderate 
to severe increase in 
SAS and/or moderate to 
severe ventriculomegaly 
Life-threatening 
consequences; 
extensive 
T2/FLAIR 
hyperintensities, 
involving periventricular 
white matter involving 
most 
of 
susceptible 
areas of cerebrum +/- 
moderate 
to 
severe 
increase in SAS and/or 
moderate 
to 
severe 
ventriculomegaly 
Death 

 
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CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Memory impairment 
Mild 
memory 
impairment 
Moderate 
memory 
impairment; 
limiting 
instrumental ADL 
Severe 
memory 
impairment; limiting self 
care ADL 
 - 
 - 
Meningismus 
Mild symptoms 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care ADL 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Movements 
involuntary 
Mild symptoms 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care ADL 
 - 
 - 
Muscle weakness left-
sided 
Symptomatic; perceived 
by 
patient 
but 
not 
evident 
on 
physical 
exam 
Symptomatic; 
evident 
on 
physical 
exam; 
limiting 
instrumental 
ADL 
Limiting self care ADL 
 - 
 - 
Muscle 
weakness 
right-sided 
Symptomatic; perceived 
by 
patient 
but 
not 
evident 
on 
physical 
exam 
Symptomatic; 
evident 
on 
physical 
exam; 
limiting 
instrumental 
ADL 
Limiting self care ADL 
 - 
 - 
Myasthenia gravis 
Asymptomatic or mild 
symptoms; clinical or 
diagnostic observations 
only; intervention not 
indicated 
Moderate; minimal, local 
or 
noninvasive 
intervention 
indicated; 
limiting age-appropriate 
instrumental ADL 
Severe 
or 
medically 
significant 
but 
not 
immediately 
life-
threatening; 
hospitalization 
or 
prolongation of existing 
hospitalization 
indicated; limiting self 
care ADL 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Nervous 
system 
disorders 
- 
Other, 
specify 
Asymptomatic or mild 
symptoms; clinical or 
diagnostic observations 
only; intervention not 
indicated 
Moderate; minimal, local 
or 
noninvasive 
intervention 
indicated; 
limiting age-appropriate 
instrumental ADL 
Severe 
or 
medically 
significant 
but 
not 
immediately 
life-
threatening; 
hospitalization 
or 
prolongation of existing 
hospitalization 
indicated; limiting self 
care ADL 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Neuralgia 
Mild pain 
Moderate pain; limiting 
instrumental ADL 
Severe pain; limiting self 
care ADL 
 - 
 - 
Nystagmus 
 - 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care ADL 
 - 
 - 

 
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CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Oculomotor 
nerve 
disorder 
Asymptomatic; clinical or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
limiting instrumental ADL 
Severe 
symptoms; 
limiting self care ADL 
 - 
 - 
Olfactory 
nerve 
disorder 
 - 
Moderate 
symptoms; 
limiting instrumental ADL 
Severe 
symptoms; 
limiting self care ADL 
 - 
 - 
Paresthesia 
Mild symptoms 
Moderate 
symptoms; 
limiting instrumental ADL 
Severe 
symptoms; 
limiting self care ADL 
 - 
 - 
Peripheral 
motor 
neuropathy 
Asymptomatic; clinical or 
diagnostic 
observations 
only 
Moderate 
symptoms; 
limiting instrumental ADL 
Severe 
symptoms; 
limiting self care ADL 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Peripheral 
sensory 
neuropathy 
Asymptomatic 
Moderate 
symptoms; 
limiting instrumental ADL 
Severe 
symptoms; 
limiting self care ADL 
Life-threatening 
consequences; 
urgent 
intervention indicated 
 - 
Phantom pain 
Mild pain 
Moderate pain; limiting 
instrumental ADL 
Severe pain; limiting self 
care ADL 
 - 
 - 
Presyncope 
 - 
Present 
(e.g., 
near 
fainting) 
 - 
 - 
 - 
Pyramidal 
tract 
syndrome 
Asymptomatic; clinical or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
limiting instrumental ADL 
Severe 
symptoms; 
limiting self care ADL 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Radiculitis 
Mild symptoms 
Moderate 
symptoms; 
medical 
intervention 
indicated; 
limiting 
instrumental ADL 
Severe 
symptoms; 
limiting self care ADL 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Recurrent 
laryngeal 
nerve palsy 
Asymptomatic; clinical or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate symptoms 
Severe 
symptoms; 
medical 
intervention 
indicated 
(e.g., 
thyroplasty, vocal cord 
injection) 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Reversible 
posterior 
leukoencephalopathy 
syndrome 
 - 
Moderate 
symptoms; 
limiting instrumental ADL 
Severe 
symptoms; 
limiting self care ADL; 
hospitalization 
Life-threatening 
consequences 
Death 
Seizure 
Brief partial seizure and 
no loss of consciousness 
Brief generalized seizure 
New 
onset 
seizures 
(partial or generalized); 
multiple seizures despite 
medical intervention 
Life-threatening 
consequences; 
prolonged 
repetitive 
seizures 
Death 
Somnolence 
Mild but more than usual 
drowsiness or sleepiness 
Moderate 
sedation; 
limiting instrumental ADL 
Obtundation or stupor 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 

 
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CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Spasticity 
Mild or slight increase in 
muscle tone 
 
Moderate 
increase 
in 
muscle tone and increase 
in 
resistance 
through 
range of motion 
Severe 
increase 
in 
muscle tone and increase 
in 
resistance 
through 
range of motion 
Life-threatening 
consequences; unable to 
move active or passive 
range of motion 
Death 
Spinal 
cord 
compression 
 - 
 - 
Severe 
symptoms; 
limiting self care ADL 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Stroke 
Incidental 
radiographic 
findings only 
Mild 
to 
moderate 
neurologic deficit; limiting 
instrumental ADL 
Severe neurologic deficit; 
limiting self care ADL; 
hospitalization 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Syncope 
 - 
 - 
Fainting; 
orthostatic 
collapse 
 - 
 - 
Tendon 
reflex 
decreased 
Ankle reflex reduced 
Ankle reflex absent; other 
reflexes reduced 
Absence of all reflexes 
 - 
 - 
Transient 
ischemic 
attacks 
Mild 
neurologic 
deficit 
with or without imaging 
confirmation 
Moderate 
neurologic 
deficit with or without 
imaging confirmation 
 - 
 - 
 - 
Tremor 
Mild symptoms 
Moderate 
symptoms; 
limiting instrumental ADL 
Severe 
symptoms; 
limiting self care ADL 
 - 
 - 
Trigeminal 
nerve 
disorder 
 
Asymptomatic; clinical or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
limiting instrumental ADL 
Severe 
symptoms; 
limiting self care ADL 
 - 
 - 
Trochlear 
nerve 
disorder 
 
Asymptomatic; clinical or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
limiting instrumental ADL 
Severe 
symptoms; 
limiting self care ADL 
 - 
 - 
Vagus nerve disorder 
 
Asymptomatic; clinical or 
diagnostic 
observations 
only; 
intervention 
not 
indicated 
Moderate 
symptoms; 
limiting instrumental ADL 
Severe 
symptoms; 
limiting self care ADL 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
Vasovagal reaction 
 - 
 - 
Present 
Life-threatening 
consequences; 
urgent 
intervention indicated 
Death 
 
 
 

 
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Appendix 18.4 References  
 
1  
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50 
 
 
 

 
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18.5 
Patient and Physician-Reported Outcomes Instruments 
 
a. 
European Organization for Research and Treatment of Cancer (EORTC) QLQ-
CIPN20 (CIPN-20) (1)  
 
The S1714 EORTC QLQ-CIPN20 is a 20-item questionnaire that evaluates CIPN 
using 3 subscales that assess sensory (9 items), motor (8 items), and autonomic 
(3 items) symptoms and functioning with each item measured on a 1-4 scale (1, 
not at all; 4, very much). The sensory subscale raw scores range from 1 to 36.  The 
CIPN-20 subscale raw scores are linearly converted to a 0-100 scale such that a 
high score corresponds to a worse condition or more symptoms.  This 
questionnaire has been extensively used in prior clinical trials evaluating 
interventions for treatment of CIPN.  The questionnaire is available in English and 
Spanish.  Assessment will occur at baseline prior to registration and beginning 
chemotherapy, 4 weeks, 8 weeks, and 12 weeks (± 14 days), at 24 weeks, 52 
weeks (± 28 days), and at 104 weeks (2 years) and 156 weeks (3 years) (± 90 
days) as outlined in Section 9.0.  Efforts should be made to perform the 4-week, 
8-week, and 12-week assessments on a day of taxane-treatment that falls within 
the study window period and prior to taxane administration.  The questionnaire 
takes approximately 2-5 minutes to complete. 
 
b. 
Patient-Reported Outcomes Measurement Information System 29 (PROMIS-29) 
(2)  
 
The S1714 Patient-Reported Outcomes Measurement Information System 29 
(PROMIS-29) is a well validated assessment tool that offers both qualitative and 
quantitative measures of health-related quality of life. The PROMIS-29 includes 29 
questions evaluating areas of physical function, anxiety, depression, fatigue, 
sleep, social functioning, and pain interference. The PROMIS-29 assesses 
severity levels of symptoms and their effect on the patient’s functioning. The 
questionnaire is available in English and Spanish.  Patients will complete the 
questionnaire at baseline prior to registration and beginning chemotherapy, then 4 
weeks, 8 weeks, and 12 weeks (± 14 days), and at 24 weeks and 52 weeks (± 28 
days) as outlined in Section 9.0.  Efforts should be made to perform the 4-week, 
8-week, and 12-week assessments on a day of taxane-based treatment that falls 
within the study window period and prior to taxane administration.  The 
questionnaire takes approximately 6-14 minutes to complete.   
 
c. 
Godin-Shephard Leisure-Time Physical Activity Questionnaire (GSLTPAQ) (3,4) 
 
The S1714 Godin-Shephard Leisure-Time Physical Activity Questionnaire is a 
brief 4 item self-administered questionnaire of usual leisure-time exercise habits 
over a typical 7-day period.  The Leisure Score Index (LSI) is calculated based on 
the first 3 questions.  The LSI scores can be used to classify respondents into 
active (LSI > 24) and insufficiently active (LSI < 23) categories.  The questionnaire 
is available in English and Spanish.  (5)  Patients will complete the questionnaire 
at baseline prior to registration and beginning chemotherapy, then 4 weeks, 8 
weeks, and 12 weeks (± 14 days), and at 24 weeks and 52 weeks (± 28 days) as 
outlined in Section 9.0.  Efforts should be made to perform the 4-week, 8-week, 
and 12-week assessments on a day of taxane-treatment that falls within the study 
window period and prior to taxane administration.  The questionnaire takes less 
than 5 minutes to complete and has been used in several cancer survivor studies 
as a measure of physical activity.   
 
 

 
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d. 
Visual Analog Toxicity Score and Patient Reported Symptom (and Side Effect) 
Burden Score 
 
For the physician, the Visual Analog Toxicity Score is a single question asking the 
physician to rate how the physician feels the patient’s disease and treatment 
affects their daily life on a scale from 0 (no symptoms and no effect on life) to 10 
(severe effects of treatment and patient would rather be dead).  At baseline, the 
instrument is incorporated into the S1714 Onstudy Form; at follow-up, the 
instrument appears on the S1714 Follow-Up Physician Assessment Form. 
 
For the patient, the Symptom Burden Score at baseline contains one question to 
assess how cancer symptoms affect the patient’s life (scale 0 [no burden at all] to 
10 [a great burden]); this is submitted on the S1714 Baseline Patient Reported 
Symptom Burden Questionnaire.  At follow-up, the Symptom Burden Score 
contains five questions: 1) to assess burden of side effects of cancer treatment on 
life (scale 0 [no burden at all] to 10 [a great burden]), 2) to assess severity of side 
effects from cancer treatment (scale 0 [no side effects]) to 10 [side effects 
extremely severe and unbearable]), 3) to assess tolerability of side effects for set 
time periods (yes/no), 4) to assess level at which treatment would be considered 
intolerable (scale 0 [side effects not severe at all] to 10 [side effects extremely 
severe and unbearable]), and 5) to assess the burden of cancer symptoms and 
treatment symptoms (scale 0 [no burden at all] to 10 [a great burden]).  Responses 
to this questionnaire will be submitted via the S1714 Follow-up Patient Reported 
Symptom and Side Effect Burden Questionnaire.  Baseline and Follow-up patient 
questionnaires are available in English and Spanish. 
 
The patient and physician will complete the baseline questionnaire prior to 
registration and prior to the start of chemotherapy, then patient and physician will 
complete the follow-up questionnaires on the same day as taxane-based 
chemotherapy at 4 weeks, 8 weeks, and 12 weeks (± 14 days), and at 24 weeks 
and 52 weeks (± 28 days) as outlined in Section 9.0.  Efforts should be made to 
perform the 4-week, 8-week, and 12-week assessments on a day of taxane-based 
treatment that falls within the study window period and prior to taxane 
administration.  The questionnaire takes less than 2-3 minutes for the patient to 
complete and 1-2 minutes for the physician to complete.   
 
e. 
Patient-Reported Outcomes version of the Common Terminology criteria for 
Adverse Events (PRO-CTCAE) (6)  
 
The US National Cancer Institute’s Patient-Reported Outcomes version of the 
Common Terminology criteria for Adverse Events (PRO-CTCAE [CTCAE Version 
5.0]) assesses 78 adverse events by self-report with 124 items.  Each item uses a 
plain language term for the adverse event, the attribute of interest, and the 
standard recall period of “the past 7 days”.  The tool has been validated in a large, 
heterogeneous US sample of patients. The following five items will be assessed: 
1) severity of numbness & tingling, 2) interference caused by numbness & tingling, 
3) frequency of general pain, 4) severity of general pain, and 5) interference of 
general pain.  The questionnaire is available in English and Spanish.  Responses 
to this questionnaire will be submitted via the S1714 PRO-CTCAE Form.  Patients 
will complete the questionnaire at baseline prior to registration and beginning 
chemotherapy, then on the same day as taxane-containing chemotherapy at 4 
weeks, 8 weeks, and 12 weeks (± 14 days), at 24 weeks and 52 weeks (± 28 days), 
and at 104 weeks (2 years) and 156 weeks (3 years) (± 90 days) as outlined in 
Section 9.0.  Efforts should be made to perform the 4-week, 8-week, and 12-week 
assessments on a day of taxane-treatment that falls within the study window period 
and prior to taxane administration.  The questionnaire takes approximately 3-5 
minutes to complete. 

 
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f. 
National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-
CTCAE) Grading Scale (7) 
 
The NCI-CTCAE is a subjective method to evaluate CIPN performed by a 
healthcare professional. The treating physician will grade the subject’s 
dysesthesia, paresthesia, neuralgia, peripheral sensory neuropathy, and 
peripheral motor neuropathy on a scale of 0 to 5 depending on the severity. The 
advantage of the NCI-CTCAE is that the assessment is quick and easy for 
providers to perform, (8) but it is limited by the subjectivity of interpretation, lack of 
detail about location, type, and severity of impairment, narrow scoring range, and 
lack of direct patient involvement in rating/reporting. (9) The investigators will be 
able to compare patient reported neuropathy measures (CIPN-20, PROMIS-29 
pain scale, PRO-CTCAE [CTCAE Version 5.0]) to the physician assessed grading.  
CTCAE data will be collected at baseline and reported on the S1714 Baseline 
Physician CTCAE Assessment Form, and then collected and reported on the 
S1714 Solicited Neuropathy Events Form on the same day as taxane-containing 
chemotherapy at 4 weeks, 8 weeks, and 12 weeks (± 14 days), at 24 weeks and 
52 weeks (± 28 days), and at 104 weeks (2 years) and 156 weeks (3 years) (± 90 
days) as outlined in Section 9.0.  Efforts should be made to perform the 4-week, 
8-week, and 12-week assessments on a day of taxane-treatment that falls within 
the study window period and prior to taxane administration.  A table of the nervous 
system disorders category of the CTCAE is included in Section 18.4 
 
g. 
Functional Assessment of Cancer Therapy/ Gynecologic Oncology Group 
Neurotoxicity (FACT/GOG-NTX-4) 
 
 
The FACT/GOG-NTX-4 is a patient reported outcome measure to evaluate 
neurotoxicity symptoms.  This questionnaire includes the first 4 items from the (10)  
11-item FACT/GOG-NTX and assesses numbness or tingling and discomfort in 
the hands and feet over the recall period of the “past 7 days”. Each item is scored 
from 0-4 (corresponding to “Not at all” to “Very much”). The total score is the sum 
of the scores for the 4 items multiplied by 4 and divided by the number of items 
answered (range, 0-16). The questionnaire is available in English and Spanish.  
Responses to this questionnaire will be submitted via the S1714 FACT-GOG-NTX-
4 Form.  Patients will complete the questionnaire at baseline and beginning 
chemotherapy, then on the same day as taxane-containing chemotherapy at 12 
weeks (± 14 days), at 24 weeks and 52 weeks (± 28 days), and at104 weeks (2 
years) and 156 weeks (3 years) (± 90 days) as outlined in Section 9.0.  Efforts 
should be made to perform the 12-week assessments on a day of taxane-
treatment that falls within the study window period and prior to taxane 
administration.  The questionnaire takes approximately 2-3 minutes to complete.  
 
 

 
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Appendix 18.5 References
 
1  
Postma TJ, Aaronson NK, Heimans JJ, et al. The development of an EORTC quality of life 
questionnaire to assess chemotherapy-induced peripheral neuropathy: the QLQ-CIPN20. 
European journal of cancer. 2005;41(8):1135-1139. 
 
2  
Jensen RE, Potosky AL, Reeve BB, et al. Validation of the PROMIS physical function measures in 
a diverse US population-based cohort of cancer patients. Quality of life research: an international 
journal of quality of life aspects of treatment, care and rehabilitation. 2015;24(10):2333-2344. 
 
3  
Amireault S, Godin G, Lacombe J, Sabiston CM. The use of the Godin-Shephard Leisure-Time 
Physical Activity Questionnaire in oncology research: a systematic review. Bmc Med Res Methodol. 
2015;15. 
 
4  
Godin G, Shephard, R. J. . Godin Leisure-Time Exercise Questionnaire. Medicine and science in 
sports and exercise. 1997;29:S36-S38. Godin G, Shephard, R. J. . Godin Leisure-Time Exercise 
Questionnaire. Medicine and science in sports and exercise. 1997;29:S36-S38. 
 
5  
Cancela Carral JM, Lago Ballesteros J, Ayan Perez C, Mosquera Morono MB. Analysis of the 
reliability and validity of three self-report questionnaires to assess physical activity among Spanish 
adolescents. Gac Sanit. 2016;30(5):333-338. 
 
6  
Dueck AC, Mendoza TR, Mitchell SA, et al. Validity and Reliability of the US National Cancer 
Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse 
Events (PRO-CTCAE). JAMA oncology. 2015;1(8):1051-1059. 
 
7  
Services USDoHaH. Common Terminology Criteria for Adverse Events (CTCAE). 2009. 
 
8  
Cavaletti G, Frigeni B, Lanzani F, et al. Chemotherapy-Induced Peripheral Neurotoxicity 
assessment: a critical revision of the currently available tools. European journal of cancer. 
2010;46(3):479-494. 
 
9  
Cavaletti G, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity. Nature reviews 
Neurology. 2010;6(12):657-666. 
 
10  
Psychometric evaluation of the Functional Assessment of Cancer Therapy/Gynecologic Oncology 
Group-Neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy. 
EA Calhoun, EE Welshman , C-H Change, etc. PMID: 14675309. Int J Gynecol Cancer. Nov-Dec 
2003;13(6):741-8. doi: 10.1111/j.1525-1438.2003.13603. 
 
 
 
 

 
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18.6 
Causes of Neuropathy (1,2) 
 
a. 
Diabetic neuropathy 
 
b. 
Idiopathic neuropathy (also called cryptogenic neuropathy) 
 
c. 
Chronic inflammatory demyelinating polyradiculoneuropathy 
 
d. 
Neuropathy associated with B12 deficiency 
 
e. 
Neuropathy associated with other vitamin or mineral deficiency (i.e. Niacin 
deficiency (pellagra), B1 deficiency, B6 deficiency, Vitamin D deficiency, Copper 
deficiency, Vitamin E deficiency, etc) 
 
f. 
Neuropathy associated with alcohol abuse 
 
g. 
Charcot Marie Tooth 
 
h. 
Hereditary neuropathy (sensory and autonomic neuropathy, motor neuropathy, or 
with tendency to pressure palsy) 
 
i. 
Neuropathy associated with a genetic disorder (Adrenomyeloneuropathy, MNGIE 
[mitochondrial neuropathy, with gastrointestinal symptoms and encephalopathy], 
NARP [neuropathy ataxia retinal pigmentosa], CANOMAD [chronic ataxic 
neuropathy, with ophthalmoplegia, monoclonal protein, cold agglutins and 
disialosyl antibodies], etc) 
 
j. 
Amyloid associated neuropathy (Transthyretin familial amyloid polyneuropathy, AL 
amyloidosis, POEMS (polyneuropathy, organomegaly, endocrinopathy, m protein, 
skin changes) 
 
k. 
Neuropathy associated with other autoimmune disorder (i.e. Anti myelin 
associated glycoprotein (MAG) neuropathy, Anti-sulfatide antibody neuropathy, 
Multifocal motor neuropathy, Guillain barre syndrome, Celiac disease, etc) 
 
l. 
Neuropathy associated with rheumatologic autoimmune disease (i.e. Systemic 
lupus erythematosus, Vasculitis, Sjogren’s disease, Wegener’s granulomatosus, 
Churg-Straus, cryoglobulinemia, Sarcoidosis, Rheumatoid arthritis, etc) 
m. 
Toxic neuropathy (i.e. Pyridoxine (B6) toxicity, Amiodarone, Colchicine, Isoniazid, 
Dapsone, Phenytoin, disulfiram, Dideoxynucletides, Metronidazole, Nitrofurantoin, 
Arsenic, Lead, Mercury, Thallium, Acrylamide, N-hexane, etc) 
 
n. 
Neuropathy associated with infectious etiology (i.e. HIV, Leprosy, Lyme disease, 
Hepatitis C, Diphtheria, etc) 
 
o. 
Paraneoplastic neuropathy (i.e. associated with Anti-hu antibodies or Anti-CV2 
(crmp5) antibodies, etc) 
 
p. 
Critical illness neuropathy 
 
q. 
Uremic Neuropathy 
 
r. 
Neuropathy associated with thyroid disease (Hyperthyroidism or Hypothyroidism) 
 
s. 
Other cause of neuropathy 
 
t. 
Unknown cause of neuropathy 
 
 
 

 
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Appendix 18.6  References  
 
1  
Peter J Dyck, PK Thomas, eds.  Peripheral Neuropathy.  Philadelphia:  WB Saunders, 2005. 
 
2 
Farhad K, Traub R, Ruzhansky KM, Brannagan TH, 3rd.  Causes of neuropathy in patients referred 
as idiopathic neuropathy.  Muscle Nerve 2016; 53:856-861. [PMID: 26561790] 
 
 
 

 
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18.7 
Foot Diagram 
 
 
 
 
 
 

 
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18.8 
Translational Medicine - Pharmacokinetic Prediction of Taxane-Induced Peripheral 
Neuropathy 
 
a. 
Primary Objectives 
1. 
The primary pharmacokinetic (PK) objective is to confirm the association 
between paclitaxel maximum concentration (Cmax) at the end of first 
infusion and the occurrence of peripheral neuropathy (PN) in patients 
receiving weekly 1-hour paclitaxel infusions of 80 mg/m2. 
 
b. 
Secondary Objectives 
1. 
Investigate the association between paclitaxel Cmax at the end of first 
infusion and the occurrence of PN in patients receiving other paclitaxel 
regimens. 
 
2. 
Investigate the association between docetaxel Cmax at the end of first 
infusion and the occurrence of PN in patients receiving any docetaxel 
regimen. 
 
c. 
Other Objectives 
1. 
Investigate the association between paclitaxel or docetaxel Cmax at the 
end of first infusion with a secondary phenotype of the cumulative dose at 
occurrence of treatment-limiting PN (dose delay, decrease, or 
discontinuation. 
 
d. 
Background 
Paclitaxel pharmacokinetics, or exposure, has been associated with peripheral 
neuropathy (PN) in retrospective analyses of multiple patient cohorts receiving 
mixed paclitaxel regimens. (1) In a randomized clinical trial of lung cancer patients 
receiving 3-hour paclitaxel infusions in combination with a platinum agent every 2 
weeks, patients randomized to PK-guided paclitaxel had significantly decreased 
PN incidence (grade ≥2 (38% vs. 23%, P < 0.001) and grade ≥3 (9% vs. 2%, P < 
0.001)), with no corresponding decrease in treatment efficacy. (2,3) This confirms 
the importance of exposure from 3-hour paclitaxel infusions in PN occurrence. The 
paclitaxel exposure parameter used within this study was the “Time Above 
Threshold,” which is the number of hours that the patient’s systemic concentration 
remains above a concentration threshold of 0.05 uM (Tc>0.05). This parameter 
requires collection of a sample 16-26 hours after paclitaxel infusion, limiting its 
clinical use. Cmax can be collected at the end of infusion, providing a much more 
clinically feasible biomarker for personalizing taxane treatment.   
 
 

 
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e. 
Rationale and Hypothesis 
Our preliminary data, prospectively collected within an observational clinical trial 
of 60 patients with breast cancer receiving weekly 1-hour infusions of 80 mg/m2 
paclitaxel, confirmed an increased incidence of treatment-limiting PN in patients 
with higher paclitaxel Tc>0.05 (odds ratio (OR)=1.79, 95% confidence interval (CI): 
1.06-3.01, p=0.029) or maximum concentration (Cmax) (OR=2.74, 95% CI: 1.45-
5.20, p=0.002) after the first dose. (4) Importantly, Cmax, conveniently collected 
at the end of infusion, was a stronger predictor of PN than Tc>0.05. The primary 
objective of this analysis is to confirm that paclitaxel Cmax at the end of standard 
1-hour infusion is associated with risk of PN.  
 
There is limited evidence about the relationship between paclitaxel Cmax and PN 
for other commonly used regimens and there is a paucity of data regarding the 
relationship between docetaxel exposure and PN, likely because PN is not typically 
the dose-limiting toxicity of docetaxel. This study provides a unique opportunity to 
investigate the relationships between paclitaxel and docetaxel Cmax in the first 
cycle and the eventual onset of PN, in order to identify evidence-based exposure 
targets for prospective clinical trials of exposure-guided treatment. 
f. 
Eligibility  
All patients enrolled on S1714 with a plasma specimen collected at the end of 
infusion (PK) will be eligible for analysis. 
 
g. 
Experimental Approach and Assays 
 
1. 
Specimen Collection and Timepoints 
 
 
Sites have collected and processed 10 mL of whole blood for PK as 
outlined in Section 15.0. Samples were collected before infusion ends, but 
no more than 10 minutes prior to the end of infusion. 
 
2. 
Laboratory Plan 
 
 
University of Michigan Pharmacokinetics Core 
 
Amit Pai, PharmD, Deputy Director:  
 
Room 3400, Building 520 
 
North Campus Research Complex 
 
1600 Huron Parkway, Ann Arbor, MI 48109 
 
Phone: 734-615-3470 
 
Email: amitpai@med.umich.edu  
 
3. 
Description of Assay or Platform 
 
 
Similar to the previous work of Dr. Hertz (5), plasma samples will be 
analyzed at the UM PK Core (Directors Duxin Sun, PhD, and Amit Pai, 
PharmD) to measure Cmax via a validated liquid chromatography/mass 
spectroscopy assay described below. 
 
 

 
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4. 
Methods 
 
 
Measurement of plasma paclitaxel concentration for all samples in a single 
batch was conducted by the University of Michigan College of Pharmacy 
Pharmacokinetics Core using a liquid chromatography/mass spectroscopy 
assay. Briefly, a Shimadzu HPLC system, and chromatographic 
separation of tested compound was achieved using a Waters XBridge-
C18 column (5 cm × 2.1 mm, 3.5 μm). An AB Sciex QTrap 5500 mass 
spectrometer equipped with an electrospray ionization source (Applied 
Biosystems, Toronto, Canada) in the positive-ion multiple reaction 
monitoring (MRM) mode was used for detection. This assay is highly 
sensitive (lower limit of quantification=5 ng/mL), with a dynamic range of 
5-5000 ng/mL and has inter-batch coefficient of variation <15%. Briefly, 
proteins were removed from plasma samples by precipitation with 
Acetonitrile and centrifugation for 10 minutes at 14,000 rpm. Supernatants 
were collected and further separated using liquid chromatography with 
gradient elution containing mobile phases of water and acetonitrile ACN 
with 1% formic acid. Paclitaxel and internal standard docetaxel were 
detected using multiple reaction monitoring transitions from 854.5 to 286.1 
m/z and 808.6 to 226.0 m/z, respectively. Mass spectrometry parameter r 
optimization was performed using an automated quantitative method 
provided by the manufacturer. The highest signal intensities were obtained 
using a declustering potential of 27.80 V, entrance potential of 9.00 V, 
collision energy of 22.00 V, and collision cell exit potential of 2.5 V. 
Optimized parameters enable quantitation of paclitaxel concentrations 
over the linear range of 5 – 5000 ng/ml. 
 
h. 
Statistical Design and Underlying Assumptions 
1. 
Variable definitions: 
 
 
Primary endpoint (dependent variable): Development of peripheral 
neuropathy (PN) 
The primary endpoint in this study is development of peripheral 
neuropathy, as defined in Section 10.1. We will code patients in binary 
categories; specifically, patients will be coded as a 1 if they have 
experienced an increase of ≥8 points and 0 if they have not. A continuous 
score will also be analyzed, and additional cut points will also be explored. 
 
Secondary endpoints (dependent variable): Treatment limiting PN and 
Cumulative dose at occurrence of treatment-limiting PN 
Dose delay, decrease, or discontinuation is collected on the treatment 
form as a delay, change or discontinuation of the regimen due to 
symptoms of peripheral neuropathy (and not other reasons). We will 
examine the occurrence of treatment-limiting PN as 0 (no) and 1 (yes). 
 
For patients who report one of these outcomes, we will use the total 
reported dose in mg/m2 at the time of the event. 
 
2. 
Main independent variables: 
 
• 
Cmax (maximum concentration) at the end of the first infusion. 
o 
As a continuous measure 
o 
Classified as above/below a cutoff (if a cutoff of interest can be 
identified) 
 
i. 
Data Analysis 

 
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1. 
Analysis population  
 
We expect 60% of eligible patients to enroll to the paclitaxel cohort and 
40% to the docetaxel cohort. All patients are required to have a PK sample 
collected at the end of the first infusion. 
 
2. 
Analytic Plan 
 
a. 
Primary/integrated pharmacokinetic (PK) objective 
 
We will explore the relationship of Cmax with occurrence of PN as 
follows: 
• 
Logistic regression, with PN as the endpoint and Cmax as a 
continuous measure (transformations will be explored if Cmax 
is poorly distributed) 
• 
Linear regression, with the CIPN-20 sensory subscale as the 
endpoint 
and 
Cmax 
as 
a 
continuous 
measure 
(transformations will be explored if the sensory subscale 
and/or Cmax are poorly distributed) 
• 
If possible, using a classification tree to define a cutoff beyond 
which Cmax is associated with occurrence of PN, then using 
this cutoff in a logistic regression model to describe the 
applicable increase in risk. 
 
b. 
Secondary/integrated PK objectives 
 
Similar analyses will be performed within the other Paclitaxel 
regimens. Within the docetaxel regimens, all regimens will be 
examined individually with linear regression, logistic regression 
and a classification tree followed by logistic regression. All 
Paclitaxel regimens and all Docetaxel regimens will be combined 
into single Paclitaxel/Docetaxel analyses to look for a regimen-
independent cutoff for Cmax. 
 
 
 

 
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Appendix 18.8 References 
 
1  
Hertz DL. Exploring pharmacogenetics of paclitaxel- and docetaxel-induced peripheral neuropathy 
by evaluating the direct pharmacogenetic-pharmacokinetic and pharmacokinetic-neuropathy 
relationships. 
Expert 
Opin 
Drug 
Metab 
Toxicol. 
2021 
Feb;17(2):227-239. 
doi: 
10.1080/17425255.2021.1856367. Epub 2021 Jan 6. PMID: 33401943; PMCID: PMC7864890. 
 
2  
Joerger M, von Pawel J, Kraff S, Fischer JR, Eberhardt W, Gauler TC, Mueller L, Reinmuth N, Reck 
M, Kimmich M, Mayer F, Kopp HG, Behringer DM, Ko YD, Hilger RA, Roessler M, Kloft C, Henrich 
A, Moritz B, Miller MC, Salamone SJ, Jaehde U. Open-label, randomized study of individualized, 
pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in 
patients with advanced non-small-cell lung cancer (NSCLC). Ann Oncol. 2016 Oct;27(10):1895-902. 
doi: 10.1093/annonc/mdw290. Epub 2016 Aug 8. PMID: 27502710. 
 
3  
Hertz DL, Kidwell KM, Vangipuram K, Li F, Pai MP, Burness M, Griggs JJ, Schott AF, Van Poznak 
C, Hayes DF, Lavoie Smith EM, Henry NL. Paclitaxel Plasma Concentration after the First Infusion 
Predicts Treatment-Limiting Peripheral Neuropathy. Clin Cancer Res. 2018 Aug 1;24(15):3602-3610. 
doi: 10.1158/1078-0432.CCR-18-0656. Epub 2018 Apr 27. PMID: 29703818; PMCID: PMC6386454. 
 
4  
Hertz DL, Kidwell KM, Vangipuram K, Li F, Pai MP, Burness M, Griggs JJ, Schott AF, Van Poznak 
C, Hayes DF, Lavoie Smith EM, Henry NL. Paclitaxel Plasma Concentration after the First Infusion 
Predicts Treatment-Limiting Peripheral Neuropathy. Clin Cancer Res. 2018 Aug 1;24(15):3602-3610. 
doi: 10.1158/1078-0432.CCR-18-0656. Epub 2018 Apr 27. PMID: 29703818; PMCID: PMC6386454. 
 
5  
Hertz DL, Kidwell KM, Vangipuram K, Li F, Pai MP, Burness M, Griggs JJ, Schott AF, Van Poznak 
C, Hayes DF, Lavoie Smith EM, Henry NL. Paclitaxel Plasma Concentration after the First Infusion 
Predicts Treatment-Limiting Peripheral Neuropathy. Clin Cancer Res. 2018 Aug 1;24(15):3602-3610. 
doi: 10.1158/1078-0432.CCR-18-0656. Epub 2018 Apr 27. PMID: 29703818; PMCID: PMC6386454. 
 
 
 

 
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18.9 
Translational Medicine – Genome-wide Pharmacogenetic Prediction of Taxane-Induced 
Peripheral Neuropathy (TIPN) (Funded R01) 
 
a. 
Objectives 
1. 
Primary 
 
The primary pharmacogenetic (PGx) objective is to examine the 
association of EPHA5 (rs7349683) with sensitivity to TIPN after adjusting 
for systemic exposure and other clinical TIPN predictors.  
 
2. 
Secondary 
 
The secondary PGx objective is to conduct genome-wide association of 
all genotypes and imputed genetic variants with sensitivity to TIPN after 
adjusting for systemic exposure and other clinical TIPN predictors.  
 
3. 
Exploratory 
 
Another objective is to explore whether SNP associations identified in 
primary and secondary objectives are taxane-specific or shared between 
the two drugs. 
  
Additionally, 
exploratory 
analyses 
will 
determine 
whether 
SNP 
associations with TIPN sensitivity are also associated with other TIPN 
endpoints (e.g., CTCAE, quality of life, objective measures) and the 
clinically relevant endpoint of taxane treatment alteration due to TIPN.  
 
Finally, exploratory analyses will determine whether gene-based analyses 
identify genes or genetically-defined pathways that are associated with 
TIPN sensitivity or other TIPN-related endpoints.  
 
b. 
Background 
Many candidate single nucleotide polymorphisms (SNPs) have been reported as 
predictors of taxane-induced PN, however, most of these studies were conducted 
in small, heterogeneous patient cohorts and used liberal statistical cutoffs. The 
strongest candidate SNPs have derived from unbiased genome-wide association 
studies (GWAS) conducted within large, prospective clinical trial cohorts. There 
have been several GWAS of taxane-induced PN, some of which have yielded 
candidate SNPs that have been challenging to replicate. (1, 2) Of these 
candidates, the EPHA genes have been replicated most consistently (3, 4, 5) 
strongly suggesting that the EPHA gene family, which are known to be critical to 
nervous system development and nerve injury repair, is involved in determining 
genetic predisposition to paclitaxel-induced neuropathy.  
 
Paclitaxel systemic concentration is a validated biomarker of TIPN (6). Paclitaxel 
dose reduction to achieve target systemic concentrations decreases TIPN, but 
~10% of patients still experience TIPN (7). These patients have an inherent 
sensitivity to TIPN, likely due to some genetic predisposition. Previous studies 
have been unable to validate genetic TIPN predictors due to their inability to adjust 
for systemic taxane concentrations.   
 
 

 
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c. 
Rationale and Hypothesis 
This large cohort of paclitaxel and docetaxel treated patients (n=1,321) with 
systematically collected, patient-reported PN data provides a unique opportunity 
to validate previously reported candidate SNPs and determine whether validated 
associations are shared between the taxanes or are taxane-specific. This is critical 
for clinical translation, as taxane-specific markers would provide an evidence-
based reason to select one taxane or the other.  
 
Dr. Hertz previously conducted a proof-of-principle analysis in his cohort of 
paclitaxel treated patients with patient-reported TIPN data (UMCC2014.002, 
n=60). (8) First, a Clinical TIPN Prediction Model including patient (age, baseline 
neuropathy), treatment (cumulative paclitaxel dosing), and systemic paclitaxel 
exposure was generated. (9) Then, genetic variants in hereditary neuropathy-
linked genes previously associated with TIPN risk, including EPHA4/5/6, 
ARGHEF10, and FZD3, were sequenced and tested for association with TIPN by 
incorporating them into the Clinical TIPN Prediction Model that adjusted for 
measured systemic paclitaxel concentrations. These studies demonstrated that 
EPHA5 rs7349683, which had been reported to increase TIPN in several studies, 
increases TIPN and this association was only detectable when controlling for other 
TIPN risk factors including systemic exposure. (10) Our hypothesis is that genetic 
variants associated with TIPN sensitivity can be validated (EPHA5 rs7349683) and 
discovered (genome-wide association) in S1714 by following this model of 
integrating PGx into a clinical TIPN Risk Prediction Model.    
 
d. 
Experimental Approach and Assays 
1. 
Sample Collection and Timepoints 
 
 
Sites have processed 10 mL of whole blood for PGx into lavender top 
EDTA tubes as outlined in Section 15.0.  PGx samples were collected at 
baseline (within 14 days after registration to S1714 and prior to first taxane 
administration). 
 
2. 
Laboratory Plan  
 
University of Michigan Advanced Genomics Core  
C560 MSRB II, 1150 W. Medical Center Dr.  
Ph. 734-647-4776 
Fax. 734-936-2622 
Email: okoues@med.umich.edu  
Personnel: Olivia Koues, PhD, Director of UM Advanced Genomics Core 
 
3. 
Description of Assay or Platform 
 
Genome-wide genotyping panel.  
 
 

 
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4. 
Methods 
 
Germline DNA will be genotyped on the Infinium Global Diversity Array 
with Enhanced PGx-8 v1.0 in the University of Michigan Advanced 
Genomics Core. This array contains more than 1.9M variants, including a 
robust genome-wide backbone and comprehensive coverage of 
functionally consequential variants in relevant pharmacogenes based on 
data from CPIC, PharmGKB, and other curated sites. The PI has 
previously conducted GWAS in collaboration with the UM Advanced 
Genomics Core using this same GWAS array. (11,12)  
 
e. 
Statistical Design and Underlying Assumptions 
1. 
Variable definitions: 
 
 
Primary endpoint (dependent variable): Development of peripheral 
neuropathy (PN) 
The primary endpoint in this study is the development of peripheral 
neuropathy, as defined in Section 10.1. We will code patients in binary 
categories; specifically, patients will be coded as a 1 if they have 
experienced an increase of ≥8 points and 0 if they have not. A continuous 
score will also be analyzed, and additional cut points will also be explored. 
 
Secondary endpoints (dependent variable): Treatment limiting PN and 
Cumulative dose at occurrence of treatment-limiting PN 
Dose delay, decrease, or discontinuation is collected on the treatment 
form as a delay, change or discontinuation of the regimen due to 
symptoms of peripheral neuropathy (and not other reasons). We will 
examine the occurrence of treatment-limiting PN as 0 (no) and 1 (yes). 
 
For patients who report one of these outcomes, we will use the total 
reported dose in mg/m2 at the time of the event. 
 
2. 
Main independent variables: 
 
• 
Variant genotype (genotyped or imputed) at each genetic position. 
o 
Assuming a dominant genetic effect 
o 
Assuming an additive genetic effect) 
 
f. 
Data Analysis 
The primary analysis will test the association of each variant with our PN endpoint 
after adjustment for measured systemic taxane concentration and other clinical 
variables associated with PN from the primary analysis of S1714 using a trend test 
assuming an additive genetic effect. Each genotyped or imputed variant that 
passes quality control will be tested for an association using a standard genome-
wide significance threshold (α=5x10-8) in PLINK 2.0. The primary analysis will 
attempt to validate that patients who carry candidate variants in EPHA5 rs7349683 
have increased TIPN risk after accounting for systemic taxane exposure and other 
clinical variables. Prior to analysis, we will review all TIPN pharmacogenetics 
literature to generate a list of candidate variants, particularly those listed previously 
in genes related to hereditary neuropathy, to test in pre-specified, Bonferroni-
corrected confirmatory secondary analyses.  
 
Variants associated with TIPN, and those in linkage disequilibrium, will be 
investigated in secondary analyses to identify functionally consequential causal 
variants using various in silico tools commonly used in GWAS. (13, 14, 15, 16) 

 
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Gene-based approaches will also be explored to identify genes or networks that 
are enriched in our most strongly associated variants including gene set 
enrichment analysis (GSEA) methodology. (17)  
 
Since sample collection of whole blood was mandatory, we have already banked 
samples from over 1100 eligible patients (with more being submitted by SWOG 
sites). Assuming 30% of patients have PN, then for our primary analysis of EPHA5 
rs7349683, we anticipate 80% power to detect a true genetic OR of 1.30 based on 
the known minor allele frequency (MAF) ~35%. For the remaining SNPs, at the 
genome wide significance level (5x10-8), we anticipate 80% power to detect a true 
genetic OR of 1.90, 1.81, and 1.78 for a SNP with MAF of 25%, 35%, or 45%. 
Accordingly, we anticipate sufficient power for our primary analyses and modest 
power for the secondary agnostic screen, while noting that TIPN is an unusual 
phenotype as it has not been subjected to the same degree of evolutionary 
pressures as more typical complex traits such that we can anticipate larger effect 
sizes. 
 
 
 

 
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Appendix 18.9 References 
 
1  
Hertz DL, Owzar K, Lessans S et al. Pharmacogenetic Discovery in CALGB (Alliance) 90401 and 
Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced 
Neuropathy. Clin Cancer Res 2016; 22 (19): 4890-4900. 
 
2  
Baldwin RM, Owzar K, Zembutsu H et al. A genome-wide association study identifies novel loci for 
paclitaxel-induced sensory peripheral neuropathy in CALGB 40101. Clin Cancer Res 2012; 18 (18): 
5099-5109. 
 
3  
Boora GK, Kanwar R, Kulkarni AA et al. Testing of candidate single nucleotide variants associated 
with paclitaxel neuropathy in the trial NCCTG N08C1 (Alliance). Cancer Med 2016; 5 (4): 631-639. 
 
4  
Leandro-Garcia LJ, Inglada-Perez L, Pita G et al. Genome-wide association study identifies ephrin 
type A receptors implicated in paclitaxel induced peripheral sensory neuropathy. Journal of medical 
genetics 2013; 50 (9): 599-605. 
 
5  
Abraham JE, Guo Q, Dorling L et al. Replication of Genetic Polymorphisms Reported to be 
Associated with Taxane-Related Sensory Neuropathy in Early Breast Cancer Patients treated with 
Paclitaxel. 2014. 
 
6  
Hertz DL. Exploring pharmacogenetics of paclitaxel- and docetaxel-induced peripheral neuropathy 
by evaluating the direct pharmacogenetic-pharmacokinetic and pharmacokinetic-neuropathy 
relationships. 
Expert 
Opin 
Drug 
Metab 
Toxicol. 
2021 
Feb;17(2):227-239. 
doi: 
10.1080/17425255.2021.1856367. Epub 2021 Jan 6. PMID: 33401943; PMCID: PMC7864890. 
 
7  
Joerger M, von Pawel J, Kraff S, Fischer JR, Eberhardt W, Gauler TC, Mueller L, Reinmuth N, Reck 
M, Kimmich M, Mayer F, Kopp HG, Behringer DM, Ko YD, Hilger RA, Roessler M, Kloft C, Henrich 
A, Moritz B, Miller MC, Salamone SJ, Jaehde U. Open-label, randomized study of individualized, 
pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in 
patients with advanced non-small-cell lung cancer (NSCLC). Ann Oncol. 2016 Oct;27(10):1895-902. 
doi: 10.1093/annonc/mdw290. Epub 2016 Aug 8. PMID: 27502710. 
 
8  
Marcath LA, Kidwell KM, Vangipuram K et al. Genetic variation in EPHA contributes to sensitivity to 
paclitaxel-induced peripheral neuropathy. Br J Clin Pharmacol 2020; 86 (5): 880-890. doi: 
810.1111/bcp.14192. Epub 12020 Feb 14194. 
 
9  
Hertz DL, Kidwell KM, Vangipuram K, Li F, Pai MP, Burness M, Griggs JJ, Schott AF, Van Poznak 
C, Hayes DF, Lavoie Smith EM, Henry NL. Paclitaxel Plasma Concentration after the First Infusion 
Predicts Treatment-Limiting Peripheral Neuropathy. Clin Cancer Res. 2018 Aug 1;24(15):3602-3610. 
doi: 10.1158/1078-0432.CCR-18-0656. Epub 2018 Apr 27. PMID: 29703818; PMCID: PMC6386454. 
 
10  
Marcath LA, Kidwell KM, Vangipuram K et al. Genetic variation in EPHA contributes to sensitivity to 
paclitaxel-induced peripheral neuropathy. Br J Clin Pharmacol 2020; 86 (5): 880-890. doi: 
810.1111/bcp.14192. Epub 12020 Feb 14194. 
 
11  
Hertz DL, Douglas JA, Miller RM et al. Genome-wide association study of aromatase inhibitor 
discontinuation due to musculoskeletal symptoms. Support Care Cancer 2022; 1 (10): 022-07243. 
 
12  
Hertz DL, Douglas JA, Kidwell KM et al. Genome-wide association study of letrozole plasma 
concentrations identifies non-exonic variants that may affect CYP2A6 metabolic activity. 
Pharmacogenet Genomics 2021; 31 (5): 116-123. doi: 110.1097/FPC.0000000000000429. 
 
 

 
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13  
Flanagan SE, Patch AM, Ellard S. Using SIFT and PolyPhen to predict loss-of-function and gain-of-
function mutations. Genetic testing and molecular biomarkers 2010; 14 (4): 533-537. 
14  
Lin H, Hargreaves KA, Li R et al. RegSNPs-intron: a computational framework for predicting 
pathogenic impact of intronic single nucleotide variants. Genome Biol 2019; 20 (1): 254. doi: 
210.1186/s13059-13019-11847-13054. 
 
15  
Boyle AP, Hong EL, Hariharan M et al. Annotation of functional variation in personal genomes using 
RegulomeDB. Genome Res 2012; 22 (9): 1790-1797. doi: 1710.1101/gr.137323.137112. 
 
16  
The Genotype-Tissue Expression (GTEx) project. Nat Genet 2013; 45 (6): 580-585. doi: 
510.1038/ng.2653. 
 
17  
Subramanian A, Tamayo P, Mootha VK et al. Gene set enrichment analysis: a knowledge-based 
approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 2005; 102 (43): 
15545-15550. doi: 15510.11073/pnas.0506580102. Epub 0506582005 Sep 0506580130. 
 
 
 

 
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18.10 
Translational Medicine – Nutrient Prediction of Taxane-Induced Peripheral Neuropathy 
(TIPN) (Funded R01) 
 
a. 
Objectives 
1. 
Primary 
 
Evaluate the hypothesis that pre-treatment vitamin D insufficiency is 
associated with the risk of taxane-induced peripheral neuropathy.  
 
2. 
Secondary 
 
a. 
Evaluate the hypothesis that pre-treatment histidine level is 
associated with the risk of taxane-induced peripheral neuropathy. 
 
b. 
Evaluate the hypothesis that pre-treatment sphingomyelin 
42:6;O2 level is inversely associated with the risk of taxane-
induced peripheral neuropathy.  
 
c. 
To explore pre-treatment metabolomic signatures that predict 
taxane-induced peripheral neuropathy   
 
b. 
Background 
A pre-specified objective of S1714 was to collect samples in anticipation of future 
assessment of biomarkers including kinetics, genetics, and metabolomics. In prior 
work conducted in a cohort of 60 paclitaxel treated patients, Dr. Hertz 
demonstrated that patients who have vitamin D insufficiency (<20 ng/mL, n=15) 
have greater increase in patient-reported neuropathy during paclitaxel treatment 
(36.39 vs. 16.29, p=0.035) (1), which he then confirmed in a retrospective analysis 
of the prospective SWOG S0221 cohort. (2) 
 
Dr. Hertz then conducted NMR metabolomics analysis of pre-treatment blood 
samples, which identified three amino acids that were inversely associated with 
patient-reported neuropathy severity, of which the strongest association was for 
histidine (r=-0.38, p=0.008). (3) He is currently analyzing these amino acids in 
S0221 using ACS funding.  
 
Lipidomics is a subtype of metabolomics that focuses on circulating lipid levels. 
Our lipidomics analysis quantified 821 lipids, of which 18 were associated with 
TIPN severity (false discovery rate (FDR)<0.05), including a shorter-chain 
sphingomyelin SM 42:6;O2 (β=3.5, 95% CI: 1.8, 5.1, p<0.001, FDR=0.04, 
unpublished data). Other investigators have reported that baseline and on-
treatment concentrations of shorter-chain sphingomyelin (34:1;O2) and 1-
deoxysphinganine were associated with vincristine- and paclitaxel-induced 
neuropathy. (4, 5) 
 
We will attempt to validate these prior findings and conduct further neuropathy 
biomarker discovery using this large cohort with uniquely detailed neuropathy 
phenotype data and banked biosamples.  
 
 

 
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c. 
Rationale and Hypothesis 
This large cohort of paclitaxel and docetaxel treated patients (n=1,321) with 
systematically collected, patient-reported PN data provides a unique opportunity 
to validate previously reported candidate nutrient and metabolomic biomarkers. 
We will attempt to validate our previously identified biomarker candidates and 
conduct additional biomarker discovery using this large cohort of patients with 
comprehensive TIPN data.   
 
d. 
Experimental Approach and Assays 
1. 
Sample Collection and Timepoints 
 
Sites have processed 6 aliquots each of baseline serum and plasma. The 
requested samples for this analysis include 1 aliquot (0.6 mL) of plasma 
for vitamin D and metabolomics.  
 
2. 
Laboratory Plan  
 
Vitamin D Analysis 
Heartland Assays  
Iowa State University Research Park, 2711 S. Loop Dr.,  
Ste 4400, Ames, IA 50010 
Ph.515-296-0909, Fax.515-296-0908 
Email: John.Rathmacher@heartlandassays.com 
Personnel: Andrew J Makowski, Analytical Chemist 
 
Amino Acid Metabolomics and Lipidomics Analyses 
Metabolon, Inc 
617 Davis Dr Suite 100, Morrisville, NC 27560 
Scott Evans (regional Metabolon representative) 
Ph. 734-972-2195 
Email: sevans@metabolon.com 
Personnel: per Metabolon 
 
3. 
Description of Assay or Platform and Methods 
 
Measurement of Serum Vitamin D 
25-hydroxyvitamin D will be measured via HPLC/MS/MS by Heartland 
Assays (6), who are certified through the CDC’s Vitamin D 
Standardization-Certification Program and the DEQAS proficiency 
program.  
 
Measurement of Serum Amino Acids and Lipids 
Amino acid metabolomics and plasma lipidomics will be measured 
simultaneously by Metabolon (Durham, NC). We will use Metabolon’s 
Global Discovery Panel, which identifies >5,000 metabolites including 
>450 metabolites (i.e., amino acids, cofactors, nutrients) and >1,000 lipids 
(i.e., phospholipids, sphingolipids). Metabolon is the industry leader in 
metabolomics analysis, with >3,500 publications using their metabolomics 
panels. Dr. Kathleen Stringer (Co-I of the S1714 R37) is a metabolomics 
expert who has recent experience analyzing Metabolon data.                                              
 

 
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e. 
Statistical Design and Underlying Assumptions 
1. 
Variable definitions: 
 
 
Primary endpoint (dependent variable): Development of peripheral 
neuropathy (PN) 
The primary endpoint in this study is development of peripheral 
neuropathy (PN), as defined in Section 10.1. We will code patients in 
binary categories; specifically, patients will be coded as a 1 if they have 
experienced an increase of ≥8 points and 0 if they have not. A continuous 
score will also be analyzed, and additional cutpoints will also be explored. 
 
Secondary endpoints (dependent variable): Treatment limiting PN and 
Cumulative dose at occurrence of treatment-limiting PN 
Dose delay, decrease, or discontinuation is collected on the treatment 
form as a delay, change or discontinuation of the regimen due to 
symptoms of peripheral neuropathy (and not other reasons). We will 
examine the occurrence of treatment-limiting PN as 0 (no) and 1 (yes). 
 
For patients who report one of these outcomes, we will use the total 
reported dose in mg/m2 at the time of the event. 
 
2. 
Main independent variables: 
 
• 
Vitamin D  
o 
Deficiency defined by <20 ng/mL  
o 
Measured concentration on a continuous scale 
 
• 
Histidine  
o 
Measured concentration on a continuous scale 
 
• 
Sphingomyelin 42:6;O2  
o 
Measured concentration on a continuous scale 
 
 
f. 
Data Analysis 
Primary Objective 1: To assess whether pre-treatment VitD insufficiency (<20 
ng/mL) is associated with PN, we will use logistic regression to regress PN status 
on dichotomous VitD insufficiency. Significance will be called at the 2-sided α=0.05 
level using a 1-df test. Assuming that the rate of PN is approximately 30% in 
patients without VitD insufficiency and that 35% (350) patients are VitD insufficient 
prior to treatment, then we anticipate 80% power to detect a relative risk of 1.29.  
 
Secondary Objective 1: To assess whether pre-treatment histidine levels are 
inversely associated with PN, we will use logistic regression to regress PN status 
on quantitative histidine levels, again using a 1-df test at the 2-sided α=0.05 level. 
Then assuming population risk of PN of 30%, we anticipate 80% power to detect 
relative risks of 1.21, 1.22, and 1.23 per standard deviation increase in histidine 
levels if the observed proportion of patients with PN is 35%, 30% and 25%, 
respectively. 
 
Secondary Objective 2: To assess whether pre-treatment sphingomyelin 42:6;O2 
levels are associated with PN, we will use logistic regression to regress PN status 
on quantitative sphingomyelin 42:6;O2 levels, again using a 1-df test at the 2-sided 

 
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α=0.05 level. Then assuming population risk of PN of 30%, we anticipate 80% 
power to detect relative risks of 1.21, 1.22, and 1.23 per standard deviation 
decrease in sphingomyelin 42:6;O2 levels if the observed proportion of patients 
with PN is 35%, 30% and 25%, respectively. 
 
Secondary Objective 3: To further discover potential pre-treatment metabolomic, 
lipidomic, and proteomic signatures that predict PN, we will apply sure-
independence screening(61) to reduce the number of potential metabolites, lipids 
and proteins. Then we will use sparse penalized regression to regress PN status 
on the remaining metabolites and proteins, using cross-validation to select the 
regularization parameters. The regression coefficients will be used as weights to 
construct the final signature. The in-sample prediction error and the (doubly) cross-
validated prediction error will serve as theoretical upper and lower-bounds on the 
true prediction error. As secondary analysis, we will consider the use of alternative 
tree-based, margin-based, and boosting classifiers. Separate analyses will be 
conducted focused on targeted and named proteins. 
 
For all analyses, we will carefully consider adjustment for covariates, including age, 
diabetes, taxane regimen, and relative dose intensity, and potential technical 
confounders (e.g. batch variables). Continuous variables will be carefully 
transformed to encourage normality. Alternative, including robust and rank based, 
approaches will be considered in the situation in which regression models are 
unstable or when distributional assumptions are violated. Possible nonlinearity and 
interactive effects will be considered.  
 
 
1.  
Jennaro TS, Fang F, Kidwell KM, Smith EML, Vangipuram K, Burness ML, et al. Vitamin D deficiency 
increases severity of paclitaxel-induced peripheral neuropathy. Breast Cancer Res Treat 
2020;180(3):707-14. doi: 10.1007/s10549-020-05584-8. Epub 2020 Mar 12. 
 
2.  
Chen C-SC, Zirpoli G, McCann S et al. Vitamin D insufficiency as a peripheral neuropathy risk factor 
in white and black patients in SWOG 0221. Journal of Clinical Oncology 2022; 40 (16_suppl): 12023-
12023. 
 
3.  
Sun Y, Kim JH, Vangipuram K, Hayes DF, Smith EML, Yeomans L, et al. Pharmacometabolomics 
reveals a role for histidine, phenylalanine, and threonine in the development of paclitaxel-induced 
peripheral neuropathy. Breast Cancer Res Treat 2018 doi 10.1007/s10549-018-4862-3. 
 
4.  
P. Verma, J. Devaraj, J. L. Skiles, T. Sajdyk, R. H. Ho, R. Hutchinson, E. Wells, L. Li, J. Renbarger, 
B. Cooper and D. Ramkrishna: A Metabolomics Approach for Early Prediction of Vincristine-Induced 
Peripheral Neuropathy. Sci Rep., 10(1), 9659. doi: 10.1038/s41598-020-66815-y. (2020)  
 
5.  
R. Kramer, J. Bielawski, E. Kistner-Griffin, A. Othman, I. Alecu, D. Ernst, D. Kornhauser, T. 
Hornemann and S. Spassieva: Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral 
neuropathy. FASEB J., 29(11), 4461-72. doi: 10.1096/fj.15-272567. Epub 2015 Jul 21. (2015)  
 
6.  
Makowski AJ, Rathmacher JA, Horst RL, Sempos CT. Simplified 25-Hydroxyvitamin D 
Standardization and Optimization in Dried Blood Spots by LC-MS/MS. Journal of AOAC International 
2017;100(5):1328-36 doi 10.5740/jaoacint.17-0086. 
 

 
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18.11 
Imaging Study – Personalized Taxane Infusion Rate Recommendations to Reduce 
Neuropathy Risk in Patients with Low Skeletal Muscle Area 
 
a. 
Objectives 
1. 
Primary:  
 
Estimate SMA-based taxane infusion rates for 1-hour paclitaxel (Pac1h) 
and docetaxel (Doc1h) to prevent supratherapeutic Cmax and reduce 
TIPN risk in female patients with breast cancer. 
 
2. 
Secondary 
 
a. 
Estimate SMA-based taxane infusion rates for other regimens 
(i.e., 3-hour paclitaxel), tumor types (i.e., lung, ovarian), and sexes 
(males) to prevent supratherapeutic Cmax and reduce TIPN risk.  
 
b. 
Generate a longitudinal TIPN prediction model to simulate the 
potential TIPN reduction from SMA-based personalized taxane 
infusion rate dosing.  
 
b. 
Background 
Approximately 70% of patients who receive taxanes (e.g., paclitaxel, docetaxel) 
are affected by taxane-induced peripheral neuropathy (TIPN), which diminishes 
long-term functional ability and quality of life. Since there are no effective TIPN 
treatments, ~25% of patients require treatment alterations (e.g., delay, decrease, 
discontinue dosing) that compromise efficacy. Taxanes are dosed by body surface 
area and typically infused over one hour: paclitaxel 80 mg/m2 (Pac1h), docetaxel 
75 mg/m2 (Doc1h). Patients with higher systemic paclitaxel concentrations at the 
end of infusion (Cmax) experience 
greater TIPN (1). Reducing paclitaxel 
doses in patients with supratherapeutic 
concentrations (i.e., therapeutic drug 
monitoring) reduces TIPN (2), but 
measuring concentrations is clinically 
impractical and reducing doses could 
reduce efficacy. There is a need to 
develop clinically practical personalized 
dosing strategies that reduce TIPN 
while preserving full taxane dosing and 
efficacy. 
 
Patients with the same BSA can have 
different body composition, including 
differences in skeletal muscle area 
(SMA) that can be estimated from 
clinical computed tomography (CT) 
scans. Our UM Rogel Pilot (UMCC 
2015.02, NCT02338115, PI: DL Hertz) enrolled 59 patients with breast cancer 
receiving adjuvant weekly 80 mg/m2 Pac1h. Higher Cmax was associated with 
greater TIPN-induced treatment alteration (n=19, 32%, OR = 2.74, p = 0.002) (1). 
Our modeling estimated the supratherapeutic Cmax, above which the risk of TIPN-
induced treatment alteration was unacceptable (>25%), is 2,885 ng/mL (Figure 1) 
(1).  
 
Figure 
1: 
Supratherapeutic 
Cmax=2,885 ng/mL for Pac1h, above 
which risk of TIPN is >25%. Adapted 
from Ref 1. 

 
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Patients with lower skeletal muscle area (SMA), also referred to as “sarcopenia,” 
have higher rates of chemotherapy toxicity, including taxanes (3). 39 (66%) 
participants in our Pilot had a clinical CT scan to estimate >200 body composition 
measures using an automated image analysis process developed by the UM 
Morphomics Analysis Group. The optimal Pac1h pharmacokinetic model included 
SMA at the Thoracic 11 (T11) vertebra as a covariate on volume of distribution, 
which determines Cmax; patients with lower SMA have higher paclitaxel Cmax, likely 
explaining their higher risk of toxicity.  
 
The SMA-Cmax model was used to estimate the likelihood of exceeding 
supratherapeutic Cmax (i.e., 2,885 ng/mL) for a patient with any physiological SMA 
receiving the standard Pac1h 80 mg/m2 infusion. Using an acceptability threshold 
of <50% risk of exceeding supratherapeutic Cmax (Figure 2, horizontal hatched 
line), patients with SMA<7080 mm2 have unacceptable risk (Solid curved Line). 
We then simulated the risk of supratherapeutic Cmax in patients with any 
physiological SMA who received the standard 80 mg/m2 dose over a slower 2-hour 
(Dashed Line) or 3-hour (Dotted Line) infusion. Based on these simulations, 
patients with SMA 4907-7080 mm2 (~23% of age-adjusted females) should receive 
a 2-hour infusion and patients with sarcopenic SMA (SMA<4907 mm2, ~2%) 
should receive a 3-hour infusion of paclitaxel 80 mg/m2 to avoid supratherapeutic 
Cmax and unacceptable TIPN risk. (4) 
 
Slowing taxane infusion rates in patients with low SMA, based on existing CT 
scans, is a clinically practical personalized dosing strategy that could reduce TIPN 
while preserving full dosing (i.e., 80 mg/m2). An ongoing Interventional 
Pharmacokinetics study is investigating whether slowing taxane infusion rates in 
 
Figure 2: Model simulations were conducted to estimate SMA-based 
infusion rate recommendations for paclitaxel 80 mg/m2. The threshold 
for supratherapeutic Cmax was set at 50% (horizontal hatched line). 
Patients with SMA>7,080 mm2 should receive a standard 80 mg/m2 1-
hour infusion. Extended 2-hour and 3-hour infusions of 80 mg/m2 are 
recommended for patients with Low-SMA (4,907-7,080 mm2) and 
sarcopenic SMA (<4,907 mm2), respectively. 
 

 
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patients with low SMA receiving Pac1h normalizes their taxane Cmax (UMCC 
2021.109, PI: DL Hertz). This SWOG proposal will allow us to validate our SMA-
based Pac1h dosing recommendations in patients with breast cancer and extend 
this approach to Doc1h and Pac3h, and other tumor types, using SWOG S1714 
data. This preliminary data is critical to design a prospective SWOG trial to 
investigate whether SMA-based taxane infusion rate dosing reduces TIPN and 
treatment alterations, thus preserving treatment efficacy. This would justify using 
this strategy as standard of care to reduce TIPN and improve treatment outcomes 
in patients with cancer. 
 
c. 
Rationale 
Existing clinical CT scans will obtained for S1714 participants and analyzed by the 
UM Morphomics Analysis Group to estimate SMA and other body composition 
metrics (4) to be used in modeling similar to that performed in our Rogel Pilot. All 
other data are already available within the S1714 clinical trial including taxane 
Cmax and TIPN. 
 
d. 
Eligibility 
All S1714 participants (n=1,353) who have a clinical CT scan available at their 
enrolling institution will be eligible, though the primary analysis will be conducted 
in female patients with breast cancer who received Pac1h (n=562) or Doc1h 
(n=489). Clinical CT scans of the chest, abdomen, or thorax within 6 months prior 
or 1 month after S1714 enrollment will be collected for S1714 participants following 
the process used by Co-I Dr. Richard Dunne to obtain CT scans from participants 
on the URCC13059 NCORP trial. One of the highest accruing S1714 sites 
randomly selected n=20 S1714 participants and found 6 (30%) had an evaluable 
CT scan, yielding an estimated n≈400 S1714 participants with evaluable CT scans.  
 
e. 
Clinical Data 
The primary endpoint for our modeling is the taxane Cmax, which we have already 
measured for S1714 participants in the UM Pharmacokinetics Core. In order for 
our group to conduct all of the modeling we propose, we will need the S1714 
primary endpoint data, specifically the sensory subscale of the CIPN20 (CIPN8) 
from baseline to 24-weeks. (5) Additionally, we will need patient (height, weight 
and calculated BSA) and taxane treatment (infusion start and stop time and taxane 
doses administered, pharmacokinetic sample collection time) data for our 
modeling.   
 
f. 
Experimental Approach:  

 
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The experimental approach follows the approach we used in our Rogel Pilot 
(Described in Brief Justification) to model the SMA-Cmax and Cmax-TIPN 
relationships, and use simulations to determine the SMA thresholds below which 
patients require an extended infusion to prevent supratherapeutic Cmax and 
unacceptable TIPN risk (Figure 3).  
The PI, Daniel Hertz, PharmD, PhD, is a clinical pharmacologist with expertise in 
TIPN biomarker analysis and taxane clinical pharmacology. He is the translational 
medicine chair of S1714 and the submitting MPI of a funded R37 (1R37CA277043) 
to conduct TIPN biomarker analyses in S1714. This proposal describes an analysis 
workflow that is nearly identical to that which he already completed in the Rogel 
Pilot for Pac1h (4). He is collaborating with a team of Co-I who have already used 
this process to: collect existing clinical CT scans for an NCORP study (Dr. Richard 
Dunne), analyze CT scans to estimate SMA (Dr. Sven Holcombe), PK modeling 
and simulation to estimate SMA-based infusion rate recommendations (Dr. Amit 
Pai), and the clinical PI of S1714 (Dr. Meghna Trivedi) and co-chair of the SWOG 
Symptom Control and Quality of Life committee (Dr. Lynn Henry).   
 
g. 
Statistical Plan: 
Our primary analysis will use PK modeling to generate SMA-based infusion rate 
recommendations for Pac1h (n=562) and Doc1h (n=489) in females with breast 
cancer with existing clinical CT scans.  
 
S1714 also enrolled n=52 participants who received paclitaxel 175 mg/m2 infused 
over 3-hours, n=123 participants with ovarian or lung cancer, and n=8 males. We 
will use the Cmax data from these participants and attempt to extrapolate from the 
Pac1h SMA-Cmax and Cmax-TIPN models to generate SMA-based taxane infusion 
rate recommendations for Pac3h, and patients with other tumor types and male 
patients in secondary analyses. 
 
The other secondary analysis will use the Cmax-TIPN model to simulate the 
longitudinal effect of SMA-based taxane infusion rate dosing throughout treatment 
on the predicted incidence of TIPN. We anticipate the simulations will support our 
 
Figure 3: Workflow for Preliminary Data (Pac1h) and this SWOG TM Proposal (Pac 1h, Doc1h) to 
estimate SMA-based infusion rates to prevent supratherapeutic Cmax and reduce TIPN risk. 

 
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hypothesis that SMA-based infusion rate dosing will limit the risk of TIPN to <25% 
in all patients.   
 
h. 
Data analysis performed by:  
Image analysis will be performed by Co-I Sven Holcombe and the University of 
Michigan Morphomics Analysis Group within the Department of Surgery: 
https://www.med.umich.edu/surgery/morphomics/, 1150 W. Medical Center Drive, 
3328 Med Sci 1-SPC 5677, Ann Arbor, Michigan 48109, 734.764.7841, 
morphomics@umich.edu 
 
Modeling and simulation will be performed by Yuchen Sun, a PhD candidate being 
advised by Co-Is Drs. Hertz, Pai, and Henry. Dr. Pai conducted the modeling and 
simulation for the Rogel Pilot study described in the preliminary data6 (4). Dr. Henry 
is a co-author on this prior work and co-Chair of the SWOG Symptom Management 
and Survivorship Committee that ran S1714.  
 
Data to be correlated with images: 
Cmax: Measured in plasma samples collected at the end of first infusion in S1714 
(data already exist) 
TIPN: Sensory CIPN8 subscale from CIPN20 collected during SWOG S1714 (data 
already exist) 
i. 
Image Requirements and Timepoints:  
Patients are being asked to provide clinical CT scans that were performed as part 
of standard of care. No new scans will be performed.  The clinical CT scans of the 
chest, abdomen, or thorax performed within 6 months prior or 1 month after S1714 
registration will be submitted via TRIAD.  See Section 15.2 for submission details. 
 
 
 

 
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1  
Hertz DL, Kidwell KM, Vangipuram K et al. Paclitaxel Plasma Concentration after the First Infusion 
Predicts Treatment-Limiting Peripheral Neuropathy. Clin Cancer Res 2018; 24 (15): 3602-3610. 
 
2  
Joerger M, von Pawel J, Kraff S et al. Open-label, randomized study of individualized, 
pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in 
patients with advanced non-small-cell lung cancer (NSCLC). Ann Oncol 2016; 27 (10): 1895-1902. 
 
3  
Shachar SS, Deal AM, Weinberg M et al. Skeletal Muscle Measures as Predictors of Toxicity, 
Hospitalization, and Survival in Patients with Metastatic Breast Cancer Receiving Taxane-Based 
Chemotherapy. Clin Cancer Res 2017; 23 (3): 658-665. doi: 610.1158/1078-0432.CCR-1116-0940. 
Epub 2016 Aug 1153. 
 
4  
Hertz DL, Chen L, Henry NL et al. Muscle mass affects paclitaxel systemic exposure and may 
inform personalized paclitaxel dosing. Br J Clin Pharmacol 2022; 88 (7): 3222-3229. doi: 
3210.1111/bcp.15244. Epub 12022 Feb 15214. 
 
5  
Trivedi MS, Unger JM, Hershman D et al. Abstract PD8-06: Incidence of Acute and Persistent 
Clinically Meaningful Chemotherapy Induced Peripheral Neuropathy in Patients with Early-Stage 
Breast Cancer Receiving Taxane Therapy: SWOG S1714 (NCT# 03939481). Cancer Research 
2023; 83 (5_Supplement): PD8-06-PD08-06.