Clinical trial NCT01882816
Conditions: Thyroid Cancer
Keywords: non-anaplastic non-medullary radiation IMRT Doxorubicin 13-070
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2013-06-13; Completion date: 2021-11-04
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this Phase 2 study is to find out what effect, good and/or bad, external beam radiation therapy, has on the patient and their thyroid cancer where surgery is not an option or where despite surgery, the disease is still present.

Detailed description:

Arms: arm 1: All patients will undergo radiation treatments using IMRT with concurrent low-dose radiosensitizing doxorubicin at 10 mg/m2 will be administered.
Interventions: intervention 1: IMRT intervention 2: DWI MRI intervention 3: Doxorubicin intervention 4: Modified Barium Swallow Impairment Profile (MBSImP)
Intervention descriptions: intervention 1: Patients will receive intensity-modulated radiation therapy (IMRT) in once-daily fractions (Monday through Friday, excluding holidays). A total dose of 70Gy is planned. Patients will be seen weekly during radiation as per standard procedure at MSKCC intervention 2: The DW and multiparametric MRI will be recommended for 3 months, 6 months, and then every 6 months (all +/- 4 weeks) until 2 years post-RT unless contraindicated for main campus patients only. This schedule may be altered, as clinically indicated. intervention 3: Low dose radiosensitizing doxorubicin at 10 mg/m2 will be administered weekly. intervention 4: The MBSImP is a standardized tool which assesses swallowing impairment as it relates to oral, pharyngeal, and esophageal impairments.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 13-070 A(14) 
Approval date: 11-Dec-2019 
Page 1 of 25 
 
 
 
 
 
 
A Phase II Study of Intensity-Modulated Radiation Therapy (IMRT) in the Treatment 
of Non-Anaplastic Non-Medullary Thyroid Cancer 
 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC   PROTOCOL 
 
Principal Investigator/Department: 
Nancy Lee, MD 
Radiation Oncology 
Co-Principal  Investigator(s)/Department: 
Eric Sherman, MD 
Michael Tuttle, MD 
Amita Dave, PhD 
Medicine 
Medicine 
Medical Physics 
Investigator(s)/Department: 
Ronald Ghossein, PhD 
Paul Romesser, MD 
Suzanne, Wolden, MD 
Sean McBride, MD, MPH 
Nadeem Riaz, MD 
James Fagin, MD 
Mona Sabra, MD 
Stephanie Fish, MD 
David Pfister, MD 
Shrujal Baxi, MD 
Alan Ho, MD, PhD 
Stephen Veach, MD 
Neelam Tyagi, PhD 
Kristen Zakian, PhD 
Ravinder Grewal, MD 
Duan Li, MD 
Hilda Stambuk, MD 
Robert Young, MD 
Margaret Ho, MS 
Cherry Estilo, DMD 
Jillian Tsai, MD 
Marsha Reyngold, MD 
Avni Desai, MD 
John Fiore, MD 
Stuart Lichtman, MD 
Jahan Aghalar, MD 
Han Xiao, MD 
Sree Chalasani, MD 
Afsheen Iqbal, MD 
Marina Shcherba, MD 
Borys Mychalczak, MD 
Boris Mueller, MD 
Richard Gewanter, MD 
Arlyn Apollo, MD 
Pamela Drullinsky,  MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
Zhigang Zhang, PhD 
Melissa Remis Zinovoy, MD 
Pathology Radiation 
Oncology Radiation 
Oncology Radiation 
Oncology Radiation 
Oncology Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medical Physics 
Medical Physics 
Radiology 
Radiology 
Radiology 
Radiology 
Surgery Surgery 
Radiation Oncology 
Radiation Oncology 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Biostatistics and Epidemiology 
Radiation Oncology 


Page 2 of 25 
 
 
 
 
 
 
 
 
 
Oncology 
Oncology 
Oncology 
 
 
 
 
 
 
Oncology 
Oncology 
 
 
 
 
 
 
 
 
 
Oncology 
Memorial Sloan Kettering Cancer 
Center IRB Number: 13-070 A(14) 
Approval date: 11-Dec-2019 
Daphna Gelblum, MD 
Radiation 
Annemarie F. Shepherd, MD     Radiation 
John Cuaron, MD 
Radiation 
Jason Konner, MD 
Medicine 
Serena Wong, MD 
Medicine 
Jacqueline Bromberg, MD, PhD  Medicine 
Azadeh Namakydoust, MD 
Medicine 
Colette Owens, MD 
Medicine 
Loren Michel, MD 
Medicine 
Carla Hajj, MD 
Radiation 
Lior Braunstein, MD 
Radiation 
Carly Osborne, APN 
Nursing 
Janice Terlizzi, APN 
Nursing 
Jia Li, MD 
Medicine 
Wanqing Iris Zhi, MD, PhD 
Medicine 
Juliana Eng, MD 
Medicine 
Carol Ann Milazzo, NP 
Nursing 
Daniel McFarland, DO 
Medicine 
Alice Zervoudakis, MD 
Medicine 
Parisa Momtaz, MD 
Medicine 
Beryl McCormick, MD 
Radiation 
Consenting  Professional(s)/Department: 
Nancy Lee, MD 
Radiation Oncology 
Sean McBride, MD, MPH 
Radiation Oncology 
Suzanne Wolden, MD 
Radiation Oncology 
Nadeem Riaz, MD 
Radiation Oncology 
David Pfister, MD 
Medicine 
Shrujal Baxi, MD 
Medicine 
Alan Ho, MD, PhD 
Medicine 
Eric Sherman, MD 
Medicine 
Stephen Veach, MD 
Medicine 
Jillian Tsai, MD 
sRadiation Oncology 
Marsha Reyngold, MD 
Radiation Oncology 
Avni Desai, MD 
Medicine 
John Fiore, MD 
Medicine 
Stuart Lichtman, MD 
Medicine 
Jahan Aghalar, MD 
Medicine 
Han Xiao, MD 
Medicine 
Sree Chalasani, MD 
Medicine 
Afsheen Iqbal, MD 
Medicine 
Marina Shcherba, MD 
Medicine 
Borys Mychalczak, MD 
Radiation Oncology 
Boris Mueller, MD 
Radiation Oncology 
Richard Gewanter, MD 
Radiation Oncology 
Arlyn Apollo, MD 
Medicine 
Pamela Drullinsky,  MD 
Medicine 
Zoe Goldberg, MD 
Medicine 
Kenneth Ng, MD 
Medicine 
Tiffany Troso-Sandoval, MD 
Medicine 
Melissa Remis Zinovoy, MD 
Radiation Oncology 
Daphna Gelblum, MD 
Radiation Oncology 
Annemarie F. Shepherd, MD     Radiation Oncology 
John Cuaron, MD 
Radiation Oncology 


Page 3 of 25 
Memorial Sloan Kettering Cancer Center 
IRB Number: 13-070 A(14) 
Approval date: 11-Dec-2019 
 
 
 
 
 
Jason Konner, MD 
Medicine 
Serena Wong, MD 
Medicine 
Jacqueline Bromberg, MD, PhD 
Medicine 
Azadeh Namakydoust, MD 
Medicine 
Colette Owens, MD 
Medicine 
Loren Michel, MD 
Medicine 
Carla Hajj, MD 
Radiation Oncology 
Lior Braunstein, MD 
Radiation Oncology 
Jia Li, MD 
Medicine 
Wanqing Iris Zhi, MD, PhD 
Medicine 
Juliana Eng, MD 
Medicine 
Daniel McFarland, DO 
Medicine 
Alice Zervoudakis, MD 
Medicine 
Parisa Momtaz, MD 
Medicine 
Beryl McCormick, MD 
Radiation Oncology 
Please Note: A Consenting  Professional  must  have completed the mandatory Human Subjects 
Education and Certification Program 
 
OneMSK  Sites 
Manhattan 
Rockville Centre 
Westchester 
Basking Ridge 
Commack 
Monmouth 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-070 A(14) 
Approval date: 11-Dec-2019 
Page 4 of 25 
 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .......................................................................... 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................... 5 
3.0 
BACKGROUND AND RATIONALE ......................................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................................................ 9 
4.1 
Design ...................................................................................................................................... 9 
4.2 
Intervention ................................................................................................................................... 10 
5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................... 10 
5.2 IMRT ............................................................................................................................................... 10 
Definitive IMRT to 70Gy is standard as per MSKCC guidelines .................................................................. 10 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .................................................................................. 10 
6.1 
Subject Inclusion Criteria ........................................................................................................ 10 
6.2 
Subject Exclusion Criteria ....................................................................................................... 11 
7.0 
RECRUITMENT PLAN with limited waiver of authorization .................................................. 11 
8.0 
PRETREATMENT EVALUATION .......................................................................................... 12 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................... 12 
9.2 Chemotherapy ............................................................................................................................... 14 
9.3 Specimen Collection and Tissue Banking and Translational Research .................................. 14 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ........................................................ 15 
11.0 
TOXICITIES/SIDE EFFECTS ......................................................................................................... 17 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ............................. 18 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 18 
14.0 
BIOSTATISTICS .................................................................................................................... 18 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ... 19 
15.1 Research Participant Registration ............................................................................................. 19 
16.0 
DAT A M ANAGEMENT ISSUES ............................................................................................ 19 
16.1 
Quality Assurance .................................................................................................................. 19 
16.2 
Data and Safety Monitoring ......................................................................................................... 20 
17.0 
PROTECTION OF HUMAN SUBJECTS ................................................................................ 20 
17.1 
Privacy ................................................................................................................................... 20 
17.2 
Serious Adverse Event (SAE) Reporting .................................................................................... 20 
18.0 
INFORMED CONSENT PROCEDURES ....................................................................................... 22 
19.0 
REFERENCES .......................................................................................................................... 22 
20.0 
APPENDICES ....................................................................................................................... 25 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-070 A(14) 
Approval date: 11-Dec-2019 
Page 5 of 25 
 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a single-institution, non-randomized, phase II study. The primary endpoint is to 
determine the 2-year loco-regional progression-free interval for non-anaplastic and non- 
medullary thyroid cancer patients with unresectable disease or gross residual disease after 
surgical resection treated with definitive IMRT. Eligible patients will be enrolled and will 
receive standard definitive IMRT to 70Gy in once-daily fractions with concurrent weekly 
doxorubicin (10 mg/m2). This is a standard of care protocol to capture acute and late 
toxicities prospectively. 
All patients will undergo baseline history and physical exam, laboratory studies and biopsy as 
part of the initial assessment for protocol eligibility. Baseline imaging will include FDG 
PET/CT scan, according to our standard of care. Standard FDG PET/CT can be done prior to 
radiation simulation or can be incorporated as part of the standard FDG PET/CT radiation 
simulation. Recommended approximate weekly DW and multiparametric MRI will be  
available to both Main Campus and regional patients unless contraindicated. Research 
multiparametric MR scans for both Main Campus and regional patients will be performed on 
the same designated Philips 3T scanner located in the Main Hospital in the Department of 
Radiation Oncology according to the standard IVIM departmental protocol. MSKCC Physics 
and Radiation Oncology team utilize modern fusion soft wares that allows for the fusion of 
anatomy with or without the use of immobilization devices during research MRI scans. As 
fusion soft wares help ensure patients’ are in the same position, patients are allow to  
undergo optional research MRI's without utilizing immobilization devices. DWI-MR images  
will also be acquired according to the standard IVIM departmental protocol when available. 
Patients will be seen weekly during radiation as per standard procedure at MSKCC. 
 
Three months (+/- 4 weeks) after completion of radiation, radiologic response assessment 
will be performed as per our standard guideline. This will include a diagnostic FDG PET/CT 
scan. Cross-sectional imaging of the primary tumor (with CT scan and/or MRI) will be 
recommended as well. Imaging will be repeated at 6 months (+/- 4 weeks), and then every 
six months (+/- 6 weeks) until 2 years post-RT. Clinic visits will take place approximately 
every 3 months for 2 years, approximately every 6 months for the next 3 years, and 
approximately annually thereafter. The DW and multiparametric MRI will be recommended 
for 3 months, 6 months, and then every 6 months (all +/- 4 weeks) until 2 years post-RT for 
noncontraindicated  patients. 
 
27 patients will be enrolled in approximately two years. 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objective: To determine the two-year rates of local-regional progression-free 
interval 
 
Secondary Objectives: 
 
2.2.1 
To determine the overall survival rates 
 
2.2.2 
To evaluate the rates of acute toxicities (CTCAE, v. 4) during treatment 
 
2.2.3 
To evaluate the rates of late dysphagia, dry mouth, and other toxicities (CTCAE, v. 4) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-070 A(14) 
Approval date: 11-Dec-2019 
Page 6 of 25 
 
 
 
 
2.2.4 
To assess objective measures of late dysphagia using standard Modified Barium 
Swallow-Imp and Penetration-Aspiration scale (pre-treatment, 6 months, 12, months, 
18 months, and 24 months post-treatment. 
 
2.2.5 
To evaluate BRAF and other exploratory mutations at baseline and correlate with 
treatment outcome. 
2.2.6 
To assess changes in tumor heterogeneity over the course of external beam RT 
using serial multiparametric MR scans 
 
2.2.7 
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 
 
3.0 
BACKGROUND AND RATIONALE 
 
Thyroid cancers have an incidence of about 18,000 per year in the US, the majority of which 
are  differentiated (follicular or papillary) cancers.[1] While there has been an increase in 
incidence of these cancers, there has also been a decrease in mortality.[1]  Ten-year survival 
for papillary cancer is 95% and 85% in follicular cancer.[2] However, with continued follow- 
up one-third of all patients recur of which two-thirds of these recur locally.[3] 
 
The standard approaches to the treatment of differentiated thyroid cancer include surgical 
resection, radioactive iodine treatment (RAI), and thyroid-stimulating hormone suppression. 
Efforts to improve on surgical outcome have focused mainly on radioiodine treatment where 
RAI can destroy occult cancer, increase sensitivity of I131  scanning by eliminating uptake by 
normal residual tissue, and improve the value of serum thyroglobulin as a tumor marker 
during follow-up.[3]  As a result, RAI has led to improvement in local control,[3-6] distant 
metastasis rate,[7, 8] and overall survival.[8-10]  Consequently, for high-risk patients, 
radioiodine is routinely incorporated into initial treatment strategies universally.  However, 
there is a group of patients where their tumors are refractory to RAI but can potentially 
benefit from external beam radiotherapy (EBRT), [10a] 
 
The role of external beam radiotherapy (EBRT), however, remains controversial.  In the 
absence of prospective trials, the current indications for EBRT have largely been determined 
from retrospective data.  A randomized trial that opened in Europe failed to accrue because 
of the reluctance of multiple centers to adopt EBRT.[11]  Multiple single institution 
experiences have shown EBRT to improve local control in select patients, in particular, those 
with unresectable and/or gross residual disease after surgical resection.[6, 12-23]  Studies 
have supported the use of EBRT in populations  that included unresectable and gross 
residual disease after surgical resection as well as those tumors that are refractory to RAI 
therapy.[6, 10a, 16-24] Chow et al.[12] demonstrated a significant improvement in 2-year 
loco-regional control (risk reduction of 0.36) in patients with either nonpalpable or palpable 
gross residual disease with the addition of EBRT. 
 
Loco-regional control is an important endpoint when examining outcomes after EBRT for 
thyroid cancer.  Progression of loco-regional recurrent disease despite the presence of 
metastatic disease can significantly affect morbidity and quality of life because of the 
proximity of critical organs, including the esophagus, larynx, and spinal cord.  By adding 
EBRT to improve loco-regional control despite the presence of metastatic disease, there is 
the potential to avoid the morbidity associated with uncontrolled loco-regional cancer such as 
obstruction of the esophagus and/or trachea, need for a laryngectomy, neurovascular 
compromise, pain, hemorrhage and avoiding repeated surgical procedures. Therefore, EBRT 
is frequently recommended for patients with and without metastatic disease when 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-070 A(14) 
Approval date: 11-Dec-2019 
Page 7 of 25 
 
 
 
 
 
locoregional recurrent disease is unresponsive to RAI.  Furthermore, there is no role for 
salvage RAI as these tumors are already refractory to RAI therapy.  Systemic therapy is not 
the first line for this RAI refractory, unresectable non-anaplastic thyroid cancer as controlling 
the disease loco-regionally takes precedence.  Our thyroid disease management team 
consisting of head and neck surgery, medical oncology, and endocrine service routinely 
discuss all patients undergoing EBRT in a multidisciplinary meeting prior to the initiation of 
radiotherapy. 
 
 
A retrospective review of 66 patients with gross residual or unresectable non-anaplastic non- 
medullary thyroid cancer that underwent EBRT with or without low dose concurrent 
chemotherapy at Memorial Sloan-Kettering Cancer Center showed that the 3-year 
locoregional progression-free survival rate was 77.3%, with a 3-year overall survival rate of 
54.4%. [51]. The median radiation dose was 6630 cGy (Interquartile  range 6000-7000cGy). 
Concurrent low dose radiation sensitizing chemotherapy was administered to 21 of the 66 
patients (31.8%) with a non-significant increase in the 3-year locoregional progression-free 
survival rate (90.0% versus 73.0%). Despite this improvement in local control, there was no 
difference in the median overall survival (43.1 versus 37.1 months) likely secondary to the 
fact that patients treated with concurrent chemotherapy had larger volume of disease and a 
greater incidence of poorly differentiated histology both of which are known negative 
prognostic factors. These promising results were in a heterogeneous cohort of patients with 
multiple poor prognostic risk factors, majority of whom had RAI refractory disease.  This is 
the only published series focused on patients with gross residual or unresectable disease. 
Grade 3 acute mucositis and dysphagia occurred in 11 (16.7 %) and 13 (19.7 %) patients, 
respectively. The addition of concurrent chemotherapy only resulted in a 10% increase in 
acute grade 3 hoarseness (10% versus 0%), with no differences in acute or late toxicities for 
dermatitis, dysphagia, mucositis, nausea, vomiting, fatigue, or need for a reactive feeding 
tube. Late adverse toxicity was notable for percutaneous endoscopic gastrostomy tube use 
in 4 patients (6.1 %), though 2 of these patients had the percutaneous endoscopic 
gastrostomy tube placed prior to EBRT. There was no difference in the late toxicities 
between EBRT and CCRT patients including hoarseness and need for a feeding tube. 
Although patients with metastatic disease fared worse than patients with localized thyroid 
cancer, loco-regional control was still achieved in a significant number of patients (61.4% 
versus 88.4%). Thus, EBRT should be considered, even for patients with metastatic disease, 
because progression in the thyroid bed or neck can cause significant morbidity.  Thus our 
update of the MSKCC experience demonstrated that in patients with unresectable disease or 
gross residual disease, the 3 year locoregional progression-free interval was 73.0% in 
patients treated with EBRT alone and 90.0% in patients who underwent concurrent low dose 
radiation sensitizing chemotherapy with only a slight increase in hoarseness that was self 
resolving. 
The American Thyroid Association Task Force recommends EBRT for gross residual disease 
not amenable to surgery or RAI treatment.[25]  However, in all patients, the potential benefit 
of EBRT should be weighed against the acute and long-term risks.  Non-randomized studies 
have identified a potential role for adjuvant treatment of high-risk patients with external beam 
radiation therapy,[20, 26] documenting improved local control,[18, 21, 23, 27-30] with no 
survival benefit.[30]  The inclusion criteria for receiving external beam radiation therapy have 
included advanced age (>40 years), extrathyroidal extension, high EORTC score or other 
scoring system for prognostic variables.  Local recurrence has purportedly declined from 20- 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-070 A(14) 
Approval date: 11-Dec-2019 
Page 8 of 25 
 
 
 
 
 
25% to 4-7% with the addition of external beam radiation therapy in these studies.  This 
translates to a 65-85% decrease in local recurrence.  Of note, these are patients who present 
with gross residual disease where a second surgery is unlikely. 
 
Given that the data to date are largely retrospective and hypothesis generating, that these 
retrospective studies reported a heterogenous group of non-anaplastic thyroid cancer 
patients who underwent EBRT, i.e., both resectable with positive margin to an unresectable 
cohort, a prospective study is needed to settle the controversies associated with the role of 
 
 
EBRT in thyroid cancer management.  Furthermore, we would like to gather both the acute 
and late complications associated with EBRT in a prospective manner.  In order to minimize 
heterogeneity, we chose to focus on patients who we believe benefit the most from EBRT, 
i.e., those with unresectable or gross residual disease. 
 
Although mutations such as BRAF are present in greater than 70% of all papillary thyroid 
cancers and are known to be associated with a poorer prognosis with increased risk of 
insensitivity to RAI [31-33], to our knowledge, there is no data on what effects external beam 
radiation has on tumors with these mutations. Hence, one of the goals of this protocol is to 
collect tissue in a prospective manner and perform exploratory analyses pre-radiation (at 
baseline) so that we may further understand this disease and these mutations. 
 
MRI is a non-invasive technique to assess morphological and physiological changes in tumor 
and irradiated normal structures. 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 
technique employed during CT simulation and MR scan will help in co-registering MR images 
with CT and PET scans. 
 
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. 
 
DWI 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. [Ref 28, 29]. In 
addition to molecular diffusion of water in biological tissue, microcirculation of blood (or 
“perfusion”) in the capillary network can also be captured using low ‘b’ values. DW I MRI 
using both low and high b values (also called intravoxel incohenerent motion sequence or 
IVIM)  gives a quantitative measure of true diffusion (D) and perfusion fraction (f) [ref 30] 
without the use of an intravenous contrast agent. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-070 A(14) 
Approval date: 11-Dec-2019 
Page 9 of 25 
 
 
 
 
 
 
DWI MRI technique has been successfully applied for various disease sites. Its clinical 
applications in head and neck cancer has been in differentiating malignant tumors from 
benign lesions [ref 31,32], characterizing and staging of lymph nodes in the head and neck 
region [ref 33] and monitoring tumor response [ref 34,35,36,37]. A few studies have 
investigated the salivary gland response based on changes in ADC value. [Ref 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% 
accuracy respectively [ref 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] 
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 
[ref 40] in head and neck cancer patients to predict short-term response to treatment. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a single-institution, non-randomized, phase II study. The primary endpoint is to 
determine the 2-year loco-regional progression-free interval for non-anaplastic non-medullary 
thyroid cancer patients with unresectable disease or gross residual disease after surgical 
resection treated with definitive IMRT and doxorubicin at 10mg/m2  weekly. 
 
MR Scan Protocol 
Multi parametric MR scan 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. MSKCC Physics and Radiation Oncology team utilize 
modern fusion soft wares that allows for the fusion of anatomy with or without the use of 
immobilization devices during research MRI scans. As fusion soft wares help ensure  
patients’ are in the same position, patients are allow to undergo optional research MRI's 
without utilizing immobilization devices. DWI-MR images will also be acquired according to 
the standard IVIM departmental protocol when available. At the pre-treatment scan only, an 
additional scan will be acquired based on a research sequence provided by Philips 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. 
The scan duration will be approximately 45 minutes during the first MR acquisition obtained 
at the time of CT simulation and approximately 30 minutes during the followup MRs Scans 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-070 A(14) 
Approval date: 11-Dec-2019 
Page 10 of 25 
 
 
 
 
which occur during chemoradiation. Information collected will not affect the standard of care. 
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. 
 
4.3 
Intervention 
 
All patients will undergo baseline history and physical exam and laboratory studies as part of 
initial assessment for protocol eligibility.  Baseline imaging will include a FDG PET/CT scan, 
according to our standard of care. All patients will provide written informed consent. A 
recommended DW and multiparametric MRI will also take place pre-treatment, during and 
post treatment for noncontraindicated patients. Patients will receive intensity-modulated 
radiation therapy (IMRT) in once-daily fractions (Monday through Friday, excluding holidays). 
A total dose of 70Gy is planned. Patients will be seen weekly during radiation as per 
standard procedure at MSKCC.  Patients will also receive concurrent doxorubicin at 10 
mg/m2. A recommended DW and multiparametric MRI may also take place approximately 
weekly unless contraindicated for patients. Approximately 3 months after completion of 
radiation, radiologic response assessment will be performed as per our standard guideline. 
This will include a FDG PET/CT scan, as well as a recommended cross-sectional imaging of 
the primary tumor (with CT scan and/or MRI). Clinic visits will take place approximately every 
3 months for 2 years, approximately every 6 months for the next 3 years, and approximately 
annually thereafter. The DW and multiparametric MRI will be recommended for 3 months, 6 
months, and then every 6 months (all +/- 4 weeks) until 2 years post-RT unless 
contraindicated for main campus patients only. This schedule may be altered, as clinically 
indicated. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 IMRT 
 
Definitive IMRT to 70Gy is standard as per MSKCC guidelines. IMRT is a sophisticated 
technique that uses a computer controlled multileaf collimator to shape the intensity of each 
treatment beam to optimally deliver the dose to the tumor and protect normal tissue.  The 
radiotherapy delivery systems used is standard and FDA approved. The dose fractionation 
scheme has also been used routinely at MSKCC. 
5.2 Chemotherapy 
 
Low dose radiosensitizing doxorubicin at 10 mg/m2   will be administered weekly . The 
chemotherapy delivered will be standard, FDA approved, and administered per institution’s 
guidelines. 
Doxorubicin is a commercially available medication with a complete description of the drug, 
clinical pharmacology, contraindications, warnings, precautions and adverse reactions 
available in the package insert. 


Memorial Sloan Kettering Cancer Center 
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Doxorubicin is administered intravenously, according to institutional procedures. 
5.3 Modified Barium Swallow Impairment  Profile (MBSImP) 
 
The MBSImP is a standardized tool which assesses swallowing impairment as it relates to 
oral, pharyngeal, and esophageal impairments. 
 
 
 
 
 
 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
6.2.1 
Pathologically confirmed diagnosis of non-anaplastic non-medullary thyroid 
cancer that is either grossly recurrent after surgery or unresectable with or without 
metastatic disease. 
 
6.2.2 
Age ≥18 years 
 
6.2.3 
Karnofsky performance status ≥70% 
 
 
6.2.4 
Men and women of childbearing potential must be willing to consent to using 
effective contraception while on treatment and for at least 3 months after treatment. 
 
6.2.5 
Patients must have ability to understand and the willingness to sign a written 
informed consent document. 
 
6.3 
Subject Exclusion Criteria 
 
6.3.1 
Women who are pregnant or lactating 
 
6.3.2 
Inability to comply with study and/or follow-up procedures 
 
7.0 
RECRUITMENT PLAN with limited waiver of authorization 
 
Potential research subjects will be identified  by a member of the patient‘s treatment team, the protocol 
investigator,  or research team in the Head and Neck Cancer Clinics at Memorial Sloan-Kettering 
Cancer Center (MSKCC) Main Campus and/or Network Sites. 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. 


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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. 
 
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 
maintaining information in a screening log of patients approached (if applicable). 
8.1 
PRETREATMENT EVALUATION 
 
• 
Pretreatment biopsy must confirm diagnosis of non-anaplastic non-medullary thyroid 
cancer prior to treatment. A core biopsy may be obtained from the primary tumor or 
regional lymph node metastases. If the diagnostic biopsy was performed outside of 
MSKCC, and tissue cannot be obtained, a repeat core biopsy may be required. 
 
Within 8 weeks prior to start of treatment 
• 
Electrocardiogram as per institution standard 
• 
Standard pretreatment dental evaluation and initiation of dental prophylaxis (unless 
patient is edentulous) 
• 
FDG PET/CT with calculation of metabolic tumor volume 
• 
Recommended research MRI 
 
Within 30 days prior to start of treatment: 
• 
Complete medical history including current medications, and physical examination 
including evaluation of Karnofsky Performance Status 
• 
The following laboratory studies: Complete blood count with white blood cell 
differential and platelet counts; Comprehensive Metabolic  Panel. 
• 
Baseline TSH, T3, T4, thyroglobulin 
• 
Mandatory pre-treatment evaluation in the Speech and Swallowing Center with 
Standard objective measures of pre-treatment swallow evaluation using Modified 
Barium Swallow Impairment Profile (MBSImP) and Penetration-Aspiration scale 
 
Within 14 days prior to the start of treatment 
• 
Serum pregnancy test for women of childbearing potential within 14 days prior to 
therapy. 
• 
Complete blood count with white blood cell differential and platelet counts; 
Comprehensive profile (including electrolytes, bicarbonate, blood urea nitrogen 
(BUN), creatinine, glucose, alkaline phosphatase, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), total bilirubin, total protein, albumin, and glucose); 
magnesium level; prothrombin time with INR, and activated partial thromboplastin 
time. 
 
9.1 
TREATMENT/INTERVENTION  PLAN 


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All patients will undergo radiation treatments using IMRT with concurrent low-dose 
radiosensitizing doxorubicin at 10 mg/m2 will be administered as per standard MSKCC 
guidelines. 
 
Exploratory analyses will be performed on the standard care pre-treatment biopsy. 
 
9.2 Radiation Therapy Treatment Plan 
 
9.2.1 External beam equipment and techniques 
6 MV photon beams produced will be used to deliver computer controlled multi-segmental 
therapy with multi-leaf collimators (MLCs) in dynamic mode. The number of fields will be 
determined by the treatment planning system. All fields will be treated each day. Portal 
images will be taken of each field. The accuracy of patient position and MLC aperture will be 
monitored weekly by portal images for selected fields. 
 
9.2.2 Standard treatment planning 
Treatment will be directed to the primary tumor and bilateral cervical lymph nodes, if 
applicable. The target volumes and normal tissue structures will be defined using CT (or  
MRI) and PET images. Patients will be simulated in the treatment position with individualized 
Aquaplast immobilization masks. All patients will undergo standard of care positron emission 
and computed tomography (PET/CT) simulation for treatment planning.  If a FDG PET/CT 
was already performed as part of the pretreatment workup, the investigator can fuse the FDG 
PET/CT with the CT portion of the radiation simulation as per standard of care guidelines in 
the department of radiation oncology.  Standard uptake value, metabolic tumor volume, and 
total lesion glycolysis from PET/CT scans will be reported. A CT scan with slices of 3mm 
thickness or less will be acquired through the target region. A margin of 5-10 cm superior and 
inferior to the target will be scanned with slices of 5mm thickness or less. All patients will be 
treated with standard IMRT plans.  The volumes of interest will be identified on each axial CT 
slice. GTV will consist of the gross primary tumor and involved lymph nodes. A high risk 
subclinical clinical target volume (CTV high risk) as well as a lower risk subclinical volume 
(CTV low risk) will be defined according to the risk associated with the disease site. A 
planning target volume (PTV) will also be defined to account for biologic and technical 
uncertainties. Normal structures of interest including the spinal cord, parotid glands, 
submandibular glands, oral cavity, and larynx will be outlined in 3 dimensions. 
 
The CT data will be transferred to the 3D treatment planning system. A plan using multiple 
beams will be tailored to the patient‘s anatomy and disease distribution. The method of 
inverse-planning will be utilized to determine the intensity profiles of the treatment beams. 
All dose constraints, maximum, mean, and minimum are standard as per our MSKCC 
treatment planning guidelines for patients undergoing IMRT for their thyroid cancer. 
 
9.2.3 Treatment schedule 
Treatment will be delivered as one fraction per day on a standard 5 day per week schedule 
(excluding weekends and holidays), to a total dose of 7000 cGy.  Each radiation treatment 
will last approximately 15 to 30 minutes. If the patient misses a scheduled treatment, this 
treatment will be added on the end of the treatment plan. 
 
9.2.4 Treatment delivery 
Photon beams with an energy of 6 MV will be used to deliver computer controlled multi- 
segmental therapy, and multileaf collimators in a dynamic mode will be used to produce the 
intensity modulated treatments. Electron beams may also be used if clinically indicated. 
9.2.5 PEG tube 


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PEG placement is optional, if the investigator determined that PEG tube placement is 
appropriate either prior to or during IMRT. 
 
9.2 Chemotherapy 
 
9.2.1 Radiosensitizing low dose doxorubicin at 10 mg/m2 will be administered weekly. Dose 
reduction or missed scheduled chemotherapy session will be dealt with at the treating 
physician’s discretion. 
 
Every attempt will be made to administer treatment on schedule. Doxorubicin may be given 
up to 3 days before or after the scheduled dates, if necessary for medical or personal 
reasons. 
 
Guidelines regarding dose delays and/or reductions are provided in Section 11. Reasons for 
such changes will be outlined in the medical record. 
 
9.2.2 Complete blood cell count should be obtained within 48 hours prior to each scheduled 
chemotherapy treatment date. 
 
Dose recalculation by weight is only required if the weight has change by > 10% from the 
BSA being used. 
 
Day 1 refers to the first day of IMRT. 
 
9.2.3 Day 1 : During week 1 of IMRT, patients will receive doxorubicin 10 mg/m2 
intravenously. The weekly start day of doxorubicin 10 mg/m2  will be at the discretion of the 
treating physician. Recommended anti-emetic administration will be given per MSKCC 
Guidelines but may be given as per the treating physician’s discretion. 
 
Note in clarification regarding MD clinic visits: Patients should be seen by an MD in clinic 
weekly during chemoradiation. Missed visits for reasons such as inpatient admission, 
logistical difficulties, or other medical reasons will be addressed on a case by case basis by 
the Principal Investigator and/or Treating Physician. 
 
 
9.3 Specimen Collection and Tissue Banking and Translational Research 
 
Mutational profile of the tumors: 
 
As part of the main consent patients will consent to required pre-treatment tissue analysis. 
This analysis will only be required for those patients who have sufficient tissue available. 
 
General sequence of events after tissue is obtained: Dr. Ghossein will mark the regions of 
the slides enriched for tumor cells.  Dr. Fagin’s lab will then dissect the tissue from the slide 
and send the samples to Beene Core for DNA isolation and mass spectroscopy.  Dr. Fagin’s 
lab will analyze the traces and perform confirmatory sequencing if needed to clarify 
ambiguous cases.  Tissue will be stored at Dr. Fagin’s laboratory. 
 
In detail, to evaluate the molecular profile in these patients, 6 sections of 10 microns from 
formalin-fixed paraffin embedded primary or recurrent tumor tissue will be subjected to DNA 
extraction and mutation detection as previously described [34]. Briefly, a Mass spectrometry 
Sequenom–based genotyping assay (Sequenom Mass array; Sequenom, San Diego CA) 
platform for thyroid carcinomas developed at MSKCC by Dr Fagin’s laboratory will be used 


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for mutation analysis. The latter consists of 116 assays, to interrogate mutations in 16 genes, 
including the most common thyroid oncogenes such as BRAF, NRAS, HRAS, KRAS, 
PIK3CA, and AKT1. As the mass spectrometry genotyping assays for codons 12 and 13 of 
HRAS are not informative in this platform, all the tumors that are wild type for BRAF or RAS 
mutations will be sequenced using primers designed for this regions (codon 12 and 13 of 
HRAS) [34]. All these mutation analysis will be performed at MSKCC in Dr Fagin’s laboratory 
and MSKCC core facilities. 
 
 
10.1 EVALUATION DURING TREATMENT/INTERVENTION 
 
10.1 Evaluation during IMRT 
Patients will be assessed at weekly status check as per institutional standard practice. At the 
weekly assessments patients will have a limited physical exam, KPS evaluation, and toxicity 
assessments. CBC will also be completed weekly during treatment. A recommended DW  
and multiparametric MRI should also take place approximately weekly unless contraindicated 
for patients. 
 
10.2 Follow-up after IMRT 
 
10.2.1 Clinic visits will take place approximately every 3 months for 2 years, approximately 
every 6 months for the next 3 years, and approximately annually thereafter with Radiation 
Oncology and/or Medical Oncology. This schedule may be altered, as clinically indicated. 
 
Patients who are removed from study for toxicity (but who maintain active follow-up) will be 
followed according to the same post-treatment surveillance plan as patients who complete 
study treatment. The following will be completed at these visits: physical exam, KPS 
assessment, toxicity assessment (according to NCI CTCAE v 4.0) 
 
10.2.2 Three months (+/- 4 weeks) after completion of IMRT, radiologic assessment will be 
performed. This will include a diagnostic FDG PET/CT scan, along with a recommended CT 
and/or MRI scan of the primary tumor/neck, mean and maximum standardized uptake value, 
metabolic tumor volume, and total lesion glycolysis will be recorded prospectively for all FDG 
PET/CT scans. The MRI scan may be performed in addition to the CT scan, or instead of the 
CT scan, as clinically indicated. Imaging will then be repeated at 6 months (+/- 4 weeks) 
post-RT and then every 6 months (+/- 6 weeks) until 2 years post-RT. The DW and 
multiparametric MRI will be recommended for 3 months, 6 months, and then every 6 months 
(all +/- 4 weeks) until 2 years post-RT unless contraindicated for main campus patients only. 
 
10.2.3 Patients will be advised to undergo routine surveillance dental exams approximately 4 
to 8 months after completion of definitive locoregional therapy. The dental visit dates may 
vary due to logistical considerations, but all patients will be advised to maintain dental follow 
up. Assessments of salivary flow may be performed at dental visits, but are not mandatory. 
Additional  dental evaluations may be performed, as clinically indicated. 
 
10.2.4 Mandatory post-treatment evaluation in the Speech and Swallowing Center with 
Standard objective measures of pre-treatment swallow evaluation using Modified  Barium 
Swallow Imp and Penetration-Aspiration scale. (See Appendix 1). 
Speech and Swallowing assessment should be performed at baseline, and after 
radiation at approximately 6 months, 12 months, 18 months, and 24 months post 
treatment. 


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Pre-Rx 
(w ithin 30 days 
prior to RT unless 
otherw ise 
indicated) 
Weekly 
during 
RT 
Follow up 
(Q3 mos until 2yrs, Q 
6 mos until 5yrs; 
annually thereafter) 
Confirmation of Non- 
Anaplastic  Non-Medullary 
Thyroid Cancera 
X 
Collection of tumor tissue 
for translational research if 
availablea 
X 
H & P by MD 
X 
Xb 
X 
KPS 
X 
X 
X 
CBC 
X 
X 
Comprehensive Metabolic 
Panel 
X 
TSH, Thyroglobulin, T3, T4 
X 
EKG 
Xc 
Recommended CT and/or 
MRI of the neckwith 
contrast 
Xj 
Xd 
Recommended DW and 
multiparametric MRI unless 
contraindicated for patients 
Xc 
X 
Xd 
FDG PET/CT 
Xc 
Pregnancy Test (for 
women of child bearing 
potential) 
Xe 
Speech and Swallowing 
Evaluation 
X 
Xf 
Dental Evaluation (unless 
patient is edentulous) 
Xc 
Xg 
Low dose radiosensitizing 
doxorubicin (10 mg/m2) 
X 


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IMRT 
Xh 
AE monitoringi 
X 
X 
Co-morbidities 
X 
a) Any time prior to RT start 
b) Weekly status check 
c) Within 8 weeks of RT start 
d) At 3 months (+/- 4 weeks) and 6 months (+/- 4 weeks), and then every 6 months 
(+/- 8 weeks) until 2 years 
e) Within 14 days of RT start 
f) Performed after radiation at approximately 6 months, 12 months, 18 months, and 24 months 
post-treatment. 
g) At approximately 4-8 months post-RT only 
h) Daily except for weekends and holidays 
i) AEs will be assessed according to CTCAE v 4.0 throughout the treatment course and in 
follow up. 
j) Pre-treatment MRI to be completed within 8 weeks prior to treatment start, if recommended 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
During radiation, adverse events will be graded using the NCI Common Terminology Criteria 
for Adverse Events—Version 4.0. A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP home page (http://ctep.info.nih.gov). 
 
Treatment modifications are based on CTCAE version 4.0. Once a patient has had a 
doxorubicin dose reduction for toxicity, the dose will not be re-escalated. 
 
Reproductive risks: There is a risk of birth defects associated with this study. Patients must 
use birth control while on this study. Women should not breastfeed while on this study. 
 
11.1 Radiation Therapy-Associated Adverse Events 
Reversible radioepithelitis of pharyngeal mucosa is expected and its timing with dose and 
severity will be noted and graded according to NCI CTCAE v4.0. Epilation of treated areas 
and various degrees of skin reaction are expected. Other expected acute reactions include 
hypogeusia, dysphagia, thick saliva, hoarseness, radiation dermatitis, nausea, vomiting, 
anemia, fatigue, and weight loss. 
 
Late toxicities are those that occur at least 3 to 4 months post radiation. Late effects may 
include permanent xerostomia, hypogeusia, dysphagia, ototoxicity, nasal dryness, serous 
otitis media, dental decay, hypothyroidism, dysphagia, and trismus. Osteoradionecrosis may 
occur in 5% or less of patients, but can be reduced by dental evaluation before radiation. 
 
11.2 Chemoradiation Therapy-Associated  Adverse Events 
The following may be experienced with doxorubicin:  myelosuppression, decreased albumin, 
decreased calcium, abnormal liver function tests, kidney problems, digestive, or pancreas 
problems, high blood sugar, nausea, vomiting, loss of appetite, heartburn, hair loss, fatigue, 
skin rash, diarrhea, belly pain, weight loss. In rare instances, heart damage manifested as 
congestive heart failure may occur. 


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Previous data have noted that the additional of concurrent chemotherapy only resulted in a 
10% increase in acute grade 3 hoarseness, but with no difference in late toxicity with a 
 
median follow up of 35 months. There were no differences in acute or late toxicities for 
dermatitis, dysphagia, mucositis, nausea, vomiting, fatigue, or need for a feeding tube. 
Chemotherapy will be held for ANC < 1, platelets < 75,000. Dose adjustments for intolerable 
Grade 2 or Grade 3-4 toxicities associated with the chemotherapy will be up to the treating 
physician. 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
The primary endpoint of this study is to assess the 2-year loco-regional progression-free 
interval using standard post-radiation imaging studies. Scans will be performed at 3 months 
(+/- 4 weeks) and 6 months (+/- 4 weeks) post-RT and then every 6 months (+/- 6 weeks) 
until 2 years post-RT. Patients will be followed for life with standard screening for disease 
recurrence, according to the schedule in Sections 9 and 10.Patients will be classified as loco- 
regional progression free as long as there is no evidence of loco-regional progression of 
disease. Loco-regional failure will be defined as infield progression if included in the RT field 
and meets one of the following criteria: 25% increase in tumor volume, new lesions, and/or 
25% increase in metabolic tumor volume or total lesion glycolysis. 
 
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. Patients who develop distant metastases will not be removed 
from protocol therapy. 
 
If at any time the patient develops unacceptable toxicity he/she will be removed from study 
and considered a treatment failure. 
 
If the patient is unable to receive doxorubicin due to doxorubicin -related toxicities, he/she 
may remain on study to continue IMRT. 
 
Patients may be removed from the study for protocol non-compliance. 
 
Patients who exhibit continual non-compliance with the follow-up schedule may be removed 
from the protocol at the discretion of the Principal Investigator. 
 
All patients enrolled on the study will be included in an intent-to-treat analysis. 
 
14.0 BIOSTATISTICS 
 
The primary objective of this study is to determine the 2-year loco-regional progression-free 
rate. Current literature showed that the 2-year loco-regional progression-free rate is about 
40% [16-24]. We expect to improve this rate substantially to 90% by applying the proposed 
chemoradiation treatment strategy. It should be mentioned that according to previous 
versions of the protocol 8 patients had been treated with IMRT alone. But prospectively we 
will treat patients with the current standard which is chemoradiation. To this end we will still 
employ a single-stage binomial design. We will recruit 19 patients, and we will claim the 
proposed treatment promising when at least 14 patients are without progression of disease 
at 2 years from the end of the treatment. This decision rule gives a power (that is, probability 
of declaring success when the true 2-year progression rate is 90% or higher) of 0.99 with the 


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type 1 error rate (that is, probability of declaring success when the true 2-year progression 
rate is 40% or lower) less than 0.01. Patients who died due to any reason, or were lost to F/U 
within 2 years will be regarded as having loco-regional progression. Patients who do not 
complete treatment due to excessive toxicity will be excluded from the primary endpoint 
analysis and replaced by new eligible patients. We expect to accrue the total of 19  
analyzable patients in 2 years. The 8 patients who had received IMRT alone will not be 
counted towards this endpoint and will be summarized separately. 
 
To better understand the loco-regional progression we will also use the cumulative incidence 
function for summaring the endpoint of time to loco-regional failure, which will be carried out 
by a competing risks anlaysis. Overall survival rates will be assessed by Kaplan-Meier 
method. Rates of (acute or late) toxicities will be computed by sample proportions and 
confidence intervals will also be provided. Summary statistics and/or longitudinal plots for the 
Modified  Barium Swallow-Imp and Penetration-Aspiration scales will be supplied for 
assessing objective measures of late dysphagia. BRAF and other mutation measurements at 
baseline will be correlated with clinical outcomes such as overall survival and local-regional 
control using survival analysis tools. All secondary endpoints will be analyzed for the 19 
patients under chemoradiation. The 8 patients who had received IMRT alone will be 
summarized separately. 
 
Multiparametric and DW scans will also be obtained. 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. 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
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 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). 
 
16.1 
DATA MANAGEMENT ISSUES 
 
A Clinical Research Associate (CRA) and Clinical Research Coordinator (CRC) will be 
assigned to the study. The responsibilities of the CRA and CRC 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. 
 
 
16.2 
Quality Assurance 


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Weekly registration reports will be generated to monitor patient accruals and completeness  
of registration data. Routine data quality reports will be generated to assess missing data  
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. Random-sample data quality and 
protocol compliance audits will be conducted by the study team, at a minimum of two times 
per year, more frequently if indicated. 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled ―Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials‖ which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and 
Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm 
 
 
There are several different mechanisms by which clinical trials are monitored for data, 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. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be established at 
the time of protocol activation. 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Inclusion  of Children in Research: This protocol/project  does not include children 
because the number of children is limited and because the majority are already  accessed 
by a nationwide  pediatric  cancer research network.  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. 
17.2 
Privacy 
 
MSKCC’s Privacy Office may allow 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 individuals 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 (IRB/PB). 
17.3 
Serious Adverse Event (SAE) Reporting 


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An adverse event is considered serious if it results in ANY of the following outcomes: 
 
• Death 
• A life-threatening adverse event 
• An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
• Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention.  SAE reporting is required for 30-days after the participant’s last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per 
IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted 
within 5 calendar days of the event.  All other SAEs must be submitted within 30 calendar 
days of the event. 
 
The report should contain the following information: 
 
• The date the adverse event occurred 
• The adverse event 
• The grade of the event 
• Relationship of the adverse event to the treatment(s) 
• If the AE was expected 
• Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
 
• If an amendment will need to be made to the protocol and/or consent form 
• If the SAE is an Unanticipated Problem 
 
 
 
17.4 
Financial  Costs/Burdens 
 
Pathology DNA studies will not be charged to the patient or insurance. The patient will be 
responsible for all other costs related to treatment and complications of treatment. Costs to 


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the patient (third party insurer) will include the cost of radiation therapy, chemotherapy, 
hospitalizations, routine blood tests and diagnostic studies, office visits, baseline EKG, and 
doctor‘s fees. 
18.1 
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. 
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 
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20.0 
APPENDICES 
 
20.1 Modified Barium Swallow Impairment Profile and Penetration-Aspiration  scale