Randomized Phase II Study of DCE-MRI-based Dose Escalation for Poor-prognosis and Neck Cancer
Phase: PHASE2
Conditions: Squamous Cell Carcinoma of the Head and Neck
Sponsor: University of Michigan Rogel Cancer Center

ID: UMCC 2013.062    
Randomized Phase II Study of DCE-MRI-based Dose Escalation for Poor-prognosis and Neck Cancer 
NCT02031250

1 
Randomized Phase II study of DCE-MRI-based dose escalation for poor-prognosis head and neck 
cancer 
Principal Investigator: 
Michelle Mierzwa, M.D. (Radiation Oncology) 
Biostatistician: 
Matthew Schipper, Ph.D. 
Protocol version: 07-01-2020 

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Table of Contents 
1.0  
Introduction 
2.0  
Study Hypothesis and Rationale 
3.0  
Objectives 
4.0  
Eligibility 
5.0  
Exclusion criteria 
6.0  
Study design 
7.0  
Initial clinical evaluation 
8.0  
Radiotherapy 
9.0 
MRI  
10.0 
Chemotherapy 
11.0 
FDG/PET 
12.0 
Liquid biopsy 
13.0 
Evaluation of response to treatment 
14.0 
Chemotherapy Dose Delays and Treatment Modifications 
15.0 
Drug Information 
16.0 
Evaluation of Toxicity and Quality of Life 
17.0 
Study calendars 
18.0 
Criteria for discontinuation of treatment 
19.0 
Other Therapy 
20.0 
Patient screening and registration 
21.0 
Multisite Data Management 
22.0 
Reporting adverse events 
23.0 
Data and Safety Monitoring 
24.0 
Clinical Monitoring Procedure 
25.0 
Quality Assurance and Audits 
26.0 
Statistical considerations 
27.0 
References 
28.0 
Appendices 
 
 

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1.0 INTRODUCTION 
HNC accounts for 3% of all new cancer sites and 2% of all cancer death in the United States, however it 
is the fifth most common malignancy worldwide. 37,000 new cases of HN cancer will be diagnosed and 
11,000 will die due to this cancer in the US in 2003 [2]. The treatment of locally advanced cancer has 
traditionally been surgery followed with postoperative irradiation. In recent years, altered fractionated 
radiation and the addition of concurrent chemotherapy have yielded significant improvements in the 
rate of tumor control using non-surgical approaches [2]. However, specific patient groups still suffer 
poor prognosis following chemo-irradiation (chemo-RT), and their predominant mode of treatment 
failure is local-regional (LR). These groups include oropharyngeal cancers not associated with Human 
Papillomavirus Virus (HPV-negative tumors) or in heavy smokers, unresectable tumors (tumor stage 4b), 
and recurrent tumors treated with re-irradiation [3-7].  A major recent effort to improve outcome in 
locoregionally advanced, non-metastatic HNC has focused on the addition of induction chemotherapy or 
novel targeted agents such as EGFR or VEGFR blockers.  Unfortunately, there is no evidence yet that 
these approaches are more effective than the use of concurrent chemo-irradiation with currently 
available cytotoxic agents.  For instance, recent reports from the Dana-Farber and the Chicago groups 
showed no local-regional, disease-free survival, or overall survival gains with induction chemotherapy 
followed by chemo-irradiation compared with chemo-irradiation alone [8].  In addition, the recently 
reported large randomized RTOG 0522 study demonstrated no benefit for the addition of the EGFR 
inhibitor cetuximab to the combination of cisplatin-irradiation, compared with cisplatin-irradiation 
alone, in the treatment of locoregionally advanced advanced HNC [9]. New approaches are needed for 
improving LR disease control rates in poor-prognosis patients.  
2.0 HYPOTHESIS, RATIONALE, AND PRELIMINARY STUDIES 
Given that the predominant mode of failure in the poor-prognosis patient groups detailed above is LR, a 
substantial improvement in LR control rates is likely to translate into an improvement in overall survival. 
Based on our experience and that of others [10-14], the vast majority of LR failures in patients receiving 
intensity-modulated radiation therapy (IMRT) occur in-field, within the targets that received the full 
prescription dose. Thus, to improve LR control rates, we propose using highly conformal radiotherapy 
(RT) to redistribute the doses within the tumor such that the dose to sub-volumes likely to be 
resistant to standard RT doses is increased, while standard doses to the rest of the tumor and 
surrounding normal tissues are maintained. This approach depends on achieving two main 
requirements: (1) identifying relatively radioresistant tumor subvolumes that are spatially and 
temporally stable in order to allow their selective targeting for a radiotherapy boost, and (2) safely 
delivering higher doses to these subvolumes without exceeding normal tissue tolerance, in order to 
improve local-regional tumor control without increasing treatment-related complications.  
This study aims to improve locoregional control of poor prognosis HNC patients by selectively escalating 
the radiotherapy dose to radioresistant subvolumes of tumor that demonstrate persistent 
hypoperfusion after 2 weeks of therapy. Dynamic contrast enhanced (DCE) CT or MRI can now be used 
to characterize key tumor vascular properties, including blood volumes, blood flow, vascular 
permeability, and mean transit time, as well as distribution volume and available interstitial space for 
the contrast agent [15]. This is important as newly synthesized tumor-related blood vessels, which 
exhibit poor functionality and manifest high permeability, tortuosity, and density heterogeneity, have 

4 
 
been shown to serve as a prognostic indicator of tumor aggressiveness [15].  Low pre-therapy tumor 
perfusion has been found to be correlated with local failure and poor response to therapy of head and 
neck cancer, independent of other known prognostic factors, in multiple studies [16-21]. While a 
significant inverse correlation exists between hypoxia and perfusion [22, 23], they do not measure the 
exact same physiological processes [15]. We have opted to use perfusion imaging in our studies, rather 
than hypoxia imaging, due to several factors.  First, spatial and temporal stability of tumor sub-volumes 
identified by an imaging modality is essential to accurately and reproducibly determine the highest risk 
tumor sub-volumes for potential boosting. Longitudinal assessments of the spatial distributions of 
hypoxic subvolumes assessed by F-18-labeled fluoromizonidazole at Memorial Sloan Kettering Cancer 
Center showed variability in the spatial uptake between repeated images pre-therapy [24], which 
compromised the ability to specifically target hypoxic tumor volumes by dose-painting IMRT [25]. 
Furthermore, in almost all patients, hypoxia resolved completely at mid-therapy [26], similar to previous 
findings by Rischin et al [27]. In contrast to the spatial and temporal variability of hypoxia-specific 
functional imaging studies, our data using DCE-MRI at 2 weeks after beginning chemoradiotherapy 
demonstrate that although reductions in hypoperfused sub-volumes were seen in some patients, the 
hypoperfused regions in all patients remained within the initial pre-therapy hypo-perfused 
subvolumes, suggesting relative spatial stability. This issue will be assessed in detail by comparing the 
pre- and during-therapy hypoperfused subvolumes in protocol patients. Second, the spatial resolution of 
perfusion measurements using dynamic contrast enhanced MRI (DCE-MRI) is superior to that of current 
methods of hypoxia measurements using various PET tracers [22]. DCE-MRI may therefore be a better 
modality to define hypoperfused tumor subvolumes for boosting using IMRT. 
In order to serve as an adequate target for dose redistribution, the imaging-based target needs to be the 
predominant site of LR failure following therapy, rather than just a general marker of high risk of failure. 
For example, some local-regional recurrences were found to be outside the boosted subvolumes 
defined by pre-therapy FDG-PET [28]. Our preliminary results suggest that the sites of LR failures are 
within the hypo-perfused subvolumes identified on DCE-MRI [1]. We conducted a preliminary evaluation 
of the spatial relationship between the subvolumes of the tumors with low blood volume (BV) and 
patterns of local failure.  In two of the patients with LR recurrences for whom imaging early after 
recurrence was available, images were registered with the pre- and during-treatment DCE-MRI images. 
In both cases, the local recurrences occurred within sites corresponding to the tumor sub-volumes with 
low BV on pre-therapy and during therapy DCE-MRI. Additional supporting data is needed, however, and 
will be accumulated during the current study.   
Pre-therapy tumor blood volume (BV) is a major prognostic factor measured by DCE-MRI [19]. Our 
preliminary results suggest that its change at 2 weeks after the beginning of therapy may provide an 
even better prognostic value than the pre-therapy value. We have evaluated DCE-MRI early during the 
course of chemo-RT, and found that patients demonstrating increased BV after 2 weeks compared with 
pre-therapy had significantly better outcome than those whose BV did not increase, a prediction that 
was more accurate than the extent of tumor shrinkage after 2 weeks [19]. As part of this study, 14 
patients with unresectable HNC underwent DCE-MRI prior to and 2 weeks after the initiation of chemo-
RT. Four patients experienced local failures. The BV in the primary tumors increased significantly from 
pretherapy to 2 weeks  in the locally controlled patients compared with the locally failed patients 
(p<0.03), while no significant differences were noted in tumor shrinkage between failures and non-

5 
 
failures [19]. This analysis used mean whole-tumor parameters. We have recently analyzed the 
predictive value of heterogeneous tumor perfusion in these patients. When sub-volumes of the tumors 
with low BV or blood flow (BF) before and during treatment were evaluated for their associations with 
local failure, we found that the sub-volumes of the tumors with low BV before and during treatment 
significantly differentiated local failure from local control (p=0.02 and 0.01, respectively)[1]. The tumor 
sub-volumes with low BV before and during treatment had greater specificity for prediction of local 
failure, with a given sensitivity, than the pre-therapy total tumor volume, the percent change in tumor 
volume during therapy, or the change in mean tumor BV during therapy. Similar results have recently 
been reproduced by others [17]. BV at 2 weeks compared with pre-therapy promises to be a marker of 
the individual tumor response to therapy that can accurately predict treatment failure in areas of 
persistently low BV. In the current protocol we will target low-BV sub-volumes (which in almost all the 
cases in our previous study included a contiguous volume of tumor >1cc) for radiation dose 
intensification using highly conformal radiotherapy, in an effort to overcome the relative treatment 
resistance represented by these sub-volumes and improve LR tumor control rates. 
In this study we propose to increase the nominal dose delivered to the hypoperfused tumor subvolumes 
to 80 Gy while other tumor subvolumes receive a standard dose of 70 Gy, all in 35 fractions, using IMRT.   
Diffusion-weighted (DW) MRI has been studied extensively as a predictor of recurrences in brain tumors 
[29-33]. There are strong reasons to anticipate that a similar utility of diffusion MRI will be found in HNC, 
and preliminary studies both at our institution (36) and by others (Vandecaveye et al 2012) support this 
proposition. We will assess it in our proposed studies.  The MRI studies performed in this protocol will 
also be used to obtain diffusion-related data which will supplement perfusion (DCE-MRI) data. Our 
preliminary results, as well as others’, suggest that diffusion-weighted MRI can predict tumor response 
both on a global and on a local-spatial tumor level [34-37]. Changes in whole-tumor mean Apparent 
Diffusion Capacity (ADC) from pre-therapy to 1 week into therapy have been shown to correlate with 
clinical and pathologic response in HN cancer [36]. Recently, a voxel-wise approach to evaluate ADC 
changes within tumor has been developed at our institution as an early biomarker for quantifying the 
spatial heterogeneous response of tumor to therapy [29]. This approach (parametric response map, 
PRM, or functional diffusion map) uses registered baseline and early-treatment ADC maps to calculate 
regional responses that may be more sensitive to cellular changes than measurements of the mean 
change in ADC. We will analyze the diffusion MRI maps derived from the DW-MRI studies to determine 
their potential as a complementary modality to perfusion (DCE) MRI in defining the boosted tumor 
subvolumes. If it is found to provide complementary information, diffusion MRI will be integrated into 
the decision-making related to defining tumor subvolumes for boosting in the future. The addition of 
diffusion-weighted images to DCE-MRI will lengthen the MRI procedure by approximately 2 minutes. 
 
While the MRIs performed pre-therapy and at week 2 of therapy will be used for decisions about 
treatment modification in the current protocol, we will also add an MRI (with both DCE and DW 
sequences) during the last week of therapy to assess its predictive value. This additional research MRI 
will be performed at the discretion of the treating physician, with consideration of the individual 
patient’s tolerance of treatment and accompanying toxicities.  If persistent hypoperfused subvolumes or 

6 
 
low apparent diffusion coefficient (see Vandecaveye et al 2012) at the end of therapy will be predictive 
of LR failure, future intervention such as a final boost will be contemplated. 
Acute and late toxicity of chemo-RT for HNC are issues that need to be addressed when intensive 
chemo-RT is contemplated. Specifically, severe acute mucositis and consequential late dysphagia are the 
major factors limiting treatment intensification [38]. In a phase I dose escalation study from the Medical 
College of Virginia in which escalated doses were delivered to the entire gross tumor volume (GTV), 
severe acute mucositis was determined to be the dose limiting toxicity (DLT) at a dose of 73.8 Gy in 30 
fractions (2.46 Gy per fractions), necessitating treatment breaks in the two patients treated at this dose 
level, and leading the investigators to define 70.8 Gy in 30 fractions of 2.36 Gy to the GTV as the 
maximum tolerable dose [39]. In contrast, a dose escalation study at Ghent University Hospital in which 
sub-volumes of the GTV were boosted based on pre-treatment and 2-week FDG-PET scans did not 
demonstrate any acute grade > 4 toxicities during treatment, but did encounter excessive rates of 
unexpected late mucosal ulceration [40]. Specifically, at the highest dose level of 85.9 Gy in 32 fractions, 
5 of out 14 patients (36%) developed late mucosal ulceration at a median 7 months follow-up (range 4-
10 months), compared with only 1 out of 7 patients at the lower dose level of 80.9 Gy in 32 fractions, 
which the investigators determined to be the MTD for dose escalation to GTV sub-volumes. Of note, the 
use of concurrent chemotherapy in the Ghent study did not appear to increase the incidence of late 
mucosal ulceration. Given the apparent tolerability of dose escalation to tumor sub-volumes to 80.9 Gy 
in 32 fractions, we expect our proposed high dose arm delivering 80 Gy in 35 fractions to a sub-volume 
of the GTV, while limiting the dose to the mucosa to 70 Gy, to be similarly well tolerated. In light of the 
DLTs encountered by the MCV and Ghent dose escalation experiences, however, we will apply early 
stopping rules should either acute non-hematological grade 4 toxicities or late grade 4 toxicities exceed 
15%.  
Dysphagia after chemo-radiotherapy of HN cancer is a major late sequel of therapy. We have 
concentrated in recent years on reducing the dysphagia resulting from chemo-irradiation of HN cancer, 
having identified the anatomic structures whose damage causes dysphagia, established dose-effect 
relationships for these structures, and devised IMRT strategies to reduce their doses [41-46]. UMCC 
protocol 2-21 tested our ability to use IMRT to spare the swallowing structures, assessing whether 
swallowing function can be preserved while maintaining high rates of disease control. The long-term 
results show excellent tumor control rates (only 3 local-regional recurrences out of 73 patients with 
median follow-up 36 months), as well as excellent functional results related to dysphagia. We will use 
the treatment planning guidelines that yielded these excellent oncologic and functional results as the 
basis for the dosimetric constraints in the herein proposed protocol.   
We have also recently modeled dose-response relationships for the parotid glands based on updated 
data from chemo-IMRT treated patients. These data suggest a continuous dose-response relationship 
without a threshold effect, with 26 Gy corresponding to a normal tissue complication probability (NTCP) 
of 25% and 39 Gy to a NTCP of 50% [43]. We have also established dose-response relationships for the 
submandibular glands (SMG) [41], which have guided us in sparing the contralateral SMGs in patients 
whose contralateral neck level I was not at risk. In a recent investigation into the correlates of 
xerostomia we have reported that beyond sparing the parotid glands, sparing of the SMGs and the non-
involved oral cavity (within which minor glands are dispersed) reduces xerostomia significantly [42]. We 

7 
 
will incorporate these dose-response relationships into the treatment planning process to limit dose to 
the salivary glands and oral cavity in this new proposed protocol.  
In order to assess our ability to safely increase the dose to hypoperfused subvolumes, we have re-
optimized IMRT plans for 4 patients who underwent DCE MRI pre-therapy and again after 2 weeks of 
therapy. The optimization goal was to re-distribute the dose such that a total of 80 Gy will be delivered 
to the persistently hypoperfused tumor subvolumes after the initial 2 weeks of treatment. Optimization 
criteria were: Minimum 80 Gy, maximum 84 Gy within boost volume PTV, mean 70 Gy (maximum 75 Gy) 
elsewhere within the rest of the PTV, maximal mucosa dose 70 Gy, and to keep all other constraints 
used in previous protocols with regards to doses to swallowing structures, salivary glands (parotid, 
contralateral submandibular, minor glands within the oral cavity). We have achieved these dosimetric 
criteria within +/- 5%. Thus, in this protocol, we will limit mucosal and swallowing organ doses to 
tolerated levels, minimizing these major toxicities. In addition, early stopping rules are implemented in 
the protocol in case the rate of severe toxicities is estimated to exceed 15%.  
Additionally, we have examined DCE-MRI in critical organs affected by chemo-RT, including the 
pharyngeal constrictor muscles whose dysfunction after chemo-RT is related to late dysphagia. We have 
recently analyzed whether changes in pharyngeal constrictor (PC) muscle perfusion early during chemo-
irradiation could predict imaging findings after the completion of RT (unpublished data). In a prospective 
study, 15 patients with locally advanced HNC treated with chemo-IMRT, without intentional sparing of 
the PCs, underwent DCE-MRI prior to RT, after 2 weeks into RT, and 3 months after completion of RT. BV 
and BF were quantified for the PCs and for the sternocleidomastoid muscle ipsilateral to the primary 
tumor, which received a similar dose (59 + 16 Gy) as the PCs (56 + 15 Gy). Compared to pre-RT, BV 
increased in PC by 512% at 2 weeks and 620% at 3 months post RT, whereas little change in BV was seen 
in the sternocleidomastoid. Dose to the PCs was significantly correlated with the change in BV at both 
time points (R2 =0.89), and BV changes in PC during RT were significantly correlated with the changes at 
3 months after RT (R2 =0.87). In the PCs, BV changes during RT, possibly reflecting inflammation, also 
significantly correlated with normalized T2 signal changes on MRI at 3 months after RT, possible 
representing therapy-induced edema. Truong et al., in studies using CT-perfusion imaging, have shown 
that the severity of dysphagia at 3 and 6 months after RT may be correlated with changes in BF and BV 
of the PCs after 2 weeks of RT [47]. However, neither our prior work nor the study by Truong et al. 
attempted to limit the dose to the PCs during IMRT planning, resulting in mean doses in excess of 50 Gy 
being delivered to the PCs. As the IMRT optimization goals in the presently proposed study will attempt 
to limit mean PC dose to 50 Gy, which produced excellent preservation of swallowing function and low 
rates of dysphagia in UMCC protocol 2002-021, we will investigate whether changes in PC perfusion 
after 2 weeks correlate with patient- and observer-rated dysphagia and objective video fluoroscopy 
swallowing assessments at 3 months post-RT, in protocol patients where treatment goal was sparing the 
PCs outside the targets. 
Rationale for adding FDG-PET scan at 2 weeks after therapy started:  
UMCC 2013.062 aims to assess whether higher-than-standard radiotherapy doses to resistant tumor 
sub-volumes improves the outcome compared with standard therapy in patients with locoregionally 
advanced, poor prognosis HNC. It relies on early changes in MRI-based hypo-perfusion (HP), associated 
with hypoxia, and restricted water diffusion (RWD), associated with local cellularity, and are  identified 
using perfusion MRI and DCE-MRI, respectively. Both are associated with aggressive and less responsive 

8 
 
disease.  Once these subvolumes are identified, the subvolumes which persist spatially from pre-therapy 
to 2 weeks into therapy, are planned for escalating radiation doses during the rest of the therapy 
course. Patients are randomized to escalation or standard therapy arms. Thus far 32 patients have been 
accrued and randomized out of planned 80 patients. Interim analyses showed that the HP and RWD are 
spatially distinct, prompted us to aim at both subvolumes for dose escalation, which was included in a 
previous amendment aimed to target both subvolumes. More recently we have assessed the pre-RT and 
during-RT spatial distributions of the MRI-based tumor subvolumes HP and RWD vs. pre-therapy FDG-
PET-based metabolic tumor volumes (MTVs). We found a reduction by about 50% of the union between 
HP and RWD subvolumes at 2 weeks compared with pre-RT. This is similar to a 50% reduced total lesion 
glycolysis (TLG) defined as (SUVavg) · (tumor volume), with a threshold of 45% SUVmax in the volume of 
interest, reported in series of pre- vs during- treatment FDG-PET in head and neck cancer (Pollom WL 
Head neck 2016, Min M & Lin P, Eur J Nuc Med Mol Imag 2015). These series reported improved 
outcomes in patients whose TLG was reduced during therapy to below 50% pre-therapy levels, 
compared to patients whose TLG reduction was lower; the effect of the reduced PET parameters from 
pre to early during-treatment was more significant than the pre-therapy FDG-PET parameters in these 
studies (many previous papers reported prognostic importance of FDG-PET parameters in HNC). We 
hypothesize that FDG-PET during the second chemo-RT week will result in MTV that will be smaller than 
at pre-therapy, will be distinct spatially from HP and RWD, and that it will be possible to escalate dose to 
a limited volume combining all during-therapy 3 subvolumes, thus aiming at both MRI-based high-risk 
tumor subvolumes as well as the intra-treatment PET-based parts of the tumor that have survived the 
initial therapy, and are likely to be more resistant to therapy.  
 
This amendment will examine two hypotheses in an exploratory pilot sub-study: 
1. FDG-PET after 8-12 chemo-RT fractions will only partly overlap spatially with HP and RWD and 
its inclusion will be feasible in safe dose intensification in the future. Dice similarity coefficients 
will be used to assess overlap. 
2. The extent of reduced FDG-PET parameters, MTV and TLG, compared with pre-RT, will be 
associated with tumor outcome. This will be tested by Cox regression models for DFS where 
predictors will be the changes in MTV and TLG, accounting for different treatments (boost vs 
standard RT) and assess whether including these changes improves our ability to predict DFS 
beyond other variables. 
Rational for adding blood samples pre-, during, and after therapy to assess circulating tumor DNA 
(ctDNA). 
 “Liquid biopsy” consisting of ctDNA with specific mutations have proven to be a promising tool to 
determine early metastases or local-regional progression. At diagnosis, between 65% -86% of HNC 
patients have ctDNA detected in the serum (Bettewgoda C, Sci Transl Med 2014, Wang Y Sci Transl Med 
2015). Their concentration pre-therapy   is higher in patients with locoregionally advanced disease 
(Dahlstrom KR, Clin Ca Res 2015, Mazurek AM Oral oncol 2016) and in patients with shorter DFS or 
survival (Yanagita M Clin Ca Res 2016, Messaoudi SE Clin Cancer Res 2016), and their  presence after 
therapy is associated with the risk of recurrence  and metastases (Hamana K Br J Ca 2005, Ahn SM JAMA 
Otolaryngol HNSurg 2014). Also, those with a higher rate of genomic alterations in ctDNA had shorter 
survival (Schwaederle M Clin Ca Res 2016). Case studies in breast, colon and lung cancers suggest that 
ctDNA dynamics during therapy may provide an early indicator of tumor response (Ignatiadis M Clin Ca 
Res 2015). While tumor-specific mutations in cfDNA have been reported in pancreas, colorectal, and 

9 
 
lung carcinomas, very little has been published on HNC (Wang). Data related to potential prognostic 
implication of increase or decrease in cfDNA after therapy is conflicting (Cao H IJROBP 2012, Fakhry C 
Cancer Prev Res 2015), and there is no  data at all regarding the implications of their  levels at mid-
therapy compared to pre- and end of therapy .  
As protocol patients are at high risk for treatment failure, a non-invasive biomarker for response earlier 
in therapy is extremely important. The measurement of serum circulating tumor ctDNA as a biomarker 
for recurrence may be an important, noninvasive method to detect treatment responses. Dr Brenner’s 
group at UM have identified HPV and mutant ctDNA in blood samples of patients with advanced or 
recurrent HNSCC, suggesting this noninvasive biomarker as a way to measure disease response to 
therapy.  Using data generated from targeted next generation sequencing on tumor specimens, we can 
prioritize evaluable somatic mutations in ctDNA from blood of each patient for targeted sequencing 
studies as well as monitor for the occurrence of mutations common in tumors. Our goal is to collect 
longitudinal samples of serum as a part of our trial to determine if serum biomarkers can predict 
response to therapy and also identify emergence of resistant clones.   
This amendment will examine in an exploratory pilot study whether the level and mutational profile of 
ctDNA pre, during, and after therapy is associated with tumor outcomes. Cox regression models will be 
done for DFS. Predictors will be cfDNA and boost arm and possibly interaction, then assess whether 
cfDNA is prognostic for DFS while accounting for different treatments (boost vs standard RT). Other 
baseline covariates will be added to the model to see if cfDNA improves our ability to predict outcome.  
 
3.0 OBJECTIVES 
3.1 Primary Objective:  
Determine whether escalating the radiotherapy dose to resistant tumor subvolumes 
identified by persistent hypoperfusion on 2 week DCE-MRI (boost arm) and by persistent 
low apparent diffusion coefficients can improve disease-free survival compared to standard 
chemo-RT (control arm) 
 
3.2 Secondary Objectives: 
1. Compare local-regional control rates and overall survival between the two arms  
2. Assess the site and timing of local recurrences as they relate spatially to the site and 
volume of the hypoperfused tumor sub-volume  
3. Assess acute and late toxicities and functional outcomes  
4. Correlate changes in perfusion of pharyngeal constrictor muscles and other normal 
tissues on 2 week DCE-MRI with dosimetric parameters and toxicity/functional 
outcomes  
5. Assess the utility of diffusion-weighted MRI in predicting tumor and tumor sub-sites at 
high risk of local/regional recurrence 
 
3.3 Exploratory Objectives: 
  

10 
 
1. Assess whether FDG-PET after 8-12 chemo-RT fractions overlaps spatially with the MRI-
based high-risk tumor subvolumes and whether its inclusion will be feasible in safe dose 
intensification in the future. 
2. Assess whether the extent of reduced FDG-PET parameters, MTV and TLG, during 
therapy compared with pre-RT, are associated with tumor outcome. 
3. Correlate the level and mutational profile of ctDNA pre, during, and after therapy with 
tumor outcomes. 
 
4.0 ELIGIBILITY CRITERIA 
4.1 Patients must have pathologically-confirmed, non-metastatic locally/regionally advanced 
squamous cell carcinoma of the head and neck, stage III/IV, referred for definitive chemo-
RT, and meet one of the following criteria:   
4.1.1 
Primary tumor (T4) with or without metastatic lymph nodes.  Tumor or nodes are: 
unresectable, resection is considered by the treating surgeon or patient to result in 
unacceptable functional or oncological results, patient refuses surgery, or surgery is not 
possible due to co-morbidities. 
4.1.2 
HPV(-) or p16(-) locally/regionally  advanced (T3-4 or N2-3) oropharyngeal cancer 
4.1.3 
HPV(+) or p16(+) locally/regionally  advanced (T4 or N3) oropharyngeal cancer  
4.1.4 
T3 or T4 laryngeal or hypopharyngeal cancer that is locally advanced, bulky (>40 cc*), 
unresectable, or patient declines surgery 
4.1.5 
Stage III/IV oral cavity or paranasal sinus cancers in patients who refuse surgery or are 
unfit for surgery 
4.1.6 
Locally/regionally advanced (stage T3-4 and/or N3) nasopharyngeal cancer which is 
EBV (-) (Epstein-Barr Virus). 
 
4.2 KPS >70 (see Appendix A) within two weeks of enrollment 
4.3 Pre-treatment laboratory criteria within four weeks of enrolment:  
4.3.1 
WBC > 3500/ul, granulocyte > 1500/ul.  
Platelet count > 100,000/ul.  
Total Bilirubin < 1.5 X ULN.  
AST and ALT < 2.5 X ULN.  
Estimated Creatinine clearance >30cc/min  
4.4 Patients must be able to receive protocol chemotherapy in the judgment of the treating 
Medical Oncologist 
 
4.5 Patients are adults (Age >18) 
4.6 All patients must be informed of the investigational nature of this study and given written 
informed consent in accordance with institutional and federal guidelines. 
 
*Based on Mancuso A, Mukherji S, et al, JCO 1999;17:631-7 
 
5.0 EXCLUSION CRITERIA 
 
5.1 EBV (+) Nasopharyngeal Carcinoma in the protocol treated tumor. 
5.2 Prior head and neck radiation. 
5.3 Documented evidence of distant metastases. 
5.4 Patients with active infection 
5.5 Pregnant women 

11 
 
5.6 Patients should have no contraindications to having a contrast enhanced MRI scan. These 
contraindications will be assessed at the time of enrollment using the guidelines set up and 
in clinical use by the Institutional Standard Practice. 
 

12 
 
6.0 STUDY DESIGN  
 
RANDOMIZE (n=80) 
Stratify: 
A. Hypoperfused BV > or < 10 
cc** 
Screening  
Baseline MRI*, FDG-PET, cfDNA 
Begin Chemo-IMRT 
Repeat MRI*,  FDG-PET, cfDNA after 2 wks  
(after IMRT fraction 8 and before fraction 12) 
Hypoperfused tumor sub-volume > 1 cc 
and/or low apparent diffusion coefficient 
present?# 
Standard Chemo-IMRT 
(Observational Cohort)+ 
No 
Yes 
ARM A: 
Chemo-IMRT with  Boost 
to Hypoperfused Volumes 
(Boost Arm) + 
ARM B: 
Standard Chemo-IMRT 
(Control Arm) + 
 
 
 
 
 
 
 
 
*MRI sequences include DCE (perfusion) and diffusion-weighted sequences 
+ Patients on each study arm will have a research DCE and DW MRI in the last week of treatment, at the discretion of the 
treating physician.   
#a threshold of 1 cc would have excluded 2 out of 13 patients in our previous DCE-MRI study (Cao et al)** 10 cc was 
the median hypoperfused BV in our previous MRI-DCE study (Cao et al) 
Schema 

13 
 
6.1 Design Overview 
Patients with HN cancer referred for definitive chemo-RT and are at high risk of local-regional failure as 
detailed in Eligibility Criteria will be eligible. After clinically required work-up (including a baseline DCE-
MRI if clinically indicated for treatment planning), patients who meet eligibility criteria and provide 
informed consent will be enrolled. Enrolled patients will complete protocol-specific assessments of 
function (observer and patient-reported measures as well as objective swallowing evaluations) and 
undergo baseline DCE-MRI and diffusion MRI (if not previously done for clinical purposes), with 
documentation of hypo-perfused tumor subvolumes and subvolumes with low apparent diffusion 
coefficients. Patients will subsequently begin standard treatment, consisting of concurrent chemo-
radiotherapy with cisplatin dosed at 40 mg/m2 (or carboplatin AUC 2 weekly, per the prescribing 
physician’s discretion in patients unfit to receive cisplatin - see Chemotherapy in section 10.0 for details) 
concurrent with IMRT, planned to deliver 70 Gy to gross tumor and 56-59 Gy to subclinical disease over 
35 fractions, 5 days weekly, over 7 total weeks. No patient will receive 2 treatments daily.   Holidays or 
missed treatments of one or two days will be accounted for by treatment on weekend or extending total 
treatment time.  
DCE-MRI and diffusion-weighted MRI will be repeated at the end of 2 weeks of chemo-RT, between RT 
fractions 9 and 12. Patients with hypoperfused tumor subvolumes and/or low apparent diffusion 
coefficients (with contiguous volume > 1 cc) that are spatially stable compared to the pre-treatment 
DCE-MRI and Diffusion-weighted MRI  (overlapping spatially with part or all of the pre-therapy  
subvolumes) will be randomized to either (a) IMRT replanning, with an RT boost delivered to the 
persistently hypoperfused/low diffusion subvolumes beginning in week 4 (boost arm), or (b) continued 
standard chemo-RT (control arm). Patients with no persistently hypoperfused/low diffusion tumor 
subvolumes, contiguous hypoperfusion/low diffusion < 1 cc in volume, or hypoperfused/low diffusion  
volumes that do not overlap with the hypoperfused/low diffusion  volume identified on pretreatment 
DCE-MRI and Diffusion-weighted MRI, respectively,  (in which case hypoperfusion/low diffusion are 
assumed to not be stable in space), will be entered onto an observational cohort and continue to receive 
standard chemo-IMRT.   
The radiotherapy boost in the boost arm will involve increasing the planned fraction dose to 2.5 Gy for 
the hypo-perfused and low-diffusion subvolumes while keeping the dose to the rest of the gross disease 
at 2 Gy/fraction. The maximal total dose to the mucosa, which is expected to be a major dose-limiting 
organ, will be limited to 70 Gy. Treatments according to the new plan will start at the start of week 4, 
such that 4 weeks (20 fractions of 2.5 Gy each) of boosted treatments will be delivered to the hypo-
perfused sub-volumes, to a total of 80 Gy over 7 weeks (2Gy x 15 fractions in the initial 3 weeks, then 
2.5 Gy x 20 fractions in the latter 4 weeks). This dose will be equivalent to approximately 87 Gy delivered 
at 2 Gy fractions to the tumor, and 85 Gy delivered at 2 Gy/fractions to late-responding tissue, using the 
linear-quadratic model.  
The primary objective is to improve 3-year disease-free survival from an expected 50% in the control 
arm to 70% in the boost arm. Stopping rules are as detailed in section 24.4 and will be implemented in 
case of excess acute or late toxicities.  

14 
 
Follow-up will include observer-rated toxicities according to CTCAE version 4, patient-reported QOL 
(European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 
(QLQ)-C30 and QLQ-H&N35 [48], and objective assessments of dysphagia (videofluoroscopy). 
Assessments of tumor response and disease status will be performed according to standard care.    
7.0 INITIAL CLINICAL EVALUATION (WITHIN 4 WEEKS PRIOR TO ENROLLMENT) 
 
 
7.1 Complete history and physical examination, multidisciplinary examination by Radiation 
Oncology, Medical Oncology and any department treating with head and neck surgery and/or 
maxillofacial surgery, with documentation of extent of primary tumor and regional disease.  
7.2 Complete dental evaluation in dentulous patients.  
7.3 Completion of laboratory studies: Comprehensive panel, CBC with platelets and differential, 
magnesium  
7.4 Diagnostic CT scan or MRI of the head and neck and/or PET-CT. 
7.5 Chest X-Ray or diagnostic CT of chest/thorax as determined by the treating physicians. (CT/PET 
may be used as an alternative to the diagnostic chest x-ray or CT). 
7.6 Creatinine clearance, calculated or measured 
7.7 Baseline toxicity evaluation. 
7.8 Audiograms for patients with hearing complaints or hearing loss at the discretion of the 
prescribing physician. 
 
8.0 RADIOTHERAPY 
8.1 Immobilization, imaging and target definitions 
All patients will undergo immobilization using thermoplastic mask as described previously [49] 
or another device providing similar or better immobilization. Targets will be defined on the 
planning CT images. Patients with tumors near the base of skull will undergo diagnostic MRI in 
addition to CT to aid in target delineation. The targets will consist of the primary tumor and 
lymph nodes containing metastases (gross tumor volume, GTVs), as well as lymph node groups 
at risk of metastases and the postoperative tumor bed, where applicable (clinical target 
volumes, CTVs). The GTVs will be expanded to yield the corresponding CTVs according to 
clinical assessment in each case. All CTVs will be expanded uniformly by 0.3 cm to yield the 
corresponding planning target volumes (PTVs). Organs at risk (OARs) that will be defined and 
contoured for each case for IMRT optimization will include the parotid and submandibular 
glands, lips, oral cavity (encompassing the oral surfaces of the lips, cheeks (buccinator muscle), 
hard and soft palate, tongue, base of tongue and floor of mouth), glottic larynx, pharyngeal 
constrictor muscles, upper esophagus, spinal cord, and mandible. The brain stem, eyes, optic 
nerve and optic chiasm will be contoured and specified if the target lies in vicinity to these 
structures. Additional OARs may be defined in specific cases as clinically indicated.   
 
8.2 Initial Treatment planning 
 
All targets will be treated in each treatment fraction. The planning objectives will be adequate 
target irradiation and achieving maximal sparing of OARs, as per the optimization goals 
described below. Adequate PTV coverage and relative dose homogeneity, however, will be 
constraints which will bear a higher weight in optimization and will usually override 

15 
 
noninvolved tissue sparing goals, with the exception of the constraints on the spinal cord and 
non-involved lips, for which the highest priority will be assigned due to prohibitive risks of late 
and acute toxicity, respectively, for these two OARs. Adequate target coverage of the non-
involved lymph node CTVs will prioritize below the sparing constraints for the glottic larynx, 
inferior pharyngeal constrictor muscle, and upper esophagus, as per our routine clinical 
practice. Sparing of the remaining OARs will be prioritized below that of the CTVs.  
 
8.3 Target Doses:  
8.3.1 
PTV1 (Gross tumor): 70 Gy in 35 fractions 
8.3.2 
PTV2 (High risk subclinical targets): 59 Gy in 35 fractions 
8.3.3 
PTV3 (Low risk subclinical targets): 56 Gy in 35 fractions 
 
8.4 Optimization goals will be: 
8.4.1 
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. 
8.4.2 
The maximal dose to the spinal cord, expanded 0.5 cm, will be < 50 Gy, to the 
non-expanded cord < 45 Gy, to the optic pathways < 50 Gy and to the brainstem 
<54 Gy. 
8.4.3 
Mean dose to each parotid gland will be < 24 Gy 
8.4.4 
Mean dose to each submandibular gland will be < 30 Gy 
8.4.5 
Mean dose to the non-involved oral cavity will be < 30 Gy 
8.4.6 
Mean dose to the non-involved glottic larynx will be < 20 Gy 
8.4.7 
Mean dose to the non-involved upper and middle pharyngeal constrictors will 
be < 50 Gy 
8.4.8 
Mean dose to the non-involved lower pharyngeal constrictors and esophagus 
will be < 20 Gy 
8.4.9 
Maximal dose to the mandible will be <70 Gy or < 105% of the prescribed dose 
delivered to a volume of at least 0.5 cc, whichever is lower. 
8.4.10 Mean dose to the lips will be < 30 Gy 
8.4.11 Maximum dose to the eyes will be < 40 Gy 
8.4.12 Maximal dose to the brachial plexus will be < 65 Gy 
8.4.13 Maximal dose to each cochlea will be < 40 Gy 
 
8.5 The planning process:  
8.5.1 
When target expansion to yield the PTV causes its extension beyond the skin 
contour, incorporation of zero dose (outside the tissue) should be avoided in 
the PTV dose calculations. This may be achieved by editing the PTV or by taking 
into account only the PTV residing within the external contour, in DVH 
calculations. 
 
8.6 Planning of the adaptive boost doses (Boost arm only) 
8.6.1 
The IMRT boost plan will be identical to the original plan with the following 
modification: Hypo-perfused and low-diffusion sub-volumes (Hypo-GTVs) within 

16 
 
the gross tumor will be defined and delineated on the pre-therapy and the 2-
week DCE-MRI and diffusion-weighted MRI. After registration of the pre-therapy 
and the 2-week MRI data sets, an overlapping hypoperfused and low diffusion 
sub-volumes will be defined. The overlapping hypoperfused and low-diffusion 
subvolume (=pre-therapy hypoperfused and low diffusion subvolume which did 
not become perfused or increased diffusion after 2 weeks of therapy, HypoGTV) 
will be transferred to the planning CT after registration. If there is no 
hypoperfused and/or low diffusion sub-volume at 2 weeks, no contiguous 
hypoperfused and /or low diffusion subvolume < 1 ml, or no overlap between 
the hypoperfused and/or low diffusion subvolumes from 2 weeks and pre-MRI, 
the patient will not be randomized and will be assigned to the observational 
cohort to continue standard chemo-RT.  
8.6.2 
The adaptive new plan will deliver 2.5 Gy per fraction to the HypoGTVs while 
the rest of the PTVs receive 2 Gy fractions, beginning week 4 (fraction 16) for 
the remaining 20 fractions. The planning of the boost will limit the mucosal 
fraction doses to < 2 Gy, which will limit total mucosal dose to <70 Gy.  Non-
resectable lymph node GTVs will be planned in the same manner. For patients in 
whom delivery of the full boost dose of 2.5 Gy per fraction to the HypoGTVs will 
result in mucosal dose exceeding 2 Gy per fraction, the boost dose to portions 
of the HypoGTVs will be reduced as necessary such that the mucosal < 2 Gy per 
fraction limit is not exceeded. 
 
9.0 MRI  
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. 
9.1  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),[50] 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, [51] 
 
¦¦
¦¦
 
 
 
 



 
c
i
N
k
i
k
m
ik
c
i
N
k
i
k
m
ik
m
v
x
u
v
x
u
J
1
1
2
1
1
2
D

17 
 
¦
 










 
c
j
j
k
j
k
i
k
i
k
ik
m
m
v
x
v
x
v
x
v
x
u
1
2
2
2
2
)
1
(
1
)
1
(
1
)
(
)
(
D
D
¦
¦
 
 


 
n
k
m
ik
n
k
k
k
m
ik
i
u
x
x
u
v
1
1
)
1(
)
(
D
D
 (1) 
is to be minimized. 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, 
kx 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: 
 
and
 
(2) 
 
 
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. 
 
9.2 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 

18 
 
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: 


)1(
b
b
S
S
ln
ADC
0
1
b
b
1
0

»
»
¼
º
«
«
¬
ª
 
                             
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.  
 
9.3 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 Practice guidelines, 
which is based upon the FDA guideline, to screen the patients with renal disease, dysfunction, 
and dialysis for this study.   

19 
 
 
10.0 
CHEMOTHERAPY (BOTH ARMS A AND B) 
 
NOTE: Carboplatin may be substituted for cisplatin at any time if patients are not candidates for 
cisplatin or are not able to tolerate cisplatin secondary to toxicity, as deemed necessary by the 
patient’s prescribing medical oncologist.  Missed chemotherapy doses will not be made up at a 
later time.   
10.1 Cisplatin 40 mg/m2 administered as an IV infusion will be delivered prior to radiotherapy 
on day 1 of each week of chemoirradiation, typically on Mondays, but other days are 
allowed if judged necessary by the treating medical oncologist. Chemotherapy schedule 
will not be affected if radiotherapy is held (as judged by the treating medical oncologist) 
10.1.1 Patients considered medically unfit to receive cisplatin as determined by the 
prescribing physician (i.e. due to creatinine clearance < 60 cc/min, hearing 
impairment < 30 decibels, or neuropathy > grade 1) will receive carboplatin 
(AUC 2) via IV infusion on day 1 of each week of chemoirradiation 
10.2 An aggressive antiemetic regimen is required before the administration of cisplatin, 
consisting of a neurokinin 1 antagonist, sertotonin (5-HT3) antagonist and a steroid 
(dexamethasone). Alternative antiemetic regimens may also be administered at the 
discretion of the prescribing physicians. 
10.3 Pre-cisplatin hydration: normal saline plus 1 gram/L Magnesium Sulfate plus KCl 20 mEq/L 
i.v. infusion at 500 mL/hr x 3 hours before cisplatin. Alternative pre-hydration regimens 
may also be administered at the discretion of the prescribing physicians. 
10.4 Mannitol 12.5 gm i.v. bolus may be given immediately prior to cisplatin, followed by 25 gm 
of mannitol in 500 mL of normal saline with cisplatin, as deemed necessary by the 
prescribing physician.  
10.5 Post-cisplatin: Normal saline plus KCl 20 mEq/L plus MgS04 1 gm/L at 500 mL/hr x 3 hours. 
Alternative post-hydration regimens may also be administered at the discretion of the 
prescribing physicians. 
 
 
11.0 
FDG-PET/CT 
Patient Preparation 
FDG-PET/CT will be performed prior to treatment initiation per clinical indications, and at approximately 
8-12 days after commencement of chemo-radiation therapy (RT). In preparation for FDG PET/CT imaging 
at baseline (pre-treatment) and during EBRT, all patients will be fasted for >4-6 hours and have glucose 
levels <250 mg/dL at the time of FDG injection.  
 
Imaging Acquisition 
At least sixty minutes following intravenous administration of 300 MBq (8 mCi) of FDG, sequential CT 
and PET imaging will be performed from the vertex of the skull to the mid thigh on an integrated PET/CT 
scanner (Siemens Biograph T6; Siemens Medical Solutions, Hoffman Estates, IL, USA).  
 

20 
 
Per institutional protocol, helical CT from skull vertex to mid-thigh will be performed (CareDose 4D, 
reference mAs 50, kV 120, 5 mm collimation, pitch 1.0), followed by whole body PET with multiple 
overlapping bed positions from skull vertex to mid-thigh. Immediately thereafter, with the patient 
remaining still, 100 ml of non-ionic radioopaque contrast is administered intravenously and dedicated 
head and neck helical CT from skull base to thoracic inlet is performed (CareDose 4D, reference mAs 
150, kV 120, 2 mm collimation, pitch 0.8).  
Attenuation-corrected FDG-PET tomographic images are reconstructed (TrueD, iterative reconstruction 
3 orders, 24 subsets, Gaussian filter 5.0, zoom 1.0) and co-registered to both the whole body and the 
contrast-enhanced head and neck CT. Co-registered non-contrast enhanced CT and attenuation 
corrected FDG PET images will be reviewed on a workstation using software with fusion capability 
(MedImage; MedView Pty, Canton, MI, USA) by a Nuclear Medicine Physician (KKW) providing a single 
read per study.  
 
Imaging Interpretation and SUV Measurement 
Objective quantification of FDG uptake in regions of interest (ROI) will be defined for each primary 
tumor and for cervical lymph nodes (LNs) displaying FDG uptake above background using the 
corresponding CT images for anatomic orientation. The maximum standardized uptake values (SUVmax) 
for the primary tumor and for the involved LN with the highest SUVmax on the pre-treatment and during 
PET/CT will be recorded. Additional parameters for investigation will include SUVpeak, total glycolytic 
volume (TGV). 
Qualitative response during RT will be categorized into four bins according to metabolic response 
criteria primarily based on visual assessment: progressive disease (PD), stable disease (SD), partial 
response (PR), complete response (CR). The actual percentage decline of SUVmax and SUVpeak, will be 
analyzed as a continuum.  
Liquid Biopsy: cfDNA: Experimental design: We will isolate ctDNA from blood samples of patients and 
perform integrative targeted sequencing. 
 
12.0 
CIRCULATING DNA LIQUID BIOPSY 
Blood will be collected using BCT or PAXgene tubes at pre-defined intervals (pre-therapy, at 2 and 4 
weeks after therapy started, at the end of therapy, and at 3, 6, 12 months post therapy) for each 
patient. At each blood draw, 6 ml of whole blood will be obtained in one 10 ml EDTA or PAXgene 
collection tube for the ctDNA analysis.  We will then use the QIAamp Circulating Nucleic Acid Kit will be 
used to extract and purify DNA or RNA from cell-free plasma as in Fig 1 (which shows relative cfDNA 
analysis of HPV16 or control DNA content isolated from our index HPV16 positive patient at the time of 
surgery as compared to cfDNA of a stage matched HPV negative patient isolated at surgery, 
representative qPCR data shows detectable levels in circulation). Trizol solution combined with RNeasy 
Mini Kit (Qiagen) will be used to extract and purify total RNA from cfDNA fractions depending on the 
blood volume. At least 6mL blood per time point will be used for DNA/RNA extraction and protocols 
optimized by our group which has been used to isolate assayable DNA (median 25 ng) and RNA (median 
20 ng) quantified using the Qubit fluorometer. As little as 2mL blood yields sufficient DNA and RNA for 
the studies proposed herein. 

21 
 
 
 
 
13.0 
EVALUATION OF RESPONSE TO TREATMENT 
13.1 Evaluation of tumor extent will be recorded for the primary tumor and 
regional nodes at each follow up interval. PET-CT scans will be performed 
10 to 14 weeks after the completion of therapy to assess response and at 
11 to 13 months following treatment. 
13.2 A patient will be considered to have a complete response (CR) if there is no 
measurable or palpable tumor either on clinical or radiographic (CT-PET 
scan) examination assessed within 3 months after the completion of 
treatment. Complete response will be defined as complete disappearance 
of disease or residual radiographic abnormality that is not considered to be 
tumor. 
13.3 Patients with any nodes who are PET-CT positive at 12 weeks (+/- 1 month) 
RT may be considered for neck dissection. Patients with palpable residual 
nodes at 3 months whose PET-CT shows a complete response (CR) may 
undergo clinical observation and periodic PET scans according to the judgment of the 
treating clinician 
13.4 Clinical examinations will be performed as comparable to clinical practice: at 
approximately 1 month after the completion of therapy and then every 2 months during 
years 1 and 2, and at 3-month intervals during year 3, after which follow-up will be 
performed according to clinical practice. Allowable windows for these exams are +/- 1 
month. Clinical examinations will be performed by medical oncology, radiation oncology, 
and/or surgical oncology. To meet the examination requirements, patients need to be 
seen by at least one discipline (but not all three) during the aforementioned time 
intervals.  
13.5 Patients with tumor progression or recurrence will be followed as clinically indicated 
 
14.0 
DOSE DELAYS AND TREATMENT MODIFICATIONS 
Non- Hematologic Toxicity  
Action Taken  
Abdominal Pain/Nausea/Vomiting 
See Section 12.1 of the Protocol  
 
• Total bilirubin is > 2.5 x ULN  
 
• AST and/or ALT is > 2.5 x ULN  
• Alkaline phosphatase ≥ 2.5 x ULN and AST and 
Step 1: Interrupt chemotherapy 
until the toxicity has resolved, up 
to 2 weeks (14 days). If not 
resolved at 14 days, then 
radiation will continue without 
chemotherapy. 
Step 2: Cisplatin should be 
Figure 1. cfDNA isolated 
from serum of patients 
shows high yield of viral 
DNA in circulation. Cell lines 
with integrated HPV DNA 
were used as controls by 
spiking control blood with 5ng 

22 
 
ALT is > 2.5 x ULN  
 
reduced by 10 mg/m2 and 
Carboplatin by an AUC 0.5.  
Monitor as clinically indicated.  
Hematologic Toxicity  
 
• Neutrophil count is < 1000 cells/ mm3 
  
• Platelet count is < 75,000 cells/mm3  
 
Step 1: Interrupt chemotherapy 
until the toxicity has resolved to < 
Grade 1 or pre-therapy baseline, 
up to 2 weeks (14 days). If not 
resolved at 14 days, then 
radiation will continue without 
chemotherapy. 
 
Step 2: Restart chemotherapy; 
monitor as clinically indicated.  
 
• Grade 4 neutropenia (< 500 cells/mm3) lasting 
7 days or more  
 
• Grade 3 or 4 neutropenia with an oral 
temperature of at least 38.5°C  
 
Step 1: Interrupt chemotherapy 
until resolved to ≤ Grade 1, up to 
2 weeks (14 days). If not resolved 
at 14 days, then radiation will 
continue without chemotherapy. 
 
Step 2:  At discretion of medical 
oncology provider, Cisplatin 
reduced by 10 mg/m2   and 
carboplatin by AUC 0.5.  
Monitor as clinically indicated. 
Other Toxicities  
 
• Any Grade 1  
 
Continue chemotherapy  

23 
 
 
• Any Grade 2 or 3, if clinically significant with 
the exception of toxicities expected from 
chemo-RT such as grade 2-3 mucositis, skin 
toxicity, transient nausea/vomiting, 
dysphagia/esophagitis, or other toxicities judged 
to be prevalent in standard clinical practice. 
Step 1: Interrupt chemotherapy 
up to 2 weeks (14 days), until 
toxicity resolves to < Grade 1. If 
not resolved at 14 days, then 
radiation will continue without 
chemotherapy. 
 
Step 2: Cisplatin should be 
reduced by 10 mg/m2   and 
Carboplatin by an AUC 0.5.  
Monitor as clinically indicated. 
 
• Any recurrent Grade 2 or 3 after two (2) dose 
reductions, if clinically significant toxicities 
expected from chemo-RT such as grade 2-3 
mucositis, skin toxicity, transient 
nausea/vomiting, dysphagia/esophagitis, or 
other toxicities judged to be prevalent in 
standard clinical practice (see above) 
 
Discontinuation of chemotherapy 
and continue RT and follow-up 
per protocol.  
 
• Any Grade 4 attributable to chemotherapy 
with the exception of grade 4 neutropenia  
 
Discontinuation of chemotherapy 
and continue RT and follow-up 
per protocol. 
NOTE: Carboplatin may be substituted for cisplatin at any time if patients not able to 
tolerate cisplatin secondary to toxicity, as deemed necessary by the patient’s 
prescribing medical oncologist. 
 See Section 13.1 for additional guidelines 
 
14.1 Guidelines for Nausea, Vomiting or Abdominal Pain  
14.1.1 If a patient has ≥ Grade 2 nausea, ≥ Grade 2 vomiting, or any abdominal pain 
that lasts for longer than 48 hours, chemotherapy should be held and the 
following actions are recommended:  
1. Physical examination, including the performance of vital signs  
2. Screening abdominal radiography to include an abdominal series to exclude I 
 
ileus, SBO, or pneumatosis intestinalis  
3. Consideration for obtaining a CT scan with contrast of the abdomen should be 

24 
 
made based on clinical judgment  
4. If ileus, SBO, or pneumatosis intestinalis are excluded, dosing of 
chemotherapy may be reinstated following the provisions in Section 8.0, Dose 
Delays and Dose Modifications for Toxicity.   If a patient is determined to have 
ileus, SBO, or pneumatosis intestinalis, dosing of chemotherapy will be held and 
expectant management with supportive care is recommended, unless clinical 
signs or symptoms are present that suggest septicemia or abdominal 
catastrophe that warrants surgical management.  No further chemotherapy can 
be administered following recovery from these events. 
14.2 
Radiation Dose Modification 
14.2.2  No radiation dose modification or delay will be planned unless clinically 
necessary according to the judgement of the treating physician.  Per Radiation 
Oncology department procedures, radiation is not given over holidays.  
Compensation for missed treatments (up to three days) will determined by 
treating physician.   Delays of treatment longer than three days will be 
considered deviations.   
 
15.0 
DRUG INFORMATION 
 
15.1 Cisplatin  
 
15.1.1 Biochemistry: cis-diamminedichloroplatinum (cis-DDP) is a heavy metal 
compound which a divalent platinum molecule binds two potential leaving 
groups, the chloride ions. Two NH3 groups are bound in a firm covalent linkage 
in transposition to the chloride moieties. Both chloride ions undergo a slow 
displacement by water, generating a positively charged aquated complex, which 
is capable of interacting with a nucleophilic site on DNA, RNA, or protein. 
15.1.2 Pharmacokinetics: The dominant action of cisplatin appears to be inhibition of 
the incorporation of DNA precursors, although protein and RNA synthesis are 
also inhibited. Plasma levels of cisplatin decay in a biphasic mode with an initial 
half-life of 25-49 minutes, and a secondary phase ranging from 58-73 hours. This 
prolonged phase is due to protein binding, which exceeds 90% of the activity in 
the second phase. Urinary excretion is incomplete with only 27-45% excreted in 
the first five days. Largely unchanged drugs are the initial fraction excreted. 
Although this drug seems to act as an alkylating agent, there are data to indicate 
that its mode and sites of action are different from those of nitrogen mustard 
and the standard alkylating agents. 
15.1.3 Pharmaceutical Data:  
15.1.3.1 Formulation: Cisplatin (Platinol ®) is available as an aqueous solution in 
a concentration of 1 mg/mL. 
15.1.3.2 Storage and Stability: The aqueous solution is stored at room 
temperature protected from light. Cisplatin is stable in mannitol/NS/ 
D5W mixtures for 48 to 72 hours at room temperature and up to 72 
hours when refrigerated (per Trissel’s Handbook on Injectable Drugs, 
11th edition).  
15.1.4 Human Toxicology: Human toxicity from cisplatin includes: nausea, vomiting, 
anorexia, loss of taste, renal toxicity (with an elevation of BUN, creatinine, and 
impairment of endogenous creatinine clearance, as well as renal tubular 
damage, which appears to be transient), ototoxicity (with hearing loss, which 
initially is in the high-frequency range, as well as tinnitus), peripheral 

25 
 
neuropathy, allergic reactions, and uricemia. Much more severe and prolonged 
toxicity has been observed in patients with abnormal or obstructed urinary 
excretory tracts. Myelosuppression, often with delayed erythrosuppression, is 
expected. In the high-dose treatment regimen with osmotic diuresis, the nadir 
of white blood cells and platelets occurred regularly at about two weeks with 
recovery generally at about three weeks after the initiation of therapy. 
15.1.5 Supplier: Cisplatin is commercially available, and should therefore be purchased 
by the third party. 
 
15.2 Carboplatin 
 
15.2.1 Biochemistry: Carboplatin (CBDCA) is a hydrophilic platinum coordination 
compound and is an analog of cisplatin, producing intrastrand DNA cross-links. 
15.2.2 Pharmaceutical Data 
15.2.2.1 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.  
15.2.2.2 Formulation: Carboplatin is supplied as a sterile lyophilized powder in 
single-dose vials containing 150 mg and as 10mg/mL solution in 5, 15, 
45, and 60mL vials. Each lyophilized powder vial contains equal parts 
by weight of carboplatin and mannitol. Immediately before use, the 
content of the 150 mg lyophilized powder vial must be reconstituted 
with 15 mL of either sterile water for injection, D5W, or normal saline 
to a concentration of 10 mg/mL. Carboplatin solution can be further 
diluted to concentrations as low as 0.5 mg/mL with D5W or normal 
saline injection. 
15.2.2.3 Storage and Stability: Unopened vials of carboplatin for injection are 
stable for the life indicated on the 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. 
15.2.3 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 

26 
 
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. 
15.2.4 Administration: Intravenous infusion. 
15.2.5 Supplier: Carboplatin is commercially available and should be purchased by a 
third party. 
 
 
16.0  EVALUATION OF TOXICITY AND QUALITY OF LIFE  
16.1 
Validated quality of life questionnaires: EORTC QLQ-C30 and EORTC QLQ-H&N35 
(Appendix B) will be given to patients before and periodically after radiation (1, 3, 6, 12, 
18, 24 and 36 months, with a +/- 1 month window for each).  All Head and Neck 
Common Toxicity Criteria Adverse Events (CTCAE, v.4.0) observer related items will be 
gathered weekly during radiation and at every follow- up clinic visit through 3 years. As 
part of data collection related to the quality of life measures, pre and post-treatment 
employment status will also be recorded, as well as Performance Status Scale. Patients 
may be asked for this information during a clinic visit or contacted via phone. The study 
team will attempt to obtain this information from all enrolled patients.  
 
16.2  
Objective evaluation of swallowing will be performed by videofluoroscopy and 
esophagogram. A baseline study will be performed either before RT starts or on one of 
the first five days of RT. Three follow-up studies will be done: one study at 3 following 
RT completion (+/- 1 month), one study at 12 months following RT completion (+/- 1 
month), and one study at 24 months following RT completion (with the acceptable 
window of 2 months prior or 6 months post). Each subject will be asked to swallow 
various food consistencies in varying amounts (5-15 ml). The consistencies included thin 
liquid barium (diluted with water) followed with non- diluted barium, followed with a 
puree, soft food (fruit mixed with barium) and a solid (shortbread cookie) coated with 
barium. The examinations will be recorded and analysis of the 3 phases of swallowing: 
oral, pharyngeal and esophageal will be made. Assessment will focus on bolus 
manipulation and control, bolus passage including cohesion, motility, and timing. The 
timing or duration of each swallowing phase will be determined. Also, the amount and 
incidence of aspiration and penetration, laryngeal sensation (response to penetrant/ 
aspirate) and residue/pooling after the swallow will be recorded. Laryngeal sensation 
will be determined to be good, reduced or poor. Reduced sensation would be consistent 
with a cough reflex that is delayed or intermittent. Poor sensation is defined when 
subjects elicit no spontaneous cough reflex or throat clear. These subjects are 
considered to be "silent" aspirators.  
 
 
 
 

27 
 
 
 
 
 
 
 
17.0 Study Calendar 
 
Assessment 
Pre-
Treatment 
Day 
10-16 
Day 28 
(+/- 3 
days) 
Weekly 
During 
RT 
12-14 wks post 
chemo-RT (+/- 
1 mo) 
Follow 
Up4 
H&P/Physician 
assessment* 
X 
 
 
X 
X 
X 
HPV or p16 Testing 
X 
 
 
 
 
 
 CT or diagnostic MRI of 
head and neck1 
X 
 
 
 
 
 
PET-CT  
X 
X 
 
 
X2 
X2 
CT Thorax or Chest      
X-Ray3 
X 
 
 
 
 
 
DCE&diffusionMRI 
X9 
X5 
 
X10 
 
 
Labs: Cbcpd, Comp, 
magnesium, calculated 
or measured CrCl 
X 
 
 
X 
 
 
Audiogram as deemed 
necessary  
X 
 
 
 
 
 
Begin initial RT plan  
X 
 
 
 
 
 
Begin boost RT plan 
(patients randomized 
to Arm A /Boost only) 
 
 
X 
 
 
 
Dental Evaluation 
X 
 
 
 
 
 
Toxicity6 and QOL7 
Evaluation 
X 
 
 
X 
X 
X 
Videofluoroscopy8 
X 
 
 
 
X 
X 

28 
 
Cisplatin (40 mg/m2) or 
Carboplatin (AUC 2 ) 
Arms A and B 
 
 
 
X  
 
 
cfDNA11 
X11 
 
 
X11 
 
X11 
*H&P with PE required by otolaryngology, Radiation Oncology, and Medical Oncology pretreatment 
only.  During follow up, clinic visits may be completed in person or virtually via phone or video visit, as 
per standard clinical practice.   
1 CT or MRI of Head and Neck are not required if a PET-CT was performed. 
2Restaging PET-CT will be obtained at 10-14 weeks and at 11-13 months following treatment 
3 CT Thorax or Chest X-Ray are not required if a PET-CT was performed. 
4Follow Up: Examinations will be performed as comparable to clinical practice: at 1 month after the 
completion of therapy and then approximately every 2 months during years 1 and 2 (+/- 6 weeks), and 
at approximately 3-month intervals during year 3 (+/- 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.   
5 DCE and diffusion MRI after approximately 2 weeks to be performed after delivery of RT fraction 9 and 
before delivery of RT fraction 12 
6Toxicity evaluation will be collected at each visit.  
7Quality of Life Questionnaires will be given to patients at baseline and at follow-up visits at 1, 3, 6, 12, 
18, 24 and 36 months.  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.  QOLs may be mailed 
to the patient, or a study coordinator may call the patient to complete the questionnaire.   
8 Pre treatment videofluoroscopy will be performed prior to treatment or during the first week of 
treatment.  Follow-up videoflouroscopy will be done at 3 and 12 months after therapy, +/- 1 month, and 
at 24 months after therapy, with an allow windows of 22 to 30 months.   
9 If a patient will have a clinical MRI scan for simulation, the patient is not required to have an additional 
MRI scan for this research study. 
10 A third research DCE and DW MRI will be performed at the end of treatment, at the discretion of the 
treating physician.   
11cfDNA will be checked pre, at 2 and 4 weeks of radiation therapy, end of radiation therapy, and at 3, 6, 
12 months post radiation therapy.  If the corresponding clinic visit is done virtually in lieu of an in-person 
visit, cfDNA may not be collected.  Missing correlative blood draws due to virtual visits will not be 
reported as deviations.   
 
 
 
 
18.0 CRITERIA FOR DISCONTINUATION OF TREATMENT 
18.1 
Unacceptable adverse event(s), intercurrent illness which prevents further 
administration of treatment, patient preference, progressive disease, life threatening or 
other unacceptable drug-related toxicity, changes in the patient's condition that render the 
patient unacceptable for further treatment in the judgment of the investigators 
18.2 
Stopping rules are specified in Statistics (section 24.4) 
18.3 
Off Study Conditions:  Patients may be removed from study for the following conditions.  
Once off study, patients will no longer follow the study calendar and toxicities and adverse 
events will no longer be collected for these subjects: 

29 
 
18.3.1 Patient withdraws consent 
18.3.2 Patient is unable or unwilling to comply with protocol requirements 
18.3.3 Patient exhibits tumor progression (Note: unless patient specifies, data from 
these subjects may still be used for analysis, up to the point when tumor 
progression occurred). 
18.3.4 Patient begins another therapy (outside of a surgical intervention to remove 
his/her disease).  
18.3.5 Physician discretion.  
 
19.0 OTHER THERAPY 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented 
as concomitant medication. 
 
 
20.0 PATIENT SCREENING AND REGISTRATION 
Patient registration for this trial will be centrally managed by the Coordinating Center of The 
University of Michigan Comprehensive Cancer Center as described below: 
 
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 provided by the Coordinating Center. 
 
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 Clinical Trials Office, 
either by fax or by email to CTSU-Oncology-Multisite@med.umich.edu.   
 
A Multi-Site Coordinator of the Coordinating Center, 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 Section Two of the Eligibility Worksheet signed and dated by the registrar, 
will be faxed back or emailed 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. 
 
21.0 MULTISITE DATA MANAGEMENT 

30 
 
All information will be recorded locally and entered into Case Report Forms (CRFs) on the web-based 
Velos data management 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:  
x 
At the time of registration   
o Subject entry into Velos 
 
Subject Status 
 
Demographics 
x 
During study participation 
o All data should be entered online within 10 business days of data acquisition. 
[Information on Serious Adverse Events must be entered within the reporting timeframe 
specified in Section 21 of the protocol.  
  
All study information should be recorded in an appropriate source document (e.g. clinic chart).  
 
22.0 REPORTING ADVERSE EVENTS  
All Head and Neck toxicities, regardless of grade and attribution, will be collected in the study database 
from the initiation of treatment to the end of study.  These include but are not limited to:  dysphagia, 
mucositis, xerostomia, and salivary gland changes.  All Non-Head and Neck toxicities grade 2 or greater 
will be collected from the initiation of treatment until 30 days following the last day of treatment.  
Abnormal laboratory findings will only be collected if they cause a change in treatment.   Serious 
adverse events will continue to be followed until resolution or clearly determined to be due to a 
patient’s stable or chronic condition or intercurrent illness(es). The investigator is responsible for the 
detection and documentation of events meeting the criteria and definition of an AE or SAE as provided 
in this protocol. During the study, when there is a safety evaluation, the investigator or site staff will be 
responsible for detecting AEs and SAEs, as detailed in this section of the protocol. 
 
22.1 Definitions: The definitions of adverse events (AEs) and serious adverse events (SAEs) are 
given below. The following definitions of terms are guided by the International Conference 
on Harmonization and the US Code of Federal Regulations and are included here verbatim. 
It is the responsibility of the principal investigator to ensure that all staff involved in the trial 
is familiar with the content of this section.  
22.1.1 Adverse Events (AE) - An AE is any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product which does 
not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (i.e. abnormal laboratory 
finding, symptom, or disease temporally associated with the use of a medicinal 
(investigational) product), whether or not related to the medicinal 
(investigational) product. Examples of an AE include: 
 

31 
 
22.1.1.1 Significant or unexpected worsening or exacerbation of the 
condition/indication under study. 
22.1.1.2 Exacerbation of a chronic or intermittent pre-existing condition 
including either an increase in frequency and/or intensity (grade) of 
the condition. 
22.1.1.3 New conditions detected or diagnosed after investigational treatment 
delivery even though may have been present prior to the start of the 
study. 
22.1.1.4 Signs, symptoms, or the clinical sequelae associated with a suspected 
interaction of the investigational treatment with a concomitant 
medication. 
22.1.1.5 Any medical condition or laboratory abnormality with an onset date 
before initial treatment administration is considered to be pre-
existing in nature. 
22.1.1.6 Any known pre-existing conditions that are ongoing at time of study 
entry, and any events of Grade 3 or 4 severity that occur up to 30 days 
before study entry (even if resolved prior to study entry) should be 
considered medical history and recorded in the appropriate section of 
the case report form. 
22.1.1.7 In addition to new events, any increase in the frequency or severity 
(i.e. toxicity grade) of a pre-existing condition that occurs after the 
patient begins chemo-radiation is also considered an adverse event. 
 
22.1.2 Serious Adverse Events (SAE) - A serious adverse event is an AE which occurs 
after the initiation of chemo-RT, during treatment, or within 30 days of the last 
day of chemo-RT that fulfills one or more of the following criteria regardless of 
cause or assessed relationship to therapy. Any untoward medical occurrence 
that at any dose: 
 
22.1.2.1 Results in death, 
22.1.2.2 Is life-threatening (NOTE: The term ‘life-threatening’ in the definition 
of ‘serious’ refers to any adverse drug experience that places the 
patient or subject, in the view of the investigator, at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a 
reaction that, had it occurred in a more severe form, might have 
caused death.) 
22.1.2.3 Requires inpatient hospitalization or prolongation of hospitalization 
(NOTE: In general, hospitalization signifies that the patient or subject 
has been detained (usually involving at least an overnight stay) at the 
hospital for observation and/or treatment that would not have been 
appropriate in the physician’s office or out-patient setting. 
Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be 
considered serious. Hospitalization for elective treatment of a pre-
existing condition that did not worsen from baseline is not considered 
an AE. Planned hospitalization for surgical procedures, either related 
or unrelated to the patients cancer is not considered a serious 
adverse event) 

32 
 
22.1.2.4 Results in persistent or significant disability/incapacity (NOTE: The 
term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. 
22.1.2.5 Is a congenital abnormality/birth defect. 
Or 
22.1.3 Important medical events 
22.1.3.1 Events which may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
22.2 
Adverse Event Reporting Requirements 
 
22.2.1.1 Serious Adverse Event Reporting 
Serious Adverse Events meeting the reporting guidelines in 20.2.1.2 
will be reported to the IRB using the CTSU Oncology Serious Adverse 
Event Form. SAEs will also be reported to the multi-site coordinator 
and the Principal Investigator.   AEs reported as Serious Adverse 
Events must also be reported in routine study data submissions 
including the Data and Safety Monitoring Report, in addition to the 
IRB. 
 
22.2.1.2 Serious Adverse Event Reporting Timeline 
The Principal Investigator must be notified within 10 business days of 
study team’s knowledge of any event meeting the criteria and 
definition of a serious adverse event.  
 
All Serious Adverse Events that are unexpected and possibly related 
(definite, probable or possible) to study treatment will be reported to 
the IRB using CTSU Oncology Serious Adverse Event form. 
 
The following types of hospitalizations do not constitute SAEs:  
20.2.1.2.1 Hospitalization or Emergency room visits secondary to expected 
cancer morbidity: Admission for palliative care or pain management 
20.2.1.2.2 Planned hospitalizations for surgical procedures, either related or 
unrelated to the patient’s cancer. 
 
22.2.1.3 Grading of Adverse Events 
22.2.1.3.1 The severity of all adverse events and laboratory 
abnormalities will be graded according to the US National 
Cancer Institute’s Common Terminology Criteria for Adverse 
Events version 4.0 (CTCAE). 
 
22.2.1.4 Relationship to Chemo-RT Related Event 

33 
 
Any adverse event that has a temporal relationship to the research 
intervention, follows a known or suspected pattern of response, and 
for which an alternative cause may not be present, is definitely, 
probably, or possibly associated with the research intervention. 
Investigator needs to judge relatedness and be prepared to justify the 
judgment. 
22.2.1.4.1 Definitely Related: The adverse event is clearly related to 
the research intervention: the adverse event has a temporal 
relationship to the administration of the research 
intervention, follows a known pattern of response, and no 
alternative cause is present. 
22.2.1.4.2 Possibly Related: There is a reasonable possibility that the 
event may have been caused by or is linked in a significant 
way to the research; the adverse event has a temporal 
relationship to the administration of the research 
intervention, follows a suspected pattern of response, but 
an alternative cause is present. 
22.2.1.4.3 Probably Related: The adverse event is likely related to the 
investigational intervention: the adverse event has a 
temporal relationship to the administration of the research 
intervention, follows a known or suspected pattern of 
response, but an alternative cause may be present. 
22.2.1.4.4 Unlikely to be related: The adverse event is doubtfully 
related to the investigational intervention: the adverse 
event has a temporal relationship to the administration of 
the research intervention, but follows no known or 
suspected pattern of response, and an alternative cause is 
present. 
22.2.1.4.5 Unrelated (or Not Related): The adverse event is clearly 
NOT related to the investigational intervention: the adverse 
event has no temporal relationship to the administration of 
the investigational or research intervention, follows no 
known or suspected pattern of response, and an alternative 
cause is present. 
 
 
 
23.0 
DATA AND SAFETY MONITORING 
The Data and Safety Monitoring Committee (DSMC) of The University of Michigan Comprehensive 
Cancer Center (UMCCC) is the DSMC for this study.  This committee is responsible for the review and 
monitoring the study’s scientific progress, accrual rate and any serious adverse events. 
At each site the study team is required to meet quarterly to discuss matters related to: 
¾ Enrollment rate relative to expectations, characteristics of participants 
¾ Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
¾ Adherence to protocol (protocol deviations) 
¾ Completeness, validity and integrity of study data 
¾ Retention of study participants 
 

34 
 
These meetings are to be documented by the site data manager or study coordinator using the Protocol 
Specific Data and Safety Monitoring Report (DSMR), signed by the site principal investigator or co-
investigator.  Each site is required to submit the completed DSMR to the Multi-Site Coordinator at the 
University of Michigan Coordinating Center on a quarterly basis together with other pertinent 
documents. 
Similarly, protocol deviations are to be documented using the Notice of Protocol Deviation Form and 
requires the signatures of both the sites data manager or study coordinator and the site principal 
investigator or co-investigator. These reports are to be sent to the University of Michigan Coordinating 
Center within 7 calendar days of awareness of the event and on a quarterly/ basis with the Protocol 
Specific Data and Safety Monitoring Report. 
The Coordinating Center is responsible for collating all the Data and Safety Monitoring Reports from all 
the participating sites, and providing the information to the Data and Safety Monitoring Committee. 
 
24.0 
CLINICAL MONITORING PROCEDURE 
Clinical studies coordinated by The University of Michigan Comprehensive Cancer Center (UMCCC) 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 UMCCC. 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 UMCCC 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 first treatment cycle.  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: 

35 
 
¾ Adherence to the protocol 
¾ Completeness and accuracy of study data and samples collected 
¾ Proper storage, dispensing and inventory of study medication 
¾ 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 if all of the following apply: 
¾ No patient has signed the Informed Consent Form and has enrolled into the study 
¾ Investigational agent has not been dispensed 
¾ All investigational agent and materials have been returned as defined for the study or destroyed and 
accounted for properly. 
 
25.0 
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. 
 
 
26.0 
STATISTICAL CONSIDERATIONS 
26.1 
General  
This is a randomized phase II trial to assess whether the adaptive RT plan described in 
detail above, improves disease free survival, relative to standard treatment.  Patients 
with hypoperfused and /or low-diffusion tumor subvolumes (with contiguous volume > 
1 cc) that are spatially stable compared to the pre-treatment MRI (overlapping spatially 
with part or all of the pre-therapy hypoperfused subvolumes) will be randomized in a 
1:1 ratio to either standard or adaptive treatment.  Randomization will be stratified by 

36 
 
the volume of the hypoperfused and low-diffusion subvolumes (dichotomized as > or < 
10 cc) and by pre-therapy tumor volume (dichotomized as > or < 56 cc, which is the 
median tumor size in our advanced disease population).  Patients with small or non-
spatially stable hypoperfused and/or low diffusion subvolumes will not be included in 
primary aim analysis but will still be enrolled in an observational cohort and followed for 
outcome.  While the numbers of such patients is likely to be small, their data will be 
used in analyses addressing secondary objectives.    A total of 40 evaluable patients will 
be randomized to each arm.  Patients will be considered evaluable for the primary aim if 
they are able to complete study treatment regardless of reductions or modifications and 
also 1) complete at least 3 months of follow-up post-RT or 2) die or progress within 3 
months of completing treatment. Non-evaluable patients may be included in toxicity 
analyses but will be replaced for the primary aim.  
 
26.2 
Justification of Design 
Several recent studies of patients with locoregionally advanced, unresectable HNC have 
reported DFS at 3 years to be near 50% (Allen A et al).  Thus, based on an assumed DFS 
rate at 3 years of 50% in the control arm, we calculate the power to detect an 
improvement in the adaptive RT arm, to 70% DFS at 3 years.  Based on an expected 
enrollment period of 4 years, 2 additional years of FU, an exponential loss to FU function 
with 10% of patients lost to FU by 2 years, and a 1-sided .10 level test, 40 patients per 
arm will give 83% power.  Based on our preliminary data we expect approximately 8-10 
(10%) of all enrolled patients to be ineligible for the week 2 randomization.  These 
patients will be used in addressing questions of the prognostic effect of hypoperfused 
volumes in the secondary objectives.  Although the number of these patients will be 
small they will allow analyses designed to detect relationships between outcome and 
hypoperfused volumes in the absence of intervention.    
 
26.3 
Analysis Plan:  
 
Here we describe the analyses for each of the protocol objectives. 
 
Primary Objective:  
26.3.1 Determine whether escalating the radiotherapy dose to resistant tumor 
subvolumes identified by persistent hypoperfusion and low diffusion on 2 week 
DCE-MRI (boost arm) can improve disease-free survival compared to standard 
chemo-RT (control arm) 
 
Disease free survival (DFS) time is defined as the time to disease recurrence or 
death, whichever occurs first.  Patients who are alive without evidence of 
disease at the end of follow-up will be censored at the date of their last clinical 
follow-up.  Kaplan-Meier curves with point-wise 90% confidence intervals will 
be generated for each treatment arm, overall and by strata.  Estimates with 
confidence intervals will be generated from these curves for the usual summary 
statistics, including median DFS times and DFS at 1, 2, and 3 years.  The primary 
analysis for this aim will utilize a 1-sided .10 level stratified log-rank test to 
compare the two treatment arms with respect to disease free survival. There 
will be two strata corresponding to the strata used in randomization. 
 
Secondary Objectives: 
26.3.2 Compare local-regional control rates and overall survival between the two arms  
 

37 
 
Local-regional control is defined as the absence of local-regional progression.  
Subjects without documented progression at the time of analysis will be 
censored at the last visit in which imaging was performed to assess for 
progression.  Analysis will otherwise mirror that described above for the primary 
aim of DFS.   
 
26.3.3 Assess the site and timing of local recurrences as they relate spatially to the site 
and volume of the hypoperfused tumor sub-volume   
 
The first part of this aim is to assess the spatial relation between the site of the 
hypoperfused sub-volume and the site of any local recurrence.  Several 
approaches are possible here.  In simple analyses, we will assess whether the 
hypoperfused subvolumes overlap with the recurrence volumes (rVOI) and 
calculate the proportion of patients for which this is the case.  Of course this 
proportion could be made large by increasing the size of the sub-volumes and 
thus making overlap more likely.  Thus more quantitative assessments utilizing 
diagnostic testing methods will also be used.  For each patient we will compute 
the following quantities: 
 
P1=Proportion of the imaging sub-volume overlapping with recurrence volume 
(rVOI) 
P2=Proportion of the non-imaging sub-volume overlapping with rVOI 
 
If P1>P2, then there will be evidence that DCE-MRI is able to determine tumor 
sub-volumes at high risk of recurrence.  Across the population of patients, we 
could test whether E[P1] > E[P2] using a paired t-test.  One confounding factor 
in these analyses is dose. In the adaptive arm, high dose will be confounded 
with hypoperfused sub-volume, by design.  Thus primary analysis of this aim will 
be based on data from the randomized control arm.  However, even in this arm, 
dose varies spatially.  We will adjust for the impact of dose by including it as 
covariate in regression models or by stratifying above calculations by dose bins.    
 
The second part of this aim involves an assessment whether, at the patient 
level, the volume of the hypoperfused sub-volumes is related to the time to 
local recurrence.  To do this we will utilize a Cox proportional hazards regression 
model in which volume is included as a covariate.  These analyses will include 
patients randomized to standard treatment and patients in the observational 
cohort (who also receive standard treatment).   
 
An additional complication of the proposed analyses is that the recurrence 
volumes are not static over time.  The more frequently imaging is performed, 
the smaller the rVOI will be when first visualized, and the cleaner the analysis 
will be.  Fortunately however, in head and neck cancer, recurrences tend to be 
small when first visualized.   In addition this factor should not result in any 

38 
 
systematic bias relative to above analysis, but will rather add noise to the 
measured quantities.  
 
26.3.4 Assess acute and late toxicities and functional outcomes  
 
Acute and late toxicities will be summarized descriptively by grade and type for 
each treatment group.  The proportion of patients experiencing certain toxicity 
types will be calculated with score based confidence intervals.  Chi-square tests 
will be used to test whether the proportion of patients with toxicity differs 
between treatment groups.  
 
26.3.5 Correlate changes in perfusion of pharyngeal constrictor muscles and other 
normal tissues on 2 week DCE-MRI with dosimetric parameters and 
toxicity/functional outcomes  
 
Two distinct questions are of interest.  First whether dose is correlated with 
perfusion and second whether perfusion is correlated with toxicity/function 
outcomes. Perfusion and dose summary measures (likely mean) will be 
calculated at the level of a normal tissue for each patient.  Pearson or Spearman 
rank based correlation between the continuous dose and perfusion summary 
measures will be calculated. Similarly the correlation between perfusion and 
continuous functional measures and ordinal toxicity grades will be calculated. 
AUC values will be calculated for binary toxicity outcomes to quantify the ability 
of week 2 perfusion to discriminate between patients who do and do not 
develop toxicity.  Null hypotheses of no relation will be tested.  
 
26.3.6 Assess the utility of diffusion-weighted MRI in predicting tumor and tumor sub-
sites at high risk of local/regional recurrence.  
 
Statistical approaches here will mirror those described above under the first 
part of secondary objective 26.3.2.   
                       Exploratory Objectives: 
26.3.7  FDG-PET-based MTV  after 8-12 chemo-RT fractions spatial  overlap  with the 
MRI-based high risk subvolumes: Dice similarity coefficients will be used to 
assess overlap. 
26.3.8  Assess whether the extent of reduced FDG-PET parameters, MTV and TLG, 
compared with pre-RT, will be associated with tumor outcome.  
This will be tested by Cox regression models for DFS where predictors will be the 
changes in MTV and TLG, accounting for different treatments (boost vs standard 
RT) and assess whether including these changes improves our ability to predict 
DFS beyond other variables. 

39 
 
26.3.9  Assess whether the level and mutational profile of ctDNA pre, during, and after 
therapy is associated with tumor outcomes.  
Cox regression models will be done for DFS. Predictors will be cfDNA and boost 
arm and possibly interaction, then assess whether cfDNA is prognostic for DFS 
while accounting for different treatments (boost vs standard RT). Other baseline 
covariates will be added to the model to see if cfDNA improves our ability to 
predict outcome.  
 
26.4 
Stopping rules  
Stopping for the current protocol will be based upon the occurrence of excessive acute 
toxicity in patients randomized to the boost arm of the protocol. We will stop the trial 
and halt enrollment if we become reasonably confident that the rate of grade 4 acute 
non-hematologic toxicity (as scored by CTCAE version 4) exceeds 15%, as detailed in the 
table below. The stopping rule specifies that the trial will stop if the number of patients 
with toxicity is at least as great as the number in the second column.  The operating 
characteristics of this rule, specifically the cumulative proportion of simulated trials that 
stopped early, are given in the table below. For example if the true probability of 
toxicity is .1, just 1% of trials would stop after 10 patients, and just 3% of trials would 
ever stop early.  On the other hand if the true probability of toxicity is 35%, there is a 
50% chance of stopping after just 10% patients and a nearly 80% chance of stopping by 
20 patients.   
 
 
 
 
True Probability of Toxicity  
Number of Patients 
Evaluable for Toxicity 
Threshold 
for Stopping 
0.1 
0.25 
0.35 
0.5 
10 
4 
0.01 
0.22 
0.5 
0.84 
20 
6 
0.02 
0.44 
0.78 
0.98 
30 
7 
0.03 
0.7 
0.95 
1 
  
 
 

40 
 
27.0 
REFERENCES 
 
1. 
Wang, P., et al., An approach to identify, from DCE MRI, significant subvolumes of tumors related 
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Haddad, R.I. and D.M. Shin, Recent advances in head and neck cancer. N Engl J Med, 2008. 
359(11): p. 1143-54. 
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Allen, A.M., et al., Acceleration of hyperfractionated chemoradiation regimen for advanced head 
and neck cancer. Head Neck, 2007. 29(2): p. 137-42. 
4. 
Ang, K.K., et al., Human papillomavirus and survival of patients with oropharyngeal cancer. N 
Engl J Med, 2010. 363(1): p. 24-35. 
5. 
Popovtzer, A., et al., The pattern of failure after reirradiation of recurrent squamous cell head 
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Salama, J.K., et al., Long-term outcome of concurrent chemotherapy and reirradiation for 
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Phys, 2006. 64(2): p. 382-91. 
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Sulman, E.P., et al., IMRT reirradiation of head and neck cancer-disease control and morbidity 
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8. 
Haddad, R.I.R., Guilherme , et al., The PARADIGM trial: A phase III study comparing sequential 
therapy (ST) to concurrent chemoradiotherapy (CRT) in locally advanced head and neck cancer 
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9. 
Ang, K.K., et al., A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation 
plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas 
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10. 
Dawson, L.A., et al., Patterns of local-regional recurrence following parotid-sparing conformal 
and segmental intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol 
Biol Phys, 2000. 46(5): p. 1117-26. 
11. 
Eisbruch, A., et al., Recurrences near base of skull after IMRT for head-and-neck cancer: 
implications for target delineation in high neck and for parotid gland sparing. Int J Radiat Oncol 
Biol Phys, 2004. 59(1): p. 28-42. 
12. 
Studer, G., U.M. Luetolf, and C. Glanzmann, Locoregional failure analysis in head-and-neck 
cancer patients treated with IMRT. Strahlenther Onkol, 2007. 183(8): p. 417-23; discussion 424-
5. 
13. 
Oksuz, D.C., et al., Recurrence patterns of locally advanced head and neck squamous cell 
carcinoma after 3D conformal (chemo)-radiotherapy. Radiat Oncol, 2011. 6: p. 54. 
14. 
Farrag, A., et al., Pattern of failure after helical tomotherapy in head and neck cancer. 
Strahlenther Onkol, 2010. 186(9): p. 511-6. 
15. 
Cao, Y., The promise of dynamic contrast-enhanced imaging in radiation therapy. Semin Radiat 
Oncol, 2011. 21(2): p. 147-56. 
16. 
Shukla-Dave, A., et al., Dynamic contrast-enhanced magnetic resonance imaging as a predictor 
of outcome in head-and-neck squamous cell carcinoma patients with nodal metastases. Int J 
Radiat Oncol Biol Phys, 2012. 82(5): p. 1837-44. 
17. 
Truong, M.T., et al., Prediction of locoregional control in head and neck squamous cell carcinoma 
with serial CT perfusion during radiotherapy. AJNR Am J Neuroradiol, 2011. 32(7): p. 1195-201. 
18. 
Chawla, S., et al., Prediction of disease-free survival in patients with squamous cell carcinomas of 
the head and neck using dynamic contrast-enhanced MR imaging. AJNR Am J Neuroradiol, 2011. 
32(4): p. 778-84. 
19. 
Cao, Y., et al., Early prediction of outcome in advanced head-and-neck cancer based on tumor 
blood volume alterations during therapy: a prospective study. Int J Radiat Oncol Biol Phys, 2008. 
72(5): p. 1287-90. 

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20. 
Zima, A., et al., Can pretreatment CT perfusion predict response of advanced squamous cell 
carcinoma of the upper aerodigestive tract treated with induction chemotherapy? AJNR Am J 
Neuroradiol, 2007. 28(2): p. 328-34. 
21. 
Hermans, R., et al., Tumor perfusion rate determined noninvasively by dynamic computed 
tomography predicts outcome in head-and-neck cancer after radiotherapy. Int J Radiat Oncol 
Biol Phys, 2003. 57(5): p. 1351-6. 
22. 
Jansen, J.F., et al., Noninvasive assessment of tumor microenvironment using dynamic contrast-
enhanced magnetic resonance imaging and 18F-fluoromisonidazole positron emission 
tomography imaging in neck nodal metastases. Int J Radiat Oncol Biol Phys, 2010. 77(5): p. 
1403-10. 
23. 
Cho, H., et al., Noninvasive multimodality imaging of the tumor microenvironment: registered 
dynamic magnetic resonance imaging and positron emission tomography studies of a preclinical 
tumor model of tumor hypoxia. Neoplasia, 2009. 11(3): p. 247-59, 2p following 259. 
24. 
Nehmeh, S.A., et al., Reproducibility of intratumor distribution of (18)F-fluoromisonidazole in 
head and neck cancer. Int J Radiat Oncol Biol Phys, 2008. 70(1): p. 235-42. 
25. 
Lin, Z., et al., The influence of changes in tumor hypoxia on dose-painting treatment plans based 
on 18F-FMISO positron emission tomography. Int J Radiat Oncol Biol Phys, 2008. 70(4): p. 1219-
28. 
26. 
Lee, N., et al., Prospective trial incorporating pre-/mid-treatment [18F]-misonidazole positron 
emission tomography for head-and-neck cancer patients undergoing concurrent 
chemoradiotherapy. Int J Radiat Oncol Biol Phys, 2009. 75(1): p. 101-8. 
27. 
Rischin, D., et al., Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients 
with advanced head and neck cancer. J Clin Oncol, 2001. 19(2): p. 535-42. 
28. 
Olteanu, L.A., et al., Evaluation of deformable image coregistration in adaptive dose painting by 
numbers for head-and-neck cancer. Int J Radiat Oncol Biol Phys, 2012. 83(2): p. 696-703. 
29. 
Galban, C.J., et al., Prospective analysis of parametric response map-derived MRI biomarkers: 
identification of early and distinct glioma response patterns not predicted by standard 
radiographic assessment. Clin Cancer Res, 2011. 17(14): p. 4751-60. 
30. 
Ellingson, B.M., et al., Volumetric analysis of functional diffusion maps is a predictive imaging 
biomarker for cytotoxic and anti-angiogenic treatments in malignant gliomas. J Neurooncol, 
2011. 102(1): p. 95-103. 
31. 
Barajas, R.F., Jr., et al., Diffusion-weighted MR imaging derived apparent diffusion coefficient is 
predictive of clinical outcome in primary central nervous system lymphoma. AJNR Am J 
Neuroradiol, 2010. 31(1): p. 60-6. 
32. 
Yamasaki, F., et al., Glioblastoma treated with postoperative radio-chemotherapy: prognostic 
value of apparent diffusion coefficient at MR imaging. Eur J Radiol, 2010. 73(3): p. 532-7. 
33. 
Ellingson, B.M., et al., Graded functional diffusion map-defined characteristics of apparent 
diffusion coefficients predict overall survival in recurrent glioblastoma treated with bevacizumab. 
Neuro Oncol, 2011. 13(10): p. 1151-61. 
34. 
Vandecaveye, V., et al., Applications of diffusion-weighted magnetic resonance imaging in head 
and neck squamous cell carcinoma. Neuroradiology, 2010. 52(9): p. 773-84. 
35. 
Srinivasan, A., et al., Utility of pretreatment mean apparent diffusion coefficient and apparent 
diffusion coefficient histograms in prediction of outcome to chemoradiation in head and neck 
squamous cell carcinoma. J Comput Assist Tomogr, 2012. 36(1): p. 131-7. 
36. 
Kim, S., et al., Diffusion-weighted magnetic resonance imaging for predicting and detecting early 
response to chemoradiation therapy of squamous cell carcinomas of the head and neck. Clin 
Cancer Res, 2009. 15(3): p. 986-94. 
37. 
Galban, C.J., et al., A feasibility study of parametric response map analysis of diffusion-weighted 
magnetic resonance imaging scans of head and neck cancer patients for providing early 
detection of therapeutic efficacy. Transl Oncol, 2009. 2(3): p. 184-90. 

42 
 
38. 
Eisbruch, A., Dysphagia and aspiration following chemo-irradiation of head and neck cancer: 
major obstacles to intensification of therapy. Ann Oncol, 2004. 15(3): p. 363-4. 
39. 
Lauve, A., et al., Simultaneous integrated boost intensity-modulated radiotherapy for locally 
advanced head-and-neck squamous cell carcinomas: II--clinical results. Int J Radiat Oncol Biol 
Phys, 2004. 60(2): p. 374-87. 
40. 
Madani, I., et al., Maximum tolerated dose in a phase I trial on adaptive dose painting by 
numbers for head and neck cancer. Radiother Oncol, 2011. 101(3): p. 351-5. 
41. 
Murdoch-Kinch, C.A., et al., Dose-effect relationships for the submandibular salivary glands and 
implications for their sparing by intensity modulated radiotherapy. Int J Radiat Oncol Biol Phys, 
2008. 72(2): p. 373-82. 
42. 
Little, M., et al., Reducing xerostomia after chemo-IMRT for head-and-neck cancer: beyond 
sparing the parotid glands. Int J Radiat Oncol Biol Phys, 2012. 83(3): p. 1007-14. 
43. 
Dijkema, T., et al., Parotid gland function after radiotherapy: the combined michigan and utrecht 
experience. Int J Radiat Oncol Biol Phys, 2010. 78(2): p. 449-53. 
44. 
Feng, F.Y., et al., Intensity-modulated chemoradiotherapy aiming to reduce dysphagia in patients 
with oropharyngeal cancer: clinical and functional results. J Clin Oncol, 2010. 28(16): p. 2732-8. 
45. 
Feng, F.Y., et al., Intensity-modulated radiotherapy of head and neck cancer aiming to reduce 
dysphagia: early dose-effect relationships for the swallowing structures. Int J Radiat Oncol Biol 
Phys, 2007. 68(5): p. 1289-98. 
46. 
Eisbruch, A., et al., Chemo-IMRT of oropharyngeal cancer aiming to reduce dysphagia: 
swallowing organs late complication probabilities and dosimetric correlates. Int J Radiat Oncol 
Biol Phys, 2011. 81(3): p. e93-9. 
47. 
Truong, M.T., et al., Correlating computed tomography perfusion changes in the pharyngeal 
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Biol Phys, 2012. 82(2): p. e119-27. 
48. 
Bjordal, K., et al., Quality of life in head and neck cancer patients: validation of the European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire-H&N35. J Clin 
Oncol, 1999. 17(3): p. 1008-19. 
49. 
Marsh, R., et al., Design and analysis of an immobilization and repositioning system for 
treatment of neck malignancies. Med Dosim, 1997. 22(4): p. 293-7. 
50. 
Wismuller, A., et al., Cluster analysis of dynamic cerebral contrast-enhanced perfusion MRI time-
series. IEEE Trans. Med. Imag., 2006. 25(1): p. 62-73. 
51. 
Chen, S.C. and D.Q. Zhang, Robust image segmentation using FCM with spatial constraints based 
on new kernel-induced distance measure. IEEE Trans. Syst. Man Cybern. B Cybern., 2004. 34(4): 
p. 1907-1916. 
 
 
 
 

43 
 
28.0 
APPENDICES 
 
 
 
Appendix A: Karnofsky Performance Status Scale 
 
 
 
 
 
 

44 
 
Appendix B: EORTC Quality of Life Questionnaire (QLQ) C-30 and H&N35  
 
EORTC QLQ – C30 and H&N35 
 
Study UMCC: _____________         Study ID#: _________________           Date:  ____________________ 
 
C30 (questions: 1-30):  We are interested in some things about you and your health.  Please answer all 
of the questions by circling the number that best applies to you.  There are no “right” or “wrong” 
answers.  The information you provide will remain strictly confidential.   
 
 
Not at 
all 
A little 
Quite 
a bit 
Very 
much 
1. 
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. 
Do you have any trouble taking a short walk outside of the 
house? 
1 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
 
During the past week: 
Not at 
all 
A little 
Quite 
a bit 
Very 
much 
6. 
Were you limited in doing either your work or other daily 
activities? 
1 
2 
3 
4 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10. 
Did you need to rest? 
1 
2 
3 
4 
11. 
Have you had trouble sleeping? 
1 
2 
3 
4 

45 
 
12. 
Have you felt weak? 
1 
2 
3 
4 
13. 
Have you lacked appetite? 
1 
2 
3 
4 
14. 
Have you felt nauseated? 
1 
2 
3 
4 
15. 
Have you vomited? 
1 
2 
3 
4 
16. 
Have you been constipated? 
1 
2 
3 
4 
17. 
Have you had diarrhea? 
1 
2 
3 
4 
18. 
Were you tired? 
1 
2 
3 
4 
19. 
Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. 
Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
1 
2 
3 
4 
21. 
Did you feel tense? 
1 
2 
3 
4 
22. 
Did you worry? 
1 
2 
3 
4 
23. 
Did you feel irritable? 
1 
2 
3 
4 
24. 
Did you feel depressed? 
1 
2 
3 
4 
25. 
Have you had difficulty remembering things? 
 
1 
2 
3 
4 
26. 
Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
27. 
Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
28. 
Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 

46 
 
 
 
 
 
 
Study UMCC: _____________         Study ID#: _________________           Date:  ____________________ 
 
For the following questions please circle the number between 1 and 7 that best applies to you. 
 
29. 
How would you rate your overall health during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
 
Very poor 
 
 
 
Excellent  
30. 
How would you rate your overall quality of life during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
 
Very poor 
 
 
 
Excellent  
 
 
 
 
 
H&N-35 (questions: 31-65) 
 
Patients sometimes report that they have the following symptoms or problems.  Please indicate the 
extent to which you have experience these symptoms or problems during the past week. 
 
 
During the past week: 
Not at 
all 
A little 
Quite 
a bit 
Very 
much 
31. 
Have you had pain in your mouth? 
1 
2 
3 
4 
32. 
Have you had pain in your jaw? 
1 
2 
3 
4 
33. 
Have you had soreness in your mouth? 
1 
2 
3 
4 
34. 
Have you had a painful throat? 
1 
2 
3 
4 

47 
 
35. 
Have you had problems swallowing liquids? 
1 
2 
3 
4 
36. 
Have you had problems swallowing pureed food? 
1 
2 
3 
4 
Study UMCC: _____________         Study ID#: _________________           Date:  ____________________ 
 
37. 
Have you had problems swallowing solid food? 
1 
2 
3 
4 
38. 
Have you choked when swallowing? 
1 
2 
3 
4 
39. 
Have you had problems with your teeth? 
1 
2 
3 
4 
40. 
Have you had problems opening your mouth wide? 
1 
2 
3 
4 
41. 
Have you had a dry mouth? 
1 
2 
3 
4 
42. 
Have you had sticky saliva? 
1 
2 
3 
4 
43. 
Have you had problems with your sense of smell? 
1 
2 
3 
4 
44. 
Have you had problems with your sense of taste? 
1 
2 
3 
4 
45. 
Have you coughed? 
1 
2 
3 
4 
46. 
Have you been hoarse? 
1 
2 
3 
4 
47. 
Have you felt ill? 
1 
2 
3 
4 
48. 
Has your appearance bothered you? 
1 
2 
3 
4 
49. 
Have you had trouble eating? 
1 
2 
3 
4 
50. 
Have you had trouble eating in front of your family? 
1 
2 
3 
4 
51. 
Have you had trouble eating in front of other people? 
1 
2 
3 
4 

48 
 
52. 
Have you had trouble enjoying your meals? 
1 
2 
3 
4 
53. 
Have you had trouble talking to other people? 
1 
2 
3 
4 
 
 
 
Study UMCC: _____________         Study ID#: _________________           Date:  ____________________ 
 
54. 
Have you had trouble talking on the telephone? 
1 
2 
3 
4 
55. 
Have you had trouble having social contact with your family? 
1 
2 
3 
4 
56. 
Have you had trouble having social contact with friends? 
1 
2 
3 
4 
57. 
Have you had trouble going out in public? 
1 
2 
3 
4 
58. 
Have you had trouble having physical 
contact with family or friends? 
1 
2 
3 
4 
59. 
Have you felt less interest in sex? 
1 
2 
3 
4 
60. 
Have you felt less sexual enjoyment? 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
Yes 
No 
 
 
61. 
Have you used pain-killers? 
1 
2 
 
 
62. 
Have you taken any nutritional supplements (excluding 
vitamins)? 
1 
2 
 
 
63. 
Have you used a feeding tube? 
1 
2 
 
 

49 
 
64. 
Have you lost weight? 
1 
2 
 
 
65. 
Have you gained weight? 
1 
2 
 
 
 
 
 
 
 
 
Study UMCC: _____________         Study ID#: _________________           Date:  ____________________