Optimized Diffusion-Weighted Imaging for the Evaluation of Post-Treatment Squamous Cell Carcinoma in the Neck: Comparative Study With FDG PET/CT
Phase: NA
Conditions: Squamous Cell Carcinoma
Sponsor: Washington University School of Medicine

Title:   
Optimized Diffusion-Weighted Imaging for the Evaluation of Post-
Treatment Squamous Cell Carcinoma in the Neck: Comparative study 
with FDG PET/CT 
NCT#:   
 
NCT04685798 
Protocol Version:   
06/05/2023 

 
 
Title: 
Optimized diffusion-weighted imaging for the evaluation of post-treatment squamous cell 
carcinoma in the neck: Comparative study with FDG PET/CT. 
 
Investigators:  
Gloria J. Guzmán Pérez-Carrillo MD, MSc: Principal Investigator 
Matthew Parsons MD, Assistant Professor of Neuroradiology: Co-Investigator 
Jose Zevallos, MD, MPH, Associate Professor of Otolaryngology: Collaborator 
Sophie Gerndt, MD; Research Coordinator 
Robin Haverman; Research Coordinator 
Esther Lu PhD, Department of Surgery: Statistician 
Hongyu An, PhD, Associate Professor of Radiology: Collaborator 
 
Glossary of Abbreviations 
ASNR= American Society of Neuroradiology 
ADC= apparent diffusion coefficient  
DWI= diffusion-weighted imaging  
fMRI = functional MRI  
MUSE= multiplexed sensitivity encoding algorithm  
QIBA= Quantitative Imaging Biomarkers Alliance 
SCC= squamous cell carcinoma  
WIP= work in progress  
 
 
 
 
Protocol Revisions History 
 
Version 
20May2020 
 
24Aug2020 
 
27Jan2021 
 
7Apr2021 
 
2Feb2023 
 
8Feb2023 
 
5June2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
PI- Guzmán Pérez-Carrillo, GJ 
2
 
 
 
 
 
 
 
Table of Contents 
 
1.0 BACKGROUND AND RATIONALE ...............................................................................3 
2.0 OBJECTIVES .................................................................................................................4 
3.0 PARTICIPANT SELECTION ..........................................................................................4 
 
3.1 Inclusion Criteria .................................................................................................4 
 
3.2 Exclusion Criteria ................................................................................................4 
 
3.3 Inclusion of Women and Minorities .................................................................... 4 
4.0 STUDY PROCEDURES .................................................................................................5 
5.0 ADVERSE EVENT MONITORING AND REPORTING ..................................................8 
 
5.1 Adverse Events (AEs) .........................................................................................8 
 
5.2 Unanticipated Problems ......................................................................................8 
 
5.3 Noncompliance ....................................................................................................8 
 
5.4 Serious Noncompliance .......................................................................................8 
 
5.5 Protocol Exceptions .............................................................................................9 
 
5.6 Reporting to the Human Research Protection Office (HRPO) .............................9 
5.7 Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) 
at Washington University…….………………………………………………………..9 
 
5.8 Time Frame for Reporting Required Events ........................................................9  
 
5.9 Incidental Findings................................................................................................9 
6.0 DATA AND SAFETY MONITORING ...............................................................................9 
7.0 STATISTICAL CONSIDERATIONS................................................................................10 
 
REFERENCES ................................................................................................................... 12 
 
 
 

 
PI- Guzmán Pérez-Carrillo, GJ 
3
1.0 BACKGROUND AND RATIONALE 
Head and neck tumors can be a significant imaging diagnostic challenge. Anatomic imaging 
alone is insufficient to differentiate between post-treatment change and recurrent tumor, as 
both demonstrate increased T2/FLAIR signal and enhancement. Diffusion-weighted sequences 
(DWI) is a more sensitive and specific sequence that can be used to evaluate this tumor, and 
that can more easily differentiate between residual/recurrent tumor and post-treatment change 
(Vandecaveye, 2007). Metabolic imaging with FDG PET/CT is impacted by false-positives in 
the setting of inflammation or post-radiation necrosis and thus, data must be acquired 8-12 
weeks post-treatment to avoid this pitfall. Moreover, PET/CT imaging is less available 
compared to MRI or CT. MRI does not require ionizing radiation, which is an important factor in 
head and neck squamous cell cancer patients, as they have an increased risk of secondary 
tumors such as lung cancer. 
 
MRI systems that include diffusion-weighted imaging (DWI) and apparent diffusion coefficient 
(ADC) measurements hold promise to facilitate differentiation of tumor recurrence from post-
treatment changes and associated complications, since areas of tumor demonstrate restricted 
diffusion and post-treatment changes do not [Chawla, 2009; Friedrich, 2008; Hermans, 2010; 
Jansen 2010; King, 2010 and 2013; Maeda, 2008; Mudana, 2018; Perrone, 2011; 
Vandecaveye, 2007 and 2010]. However, there are multiple pitfalls associated with conventional 
DWI related to artifacts such as fat saturation, distortion, aliasing/ghosting and spatial 
resolution. These limit the utility of this technique. 
 
We propose a longitudinal study evaluating post-treatment changes in patients with squamous 
cell carcinoma (SCC) of the neck using an innovative optimized DWI pulse sequence to 
identify more accurately recurrent tumors as well as early non-responders to therapy. 
Our optimized DWI pulse sequence includes a combination of new improvements in data 
acquisition—, specifically multiband echo planar imaging (MultiBand, Siemens Medical 
Solutions, Erlangen, Germany) and multi-segment K-space readout algorithm (RESOLVE, 
Siemens Medical Solutions, Erlangen, Germany), i.e. SMS/RESOLVE WIP 1051a. The 
multiplexed sensitivity encoding algorithm (the MUSE method pioneered by Dr. Nan-Kuei Chen 
of the University of Arizona, Figure 1) is applied at post processing. Our optimized DWI 
sequence follows QIBA-recommended guidelines. We found that our DWI pulse sequence 
improved quantitative artifact parameters [Guzmán Pérez-Carrillo, 2019] which in turn 
should increase the diagnostic accuracy of our technique.  
 
We plan to enroll 60 biopsy-proven neck SCC patients after treatment with surgery, radiation or 
chemo-radiation.  The Otolaryngology, Head and Neck Surgery physicians and their clinic staff 
will coordinate enrollment. The patients will undergo an optimized research neck DWI protocol 
up to 3 weeks post-treatment and then a standard-of-care 3-6 months post-treatment FDG 
PET/CT examination. The optimized research DWI images will be acquired on a dedicated 
research Siemens 3T Scanner belonging to Washington University’s Center for Clinical Imaging 
Research. The standard-of-care FDG PET/CT will be acquired at one of the Siemens Biograph 
clinical PET/CT units located throughout the Barnes-Jewish Hospital Systems that adhere 
to QIBA FDG PET/CT protocols. We will compare the ADC values (ADCmin and ADCmean) 
from the optimized DWI pulse sequence to FDG PET SUVmax. We will follow patients for 1 year 
to assess their clinical outcomes, including histological results associated with re-biopsy or 
surgery. 
 
 

 
PI- Guzmán Pérez-Carrillo, GJ 
4
2.0 OBJECTIVES 
The Specific Aim of this application is as follows: To compare SUVmax and ADCmean/min 
values to assess the capability of the new DWI pulse sequence to differentiate post-treatment 
change from residual or early recurrent tumor.  
Hypothesis: The optimized research DWI pulse sequence obtained up to3 weeks post 
treatment will accurately identify residual/recurrent tumor, as confirmed by the clinical FDG 
PET/CT obtained at 3-6 months. This would potentially result in a modification of imaging 
follow-up algorithms, increased cost-savings and eliminate radiation exposure to patients 
inherent in PET/CT. This would also result in earlier changes to treatment regimens and 
stratify patients into more or less aggressive tumor response to treatment. The gold-standard 
will be histological tissue where available and/or 1-year clinical and imaging outcomes, 
including imaging outcome measurements such as RECIST 1.1 [De Bree, 2017], PERCIST 
[Joo Hyun, 2016] and iRECIST [Persigehl, 2020]. 
 
 
Figure 1: DWI data obtained from a healthy volunteer with a GE 3 Tesla system and eight-
channel neurovascular array coil. Single-shot EPI-based DWI was obtained: matrix size = 128 
× 128; parallel imaging acceleration factor = 2; field of view = 24 cm × 24 cm; b-value = 1000 
s/mm2. B, High-resolution DWI data obtained with four-shot interleaved EPI pulse sequence 
(matrix size = 256 × 256; field of view = 24 cm × 24 cm; b-value = 1000 s/mm2) and 
reconstructed with our developed MUSE algorithm. 
 
3.0 PARTICIPANT SELECTION  
 
ELIGIBILITY CRITERIA 
 
Inclusion Criteria:  
1) Histologically-proven newly diagnosis or recurrence as indicated by tissue diagnosis of T3 
or T4 squamous cell carcinoma of the head and neck 
2) Must have had or be scheduled for standard-of-care surgical resection, radiation, and/or 
chemo-radiation of the diagnosed squamous cell carcinoma of the head and neck 
3) At least 18 years of age 
4) Patient must be able to understand and willing to sign a written informed consent 
document. 
 
Exclusion Criteria:  
1) Contraindications to MRI, including: 
a. MRI-incompatible implantable devices 
b. severe claustrophobia; and  
2) Pregnant and/or breastfeeding, with women of childbearing potential having a negative 
urine or serum pregnancy test 

 
PI- Guzmán Pérez-Carrillo, GJ 
5
 
Inclusion of Women and Minorities: Both male and female patients and members of all races and 
ethnic groups are eligible for this trial. 
 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center.  
 
The following steps must be taken before registering patients to this study:  
1) confirmation of patient eligibility;  
2) registration of patient in the Siteman Cancer Center database;  
3) assignment of unique patient number (UPN). The research coordinator(s), Robin Haverman 
and/or Rachel Reed will perform these tasks and obtain consent form the patients 
 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the following information:  
1) the patient’s physician’s name;  
2) the patient’s race, sex, and date of birth;  
3) three letters (or two letters and a dash) for the patient’s initials;  
4) a copy of the signed consent form;  
5) a completed eligibility checklist, signed and dated by a member of the study team;  
6) a copy of the appropriate source documentation confirming the patient’s eligibility. Robin 
Haverman and/or Rachel Reed will perform these tasks and obtain informed consent from the 
patients. 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial. 
 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data will be 
recorded with this identification number on the appropriate CRFs. 
 
4.0 STUDY PROCEDURES  
 
IMAGING PLAN  
 
Overview: 60 biopsy-proven neck SCC patients after treatment with surgery, radiation or 
chemo-radiation will be enrolled for this trial.  The Otolaryngology, Head and Neck Surgery 
physicians and their clinic staff will assist in coordinating enrollment. The patients will undergo 
an optimized research neck DWI MRI, up to 3 weeks post-treatment and then a standard-of-
care 3-6 months post-treatment FDG PET/CT examination. (**Note: Patients who do not 
undergo SOC PET/CT at the 3-6 month time point will be considered inevaluable and will be 
replaced.)  Patients who sign the consent form but do not have the MRI will not be considered 
accrued on this study. The optimized DWI images will be acquired on a dedicated research 
Siemens 3T Scanner belonging to Washington University’s Center for Clinical Imaging 
Research. The standard-of-care FDG PET/CT mages will be acquired at one of the Siemens 
Biograph clinical PET/CT units located throughout the Barnes-Jewish Hospital Systems. We will 
compare the ADC values (ADCmin and ADCmean) to the optimized DWI sequence to FDG PET 

 
PI- Guzmán Pérez-Carrillo, GJ 
6
SUVmax. For up to 1 year post-treatment, patients’ medical records will be reviewed after 
scheduled SOC visits r to additionally assess for clinical outcomes. 
 
 
Baseline 
up to 3 Weeks 
Post-Treatment 
3-6 Months Post-
Treatment 
Follow up for up 
to 1 year post-
treatment 
Screening 
X 
 
 
 
Enrollment 
X 
 
 
 
Medical Record 
Review 
X 
X 
X 
X 
DWI MRI 
 
X 
 
 
FDG PET/CT 
 
 
SOC 
 
 
Clinical Data to be Collected 
 
The following clinical data points will be collected and recorded in REDCAP (Please see 
attached data sheet): 
• 
Age 
• 
Birth Gender 
• 
Original Cancer Stage 
 
• 
Date of original diagnosis 
 
• 
Cancer Location 
• 
Cancer Stage  
• 
HPV Status 
 
• 
Cancer Treatment (choice=Surgery)  
• 
Cancer Treatment (choice=Chemotherapy)  
• 
Cancer Treatment (choice=Radiation) 
 
• 
Surgery Date  
• 
Radiation Dosage 
 
• 
Chemotherapy Type/Dosage  
• 
Chemotherapy treatment range 
 
• 
Date of Completion of Initial Treatment 
 
• 
Smoking Pack Year History  
• 
Date of Study MRI 
 
• 
Why enrolled?  
• 
MRI Imaging uploaded 
 
• 
Biopsy Obtained 
 
• 
Pathology confirms recurrence 
 
• 
Date of recurrence diagnosis  
• 
Length of time from MRI to clinical/radiographic progression 
 
• 
Last clinical F/U 
 
 
• 
Last imaging F/U 
 
• 
Treatment after repeat biopsy/surgery 
 
Duration of Imaging:  MRI data to include anatomical MPRAGE volumetric T1, fat-saturated T2-
weighted image (for anatomical localization and cystic/necrotic changes) and optimized research 
DWI sequence will be acquired in 30 minutes. If at any time the constraints of this protocol are 
considered detrimental to the patient’s health and/or the patient no longer wishes to continue 

 
PI- Guzmán Pérez-Carrillo, GJ 
7
imaging, the protocol should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
Post-imaging: While there are no anticipated problems during the research imaging, continuous 
monitoring for any adverse events or abnormal events will occur during imaging.  Once the 
research MRI is complete, the subject will be asked by a member of the study team how they 
are feeling prior to leaving the CCIR.  If for any reason, the subjects is feeling abnormal, Dr. 
Gloria Guzmán or Dr. Matthew Parsons, the on-site neuroradiologist, will be notified and will 
address any adverse events. 
 
Patient Compensation: Subject will receive $100 at the completion of their research DWI MRI 
imaging.  Subjects will be provided compensation by check. 
 
IMAGE ARCHIVING 
 
Our image cloud computer system is the CNDA archive maintained at the Washington 
University School of Medicine, and it will serve as a central repository for all data collected as 
part of this project. Data will be securely transferred from the scanning facilities to CNDA. CNDA 
data are anonymized and can be accessed remotely. 
 
MRI PROCESSING GUIDELINES 
 
Overview: All MRI studies will be blindly evaluated by at least two experienced neuroradiologists 
(Drs. Guzmán and Parsons). If there is an urgent or emergent finding obtained by the research 
MRI study, this will be communicated by one of the neuroradiologists directly to the ENT 
physician for follow up who is caring for the patient, as per normal departmental protocol.  In the 
case of this study, incidental findings are defined as anything not already noted in the medical 
record.  
 
Methodology of MRI Evaluation: The research MRI study of the head and neck will be 
performed on a Siemens 3T MRI Scanner system located in the Center for Clinical Imaging 
Research (CCIR). Multiplanar / multisequence MRI data including the optimized research DWI 
sequence will be acquired. MRI subjects must complete an MRI screening evaluation form 
before entering MRI zone 3 or the scanning room. Images will be anonymized and sent to 
CNDA for archiving after diagnostic reports are complete. All anonymized MRI studies will then 
be blindly evaluated by at least two experienced neuroradiologists (Drs. Guzmán and Parsons). 
MUSE image processing will be applied post-acquisition. 
 
Methodology of ADC Evaluation: The primary tumor, suspicious lesion, and/or area of post-
treatment change will be first identified in the anatomical images and then outlined in the ADC 
sequence by experienced neuroradiologists (Drs. Guzmán and Parsons), excluding areas of 
cystic change and necrosis. If there are multiple lesions, only the dominant lesion with the 
lowest ADC will be utilized for analysis, akin to RECIST criteria. If there is geometric distortion, a 
region of interest will be placed in the undistorted region only. A histogram analysis method will 
be used to examine the distribution of ADC values within each region of interest (ROI). Only 
measurable disease defined as a primary tumor, a suspicious lesion, and/or an area of post-
treatment change measuring at least 0.5 cm in two perpendicular dimensions will be used. 
Technically poor or non-diagnostic MR images will be excluded. ADCmean/min will be 
computed. 
 

 
PI- Guzmán Pérez-Carrillo, GJ 
8
PET/CT IMAGING PROCESSING GUIDELINES 
 
Overview: When the PET/CT is ordered as a clinical workup, a diagnostic report will be issued 
by the Nuclear Medicine Department faculty. Neither Dr. Guzmán nor Dr. Parsons will 
participate in the preparation or issuing of this report. 
 
Methodology of SUV Evaluation: Anonymized FDG PET/CT data from CNDA will be uploaded 
into a MIM workstation (MIM Software Inc., Cleveland, Ohio). Fused MPRAGE/DWI images will 
be used. The region of interest chosen for the evaluation of ADC values will be copied onto the 
FDG CT/PET, and the SUVmax will be measured. While there is significant variability in SUV 
measurements [Kinehan, 2010], the reported literature suggest SUVmax > 9.0 -with interquartile 
range (IQR) 7.4–13.9 and range of 1.5-20.1 - is diagnostic of squamous cell carcinoma 
[Schwartz, 2004; Morand, 2018] for the primary mass and >4.5 for nodal tumor [Paidpally, 
2012]. PET/CT studies are standard of care and are reported as clinical studies. 
 
5.0 ADVERSE EVENT MONITORING AND REPORTING  
 
5.1 Adverse Events (AEs)  
Definition: any unfavorable medical occurrence in a human subject including any abnormal sign, 
symptom, or disease related to this study protocol. For purposes of this research project, AEs 
associated with the MRI will be tracked. 
 
Attribution (Relatedness), Expectedness, and Seriousness: the definitions for the terms listed 
that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP). A copy of this guidance can 
be found on OHRP’s website at: http://www.hhs.gov/ohrp/policy/advevntguid.html. 
 
5.2 Unanticipated Problems  
Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB approved research protocol 
and informed consent document; and (b) the characteristics of the subject population being 
studied; 
 
Related or possibly related to participation in the research (in this guidance document, possibly 
related means there is a reasonable possibility that the incident, experience, or outcome may 
have been caused by the procedures involved in the research); and 
 
Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
5.3 Noncompliance  
Definition: failure to follow any applicable regulation or institutional policies that govern human 
subject research or failure to follow the determinations of the IRB. Noncompliance may occur 
due to lack of knowledge or due to deliberate choice to ignore regulations, institutional policies, 
or determinations of the IRB. 
 
5.4 Serious Noncompliance 
Definition: noncompliance that materially increases risks, and results in substantial harm to 
subjects or others, or that materially compromises the rights or welfare of participants.  
 
 

 
PI- Guzmán Pérez-Carrillo, GJ 
9
5.5 Protocol Exceptions  
Definition: A planned deviation from the approved protocol that are under the research team’s 
control. Exceptions apply only to a single participant or a singular situation. Preapproval of all 
protocol exceptions must be obtained prior to the event. 
 
5.6 Reporting to the Human Research Protection Office (HRPO)  
Reporting will be conducted in accordance with Washington University IRB Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the change.   
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event. The death of a research participant that qualifies as a 
reportable event should be reported within 1 working day of the occurrence of the event or 
notification to the PI of the event. 
 
5.7 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
The PI is required to notify the QASMC of any unanticipated problems involving risks to 
participants occurring at WU or any BJH or SLCH institution that has been reported to and 
acknowledged by HRPO.  (Unanticipated problems reported to HRPO and withdrawn during the 
review process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email 
qasmc@wustl.edu.  Submission to QASMC must include the myIRB form and any supporting 
documentation sent with the form. 
 
5.8 Time Frame for Reporting Required Events  
Any events that require reporting will be submitted per current IRB guidelines. 
 
5.9 Incidental Findings 
The research MRI scan is not a clinical MRI examination and is not conducted to diagnose brain 
abnormalities. However, some of the sequences are similar to clinical tests, and these images 
are reviewed for incidental findings by a board-certified radiologist. If there is an incidental 
observation from the testing which may be clinically significant, such as a suspected tumor or 
aneurysm, the Principal Investigator will communicate this information to the treating physician 
for review; this includes incidental finding of new tumor. If indicated, the Principal Investigator 
will contact the participant with this information. With your permission your doctor may also be 
contacted so that follow-up may occur as appropriate.* 
 
6.0 DATA AND SAFETY MONITORING  
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least one patient has been enrolled) or one 
year after accrual has opened (if no patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• 
HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 

 
PI- Guzmán Pérez-Carrillo, GJ 
10 
• 
Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of 
study 
• 
History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol 
exceptions, error, or breach of confidentiality including start/stop dates and reason 
• 
Study-wide target accrual and study-wide actual accrual 
• 
Protocol activation date 
• 
Average rate of accrual observed in year 1, year 2, and subsequent years 
• 
Expected accrual end date 
• 
Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• 
Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• 
Power analysis and/or interim analysis (if described in the protocol) 
• 
Summary of toxicities  
• 
Abstract submissions/publications 
• 
Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
7.0 STATISTICAL CONSIDERATION  
STATISTICAL ANALYSIS 
Study Design and Endpoints: This is a pilot study designed as a paired, prospective, single-
blinded study in which we compare the sensitivity and specificity of the optimized DWI 
sequence ADCmean/min versus FDG PET/CT SUVmax for the evaluation of recurrent SCC in 
post-treatment patients. The primary endpoints of sensitivity and specificity will evaluate 
the diagnostic accuracy of the optimized DWI sequence ADCmean/min versus the standard-of-
care FDG PET/CT SUVmax. The secondary endpoint will evaluate if the enhanced DWI 
sequence can more expediently assess non-responders to treatment as compared to FDG 
PET/CT. 
 
Aim 1: The 60 subject sample size for this pilot study was chosen for feasibility of recruitment 
based on the approximately 650 PET/CT exams performed for head and neck tumor in 2018. 
ROI will be used for statistical assessments of ADC measurements (see methodology of ADC 
measurement, above). FDG-PET SUVmax results will be used as the reference standard for 
tumor or non-tumor tissue. ADCmean, ADCmin and standard deviation will be used to describe 
distribution of ADC measurements (AADC) in tumor and non-tumor tissues and independent 
sample t-test will be used to compare ADC measurements between the two groups. Mean 
difference and 95% confidence interval around that will be used to interpret our results. For 
ROC analysis, the area under the curve (AUC) will be calculated and the Youden’s J index will 
be used to identify the value of the predictor variable that optimized sensitivity and specificity. 
Youden’s J index varies from 0-1. The threshold value that provides the value of the J index 
closer to 1 is the value with the best performance and discriminative power. PPV and NPV will 
also be evaluated. The logistic regression model allows for evaluating this impact after 
controlling for potential confounders. We will explore the linearity assumption of relationship of 
delta ADC with logit of outcome (response to treatment) and if the assumption is violated, 

 
PI- Guzmán Pérez-Carrillo, GJ 
11 
polynomial effects will be explored, and data transformation will be employed as needed. All 
statistical analysis will be carried out by Dorina Kallogjeri, a biostatistician in the ENT 
Department with extensive experience in head and neck cancer research. A 90% confidence 
interval will be calculated for the differences in sensitivity and specificity of the enhanced DWI 
sequence ADCmean/min as compared with the standard-of-care FDG PET/CT SUVmax. The 
positive and negative predictive values will also be evaluated. Since this is a pilot study, no 
existing data can be utilized to calculate a power analysis. 
 
A binary logistic regression model will be utilized to evaluate the impact of the change in ADC in 
predicting early non-responders to treatment. A p-value will be calculated to evaluate if 
the enhanced DWI sequence can more expediently identify non-responders to treatment as 
compared to FDG PET/CT. 
 
(**Note: Patients who do not undergo SOC PET/CT at the 3-6 month time point will be 
considered inevaluable and will be replaced.) 
 

 
PI- Guzmán Pérez-Carrillo, GJ 
12 
 
REFERENCES 
Chawla S, Kim S, Wang S et al. Diffusion-weighted imaging in head and neck cancers. Future 
Oncology 2009; 5(7): 959-975. 
 
Chen NK, Guidon A, Chang HC, Song AW. A robust multi-shot scan strategy for high-resolution 
diffusion weighted MRI enabled by multiplexed sensitivity-encoding (MUSE). Neuroimage 2013; 
15(72):41-47. 
 
Chen N.K, Wyrwicz AM. Correction for EPI distortions using multi-echo gradient-echo 
imaging. Magnetic resonance in medicine 1999; 41(6): 1206-1213. 
 
De Bree R, Wolf GT, de Keizer B, Nixon IJ, Hartl DM, Forastiere AA, Haigentz Jr M, Rinaldo A, 
Rodrigo JP, Saba NF, Suárez C. Response assessment after induction chemotherapy for head 
and neck squamous cell carcinoma: From physical examination to modern imaging techniques 
and beyond. Head & neck. 2017 Nov;39(11):2329-49. 
 
Friedrich KM, Matzek W, Gentzsch S et al. Diffusion-weighted magnetic resonance imaging of 
head and neck squamous cell carcinomas. European Journal of Radiology 2008; 68(3): 493-
498. 
 
Guzmán G, Han S, Khan R et al. “Diffusion-Weighted Imaging for the Evaluation of Post-
Treatment Squamous Cell Carcinoma in the Neck: Image Optimization and a New Quantitative 
Assessment Metric”. Oral presentation at American Society of Neuroradiology (ASNR), Boston, 
May 2019. 
 
Hermans R. "Diffusion-weighted MRI in head and neck cancer." Current Opinion in 
Otolaryngology & Head and Neck Surgery 2010; 18.2: 72-78. 
 
Jansen JF, Stambuk HE, Koutcher JA et al. Non-Gaussian analysis of diffusion-weighted MR 
imaging in head and neck squamous cell carcinoma: a feasibility study. American Journal of 
Neuroradiology, 2010; 31(4): 741-748. 
 
Jemal A, Siegel R, Xu J et al. Cancer statistics, 2010. CA: A Cancer Journal for Clinicians 2010; 
60(5): 277-300. 
 
Joo Hyun O, Lodge MA, Wahl RL. Practical PERCIST: a simplified guide to PET response 
criteria in solid tumors 1.0. Radiology. 2016 Aug;280(2):576. 
 
Kinehan PE and Fletcher JW. PET/CT standardized uptake values (SUVs) in clinical practice 
and assessing response to therapy. Semin Ultrasound CT MR 2010, 31(6), 496-505. 
 
King AD, Mo FK, Yu KH et al. Squamous cell carcinoma of the head and neck: diffusion-
weighted MR imaging for prediction and monitoring of treatment response. European Radiology 
2010; 20(9): 2213-2220. 
 
King AD, Chow KK, Yu KH et al. Head and neck squamous cell carcinoma: diagnostic 
performance of diffusion-weighted MR imaging for the prediction of treatment response. 
Radiology 2013; 266: 531-538. 
 

 
PI- Guzmán Pérez-Carrillo, GJ 
13 
Maeda M and Maier SE. Usefulness of diffusion-weighted imaging and the apparent diffusion 
coefficient in the assessment of head and neck tumors. Journal of Neuroradiology 2008; 35(2): 
71-78. 
 
Morand GB, Vital DG, Kudura K et al. Maximum Standardized Uptake Value (SUV max) of 
Primary Tumor Predicts Occult Neck Metastasis in Oral Cancer. Scientific reports. 2018 Aug 
7;8(1):1-7. 
 
Mundada, Pravin, et al. "Utility of MRI with morphologic and diffusion weighted imaging in the 
detection of post-treatment nodal disease in head and neck squamous cell carcinoma." 
European Journal of Radiology 101 (2018): 162-169. 
 
National Cancer Institute. (2019, June). Head and Neck Cancer – Health Professional Version. 
Retrieved from: https://www.cancer.gov/types/head-and-neck/hp.  
 
Paidpally V, Chirindel A, Lam S, Agrawal N, Quon H, Subramaniam RM. FDG-PET/CT imaging 
biomarkers in head and neck squamous cell carcinoma. Imaging in medicine. 2012 
Dec;4(6):633. 
 
Parkin DM, Bray F, Ferlay J et al. Global cancer statistics, 2002. CA: A Cancer Journal for 
Clinicians 2005; 55(2): 74-108. 
 
Perrone A, Guerrisi P, Izzo L et al. Diffusion-weighted MRI in cervical lymph nodes: 
differentiation between benign and malignant lesions. European Journal of Radiology 2011; 
77(2): 281-286. 
 
Persigehl T, Lennartz S, Schwartz LH. iRECIST: how to do it. Cancer Imaging. 2020 
Dec;20(1):1-7. 
 
Quantitative Imaging Biomarker Alliance. (2019, Feb 5). QIBA Profile: Diffusion-Weighted 
Magnetic Resonance Imaging (DWI). Retrieved from: 
https://qibawiki.rsna.org/images/7/7e/QIBADWI Profile_as_of_2019-Feb-05.pdf. 
 
Schwartz DL, Rajendran J, Yueh B, Coltrera MD, LeBlanc M, Eary J, Krohn K. FDG-PET 
prediction of head and neck squamous cell cancer outcomes. Archives of Otolaryngology–Head 
& Neck Surgery. 2004 Dec 1;130(12):1361 
 
Vandecaveye V, De Keyzer F, Nuyts S et al. Detection of head and neck squamous cell 
carcinoma with diffusion weighted MRI after (chemo) radiotherapy: correlation between 
radiologic and histopathologic findings. International Journal of Radiation Oncology* Biology* 
Physics 2007; 67(4): 960-971. 
 
Vandecaveye V, De Keyzer F, Dirix P et al. Applications of diffusion-weighted magnetic 
resonance imaging in head and neck squamous cell carcinoma. Neuroradiology 2010; 52(9): 
773-784. 
 
Vandecaveye V, Dirix, P, De Keyzer F et al. Predictive value of diffusion-weighted magnetic 
resonance imaging during chemoradiotherapy for head and neck squamous cell carcinoma. 
European Radiology 2010; 20(7): 1703-1714.