Clinical trial NCT03416153
Conditions: Oropharynx Cancer
Sponsor: University of Michigan Rogel Cancer Center
Start date: 2018-05-21; Completion date: 2025-05-05
Enrollment: 91 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This prospective study aims to utilize pre- and mid-treatment PET-CT to guide de-escalation of radiation therapy in HPV-related squamous cell carcinoma of the oropharynx.

Detailed description:

Arms: arm 1: Patients will receive a single prescription of 70 Gy in 35 fractions with RT given once daily, 5 days a week along with weekly carboplatin and paclitaxel (standard therapy) arm 2: Patients will initially receive a single prescription of 70 Gy in 35 fractions with RT given once daily, 5 days a week along with weekly carboplatin and paclitaxel (standard therapy). If certain parameters are met radiation therapy will be reduced to 54Gy to high risk Planned Target Volume (PTV) and 43.2Gy to low risk PTV all in 27 fractions.
Interventions: intervention 1: Carboplatin intervention 2: Radiation Therapy intervention 3: Paclitaxel
Intervention descriptions: intervention 1: AUC=1 weekly during radiation therapy. Carboplatin will be given once a week in combination with paclitaxel (standard treatment), concurrent with radiation therapy. Given IV. intervention 2: Patients will initially receive a single prescription of 70 Gy to PTV1 in 35 fractions with RT given once daily, 5 days a week along with weekly carboplatin and paclitaxel (standard therapy). Dose will be reduced to 54Gy to high risk PTV and 43.2Gy to low risk PTV all in 27 fractions for patients who meet pPET-CT and iPET-CT parameters. intervention 3: 30 mg/m2 weekly during radiation therapy. Paclitaxel will be given once a week in combination with carboplatin (standard treatment), concurrent with radiation therapy. Given IV.

Protocol documents:
Prot_SAP_001.pdf: 
ID: UMCC 2017.113 
Individualized Adaptive De-escalated Radiotherapy for HPV-related Oropharynx Cancer 
NCT03416153


1 
 
UMCC 2017.113 
A MULTI‐CENTER PHASE II TRIAL OF INDIVIDUALIZED ADAPTIVE DE‐ESCALATED RADIOTHERAPY USING PRE and 
MID‐TREATMENT FDG‐PET/CT FOR HPV‐RELATED OROPHARYNX CANCER 
 
 
Principal Investigator: 
Michelle Mierzwa 
 
 
Coordinating Center: 
University of Michigan 
 
Biostatistics: 
Matt Schipper 
 
Otolaryngology lab: 
Chad Brenner 
 
 
Version:  8.0 12 April 2022 


2 
 
DEFINITIONS 
 
AIDS: Acquired Immune Deficiency Syndrome 
ASTRO: American Society for Therapeutic Radiation Oncology ANC: Absolute neutrophil count 
AUC: Area under the concentration curve (chemotherapy) or area under the curve (statistics) 
BED: Biologic equivalent dose 
CMR: Complete metabolic response 
CR: Complete response 
CTV: Clinical target volume 
ECG or EKG: Electrocardiogram 
ED: Effective dose 
FDG: 18F‐Florodeoxyglucose, a PET/CT imaging agent 
GTV: Gross tumor volume 
Gy: Gray 
HIV: Human immunodeficiency virus 
HPV: human papilloma virus 
IGRT: Image‐guided radiation therapy 
IMRT: Intensity modulated radiation therapy 
iPET: midtreatment PET/CT 
IV: Intravenous 
LRC: Local‐regional control 
LRR: Local‐regional recurrence 
LRPF: Freedom from local‐regional progression 
MTV: Metabolic tumor volume 
NRG: NRG Oncology 
OARs: Organs at risk 
OPSCC: squamous cell carcinoma of the oropharynx 
OS: Overall survival 
pPET: pre‐treatment PET/CT 
PD: Progressive disease 
PFS: Progression‐free survival 
PMR: Partial metabolic response 
PR: Partial response 
PTV: Planning target volume 
RT: Radiation therapy or radiation treatment RTOG: Radiation Therapy Oncology Group SD: Stable disease 
SMD: Stable metabolic disease 
SUV: Standardized uptake value 
SUVmax: The SUV of the most intense voxel within a tumor 
SUVpeak: The average SUV within a 1.2‐cm diameter sphere centered on the most metabolically active region of 
the tumor 
3D‐CRT: Three dimensional‐conformal radiation therapy 


3 
 
SCHEMA 
 
 
 
All patients will undergo FDG PET/CT at baseline for staging and RT planning and during RT for treatment response 
assessment and adaptive planning. This baseline scan should be performed within 4 weeks prior to registration, 
while the during‐RT scan should be performed between fractions 8 and 12 for both arms. 
 
 
 
 
 
Figure 1 parameters for de‐escalation 


4 
 
1.0 
INTRODUCTION 
 
Oropharyngeal Carcinoma 
Over the past three decades, there has been an increase in the incidence of HPV‐related oropharyngeal 
squamous cell carcinoma (OPSCC) with good overall prognosis and high rates of loco‐regional control 
(d’souza 2007, Gillison, 2000, Fahkry, 2008, Ang 2010).  Current standard of care therapy includes 
definitive chemoradiation as well as resection followed by adjuvant radiation or chemoradiation. Due to 
the good prognosis and relatively good health of most patients with HPV‐related OPSCC, there has been 
widespread interest in treatment de‐intensification strategies including decreased doses of radiotherapy 
and chemotherapy. Ideally, pre‐ or mid‐treatment biomarkers of response would be used to adapt 
therapy. However, no proven clinical or radiographic biomarkers exist to monitor response during therapy. 
 
Post‐treatment PET‐CT obtained 12 weeks after therapy has been shown to be a reliable predictor of 
treatment response and has been widely adopted. A recently published prospective, randomized control 
trial studying PET surveillance at 12 weeks post‐treatment found PET‐CT surveillance was not inferior to 
planned neck dissection for advanced (N2/N3) SCC of the head and neck (Mehenna et al., NEJM 2016). 
While PET‐CT surveillance at this interval was non‐inferior in terms of survival benefit, this group resulted 
in fewer neck dissections overall, no difference in complication rate, and similar 2‐year survival rate. 
Furthermore, PET‐CT was more cost effective, saving about $2000 per patient over the trial duration in 
decreased number of operations (Mehenna et al NEJM 2016). 
 
Prospective trials have demonstrated value of pre‐ treatment PET‐CT (pPET) and mid‐treatment interval 
PET‐CT (iPET) as a potential radiographic biomarker to predict loco‐regional control (LRC), disease‐free 
survival (DFS) and distant metastasis free survival (DMFS). For example, Pollom, et al. studied iPET at 
median radiation dose of 33.5Gy in OPSCC where 88% of patients were p16 positive and 40% were 
“smokers”. They found that pre‐treatment MTV50% and iPET MTV2.0 were correlated with PFS (p=0.015), 
where MTVx was defined as the metabolic tumor volume above a threshold “x”. Additionally, they found 
that nodal total lesion glycolysis (TLG) of > 5% per week correlated with PFS (p=0.03). 


5 
 
 
 
 
 
 
Schwartz, et al. performed a retrospective analysis of pPET in 74 patients treated on RTOG 0522 patients. 
They found that the SUVmax and SUVmean were non‐prognostic, but that MTV40% of the primary tumor as 
well as the total MTV (primary tumor + involved lymph nodes) higher than cohort mean correlated with 
worse PFS (HR 2.34, 95% CI [1.02, 5.37], p=0.05) and LRC (HP 4.01, CI [1.28,12.52], p=0.02).  Primary MTV 
remained prognostic in the 56 patients of this study who had p16+ OPSCC. 


6 
 
 
 
Figure 4. Schwartz, et al. Cumulative incidence estimates of local‐regional relapse (Panel A) and 
distant metastasis (Panel B) and Kaplan‐Meier estimates of progression‐free survival (Panel C) and 
OS (Panel D) for patients with baseline primary MTV ≤ median or > median. Two‐year 
local‐regional relapse rates were 5.7% (95% CI: 0, 13.5) for patients with MTV ≤ median 
and 30.3% (95% CI: 14.3, 46.3) for patients with MTV > median. Two‐year distant 
metastases rates were 2.9% (95% CI: 0, 8.5) for patients with MTV ≤ median and 12.1% 
(95% CI: 0.8, 23.4) for patients with MTV > median. Two‐year progression‐free survival 
rates were 88.6% (95% CI: 78.0, 99.1) for patients with MTV ≤ median and 63.6% (95% CI: 
47.2, 80.0) for patients with MTV > median. Two‐year overall survival rates were 94.3% 
(95% CI: 86.6, 100) for patients with MTV ≤ median and 84.9% (95% CI: 72.6, 97.1) for 
patients with MTV > median. 
 
An Australian study of pPET and iPET in 75 patients by Lin, et al. evaluated all head and neck mucosal sites 
of cancer.  They performed iPET at a mean of 18.5 days from the start of RT, and evaluated SUVmax, 
SUVmean, MTV and TLG in both primary tumor and lymph nodes. They found that the pPET parameters 
were not predictive of treatment response. However, multi‐variate analysis demonstrated iPET reduction 
of total node MTV by 50% from baseline to correlate with loco‐regional failure ‐free survival (FFS), DFS and 
OS (p=0.026, 0.003, and 0.014, respectively). iPET reduction of nodal TLG by > 50% from baseline was 
predictive of FFS, DFS and OS in multi‐variate analysis (p=0.01, 0.01, 0.014). 


7 
 
 
 
Figure 5.  Kaplan‐Meier survival rates in relation to the optimum total node TLG cut‐off value of 50 
% on iPET for locoregional failure‐free survival (LRFFS), b regional failure‐free survival (RFFS), c 
disease‐free survival (DFS) and d overall survival (OS). 
 
In non‐small cell lung cancer (NSCLC), the University of Michigan has conducted 2 consecutive 
prospective dose escalation trials to test a hypothesis that radiation dose can be escalated safely above 
74 Gy when the radiation dose prescription is individualized at the beginning (UMCC 2003‐073) and 
adapted to the reduced MTV on during‐RT FDG‐PET/CT (UMCC 2007‐123). The prescription dose of the 
first trial was individually set to correspond to a 15% risk of RT‐induced lung toxicity (RILT) according to a 
NTCP model at the baseline. RT dose was further escalated in the second trial by adapting dose 
individually to the residual metabolic volume on FDG‐PET/CT obtained during RT, so the residual 
metabolic volume would  receive  the maximal  dose  that  would maintain  a  tolerable  risk  of  RILT 
while the pre‐RT CTV on CT was not compromised (would receive at least 60 Gy). On the first trial, 
patients treated to a higher dose had significantly better survival (p=0.02).  The median survival on the 
second trial has not yet been reached. 
 
This prospective study aims to utilize pre‐ and mid‐treatment PET‐CT to guide de‐escalation of radiation 
therapy in HPV‐related squamous cell carcinoma of the oropharynx. Early timing of mid‐treatment PET‐CT 
between fractions 8‐12 has been planned to minimize risk of mucositis induced false positivity. 


8 
 
University of Michigan experience with definitive chemoradiation treatment of 515 patients with HPV+ 
oropharyngeal cancer, AJCC 8th edition, stage 1 and 2 patients had 88 % LRC at 2 years and 2 year 
progression free survival (PFS) of 80%. These patients were treated with IMRT to 70Gy as well as 
concurrent carboplatin and paclitaxel. 
 
Figure  6. 
Kaplan‐  Meier  loco‐regional  control  curve  for  HPV+  OPSCC  treated  with  definitive 
chemoradiation at UM 2003‐2015 staged according to AJCC 8. 
 
Furthermore, we have explored the association of smoking with loco‐regional control and overall survival. 
On multivariate analysis, any 1+ pack year smoking history correlated with OS (HR 1.98, 95%CI 1.2‐3.2, 
p<0.01) but not LRRFS or DRFS as seen in Table 1 below. 
 
Table 1. Multivariate analysis, accounting for group stage (per AJCC 8th Ed.), correlating smoking history 
and age with OS, LRRFS, and DRFS. 
 
 
OS 
LRRFS 
DRFS 
HR (95% CI) 
P 
HR (95% CI) 
P 
HR (95% CI) 
P 
Any smoking 
1.98 (1.2 – 3.2) 
<0.01 
1.27 (0.7 – 2.2) 
0.42 
1.32 (0.8 – 2.3) 
0.33 
10+ pack years 
1.52 (1.0 – 2.3) 
0.05 
1.26 (0.7 – 2.2) 
0.41 
1.0 (0.6 – 1.7) 
0.95 
20+ pack years 
1.22 (0.8 – 1.9) 
0.38 
1.03 (0.6 – 1.8) 
0.93 
1.0 (0.6 – 1.8) 
0.98 
Current smoking 
1.09 (0.7 – 1.8) 
0.72 
0.77 (0.4 – 1.5) 
0.43 
1.05 (0.6 – 1.9) 
0.88 
Age (per year increase) 
1.04 (1.0 – 1.1) 
<0.01 
1.03 (1.0 – 1.1) 
0.03 
1.02 (1.0 ‐ 1.1) 
0.14 
Each row represents a separate Cox model. HR = hazard ratio. CI = confidence interval. 
 
AJCC 8th edition staging begins clinical use in January 2018 and our 8th ed stage 1 and 2 patients have high 
rates of LRC without effect from smoking status. These patients are thus candidates for de‐escalation of 
local therapy and are included in the present trial. 


9 
 
Exploratory Potential BioMarkers Predictive of Treatment Response and Long‐Term Outcome 
 
Circulating tumor DNA (ctDNA) 
 
An additional exploratory aim of this study is to study circulating tumor DNA in the blood 
of patients undergoing therapy on this study. Based on review of our previous experience at UM, we 
estimate the 2 year LRC of our study population to be 88% in patients with less than 20 pack year history of 
cigarette smoking and 82% in patients with greater than 20 pack year history. Furthermore, 15‐20% of 
HPV‐related oropharynx cancer patients will go on to develop distant metastases. We hypothesize that 
additional biomarkers will aid in personalized care with potential selective treatment de‐intensification for 
our patients. 
 
One promising non‐invasive biomarker is quantification of circulating tumor DNA (ctDNA). It is known that 
tumor cell division and death causes release of cell free fragmented DNA into circulation. ctDNA is 
composed of small fragments of nucleic acid that are not associated with cells. ctDNA is currently being 
explored in many cancers in early stage and metastatic settings to evaluate response (Schwarzebach, et al, 
Tie, et al). Circulating tumor DNA has been detected in 70‐100% at diagnosis in a cohort of 640 patients 
with multiple types of advanced stage cancers (Bettegowda, et al). This study included 14 head and neck 
cancer patients of all stages and found 73% were positive for detectable ctDNA. 
 
The concept of ctDNA is not new to head and neck cancer. In EBV (Ebstein Barr virus)‐related endemic 
nasopharynx cancer, multiple publications have demonstrated detectable serum EBV (Ebstein Barr virus) 
DNA in > 80% patients with pre‐treatment levels correlated to tumor stage (Le 2005, Chan 2002). 
Furthermore, clearance of EBV DNA after definitive chemoradiation is associated with improved PFS 
(Wang, 2012, Lin 2004). 
 
Serum detection of ctDNA has been largely unexplored in other head and neck cancers. Two small studies 
have been published that explored serum detection of HPV DNA. Sturgis, et al, evaluated pre‐treatment 
HPV DNA in blood and found no significant correlation with response in a small number of patients. To 
date, no group has attempted to detect ctDNA in head and neck cancer through somatic mutations.  Dr. 
Brenner’s lab has the technical ability to detect HPV DNA as well as the capability to detect the most 
commonly mutated oropharynx cancer genes through a next generation sequencing approach to ctDNA 
cell fragments. In this trial, we plan to collect 6ml of EDTA blood at several time points correlated with 
clinical blood draw times in order to explore correlation with ctDNA and treatment response as well and 
potential early detection of recurrence. 
 
DCE‐MRI 
 
Several physiological and metabolic imaging modalities, most in isolation, have been investigated for 
prediction of treatment failure in head and neck cancer. Fludeoxyglucose (FDG) positron emission 
tomography (PET), a marker for glucose metabolism, has shown high FDG uptake associated with poorer 
prognosis, whereas rapid metabolic response on PET/CT has been associated with high LRC. Hypoxic PET, 
and perfusion CT/MRI and diffusion MRI have shown to be biomarkers for outcomes in HNSCC. Persisting 
poorly perfused tumors during the early course of RT is associated with high risk for local and regional 
failure. Diffusion imaging, a measure of water mobility in tissue and sensitive to cellularity, has shown that 
an increase in apparent diffusion coefficient (ADC) of the HNSCC during RT is associated with positive 
therapy response. Most clinical trials currently underway use a single imaging modality to guide radiation 
escalation or de‐escalation and single imaging modalities are limited to image only one aspect of tumor 
biology.  The spatial relationship between imaging risk‐factor parameters in HNSCC are largely unknown. 


10 
 
One exploratory aim of this study is to investigate whether FDG uptake, low blood volume, and low 
diffusion coefficient in HPV‐related oropharynx cancer have any spatial correspondence and their early 
responses to RT to determine the implication of this overlap or lack thereof for adaptive boosting strategy. 
 
2.0 
OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 
To determine whether tumor dose can be de‐escalated with equivalent/non‐inferior loco‐regional control 
as compared to historical standard when an individualized adaptive radiation treatment (RT) plan is 
applied by the use of a FDG‐PET/CT scan acquired during the course of fractionated RT in patients with 
HPV‐related squamous cell carcinoma of the oropharynx. 
2.1.2 
To determine whether the relative change in MTV2.5 of  50 %  from the baseline to the mid‐ treatment 
FDG‐PET/CT is a prognostic biomarker for local regional tumor control. 
 
2.2 
Secondary Objectives 
2.2.1 
To determine patterns of failure (locoregional relapse versus distant) and survival (overall and progression‐ 
free) at 3 months and 2 years; 
2.2.2 
To determine acute toxicity profiles at the end of radiation therapy and at 3 and 6 months; 
2.2.3 
To determine late toxicity profiles at 1 and 2 years; 
2.2.4 
In patients with detectable ctDNA pre‐treatment, to determine the fraction of patients ctDNA in the blood 
at week 4 of RT 
 
 
2.3 
Exploratory Correlative Science Objectives 
2.3.1 
To quantify the fraction of patients in whom ctDNA is detectable pre‐treatment and to characterize 
detectable ctDNA in those patients during RT, post‐treatment and at recurrence 
2.3.2 
To quantify circulating tumor DNA in the blood pre‐, mid‐ and post‐treatment. 
2.3.3 
To quantify the low blood volume and apparent diffusion coefficient in DCE‐MRI of HPV‐related 
oropharynx cancer 
2.3.4 
To determine patient‐reported quality of life at 3, 6 months and 1 year using FACTHN, U Washington QOL, 
CTCAE PRO as well as xerostomia questionnaire; 
2.3.5 
To determine swallowing outcomes using barium swallow pre‐treatment as well as 3‐ and 12‐ months post 
treatment 
2.3.6 
To correlate physician and patient reported CTCAE scores during and after therapy 
 
 
3.0 
PATIENT SELECTION 
3.1 
Conditions for Patient Eligibility 
3.1.1 
Patients must have FDG‐avid (maximum SUV ≥ 4.0) (from PET scan of any date, any scanner) and 
histologically or cytologically proven squamous cell carcinoma of the oropharynx (tonsil, base of tongue, 
oropharyngeal wall, soft palate) that is p16 positive by immunohistochemistry or HPV positive by in situ 
hybridization 
3.1.2 
Clinical stage: stage I‐II AJCC 8th edition staging 
3.1.3 
Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum 
diagnostic workup: 
• 
History/physical examination, including documentation of weight within 4 weeks prior to 
registration; 
• 
FDG‐PET/CT scan for staging and RT plan within 4 weeks prior to registration; 
• 
Zubrod Performance Status 0‐1 within 4 weeks prior to registration; 
• 
Age ≥ 18; 


11 
 
• 
Able to tolerate PET/CT imaging required to be performed 
3.1.4 
CBC/differential obtained within 4 weeks prior to registration on study, with adequate bone marrow 
function defined as follows: 
• 
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3; 
• 
Platelets ≥ 100,000 cells/mm3; 
• 
Hemoglobin ≥ 8.0 g/dL 
3.1.5 
Serum creatinine within normal institutional limits or a creatinine clearance ≥ 45 ml/min within 4 weeks 
prior to registration; 
3.1.6 
Women of childbearing potential and male participants must agree to use a medically effective means of 
birth control throughout their participation in the treatment phase of the study. 
3.1.7 
The patient must provide study‐specific informed consent prior to study entry. 
 
3.2 
Conditions for Patient Ineligibility 
3.2.1 
cT4, cN3 or cM1 disease (also explained as AJCC 8th ed staging Stage 3 or 4 disease) 
3.2.2 
“Matted nodes” as determined by review with Neuroradiology 
3.2.3 
Gross total excision of both primary and nodal disease with curative intent; this includes tonsillectomy, 
local excision of primary site, and nodal excision that removes all clinically and radiographically evident 
disease. In other words, to participate in this protocol, the  patient  must  have  clinically  or 
radiographically  evident  gross  disease  for which disease response can be assessed. 
3.2.4 
Carcinoma of the neck of unknown primary site origin (even if p16 positive); 
3.2.5 
Prior invasive malignancy (except non‐melanomatous skin cancer) unless disease free for a minimum of 3 
years (For example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible); 
3.2.6 
Any prior therapy for the study cancer; note that prior chemotherapy for a different cancer is allowable if 
> 3 years prior to study; 
3.2.7 
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields; 
3.2.8 
Severe, active co‐morbidity, defined as follows: 
• 
Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months; 
• 
Transmural myocardial infarction within the last 3 months; 
• 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; 
• 
Chronic Obstructive Pulmonary Disease (COPD) exacerbation or other respiratory illness requiring 
hospitalization or precluding study therapy at the time of registration; 
• 
Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition. Note, however, 
that  HIV  testing  is  not  required  for  entry  into  this  protocol.  The  need  to  exclude patients with 
AIDS from this protocol is necessary because the treatments involved in this protocol may be 
significantly immunosuppressive. 
• 
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that 
laboratory tests for liver function and coagulation parameters are not required for entry into this 
protocol. 
3.2.9 
Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to 
use medically acceptable forms of contraception; this exclusion is necessary because the treatment 
involved in this study may be significantly teratogenic. 
3.2.10 Poorly controlled diabetes (defined as fasting glucose level > 200 mg/dL)  despite  2  attempts  to 
improve glucose control by fasting duration and adjustment of medications. Patients with diabetes will 
preferably be  scheduled  in  the  morning  and  instructions  for  fasting  and  use  of  medications  will  be 
provided  in consultation with the patients’ primary physicians; 
 
4.0 
REGISTRATION PROCEDURES 
Patient registration for this trial will be centrally managed by the Coordinating Center of The University of 
Michigan Rogel Cancer Center as described below: 


12 
 
A potential study subject who has been screened for the trial and who has signed the Informed Consent 
document will be initially documented by the participating site on the Screening and Enrollment Log. 
 
It is the responsibility of the local site investigator to determine patient eligibility prior to submitting 
patient registration request to the Coordinating Center. After patient eligibility has been determined, a 
copy of the completed Eligibility Worksheet together with all the pertinent de‐identified source 
documents will be submitted by the requesting site to the Coordinating Center, by email to CTSU‐ 
Oncology‐Multisite@med.umich.edu. 
 
The Multi‐Site Coordinator, who acts as the registrar, will review the submitted documents and process 
the registration. Sites should inform the Multi‐Site Coordinator of a potential registration by 5 p.m. on the 
day prior to registration.  Same day registrations cannot be guaranteed. 
 
An email will be sent by the registrar to the requesting site registrar to confirm patient registration and to 
provide the study identification number that has been assigned to the patient. In addition, a copy of the 
completed Eligibility Worksheet signed and dated by the registrar, will be sent back to the requesting site 
registrar. 
 
Patients found to be ineligible for participation after being consented will be considered screen failures, 
and documented as such in the Screening and Enrollment Log. These patients will not have study 
identification number assigned to them, and will not receive study treatment. 
 
4.1 
PRETREATMENT EVALUATIONS/MANAGEMENT 
NOTE: This section lists required baseline evaluations needed before the initiation of protocol treatment 
that do not affect eligibility. 
 
4.1.1 
A complete panel of electrolytes within 4 weeks prior to treatment 
4.1.2 
Quantification of patients smoking history including number of pack years (# packs per day x # years) and 
whether they have smoked more than 5 packs within last 365 days 
4.1.3 
Pre‐treatment DCE‐MRI protocol completed in UM Department of Radiation Oncology; unless 
contraindicated or patient refusal 
4.1.4 
Pre‐treatment blood draw collected for ctDNA, if the local lab is available for processing 
4.1.5 
Pre‐treatment patient reported quality of life questionnaire. Patients have the option to complete these 
remotely and mail, fax, or send through the patient portal to the study clinic. 
4.1.6 
Pre‐treatment barium swallow videofluoroscopy examination should be performed prior or during the first 
week of chemo‐radiation. When staff is not available to complete the videofluoroscopy tests, these will be 
skipped and listed as protocol deviations. 
4.1.7 
A nutritional assessment (virtual or in‐person) by MD, should be performed within 6 weeks prior to start of 
treatment. The assessment should include an evaluation of the need for prophylactic gastrostomy tube 
placement. 
4.1.8 
Tumor biopsy submission to coordinating center for tumor sequencing analysis. If core sample is not 
available, contact the Study PI. 
 
5.0 
TREATMENT PLAN 
5.1 
OVERALL TREATMENT PLAN: 
All patients will undergo a pre‐treatment study PET‐CT (pPET‐CT) within 4 weeks of registration, and 
then proceed with standard chemoradiation including RT prescribed to 70Gy in 35 fractions to gross 
disease and weekly carboplatin/paclitaxel for 7 weeks.  PET scans from outside institutions may be 
acceptable and this will be evaluated by PI (Michelle Mierzwa) and physicist (Ben Rosen) on an 
individual basis.  All patients will then undergo a mid‐treatment PET‐CT (iPET) between fractions 8 and 12 
and the following parameters will be calculated 


13 
 
on primary tumor and each pathologic lymph node of the pPET and iPET: MTV50%, MTV2.5, TLG, SUVmax 
and SUVmean. Patients who meet criteria for treatment de‐escalation will have chemoradiation plans 
decreased as follows: radiation prescription will be changed to 54Gy total dose and only 6 doses of 
concurrent carboplatin/paclitaxel will be given. 
 
5.2 
RADIATION THERAPY 
 
Simulation and Treatment Planning 
 
Patients should undergo simulation to include 5‐point aquaplast masking and CT scan with IV contrast 
unless contraindicated in the Department of Radiation Oncology at the University of Michigan. The 
treatment planning CT scan should be obtained in the immobilization device and in the treatment position 
with a slice thickness of 3 mm or less. After mask is made, patient will undergo PET‐CT in the Department 
of Nuclear Medicine on flat tabletop with mask in place. This PET‐CT will be defined as the pre‐treatment 
PET‐CT (pPET‐CT). 
 
Adequate image registration between FDG‐PET and the CT from the PET/CT scanner and the CT of the 
PET/CT with a simulating CT is required. Deformable registration is not permitted. 
 
Dose Specifications 
 
GTVp is gross primary tumor volume. GTVn is gross nodal tumor volume. 
CTV1 is gross clinical volume with tight (typically 0.5 cm) margins around the GTV. 
CTV2 includes areas containing sub‐clinical at‐risk around the gross disease and at areas at risk of lymph 
node metastases. 
PTV1 and PTV2 consist of uniform 3 mm expansions of the CTV1 and 2 respectively. 
 
Patients will initially receive a single prescription of 70 Gy to PTV1 in 35 fractions with RT given once 
daily, 5 days a week along with weekly carboplatin/paclitaxel (standard therapy). All fields must be 
treated daily. On days when chemotherapy is given, it will be administered prior to RT.  Prescription to 
high risk PTV will be 70Gy in 35 fractions and to PTV2 will be 56Gy in 35 fractions. 
 
Patients who meet the following pPET‐CT and iPET‐CT parameters are candidates for de‐escalation: pre‐ 
treatment MTV50% < 22cc, iMTV2.5 is decreased >50% from baseline. Two independent physicians will 
review all PET‐CTs for de‐escalation (this will likely be a Nuclear Medicine physician and a Radiation 
Oncology physician). Review of scans and decision for de‐escalation will be made by fraction 20. PET‐CTs 
will be standardly reviewed by 2 treating physicians: Dr. Wong (Nuclear Medicine) and Dr. Mierzwa 
(Radiation Oncology) independently.  Treating physicians from Otolaryngology and or Radiation 
Oncology will serve as a surrogate if either Drs. Wong or Mierzwa are unavailable. In reference to timing 
of evaluation: the mid‐treatment PET‐CT is performed between fractions 8‐12 of RT and the decision to 
de‐escalate therapy will not be necessary until fraction 20 (2 weeks later), so it extremely unlikely that 
these 3 physicians will be unavailable for scan review. 
 
Drs. Wong, Mierzwa or alternate will use UM software for analysis where the initial volumes and 
parameters (primary tumor as well as individual lymph nodes/nodal conglomerate masses) will be 
defined by physician. The MTV is then autogenerated by UM software and values will be recorded on a 
common Excel spreadsheet. Any disagreement regarding treatment de‐escalation will be resolved 
through direct communication between physicians and a 3rd physician tie‐breaker when necessary. TLG 
for primary tumor and each lymph node conglomerate will also be collected for analysis. 


14 
 
These patients will proceed to de‐escalation as follows: prescription and plan will be amended to deliver 
a total dose of 54Gy to high risk PTV and 43.2Gy to low risk PTV all in 27 fractions. 
 
Patients who do not meet pPET‐CT and iPET‐CT parameters for de‐escalation will proceed with original 
prescription to 70Gy. 
 
Optimization goals: 
 
The primary PTV dose will be 99% + 7% of the prescribed dose and to sub‐ clinical PTVs within +/‐ 5% of 
the prescribed dose. The maximal “hot spot” within a PTV will be <115% of the prescribed dose to that 
target delivered to a volume of at least 0.5 cc. The maximal dose outside the targets will be <105% of the 
prescribed dose delivered to at least 0.5 cc. volume. The maximal dose to the spinal cord, expanded by 
0.5 cm, will be < 50 Gy, to the non‐expanded cord < 45 Gy, and where applicable, to the optic pathways < 
50 Gy and to the brainstem <54 Gy.  Other normal tissue optimization are per institutional standards. 
 
Treatment Interruptions: It is expected that the entire treatment for definitive irradiation will be 
completed in approximately 7.5 weeks. Treatment interruptions due to symptomatic mucositis or skin 
reactions should be minimal. In the case of severe mucositis impairing oral intake, a gastric tube will be 
inserted and radiation will continue uninterrupted at the discretion of the treating physician. Weight will 
be recorded weekly in the Radiation Oncology Chart. If the patient's unintentional weight loss exceeds 10% 
of the initial weight or if the patient is malnourished before radiation, a feeding tube will be considered. 
 
5.3 
Chemotherapy 
All patients will undergo radiation therapy in combination with weekly Carboplatin and paclitaxel. 
 
6.0 
PET‐CT scans 
 
Serial FDG‐PET/CT scans of the same patient must be done on the same scanner for this study. 
 
The PET/CT scanner calibrations should be routinely verified according to  manufacturer 
recommendations. The scanner should be assessed regularly for quantitative integrity and stability by 
scanning a standard quality control phantom with the same acquisition and reconstruction protocols used 
for study participants. The SUV verification measurements must include the dose calibrator used to 
measure the doses of study participants to ensure that the dose calibrator and PET scanner are properly 
cross calibrated, i.e. the dose measured in the dose calibrator and injected into the phantom matches the 
results obtained from analysis of the phantom images. 
 
A quality control (QC) check must be performed at the beginning of the day for the dose calibrator and 
well counter, in accordance with the manufacturer recommendations. If any of the QC results are outside 
of the manufacturer’s guidelines, the study must be rescheduled and the problem rectified before 
scanning any patients. 
 
FDG‐PET/CT  will  be  performed  in  all  patients  at  baseline  for  staging  RT  planning  and  tumor  activity 
assessment. Patients who have already undergone staging FDG‐PET/CT at the time of registration may 
need to repeat the FDG‐ PET/CT in a treatment planning position due to time lapse or image quality 
issues.  PI and physicist will make a determination if outside institution PET scans are acceptable on an 
individual basis.  
 
If the baseline FDG‐PET/CT is not performed on a flat palette in treatment planning position, it can still be 
used as the baseline scan only if all of the following conditions are met: 


15 
 
 
done within 4 weeks prior to registration 
 
acceptable imaging parameters: 4 hour fast, blood glucose < 200 mg/dl, 8‐20 mCi F‐18 FDG dose, 
injection to scan interval 50‐70 minutes 
 
conducted on UM PET‐CT scanner OR outside PET‐CTs reviewed by Nuclear Medicine and deemed to 
be of good quality for study purposes 
 
can be acceptably registered to the simulation CT; the simulation CT must also be submitted as a 
reference scan for registration 
 
Pre‐FDG‐PET/CT Patient Preparation: 
• 
Prior to injection, the patient must fast for at least 4 hours; 
• 
Patients are encouraged to be well hydrated prior to the scan; 
• 
Blood glucose measurement is required (ideally within one hour of FDG administration) before the 
injection of FDG and must be < 200mg/dL; 
• 
If the serum glucose concentration is found to be greater than 200 mg/dL, the study should be 
rescheduled. The referring physician or primary physician of the patient will be contacted to optimize 
blood glucose control; 
• 
The patient’s height and weight must be measured using calibrated and medically approved devices 
(not verbally relayed by the patient); 
 
Injection of FDG: 
• 
An IV catheter access lines (18 or 20 gauge is preferred) are placed in one arm (ideally contralateral 
to the side of the primary tumor) for the FDG injection; 
• 
The dose of FDG will be 296‐740 MBq (8‐20 mCi) depending on institutional procedure and in 
accordance with manufacturer recommendations; 
• 
A saline flush of at least 10 mL should follow the FDG injection; 
• 
The exact time of calibration of the dose should be recorded using a global time piece consistently 
used throughout the study for time recording. The exact time of injection should be noted and 
recorded to permit correction of the administered dose for radioactive decay. In addition, any of the 
dose remaining in the tubing or syringe, or that was spilled during injection, should be recorded. The 
injection should be performed through an IV catheter and 3‐way stopcock. 
 
FDG‐PET/CT Imaging: 
• 
All PET exams should contain 3 trans‐axial whole body series, attenuated and non‐attenuated, 
corrected PET and CT images; 
• 
The emission PET scan will begin 60 +/‐ 10 minutes after injection; 
• 
The patient will empty his/her bladder immediately before the acquisition of images; 
• 
The patient will be positioned on the flat table imaging couch in treatment planning position. 
• 
The transmission  scan should be a low‐dose CT scan without IV contrast (oral contrast is 
permitted  per  institutional  procedure) for  the  PET/CT,  done  before  the  emission  imaging.  The 
transmission scan type, length, etc., should exactly match that used in the calibration and 
qualification procedure. 
• 
An emission scan from the skull base to thighs will be performed. The number of bed positions will 
be determined by the patient’s height.  The acquisition time per bed position will be 2 minutes. 
Typical parameters are 6‐8 bed positions, leading to an emission scan time of 12‐16 minutes. 
 
Minimum Acceptable Tumor FDG Uptake: 
If the FDG uptake of the tumor tissue is too low for quantitative analysis (maximum SUV < 4.0) the 
patient will be removed from participation. 
 
In patients whose measurable tumor has an absolute baseline SUVmax of less than 4.0, a 25% decrease 


16 
 
of tumor FDG uptake would result in a decrease in SUV of ≤ 1 to the tumor. Data on the test/retest 
reproducibility of FDG‐PET/CT suggest that in an individual patient such a small absolute change in tumor 
FDG uptake cannot be reliably identified by PET/CT imaging given background uptake in the liver/blood is 
an SUV of 1.5. Therefore, a baseline absolute SUVmax of at least 4.0 is required for the present study. 
We expect that the tumor absolute SUVmax will be less than 4.0 in fewer than 5% of patients. This 
estimate is based on data on FDG uptake of untreated, advanced SCCOP were patients normally have 
absolute SUVmax in the low teens. 
 
6.1 
Calculations and Criteria for de‐escalation 
 
To be a candidate for de‐escalation, patients must meet ALL criteria listed below: 
1)pPET MTV50% (largest GTV) ≤ 22cc 
2)iPET MTV2 .5 decrease by >50% in primary tumor OR largest pathologic lymph nodes 
 
Pre‐treatment PET/CT: The Suvmax, SUVmean, MTV50%, and TLG will be calculated for each research scan 
on primary tumor and the largest pathologic lymph nodes. MTV(total)= MTVprimary + MTVnodes. For the 
purpose of de‐escalation, each separate geographic area of gross tumor will be considered separately on 
the iPET. For example, if patient meets criteria for de‐escalation in the primary tumor but not lymph 
nodes, the primary tumor will receive 54Gy and the lymph nodes that did not meet criteria will receive 
70Gy. 
 
6.2 
Expected Adverse Events Related to FDG‐PET Imaging 
 
Adverse events (AEs) from FDG‐PET/CT are exceedingly rare. If an AE from functional imaging is to 
occur, it would most likely be related to the intravenous catheter infusion site, consisting of erythema 
and discomfort from the IV. An allergic reaction to the FDG is possible as well. The most expected AEs 
from a PET scan include discomfort and claustrophobia. 
 
Expected Adverse Events from the FDG Injection: 
• 
Bruising; 
• 
Bleeding; 
• 
Phlebitis; 
• 
Infection at the site of injection; 
• 
Allergic‐type or other adverse reaction to FDG. 
 
Expected Adverse Events from the PET Scan: 
• 
Discomfort; 
• 
Claustrophobia. 
 
Expected Adverse Events from the CT Scan: 
• 
Discomfort; 
• 
Claustrophobia; 
• 
Malfunction of implanted electronic medical devices, e.g., pacemakers, neurostimulators, insulin 
pumps. 
 
Estimation of Radiation Doses Due to FDG‐PET/CT 
Reports of radiation doses from PET/CT scanning have varied in the literature. These differences can be 
attributed to different methods of attenuation correction, the timing of the scan, the area of the body 
being evaluated, and the radiopharmaceutical being investigated. This research study involves radiation 
exposure from 2 FDG‐PET/CT scans for patients. The radiation exposure from each FDG‐PET/CT scan is 


17 
 
equal to a uniform whole‐body exposure of approximately 14 mSv, with approximately 11 mSv from the 
injected radioactive FDG and 3 mSv from the CT component. 
 
 
7.0 
Drug Information 
 
Carboplatin 
 
Dose: AUC=1 weekly during RT 
 
Chemistry: Carboplatin (CBDCA) is a hydrophilic platinum coordination compound and is an analog of 
cisplatin, producing intrastrand DNA cross‐ links. 
 
Human Toxicology: Side effects of CBDCA include: myelosuppression, nausea, vomiting, abdominal pain, 
diarrhea, and constipation. Other toxicities include: allergic reactions (including hypersensitivity, i.e. rash, 
urticaria, erythema, pruritis, bronchospasm, and profound hypotension), peripheral neuropathy, 
paresthesias, loss of hair, hearing loss, visual disturbances, and change in taste. Serum creatinine 
elevations and blood urea elevations have occurred as well as abnormal liver function tests and 
decreased serum electrolyte values. Although rare, pain asthenia, cardiovascular, respiratory, 
genitourinary, and mucosal side effects have occurred in some patients. Cancer‐associated hemolytic 
uremic syndrome has been reported rarely carboplatin may cause fetal harm; therefore, women of 
childbearing potential should be advised to avoid becoming pregnant. The renal effects of nephrotoxic 
compounds may be potentiated by carboplatin. Carboplatin is contraindicated in patients with a history 
of severe allergic reactions to cisplatin or to other platinum‐containing compounds or mannitol. This 
drug should not be used in patients with severe bone marrow depression or significant bleeding. The 
occurrence of acute leukemia has been reported rarely in patients treated with anthracycline/alkylator 
combination chemotherapy. 
 
Pharmaceutical Data 
Kinetics: The differences in potencies of carboplatin as cisplatin are due to differences in equation rates. 
The initial half‐life of carboplatin is 1.1‐ 
2.0 hours and the post‐distributional half‐life is 2.5‐5.0 hours. Sixty‐five percent of the dose is 
excreted into the urine within twelve hours. Carboplatin is not bound to plasma proteins. 
 
Formulation: Carboplatin is supplied as a sterile lyophilized powder available in single‐dose vials 
containing 50 mg, 150 mg, and 450 mg of carboplatin for administration by intravenous injection. Each 
vial contains equal parts by weight of carboplatin and mannitol. Immediately before use, the content of 
each vial must be reconstituted with either sterile water for injection, USP, D5W, or normal saline 
injection, USP, according to the following schedule: 
 
Vial Strength 
Diluent Volume 
50 mg 
5 mL 
150 mg 
15 mL 
450 mg 
45 mL 
 
These dilutions all produce a carboplatin concentration of 10 mg/mL. Carboplatin can be further diluted 
to concentrations as low as 0.5 mg/mL with D5W or normal saline injection, USP. 
 
Storage and Stability: Unopened vials of carboplatin for injection are stable for the life indicated on the 


18 
 
package when stored at controlled room temperature (15‐30oC), and protected from light. When 
reconstituted as directed, the solution of carboplatin exhibits no decomposition for eight hours at room 
temperature (25 oC). Like cisplatin, this drug should not be given through aluminum needles. Caution: 
The single‐use lyophilized dosage form contains no antibacterial preservatives. Therefore, it is advised 
that the reconstituted product be discarded eight hours after dilution. 
 
Administration: Intravenous infusion. 
 
Supplier: Carboplatin is commercially available and should be purchased by a third party. 
 
Paclitaxel 
 
Dose: 30mg/m2 weekly during RT 
 
Chemistry: Paclitaxel is a semi‐synthetic antimicrotubule agent that promotes the assembly of 
microtubules from tubulin dimers and stabilizes 
microtubules by preventing depolymerization hence producing abnormal bundles of microtubules 
throughout the cell cycle. As a result, paclitaxel inhibits interphase and cellular function. 
 
Human Toxicology: Side effects of paclitaxel include: hypersensitivity reaction, myelosuppression, 
alopecia, peripheral neuropathy, nausea/vomiting, mucositis, alkaline phosphatase elevation, abnormal 
EKG, myalgia/arthlagia, asthenia, and hypotension. The development of severe hypersensitivity 
reactions is rare and documented in 1% of patients overall. 
 
Pharmaceutical Data 
Kinetics: Following IV administration, plasma concentrations decline in a biphasic manner due initially to 
distribution and later due to slow efflux of the drug from the peripheral compartment. Pharmacokinetic 
studies have demonstrated extensive extravascular distribution and/or tissue binding of paclitaxel. In 
addition, paclitaxel has been demonstrated to be highly protein bound (89‐98% of infused sample). The 
drug is extensively non‐renally cleared with 71% excreted via GI tract and 14% via renal clearance. It has 
been demonstrated to be metabolized primarily by CYP450 2C8 and to a lesser extent 3A4. As a result, 
the pharmacokinetics of paclitaxel may be altered in vivo as a result of interactions with compounds that 
are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4 
 
Formulation: Paclitaxel is a clear, colorless slightly yellow viscous solution intended for dilution prior to 
intravenous infusion. Each mL of sterile non‐pyrogenic solution contains 6 mg paclitaxel, 527 mg of 
purified Cremophor, and 49.7% dehydrated alcohol: 
 
Storage and Stability: Unopened vials of paclitaxel for injection are stable for the life indicated on the 
package when stored at controlled room temperature (20‐25oC), and protected from light. Neither 
freezing nor refrigeration adversely affects the stability of the product. When reconstituted as directed, 
the solution of carboplatin exhibits no decomposition for up to 27 hours at room temperature (25 oC). 
Administration: Intravenous infusion. 
 
Supplier: Paclitaxel is commercially available and should be purchased by a third party. 


19 
 
 
 
 
 
 
Pre‐ 
Therapy 
Between 
fraction 8 
and 12 
Weekly 
during 
CRT6 
 
+ 1 
Month7 
 
+ 3 
month7 
 
+ 6 month7 
 
+ 12 month7 
 
+ 24 month7 
Rad Onc eval7 
X 
 
X 
X 
X 
X 
X 
X 
CBC with diff 8 
X 
 
 
 
 
 
 
 
CMP, Mg 8 
X 
 
X 
 
 
 
 
 
PET/CT3 
X 
X 
 
 
X 
 
 
 
DCE‐MRI10 
X 
X 
 
 
 
 
 
 
Toxicity 
Evaluation4 
X 
 
X 
X 
X 
X 
X 
X 
Nutritional assessment 
by MD 
X 
 
 
 
 
 
 
 
QOL 
Questionnaire5 
X 
 
X 
X 
X 
X 
X 
 
Videofluoroscopy1 
X 
 
 
 
X 
 
X 
 
Dental 
Evaluation2 
X 
 
 
 
 
 
 
 
Carboplatin/paclitaxel   
 
X 
 
 
 
 
 
Blood for correlatives9 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Primary tumor 
specimen for 
correlatives11 
 
X 
 
 
 
 
 
 
 


20 
 
1) Videofluoroscopy to be completed prior to or during the first week of chemoradiation, 3 mo post RT and 12 mo post‐RT per standard of care. 
When staff is not available to complete the videofluoroscopy tests, these will be skipped and listed as deviations. 
2) Pre‐therapy dental evaluation is encouraged but not required for all patients due to insurance issues 
3) PET‐CT to be completed at baseline within 4 wks of registration, mid‐treatment (fx 8‐12) and 3 mo post‐RT (+/‐ 3 weeks) 
4) Toxicity evaluation per CTCAE v 5.0 
5) QOL suggested but not required. Patients have the option to complete these remotely and mail, fax, or send through the patient portal to the 
study clinic. Financial toxicity will only be given at one‐time point 3 months post RT. All other questionnaires given pre‐therapy and all follow‐ups 
through 1 year.  The CTCAE PRO will be given weekly during RT (this will be the only questionnaire administered during RT). 
6) Weekly during CRT: Virtual monitoring visits will be allowed at the discretion of the provider. 
7) Follow Up: Examinations will be performed as comparable to clinical practice: at 1 month (+/‐ 2 weeks) after the completion of therapy and then 
approximately every 3 months (+/‐ 1 month) for 2 years (+/‐ 2 months). This follow up schedule will adhere to standard of care clinical follow up. 
Therefore, missed visits and visits that diverge from this regimen will not be considered protocol deviations. RadOnc evaluation must be 
completed at baseline, but follow‐up visits may be completed by RadOnc, Oto, or MedOnc. Virtual monitoring visits will be allowed at the 
discretion of the provider. 
8) Within 4 weeks of registration 
9) Serum samples will be obtained if the local lab is available for processing pre‐therapy, weekly during chemoradiation, 1 month and every 3 
months post therapy and at recurrence. Subjects who do not provide some samples, miss time‐points or decline any or all of the sample 
collections will not be reported as protocol deviations. 
10) DCE‐MRI is not required if contraindicated or patient refuses 
11) Contact the PI if sample is not available 


21 
 
8.0 
Evaluation of Response to Therapy 
 
Toxicities related to treatment will be evaluated using the Common Toxicity Criteria Adverse Events 
(CTCAE, version 5.0) weekly during treatment and at every follow‐up visit for 2 years. 
 
Quality of Life Questionnaires (U Washington QOL, xerostomia questionnaire (XQ), FACT HN, CTCAE 
PRO, financial toxicity) will be given to patients at follow‐up research visits after completion of 
definitive therapy through 1 year. As patients can be seen in a variety of clinics, and occasionally do not 
follow a standard clinic schedule, missed QOLs will not be reported as a protocol deviation. Patients 
have the option to complete these remotely and mail, fax, or send through the patient portal to the 
study clinic. 
 
PET/CT will be obtained at 3 months (+/‐ 2 weeks) post definitive therapy. 
 
Repeat videofluoroscopy will be performed at approximately 3 and 12 months (+/‐ 1 month) after 
completion of radiotherapy to correlate with clinical follow‐up. When staff is not available to complete 
the videofluoroscopy tests, these will be skipped and listed as protocol deviations. 
 
Blood/plasma draws for correlative studies will be collected at each follow up visit through 1 
year. These will only be collected if the local lab is available for processing. 
 
Response Assessment Criteria 
 
Response will be captured by standard clinical and radiological documentation. The designations will 
be: (1) NED; (2) failure primary tumor; (3) failure regional node; (4) distant metastasis. Any notation of 
failure at the primary tumor or regional node is considered local‐regional progression. Initial staging 
imaging will be obtained at registration; then routine imaging will be obtained at 3 months (+/‐ 1 
month) from completion of definitive therapy. Imaging will be combined to make as few visits and 
encounters as possible for the patient. 
 
Decision to obtain further imaging will be left to the provider (i.e. if on clinical exam there are signs 
concerning for disease recurrence). 
 
If there is clinical or radiologic evidence concerning for recurrent malignancy, confirmatory biopsy will be 
required before designating the patient to have recurrent disease. 
 
9.0 
Criteria for Discontinuation of Treatment 
 
 
Unacceptable adverse event(s). 
 
Intercurrent illness, which prevents further administration of treatment. 
 
Patient preference. 
 
Progressive disease. 
 
Life threatening or other unacceptable drug‐related toxicity. 
 
General or specific changes in the patient’s condition that render the patient unacceptable 
for further treatment in the judgment of the investigator(s). 


22 
 
Duration of Follow‐Up 
 
Patients will be followed for 2 years after removal from treatment or until death, whichever occurs first. 
Patients removed from treatment for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. 
 
Examinations (virtual or in‐person) will be performed as comparable to clinical practice: at 1 month after 
the completion of therapy and then approximately every 3 months for 2 years (+/‐ 2 months). This follow 
up schedule will adhere to standard of care clinical follow up. Therefore, missed visits and visits that 
diverge from this regimen will not be considered protocol deviations. 
 
Off Study Criteria 
 
Patient withdraws consent (termination of treatment and follow‐up); 
 
Loss of ability to freely provide consent through imprisonment or involuntary incarceration for 
treatment; 
 
Patient is unable to comply with protocol requirements; 
 
Treating physician judges continuation on the study would not be in the patient’s best interest; 
 
Patient becomes pregnant (pregnancy to be reported along same timelines as a serious adverse 
event); 
 
Development of second malignancy (except for basal cell carcinoma or squamous cell carcinoma of the 
skin) that requires treatment, which would interfere with this study; 
 
If a research subject cannot be located to document survival after a period of 2 years, the subject may 
be considered “lost to follow‐up.” All attempts to contact the subject during the two years must be 
documented; 
 
Termination of the study by The University of Michigan; 
 
Patient completes protocol treatment and follow‐up criteria. 
 
10.0 
Adverse Event Reporting 
 
An adverse event is any new, undesirable medical experience or change of an existing condition which 
occurs during or after treatment, whether or not considered product‐related. 
 
A serious adverse event is any untoward medical occurrence that suggests significant hazard 
or side effect that: 
1. is fatal or life‐threatening 
2. required or prolonged hospitalization 
3. results in persistent or significant disability/incapacity 
4. constitutes a congenital anomaly or a birth defect 
5. is medically significant, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
The definition of serious adverse event (experience) also includes important medical events. Medical and 
scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other 
situations, such as important medical events that may not be immediately life‐threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should also usually be considered serious. Examples 
of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization. 


23 
 
Attribution: Definitions of relationship to study are as follows: 
 
UNRELATED: The AE is clearly NOT related to the intervention/investigational agent. 
UNLIKELY: The AE is doubtfully related to the intervention/investigational agent. 
POSSIBLY: The AE may be related to the intervention/investigational agent. 
PROBABLY: The AE is likely related to the intervention/investigational agent. 
DEFINITELY: The AE is clearly related to the intervention/investigational agent. 
 
Adverse events attributable to the chemotherapy will be reported if the adverse events are at an 
intensity that is more severe than previously documented or considered significant by the 
investigator. The definition of “related” is that there is a reasonable possibility that the drug caused 
the adverse experience. 
If required on the  adverse event  case report  forms,  the  investigator will  use the following definitions of 
severity in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0 to describe the maximum intensity of the adverse event. If the event is serious, the 
CTCAE grade reported in the adverse event CRF must be consistent with the description of CTCAE grade 
included in the narrative section of the serious adverse event report. 
GRADE        Clinical Description of Severity 
0 
no change from normal or reference range 
1 
mild adverse event 
2 
moderate adverse event 
3 
severe adverse event 
4 
life‐threatening or disabling adverse event 
5 
death related to adverse event 
 
Information  about all adverse events,  whether volunteered  by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be collected 
and recorded and followed as  appropriate.  An adverse event is any undesirable sign, symptom or medical 
condition occurring after starting study drug (or therapy) even if the event is not considered  to be related 
to study drug (or therapy). Study drug (or therapy) includes the drug (or therapy) under evaluation, and any 
reference or placebo drug (or  therapy)  given during any phase of the trial. If it is unclear  what  study 
treatment includes, list all drug(s), other therapies, changes to existing therapy, diagnostic procedure, etc. 
that are specified by the protocol 
Medical conditions/diseases present before starting study treatment  are  only considered  adverse events 
if they worsen after starting study treatment (any procedures specified in the protocol). Adverse events 
occurring  before  starting  study  treatment  but  after  signing  the  informed  consent  form  are  recorded. 
Abnormal laboratory values or test results constitute adverse events only if they induce clinical signs or 
symptoms or require therapy, and are recorded. 


24 
 
Events not considered to be serious adverse events are hospitalizations for the: 
 
routine treatment or monitoring of the studied indication, not associated with any deterioration in 
condition. 
 
treatment, which was elective or pre‐planned, for a pre‐existing condition that did not worsen 
 
treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions of 
serious given above and not resulting in hospital admission. 
 
Pregnancy, although not itself a serious adverse event, should also be reported on a serious 
adverse event form or pregnancy form and be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any birth 
defects or congenital abnormalities. 
 
Any serious adverse event occurring after the patient has provided informed consent, has started 
taking the study medication, and until 4 weeks after the patient has stopped study treatment 
discontinuation must be reported. This includes the period in which the study protocol interferes 
with the standard medical treatment given to a patient (e.g. treatment withdrawal during washout 
period, change in treatment to a fixed dose of concomitant medication). The period after 
discontinuing study drug may be extended if there is a strong suspicion that the drug has not yet 
been eliminated. 
 
Instructions for rapid notification of serious adverse events 
All  serious  adverse  events  (SAEs)  and  unanticipated  problems  (UPs),  regardless  of  causality  to  study 
treatments, will be reported to the Principal Investigator and also to the Coordinating Center.  All SAEs and 
UPs must be reported to the Coordinating Center within 24 hours of first awareness of the event. Events 
should  be  reported  using  the  Coordinating  Center  SAE  form  as  available  in  the  study.  A  copy  of  the 
Coordinating Center SAE form as available in the study database should be sent to the Coordinating Center 
via fax at 734‐232‐0744 or via email to CTSU‐Oncology‐Multisite@med.umich.edu within 24 hours of the 
site’s knowledge of the event. 
 
Contact information for Principal Investigator SAE Reporting: 
Name: Michelle Mierzwa, MD 
Email: mmierzwa@med.umich.edu 
 
Follow‐up information must also be reported within 24 hours of receipt of the information by the 
investigator. 
 
All SAEs and UPs will be reported to the IRB per local site’s current institutional standards. 
 
The Coordinating Center will disseminate information regarding SAEs and UPs to the participating sites 
within 5 days of review of the information by the Coordinating Center’s Principal Investigator (or designee 
in the event of extended absence) only in the case that the event(s) is believed to be related (i.e., possibly, 
probably, or definitely) to the study treatment(s). 
 
All adverse events will be noted in the case report forms 
 
11.0 
Data and Safety Monitoring 
 
This study will be monitored in accordance with the NCI approved University of Michigan Rogel Cancer 
Center Data and Safety Monitoring Plan, with oversight by the Rogel Cancer Center Data and Safety 


25 
 
Monitoring Committee (DSMC). 
 
The Sponsor Investigator (S‐I)/Study Principle Investigator will provide ongoing monitoring of data and 
patient safety in this trial and conduct regular data review with participating sites. 
 
The Sponsor Investigator (S‐I)/Study Principle Investigator and/or the Project Manager/Delegate will 
review data and patient safety issues with participating sites per defined quarterly meeting cadence. 
Depending on the protocol activity, the meeting cadence may be more frequent. This data review meeting 
may be achieved via a teleconference or another similar mechanism to discuss matters related to: 
 
 
Enrollment rate relative to expectations, characteristics of participants 
 
Safety of study participants (SAE reporting, unanticipated problems) 
 
Adherence to protocol (protocol deviations) 
 
Completeness, validity and integrity of study data 
 
Retention of study participants 
 
Participating sites are required to ensure all pertinent data for the review period are available in the 
database at the time of the discussion. 
 
Participating sites unable to participate in the data review meeting are required to provide written 
confirmation that their site has reviewed the relevant data and patient safety issues for the review period 
and their site’s data are in alignment with the data reported in the database. Written confirmation is to be 
provided to the Project Manager/Delegate within the timeline requested to retain compliance with 
monitoring timelines. 
 
Documentation of the teleconference or alternate mechanism utilized to review items above is to be 
retained in the Trial Master File. 
 
The Project Manager/Delegate is responsible for collating the data from all participating sites and 
completing the Protocol Specific Data and Safety Monitoring Report (DSMR) form to document the data 
review meeting discussion. 
 
The DSMR will be signed by the Sponsor‐Investigator (S‐I)/Study Principal Investigator or designated Co‐ 
Investigator and submitted to the DSMC on a quarterly basis for independent review. 
 
 
12.0 
Data Handling and Record Keeping 
 
All information will be recorded locally and entered into Case Report Forms (CRFs) on the web‐based 
electronic data capture (EDC) system of the University of Michigan. Online access will be provided to each 
site by the Coordinating Center. 
 
CRFs will be reviewed and source verified by the MSC during annual monitoring visits and prior to and 
between visits. Discrepant, unusual and incomplete data will be queried by the MSC. The investigator or 
study coordinator will be responsible for providing resolutions to the data queries, as appropriate. The 
investigator must ensure that all data queries are dealt with promptly. 
 
The data submission schedule is as follows: 
 
At the time of registration 


26 
 
 
Subject entry into EDC 
o Subject Status 
o Demographics 
 
During study participation 
 
All data should be entered online within 10 business days of data acquisition. [Information on dose 
limiting toxicity events must be entered within one business day.] Information on Serious Adverse 
Events must be entered within the reporting timeframe specified in Section 10 of the protocol. 
 
All study information should be recorded in an appropriate source document (e.g. clinic chart). 
 
Record Retention 
To enable evaluations and/or audits from regulatory authorities, the investigator agrees to keep records, 
including the identity of all participating subjects (sufficient information to link records, e.g., CRFs and 
hospital records), all original signed informed consent forms, copies of all CRFs, serious adverse event 
forms, source documents, and detailed records of treatment disposition. The records should be retained 
by the investigator according to the Coordinating Center’s Standard Practice Guidelines. 
 
13.0 
Statistical Considerations and Justification of Sample Size 
Description and Justification of Design 
 
This is a two arm, non‐randomized, phase II study. A total of 85 evaluable patients will be enrolled and 
treated. Subjects will be considered evaluable for the primary  endpoint after completing the baseline 
PET‐CT scan, beginning protocol treatment, and completing the mid‐treatment PET‐CT scan.  Patients that 
do not meet evaluability criteria will be replaced.   
 
All patients will initially receive the same treatment. Based on the mid‐treatment PET scan, patients who 
meet the criteria described in section 6.1 will receive de‐escalated treatment (54 Gy) while patients not 
meeting all of these criteria will receive standard treatment (70 Gy). Both the de‐escalation criteria and 
the de‐escalated treatment (RT) will be applied separately to the primary tumor and the lymph nodes. 
Arm 1 will be all patients who did not qualify for de‐escalation in either the primary tumor or lymph 
nodes; Arm 2 will include all patients who qualified for de‐escalation in either the primary tumor or the 
lymph nodes. 
 
The overall goal is to reduce dose of RT and thus toxicity in patients with very favorable prognosis with 
minimal  reduction  in  tumor  control.  The  sample  size  is  justified  with  respect  to  the  primary  aim  of 
estimating the risk of local‐regional recurrence (LRR) within 2 years of treatment for all patients treated on 
this protocol.  The estimated proportion of patients with LRR at 2 years was 12% in a retrospective analysis 
of 515 previously treated patients at UM or VA who were treated with standard treatment (ChemoRT with 
Radiation Dose of 70Gy) and would have been eligible for this study. By selectively lowering radiation doses, 
we cannot decrease LRR rates. However, we would like high power to demonstrate that the true overall 
LRR at 2 years is less than 25%. The null hypothesis to be tested in this non‐inferiority analysis is H0: LRR > 
25% and the alternative hypothesis is HA: LRR < 25%. When the true LRR is 15% (slightly higher than the 
historical control rate of 12%), a sample size of 68 patients provides 80% power at a significance level of 
.10 based on a one sample binomial test with a normal approximation. Based on the retrospective analysis 
of prior patients, we expect few deaths without prior LRR (< 5%) and few patients in this population to be lost 
to follow‐up during the 2 years following treatment. However, to allow for 10% of patients lost to follow‐
up prior to 2 years, we will enroll 85 evaluable patients. If more patients are lost to follow‐up than we expect, 
we will estimate the risk of LRR at 2 years as 1 – the Kaplan‐Meier estimate of local regional control and 
compare the upper 1‐sided 90% confidence limit to 25%. Based on previous experience, a combined 60‐80 


27 
 
eligible  patients  per  year  will  be  seen  in  Radiation  Oncology  at  UM  and  AAVA.  Assuming  successful 
enrollment of 1/2 of these patients we expect to enroll 85 evaluable patients in approximately 3‐4 years. 
 
Preliminary analysis focused on toxicity presented at the ASTRO multi‐disciplinary oral plenary session in 
February 2022 (Allen, et al, 2022) showed that 50% of the first 50 patients were able to be de‐escalated 
and showed significantly improved objective measures of toxicity in the patients who were able to be de‐
escalated to 54Gy.  Additionally, while the study has not yet met its primary endpoint, we have performed 
a preliminary LRC analysis in February 2022 for the primary endpoint with a median follow‐up of 20 months 
in the first 65 patients showing LRC is >95% with only 1 patient having loco‐regional failure.  Our data to 
date suggest that patients have favorable LRC compared to historic control and favorable toxicity on this 
trial and increasing the enrollment to 85 evaluable patients will improve our power to show LRC non‐
inferiority of our approach.   
 
Interim Analysis 
We will conduct one interim analysis after 30 evaluable patients have completed their 6‐month follow‐up. 
Based on an expected accrual rate of 30 patients per year this will likely occur about 18 months after trial 
initiation or when 45 total patients have been enrolled. The goal of the interim analysis will be to halt the 
trial if there is sufficient evidence that the true LRR rate in these patients exceeds 20%.  Specifically, if more 
than 6 of the first 30 patients experience LRR, the trial will be halted. If the true LRR is 25 or 30%, the 
probability of the trial stopping early is 65% and 85%, while if the true LRR rate is 10%, the probability of 
stopping early is only 3%. 
The interim analysis was completed and results indicated no safety issues and no changes needed to the 
protocol, including the study’s de‐escalation criteria. 
 
Analysis Plan 
The primary study endpoint will be the binary occurrence of LRR within 2 years of treatment. We expect 
very few patients to be lost to follow‐up or die within the first 2 years and so expect to observe this 
endpoint in nearly all patients.  LRR rates over time will also be estimated as a survival type endpoint using 
the Kaplan‐Meier method in which patients with no observed LRR are censored at the last date they were 
assessed for LRR. The cumulative incidence of LRR will also be estimated treating death prior to LRR and 
distant failure as competing risks. The primary study analysis will be based on comparing a 1‐sided upper 
90% confidence limit for the 2 year LRR rate to 25%. An upper bound below 25% will be interpreted as 
evidence that the true rate of LRR is less than 25% which is the goal of the study. In the primary analysis, 
all patients will be analyzed together as the goal of the study is to estimate risk of LRR in this patient 
population  treated  with  this  individualized  de‐escalation  strategy  in  which  some  patients  continue  to 
receive  standard  therapy  while  others  are  de‐escalated.  Results  will  also  be  estimated  and  reported 
separately for patients receiving standard or de‐escalated therapy but recognizing that these two groups 
of patients differ in an important prognostic variable (mid‐treatment PET) as well as treatment. The second 
primary aim involves the use of an early imaging variable to predict future risk of LRR. Specifically, the 
change in MTV50% at the mid‐treatment timepoint will be calculated as percent change from baseline and 
used as a continuous variable in a Cox model for an outcome of time to LRR.  We will also evaluate more non‐ 
parametrically, the relation between hazard of LRR and mid‐treatment MTV50% using a kernel estimator in a 
Cox model. 
 
Secondary aims include estimation of toxicity, efficacy and other outcomes.  The key toxicity outcomes are 
the  patient  reported  XQ  score  (capturing  Xerostomia)  and  HNQOL  eating  domain.  Both  variables  are 
assessed longitudinally with primary interest on the 3 month values.  Due to lack of xerostomia at baseline, 
we will work with the absolute scores over time while for HNQOL we will work with change from baseline 


28 
 
(pre‐treatment). To characterize patterns of failure we will summarize at fixed timepoints, the proportion 
of patients who progressed in any location and whether the first progression was local, regional or distant 
or in multiple locations.  Overall survival will be estimated using the Kaplan‐Meier methods with associated 
90% confidence intervals. Toxicity outcomes will be estimated as proportions of patients with available 
toxicity data at 3, 6 12 and 24 months.  They will also be estimated as the proportion of all treated patients 
through cumulative incidence estimates with death treated as a competing risk and censoring for patients 
lost to FU. Quality of Life (QOL) outcomes and swallowing study results will be summarized descriptively by 
timepoint.  If  there  is  substantial  missingness  in  the  QOL  outcomes  we  will  assess  for  informative 
missingness by comparing earlier QOL scores and change in earlier QOL scores between patients missing 
QOL at later timepoints (e.g. 1 or 2 years). 


29 
 
Another secondary endpoint includes determination of the fraction of patients in whom we lose the ability 
to detect ctDNA during the fourth week of RT. Based on a recent abstract reporting similar data (Chera, 
ASTRO 2017), we expect approximately 90% of patients to have detectable ctDNA at baseline and about 
33% of these to have no detectable ctDNA at the 4 week mid‐treatment timepoint. Thus we expect that 
about 30% of all enrolled patients will fall into the category of ctDNA detectable at baseline but not 4 
weeks. A sample size of 85 evaluable patients will provide at least 85% power to rule out proportions of 
15% or less when the true proportion is 30%. The ctDNA data will be analyzed in several ways. First, the 
proportion of patients in whom ctDNA is detectable will be summarized as a binomial proportion at each 
timepoint. Patients with detectable ctDNA at baseline that disappears during treatment are potential 
targets for treatment de‐escalation and are of particular interest. One of the goals of this analysis will be 
to estimate what proportion of trial patients fall into this category. Additionally, the relation between 
ctDNA presence or other characteristics and patient outcomes including time to local or distant 
progression will be assessed by including ctDNA as a covariate in Cox models for local or distant control. 
 
Exploratory endpoints include cell free DNA (cfDNA) characterization of ADC and low blood volumes from 
DCE‐MRIADC values and low blood volumes will also be summarized descriptively. 
 
14.0 
Justification of the Correlative Science 
 
Hypothesis: Recurrent cancer in HPV positive OPSCC can be detected in serum biospecimens collected at 
routine interval time points and will identify tumor recurrence earlier than clinical exam. 
 
Correlative Justification 
 
Patients enrolling in deintensification trials for HPV+ OPSCC are at risk for treatment failure, thus careful 
monitoring in the post‐treatment period is of extreme importance. The measurement of  serum circulating 
free (cf)DNA and antitumor antibodies as a biomarker for recurrence may be an important, noninvasive 
method to detect treatment failures. We have previously examined serum antitumor antibodies (E6 and 
E7) in a longitudinal sample of patients who were treated under UMCC 2002‐0221. Our preliminary data 
indicate that patients who have decreased clearance of E6/E7 antibody from their baseline measurement are 
at risk for disease recurrence. Finally, we have funding to perform targeted next generation sequencing on 
the primary tumor specimens from all patients enrolling in this trial, which can be used to prioritize evaluable 
somatic mutations in cfDNA from the blood of each patient for targeted sequencing studies (Hypothesis 1). 
Therefore, our goal is to collect longitudinal samples of serum as a part of our trial to determine if serum 
biomarkers can predict recurrence in HPV+ OPSCC. Our hypothesis is that serum biospecimens collected at 
routine interval time points will identify tumor recurrence earlier than clinical exam. 
 
ctDNA Sample Collection 
 
We plan to collect and bank serial serum samples if the local lab is available for processing until 36 months 
from diagnosis. These samples are obtained at baseline, weekly during chemoradiation, 1 month and every 
3 months post‐therapy and at recurrence (see Study Calendar). Samples will be banked for planned analysis 
in the Brenner lab. 
 
Blood Samples 
Patient’s blood will be drawn if the local lab is available for processing at baseline, during treatment, and at 
4 wks, 3 mo, 6 mo, and 12 months post‐therapy as part of their routine follow up appointments. 


30 
 
 
Two heparinized green top 6 mL tubes and two Paxgene tubes at baseline only. 
 
Subsequent draws will include two Paxgene tubes only.  Sample tubes will be provided by Brenner Lab. 
 
We will extract measure cfDNA from serum samples using the QIAamp Circulating Nucleic Acid Kit 
according to manufacturer instructions, cfDNA will be sequenced according to standard protocol in 
the Brenner lab and we will use our previous technique with an ELISA assay to determine E6 and E7 
antibody levels. 
 
Sample Transportation 
Whenever as specimen has been obtained (i.e. after a blood draw), the study coordinator will transport the 
sample directly to the Brenner laboratory. 
 
DCE‐MRI 
 
Hypothesis: Changes in BV and apparent ADC seen on DCE‐MRI between pre‐treatment and mid‐therapy 
will be significantly inversely correlated with changes in MTV50%. 
 
Methods: 
The MRI scan will be performed in the exact patient position used for the simulation CT, including the 
same head rest and mask used for simulation. The MRI scanner installed recently at the UM Department 
of Radiation Oncology will be used for imaging. It has a large bore which facilitates imaging using these 
devices. Images will include FLAIR T2‐weighted imaging, pre contrast T1‐weighted imaging, diffusion 
weighted imaging, T1‐weighted dynamic contrast enhancement imaging with single‐bolus intravenous 
injection of Gd‐DTPA, and post Gd‐DTPA T1‐weighted imaging.  All images will be obtained with multiple‐ 
slices or 3D to cover the whole tumor volume.  The scan time will be estimated to be one hour. 
 
Identification of Subvolumes of the Tumor 
Global‐initiated regularized local fuzzy clustering (GIRLFC) is a method that is designed to first globally 
initiate training to identify fuzzy clusters of the physiological imaging parameters in the feature  space, and 
then classify each tumor volume with local regularization to subvolumes according to the global feature 
clusters. This method is designed not only to identify the subvolumes of individual tumors based upon the 
heterogeneous  distributions  of  physiological imaging  parameters  but  also  to  be  able  to  compare  the 
classified subvolumes of  the  tumors across patients and over multiple time points. The fuzzy clustering 
method, specifically fuzzy C‐ means clustering (FCM), chosen in the GIRLFC method aims to deal with (1) 
intrinsic variations of the physiological parameters in the tumors, (2) partial volume effects  due  to  the 
limited resolution of imaging sources, and (3) uncertainty due to noise. 
Fuzzy C‐Means clustering is a method of unsupervised learning to assign a set of observations to belong to 
subsets (clusters) with probability memberships. To partition a set of  observations [xk], e.g., image voxels, 
into c clusters, an objective function with local spatial regularization is to be minimized. 
 
 
 


31 
 
In Eq [1], the first term is a standard FCM cost function and the second term provides a spatial constraint 
to overcome the effect of image noise and to improve spatial connectivity. Here uik is a probabilistic (fuzzy) 
membership of observation xk belonging to class i vi is a prototype vector of class i, xk is a mean or median 
value of neighbors of voxel k, m defines fuzziness of  the membership, and α is a weighting factor of spatial 
constraints. A 2D or 3D kennel, depending upon image resolution, can be used to define neighbors of each 
voxel for spatial constraint. Solutions that minimize the objective function of Eq [1] are given by: 
 
 
which  are  solved  iteratively  until  reaching  a  stopping  criterion.  The  values  for  m  and  α  are  usually 
determined empirically. The analysis can be applied to either single‐ or multiple‐ component parameters. 
 
In order to evaluate longitudinal changes in physiological imaging parameters of interest in the tumor, 
 
 
first a set of data is  used as training  data  to determine definitions of clusters (prototype vectors  and 
relationships between fuzzy memberships and observations), and then  the  remaining sets of data are 
partitioned according to the class definitions of training  data.  To avoid a bias from large tumors in training 
data, each of the tumor volumes is up‐sampled or down‐sampled to have an equal number of  voxels 
contributing  to  the  training  data  while  maintaining  the  initial  distribution  of  the  physiological  imaging 
parameters from the original into the re‐sampled tumor. To do so, a histogram of the physiological imaging 
parameters of each tumor is generated, and re‐sampled to create a new tumor volume with the same size. 
The  re‐  created  tumor  volume,  while  preserving  the  original  distribution  (histogram)  of  the  imaging 
parameters,  cannot  maintain  the  original  spatial  relationship  between  voxels,  which  is  not  critical for 
training data to determine prototype vectors of global clusters. To partition individual tumors in the second 
data set, fuzzy membership of each voxel of each tumor is classified using the prototype vectors found in 
analysis of the training data by Eq [2], where spatial constraint is used to improve spatial continuity. Finally, 
the highest probability of fuzzy membership of each voxel is used to  assign  the voxel to a discreet class. 
As a result, the tumor is partitioned into spatial subvolumes based upon the similarity of the physiological 
parameters of interest. The temporal changes in partitioned subvolumes  of  the tumor are evaluated for 
their association with outcomes. 
To evaluate this method to identify significant subvolumes of the tumor related to outcomes, we will apply 
the method to BV and BF images derived from DCE MRI of patients with advanced head and neck cancer. 


32 
 
Diffusion‐weighted MRI 
A diffusion weighted, single shot, spin‐echo, echo planar imaging  (EPI)  series  with  diffusion sensitization 
will  be  constructed  along  three  orthogonal  directions,  with  the  diffusion‐weighted  images  (DWI) 
contributing approximately two minutes of scan time to the MRI. The product of the three orthogonal DW 
images exhibits strong sensitivity to diffusion but without sensitivity to the structural directionality of the 
tissues. This isotropic feature is crucial to follow serial changes in water diffusion without confounding 
effects due to tissue orientation. ADC maps will be calculated from the DW images 
 
as follows: 
where S is the DW image at b‐values of b0=0 and b1=800 s/mm2. 
 
Subsequent to image registration, contours will be manually drawn over tumors as delineated on T2‐ 
weighted, T1‐weighted or contrast‐enhanced images. From the volume‐of‐interest (VOI) tumor volume 
and mean ADC will be assessed pre‐ and 2 weeks post‐treatment initiation. Subsequent to contouring 
the tumors, a geometric warping interpolant, i.e. thin plate spline, algorithm will be used to map (warp) 
the  tumor  volumes  from  interval  exams  onto  the  tumor  volumes  from  pre‐therapy  b0  DW  images 
(reference  dataset).  The  Parametric  Response  Map  of  ADC  (PRMADC)  will  be  determined  by  first 
calculating the  difference between the ADC  values (∆ADC = mid‐treatment ADC – pre‐treatment ADC) for 
each voxel within the tumor pre‐ treatment and at week 2 post‐treatment initiation. Voxels yielding 
∆ADC greater than a predetermined threshold set to 25 ADC units [= x 10‐5 mm2/s]  will be  designated as 
significantly increased. Voxels whose ADC values significantly decreased by more than 25 x 10‐5 mm2/s (i.e. 
∆ADC < ‐25 x 10‐5 mm2/s) will be designated as significantly increased, and the rest of the voxels as non‐
changed. The volume fractions within the tumor as determined by PRMADC will be denoted by PRMADC+ 
(increased  ADC),  PRMADC‐  (decreased  ADC),  and  PRMADC0  (unchanged  ADC).  PRM  thresholds  of 
significant change will be empirically assessed over a range of ∆ADCs (0 to 70). PRMADC+ with a threshold 
of ±25 ADC units provided the best correlation with tumor control in our previous study (Galban et al) and 
will be tested in the current study. 
 
 
Risks in MRI 
 
Our MRI protocol has risks and discomforts similar to clinical MRI with intravenous injection of a contrast 
agent. Subjects run the risk of claustrophobia when they are lying inside the MRI scanner. They may also 
feel uncomfortable because of the loud noises made by the machines and the physical sensations they 
may feel during the process. Subjects are also exposed to some risk because of the injected contrast 
agent, gadolinium‐DTPA, which may cause headache, nausea, and local burning. Because of the use of the 
contract agent, all female subjects of child‐ bearing potential will be required to use adequate birth 
control. Patients who have implanted or internalized metallic objects cannot participate in this research. 
Recent FDA guideline indicates there is an association between exposure to gadolinium and the 
development of Nephrogenic Fibrosing Dermopathy (NFD) (also known as Nephrogenic Systemic Fibrosis 
(NSF)) in 3‐5% of the patients with advanced renal failure. We will follow the Institutional Standard 


33 
 
Practice guidelines, which is based upon the FDA guideline, to screen the patients with renal disease, 
dysfunction, and dialysis for this study. 
 
 
15.0      Quality Assurance and Audits 
 
The Data and Safety Monitoring Committee can request a ‘for cause’ quality assurance audit of the trial 
if the committee identifies a need for a more rigorous evaluation of study‐related issues. 
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its conduct 
or even after its completion. If an inspection has been requested by a regulatory authority, the site 
investigator must immediately inform the Coordinating Center that such a request has been made. 
 
16.0 
Clinical Monitoring Procedure 
Clinical studies coordinated by The University of Michigan  Rogel Cancer Center must be conducted  in 
accordance  with  the  ethical  principles  that  are  consistent  with  Good  Clinical  Practices  (GCP)  and  in 
compliance with other applicable regulatory requirements. 
 
This study will be monitored by a representative of the Coordinating Center of the University of Michigan 
Rogel Cancer Center. Monitoring visits will be made during the conduct of the study and at study close‐out. 
 
Prior to subject recruitment, a participating site will undergo site initiation meeting to be conducted by the 
Coordinating Center. This will be done as an actual site visit; teleconference, videoconference, or web‐ 
based meeting after the site has been given access to the study database and assembled a study reference 
binder. The site’s principal investigator and his study staff should make every effort in attending the site 
initiation meeting. Study–related questions or issues identified during the site initiation meeting will be 
followed‐up  by  the  appropriate  Coordinating  Center  personnel  until  they  have  been  answered  and 
resolved. 
 
Monitoring of this study will include both ‘Centralized Monitoring’, the review of source documents at the 
Coordinating Center and ‘On‐site Monitoring’, an actual site visit. The first ‘Centralized’ visit should occur 
after  the  first  subject  enrolled  completes  treatment.  The  study  site  will  send  the  de‐identified  source 
documents to the Coordinating Center for monitoring. ‘Centralized’ monitoring may be requested by the 
Coordinating Center if an amendment requires changes to the protocol procedures. The site will send in 
pertinent de‐identified source documents, as defined by the Coordinating Center for monitoring. 
 
The first annual ‘On‐site’ monitoring visit should occur after the first five study participants are enrolled or 
twelve  months  after  a  study  opens,  whichever  occurs  first.  The  annual  visit  may  be  conducted  as  a 
‘Centralized’ visit if less than three subjects have enrolled at the study site. The type of visit is at the 
discretion of the Coordinating Center. At a minimum, a routine monitoring visit will be done at least once 
a year, or once during the course of the study if the study duration is less than 12 months. The purpose of 
these visits is to verify: 
 
 
Adherence to the protocol 
 
Completeness and accuracy of study data and samples collected 


34 
 
 
Proper storage, dispensing and inventory of study medication 
 
Compliance with regulations 
 
During a monitoring visit to a site, access to relevant hospital and clinical records must be given by the site 
investigator to the Coordinating Center representative conducting the monitoring visit to verify consistency 
of data collected on the CRFs with the original source data.  While most patient cases will be selected from 
patients accrued since the previous monitoring visit, any patient case has the potential for review.  At least 
one or more unannounced cases will be reviewed, if the total accruals warrant selection of unannounced 
cases. 
 
The Coordinating Center expects the relevant investigational staff to be available to facilitate the conduct 
of the visit, that source documents are available at the time of the visit, and that a suitable environment 
will be provided for review of study‐related documents. Any issues identified during these visits will be 
communicated to the site and are expected to be resolved by the site in a timely manner. For review of 
study‐related documents at the Coordinating Center, the site will be required to ship or fax documents to 
be reviewed. 
 
Participating site will also undergo a site close‐out upon completion, termination or cancellation of a study 
to ensure fulfillment of study obligations during the conduct of the study, and that the site Investigator is 
aware  of  his/her  ongoing  responsibilities.  In  general,  a  site  close‐out  is  conducted  during  a  site  visit; 
however, site close‐out can occur without a site visit. 


35 
 
References 
 
Ang KK, Harris J, Wheeler R, et al. Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer. NEJM. 
[epub 2010 June 7]. 
 
Bonner JA, Buchsbaum DJ, Russo SM, et al. Anti‐EGFR‐mediated  radiosensitization  as  a  result  of augmented 
EGFR expression. IJROBP. 59(2 Suppl): 2‐10, 2004 
 
D'Souza G, Kreimer AR, et al. Case‐control study of human papillomavirus and oropharyngeal cancer." NEJM. 356(19): 
1944‐1956, 2007. 
 
Fahkry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus‐positive head and neck 
squamous cell carcinoma in a prospective clinical trial. JNCI. 100(4); 261‐9 [Epub 2008 Feb 12]. 
 
Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset 
of head and neck cancers. J Natl Cancer Inst. 92:709‐20, 2000. 
 
Gillison ML, D'Souza G, Westra W, et al. Distinct risk factor profiles for human papillomavirus type 16‐ positive and 
human papillomavirus type 16‐negative head and neck cancers. J Natl Cancer Inst. 100(6): 407‐20, 2008. [Epub 2008 
Mar 11]. 
 
Hawkins, P. Mierzwa, M, Bellile, E, et al. Impact of AJCC 8th Edition clinical stage and smoking history on overall survival 
and disease‐specific outcomes in human papilloma virus‐associated oropharyngeal squamous cell carcinoma. Head 
Neck 2018.  In press. 
 
Kong FM, Frey KA, et al. A pilot study of [18F]fluorodeoxyglucose positron emission tomography scans during and 
after radiation‐based therapy in patients with non small‐cell lung cancer. J Clin Oncol. 25(21): 3116‐23, 2007. 
 
Kong FM, Hayman JA, et al. Final toxicity results of a radiation‐dose escalation study in patients with non‐ small‐cell 
lung cancer (NSCLC): predictors for radiation pneumonitis and fibrosis. IJROBP. 65(4): 1075‐86, 2006. 
 
Kong FM, Ten Haken RK, et al. High‐dose radiation improved local tumor control and overall survival in patients with 
inoperable/unresectable non‐small‐cell lung cancer: long‐term results of a radiation dose escalation study. IJROBP. 
63(2): 324‐33, 2005. 
 
Mehanna H, Wong WL, McConkey CCet al. PET‐CT Surveillance versus Neck Dissection in Advanced Head and Neck 
Cancer. The New England journal of medicine 2016; 374:1444‐1454. 
 
Pollom EL, Song J, Durkee BYet al. Prognostic value of midtreatment FDG‐PET in oropharyngeal cancer. Head & neck 
2016; 38:1472‐1478. 
 
Schwartz, D, Harris, J, Yao, M. Metabolic tumor volume as a prognostic imaging based biomarker for head and neck 
cancer.  Pilot results for RTOG 0522. Int J Radiat Oncol Biol Phys.  91(4): 721‐9. 
 
Worden, FP, Kumar B, Lee  JS, et  al. Chemoselection as  a strategy  for organ preservation in advanced oropharynx 
cancer: response and survival associated with HPV copy number. J Clin Oncol. 26: 3138‐46, 2008. 

ICF_000.pdf: 
ID: UMCC 2017.113     
Individualized Adaptive De-escalated Radiotherapy for HPV-related Oropharynx Cancer     
NCT03416153


Page 1 of 16
Consent Subtitle: UMCC 2017.113
UM Consent Version:15JUN2022
Model Consent Version: 12APR2022
UNIVERSITY OF MICHIGAN 
CONSENT TO BE PART OF A RESEARCH STUDY
1.  KEY INFORMATION ABOUT THE RESEARCHERS AND THIS STUDY
Study title: (UMCC 2017.113) A Multi-Center Phase II Trial of Individualized Adaptive De-escalated Radiotherapy 
Using Pre and Mid-Treatment FDG-PET/CT for HPV-related Oropharynx Cancer
Company or agency sponsoring the study: University of Michigan Radiation Oncology
Principal Investigator:
Michele Mierzwa, MD, Department of Radiation Oncology, University of Michigan
1.1 Key Study Information
You may be eligible to take part in a research study.  This form contains information that will help you decide 
whether to join the study.  All information in this form is important. Take time to carefully review this information.  
After you finish, you should talk to the researchers about the study and ask them any questions you have.  You 
may also wish to talk to others such as your friends, family, or other doctors about your possible participation in 
this study.  If you decide to take part in the study, you will be asked to sign this form.  Before you do, be sure you 
understand what the study is about.
2. PURPOSE OF THIS STUDY
2.1 Study purpose: 
The purpose of this study is to see if pre-treatment and mid-treatment PET-CTs can be used as markers or guides 
to adapt the amount of radiation therapy given in combination with chemotherapy to patients with HPV-related 
squamous cell carcinoma of the oropharynx.  In this study, if the mid-treatment PET-CT shows that the protocol 
specific parameters are met, the total radiation given will be reduced (54 Gy over 27 fractions).  If the mid-treatment 
PET-CT shows that the protocol specific parameters are not met, the total radiation therapy given will remain at the 
standard of care dose (70 Gy over 35 fractions).
3. INFORMATION ABOUT STUDY PARTICIPANTS (SUBJECTS)
Taking part in this study is completely voluntary.  You do not have to participate if you don't want to.  You may 
also leave the study at any time.  If you leave the study before it is finished, there will be no penalty to you, and 
you will not lose any benefits to which you are otherwise entitled. 
3.1 Who can take part in this study?
Patients with squamous cell carcinoma of the oropharynx (tonsil, base of tongue, oropharyngeal wall, soft palate) 
that is p16 positive or HPV positive are able to participate in this study. 
There are many other inclusion and exclusion criteria which the doctors will use to determine if you can 
participate in this study.  It is important that you discuss your full medical history and all of your medications with 
your doctor.
3.2 How many people (subjects) are expected to take part in this study?
A total of approximately 92 subjects at several institutions will take part in this study, including approximately 82 
subjects from the University of Michigan.
4.  INFORMATION ABOUT STUDY PARTICIPATION
4.1 What will happen to me in this study?  
The study team will explain the research study and answer any questions you have about the study.  If you want 
to participate in the study, the study team will request you sign the consent form prior to any activities occurring 
that pertain to the study.  Once your consent is obtained, the study team will look through your medical chart, ask 
Study ID: HUM00140473   IRB: IRBMED   Date Approved: 7/12/2023   Expiration Date: 6/1/2024


Page 2 of 16
Consent Subtitle: UMCC 2017.113
UM Consent Version:15JUN2022
Model Consent Version: 12APR2022
you questions, and begin scheduling tests and procedures to determine if you are eligible for the study.  The study 
team will inform you of the types of tests and procedures required before the study begins.  
Many of the procedures that will be performed during the study, including routine blood tests, tumor evaluations 
(radiology scans), physical examinations, vital signs (blood pressure, heart rate, breathing rate, and temperature) 
and measurement of height and weight, would normally be done as part of your standard of care regardless of 
study participation.  However, some of these may be done more frequently as a result of your participation in this 
study. One PET-CT, and some blood sample collection and analysis are solely for research purposes.  Tests and 
procedures that are done more often than your regular medical care because of your study participation and that 
are solely for research purposes will be identified below.  The study staff will inform you of the types of tests and 
procedures you have to undergo during the study.  
During the study you must:

Follow the instructions you are given.

Come to the study center for your visits or complete virtual study clinic visits with the study doctor.

Tell the study doctor or study staff about any changes in your health and/or medications you are taking.

Tell the study doctor or study staff if you want to stop being in the study at any time.
Before starting the study:
You will need to have the following exams, tests or procedures to find out if you can be in this study.  If you have 
had some of them recently, they may not need to be repeated.  The screening tests and procedures do not have 
to be completed in one day and you are allowed to take breaks if you have multiple procedures in one day.
Before you begin the study you will need to have the following screening procedures:

Medical history: including any past treatments, surgeries, infection, autoimmune diseases and smoking 
history.

Medications: It is important that you tell your doctor about all of the medications that you have been 
taking, including over the counter medicines, vitamins or herbal treatments.

Physical exam: including measurement of your height, weight, blood pressure, heart rate, respiratory 
rate and temperature. Vital signs are allowed to be measured by you and your family without coming to 
the study clinic.

Performance status: Your ability to perform day to day activities and care for yourself 

Routine blood tests (approximately 2 teaspoons): will be drawn for tests to check blood counts and 
chemistry

Scans of your cancer: 
o
Computed tomography (CT) of the neck and chest.  Additional scans (CT of the abdomen/pelvis 
and/or bone scan) could be performed if your treating doctor feels they are necessary.

A CT scan uses special x-ray equipment to make detailed pictures of body tissues and 
organs.  For the CT scan, you may be given a “contrast material” (a special dye that 
makes it easier for doctors to see different tissues in your body).  You will be asked to lie 
still and may be asked to hold your breath for a few seconds.  The CT scan is done in the 
Radiology Department and takes about half an hour.
o
Magnetic Resonance Imaging (MRI) scan takes an image of your head or body to observe the 
location and size of your tumor.  For the MRI scan, you may be given a “contrast material” (a 
special dye that makes it easier for doctors to see different tissues in your body).  You will be 
asked to lie down on a narrow bed which will slide into a tunnel that is 6 feet long by 22 inches 
across and is open at each end.  You will be asked to lie quietly for about one hour, during which 
time you will hear a loud machine-like noise.  A MRI scan takes about an hour and a half to 
complete. 
Study ID: HUM00140473   IRB: IRBMED   Date Approved: 7/12/2023   Expiration Date: 6/1/2024


Page 3 of 16
Consent Subtitle: UMCC 2017.113
UM Consent Version:15JUN2022
Model Consent Version: 12APR2022

Videofluoroscopy: to evaluate swallowing problems from radiotherapy, you will undergo an evaluation of 
swallowing by videofluoroscopy (VF). VF consists of swallowing a small quantity of barium, or a barium-
coated food such as a cookie, while a series of x-rays are taken of the throat. When staff is not available, 
the videofluoroscopy will be skipped.

Dental exam

Nutritional assessment

The following will be done for research purposes:
If the exams, tests and procedures show that you can take part in the study, and you choose to take part, 
then you will have the following extra screening procedures:
o
Approximately 2-3 teaspoons (12 mL) of blood will be drawn for biomarker tests (substances in 
your blood, such as proteins).  Measuring biomarkers in the blood could help predict whether or 
not someone is likely to benefit from a therapy. 
o
Quality of life questionnaires; you are free to skip any questions that you would prefer not to 
answer.  You can complete these questionnaires at home and mail, fax, or send them through the 
patient portal to the study clinic.
o
Tumor biopsy submission – evaluation of tumor tissue that was already taken; this will include 
genetic testing
o
PET-CT

PET-CT scan uses xray equipment and a contrast dye that detects areas of high metabolic 
activity (cancer has a high metabolic activity).
Treatment
You will start out receiving standard chemoradiation which includes carboplatin and paclitaxel, intravenously 
(meaning it’s given through a vein in your arm) on a weekly schedule at the same time as radiation therapy for a 
total of 6-7 doses and 70 Gy in 35 fractions.
You will undergo a mid-treatment PET-CT and MRI between radiation therapy fraction 8 and 12.  If your PET-CT 
parameters meet the criteria for de-escalation, you will have your standard chemoradiation decreased as follows: 
radiation therapy will be changed to 54 Gy total dose and only 6 doses of carboplatin and paclitaxel at the same 
time as radiation therapy.  
If you PET-CT parameters do not meet the criteria for de-escalation, you will continue your standard 
chemoradiation as described above.
While you are receiving the chemoradiation, you will have the following weekly tests and procedures (virtual or 
in-person):

Physical exam

Routine blood tests to check blood counts and chemistry

Medication review

Toxicity evaluation: You will be asked about any side effects or illnesses you experience
The following tests will be done weekly for research purposes only:

Approximately 2-3 teaspoons (12 mL) of blood will be drawn for biomarker tests. For certain visits, blood 
draws may be skipped based on the availability of the local lab.

Quality of life questionnaire; you are free to skip any questions that you would prefer not to answer.
Study ID: HUM00140473   IRB: IRBMED   Date Approved: 7/12/2023   Expiration Date: 6/1/2024


Page 4 of 16
Consent Subtitle: UMCC 2017.113
UM Consent Version:15JUN2022
Model Consent Version: 12APR2022
Follow-up
You will be asked to return to the clinic or complete virtual clinic visits for check-ups at 1 month after completion 
of therapy and then every 3 months for a total of 2 years. 
You will have the following tests and procedures during follow-up (virtual or in-person):

Physical exam

Medication review

Toxicity evaluation

Videofluoroscopy – 3 month and 12 month only (if staff available)

PET/CT – 3 month only
The following tests will be done in follow-up (through 1 year) for research purposes only:

Approximately 2-3 teaspoons (12 mL) of blood will be drawn for biomarker tests.

Quality of life questionnaires; you are free to skip any questions that you would prefer not to answer.
OPTIONAL Research Samples Stored for Future Use:
Besides the information about the main study, the following information is specific to unspecified future use of 
identifiable data and/or biospecimens.  We would also like your permission to keep some of your blood, tumor 
tissue, and medical information collected in the main study, so that we may study it in future research. The future 
research may be similar to this study or may be completely different.
You can take part in the main study even if you decide not to let us keep your blood, tumor tissue, and medical 
information for future research.
If you give us permission, we will use your blood, tumor tissue, and medical information for future research. Even 
if you give us permission now to keep some of your blood, tissue, and medical information, you can change your 
mind later and ask us to destroy it. Keep in mind, however, that once we have analyzed your blood tissue, we may 
not be able to take the information out of our research.
We may share your blood, tumor tissue, and medical information with other researchers, so that they can use it in 
their research. Their research may be similar to this study or may be completely different. Once we have shared 
your blood, tissue and medical information with other researchers, we will not be able to get it back.  Future use 
of your identifiable data and/or specimens will be conducted in compliance with applicable regulatory 
requirements.
You will not find out the results of future research on your blood and tissue samples. Allowing us to do future 
research on your blood, tissue and medical information will not benefit you directly.
With appropriate permissions, your samples and collected information may also be shared with other researchers 
here, around the world, and with companies.
Your identifiable private information or identifiable biospecimens may be stripped of identifiers and used for 
future research studies or distributed to another researcher for future research studies without additional 
informed consent. 
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Research can lead to new discoveries, such as new tests, drugs, or devices. Researchers, their organizations, and 
other entities, including companies, may potentially benefit from the future research on your blood, tumor tissue, 
and medical information. You will not have rights to these discoveries or any proceeds from them.
You can make your choice about whether to participate in the Optional substudy (storage of research samples for 
future use) in Section 12 of the consent. 
Refer to Section 5.1 below for any additional risks as well as efforts to minimize the risks, such as the GINA statute 
(Section 9.1) for the research samples stored for future use substudy. 
Loss of Confidentiality
Your samples will be coded however there is a risk of loss of confidentiality of your information. If your samples 
are provided to research collaborators the following information may be made available: your diagnosis and 
treatments, the time the samples were collected in relation to your study regimen, your disease status, and 
demographic data (for example gender, race, age, etc.).  Please ask the Study Doctor or Study Nurse if you would 
like to know more about how your information will be protected.
4.2 How much of my time will be needed to take part in this study?  
Typically, a course of radiation lasts 6-7 weeks and treatments are delivered each day, Monday through Friday, each 
week.  Each radiation treatment lasts approximately 10-20 minutes. Carboplatin and paclitaxel infusion will require 
a couple hours once weekly during this time period. 
Follow-up visits last about 1 hour each and may be completed virtually.
4.3 When will my participation in the study be over? 
After your radiation treatment is completed, you will return for follow-up appointments one month after treatment, 
then every 3 months for up to 2 years. 
4.4 What will happen with my information and/or biospecimens used in this study? 
You collected information and biospecimens may also be shared with other researchers, both here or around the 
world, or with companies.  Any sharing is subject to contractual obligations with the Sponsor.  Additionally:

With appropriate permissions, your identifiable collected information and biospecimens may be shared, 
and/or,

Without your additional consent, your identifiable private information and identifiable biospecimens may be 
stripped of identifiers and used for future research studies or distributed to another researcher for future 
research studies.
5.  INFORMATION ABOUT RISKS AND BENEFITS
5.1 What risks will I face by taking part in the study?  What will the researchers do to protect me against these 
risks?
The drugs used in the study may cause certain side effects and discomforts. You may have all, some, or none of 
the known side effects. There is also a risk that other rare or unknown side effects may occur. Your doctors and 
nurses will check you closely for side effects, and may give you medicines or other treatments to stop or reduce 
some of these effects. Some side effects may go away soon after the study medication is stopped, but in some 
cases, side effects may be serious, long lasting, and/or permanent. There is even a chance that a side effect may 
cause death. If you have any side effects, it is important that you report them to your study doctor or research 
staff.
These risks will be minimized by monitoring you carefully. We will provide the usual supportive care that would be
routinely given to someone with your condition. If you have side effects from the study intervention,
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we will make appropriate adjustments as defined by the study protocol. You may need to discontinue the
study intervention if the side effects are too serious.
The known or expected risks are:
Risks and Side Effects Related to Radiation Therapy of the Oropharynx
Very Likely (10-25% of subjects)

Sores in the mouth and/or throat which can be painful and make it very difficult to chew and or swallow 
foods

Mouth dryness or changes in taste and/or smell that may be permanent

Hoarseness

Tanning or redness and/or irritation of the skin in the head and neck area being treated with radiation

Ear pain and/or pressure

Fatigue

Weight loss

Permanent hair loss in the area treated with radiation (face, chin, neck)

Loss of teeth, or cavities in the teeth, if strict dental care is not followed and/or hypersensitivity of teeth
Less Likely, But Serious (1-9% of subject; except if noted)

Decrease in function of the thyroid gland that may require you to take thyroid replacement medicine to 
prevent you from feeling tired or sleepy

Damage to nerves in the neck, jawbone, voice box, skin, or other parts of the head and neck that may 
require a major operation to correct and, rarely, can even be life threatening (1-5% of subjects)

Temporary pain or scarring around nerves in the shoulder that could cause numbness and/or weakness

Breathing problems

Difficulty with swallowing and eating for which you might need a long term or permanent feeding tube; 
possibility of inhaling food and/or liquids into the lungs – which could also result in pneumonia.

Serious ear infections and/or hearing loss
Rare but very serious (< 1%)

Damage to the spinal cord

Damage to carotid arteries leading to permanent weakness and/or symptoms like a “stroke.” Stroke ≥ 5 
years after radiation has been reported to be slightly higher after head and neck radiation, compared with 
the general population, due to the possibility of increased formation of plaque in the carotid artery (causing 
blockage).
All these side effects may be a result of standard radiation treatment, as well as radiation according to this 
study.  Your physicians do not know whether the chance of complications arising from participation in this study 
is different from the chance of complications arising from standard radiation.
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Risks and Side Effects Related to Carboplatin
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Carboplatin, more than 20 and up to 100 may have:
Hair loss
Vomiting, nausea
Infection, especially when white blood cell count is low
Anemia which may cause tiredness, or may require blood transfusions
Bruising, bleeding
Belly pain
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Carboplatin, from 4 to 20 may have:
Diarrhea, Constipation
Numbness and tingling in fingers and toes
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of the 
face or throat
Changes in taste
Changes in vision
RARE, AND SERIOUS
In 100 people receiving Carboplatin, 3 or fewer may have:
Damage to organs which may cause hearing and balance problems
Risks and Side Effects Related to Paclitaxel
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Paclitaxel, more than 20 and up to 100 may have:
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of the 
face or throat
Infection, especially when white blood cell count is low
Bruising, bleeding
Anemia which may cause tiredness, or may require blood transfusions
Pain
Sores in mouth which may cause difficulty swallowing
Diarrhea, nausea, vomiting
Muscle weakness
Numbness, tingling or pain of the arms and legs
Hair loss
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Paclitaxel, from 4 to 20 may have:
Abnormal heartbeat
Blood clot which may cause swelling, pain, shortness of breath 
Damage to the lungs which may cause shortness of breath
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RARE, AND SERIOUS
In 100 people receiving Paclitaxel, 3 or fewer may have:
Heart attack or heart failure which may cause shortness of breath, swelling of ankles, and tiredness
A tear or a hole in the bowels which may cause pain or that may require surgery
Severe skin rash with blisters and peeling which can involve mouth and other parts of the body
Risks of Blood Draw
Collection of blood samples may cause pain, bleeding, bruising or infection. It is also possible 
that you may feel lightheaded or faint. Please tell your study doctor or the study nurse if you do 
not feel well after having your blood drawn at any time during your study participation.
Risks of Questionnaires
There is a risk you will be asked questions that you find uncomfortable. You have the right to refuse to answer any 
question.
Risks of CT Scan
The contrast substance injected during the CT scan may cause pain, burning feeling, sweating and rarely an allergic 
reaction that can be serious. If you know you’re allergic to iodine; you must inform your doctor immediately. The 
contrast agent used in the CT scan may cause kidney damage, especially if you’re diabetic, dehydrated and if you’re 
older. In addition, your thyroid function may be affected.
CT imaging uses ionizing radiation, which increases your risk of cancer. Everyone is exposed to naturally occurring
ionizing radiation every day. The amount of radiation exposure from 1 CT scan is approximately comparable to 1-3 
years of natural background radiation.
PET/CT scanning using [18F]FDG and Diagnostic CT scan.  PET/CT scanning is associated with several risks, as 
follows:
Intravenous line (IV) for radiotracer injections: There is an infrequent risk of bruising, bleeding, infection, or 
soreness associated with intravenous catheter placement, similar to the risks associated with routine blood testing. 
Subjects might feel dizzy or lightheaded or may rarely even faint when the tube is put in or taken out. The risk of 
these side effects is minimized by using highly trained personnel. 
Low-level Radiation Exposure: During the course of this study, subjects will be exposed to radiation from the PET 
radiotracer 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), a radioactive form of sugar. The biological effect of 
radiation exposures is measured in milli-Sieverts (mSv), which is a unit of whole body radiation exposure, called the 
‘effective dose’. The effective dose from the [18F]FDG injected into your bloodstream is 5.6 mSv, and the effective 
dose from the CT scan taken at the same time is 5.8 mSv, for a total effective dose of 11.4 mSv.  
The effects on your body of this radiation exposure will be added to your overall life-time radiation risk. Your life-
time radiation risk includes the background radiation you are exposed to naturally like everyone else living on this 
planet, which averages 3 mSv per year. The radiation you will be exposed to in this study is about 4 times the yearly 
background radiation. In terms of radiation a person may get exposed to during medical care, the amount you will 
receive in this study will be less than 2 times the amount of radiation received in a CT scan of the chest, which is 
about 8 mSv. The Federal Government requires that the amount of radiation exposure of radiation workers does 
not exceed 50 mSv per year; the radiation you will be exposed to from PET/CT scans in this study is about 22% of 
that amount. Your life-time radiation risk also includes any radiation you may have received in the past for diagnosis 
or treatment, and any such radiation you may be exposed to in the future. The risk from radiation exposure of this 
amount is considered to be similar to other every day risks, such as driving a car. No PET studies will be performed 
on pregnant, nursing, or potentially pregnant women, as determined by pregnancy testing within 48 hours prior to 
the PET scanning session.
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The researchers will try to minimize the risks (above) by:
PET/CT and CT scanning: Skilled nuclear medicine technologists will perform the PET/CT and CT studies under the 
supervision of a physician who is a specialist in nuclear medicine. We will use aseptic techniques and highly trained 
personnel to minimize the risks associated with venipuncture (IV). A physician or nurse will be available at all times 
during the study, and any adverse reactions will be treated immediately. A fully equipped medical cart is located in 
the PET facility. No PET studies will be performed on pregnant, nursing, or potentially pregnant women, as 
confirmed by pregnancy testing (b-HCG) performed within 48 hours prior to each PET scanning session for women 
of childbearing potential.
Risk to embryo or fetus:
If appropriate, you will be asked if there is a possibility that you may be pregnant. You may not 
take part in this project if you are pregnant. If you are or may become pregnant, this research may 
involve unforeseeable risks to you, the embryo, or the fetus.
To minimize this risk, sexually active women with child-bearing potential must be using adequate 
contraceptive measures.  If there is a question of pregnancy, a pregnancy test
will be done.
Risks and Side Effects Related to MRI
MRIs done for research that use IV contrast have risks similar to MRIs done for clinical care.  Contrast is used to 
improve the pictures of the inside of the body made by the MRI.  Common risks of MRI include: feeling fearful of 
being in a small enclosed space (claustrophobia) when you are lying inside the MRI scanner, feeling 
uncomfortable because of the loud noises made by the machines, and feeling uncomfortable with the physical 
sensations you may feel during the process.  You are also exposed to some risk because of the injected contrast, 
gadolinium-DTPA, which may cause headache, nausea, and local burning sensation. 
The contrast agent, gadolinium has been linked to development of Nephrogenic Fibrosing Dermopathy (NFD), also 
known as Nephrogenic Systemic Fibrosis (NSF).  NFD is a thickening of the skin, organs and other tissues and is a 
rare complication in subjects with kidney disease who undergo an MRI with contrast material. To help prevent 
this, we will check how well your kidneys work before you have any MRIs.  Because of the use of contrast, all 
female subjects who are able to have children will be required to use adequate birth control. If you have 
implanted metal objects such as a pacemaker, artificial limbs, or metal joints, you will not be able to have an MRI 
done, and may not be able to take part in this research. 
Reproductive Risks
WOMEN
There could be risks to a fetus in this study. If you are pregnant or become pregnant during the study, these risks 
could affect you or your fetus. Women must agree to either abstain from sexual activities that could result in 
pregnancy or use at least one acceptable method of birth control (i.e. condom, IUD, pill) while taking part in this 
study. 
MEN
Men must agree to either abstain from sexual activities that could result in pregnancy or use an acceptable form of 
birth control while taking part in the study Acceptable forms of birth control are male latex condom (with or without 
spermicide) or vasectomy.
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Risk Reduction:
Your doctor will see you on a weekly basis during treatment to assess the side effects. Physical examinations, scans 
and other routine tests will be done to monitor the effects of the treatment.  Although many side effects disappear 
after radiation therapy has been completed, some are permanent.  You understand that you may ask your doctor 
about these side effects.  You will be informed about ways to minimize sore mouth and throat during radiation 
therapy, including rinsing the mouth with salt and soda solutions, taking appropriate pain medication and other 
measures which will be given to you by your nurses and doctors as necessary.  Close follow-up will be performed 
after radiation is completed, to assess any long-standing side effects of radiation.
Before each treatment of carboplatin and paclitaxel you will receive standard medications to decrease the chances 
that you will experience nausea, vomiting, and an allergic reaction.  These medications will be determined by your 
medical oncologist.  Your heart rate and blood pressure will be monitored during your carboplatin and paclitaxel 
treatments.  Because fever is a sign of infection, and you will be at an increased risk for infection during therapy, it 
is important that you contact your physician if you develop a fever during treatment in order that appropriate 
treatment can be started.  Frequent blood samples will be taken to monitor the number of white blood cells, red 
blood cells, and platelets you have in your blood to monitor how the treatment is affecting your body.  If your body 
can not make enough white blood cells, red blood cells, and platelets due to the treatments, your physician will 
begin appropriate treatment.  If you develop severe redness of your skin or pain in your mouth and throat your 
physician may temporarily hold or modify your carboplatin and paclitaxel treatment.  If you are able to resume 
carboplatin and paclitaxel, you may be given a lower dose of the medication(s) in order to decrease the risk of 
redness of your skin and pain in your mouth and throat.
As with any research study, there may be additional risks that are unknown or unexpected.
5.2 What happens if I get hurt, become sick, or have other problems as a result of this research?
The researchers have taken steps to minimize the risks of this study.  Even so, you may still have problems or side 
effects, even when the researchers are careful to avoid them. Please tell the researchers listed in Section 10 about 
any injuries, side effects, or other problems that you have during this study.  You should also tell your regular 
doctors.
By signing this form, you do not give up your right to seek payment if you are harmed as a result of being in this 
study.
5.3 If I take part in this study, can I also participate in other studies?
Being in more than one research study at the same time, or even at different times, may increase the risks to you.  
It may also affect the results of the studies.  You should not take part in more than one study without approval 
from the researchers involved in each study.  
5.4 How could I benefit if I take part in this study?  How could others benefit?  
You may not receive any personal benefits from being in this study.  However, there is a chance that the boost 
may improve tumor control and increase the length of disease-free survival. 
5.5 Will the researchers tell me if they learn of new information that could change my willingness to stay in this 
study?
Yes, the researchers will tell you if they learn of important new information that may change your willingness to 
stay in this study. If new information is provided to you after you have joined the study, it is possible that you may 
be asked to sign a new consent form that includes the new information.
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6.  OTHER OPTIONS
6.1 If I decide not to take part in this study, what other options do I have?
If you decide not to participate, you will be treated with the best standard therapy, according to the clinical 
judgment of your physicians.  Other treatments available for your condition include:

Radiation therapy with concurrent chemotherapy over 7 weeks

Taking part in another study of an investigational agent (such as surgical removal of your tumor)

Getting comfort care, also known as palliative care.  This type of care helps reduce pain, tiredness, 
appetite problem and other problems caused by cancer.  It does not treat the cancer
7.  ENDING THE STUDY
7.1 If I want to stop participating in the study, what should I do?
You are free to leave the study at any time.  If you leave the study before it is finished, there will be no penalty to 
you. You will not lose any benefits to which you may otherwise be entitled.  If you choose to tell the researchers 
why you are leaving the study, your reasons for leaving may be kept as part of the study record. If you decide to 
leave the study before it is finished, please tell one of the persons listed in Section 10 “Contact Information” 
(below).
7.2 Could there be any harm to me if I decide to leave the study before it is finished? 
If you decide to leave the study early, please notify someone on the study team.  They will instruct you on how to 
stop the study safely and you will be advised whether any additional test may need to be done for your safety.
7.3 Could the researchers take me out of the study even if I want to continue to participate?
Yes. There are many reasons why the researchers may need to end your participation in the study.  Some 
examples are:

The researcher believes that it is not in your best interest to stay in the study.

You become ineligible to participate.

Your condition changes and you need treatment that is not allowed while you are taking part in the study.

You do not follow instructions from the researchers.

The study is suspended or canceled.
8.  FINANCIAL INFORMATION
8.1 Who will pay for the costs of the study? Will I or my health plan be billed for any costs of the study?  
The study will pay for research-related items or services that are provided only because you are in the study.  If 
you are not sure what these are, see Section 4.1 above or ask the researchers for a list.  If you get a bill you think 
is wrong, call the researchers’ number listed in section 10.1.
You or your health plan will pay for all the things you would have paid for even if you were not in the study, like:

Carboplatin and paclitaxel 

Health care given during the study as part of your regular care

Items or services needed to give you the carboplatin and paclitaxel and/or radiation therapy

Monitoring for side effects or other problems

Deductibles or co-pays for these items or services.

Treatment complications
If you do not have a health plan, or if you think your health plan may not cover these costs during the study, 
please talk to the researchers listed in Section 10 below or call your health plan’s medical reviewer.
The study team has given you instructions about this research study. It is important that you follow these 
instructions carefully. If you get sick, have a medical complication, or are injured as a result of your being in the 
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study, call Dr. Mierzwa, at (734) 845-3914 or at (734) 936-4000 (Hospital Operator – 24-hour paging). The doctor 
will either treat you or send you to another doctor for treatment. 
If you are injured or in the event of a medical emergency, dial 911 or visit your nearest Emergency Room. If you 
believe the study has made you sick or caused you injury, contact one of the people listed in section 10 of this 
document (Contact Information). If taking part in the study makes you sick or causes you injury, you will have to 
arrange for treatment on your own, as the study will not provide medical treatment or provide any compensation 
to you. You or your insurance provider will be billed for all costs of treatment for sickness or injury caused by the 
study. It is possible that your insurance will not cover these costs.
By signing this form, you do not give up your right to seek payment if you are harmed as a result of being in this 
study.
8.2 Will I be paid or given anything for taking part in this study?
You will not be paid for taking part in this research.
8.3 Who could profit or financially benefit from the study results? 
Information obtained from this study may help the University of Michigan learn more about the causes, risks, 
treatments, or how to prevent this and other health problems.  The University of Michigan, or physicians at the 
university could profit financially from this information.
Research can lead to new discoveries, such as new tests, drugs, or devices. Researchers, their organizations, and 
other entities, including companies, may potentially benefit from the use of the data or discoveries. You will not 
have rights to these discoveries or any proceeds from them.
9. CONFIDENTIALITY OF SUBJECT RECORDS AND AUTHORIZATION TO RELEASE YOUR PROTECTED HEALTH 
INFORMATION
The information below describes how your privacy and the confidentiality of your research records will be 
protected in this study.
9.1 How will the researchers protect my privacy?
The University of Michigan has rules to protect information about you. Federal and state laws also protect your 
privacy. Upon enrolling in this study, you will be assigned a unique identification number. All records related to 
the study will use this identification number instead of your name or other personally identifying information 
whenever possible. We will take measures to protect the privacy and security of all your personal information, but 
we cannot guarantee complete confidentiality of study data.
Medical information created by this research study may become part of your hospital medical record and may be 
forwarded to your primary doctor. Information that does not become part of your medical record will be stored in 
your study file.
You have the right to request access to your protected health information that is used or shared during this 
research and that is related to your study treatment or payment for your study treatment, but you may access 
this information only after the study is completed. To request this information, please contact the researchers 
listed in Section 10 “Contact Information” (below).
Genetic Risks:
The federal Genetic Information Nondiscrimination Act (GINA) generally makes it illegal for health insurance 
companies, group health plans, and most employers to discriminate against you based on your genetic 
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information.  This law does not protect you against genetic discrimination by companies that sell life insurance, 
disability insurance, or long-term care insurance.  Under this law:

Health insurance companies and group health plans may not request your genetic information that we 
obtain from this research

Health insurance companies and group health plans may not use your genetic information when making 
decisions regarding your eligibility or premiums

Employers with 15 or more employees may not use your genetic information that we obtain from this 
research when making a decision to hire, promote, or fire you or when setting the terms of your 
employment
GINA does not apply to the following groups, however these groups have policies in place that provide similar 
protections against discrimination:

Members of the US Military receiving care through Tricare

Veterans receiving care through the Veteran’s Administration (VA)

The Indian Health Service

Federal employees receiving care through the Federal Employees Health Benefits Plans
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This 
Web site will not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.
9.2 What information about me could be seen by the researchers or by other people?  Why?  Who might see it?
Signing this form gives the researchers your permission to obtain, use, and share information about you for this 
study, and is required in order for you to take part in the study.  Information about you may be obtained from any 
hospital, doctor, and other health care provider involved in your care, including:

Hospital/doctor's office records, including test results (X-rays, blood tests, urine tests, etc.)

Mental health care records (except psychotherapy notes not kept with your medical records)

Alcohol/substance abuse treatment records

HIV/AIDS status

Sexually transmitted disease or other communicable disease status

Health plan/health insurance records

All records relating to your condition, the treatment you have received, and your response to the 
treatment

Billing information

Demographic information

Personal information
There are many reasons why information about you may be used or seen by the researchers or others during or 
after this study.  Examples include:

The researchers may need the information to make sure you can take part in the study.  

The researchers may need the information to check your test results or look for side effects.  

University of Michigan, Food and Drug Administration (FDA), and/or other government officials, auditors, 
and/or the IRB may need the information to make sure that the study is done in a safe and proper 
manner.   

Pfizer or safety monitors or committees may need the information to: 
o
Make sure the study is done safely and properly
o
Learn more about side effects 
o
Analyze the results of the study 
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
Insurance companies or other organizations may need the information in order to pay your medical bills 
or other costs of your participation in the study.

The researchers may need to use the information to create a databank of information about your 
condition or its treatment.

Information about your study participation may be included in your regular University of Michigan 
medical record.

Federal or State law may require the study team to give information to government agencies. For 
example, to prevent harm to you or others, or for public health reasons. 
The results of this study could be published in an article, but would not include any information that would let 
others know who you are. 
9.3 What happens to information about me after the study is over or if I cancel my permission?
As a rule, the researchers will not continue to use or disclose information about you, but will keep it secure until it 
is destroyed.  Sometimes, it may be necessary for information about you to continue to be used or disclosed, even 
after you have canceled your permission or the study is over.  
Examples of reasons for this include:

To avoid losing study results that have already included your information 

To provide limited information for research, education, or other activities (This information would not 
include your name, social security number, or anything else that could let others know who you are.) 

To help the University of Michigan and government officials make sure that the study was conducted 
properly
As long as your information is kept within the University of Michigan Health System, it is protected by the Health 
System’s privacy policies.  For more information about these policies, ask for a copy of the University of Michigan 
“Notice of Privacy Practices”.  This information is also available on the web at 
http://www.uofmhealth.org/patient+and+visitor+guide/hipaa. Note that once your information has been shared 
with others as described under Question 9.2, it may no longer be protected by the privacy regulations of the 
federal Health Insurance Portability and Accountability Act of 1996 (HIPAA).
9.4 When does my permission expire?  
Your permission expires at the end of the study, unless you cancel it sooner. You may cancel your permission at 
any time by writing to the researchers listed in Section 10 "Contact Information" (below).  
10. CONTACT INFORMATION
10.1 Who can I contact about this study?
Please contact the researchers listed below to:

Obtain more information about the study

Ask a question about the study procedures or treatments

Talk about study-related costs to you or your health plan 

Report an illness, injury, or other problem (you may also need to tell your regular doctors)

Leave the study before it is finished

Express a concern about the study
Principal Investigator: 
Michelle Mierzwa, DM
Mailing Address:
1500 E. Medical Center Drive
Ann Arbor, MI 48109
Telephone:
(734) 845-3914
Study ID: HUM00140473   IRB: IRBMED   Date Approved: 7/12/2023   Expiration Date: 6/1/2024


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Emergency Contact:
(734) 936-4000 (Hospital Operator – 24-hour paging)
You may also express a concern about a study by contacting the Institutional Review Board listed below.
University of Michigan Medical School Institutional Review Board (IRBMED)
2800 Plymouth Road
Building 520, Room 3214
Ann Arbor, MI 48109-2800
Telephone: 734-763-4768  (For International Studies:  US Country Code: 001)
Fax: 734-763-1234
e-mail: irbmed@umich.edu 
If you are concerned about a possible violation of your privacy or concerned about a study you may contact the 
University of Michigan Health System Compliance Help Line at 1-866-990-0111.
When you call or write about a concern, please provide as much information as possible, including the name of the 
researcher, the IRBMED number (at the top of this form), and details about the problem.  This will help University 
officials to look into your concern.  When reporting a concern, you do not have to give your name unless you want 
to.
 
11.  RECORD OF INFORMATION PROVIDED
11.1 What documents will be given to me?
You will receive a copy of the signed and dated informed consent
Your signature in the next section means that you have received copies of all of the following documents:
This "Consent to be Part of a Research Study" document.  (Note: In addition to the copy you receive,

copies of this document will be stored in a separate confidential research file and may be entered 
into your regular University of Michigan medical record.)”  

Other (specify):
Study ID: HUM00140473   IRB: IRBMED   Date Approved: 7/12/2023   Expiration Date: 6/1/2024


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12.  SIGNATURES
Consent/Assent to Participate in the Research Study
I understand the information printed on this form.  I have discussed this study, its risks and potential benefits, 
and my other choices with __________________________________________.  My questions so far have been 
answered.  I understand that if I have more questions or concerns about the study or my participation as a 
research subject, I may contact one of the people listed in Section 10 (above).  I understand that I will receive a 
copy of this form at the time I sign it and later upon request.  I understand that if my ability to consent or 
assent for myself changes, either I or my legal representative may be asked to re-consent prior to my 
continued participation in this study.
Print Legal Name: ________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Consent/Assent to Collect and Store OPTIONAL Research Samples for Unspecified Future Research
This project involves the option to allow the study team to keep your identifiable specimens/data for use in 
future research. I understand that it is my choice whether or not to take part in this optional research.  I 
understand that if my ability to consent or assent for myself changes, either I or my legal representative may 
be asked to re-consent prior to my continued participation in this study.
_____ Yes, I agree to let the study team keep and store my blood and tissue samples for future research.
_____ No, I do not agree to let the study team keep and store my blood and tissue samples for future 
research.
Print Legal Name: ________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Study ID: HUM00140473   IRB: IRBMED   Date Approved: 7/12/2023   Expiration Date: 6/1/2024


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Principal Investigator or Designee
I have provided this participant and/or his/her legally authorized representative(s) with information about this 
study that I believe to be accurate and complete.  The participant and/or his/her legally authorized 
representative(s) indicated that he or she understands the nature of the study, including risks and benefits of 
participating.
Print Legal Name: ________________________________________________________________________
Title: ______________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Study ID: HUM00140473   IRB: IRBMED   Date Approved: 7/12/2023   Expiration Date: 6/1/2024


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PERSONAL CENSUS FORM
Name _______________________________________________
Date ____________________
The National Cancer Institute requires that The University of Michigan Comprehensive Cancer 
Center report race and ethnicity information about people who participate in clinical research to 
ensure that all populations are offered the opportunity to participate. 
 Check here if you do not wish to provide some or all of the information below.
1. What race do you consider yourself to be? 
American Indian/Alaska Nativea
(Please select one or more)

Asianb

Black or African Americanc

Native Hawaiian or Other
Pacific Islanderd

Whitee

More than one racef
2. Do you consider yourself to be Hispanicg?           Yes                 No
________________________________________________________________________
a American Indian or Alaska Native- A person having origins in any of the original peoples of North, Central, or 
South America, and who maintains tribal affiliation or community attachment.
b Asian- A person having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian 
subcontinent, including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine 
Islands, Thailand and Vietnam.
c Black or African American- A person having origins in any of the black racial groups of Africa.  (Terms such as 
“Haitian” or “Negro” are sometimes used in addition to “Black” or “African American.”)
d Native Hawaiian or Other Pacific Islander- A person having origins in any of the original peoples of Hawaii, Guam, 
Samoa, or other Pacific Islands.
e White- A person having origins in any of the original peoples of Europe, the Middle East, or North Africa.
f More than one race- (It is preferred that this be selected in addition to the selection of the specific races listed 
above, but this may also be solely selected.)
g Hispanic or Latino- A person of Mexican, Puerto Rican, Cuban, Central or South American, or other Spanish 
culture or origin, regardless of race.  The term “Spanish origin” is sometimes used in addition to “Hispanic” or 
“Latino.”
Study ID: HUM00140473   IRB: IRBMED   Date Approved: 7/12/2023   Expiration Date: 6/1/2024