A Study Using Fluorine-18-Labeled Fluoro-Misonidazole Positron Emission Tomography To Detect Hypoxia in Head and Neck Cancer Patients
Phase: NA
Conditions: Head and Neck Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
Approval date: 01-Apr-2020 
 
 
 
 
A Study Using Fluorine-18-Labeled Fluoro-Misonidazole Positron Emission 
Tomography to Detect Hypoxia in Head and Neck Cancer Patients 
 
PROTOCOL FACE PAGE FOR 
MSK THERAPEUTIC/DIAGNOSTIC  PROTOCOL 
 
Principal Investigator/Department: 
Nancy Lee, M.D. 
Radiation Oncology 
Co-Principal 
Investigator(s)/Department: 
John Humm, Ph.D. 
Heiko Schoder, M.D. 
Medical Physics 
Radiology 
Investigator(s)/Department: 
Michael J. Zelefsky, M.D. 
Suzanne Wolden, M.D. 
Sean McBride, M.D. 
Nadeem Riaz, M.D. 
Karen Borofsky, M.D. 
Karen Schupak, M.D. 
Preeti Parhar, M.D. 
Daphna Gelblum, M.D. 
Melissa Remis Zinovoy, M.D 
Jillian Tsai, M.D. 
Marsha Reyngold, M.D. 
James Lee, M.D. 
Richard Gewanter, M.D. 
Pinaki Dutta, M.D. 
Boris Mueller, M.D. 
Borys Mychalczak, M.D. 
Annemarie F. Shepherd, MD 
John Cuaron, M.D. 
Carla Hajj, M.D. 
James Mechalakos, Ph.D 
Bradley Beattie, Ph.D 
Pat B. Zanzonico, Ph.D 
Amita Dave, Ph.D 
Neelam Tyagi, Ph.D 
Kristen Zakian, Ph.D 
Jung Hun Oh, M.D. 
Ramesh Paudyal, Ph.D 
Harini Veeraraghavan, Ph.D 
Hilda Stambuk, M.D 
Yiauchung  Sheh, Ph.D. 
Stephen Solomon, M.D. 
Steve M. Larson, M.D. 
Neeta Pandit-Taskar, M.D. 
Ravinder K. Grewal, M.D. 
Josef J. Fox, M.D. 
Wolfgang Weber, M.D. 
Duan Li, M.D. 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
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Medical Physics 
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Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
Approval date: 01-Apr-2020 
Page 2 of 43 
 
 
 
 
 
Robert Young, M.D. 
William Alago, M.D. 
Majid Maybody, M.D 
Lynn Brody, M.D. 
Karen Brown, M.D. 
Anne Covey, M.D. 
Joseph Erinjeri, M.D. 
George Gertrajdman, M.D. 
=. 
Constantinos Sofocleous, M.D 
Raymond Thornton, M.D. 
Jeremy Durack, M.D. 
Hooman Yarmohammadi, M.D 
Vaios Hatzoglou, M.D. 
Bhuvanesh Singh, M.D 
Snehal Patel, M.D. 
Jatin P. Shah, M.D. 
Richard Wong, M.D. 
Jay Boyle, M.D. 
Ashok Shaha, M.D 
Ian Ganly, M.D., Ph.D 
Luc Morris, M.D. 
Ronald A. Ghossein, M.D. 
Nora Katabi, M.D. 
David Pfister, M.D. 
Eric Sherman, M.D. 
Shrujal Baxi, M.D. 
Han Xiao, M.D. 
Marina Shcherba, D.O. 
Jahan Aghalar, M.D. 
Jasmeet Singh, M.D. 
Kenneth Ng, M.D. 
Chau Dang, M.D. 
Diana Lake, M.D. 
Elizabeth Won, M.D. 
Loren Michel, M.D. 
Afsheen Iqbal, M.D. 
Azadeh Namakydoust, M.D. 
Sree Chalasani, M.D. 
Avni Desai, M.D. 
Stuart Lichtman, M.D. 
Juliana Eng, M.D. 
John Fiore, M.D. 
Jia Li, M.D. 
Wanqing Iris Zhi, M.D., Ph.D. 
Daniel McFarland, D.O. 
Radiology 
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Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
Approval date: 01-Apr-2020 
Page 3 of 43 
 
 
 
 
 
Parisa Momtaz, M.D. 
Alice Zervoudakis, M.D 
Leslie Matthews, N.P. 
Janice Terlizzi, APN 
Kathleen Leary, N.P. 
Carol Ann Milazzo, N.P. 
Zhigang Zhang, Ph.D. 
Medicine 
Medicine 
Nursing 
Nursing 
Nursing 
Nursing 
Epidemiology-Biostatistics 
Consenting 
Professional(s)/Department: 
Nancy Lee, M.D. 
Michael J. Zelefsky, M.D. 
Suzanne Wolden, M.D. 
Sean McBride, M.D. 
Nadeem Riaz, M.D. 
Karen Borofsky, M.D. 
Karen Schupak, M.D. 
Preeti Parhar, M.D. 
Daphna Gelblum, M.D. 
Melissa Remis Zinovoy, M.D 
Jillian Tsai, M.D. 
Marsha Reyngold, M.D. 
James Lee, M.D. 
Richard Gewanter, M.D. 
Pinaki Dutta, M.D. 
Boris Mueller, M.D. Borys 
Mychalczak, M.D. Annemarie 
F. Shepherd, M.D. John 
Cuaron, MD 
Carla Hajj, M.D. 
David Pfister, M.D. 
Shrujal Baxi, M.D. 
Eric Sherman, M.D. 
Han Xiao, M.D. 
Marina Shcherba, D.O. 
Jahan Aghalar, M.D. 
Jasmeet Singh, M.D. 
Kenneth Ng, M.D. 
Chau Dang, M.D. 
Diana Lake, M.D. 
Elizabeth Won, M.D. 
Loren Michel, M.D. 
Afsheen Iqbal, M.D. 
Azadeh Namakydoust, M.D. 
Sree Chalasani, M.D. 
Avni Desai, M.D. 
Stuart Lichtman, M.D. 
Juliana Eng, M.D. 
John Fiore, M.D. 
Radiation Oncology 
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Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
Approval date: 01-Apr-2020 
Page 4 of 43 
 
 
 
 
 
Jia Li, M.D. 
Wanqing Iris Zhi, M.D., Ph.D. 
Daniel McFarland, D.O. 
Parisa Momtaz, M.D. 
Alice Zervoudakis, M.D 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
OneMSK Sites 
Manhattan 
Basking Ridge 
Rockville 
Commack 
Westchester 
 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
Approval date: 01-Apr-2020 
Page 5 of 43 
 
 
 
 
 
 
TABLE OF CONTENTS 
  
1.0 
PROTOCOL SUMMARY AND SCHEMA ...................................................................... 6 
2.0 
OBJEC TIVES ..................................................................................................................... 9 
3.0 
BACKGROUND AND RATIONALE ............................................................................. 10 
4.0 
OVERVIEW OF S TUDY DESIGN AN D INTERVENTION ......................................... 17 
4.1 
DES IGN ................................................................................................................ 17 
4.2 
INTERVEN TION ................................................................................................. 24 
5.0 
THERAP EUTIC/DIAGNOSTIC AGENTS ..................................................................... 25 
6.0 
CRITERIA FOR SUBJEC T ELIGIBILITY ..................................................................... 26 
6.1 
SUBJEC T INCLUSION CRITERIA FOR COHORT 1 AND COHORT 2 ........ 26 
6.2 
SUBJEC T EXCLUSION CRITERIA FOR COHORT 1 AND COHORT 2 ....... 26 
7.0 
REC RUITMEN T P LAN (WITH LIMITED WAIVER OF AUTHO RIZATION) .......... 27 
8.0 
PRETREATMENT EVALUATION ................................................................................ 28 
9.0 
TREATMENT/INTERVENTION PLAN ........................................................................ 28 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ........................................ 29 
11.0 
TOXICITIES/S IDE EFFEC TS ......................................................................................... 29 
12.0 
CRITERIA FOR THERAP EUTIC RESPONSE/OUTCOME ASSESSMENT............... 30 
13.0 
CRITERIA FOR REMOVAL F ROM STUDY ................................................................ 30 
14.0 
BIOSTATIS TICS ............................................................................................................. 31 
15.0 
SUBJEC T REGIS TRATION AND RANDOMIZATION PROCEDURES .................... 33 
15.1 
RES EARC H PARTICIPAN T REGIS TRATION................................................. 33 
15.2 
RANDOMIZATION............................................................................................. 33 
16.0 
DATA MANAGEMENT ISS UES ................................................................................... 34 
16.1 
QUALITY ASSURANCE .................................................................................... 34 
16.2 
DATA AND S AFETY MONITORING ............................................................... 34 
17.0 
PROTECTION OF HUMAN SUBJECTS ....................................................................... 35 
17.1 
PRIVACY ............................................................................................................. 36 
17.2 
SERIOUS ADVERS E EVENT (S AE) REPORTING.......................................... 36 
17.3 
INCLUSION OF CHILDREN IN RES EARCH................................................... 37 
18.0 
INFORMED CONSENT PROCEDURES ....................................................................... 37 
19.0 
REF ERENCE(S) ............................................................................................................... 38 
20.0 
APPENDICES .................................................................................................................. 43 

Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
Approval date: 01-Apr-2020 
Page 6 of 43 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND SCHEMA 
 
This  is  a  study  utilizing  the  hypoxia  tracer  fluorine-18-labeled  fluoro-misonidazole  (18F- 
FMISO) to evaluate the presence and bio-distribution of tumor hypoxia in head and neck 
cancer patients.  Two cohorts of patients will be accrued to this protocol: 
 
• 
Cohort 1 will consist of 150 head and neck cancer patients over a 5-year accrual 
period  who  are  not  expected  to  undergo  surgical resection of their cancer.  This 
cohort  will consist  of 100  patients with Human Papilloma  Virus positive  (HPV+) 
tumors and 50 patients with Human Papilloma  Virus negative  (HPV-) tumors. 
 
 
• 
Cohort  2  will  consist  of  19  head  and  neck  cancer  patients  who  will undergo 
surgery for their cancer per standard of care. 
 
When  possible,  we  will  also  obtain  multi-parametric  magnetic  resonance  (MR)  scans 
consisting   of   conventional   anatomical   MR   imaging   (e.g.   T1-   and   T2-weighted), 
diffusion-weighted   MR  imaging  (DW-MRI),   and  dynamic  contrast  enhanced  magnetic 
resonance  imaging  (DCE-MRI).  These  MR  scans  will be  utilized  to  assess  changes  in 
MR intensities and  the perfusion and  diffusion of water molecules in tumo r and irradiated 
normal  structures  during  and  after  the  course  of  fractionated  external  beam  radiation 
therapy  (RT).  The  DCE-MRI  data  will provide  insight  into  the  tumor  pathophysiology. 
With  proper  compartmental  modeling,  the  DCE-MRI  data  will  yield  results  on  tumor- 
vessel  permeability,  tumor  perfusion,  and  extracellular-extravascular  volume  fraction,  i.e. 
data  relating to  the tumor microenvironment.  These results will determine the potential of 
DCE-MRI data as a priori or early markers of tumor response to chemoradiation as well 
as long term disease-free survival after treatment. 
 
This study will further entail the first human study of 18F-FMISO PET image-guided core 
biopsy of neck node(s) in both HPV+ and HPV- head and neck squamous cell carcinoma 
(HNSCC; for Cohort 1 patients that consent to this optional biopsy). Additional tissue will 
be collected from patients who will undergo surgical resection of their cancer per standard 
of care (Cohort 2). We will correlate the intensity of the 18F-FMISO PET signal with the 
degree   of  immunohistochemical  staining   of  the  following  hypoxia  biomarkers,   among 
others:  HIF-1α,  Lysyl  Oxidase,  and  Ki67  (an  independent  marker  of  tumor 
aggressiveness). 
 
Lastly,  this  study  will evaluate  a  number  of treatment  approaches  to  HPV-related  head 
and neck cancer. The approaches applicable  to Cohort 1 of this study are outlined  below: 
 
1.   Definitive  chemoradiation  without  pretreatment  surgical  resection  in  which  both 
the primary tumor site and the neck nodes receive 70Gy. In patients who exhibit a 
complete nodal response with this treatment,  no further  treatment is necessary. 
2.   Definitive   chemoradiation   without  pretreatment  surgical  resection  in  which  the 
primary site receives 70Gy while the neck nodes receive a lower dose of radiation 
at  60Gy  instead  of 70Gy.  This  definitive  chemoradiation  is  followed  by  a FDG 
PET/CT scan at 3 months (+/- 4 weeks) post-treatment. In patients who exhibit a 

Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
Approval date: 01-Apr-2020 
Page 7 of 43 
 
 
 
 
 
complete nodal response  with this method  of treatment (as determined  by the 3- 
month post-treatment FDG PET/CT scan), no further treatment  is necessary. 
 
Patients enrolled  on to  this protocol who  will receive either of the treatments above (i.e. 
those  without  surgical resection  of their  cancer)  will be  included  in  Cohort  1,  and  will 
continue  with  standard  institutional care in the case of incomplete or no  nodal response. 
The information obtained from the use of 18F-FMISO PET scans in Cohort 1 will be used 
to  guide  these  patients’ treatment on this protocol. HPV+ head and neck cancer patients 
in Cohort 1  that exhibit no  evidence of hypoxia on their baseline 18F-FMISO PET scan 
and HPV+ head and neck cancer patients in Cohort 1 with early resolution of hypoxia on 
their repeat 18F-FMISO PET scan will receive 70Gy to the primary site and 60Gy to the 
neck nodes followed  by a FDG PET/CT scan and observation. 
 
Cohort 2  of this protocol will consist of patients who are to receive surgical resection of 
their  tumor.  Following  this  surgery,  patients  may  or  may not undergo  adjuvant radiation 
with  or  without  concurrent  chemotherapy,  which is dependent on the pathologic features 
of their disease. Within this cohort, select HPV+ tumors that demonstrate no evidence of 
hypoxia on a 18F-FMISO PET scan will receive 30Gy to the surgical bed and neck lymph 
nodes concurrent with standard  chemotherapy followed by a 3 to 4-month post-treatment 
neck   dissection.   In  patients  who   exhibit  a  complete  response  with  this  method  of 
treatment,  no  further treatment is necessary.  For patients within this select group who still 
have  pathologic  nodal  disease,  further  standard  chemoradiation  will be  given.  All other 
patients  in  this  cohort (i.e.  those who  are not in the select HPV+ tumor group  outlined 
above) will receive standard of care treatment following  their surgery. 
 
Please note the  18F-FMISO  PET imaging protocol is exactly the same for all patients on 
this protocol, regardless of cohort. 
 
 
 
Schema: 
 
1.1 
Evaluation,  determination  of cohort, and consent. 
 
1.2 
Baseline  studies (standard of care) for head and neck cancer. 
 
1.3 
Perform a pretreatment FDG PET/CT scan for Cohort 1 patients. 
 
1.4 
Perform   a   recommended   pretreatment   multiparametric   MRI   scan   for 
Cohort  1   patients.   This  scan  will  be  used  to  derive  a  pixel-by-pixel 
mapping   of   true   diffusion   (D),   perfusion   fraction   (f),   and   apparent 
diffusion   coefficient   (ADC)    using   available   software   when   available 
(unless contraindicated;  for main campus only). 
 
1.5 
Prior  to  the  injection  of the  18F-FMISO  radiotracer,  check  the patient’s 
vital signs. 

Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
Approval date: 01-Apr-2020 
Page 8 of 43 
 
 
 
 
 
1.6 
Perform a pretreatment dynamic 18F-FMISO PET/CT scan.   This scan will 
be  used  to  verify  the  constancy  of the  hypoxic  regions  within  the  gross 
tumor volume  (GTVh). 
 
1.7 
A   safety   assessment   will   be   performed:   vital   signs   and   a   toxicity 
assessment  will  be  completed  immediately  after  the  scan  session,  and  a 
follow-up  phone  call  to  assess  for  toxicities  will  be  done  on  the  next 
business  day  following  the  18F-FMISO  PET/CT  scan  (excluding  holidays 
and weekends). 
 
1.8 
An  18F-FMISO  PET  image-guided  core  biopsy  procedure  of  the  neck 
nodes will be performed  after the last  18F-FMISO  PET image acquisition 
for Cohort 1. This biopsy procedure will only occur if the patient consents 
to the procedure and if the procedure is deemed applicable by the Principal 
Investigator. 
 
1.9 
Surgical  resection  for  Cohort  2   (if  it  has  not  already  occurred)  and 
collection of the resected tissue for the correlation of 18F-FMISO PET/CT 
signal  with the  degree  of immunohistochemical  staining  of hypoxia 
biomarkers. 
 
1.10 
Prior  to  the  injection  of the  18F-FMISO  radiotracer  for  the  repeat  18F- 
FMISO PET/CT scan for patients deemed eligible for a repeat 18F-FMISO 
PET/CT scan, check the patient’s vital signs. 
 
1.11 
Perform  a  repeat  dynamic  18F-FMISO  PET/CT  scan  early  during  the 
course   of  chemoradiotherapy  (5-10   treatment  days  after  the  start  of 
radiation  therapy)  for  patients  deemed  eligible  for  a  repeat  18F-FMISO 
PET/CT  scan.  This  scan  will be  utilized  to  determine  whether there is a 
reduction of the 18F-FMISO-avid or GTVh within  the gross tumor volume. 
 
1.12 
A safety assessment will be performed  for patients who received a repeat 
18F-FMISO PET/CT scan: vital signs and a toxicity assessment will be 
completed  immediately  after  the scan session,  and  a follow-up  phone call 
to  assess for toxicities will be done on the next business day following the 
18F-FMISO PET/CT scan (excluding  holidays  and weekends). 
 
1.13 
An  18F-FMISO  PET  image-guided  core  biopsy  procedure  of  the  neck 
nodes will be performed  after the last  18F-FMISO  PET image acquisition 
for  Cohort  1.  This  biopsy  will only  occur  if the  patient  consents  to  the 
procedure and if the procedure is applicable as determined by the Principal 
Investigator. 
 
1.14 
Perform    recommended     approximately    weekly    MRI    scans    during 
treatment,  unless  contraindicated,  for  main  campus  Cohort  1  patients.  A 
DCE-MRI   is   recommended   between   the  first  and   second   weeks  of 

Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
Approval date: 01-Apr-2020 
Page 9 of 43 
 
 
 
 
 
treatment and between the third and fourth weeks of treatment, unless 
contraindicated,   for  main  campus  Cohort  1   patients.   Subjects  with  a 
known contraindication to the standard MRI contrast agent (Gadavist; a 
gadolinium-based   contrast   agent)  and/or  a  recent  estimated   glomerular 
filtration rate (eGFR) of 30 or less will be excluded from all recommended 
DCE-MRIs,  and  will instead  receive  recommended  non-contrast MRIs at 
the DCE-MRI time points. 
 
1.15 
Recommended  MRI scans,  unless contraindicated,  will also be repeated at 
3  months,  6  months,  and  1  year  post-external beam RT  for  Cohort  1 
patients. The time windows for these MRI scans will be +/- 4 weeks. Only 
Cohort 1 patients on main campus will receive these recommended  MRIs. 
 
1.16 
Perform a FDG PET/CT scan at 3 months (window +/- 4 weeks) post-RT 
for Cohort 1  patients. Perform a planned neck dissection at   three to four 
months  (+/-  four  weeks)  post-RT  for  Cohort  2  patients  who  received 
30Gy. 
 
1.17 
Standard of care follow-up. 
 
1.18 
Longitudinal   chart   review   for   adverse   event   assessment,   locoregional 
control  rates,  and  disease  status  as  assessed  through  standard  of cares 
through  two years post-treatment for Cohort 1 and Cohort 2. 
 
2.0 
OBJECTIVES 
 
Primary 
 
 
• 
To  improve  the accuracy of hypoxia  imaging for head  and  neck  cancers through 
pixel  by  pixel  kinetic  analysis  of  18F-FMISO  tracer  of  dynamic  PET  images 
(Cohort 1 and Cohort 2). 
• 
To detect on repeat 18F-FMISO PET/CT scans whether there is a reduction of the 
18F-FMISO-avid 
 or GTVh  
5 to 10 
days into 
treatment with standard 
chemoradiotherapy  for  a  series  of  locally  advanced   head   and   neck   cancers 
(Cohort 1). 
• 
To  show that it is feasible to deliver 70Gy to primary site and 60Gy to the neck 
nodes in HPV+ patients who exhibit no evidence of hypoxia on their baseline 18F- 
FMISO  PET/CT  scans  or  those  who  have  early  resolution  of hypoxia  on  their 
early repeat 18F-FMISO PET/CT scans (Cohort 1). 
• 
To  show that it is feasible to deliver 30Gy to the surgical bed and neck nodes in 
low-risk HPV+ patients who exhibit no evidence of hypoxia on their repeat 18F- 
FMISO PET/CT (Cohort 2). 
• 
To  correlate  the  intensity  of  the  18F-FMISO  PET  signal  with  the  degree  of 
immunohistochemical   staining   of   hypoxia   biomarkers   for   tissue   obtained   via 
biopsy (Cohort 1) and  surgical resection (Cohort 2): HIF-1α, Lysyl Oxidase, and 
Ki67 (an independent  marker of tumor aggressiveness),  among others. 

Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
Approval date: 01-Apr-2020 
Page 10 of 43 
 
 
 
 
 
Secondary 
• 
To  compare  tumor  heterogeneity  derived  from  pixel-by-pixel  kinetic  analysis  of 
PET scan and DWI-MRI (Cohort 1). 
• 
To  assess  changes  in  tumor  heterogeneity  over  the  course of external beam RT 
using  serial multiparametric  MR and DCE-MRI scans (Cohort 1). 
• 
To determine the potential of DCE-MRI data as a priori or early markers of tumor 
response   to   chemoradiation   as  well  as  long  term  disease-free  survival  after 
treatment (Cohort 1). 
• 
To  assess normal tissue response as a function of dose for parotid, submandibular 
glands,  muscles  and  bones  in  the  head  and  neck  region during and  after EBRT 
using  serial multiparametric  MR scans (Cohort 1). 
• 
To  bank  specimens  for  further  IRB/PB  approved  exploration  of genetic  analysis 
(Cohort 1 and Cohort 2). 
 
3.0 
BACKGROUND AND RATIONALE 
 
Hypoxia 
 
Hypoxia is a characteristic feature of malignant tumors that has been well established  (1, 
2).    Unlike healthy tissues, many tumors contain a fraction of hypoxic cells, which 
immunohistochemical  studies  suggest  consist  of  nests  of cells  of up  to  several hundred 
micrometers in diameter,  located  at poorly perfused locations within the tumor  (3).   It is 
well known that hypoxia renders tumor cells up  to  three times more resistant to  ionizing 
radiation  than  aerobic  cells  (1-3).    In  addition  to  increased  radioresistance,  hypoxia  is 
associated  with  a  more aggressive and  metastatically viable malignant phenotype.    It has 
been shown in several studies to  be an important determinant of loco -regional control of 
head  and  neck  tumors  (4,  5).    Positron  Emission  Tomography  (PET)  is  a  noninvasive 
imaging  modality  with  the  potential  to  identify  tumor  hypoxia  at  both  global and  local 
levels  through  the  use  of  hypoxia  targeting  molecules.     If  these  hypoxic  regions  are 
identified,   they   may   be   specifically   targeted   with   additional  radiation   and   perhaps 
translate into further  improvement  in local control. 
 
18F-FMISO PET/CT Scan 
 
A  recently  developed  PET  imaging-based  hypoxia  measurement  technique  using  18F- 
FMISO  can  detect  and  quantify hypoxic regions within a tumor (6).    Misonidazole is a 
hypoxic   cell   radiosensitizer,   which   is   preferentially   and   metabolically   reduced   and 
entrapped within hypoxic cells and not aerobic cells. An 18F-FMISO PET/CT scan is a 
noninvasive  imaging  method  in  detecting  tumor  hypoxia.    In  a  R3327-AT  Dunning  rat 
prostate tumor model at Memorial Sloan Kettering Cancer Center (MSKCC), microPET 
imaging of 18F-FMISO  has been used  to  detect tumor hypoxia,  followed  by direct pO 2 
verification  of the hypoxic regions by using  the pO2 Oxylite  probe. 
 
PET  studies  using  hypoxic  markers  have  also  been  performed  in  patients  at  numerous 
institutions  (e.g.  Rasey  et  al)  (6).    A  phase  I  trial of using  concurrent  tirapazamine,  a 
hypoxic cell sensitizer,  cisplatin,  and  radiotherapy in the treatment of advanced  head  and 

Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
Approval date: 01-Apr-2020 
Page 11 of 43 
 
 
 
 
 
neck cancer has been done at the Peter MacCallum Cancer Institute in Australia (8 ).   All 
patients underwent 18F-FMISO  PET to  provide evidence of tumor hypoxia.   All patients 
also  had  baseline FDG PET scans and  the scan was co-registered with the 18F-FMISO 
PET.    18F-FMISO PET scans in this study were obtained 2 hours after radiotracer 
administration.    All PET  imaging  was  performed  on  a  dedicated  PET  scanner  with the 
data   processed   using   measured   attenuation   correction   and   iterative   reconstruction. 
Fourteen  out  of the 15  patients studied  had  detectable hypoxia on baseline  18F-FMISO 
scan with focal abnormality corresponding to  a region of increased FDG uptake in either 
the primary lesion or the nodal mass.   In all cases, the intensity of 18F-FMISO uptake was 
less than the corresponding FDG abnormality.    On the co-registered  PET images,  in the 
necrotic   lesions,   evidenced   by   central  photopenia  on  FDG  PET,   18F-FMISO   was 
distributed  only  at  the  inner border of FDG  uptake,  whereas in lesions without necrosis 
on  FDG  PET,  only  the  central part  of the  metabolically  active  lesion  had  18F-FMISO 
retention.    In all but only one of the 14  cases with an initially positive  18F-FMISO PET 
showed  complete  resolution  of  the  abnormality  within  4-5  weeks  of  treatment.     The 
pattern  of  18F-FMISO  uptake  was  consistent  with  the  expected  pattern  of hypoxia  in 
tumor  tissue  being  adjacent  to  areas  of tumor necrosis or in the center of non-necrotic 
lesions.    The rapid  normalization of 18F-FMISO PET suggests successful treatment of the 
hypoxic  component. 
 
We  have  performed  preliminary  clinical studies  with  18F-FMISO  obtaining  PET  images 
at 2.5 hours post-injection for 20 head and neck cancer patients (MSKCC 04-070). These 
studies  focused  first  on determining the constancy of 18F-FMISO  PET image sets when 
repeat  scans  were  performed  3  days  apart  (an  essential pre-requisite  for  IMRT  dose 
painting).  Preliminary  results  demonstrated  that  imaging  of  hypoxic  subvolumes  (GTVh) 
is  feasible  and  that reproducible zones of hypoxic tracer uptake are observed  (7).    We 
also performed a third 18F-FMISO scan on patients at four weeks into their radiotherapy 
treatment (MSKCC  04-070).  The objective of this third  scan was to  determine whether 
tumor reoxygenation occurred, as indicated by no 18F-FMISO uptake, or whether hypoxia 
persisted throughout treatment. Our finding from this second clinical study objective, as 
evidenced  by  18/20  patients  exhibiting  no  18F-FMISO  uptake,  was  that  hypoxia  is  no 
longer  evident  late  into  a  course  of radiotherapy.  Patients  in  this cohort experienced  at 
95%  nodal  control  rate  (9).  The  possibility  of  tumor  reoxygenation  early  during  the 
course  of  fractionated  radiotherapy  cannot  be  overlooked.     Therefore,  in  the  current 
version of this protocol, our goal is to perform a repeat 18F-FMISO PET/CT scan early in 
the  course  of  standard  chemotherapy  and  fractionated  radiotherapy  (5  to  10  treatment 
days) for a series of locally advanced head and neck cancer patients (Cohort 1).   If these 
repeat  scans  also  demonstrate  no  evidence  of residual  18F-FMISO  uptake  early  in the 
course  of  fractionated   radiotherapy,   this  information  will  have  major  implications  for 
hypoxia-guided  fractionated  radiotherapy. 
 
In summary,  hypoxia is a characteristic feature of malignant tumors that can render tumor 
cells  up  to  three  times  more  resistant  to  ionizing radiation than aerobic cells.    With the 
use  of  18F-FMISO  PET,  a  noninvasive  imaging  modality,  hypoxic  subvolumes  (GTVh) 
within  a  tumor  can  be  identified.    If these  hypoxic  regions  are  identified  and  verified, 
they  may  be  specifically  targeted  by  the  delivery  of  more  ionizing  radiation  to  that 

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specific  region. 
Ultimately,  by  the  delivery  of  a  differential  dose  of  radiation  to  the 
tumor, the local control rates of head and neck cancer patients may further  be improved. 
 
Multipara metric  MRI 
 
MRI   is   a   non-invasive   technique   utilized   to   assess  morphological  and   physiological 
changes in tumor and irradiated normal structures. In this study we will be taking a series 
of  multiparametric  MR  images  around  the  same  time  as  18F-FMISO  PET/CT  that  will 
enable a direct comparison between PET defined hypoxia volume and MR defined tumor 
volume.  The  excellent  soft  tissue  contrast  will aid  in  improved  normal tissue  contouring 
of  salivary  glands  and   lymph  nodes  which  will  ultimately  help  in  further  sparing  of 
normal   structures   during   external   beam   planning.   Similar   immobilization   techniques 
employed  during CT simulation and  MR scan will help  in co-registering MR images with 
CT and PET scans, when available. 
 
Radiation of the head  and  neck  can irreversibly damage oral mucosa, vasculature, muscle 
and bone resulting in xerostomia, dental caries, trismus, soft tissue necrosis and 
osteoradionecrosis.  A  change  in  intensity  or  image  texture  over  the  course  of radiation 
obtained  from  these  MR  scans  may  be  an  indication  of  radiation  damage  to  these 
sensitive  structures.   In  addition,   we  hypothesize  that  perfusion  and  diffusion  changes 
observed in tumor and normal structures could be dose dependent. 
 
DW-MRI 
 
DWI-MRI measures differences in tissue microstructures based on the random Brownian 
motion  of water  molecules  in  biological tissues.  It  quantifies  the degree of restriction of 
water  diffusion  or  tissue  diffusivity  and  has  the  potential  to  differentiate  benign  lesions 
from malignant  tumors.  The  quantitative  measure of water mobility is calculated  in terms 
of apparent  diffusion  coefficient  (ADC)  by  varying  the diffusion weighting or ‘b’ values. 
Tumors  with  more  densely  packed  tumor  cells  and  more  cell membranes have a lower 
ADC due to greater restriction to diffusion. Non-tumoral tissue changes such as edema, 
inflammation,  fibrosis,  and  necrosis  typically  have  low  cellularity and  result in high ADC 
(28,  29).  In addition  to  molecular diffusion of water in biological tissue,  microcirculation 
of  blood  (or  “perfusion”)  in  the  capill ary  network  can  also  be  captured  using  low  ‘b’ 
values.  DWI-MRI  using  both  low  and  high  b  values  (also  called  intravoxel incoherent 
motion  sequence  or  IVIM)  gives  a  quantitative  measure  of  true  diffusion  (D)  and 
perfusion  fraction  (f) (30) without  the use of an intravenous  contrast agent. 
 
DWI-MRI has been successfully applied  for various disease sites.  Its clinical applications 
in  head   and   neck  cancer  have  been  in  differentiating  malignant  tumors  from  benign 
lesions (31,  32),  characterizing and  staging of lymph nodes in the head  and  neck  region 
(33) and monitoring tumor response (34, 35, 36, 37). A few studies have investigated the 
salivary  gland  response  based  on  changes  in  ADC  value  (38,  39).  Malignant  tumors 
usually  show  low  ADC  values  compared  to  benign  tumors.  A  mean  cut-off  value  of 
1.2x10-3  for  adult tumors and  1.25x10-3  for pediatric head  and  neck  tumors has been 
shown   to   distinguish   between   malignant   and   benign  tumors   with  87%  and   92.8% 

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accuracy,   respectively  (5).   Dirix  et  al  have  shown  superior  accuracy  of  DW-MRI 
compared  to  conventional imaging in nodal staging where DW-MRI was shown to agree 
with  pathology  with  a  sensitivity  of 89%  and  specificity  of 97%  per  lymph node (33). 
Changes  in  ADC  value  have  been  shown  to  correlate  significantly  with  2 -year  local 
regional control based  on multiple MRs taken over the course of chemotherapy (34, 35). 
In  a  chemoradiation  setting,  efficacy  of ADC  was  investigated  for  prediction  and  early 
detection  of  treatment  response.  Changes  in  ADC,  compared  with  pretreatment  value, 
after  the  first week  of chemoradiation therapy have shown high sensitivity and  specificity 
in separating  complete responders from partial responders (36). 
 
Very few studies have looked at the utility of DWI for normal tissue response. Dirix et al 
and  Zhang et al have looked  at radiation induced  changes in major salivary glands using 
DWI.   ADC  changes  were  inversely  related  to  salivary  flow  measurements  and  may 
represent a sensitive marker of salivary gland dysfunction. Both these studies have shown 
potential  to  predict  radiation-induced  xerostomia.  A  more  recent  study  from our  group 
looked  at  the  efficacy  of pre-treatment  multimodality  imaging  consisting  of MRS,  DCE- 
MRI and FDG PET (40) in head and neck cancer patients to predict short-term response 
to treatment. We are not aware of any studies that have looked at 18F-FMISO and DW- 
MRI  for  tumor  heterogeneity  in  head  and  neck  cancer  patients.  In  this  study,  when 
possible, we will obtain a MR scan before (Cohort 1 and Cohort 2 main campus patients), 
approximately weekly (Cohort 1  main campus patients only),  and post-external beam RT 
at 3 months, 6 months, and 1 year after external beam RT (+/- 4 weeks; Cohort 1 main 
campus   patients   only),   unless   contraindicated.   We   will  evaluate   changes   in   tumor 
heterogeneity  between  PET  and  MR  scans  as  markers  of tumor  response.  Changes  in 
perfusion  and  diffusion  fraction  for  normal  structures  from  serial  MR  scans  over  the 
course of radiation therapy will enable us to  evaluate markers of radiation-induced  acute 
and long term toxicities. 
 
Treatment  for Head and Neck Cancer 
 
Currently,  there are several approaches in the treatment  of head and neck cancer. 
 
1.   Definitive  chemoradiation  where  both  the primary tumor site and  the neck  nodes 
receive  70Gy.    In patients in whom a complete nodal response is achieved  with 
this treatment,  no further treatment  such as neck dissection  is needed. 
 
2.   Definitive  chemoradiation  where  the  primary  site  receives  70Gy  while  the  neck 
nodes receive a lower dose of radiation at 60Gy instead of 70Gy. This treatment is 
then followed  by a FDG PET/CT scan and continued  observation. 
 
3.   Surgical resection  of the  tumor.  Following  this surgery,  patients may or may not 
undergo   adjuvant   radiation   with   or   without   concurrent   chemotherapy.   The 
utilization  of  radiation  and/or  chemotherapy  following  surgical resection  is 
dependent  on  the  staging  and  pathologic  features  of the  disease/resected  tissue, 
among other risk factors. 

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Although a high loco-regional control rate of >90% is seen for oropharyngeal carcinoma 
treated  with  chemoradiation,  patients  still  experience  significant  acute  and  late  toxicities 
(13,    45).    These   toxicities   are   particularly   concerning   considering   the   increasing 
prevalence  of HPV-associated  head  and  neck  carcinoma  (42),  particularly  those  of the 
base of tongue and  tonsillar sites (both anatomical sites of the oropharynx) in individuals 
ages  20-44  in  the  United  States  (46).  This  latter  statistic  will ultimately  coincide  with 
longer-lasting   long-term   morbidities   associated   with   OPSCC-targeted   chemoradiation, 
which  may  have  significant  social  and  financial  implications  in  the  future  (45)  and  an 
adverse effect on the long-term quality  of life of patients who undergo this treatment. 
 
Given   the   recent   rise   in   HPV-related   oropharyngeal   carcinoma   and   the   toxicities 
associated  with  the  standard  treatment  course  for  this  disease,  an  investigation  into  the 
efficacy and safety of treatment de-escalation to reduce the morbidity associated with the 
treatment  of this  disease is warranted.  This is particularly true for the cohort of patients 
who  present with HPV-related oropharyngeal carcinoma, as these patients are more likely 
to  be  younger  and  healthier  than  those  presenting  with non-HPV-related  disease.  When 
making  the  determination  of  which  patients  should  undergo  a  less  intense  treatment 
regiment,  it  is  important  to  make  an  evidence-guided  selection.  This  cohort should  only 
include patients most likely to: (1) respond efficaciously to treatment reduction, and (2) 
maximally    benefit    from    a    decrease    in    treatment-related    toxicities.    Otherwise, 
unwarranted  tumor recurrences  may result. 
 
A  number  of  investigations  have  established  that  the  prognosis  of patients  with  HPV- 
related oropharyngeal carcinoma is superior to that of patients with non-HPV-related 
oropharyngeal  carcinoma  (41,  44,  and  47).  In  addition  to  HPV  status  serving  as  a 
mediator of overall prognosis and  treatment response,  it is well known that the presence 
of hypoxia renders tumor cells up  to  three times more resistant to  ionizing radiation than 
aerobic cells (1-3).    Hypoxia is also associated with a more aggressive and metastatically 
viable malignant phenotype, and has been shown in several studies to be an important 
determinant  of loco-regional control of head and neck tumors (4, 5). 
 
At  our  institution,  we have an active hypoxia imaging protocol,  MSKCC  IRB#  04-070, 
for all head and neck tumors regardless of HPV status. The first 20 head and neck cancer 
patients that were enrolled in this protocol were all treated with 70Gy to both the primary 
site and the neck nodes.   An exceptionally high locoregional control rate of 95% was seen 
with  a  nodal control rate  of 95%  as  well (9).    Furthermore,  all but  two  patients  had 
resolution  of their baseline hypoxia  on repeat 18F-FMISO PET/CT imaging. 
 
When considering the evidence regarding HPV status and the effects of hypoxia on tumor 
response, it can be inferred that oropharyngeal carcinoma patients with the most superior 
prognosis  are  those  who  meet  the  following  criteria:  HPV-related  and  no  evidence  of 
hypoxia. Therefore, given: (1) the rise in HPV-related oropharyngeal carcinoma, (2) the 
significance  and  burden  of  oropharyngeal carcinoma  treatment-related  toxicities,  and  (3) 
in-house  data  where  hypoxia  response  correlated  with  high  loco-regional  control,  the 
current  version  of  this  protocol  seeks  the  following  for  select  patients  in  Cohort  1 
(patients receiving  chemoradiation  without  surgical resection): 

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A. to give HPV+ oropharyngeal carcinoma patients who demonstrate no evidence of 
hypoxia  on  a  18F-FMISO  PET/CT  scan  the  option  of  an  alternative  standard 
approach to  the treatment of oropharyngeal carcinoma  through delivering 60Gy to 
the neck  nodes followed  by a  FDG PET/CT scan.   The primary site will receive 
70Gy,    and    these    patients   will   undergo    standard    chemotherapy   regimens. 
Delivering  60Gy  to  the  neck  nodes  followed  by  a  FDG  PET/CT  scan  and 
continued  observation  does  not  deviate  from one  current  standard  of care,  and 
allows for the ability to deliver a lower dose of radiation to the neck with the goal 
of    minimizing    radiation    toxicities     while     ensuring    that    no    unwarranted 
compromise   to   the   already   excellent   loco-regional  control  in  this  population 
occurs.  All the imaging  studies  will be done exactly per protocol. 
 
Similar  to  oropharyngeal  cancer,  rates  of  the  oncogenic  HPV-16  subtype  have  been 
demonstrated  to be present in as many as 79% of HPV-related anal carcinoma  cases (53). 
In  the  early  1970s,   investigators  at  Wayne  State  University  demonstrated  that  anal 
carcinoma  (Nigro  Protocol)  could  effectively  be treated  preoperatively with a concurrent 
course of chemotherapy with 30Gy (56). Results demonstrated 84% of patients to be free 
of cancer  following  treatment  per  the  Nigro  Protocol,  suggesting  30Gy could  effectively 
treat   carcinomas   when   administered   concurrently  with  chemotherapy.   Furthermore,   a 
79%   five-year   overall  survival  rate   was   demonstrated   (48).   When  utilizing  salvage 
therapy  in  the  setting  of  treatment  failure  with  the  Nigro  Protocol,  rates  of successful 
treatment response, as defined by no evidence of disease at a mean of 34-months follow- 
up, have been documented  to be as high as 95% (49). 
 
When utilizing a combination of surgery, radiation, and chemotherapy for HPV-related 
oropharyngeal cancers  today,  a  number  of cancer  treatment centers often omit  radiation 
to  the  primary  disease  site in low-risk  patients whose surgical margin is negative.  When 
taking  this  into   consideration  with  the  evidence  of  HPV  status  on  tumor  response, 
hypoxia on tumor response, and the work that has been done in anal carcinoma, it can be 
inferred   that   low-risk   HPV+   oropharyngeal  carcinoma   patients   treated   initially   with 
surgical  resection  of  their  primary  disease  site  may  optimally  respond  to  30Gy  with 
concurrent   standard   chemotherapy.   The   current   version   of  this   protocol  seeks  the 
following  for  select  patients  in  Cohort  2  (patients  receiving  surgical  resection  of  their 
cancer): 
 
B.  to   give   a   select   HPV+   tumors   an   alternative   treatment   for   oropharyngeal 
carcinoma. This select cohort will be comprised of patients who meet all of the 
following  criteria: 
 
1.   resection of their primary  tumor site 
2.   low-risk HPV-related oropharyngeal  carcinoma 
3.   demonstrate no evidence of hypoxia  on a 18F-FMISO scan obtained  5-10 
treatment days into radiation  therapy 

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These  patients  will  undergo  post-operative  standard  chemotherapy  regimens  and 
30Gy to the surgical bed and neck nodes. A planned neck dissection three to four 
months  post-treatment  will  be  given.  Should  there  be  any  evidence  of residual 
disease  at  the  time  of  this  neck  dissection,  additional  chemoradiation  will  be 
given. 
 
Please note that initially  this pilot trial was written  for 35 patients and after a 
meeting  requested by the IRB with the PI and the coPI's, and with the advice from 
the IRB, it was decided to close the trial at patient 19 and write a new trial for 
cohort B.  This new trial is MSKCC IRB 17-409. 
 
 
 
Immuno histoc he mistry 
 
Several  studies  examined  the  relationship  between  p16  expression  by  IHC  and  HPV 
DNA  viral  load   by  real-time  PCR  and  found  great  correlation.     These  studies  all 
uniformly showed  that either  is a good  prognostic marker for treatment outcome. RTOG 
0129  was a large  randomized  controlled clinical trial that was recently published for head 
and neck cancer of which there was a large tissue sample size that examined the relative 
strength of HPV DNA using in situ hybridization vis-a-vis p16 IHC as a prognostic 
marker  (13).  The  study  also  showed  that  there  was  a  very  strong  agreement 
between the presence of HPV DNA and p16 expression in head and neck tumors. 
Results of analyses using p16 expression as a stratification factor were consistent 
with those based on HPV status.   Given p16 expression measured by IHC is a 
relatively simple procedure, we will stratify patients based on p16 status.  This is 
also convenient for the patients as we will not have the need to subject the patients 
to further biopsy for HPV DNA analysis. 
 
One important  characteristic  of tumor development  is angiogenesis.   Induced by 
hypoxia,  the tumor cells secrete a variety  of cytokines and growth factors that induce 
proliferation  (evidenced  by overexpression  of Ki-67), migration,  and blood vessel 
formation  (23-25).  Ki-67 is one known prognostic marker in head and neck squamous 
cell carcinoma  (HNSCC) and is inversely  related to the presence of hypoxia.  The 
rationale  is  that  a  stronger  and  more  widespread  Ki-67  staining  intensity  signifies  a 
higher  fraction  of proliferating  cells in the tumor.   Since cellular  proliferatio n 
either does not occur or is greatly reduced within  hypoxic tissue,  we expect that high  Ki- 
67 staining  should be accompanied  by low or absent 18F-FMISO image intensity  and vice 
versa. 
 
Cellular  response to hypoxia  is regulated  primarily  through  the transcriptional factor, 
hypoxia-inducible  factor (HIF-1α), which is the central mediator of the angiogenic 
response in hypoxia.  Studies have shown that the dysregulation  of HIF -1α may play a 
role  in  the  malignant  progression  of HNSCC  (24,  25). Overexpression of HIF-1α has 
been  reported as an independent  prognostic  factor in HNSCC and is associated with poor 
prognosis as well as locally  aggressive  behavior of HNSCC. In one series where a cohort 
of 98 patients  were treated with curative  radiation  therapy for their oropharyngea l cancer, 

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94% showed overexpression  of HIF-1α as determined  by IHC (24). The degree of HIF-1α 
correlated inversely  with both the rate of complete remission  of the primary  tumor as well 
as the lymph  node metastases; local failure-free  survival,  disease-free survival,  and 
overall survival.  They concluded  that HIF-1α is overexpressed in the vast majority  of 
oropharyngeal cancer and that the degree of expression has prognostic significance  in 
individuals  undergoing  curative  radiotherapy.  In addition,  studies on gene expression 
have shown hypoxia  induces metastasis- mediated  genes.  The overexpression  of the 
recently  identified  lysyl oxidase (LOX) as a hypoxia  and HIF-1α regulated  gene was 
strongly  associated  with  increased  metastasis,  progression  and  OS  (26,  27).    LOX has 
been implicated  as a marker for metastasis  and OS for HNSCC. 
 
This  is the first human study that that uses a non-invasive imaging technique for hypoxia 
(18F-FMISO  PET/CT)  for  the  purposes  of  immunohistochemistry  (IHC)  correlation  for 
tissue  markers  of hypoxia.  To  date,  nearly 20  biopsy specimens have been obtained  on 
this  protocol  where  an  interventional  radiologist  biopsied  areas  that  demonstrated  high 
18F-FMISO  uptake on the  18F-FMISO PET/CT scan. However, initial results from these 
biopsies  have  demonstrated  that  nearly  50%  of these  specimens  did  not  contain  tumor 
cells,  despite  being  obtained  from both  FDG  avid  and  18F-FMISO  avid  regions.  Only 
stromal,  fibrous,  and  lymphoid  tissues were able to  be identified.    In order to overcome 
the sampling error associated  with small needle biopsy,  we will obtain more tumor tissue 
without  deviating  from current standards of care for head  and  neck  cancer.    Given that 
one current standard  in the treatment of loco-regionally advanced oropharyngeal cancer is 
surgical  resection  using  the  robotic  surgery  technique,  we  plan  to  utilize  the  surgical 
specimens  of  these  patients  for  our  IHC  hypoxia  studies.  Furthermore,  we  will image 
these   patients   with   an   18F-FMISO   PET/CT  scan  prior  to   their  standard   of  care 
pretreatment   surgical  resection  in  order  to   correlate  hypoxia  on  imaging  with  IHC 
performed  on  their  surgical specimen.  The  surgeons  performing  these  surgical resections 
will  be  asked  to  orient  their  surgical specimen  according  to  the  18F-FMISO  PET/CT. 
Patients undergoing this standard  of care surgical resection will make up Cohort 2 of this 
protocol. 
 
In summary, we will perform the first human study of 18F-FMISO PET image-guided core 
biopsy of neck node(s) in both HPV positive and negative HNSCC (for Cohort 1 patients 
that consent to  this optional biopsy).  Additional tissue will be collected from patients who 
will undergo  surgical resection of their HNSCC per standard of care (Cohort 2). We will 
correlate the intensity of the 18F-FMISO PET signal with the degree of IHC staining of the 
following  hypoxia  biomarkers,   among  others:  HIF-1α,   Lysyl  Oxidase,  and  Ki67  (an 
independent  marker of tumor aggressiveness ). 
 
4.0 
OVERVIEW OF STUDY DESIGN AND INTERVENTION 
 
4.1       De sign 
 
PROTOCOL SUMMARY 
 
TIMEPO INT 
COHORT  1 
COHORT  2 
Pretreatment 
All Patients 
All Patients 

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Page 18 of 43 
 
 
 
 
 
1) Patient s imulation. 
2) FDG s can with immobilizat ion. 
3) Recommended  pretreatment MR s can with 
immobilization   when pos s ible (unles s 
contraindicated, for main campus only). 
4) 18F-FMISO s can (only 1 injection). Patient 
injected on the PET s canner: 
( a ) Dynamic s can from 0-45 min 
( b ) 10 min s can at about 90 min 
( c ) 10 min s can at about 150-180  min 
5) 18F-FMISO image-guided  core biops y 
(optional, if cons ented) 
1) 18F-FMISO s can (only 1 injection). 
Patient injected on the PET s canner: 
( a ) Dynamic s can from 0-45 min 
( b ) 10 min s can at about 90 min 
( c ) 10 min s can at about 150-180 
min 
During 
Treatment 
Select Patients 
1) Repeat 18F-FMISO s can (only 1 injection) that 
occurs 5-10 treatment days after RT s tart*. Patient 
injected on the PET s canner: 
(a) Dynamic  s can from 0-45 min 
(b) 10 min s can at about 90 min 
(c) 10 min s can at about 150-180  min 
2) 18F-FMISO image-guided  core biops y 
(optional, if cons ented) 
3) Recommended  approximately  weekly MRI 
when pos s ible (unles s contraindicated, for main 
campus only). Recommended  DCE-MRI  between 
treatment weeks one and two and between 
treatment weeks three and four, when pos s ible. 
Patients who Receive Radiation 
1) Repeat 18F-FMISO s can (only 1 
injection) that occurs 5-10 treatment 
days after RT s tart*. Patient injected on 
the PET s canner: 
( a ) Dynamic s can from 0-45 min 
( b ) 10 min s can at about 90 min 
( c ) 10 min s can at about 150-180 
min 
Pos t- 
treatment 
All Patients 
1) Recommended  MR Scans at 3, 6, and 12 months 
(+/- 4 weeks ) pos t end of RT (unles s 
contraindicated, for main campus only) 
2) Longitudinal chart review for two years pos t RT 
for advers e event as s es s ment and dis eas e s tatus 
Patients Who Receive 30Gy 
1) Neck dis s ection three to four months 
pos t-chemoradiation (+/- 4 weeks ). 
(a) If no res idual dis eas e, s tandard 
of care 
(b) If res idual dis eas e, boos ter dose 
of chemoradiation 
2) Standard of care 
 
Please  note  that a window period  of 5-10  treatment days was chosen to  accommodate 
holidays, weekends, and patient scheduling issues. Also, note that the repeat dynamic 18F- 
FMISO  scan is performed  early during the course of chemoradiotherapy (5-10 treatment 
days). For Cohort 1, this scan will be used to see whether there is a reduction of the 18F- 
FMISO avid or GTVh  within the gross tumor volume. For patients in Cohort 2 receiving a 
repeat scan, this repeat scan will be used to detect tumor hypoxia. 
 
Safety  measurements  of  typical  vital  signs,  such  as  oral  body  temperature,  respiratory 
rate,  heart  rate,  and  blood  pressure will be performed  before the administration of 18F- 
MISO, and at the end of each 18F-MISO PET/CT scan session. The patient will also be 
assessed  for adverse events  at the end  of the  18F-MISO PET/CT sessions. Additionally, 
one business day (excluding holidays and weekends) following the completion of the 18F- 
MISO  PET/CT  scans,  patients  will  receive  a  follow  up  phone  call to  assess  adverse 
events. 

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Approval date: 01-Apr-2020 
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Rationale  for Change in 18F-FMISO PET/CT Imaging  Protocol 
 
The  preliminary  18F-FMISO  PET  image  data  acquired  in  patients  with  head  and  neck 
cancers have shown variable hypoxia tracer uptake at the fixed 2.5 hour time p oint used 
in the initial study.    In order to  convert the  18F-FMISO  images to parametric images of 
tumor  hypoxia,  a  group  in  Tübingen,  Germany  has  recently  shown  the  importance  of 
obtaining kinetic information of the tracer in the tumor (14-17) for an unambiguous 
interpretation  of the hypoxia  images. 
 
PET/CT Scan Protocol 
 
Dynamic  scans  will  be   acquired   on  one  of  the  PET/CT  scanners  qualified  by  the 
Department  of  Radiology  and  the  Molecular  and  Imaging  Therapy  Service  at  the  main 
hospital  of  MSKCC.  3-D  mode  and  with  listmode  option  will  be  turned  ON.    The 
listmode  option  allows  the  patient  data  to  be  reconstructed  in a cine mode (in variable 
time frames) so  that pharmacokinetics of tumor uptake of the radiotracer can be studied . 
The patient will be set up  in the radiotherapy treatment position with an intra-venous line 
for  radiotracer  injection.  A  PET/CT  scan  will be  performed  with the tumor at the field 
center.  These  images  will be used  for both attenuation correction and  registration of the 
serial image set. 
 
Approximately 5-10 mCi dose of 18F-FMISO will be injected as a bolus, and the dynamic 
scan initiated  coincident with the injection. Data will be acquired in dynamic mode for up 
to  a maximum of 45  minutes from the time of injection,  but may be shorter  (e.g.  if the 
patient  is  in  discomfort  in  the  immobilization  device  for  this  duration).  The  patient  will 
then  be removed  from the scanner,  and  instructed  to  return at  approximately 90-minutes 
for a second  PET scan and again at approximately180-minutes for a third PET scan. No 
further activity will be injected  in the  patient at these times.  The 2nd  and  3rd  PET scans 
will consist of a 10-minute image of the tumor. A low dose CT scan will be performed at 
each of these two image sessions for attenuation  correction and image registration. 
 
In up  to  10 selected  patients,  the first segment of the scan shall be performed  over the 
heart  with  the  later  segments  still being  performed  over  the  tumor.    These scans ill be 
used to calibrate the input function  currently  derived from the carotid artery. 
 
MR Scan Protocol 
 
Multiparametric  MR  scans  for  Cohort  1  and  Cohort  2  main  campus  patients  will be 
performed on the Philips 3T scanner located in the Department of Radiation Oncology 
according to the standard IVIM departmental protocol and utilization of the patient’s 
immobilization  device  when  the  immobilization  device  is  available  and  the  patient agrees 
to utilize it. DWI-MR images will also be acquired according to the standard IVIM 
departmental protocol. 
 
At  the  pretreatment  MR  scan  for  Cohort  1  and  Cohort  2  main  campus  patients,  an 
additional scan  will be  acquired  based  on a research sequence provided  by Philips  (the 

Memorial Sloan Kettering Cancer Center
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Page 20 of 43 
 
 
 
 
 
manufacturer  of the  machine on which these MRIs occur)  that will allow visualization of 
cortical  bones  in  the  head  and  neck  region  and  potentially  differentiate  bone  from air 
sinus cavity. This scan will be used to evaluate the potential of using MR alone images to 
differentiate  and  segment  normal  tissues  used  in  radiotherapy  treatment  planning.  This 
additional sequence will add  an extra 5  minutes to  the total scan time.  This sequence  is 
written, maintained, and updated by Philips. When an update to this sequence occurs, the 
sequence may become unavailable for a few weeks, at which time the updated version is 
installed  and  tested  internally  by  MSK  staff.  Therefore,  this  sequence  will only  be  run 
when it is available.  The total pre-treatment MR scan duration will be approximately 30- 
60 minutes. 
 
For Cohort 1 main campus patients, the follow-up MR scans, which will occur during 
concurrent  chemoradiation,  will  last  approximately  20-40  minutes.  Information  collected 
from all MR  scans  will not  affect  the  standard  of care,  as baseline and  post-treatment 
scans are currently a component of the standard of care. Additional scans will be acquired 
on  our  Philips  3T  research  scanner.   Images  will  be  sent  to  the  research  Pinnacle 
workstation  for  storage  and  evaluation.  These  images  may  be  used  for  contouring  of 
normal  structures   during   the   treatment   planning   process.   DW-MRI   images   will  be 
processed  on  the  Philips  research  platform  and  corresponding  diffusion  and  perfusion 
maps  will  be  analyzed  for  therapy  response  assessment  and  treatment  planning.  Spatial 
changes   during   treatment   will  also   be  evaluated   using  functional  diffusion  maps  or 
parametric response maps. No clinical decision will be made at this point based on MR 
findings. 
 
PET/CT Image-guided  Core Biopsy (Optional – Cohort 1 Patients Only) 
 
The  PET/CT  scan  will be  performed  in  the  Center  for  Image-Guided  Intervention  and 
Surgery at MSKCC, which houses a PET/CT scanner in an interventional radiology and 
operating   room   environment.   The   PET   image-guided   core   biopsy   procedure   will 
conducted as follows: 
 
On  the  day  of  18F-FMISO  PET/CT  imaging,  patients  will  be  injected  with  the  study 
tracer,  18F-FMISO.     After  the  final  18F-FMISO  PET  image  acquisition  at  each  visit 
session  (where  applicable),  biopsy  samples  will be removed  from tumor tissue exhibiting 
high and low 18F-FMISO uptake (if both are available). These high and low 18F-FMISO 
uptake   regions   correspond   to   putative   hypoxic   and   normoxic   regions,   respectively. 
Parametric   image   maps   will   also   be   retrospectively   generated   from  compartmental 
models  that  define  the  rate  of 18F-FMISO  radiotracer entrapment.  These values will be 
used,  in  addition  to  the  percent  injected  dose  per  gram,  for  correlation  with  IHC  of 
hypoxia  specific markers. 
 
The  aforementioned   biopsy  samples   will  be  obtained  by  an  interventional  radiologist 
according to  the features of the  18F-FMISO  PET/CT images.  1% lidocaine will be used 
for local anesthesia supplemented with midazolam and fentanyl citrate for light conscious 
sedation.  The biopsy needle  will be placed  in position to remove core biopsy material of 
the node(s),  and  the patient will have an additional low dose CT to  visualize the biopsy 

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needle  trajectory  and  location.  In  this  way,  we  will  obtain  information  of  the  exact 
location  of  the  biopsy  specimen  in  regard  to  the  CT  and  therefore  co-registered  PET 
image.  If movement  should  occur  between  biopsy  localizer  CT  and  the  CT  attenuation 
scan,  then  these  two  CT  images  will be  co-registered  using  mutual information  density 
software.     Immediately  following  biopsy,  the  specimen  will  be  properly  oriented  and 
pinned.  Based  upon  published  experience,  discussion  with  other  investigators,  and  our 
own experience of obtaining tissue prior and during treatment, we anticipate it will take 
approximately fifteen minutes to  perform each biopsy.  The specimen acquired  from these 
tumor  samples  will be  taken  for  paraffin  embedding,  fresh frozen (if patient consents to 
any  of  optional  banking  studies),  and  histological processing  to  our  Pathology 
Department. Ten 5µm thick sections from paraffin tumor blocks or core samples will be 
deparaffinized  and  rehydrated,  and  stored  at −80 °C  until processing.  IHC  analyses will 
also  be performed  for the following hypoxia relevant biomarkers,  among others: HIF-1α, 
LOX, and Ki-67. 
 
Pretreatment  Surgical Resection (Cohort 2 Patients Only) 
 
The  eligible  patient  will  undergo  a  pre-surgery  FDG  PET  scan  and  an  18F-FMISO 
PET/CT  scan.      Following  these  pre-surgical  scans,   the  patient  will  undergo  his/her 
standard  of care surgery.   The surgeon will annotate the location of each sample resected 
from  the  lesion  by  a  text  description  for  documentation  of  relative  position.     The 
specimen   will  be  embedded   in  paraffin  in  an  orientation  that  will  allow  sectioning 
parallel to  the  imaging  plane  of the PET/CT image.  Tissue sections will be stained  with 
H&E,   hypoxia  specific,  and  proliferation  markers  using  the  same  procedures  as  the 
described for the biopsy specimens  in this  protocol. 
 
Biospecime n  Samples 
 
Biospecimen  samples  from Cohort  1  (obtained  via  biopsy) and  Cohort 2  (obtained  via 
surgical resection)  will not used  for diagnostic  purpose.  They will instead  be utilized  for 
a research purpose.  They will be labeled with de-identified subject IDs, initials, date and 
time of specimen collection,  and  visit time  point,  which are linked to the identifiable PHI 
and  will  be  kept  confidential.  The  participant’s  personal  identity  will  not  be  used  in 
reports that are written about the research. The MSKCC IRB/PB will review all requests 
for  research  performed   involving  tissues  ascertained   through  this  protocol.  With  the 
permission   of  IRB/PB,   research  studies  on  cellular,   genetic,   immunologic,   or  other 
features  of tumor  or normal samples may be performed  with no  names attached  to  the 
samples  but  linked  by  codes  to  personal identifiers.  The  results  of any  research  using 
tissues will not be placed in the medical record. 
 
HIF-1α 
 
IHC  staining will be performed  on biospecimen samples  using the antibody against HIF- 
1α  (Novus  Biologicals,  Littleton,  Colorado,  dilution  1:1600)  utilizing  previously  reported 
techniques.  Briefly,  4  micron  formalin-fixed  paraffin  embedded  tissue  sections  will  be 
mounted  on  Superfrost  Plus  slides,  deparaffinized  with  xylene  and  rehydrated.  Tissue 

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Approval date: 01-Apr-2020 
Page 22 of 43 
 
 
 
 
 
will be then avidin/biotin blocked with blocking kit (Vector SP-2001). For HIF-1α, 
DakoCytomation   catalyzed   signal  amplification   system  (Dako,   K1500)  will  be  used 
according to the manufacturer directions. Slides will be counterstained with hematoxylin, 
dehydrated  and  cover-slipped.  Only the nuclear staining for HIF-1α will  be considered a 
positive  result.  Expression  of HIF-1a  will be  determined  by semi-quantitatively assessing 
the   percentage   of   marked   tumor   cells   and   the   staining   intensity   to   calculate   an 
immunoreactive  score  (IRS).  Therefore,  the  percentage of positive cells will be rated  as 
1–10%  positive  cells  (1×),  11–50%  positive  (2×),  51–80%  positive  (3×),  and  >  80% 
positive cells (4×). The staining intensity will be scored as weak (1×), moderate (2×), and 
intensive (3×). Scores for expression and scores for percentage of positive cells will be 
multiplied  to calculate  an IRS ranging  from 0 to 12. 
 
Lysyl Oxidase 
 
5μm  formalin-fixed   paraffin-embedded   tissues   will  be   deparaffinized   in   xylene,   then 
rehydrated  before antigen retrieval by microwaving in sodium citrate buffer (pH 6.0). The 
slides  will then  be incubated  with a peroxidase block,  followed  by the primary antibody 
lysyl   oxidase    (LOX)    according    to    the    company’s    protocol.    After   hematoxylin 
counterstain,  the  slides  will be  cover  slipped.  Cytoplasmic staining will be  considered  as 
positive.  The  intensity  and  proportion  of immunostaining  will be  scored  on  a 
semiquantitative  six-point  scale.  Negative  samples  will  receive  a  score  of  0,  whereas 
weak,   moderate,   and   intense  staining  samples  will  receive  a  score  of  1,  2,  or  3, 
respectively. For the percentage tumor cell positivity the following scoring will be used: 
negative=0, 1–25%=1, 25–50%=2, >50%=3.   Both the staining intensity and percentage 
positivity  scores  will  be  summed  and  tumors  with  scores  ranging  from 0  to  5  will be 
assigned  to  group  0=low lysyl oxidase,  whereas those with a score of 6 will be assigned 
to group 1=high lysyl oxidase. 
 
Ki-67 
 
5μm formalin-fixed  paraffin-embedded  tissue will be subjected  to  IHC  for Ki-67 staining 
using the MIB1 mouse mAb (Immunotech, Westbrook, ME) at a 1:500 dilution. Standard 
avidin–biotin–peroxidase  complex  techniques  will  be  used.  Antigen  retrieval  in  heated 
citrate  buffer  at  pH  6.0  will be  applied.  Slides  will be counterstained  with hematoxylin. 
Only nuclear staining of tumor cells will be considered positive. Ki67 expression will be 
determined  by semi-quantitatively  assessing the percentage of positive  tumor cells. 
 
Tissue Banking 
 
With  the  patient’s  consent,  we  will  bank  the  additional  and  left  over  tissue  after  the 
biopsy (Cohort 1) or surgical resection (Cohort 2) in Tissue Procurement Service (TPS). 
To further access this tissue, we will submit a plan to the Human Biospeciman Utilization 
Committee   (HBUC).   For   retrospective  feasibility  studies,   tissue  use  at  MSKCC   is 
governed by the HBUC. The HBUC 
has trans-departmental and multidisciplinary 
representation.      As  institutional  policy,   the  HBUC  will  give  special  consideration  to 
tissues requested  for correlative analysis as part of a clinical trial,  or to develop a tissue 

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IRB Number: 04-070 A(38) 
Approval date: 01-Apr-2020 
Page 23 of 43 
 
 
 
 
 
bank   at   an   academic   institution,   cooperative  group   or  corporate  entity.   While  the 
specimens  for  this  protocol  will  reside  in  local  repositories,  we  will  nevertheless  seek 
HBUC approval for use of the resources in this study as other investigators in the Center. 
We  recognize  that  specimen  resources  are  ultimately  institutional  resources,  wherever 
they are stored and by whatever means they are ascertained. Approval by the HBUC 
committee will follow institutional standards.  Each specific research use proposed  for use 
of these banked  specimens will be reviewed  in the context of the scientific study design 
and human  subjects’ protection implications. 
 
In a series of check boxes at the end of the consent form, patients in both Cohort 1 and 
Cohort 2  are asked  if: 1) they permit their biospecimen to  be stored and used in future 
research to learn about or prevent cancer or side effects of treatment, or to develop new 
treatments; 2) if they permit their samples to be stored and used in future research to learn 
about, prevent, or treat diseases other than cancer; or 3) if they permit their samples, with 
personal identifiers protected, to be used for research about inherited genetic factors; 4) if 
they permit their samples to be used for genetic analysis of the tumor and normal samples 
to learn about the causes of cancer; 5) if they agree to be contacted in the future as part of 
research studies for additional health information or to be asked to participate in future 
biospecimen  research  studies;  6)  if  they  consent  to  be  contacted  to  discuss  research 
findings  that  may  come from their sample; and  7) if he/she (the patient) is  not available 
(e.g.  deceased),  if they wish to have their designee designated on the consent form to be 
contacted. 
 
Participants will not be provided  with specific results of research tests performed on their 
collected  human  biologic specimens.  With their permission,  the patient may be contacted 
in the future to  ask  if they are interested  in joining new biospecimen research studies,  if 
they would consent to research that would allow updates of their health status and if they 
consented  to  be  contacted  to  discuss  research  findings  which  may  come  from  their 
sample. 
 
It  will be  stated  that researchers at MSKCC  may either keep  indefinitely or dispose of 
any   tissues,   including   DNA   that   the  samples  contain.   Tissues  will  be  stored   with 
identifiers  in  secure  tissue  banks.  It  is  stated  that  the  samples  could  be  lost  or  ruined 
because  of mechanical failure,  and  that  MSKCC  cannot  guarantee  that samples will be 
stored indefinitely. The samples will be store for as long as deemed useful for research 
purposes. 
 
The  protocol  consent  form  asks  participants  for  permission  for  re-contact  to  discuss 
research findings if their samples are used in an HBUC project and an incidental research 
finding is made that may be critical to their preventive care. If a participant agrees to be 
re-contacted, he/she will not be told  the specific results of the research test,  but will be 
informed  that his/her samples were used in a project and a potential risk was uncovered. 
If the participant is interested  in further discussion of the research findings, he/she will be 
asked to  come into MSKCC Clinical Genetics Service for counseling and specific genetic 
testing. 

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In  the  event  an  investigator’s research identifies a finding that he or she believes should 
be  communicated  to  the  subject,  the  investigator  shall communicate  this  to  the  Clinical 
Research  Administration-IRB.  The finding will be reviewed  by a group  convened  by the 
IRB  to  determine whether the incidental finding should  be discussed  with the subject.  In 
the event that group convened by the IRB determines that the finding should be discussed 
with  the  subject,  and  the subject has consented  to  be re-contacted,  then the 
treating/consenting  physician  shall  be  contacted  by  the  Clinical Research  Administration- 
IRB  representative  and  asked  to  refer  the  subject  to  the  Clinical Genetics  Service  for 
further  discussion  of the  research  finding.  After  appropriate  counseling  and  consent,  the 
Clinical  Genetics  Service  will  request  permission  to  confirm the  result  in  a  New  York 
DOH-approved  laboratory prior to communication of the specific test result. If the patient 
is  not  available  (e.g.  deceased),  then  the  surrogate  designated  on  the  consent  will be 
contacted and the above will occur. 
 
 
 
 
The  following  information  will  be  provided  to  the  Clinical Research  Administration-IRB 
representative  and Clinical  Genetics: 
 
• 
Participant  Name/MRN # 
 
• 
Type of Biospecimen 
 
• 
Incidental finding 
 
• 
Project# (HBUC/Waiver  #) that this analysis  occurred under 
 
• 
Collection  Protocol # 
 
Clinical  Genetics Service Contact: ocrgapirb@mskcc.org 
 
 
4.2       Inte rve ntion 
 
For patients in Cohort 1,  there will  be no  change or intervention in a patient’s treatment 
regime using chemoradiation where both the primary and the neck nodes receive 70Gy   if 
the tumors are not associated  with HPV or if there is no  resolution of hypoxia on their 
repeat 18F-FMISO PET/CT scan. This is currently  one accepted standard of care. 
 
Patients in Cohort 1 with tumors that are positive for HPV who exhibited no evidence of 
hypoxia   on   their   baseline   18F-FMISO   PET/CT  scan  or  whose  tumors  have  early 
resolution  of  hypoxia  on  their  repeat  early  response  18F-FMISO  PET/CT  scan  will 
undergo  an  alternative  treatment  where  the  primary  tumor  site  receives  70Gy  while  the 
neck nodes receive 60Gy followed  by a planned  FDG PET/CT scan and observation. 
 
Select Cohort 2 HPV+ tumors that demonstrate no evidence of hypoxia on an 18F-FMISO 
PET scan will receive 30Gy to the surgical bed and neck lymph  nodes concurrent with 
standard chemotherapy  followed  by a 3 to 4-month post-treatment neck dissection.  In 
patients who exhibit  a complete response with this method of treatment,  no further 
treatment is necessary. For patients within  this select group who still have pathologic 

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Page 25 of 43 
 
 
 
 
 
nodal disease, further standard chemoradiation  will be given.  All other patients in this 
cohort (i.e. those who are not in the select HPV+ tumor group outlined  above) will 
receive standard of care treatment  following  their surgery. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC  AGENTS 
 
DCE-MRI   studies   will  be  acquired   using  a  fast  multi-phase  spoiled   gradient  echo 
sequence.  A  Gadolinium-based  agent  will  be  used  for  DCE-MRI  studies.  This  is  the 
standard contrast agent used with MRIs. 
 
18F-FMISO is prepared and tested for quality assurance in this study at MSKCC or by an 
equivalent  qualified  supplier.     The  radiopharmaceutical  is  being  utilized  in  this  protocol 
under a MSKCC IND. 
 
Radionuc lide  dosimetry 
Biodistribution data on 18F-FMISO has been obtained for 60 patients at the University of 
Washington,  School of Medicine,  and  dosimetry was performed. The normal organ doses 
absorbed  following 18F-FMISO  administration was published  by Graham et al.  (15) and 
is summarized  in the table below. 
 
Radiation  Absorbed Doses to Organs following  18F-FMISO administration. 
Target Organ 
Median  Dos e 
(mGy/MB q) 
Dos e (cGy) 
per 
10mCi 
(370 
MBq)  injection 
Total         Procedure 
Dos e (cGy) 
Tracer 
 
+ 
 
3 
attenuation            CT 
s cans 
Adrenals 
0.0166 
0.61 
3.31 
Brain 
0.0086 
0.32 
3.02 
Breas ts 
0.0123 
0.46 
3.16 
Gall bladder wall 
0.0148 
0.55 
3.25 
Lower Large Intes tine 
0.0143 
0.53 
3.23 
Small Intes tine 
0.0132 
0.49 
3.19 
Stomach 
0.0126 
0.47 
3.17 
Upper Large Intes tine 
0.0140 
0.52 
3.22 
Heart Wall 
0.0185 
0.68 
3.38 
Kidney 
0.0157 
0.58 
3.28 
Liver 
0.0183 
0.68 
3.38 
Lungs 
0.0099 
0.37 
3.07 
Mus cle 
0.0142 
0.53 
3.23 
Ovaries 
0.0176 
0.65 
3.35 
Pancreas 
0.0179 
0.66 
3.36 
Red Marrow 
0.0109 
0.40 
3.10 
Bone Surface 
0.0077 
0.28 
2.98 
Skin 
0.0048 
0.18 
2.88 
Spleen 
0.0163 
0.60 
3.30 
Tes tes 
0.0146 
0.54 
3.24 
Thymus 
0.0155 
0.57 
3.27 
Thyroid 
0.0151 
0.56 
3.26 
Urinary Bladder Wall 
0.0210 
0.78 
3.48 
Uterus 
0.0183 
0.68 
3.38 
Eye Lens 
0.0154 
0.57 
3.27 

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Total Body 
0.0126 
0.47 
3.17 
 
The original approved protocol MSKCC 04-070 consisted of 3 injections of 370 MBq of 
18F-FMISO  per patient.  The current protocol involves up to 2 injections of 370 MBq of 
18F-FMISO  per patient.    The dose estimates derived  from the University of Washington 
data were used to provide the dose from the single 10 mCi administration of 18F-FMISO 
and  were confirmed  by our pilot study.  The urinary bladder wall is subject to the largest 
dose of 0.78 cGy.    This is an insignificant addition to the total therapeutic radiation dose 
that the patient will receive for his or her head and neck cancer.   In addition, the patient 
will receive  a  low  dose  CT  attenuation  scan  each  contributing  an  addition  of  0.9  cGy 
whole body dose to  the patient.   The dose to the eyes from the combination of an 18F- 
FMISO  and  CT  scan  would  be  0.57  +  (3X0.9)  cGy  =  3.27  cGy.  This will also  not 
significantly add  to  the total radiation dose that the patient will receive from treatment for 
his or her head and neck cancer. 
 
Also note that these radiation doses are overestimates, because the CT scan (and therefore 
dose)  will only  apply  to  a  single  15cm field  of view  surrounding  the lesion of interest. 
For  example,  for  patients  in which the lesion is remote from the eye,  the lens will only 
receive  a  dose  of  0.57  cGy  resulting  from the  18F-FMISO  administration  and  nothing 
from the CT. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1       Subje ct Inclusion Crite ria for Cohort 1 and Cohort 2 
 
• 
Histologically   confirmed   diagnosis   of   head   and   neck   carcinoma   (excluding 
nasopharynx,  paranasal  sinus,  salivary,  and  thyroid  malignancies).  Any  unknown 
primary  squamous  cell carcinoma of head  and  neck  with gross nodes is allowed 
(2002 AJCC) 
• 
18 years of age or older 
• 
Must not have received prior radiation  therapy or chemotherapy  for this diagnosis. 
• 
Patients  who  have  had  their  primary  site  tumor  removed  by  surgery  but  still 
present with grossly enlarged  lymph  nodes are eligible  for this study. 
• 
Karnofsky performance status ≥ 70. 
 
 
6.2       Subje ct Exclusion Crite ria for Cohort 1 and Cohort 2 
 
• 
All nasopharyngeal,  paranasal sinus,  salivary  cancer, and thyroid  malignancies 
• 
Prior chemotherapy  or radiotherapy  within  the last three years 
• 
Patients  that  underwent  previous  surgical resection  for  the  same  disease  (except 
for  biopsy  or  surgery  removing  primary  site  tumor  but  still present  with  grossly 
enlarged  lymph  nodes) 
• 
Any prior radiotherapy  to the head and neck region 

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• 
Pregnant  (confirmed  by  serum b-HCG  in  women of reproductive age) or breast 
feeding 
 
 
6.3       Subje ct Exclusion Crite ria for Optional Contrast MRIs – Cohort 1 Only 
 
• 
Subjects  with  a  known  contraindication  to   the  standard  MRI  contrast  agent 
(Gadavist,    a   gadolinium-based    contrast   agent)   and/or   a   recent   estimated 
glomerular  filtration  rate  (eGFR)  of 30  or  less  will be  excluded  from all DCE- 
MRIs, and will instead  receive non-contrast MRIs at the DCE-MRI time points. 
 
 
7.0 
RECRUITMENT PLAN (WITH LIMITED WAIVER OF AUTHORIZATION) 
 
Patients will be evaluated by an attending physician from the Department of Radiation 
Oncology  and   entered   onto   the  study  and   into   the  appropriate  cohort  if  they  are 
appropriate  candidates.     The  attending  physician  will obtain  informed  consent  from the 
eligible  patient. 
 
Potential research subjects will  be identified by a member of the patient’s treatment team, 
the protocol investigator, or research team at MSKCC.   If the investigator is a member of 
the  treatment  team,  s/he  will  screen  their  patient’s  medical records for suitable research 
study  participants  and  discuss  the  study  and  their  potential for  enrolling  in the research 
study.   Potential subjects contacted by their treating physician will be referred to the 
investigator/research  staff of the study. 
 
The  Principal  Investigator  may  also  screen  the  medical records  of patients  with  whom 
they  do  not  have  a  treatment  relationship  for  the  limited  purpose  of identifying patients 
who would be eligible to enroll in the study and to record appropriate contact information 
in order to approach these patients regarding  the possibility  of enrolling  in the study. 
 
During  the  initial conversation  between  the investigator/research staff and  the patient,  the 
patient  may  be  asked  to  provide  certain  health  information  that  is  necessary  to  the 
recruitment  and   enrollment  process.     The  investigator/research  staff  may  also  review 
portions of their medical records at MSKCC  in order to  further assess eligibility.    They 
will use the information provided by the patient and/or medical record to confirm that the 
patient  is  eligible  and  to  contact  the  patient  regarding  study  enrollment.    If the  patient 
turns  out  to  be  ineligible  for  the  research  study,  the  research  staff  will  destroy  all 
information  collected  on  the  patient  during  the  initial  conversation  and  medical records 
review,  except for any information  that must be maintained  for screening  log purposes. 
 
In most cases,  the initial contact with the prospective subject will be conducted either by 
the  treatment  team,  investigator  or  the  research  staff  working  in  consultation  with  the 
treatment team.    The recruitment process outlined  presents no  more than minimal risk to 
the privacy of the patients who  are screened and minimal PHI will be maintained as part 
of a screening log.   For these reasons, we seek a (partial) limited waiver of authorization 
for  the  purposes  of (1)  reviewing medical records to  identify potential research subjects 
and  obtain  information  relevant  to  the  enrollment  process;  (2)  conversing  with  patients 

Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
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Page 28 of 43 
 
 
 
 
 
regarding  possible  enrollment;  (3)  handling  of  PHI  contained  within  those  records  and 
provided  by the  potential subjects;  and  (4) maintaining information in a screening log of 
patients approached (if applicable). 
 
8.0 
PRETREATMENT EVALUATION 
 
All patients will receive the necessary scans and  tests according  to  the standard  of care 
for their head and neck cancer. 
 
9.0 
TREATMENT/INTERVENTION  PLAN 
 
For patients in Cohort 1,  there will  be no  change or intervention in a patient’s treatment 
regime using chemoradiation where both the primary and the neck nodes receive 70 Gy   if 
the tumors are not associated  with HPV or if there is no  resolution of hypoxia on their 
repeat 18F-FMISO PET/CT scan. 
 
Patients in Cohort 1 with tumors that are positive for HPV who exhibited no evidence of 
hypoxia   on   their   baseline   18F-FMISO   PET/CT  scan  or  whose  tumors  have  early 
resolution  of  hypoxia  on  their  repeat  early  response  18F-FMISO  PET/CT  scan  will 
undergo  an  alternative  treatment  where  the  primary  tumor  site  receives  70Gy  while  the 
neck nodes receive 60Gy followed  by a planned  FDG PET/CT scan and observation. 
 
Select Cohort 2 HPV+ tumors that demonstrate no evidence of hypoxia on an 18F-FMISO 
PET scan will receive 30Gy to the surgical bed and neck lymph  nodes concurrent with 
standard chemotherapy  followed  by a 3 to 4month post-treatment  neck dissection.  In 
patients who exhibit  a complete response with this method of treatment,  no further 
treatment is necessary. For patients within  this select group who still have pathologic 
nodal disease, further standard chemoradiation  will be given.  All other patients in this 
cohort (i.e. those who are not in the select HPV+ tumor group outlined  above) will 
receive standard of care treatment  following  their surgery. 
 
Please note that for patients who  receive a repeat 18F-FMISO PET/CT scan, the repeat 
18F-FMISO  PET/CT  scan  will  only  be  performed  5-10  days  into  chemoradiotherapy 
treatment.   For  Cohort  1  patients,  a  repeat  18F-FMISO  PET/CT  scan  will  only  be 
performed  if the pretreatment  baseline  18F-FMISO PET scan is positive for hypoxia. 
 
Chemotherapy  will be administered  in two doses. Chemotherapy  will begin +/- 3 days 
from the first day of radiation  therapy. The second cycle of chemotherapy  will begin 3 
weeks later (+/- 5 days), although  delays for safety (e.g., low white blood count, elevated 
creatinine)  are allowed.  Standard chemotherapy  with either Cisplatin  or Carboplatin/5- 
Fluorouracil is strongly  recommended.  Any other schedule (e.g., weekly chemotherapy) 
is discouraged  and requires approval of the principal investigator. 
 
• 
Patients should receive standard high dose Cisplatin  chemotherapy  at 100 mg/m². 
If the patient is unfit  or cannot tolerate Cisplatin,  the treating  physician  must 
discuss with study medical oncologist,  Dr. Eric Sherman,  to jointly  confirm what 
chemotherapy  should be given  in place of Cisplatin. 

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• 
If a patient is not tolerating  Cisplatin  well, dose modification(s)  must be discussed 
with study investigator,  Dr. Eric Sherman,  prior to making  any changes. 
 
Patients on main campus, unless contraindicated, will have a recommended MRI at pre- 
treatment (Cohort 1), recommended MRIs approximately weekly (Cohort 1), and a 
recommended MRI post-treatment at 3 months, 6 months, and 1-year post-treatment (+/-4 
weeks)  when  possible  (Cohort  1).  Cohort  2  patients  will  not  receive  approximately 
weekly MRIs,  and  will not receive a post-treatment MRI at 3 months, 6 months, and 1 
year post-treatment. 
 
Central review of all radiation treatment plans must be reviewed  by study PI Dr. Nancy 
Lee and/or investigator  Dr. Nadeem Riaz prior to initiating  radiation  treatment. 
 
10.0 
EVALUATION  DURING TREATMENT/INTERVENTION 
 
All patients will be evaluated  according to  the standard  of care  for their head  and neck 
cancer. 
 
11.0 
TOXICITIES/SIDE  EFFECTS 
 
No side effects are expected as a result of this study. However, in the unlikely event that 
an adverse reaction to either radiopharmaceutical occurs, these toxicities will be graded 
according  to  Common  Terminology  Criteria  for  Adverse  Events  (CTCAE)  version  4.0. 
The results will be documented and reported by the Principal Investigator to both the 
Institutional Review Board and the IND Committee  chairmen. 
 
Cohort  1  patients  who  will have  optional 18F-FMISO  PET  image-guided  core biopsies 
might  experience  the following: 
 
Likely 
• Discomfort  when the needle enters into your neck 
• Minimal if any bleeding  from your neck 
 
Less Likely 
• 
Infection 
• 
Neck pains 
Cohort 2 patients who undergo neck dissection  might  experience the following: 
Likely 
• 
Temporary postoperative discomfort 
• 
Numbness of the skin 
• 
Visible  healed scar line 
 
Less Likely 
• 
Scar tissue (fibrosis)  of the neck leading  to tightness 

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Page 30 of 43 
 
 
 
 
 
• 
Infection 
 
Rare but serious 
• 
Fluid  collection  in the neck requiring  drainage(seroma) 
• 
Bleeding (hematoma)  requiring  a second surgery 
• 
Loss of function of   a nerve (lower lip asymmetry, shoulder dysfunction, 
hoarseness, others) 
• 
Chyle leak (prolonged  fluid  drainage from the neck) 
 
Patients who  partake in the optional storage and  analysis of tissue samples will not have 
additional risks or toxicities  other than the unauthorized  and inadvertent  release of PHI. 
 
Gadavist,  a  gadolinium-based  contrast  agent,  is  the  standard  contrast  agent  utilized  in 
contrast  MRIs.  However,  adverse  reactions  to  gadolinium-based  contrast  agents  have 
been  documented,  which may include headaches,  rash,  and  itching.  Furthermore, 
gadolinium-based  contrast  agents  are  associated  with  a  risk  for  Nephrogenic  Systemic 
Fibrosis (NSF) and renal failure. Due to these associated risks, subjects enrolled on this 
protocol with a known contraindication to the standard MRI contrast agent (Gadavist, a 
gadolinium-based   contrast   agent)   and/or  a  recent  estimated   glomerular  filtration  rate 
(eGFR) of 30 or less will be excluded from all DCE-MRIs, and will instead receive non- 
contrast MRIs at the DCE-MRI time points. 
 
12.0 
CRITERIA FOR THERAPEUTIC  RESPONSE/OUTCOM E  ASSESSMENT 
 
Not applicable. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
If at any time  the patient develops progressive disease he/she will be taken off study and 
referred  for  alternative  therapy.  If at any time  the patient develops unacceptable toxicity 
he/she will be removed from study. 
 
If at  any  time  the patient is found  to  be ineligible for the protocol as designated  in the 
section  on  Criteria  for  Patient/Subject  Eligibility  (i.e.,  a  change  in diagnosis),  the patient 
will be removed from the study. 
 
If at any time a patient wishes to participate in the optional sub-study regarding additional 
banking and  analysis of tissue  via the optional biopsy (Cohort 1) or via the standard  of 
care  surgical resection  (Cohort  2),  the  patient  has a right to  withdraw participation and 
prohibit any future use of their biologic specimen that has not already been undertaken. If 
the specimen has already been sent out from the archive for research purposes, it cannot 
be  excluded  from the research,  nor would  any results derived  from the research activity 
be excluded. 

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14.0 
BIOSTATISTICS 
 
Cohort 1 will accrue a cohort of 150 head and neck cancer patients over 5 years, of 
which  100  will  be  HPV+  tumors  and  50  will  be  HPV-  tumors.  Due  to  biomarker 
screening  and  to  accommodate  a  20%  exclusion  rate,  in  order  to  reach  28  eligible 
patients,  Cohort 2 will accrue 19 patients who are expected to undergo surgical resection 
for their cancer per standard of care. 
 
This  is  a  feasibility  study  of using  18F-FMISO  PET  to  detect  tumor  hypoxia  in  HPV 
negative head and neck cancer of which patients will undergo standard chemoradiation. 
Information  obtained  from the  imaging  studies  will not  alter  from the  standard  of care . 
We  will  image  50  non-HPV  positive  patients  to  evaluate  the  ability  of  dynamic  18F- 
FMISO  PET  scanning  to  accurately  determine  the  location  hypoxia  sub-regions  within 
the  tumor  volume.      For those HPV negative patients whose  18F-FMISO  PET exhibits 
hypoxia, we will also perform a repeat 18F-FMISO PET/CT scan 5-10 days into treatment 
with chemoradiotherapy.    This will provide us the volume of hypoxic region at the 5-10 
days  time-point.    The  changes in the volume of the hypoxic regions after 5-10  days of 
therapy  will  be  summarized.  We  estimate  that  40  HPV  negative  patients  will  require 
repeat  18F-FMISO  PET.  Among  these  patients,  we  anticipate Wilcoxon rank  sum tests 
will  be used  when the imaging results are measured  continuously and Fisher’s exact tests 
will be  applied  when  the  imaging  results  are  dichotomized.  We will also  search for the 
best cut-off value for SUV and/or k3  to predict “response”. To this end, we will  examine 
all possible cut-off values and the corresponding  sensitivity  and specificity. 
 
The Youden index,  defined  as sensitivity+specificity-1,  will be used to determine the best 
cut-off  value  for  SUV.  For  long-term treatment  outcomes,  Kaplan-Meier  estimates  will 
be  calculated  for  each  stratum and  compared  using the log-rank  tests.  When competing 
risks are present (death without distant metastasis), Gray’s test will be used. Due to the 
moderate   sample   size,   we   may   not   have   enough   power   for   declaring   statistical 
significance for our tests, in which cases we will report all summary and test statistics and 
point out future  research directions. 
 
As 18F-FDG PET scans are routinely obtained  before and  after chemoradiation for head 
and   neck   cancer,   we   will  include   a   prospective   MTV   (metabolic   tumor   volume) 
calculation  in  addition  to  the  already  calculated  standard  uptake  value  (SUV)  for  the 
routine  18F-FDG  PET  scans.    We  will not  alter  any patient management based  on the 
calculated  MTV.  The  MTV,  defined  as  tumor  volume  with  42%  or  greater  of  the 
maximum    18Fluorine-fluoro-deoxyglucose     (18F-FDG)    signal    intensity    on    positron 
emission   tomography   (PET),   has   been  demonstrated   to   correlate  with  loco -regional 
control,  freedom  from  distant  metastases,  and  overall  survival  in  oropharyngeal  cancer 
patients treated with definitive chemoradiation therapy at MSKCC (21). These findings 
corroborate  those  of  previously  published  retrospective  studies  from  Stanford  Medical 
Center (22, 23). 
 
Biostatistics for HPV+  tumors with no  evidence of hypoxia on their baseline 18F-FMISO 
PET/CT or that exhibited  hypoxia  resolution  on their early repeat 18F-FMISO PET/CT. 

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100  HPV+  patients  with negative  baseline  scan  or early resolution of tumor hypoxia of 
their node(s) at 5-10 treatment days into chemoradiation, defined by an absence or 
disappearance of 18F-FMISO uptake on PET/CT, will achieve an equivalent nodal control 
with  nodal  radiation  dose  at  60Gy  in  the  setting  of  chemotherapy  with  concomitant 
reduction  in  treatment-related  complications.  To  test  if  patients  receiving  60Gy  to  the 
node(s)  followed  by  an  FDG  PET  and  observation  similar  treatment  outcomes  when 
compared  to  the  radiation  of  70Gy  to  the  nodes  both  in  the  setting  of  co ncurrent 
chemotherapy,   we   will  apply  a  one-sided   one  sample  proportion  test.      Our  past 
experience  is that the nodal control rate at 3  months for such patient with  70Gy to  the 
nodes  is  94%.     We  will  reject  our  hypothesis  of  equivalent  control  whether  patients 
receive  70Gy  to  the  nodes  or  60Gy  to  the  nodes  followed  by  an  FDG  PET  and 
observation if ≤57 patients out of the 66 in total who received 60Gy to the nodes achieve 
the same 3-month nodal control after chemoradiation.   With this rule, we have a power of 
0.93  for detecting that 60Gy will result in 3-month regional control lower than 80% with 
the  type  I  error rate lower than 0.05.    To  test if patients receiving 60Gy to  the nodes 
followed   by  an  FDG  PET  and   observation  show  superior  toxicity  outcomes  when 
compared  to  the  historical results  from similar  patients  receiving  70Gy,  we will apply a 
one-sided one sample proportion test.   Grade 2 or higher toxicities that occurred within 3 
months  from  the   completion  of  IMRT  will  be  counted  in  this  analysis.     Our  past 
experience is that this toxicity  rate for patients receiving  70Gy is around 75%. 
Using  the  total  of  66  patients  that  undergo  60Gy  to  the  nodes,  we  will  reject  our 
hypothesis  of  equivalent  or  higher  toxicity  rate  when  the  nodes  receive  10Gy  less 
radiation from 70Gy when ≤43 patients have at least one ≥ grade 2 toxicities.   With this 
rule, we have a power of 0.84 for detecting the probability of 60% of patients will have at 
least one ≥grade 2 toxicity with the type I error rate lower than 0.05.   Effort will  be made 
to  monitor all toxicities occurring beyond  3  months from chemotherapy and IMRT for all 
patients.   However, censoring can be an issue so we will not apply the proportion test for 
toxicities  after  3  months  from  chemoradiation.     Instead,  we  will  summarize  the  data 
descriptively  and  when  applicable,  we  will  use  survival analysis  tools  such  as  Kaplan- 
Meier  estimation  and  log-rank  tests to  determine whether 60Gy results in lower toxicity. 
To   examine  the  potential  correlations  between  various  evaluation  methods  for  nodal 
control status, we will  apply a series of Fisher’s exact tests. 
 
The spatial extent of 18F-FMISO PET imaging  within  the neck node(s) determines  the 
underlying  hypoxia  tumor phenotype for both HPV positive  and negative  HNSCC. To 
determine  whether baseline  18F-FMISO PET/CT and/or early-response  18F-FMISO 
PET/CT  at  5-10  treatment  days  after  chemotherapy  and  IMRT  correlate  with  selected 
proliferative/hypoxia  molecular  markers,  Wilcoxon  rank  sum tests  will  be  used  for  each 
marker. Multiple  testing  adjustments  such as Bonferroni  procedures will be used. To 
investigate  whether the extent of 18F-FMISO PET/CT measured hypoxia  at baseline 
and/or  5-10  treatment  days  into  chemoradiation  for  both  HPV  positive  and  negative 
tumors  correlates  with  the  development  of  distant  metastasis,  Kaplan-Meier  estimates 
will  be  calculated   for  each  stratum  and   compared   using  the  log-rank   tests.  When 
competing risks are present,  Gray’s test will  be used  to examine the correlation between 
the extent of 18F-FMISO PET/CT measured hypoxia with the development of distant 
metastasis.      To   examine   the   potential  correlations  between  the  baseline  and   early 

Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
Approval date: 01-Apr-2020 
Page 33 of 43 
 
 
 
 
 
response  18F-FMISO  PET  imaging  and  tumor’s  underlying  HPV  status,  we  will  apply 
Fisher’s exact tests. 
 
Multiparametric scans will also  be obtained. We will attempt comparisons to 18F-FMISO 
PET  results  and  immunohistochemistry hypoxia results,  but due to  the small pilot size of 
this exploratory aim,  we may not produce significant results. In that case, we will present 
summary  statistics  and suggest directions  for future study. 
 
> For this study cohort, 14 eligible  patients  will be needed for the analysis.  Assuming 
approximately  25% of the patients enrolled  will not be eligible,  we will plan to recruit 19 
patients upfront.  For evaluation  on the efficacy  of the regimen  in this cohort, a simple 
decision rule will be implemented,  which is as follows: If, among the total 14 eligible 
patients,  we have at least 10 patients who are alive,  followed  and have a pathologic  CR at 
4 months from the end of the treatment,  then we will declare the treatment  modality  using 
30 Gy is feasible  and worthy of further investigation. 
Any patient who died or is lost to 
follow  up within  4 months from the end of radiotherapy  will be regarded as a failure,  i.e., 
without  pathologic  CR. Feasibility  for the primary objective in cohort 2 will be defined 
according to aforementioned  decision rule. This decision rule has the following 
probabilities  of declaring  success. 
 
 
 
True Locoregional  Control Rate 
0.50 
0.55 
0.60 
0.65 
0.70 
0.75 
0.80 
0.85 
0.90 
Probability  of Declaring  Success 
0.090 
0.167 
0.279 
0.423 
0.584 
0.742 
0.870 
0.953 
0.991 
 
 
 
15.0 
SUBJECT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1     Re search Participant  Re gistration 
 
Confirm   eligibility   as   defined   in  the  section   entitled   Inclusion/Exclusion   Criteria. 
Obtain   informed   consent,   by   following   procedures   defined   in   section   entitled 
Informed  Consent  Procedures.  During  the registration process  registering individuals 
will  be  required  to  complete  a  protocol  specific  Eligibility  Checklist.  The  individual 
signing  the Eligibility  Checklist  is  confirming whether or not the participant  is eligible 
to enroll in the study. Study staff are responsible for ensuring that all institutional 
requirements  necessary  to  enroll  a  participant  to  the  study  have  been  completed. 
See related Clinical Research Policy and Procedure #401 (Protocol Participant 
Registration). 
 
15.2     Randomization 
 
Not applicable. 

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16.0 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned  to the study.   The responsibilities of 
the   RSA   include   project   compliance,   data   collection,   abstraction   and   entry,   data 
reporting,   regulatory  monitoring,   problem  resolution  and   prioritization,   and   coordinate 
the activities  of the protocol study team. 
 
The  data  collected  for  this  study  will  be  entered  into  a  secure  database.     Source 
documentation will be available to  support the computerized  patient record.   All research 
material from this  study  will  be  handled  with  the  same  confidentiality  as  patient’s other 
medical data. 
 
16.1     Quality Assurance 
 
Eligibility of patients will be verified with the Principal Investigator.   Only the designated 
investigators  can obtain informed  consent. 
 
There  are  several  different  mechanisms  by  which  clinical trials  are  monitored  for  d ata, 
safety  and  quality.    There are institutional processes in place for quality assurance (e.g., 
protocol  monitoring,  compliance  and  data  verification  audits,  therapeutic  response,  and 
staff education on clinical research QA) and  departmental procedures for quality control, 
plus   there   are   two   institutional  committees   that   are  responsible  for  monitoring  the 
activities of our clinical trials programs.   The committees: Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board  (DSMB) for Phase III clinical trials,  report to  the Center’s Research Council and 
Institutional Review Board (see section 16.2). 
 
During the protocol development and  review process,  each protocol will be assessed for 
the level of risk and the degree of required monitoring.   Every type of protocol (e.g., NIH 
sponsored,  in-house  sponsored,  industrial  sponsored,  NCI  cooperative  group,  etc.)  is 
reviewed  and monitoring  procedures are established  at the time of protocol activation. 
 
16.2     Data and Safe ty Monitoring 
 
The Data and Safe ty Monitoring (DSM) Plans at Me morial Sloan-Ke ttering Cance r 
Ce nte r we re approve d by the National Cance r Institute in Se pte mbe r 2001. The 
plans addre ss the ne w policie s set forth by the NCI in the docume nt  e ntitled “Policy 
of the National Cance r Institute for Data and Safe ty Monitoring of Clinical Trials” 
which can be found at:  http://cance rtrials.nc i. nih.gov/re se arche rs/dsm/inde x.html. 
The DSM Plans at MSKCC we re e stablished and are monitore d by the Clinical 
Re search Administration.  The MSKCC Data and Safe ty Monitoring Plans can be 
found on the MSKCC Intrane t at: 
https://one .mskcc.org/site s/pub/c linre se arch/Doc ume nts/M SKCC%20Data%20and 
%20Safe ty%20M onitoring%20Plans.pdf. 
 
The re are se veral diffe re nt me chanisms by which clinical trials are monitore d for 
data, safe ty and quality. The re are institutional  proce sses in place for quality 

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Page 35 of 43 
 
 
 
 
 
assurance (e .g., protocol monitoring,  compliance  and data ve rification audits, 
the rape utic re sponse, and staff e ducation on clinical re se arch QA) and 
de partme ntal proce dure s for quality control, plus the re are two institutional 
committe es that are re sponsible for monitoring  the activities of our clinical trials 
programs.  The committe es: Data and Safe ty Monitoring  Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safe ty Monitoring Board (DSMB) for 
Phase III clinical trials, re port to the Ce nte r’s Research Council and Institutional 
Re view Board. 
 
During the protocol de ve lopme nt and re view proce ss, each protocol will be assessed 
for its le vel of risk and de gre e of monitoring  re quire d. Eve ry type of protocol (e .g., 
NIH sponsored, in-house sponsored, industrial  sponsore d, NCI coope rative group, 
e tc.) will be addre ssed and the monitoring  proce dure s will be e stablished at the time 
of protocol activation. 
 
 
 
17.0 
PROTECTION  OF HUMAN SUBJECTS 
 
Risks  of Study  Participation:    Patients  who  will undergo  a  treatment that deviates from 
the  current  standard  of  care  for  their  disease  will be  those  patients  in  Cohort  2  who 
receive  a  dose  of  radiation  of  30Gy  to  the  surgical  bed  and  lymph  nodes,  a  neck 
dissection at three to four months post-chemoradiation, and a possible booster dose of 
chemoradiation following neck  dissection (this booster dose is dependent on the result of 
the  planned   neck   dissection).   The  risks  involved  include  those  entailed  by  giving  a 
decreased   dose  of  radiation  and   a  neck   dissection  at   three  to  four  months  post- 
chemoradiation.  However,  the  risk  associated  with  the  decreased  dose  of  radiation  is 
mediated  by  the  neck  dissection  three  to  four  months  post-chemoradiation.  Should  any 
residual  disease  be  discovered  at  the  time  of  this  neck  dissection,  the  patient  will be 
treated with a chemoradiation boost per standard of care. These patients will be closely 
monitored throughout their treatment on this protocol, and will receive standard of care 
treatment should  any complications  occur. 
 
Financial  Costs  to  Patients:    All diagnostic  and  therapeutic  interventions  except  for  the 
18F-FMISO   PET/CT   scans   and   the   neck   dissection   three   to   four   months   post- 
chemoradiation for select Cohort 2 patients are part of the current routine care of 
patients/subjects  eligible  for  this  study.  A research grant will cover the cost of the  18F- 
FMISO  -PET  scans  and  the  tracer,  the  optional 18F-FMISO  PET  image-guided  core 
biopsies,  and  the  neck  dissections.  In  addition,  the multiparametric scans on the Phillips 
MR machine will not generate a charge. There are no additional financial costs or burden 
to the patient beyond the charges routinely  incurred  as part of standard medical care. 
 
Patient   Confidentiality:      Patient/subject  privacy  and   confidentiality  will  be  maintained 
according  to  MSKCC  guidelines  and  all data derived  from this study will be kept in a 
secure  database.     All  data  and  results  will  be  anonymously  reported  with  regard  to 
individua l  subjects. 

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Voluntary nature of the study:   Subjects will be made aware of the voluntary nature of the 
study  as  part  of  the  informed  consent  process.     They  will  be  allowed  to  withdraw 
participation  at any time without  the risk of alteration  in the quality  of their medical  care. 
 
17.1     Privacy 
 
MSKCC’s   Privacy   Office   may   a ll ow   the   use   and   disclosure   of  protected   health 
information  pursuant  to  a  completed  and  signed  Research  Authorization  form.    The use 
and  disclosure of protected  health information will be limited  to  the ind ividuals described 
in  the  Research  Authorization form.    A Research Authorization form must be completed 
by the Principal Investigator  and approved by the IRB and Privacy Board. 
 
For the biospecimen banking and  analysis study,  it will be explained  that future research 
may  also  be  done  to  identify  changes  in  genes  that  predict  risk  for  cancer  or  other 
diseases;  if such  germline  genetic  research  is  performed,  then  to  be in compliance with 
New  York  State  Law  (New  York  State  Civil Rights  Law §79-1(30(a)),  it will not be 
possible  to   provide  results  of  research  tests  not  performed  in  a  New  York  State 
Department  of Health approved clinical laboratory. 
 
The consent indicates that samples and  genetic information collected  may be shared with 
other   qualified   researchers.   Such   information   will  not   include   identifying   information 
such  as  name.  It  is  also  stated  in the consent and  Research Authorization that research 
data  (e.g.  genomic  sequence)  may  be  placed  into  databases  monitored  by the National 
Institutes of Health, and may be made accessible to investigators approved by the U.S. 
government. 
 
The  requirements  for  submission  of  genotype/phenotype  data  into   the  NIH  GWAS 
Repository (or any other public database) will be outlined in the biopsecimen analysis 
application,   i.e.,   IRB   Biospecimen  Correlative  Protocol/HBUC   Application/Application 
of Exemption  for Existing  data. 
 
17.2     Se rious Adve rse Eve nt (SAE) Re porting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. SAE reporting is required for 30 days after the last 18F-FMISO PET/CT scan. Any 
SAEs that occur after the 30 day period and that are at least possibly related to the 18F- 
FMISO  isotope  must  be  reported.  The  IRB/PB  requires  a  Clinical Research  Database 
(CRDB)  SAE  report  is  submitted  electronically  to  the  SAE  Office  at   sae@mskcc.org 
containing  the following  information: 
 
Fields populated from the CRDB: 
• 
Subject’s name (generate the report with only initia ls  if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology  (if applicable) 
• 
Protocol number and title 

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Page 37 of 43 
 
 
 
 
 
 
Data needing  to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship  of the adverse event to the treatment  (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity  of the AE 
• 
The intervention 
• 
Detailed  text that includes  the following  information: 
o A explanation  of how the AE was handled 
o A description  of the subject's condition 
o Indication  if the subject remains on the study 
o If an amendment  will need to be made to the protocol and/or consent form 
 
The  Principal  Investigator’s  signature  and  the  date  it  was  signed  are  required  on  the 
completed  report. 
 
For IND/IDE protocols: 
 
The  CRDB  AE  report  should  be completed  as above and  the FDA assigned  IND/IDE 
number written at the top of the report. If appropriate, the report will be forwarded to the 
FDA by the SAE staff through  the IND Office. 
 
17.3     Inclusion of Childre n in Re search 
 
This protocol/project does not include children because the number of children is limited. 
This  statement  is  based  on  exclusion  4b  of  the  NIH  Policy  and  Guidelines  on  the 
Inclusion  of Children  as Participants  in Research Involving  Human Subjects. 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before   protocol-specified   procedures   are   carried   out,   consenting   professionals   will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants  prior  to  their  inclusion  in  the  study.  Participants  will also  be  informed  that 
they  are  free  to  withdraw  from  the  study  at  any  time.  All  participants  must  sign  an 
IRB/PB-approved  consent  form indicating  their consent to  participate.  This consent form 
meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy  Board of this Center. The consent form will include  the following: 
 
1.   The nature and objectives,  potential risks and benefits  of the intended  study. 
2.   The length  of study and the likely  follow-up  required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational   therapies.   In   addition,   patients   will  be   offered   an   option   of 
supportive  care for therapeutic  studies.) 
4.   The name of the investigator(s)  responsible  for the protocol. 

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IRB Number: 04-070 A(38) 
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Page 38 of 43 
 
 
 
 
 
5.   The right of the participant to  accept or refuse study interventions/interactions and 
to withdraw  from participation  at any time. 
 
Before  any  protocol-specific  procedures  can  be  carried  out,  the  consenting  professional 
will fully  explain  the  aspects  of patient  privacy  concerning  research  specific  information. 
In addition to  signing the IRB Informed  Consent,  all patients must agree to the Research 
Authorization component of the informed  consent form. 
 
Each  participant  and  consenting  professional will sign  the  consent  form.  The  participant 
must receive a copy of the signed  informed  consent form. 
 
19.0 
REFERENCES 
 
1.   Brown  JM,  Siim  BG.    Hypoxia  specific  cytotoxins  in  cancer  therapy.    Seminar  in 
Radiation  Oncology 1996;6(1):22-36. 
 
2.   Terris  DJ. 
Head   and   neck   cancer:  the  importance  of  oxygen. 
Laryngoscope 
2000;110:697-707. 
 
3.   Kaanders  JH,  Wijffels  KI,  Marres  HA,  et  al.     Pimonidazole  binding  and  tumor 
vascularity predict for treatment outcome in head and neck cancer.   Cancer Res 2002 
Dec 1;62(23):7066-74. 
 
4.   Brizel  DM,  Sibley  GS,  Prosnitz  LR,  et  al.     Tumor  hypoxia  adversely  affects  the 
prognosis  of  carcinoma  of  the  head  and  neck.     Int  J  Radiat  Oncol  Biol  Phys 
1997;38:285-289. 
 
5.   Popple  RA,  Ove  R,  Shen  S.     Tumor  control probability  for  selective  boosting  of 
hypoxic  subvolumes,  including  the  effect  of reoxygenation.    Int  J  Radiat Oncol Biol 
Phys 2002;54(3):921-927. 
 
6.   Rasey JS,  Koh WJ,  Evans ML,  et al.   Quantifying regional hypoxia in human tumors 
with  positron  emission  tomography  of  F-18  Fluoromisonidazole:  a  pretherapy  study 
of 37 patients.   Int J Radiat Oncol Biol Phys  1996;36(2):417-428. 
 
7.   Humm  JL,  Finn  R,  Ling  CC.    Positron  emission  tomographic  assessment  of tumor 
hypoxia  in  the  R3327-AT  rat  tumor  model:  a  comparative  study  using  microPET 
imaging of F18-miso and Cu64-ATSM with pO2 probe measurement.   (Manuscript in 
preparation). 
 
8.   Rischin D, Peters L, Hicks R, et al.   Phase I trial of concurrent tirapazamine, cisplatin, 
radiotherapy   in   patients  with  advanced   head   and  neck   cancer.      J  Clin  Oncol 
2001;19(2):535-542. 
 
9 
Lee N., Nehmeh S., Schoder H., et al.   A Phase II Trial of Incorporating Pre-treatment 
and  Mid-treatment  [18F] Misonidazole Positron Emission and  Computed  Tomography 
(18F-FMISO-PET/CT)  scans  for  a  series  of  loco-regionally  advanced  Head/Neck 

Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
Approval date: 01-Apr-2020 
Page 39 of 43 
 
 
 
 
 
Cancer   Patients  Undergoing  Concurrent  High-Dose  Platinum-Based   Chemotherapy 
with Intensity-Modulated 
Radiation 
Therapy. 
Int J Radiat Oncol   Biol   Phys 
2009;75(1):101-8. 
 
10. Frank   D.K.,   Hu   K.S.,   Gulliney   B.E.,   et   al. 
Planned   Neck   Dissection  after 
concomitant 
Radiochemotherapy 
for 
Advanced 
head 
and 
Neck 
Cancer. 
Laryngoscope 2005;115:1015-1020. 
 
11. Robbins   KT,    Shannon   K,    Vieira   F.        Superselective   neck   dissection   after 
chemoradiation:    feasibility based on clinical and pathologic comparisons.   Arch 
Otolaryngol Head Neck Surg 2007;183-188. 
 
12. Hillel A.T., Fakhry C., Pai S.I., et al.   Selective versus comprehensive neck dissection 
after  chemoradiation  for  advanced  oropharyngeal  squamous  cell  carcinoma.     Oto - 
Head Neck Surg 2009;141:737-742. 
 
13. Ang  K.K.,  Harris  J.,  Wheeler  R.,  et  al.     Human  papillomavirus  and  survival  of 
patients with oropharyngeal  cancer.  N Engl J med 2010;363(1):24-35. 
 
14. Rajendran JG,  Mankoff DA,  O'Sullivan F,  Peterson LM,  Schwartz DL,  Conrad EU, 
Spence AM,  Muzi M,  Farwell DG,  Krohn KA.   Hypoxia and glucose metabolism in 
malignant   tumors:   evaluation   by   [18F]fluoromisonidazole   and 
[18F]fluorodeoxyglucose  positron  emission  tomography  imaging.     Clin  Cancer  Res. 
2004 Apr 1;10(7):2245-52. 
 
15. Graham  MM,   Peterson  LM,   Link   JM,   et  al. 
Fluorine-18   –Fluoromisonidazole 
Radiation  Dosimetry  in Imaging  Studies.  J Nucl Med  1997; 38:1631-1636. 
 
16. Eschmann SM, Paulsen F, Reimold M, Dittmann H, Welz S, Reischl G, Machulla HJ, 
Bares  R.    Prognostic impact of hypoxia imaging with 18F-misonidazole PET in non- 
small cell lung cancer and  head  and  neck  cancer before radiotherapy.    J Nucl Med. 
2005 Feb;46(2):253-60. 
 
17. Thorwarth  D,  Eschmann  SM,  Paulsen  F,  Alber  M. 
A  kinetic  model for  dynamic 
[18F]-Fmiso  PET  data  to  analyse  tumour  hypoxia. 
Phys  Med  Biol.  2005  May 
21;50(10):2209-24. 
 
18. Lassen  P,  Eriksen  JG,  Krogdahl  A,  et  al:  The  influence  of HPV-associated  p16- 
expression   on   accelerated   fractionated   radiotherapy   in   head   and   neck   cancer: 
Evaluation of the randomised  DAHANCA 6  and 7 trial. Radiother Oncol 100:49-55, 
2011 
 
19. Posner  MR,  Lorch  JH,  Goloubeva  O,  et  al: Survival and  human  papillomavirus  in 
oropharynx cancer in tax 324: A subset analysis from an international phase III trial. 
Ann  Oncol  22:1071-1077,  2011  Weinberger  PM,  Yu  Z,  Kountourakis  P,  et  al: 
Defining   molecular   phenotypes   of   human   papillomavirus-associated   oropharyngeal 

Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
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Page 40 of 43 
 
 
 
 
 
squamous   cell  carcinoma:  Validation  of  three-class  hypothesis.   Otolaryngol  Head 
Neck Surg 141:382-389, 2009 
 
20. Lim R, Eaton A, Lee NY, et al. 18F-FDG PET/CT Metabolic Tumor Volume  and 
Total Lesion Glycolysis  Predict Outcome in Oropharyngeal Squamous Cell 
Carcinoma.  J Nucl Med 2012;53:1506-1513. 
 
21. La TH, Filion EJ, Turnbull BB, et al. Metabolic tumor volume predicts for recurrence 
and death in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2009;74:1335-1341. 
 
22. Tang C, Murphy JD, Khong B, et al. Validation that metabolic tumor volume predicts 
outcome in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2012;83:1514-1520. 
 
23. Silva SD,  Agostini M,  Nishimoto  IN,  et al: Expression of fatty acid synthase, ErbB2 
and  Ki-67  in  head  and  neck  squamous  cell carcinoma.  A  clinicopathological study. 
Oral Oncol 40:688-96, 2004 
 
24. Aebersold  DM,  Burri  P,  Beer  KT,  et  al:  Expression  of  hypoxia-inducible  factor- 
1alpha: a novel predictive and prognostic 
parameter in the radiotherapy   of 
oropharyngeal cancer. Cancer Res 61:2911-6, 2001 
 
25. Beasley NJ,  Leek  R,  Alam M, et al: Hypoxia-inducible factors HIF-1alpha and HIF- 
2alpha in head  and  neck  cancer: relationship to tumor biology and treatment outcome 
in surgically  resected patients.  Cancer Res 62:2493-7, 2002 
 
26. Erler  JT,  Giaccia  AJ: Lysyl oxidase  mediates  hypoxic  control of metastasis.  Cancer 
Res 66:10238-41, 2006 
 
27. Le  QT: Identifying  and  targeting hypoxia in head  and  neck  cancer: a brief overview 
of current approaches. Int J Radiat Oncol Biol Phys 69:S56-8, 2007 
 
28. Herneth   AM,   Guccione   S   and   Bednarski  M,   Apparent   diffusion   coefficient:  a 
quantitative parameter for in vivo  tumor characterization,  Eur J Radiol,  2003,   45(3); 
208-213 
 
29. Chenevert  TL,  Meyer  CR,  Moffatt  BA  et  al,  Diffusion  MRI:  a  new  strategy  for 
assessment of cancer therapeutic  efficacy.,  Mol Imaging,  2002, 1: 336-343 
 
 
 
30. Le  Bihan  D,  Breton  E,  Lallemand  D,  Grenier  P  et  al,  MR  imaging  of intra  voxel 
incoherent  motions:  application  to   diffusion  and  perfusion  in  neurologic  disorders, 
Radiology  1986:161:401-7 
 
31. Wang  J,  Takashima  S,  Takayama  F  et  al,  Head  and  neck  lesions: characterization 
with diffusion  weighted  echo-planar MR imaging.  Radiology.2001;220:621-630 

Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
Approval date: 01-Apr-2020 
Page 41 of 43 
 
 
 
 
 
32. Maeda  M,   Maier  S.   Usefulness  of  diffusion-weighted   imaging  and  the  apparent 
diffusion coefficient in the assessment of head and enck tumors. J Neuroradiol. 2008; 
35:71-78 
 
33. Vandecaveye  V,  De  Keyzer  F,  Hermans  R.  Diffusion-weighted  magnetic  resonance 
imaging  in neck lymphadenopathy.  Cancer Imaging  2008;8:173-180 
 
34. Vandecaveye  V,  Dirix  P  et  al,  Predictive  value  of  diffusion-weighted  MRI  during 
chemotherapy   for   head   and   enck   squamous   cell  carcinoma.   Eur  Radiol.   2010 
20:1703-1714 
 
35. King  AD,  Mo  FK,  Yu  KH  et al,  Squamous cell carcinoma of the head  and  neck: 
diffusion-weighted  MR  imaging  for  prediction  and  monitoring  of treatment  response. 
Eur Radiol (20120) 20 2213-2220 
 
36. Kim S,  Loevner L,  Quon H 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; 15:986-994 
 
37. Kato  H,  Kanematsu  M,  Tanaka  O  et al.  Head  and  neck  squamous cell carcinoma: 
usefulness   of  diffusion-weighted   MR  imaging  in  the  prediction  of  a  neoadjuvant 
therapeutic  effect.  Eur Radiol (2009) 19: 103-109 
 
38. Dirix  P,  Keyze  D  et  al.  Diffusion  weighted  MRI  to  evaluate  major  salivary  gland 
before and after radiotherapy.  IJROBP 2008;71:1365-1371 
 
39. Zhang L,  Murata  Y,  Ishida  R  et  al.  Functional evaluation with intravoxel incoherent 
motion   echo-planar   MRI   in   irradiated   salivary   glands:  A  correlative  study  with 
salivary  gland scintigraphy.  J Mag Reson imag 2001:14 223-229 
 
40. Jansen    JF,    Schoder    H,    Lee   N    et   al.    Noninvasive   assessment   of   tumor 
microenvironment  using  dynamic  contrast  enhanced  magnetic  resonance  imaging  and 
F-MISO PET imaging  in neck nodal metastasis.  IJROBP, 77 (5) 1403-1410 2010 
 
41. Adelstein  DJ.  Induction  chemotherapy  in head  and  neck  cancer.  Hematol Oncol clin 
North Am 1999;13:689-698 
 
42. Chaturvedi AK,  Engels EA,  Anderson WF,  Gillison ML: Incidence trends for human 
papillomavirus-related  and  -unrelated  oral  squamous  cell  carcinomas  in  the  United 
States. J Clin Oncol 26:612-9, 2008 
 
43. Fakhry  C,  Zhang  Q,  Nguyen-Tan  PF,  Rosenthal  D,  El-Naggar  A,  Garden  AS, 
Soulieres D, Trotti A, Avizonis V, Ridge JA, Harris J, Le QT, Gillison M. Human 
papillomavirus and overall survival after progression of oropharyngeal squamous cell 
carcinoma.  J Clin Oncol. 2014 Oct 20;32(30):3365-73. 
 
44. Gillison  ML.  Human  papillomavirus-associated  head  and  neck  cancer  is  a  distinct 
epidemiologic,  clinical,  and molecular  entity.  Semin Oncol 2004;31:744–54. 

Memorial Sloan Kettering Cancer Center
IRB Number: 04-070 A(38) 
Approval date: 01-Apr-2020 
Page 42 of 43 
 
 
 
 
 
 
45. Lee MK, Nalliah RP, Kim MK, Elangovan S, Allareddy V, Kumar-Gajendrareddy P, 
Allareddy   V.   Prevalence   and   impact   of  complications   on  outcomes  in  patients 
hospitalized  for  oral and  oropharyngeal cancer  treatment.  Oral Surg Oral Med  Oral 
Pathol Oral Radiol Endod. 2011 Nov;112(5):581-91. 
 
46. Shiboski  CH,   Schmidt  BL,   Jordan  RC:  Tongue  and  tonsil  carcinoma:  increasing 
trends in the U.S. population  ages 20-44 years. Cancer 103:1843-9, 2005 
 
47. Sudhoff HH, Schwarze HP, Winder D, Steinstraesser L, Gormer M, Stanley M, et al. 
Evidence  for  a  causal  association  for  HPV  in  head  and  neck  cancers.  Eur  Arch 
Otorhinolaryngol 2011;268:1541–7. 
 
48. Nigro  ND,  Vaitkevicius VK,  Considine B Jr.  Dynamic management of squamous cell 
cancer of the anal canal. Invest New Drugs.  1989 Apr;7(1):83-9. 
 
49. Cho CC, Taylor CW 3rd, Padmanabhan A, Arnold MW, Aguilar PS, et al. Squamous- 
cell   carcinoma   of   the   anal   canal:   management   with   combined   chemo-radiation 
therapy. Dis Colon Rectum.  1991 Aug;34(8):675-8. 
 
50. Frisch M,  Glimelius B,  van den Brule AJ,  Wohlfahrt J, Meijer CJ, Walboomers JM, 
Goldman S,  Svensson C, Adami HO,  Melbye M.  Sexually transmitted  infection as a 
cause of anal cancer. N Engl J Med. 1997 Nov 6;337(19):1350-8. 
 
51. Ravenda PS, Magni E, Botteri E, Manzotti M, Barberis M, Vacirca D, Trovato CM, 
Dell'Acqua V,  Leonardi MC,  Sideri M,  Fazio  N,  Zampino  MG.  Prognostic value of 
human    papillomavirus    in    anal   squamous    cell   carcinoma.    Cancer    Chemother 
Pharmacol.  2014 Nov;74(5):1033-8. 
 
52. Yhim HY, Lee NR, Song EK, Kwak JY, Lee ST, Kim JH, Kim JS, Park HS, Chung 
IJ,  Shim HJ, Hwang JE, Kim HR, Nam TK, Park MR, Shim H, Park HS, Kim HS, 
Yim  CY.   The   prognostic   significance  of  tumor  human  papillomavirus  status  for 
patients   with   anal   squamous   cell   carcinoma   treated   with   combined 
chemoradiotherapy.  Int J Cancer. 2011 Oct 1;129(7):1752-60. 
 
53. Rödel F, Wieland U, Fraunholz I, Kitz J, Rave-Fränk M, Wolff HA, Weiss C, Wirtz 
R, Balermpas P, Fokas E, Rödel C. Human papillomavirus DNA load and p16INK4a 
expression  predict  for  local  control  in  patients  with  anal  squamous  cell  carcinoma 
treated   with  chemoradiotherapy.   Int  J  Cancer.   2015   Jan  15;136(2):278-88.  doi: 
10.1002/ijc.28979 
 
54. Deng  Z,  Hasegawa  M,  Aoki K,  Matayoshi S,  Kiyuna A,  Yamashita Y,  Uehara T, 
Agena S, Maeda H, Xie M, Suzuki M. A comprehensive evaluation of human 
papillomavirus  positive  status  and  p16INK4a  overexpression  as  a  prognostic 
biomarker in head and neck squamous cell carcinoma. Int J Oncol. 2014 Jul;45(1):67 - 
76. 

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55. Salazar CR,  Anayannis N, Smith RV,  Wang Y,  Haigentz M Jr, Garg M, Schiff BA, 
Kawachi N, Elman J, Belbin TJ, Prystowsky MB, Burk RD, Schlecht NF. Combined 
P16  and  human  papillomavirus  testing  predicts  head  and  neck  cancer survival.  Int J 
Cancer. 2014 Nov 15;135(10):2404-12. 
 
56. Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal 
canal: a preliminary  report 1974. Dis Colon Rectum. 1993 Jul;36(7):709-11. 
 
57. Leichman L, Nigro N, Vaitkevicius VK, Considine B, Buroker T, et al. Cancer of the 
anal canal Model for  preoperative  adjuvant combined  modality therapy.  Am J Med. 
1985 Feb;78(2):211-5. 
 
20.0 
APPENDICES 
 
Not applicable.