Clinical trial NCT03274414
Conditions: Paranasal Sinus Cancer Nasal Cavity Tumor Nasal Cavity Adenocarcinoma
Keywords: squamous cell carcinoma esthesioneuroblastoma adenoid cystic carcinoma adenocarcinoma cisplatin 17-442
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2017-09-01; Completion date: 2023-01-13
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is being done to test a new treatment plan for large tumors in the sinus or nasal cavity that will include endoscopic surgery plus chemotherapy and proton-beam radiation therapy.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Cisplatin intervention 2: Adjuvant Proton Radiotherapy intervention 3: Endoscopic Resection intervention 4: cisplatin and etoposide
Intervention descriptions: intervention 1: Cisplatin should be administered on day 1 (+/- 3 days) of the start of radiotherapy and then every 3 weeks (unless there is a delay for safety concerns such as neutropenia) for a total of 3 cycles. 100 mg/m\^2 (dose reductions after the first cycle allowed for toxicity) intervention 2: Proton therapy treatment will follow the National Cancer Institute's "Guidelines for the Use of Proton Radiation Therapy in NCI-Sponsored Cooperative Group Trials". Proton therapy techniques may include passively scattered or scanning or pencil beam technology. intervention 3: In brief, an endoscope is used and two surgeons perform the intervention in a binostril manner. Tumor is generally resected with an emphasis on identification of the attachments in the paranasal sinuses, nasal cavity, or skull base. intervention 4: If the final surgical pathology report shows SNUC, at the discretion of the treating medical oncologist, the patient will receive an addition of etoposide chemotherapy to cisplatin chemotherapy. The dose of cisplatin will be decresed from 100 mg/m2 to 60 mg/m2. Cisplatin should be administered on days 1-2, 21-22 and 42-43 at a dose of 60 mg/m2 and Etoposide should be administered at days 1-3, 21-23, and 42-44 at a dose of 120 mg/m2.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 17-442 A(7) 
Approval date: 19-May-2020 
Page 1 of 37 
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A Phase II, Single-Arm Trial Assessing Local Control of Near Total Endoscopic 
Resection Followed by Concurrent Chemotherapy and Proton Radiation in the 
Treatment of Unresectable Sinonasal Tumors 
 
PROTOCOL FACE PAGE FOR 
MSK THERAPEUTIC/DIAGNOSTIC  PROTOCOL 
 
 
Principal Investigator/Department: 
Marc A. Cohen, MD 
Surgery/Head and Neck 
Co-Principal 
Investigator(s)/Department: 
Sean McBride, MD 
Loren Michel, MD 
Sasan Karimi, MD 
Radiation Oncology 
Medicine/Head  and Neck 
Radiology 
Investigator(s)/Department: 
Richard Wong, MD 
Jatin Shah, MD 
Jay Boyle, MD 
Bhuvanesh Singh, MD, PhD 
Snehal Patel, MD 
Ian Ganly, MD, PhD 
Luc Morris, MD 
Benjamin Roman, MD 
Jennifer Cracchiolo, MD 
Zhigang Zhang, PhD 
Nancy Lee, MD 
David Pfister, MD 
Viviane Tabar, MD 
Han Xiao, MD 
Anuja Kriplani, MD 
James Fetten, MD 
Sree Chalasani, MD 
Afsheen Iqbal MD 
Daniel Danila, MD 
Ping Gu, MD  
Louise Ligresti, MD 
Isabel Preeshagul, DO 
Rui Wang, MD PhD 
Jacqueline Bromberg, MD PhD 
Seth Cohen, MD 
Jason Konner, MD 
Serena Wong, MD 
Parisa Momtaz, MD 
Stephen Veach, MD 
Nadeem Riaz, MD 
Jillian Tsai, MD 
Borys Mychalczak, MD 
Daniel Higginson, MD 
Daphna Gelblum, MD 
Suzanne Wolden, MD 
Surgery/Head and Neck 
Surgery/Head and Neck 
Surgery/Head and Neck 
Surgery/Head and Neck 
Surgery/Head and Neck 
Surgery/Head and Neck 
Surgery/Head and Neck 
Surgery/Head and Neck 
Surgery/Head and Neck 
Epidemiology-  Biostatistics 
Radiation Oncology 
Medicine/Head  and Neck 
Surgery/Neuro 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 


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Oncology 
Oncology 
Oncology 
 
 
Oncology 
Oncology 
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Oncology 
Oncology 
Oncology 
Oncology 
Oncology 
Oncology 
Oncology 
Oncology 
Memorial Sloan Kettering Cancer 
Center IRB Number: 17-442 A(7) 
Approval date: 19-May-2020 
Christopher Barker, MD 
Oren Cahlon, MD 
Radiation 
Annemarie Shepherd, MD 
Radiation 
Ronald Ghossein, MD 
Radiation 
Snjezana Dogan, MD 
Pathology 
Atif Khan, MD 
Pathology 
Carla Hajj, MD 
Radiation 
Beryl McCromick, MD 
Radiation 
Erin Gillespie, MD 
Radiation 
Lior Braunstein, MD 
Radiation 
Melissa Zinovoy, MD 
Radiation 
Michael Bernstein, MD 
Radiation 
David Guttman, MD 
Radiation 
Justin Mann, MD 
Radiation 
Ariel Marciscano, MD 
Radiation 
Dhwani Parikh, MD 
Radiation 
Yao Yu, MD 
Radiation 
Geri Arnell, RN 
Radiation 
Janet Cogswell, RN 
Nursing 
Jennifer Howgate-Klingaman, RN Nursing 
Lisa Sarmasti, RN 
Nursing 
Raylene Langish, RN 
Nursing 
Nicole Heinz, RN 
Nursing 
Gloria Wasilewski, RN 
Nursing 
Sherie Mar-Chaim, RN 
Nursing 
Maureen Kennedy, RN 
Nursing 
Joanne Wells, APN 
Nursing 
Carly Osborne, APN 
Nursing 
Karen Flynn, APN 
Nursing 
Christine Anderson, APN 
Nursing 
Nursing 
Consenting  Professional(s)/Department: 
Marc A. Cohen, MD 
Surgery/Head and Neck 
Richard Wong, MD 
Surgery/Head and Neck 
Jatin Shah, MD 
Surgery/Head and Neck 
Jay Boyle, MD 
Surgery/Head and Neck 
Bhuvanesh Singh, MD, PhD 
Surgery/Head and Neck 
Snehal Patel, MD 
Surgery/Head and Neck 
Ian Ganly, MD, PhD 
Surgery/Head and Neck 
Luc Morris, MD 
Surgery/Head and Neck 
Benjamin Roman, MD 
Surgery/Head and Neck 
Jennifer Cracchiolo, MD 
Surgery/Head and Neck 
Sean McBride, MD 
Radiation Oncology 
Loren Michel, MD 
Medicine 
Sasan Karimi, MD 
Radiology 
Nancy Lee, MD 
Radiation Oncology 
David Pfister, MD 
Medicine/Head  and Neck 
Viviane Tabar, MD 
Surgery/Neuro 
Han Xiao, MD 
Medicine 
Anuja Kriplani, MD 
Medicine 


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Memorial Sloan Kettering Cancer Center 
IRB Number: 17-442 A(7) 
Approval date: 19-May-2020 
 
 
 
 
 
James Fetten, MD 
Sree Chalasani, MD 
Afsheen Iqbal MD 
Daniel Danila, MD 
Ping Gu, MD  
Louise Ligresti, MD 
Isabel Preeshagul, DO 
Rui Wang, MD PhD 
Jacqueline Bromberg, MD PhD 
Seth Cohen, MD 
Jason Konner, MD 
Serena Wong, MD 
Parisa Momtaz, MD 
Stephen Veach, MD 
Nadeem Riaz, MD 
Jillian Tsai, MD 
Borys Mychalczak, MD 
Daniel Higginson, MD 
Daphna Gelblum, MD 
Suzanne Wolden, MD 
Christopher Barker, MD 
Oren Cahlon, MD 
Annemarie Shepherd, MD 
Atif Khan, MD 
Carla Hajj, MD 
Beryl McCromick, MD 
Erin Gillespie, MD 
Lior Baurnstein, MD 
Melissa Zinovoy, MD 
Michael Bernstein, MD 
David Guttman, MD 
Justin Mann, MD 
Ariel Marciscano, MD 
Dhwani Parikh, MD 
Yao Yu, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
OneMSK  Sites 
Manhattan 
All Protocol Activites 
Basking Ridge 
All Protocol Activites 
Monmouth 
All Protocol Activites 
Bergen 
All Protocol Activites 
Westchester 
All Protocol Activities 


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Memorial Sloan Kettering Cancer Center 
IRB Number: 17-442 A(7) 
Approval date: 19-May-2020 
 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-442 A(7) 
Approval date: 19-May-2020 
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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA........................................................................... 6 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS.................................................................................... 6 
3.1 
BACKGROUND AND RATIONALE ....................................................................................... 7 
3.2 
Nasal Cavity / Paranasal Sinus Tumors ............................................................................ 7 
3.2 
Characteristics of endoscopic skull base resection ............................................................... 9 
3.3 
Characteristics of Proton Therapy (PBRT) ....................................................................... 10 
3.4 
Patient Reported Outcome (PRO) ....................................................................................... 11 
3.5 
IMPACT Testing .................................................................................................................. 11 
3.6 
Summary............................................................................................................................. 12 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ...................................................................... 12 
4.1 
Design ................................................................................................................................. 12 
4.2 
Intervention ............................................................................................................................... 13 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................... 14 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .................................................................................. 15 
6.1 
Subject Inclusion Criteria ..................................................................................................... 15 
6.2 
Subject Exclusion Criteria ................................................................................................... 16 
7.0 
RECRUITMENT PLAN ........................................................................................................................ 17 
8.0 
PRETREATMENT EVALUATION .......................................................................................... 18 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................... 19 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ........................................................ 23 
11.0 
TOXICITIES/SIDE EFFECTS ......................................................................................................... 24 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ............................ 28 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ........................................................................... 29 
14.0 
BIOSTATISTICS........................................................................Error! Bookmark  not  defined. 
15.1 
Research Participant Registration ....................................................................................... 31 
15.2 
Randomization .................................................................................................................... 31 
16.0 
DAT A M ANAGEMENT ISSUES ............................................................................................ 31 
16.1 
Quality Assurance ............................................................................................................... 31 
16.2 
Data and Safety Monitoring ..................................................................................................... 32 
17.0 
PROTECTION OF HUMAN SUBJECTS ................................................................................ 32 
17.1 
Privacy ................................................................................................................................ 32 
17.2 
Serious Adverse Event (SAE) Reporting ................................................................................. 33 
17.2.1..............................................................................................Error! Bookmark  not  defined. 
18.0 
INFORMED CONSENT PROCEDURES ....................................................................................... 34 


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19.0 
REFERENCES .......................................................................................................................... 34 
20.0 
APPENDICES ....................................................................................................................... 37 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Protocol Summary 
 
This is a phase II, single-arm trial assessing local control (ie. no local failure) after near-total 
endoscopic resection (NTR) followed by concurrent chemotherapy with proton-beam radiation 
in unresectable tumors (which we define as expected inability to perform negative margin 
surgery) of the paranasal sinuses and nasal cavity.  We will compare rate of local failure at 1 
year after treatment  in those undergoing NTR and adjuvant treatment with historical rates of 
failure in those undergoing non surgical management.  As secondary and exploratory 
endpoints, we will assess other oncologic outcomes (overall survival, progression free 
survival, etc), physician reported complications of surgery and chemoradiation toxicity, and 
patient reported outcomes, and will store tissues obtained for IMPACT testing. 
We plan to have 25 eligible patients, 15 of which will be Squamous Cell Carcinoma patients 
and the rest 10 shall be Adenoid Cystic Carcinoma, Esthesioneuroblastoma, or 
Adenocarcinoma patients. 
Protocol Schema 
 
 
 
 
 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
Adjuvant proton radiation 
Preoperative assessment 
Pts with > 80% 
Yes 
N No 
o 
Near total resection of 


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Primary Objective 
 
• 
To determine if near-total resection with minimally invasive endoscopic approach for 
unresectable paranasal sinus / nasal cavity tumors followed by concurrent 
chemotherapy and proton-beam radiation improves local control at 1 year after 
treatment compared to traditional approaches of nonsurgical management alone. Our 
historical data showed that the rate of local failure at 1 year with chemotherapy and 
IMRT alone is 50%. We hypothesize that adding NTR and proton radiation with 
chemotherapy will reduce the rate of local failure at 1-year to 25%. Local failure will be 
defined using a modification of RECIST 1.1. 
Secondary Objectives 
 
• 
To assess the complications of treatment related to minimally invasive endoscopic 
skull base surgery in patients with unresectable disease using Clavien-Dindo 
classification of surgical complications 
• 
To assess toxicity of treatment based on CTCAE v4.03 scores in the acute setting 
(throughout treatment and up to the 3 month visit after end of treatment) 
• 
To assess toxicity of treatment based on CTCAE v4.03 scores in the long-term setting 
(after the 3 month post treatment visit until the 24 month post treatment visit) 
• 
To assess toxicity of treatment related to patient reported outcomes including EORTC 
(H&N43 and C30) and Skull Base Inventory (SBI) 
• 
To determine the 1- and 2-year rates of regional/nodal,  or distant-metastasis 
progression incidence, progression-free survival, disease specific mortality, and 
overall survival in our group of patients undergoing NTR / proton-beam radiation 
therapy (PBRT) and chemotherapy 
• 
To obtain tissue of these rare tumor types for IMPACT  assessement. Results of 
IMPACT  testing will be banked for future investigation 
3.1 
BACKGROUND AND RATIONALE 
 
3.2 
Nasal Cavity / Paranasal Sinus Tumors 
 
Locally advanced malignancies of the nasal cavity and paranasal sinuses that invade the skull 
base are rare with unclear management paradigms. Beginning in the 1950s, the "gold 
standard" for treatment of these malignancies, when resectable, has been a combined 
transfacial and transcranial approach followed by adjuvant radiation1. Memorial Sloan 
Kettering Cancer Center has been a global leader in the management of these patients and 
coordinated a large retrospective multi-institutional study that set the standard for rates of  
both oncologic control and treatment related morbidity for patients with resectable disease2,3. 
This work was first published in 2003. However, when tumors are deemed unresectable by  
the multidisciplinary consensus, often because of proximity to the carotid artery, brain 
parenchymal invasion, or involvement of the orbital apex, radiation (with or without 
chemotherapy) has been the primary treatment pursued. Outcomes for locally advanced 
paranasal sinus/nasal cavity tumors that receive radiation (with or without chemotherapy) are 
significantly worse than seen in patients who undergo surgery followed by radiation (+/- 
chemotherapy)4. 


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In the past 15 years, advances in the pathologic understanding of these tumors, 
chemotherapeutic treatment options, and radiation technology, has led to significant variation 
of treatment of locally advanced nasal cavity and paranasal sinus cancers. The definition of 
"resectability" has been altered and tumors that were once considered nonsurgical (such as 
those with brain invasion) are now deemed resectable in many centers. Furthermore, single 
institution studies have demonstrated the technical and oncologic feasibility of endoscopic 
resection for select early and advanced paranasal sinus and skull base tumors, obviating the 
need for craniotomy and facial incisions, leading to decreased surgery-related treatment 
morbidity in certain patients5,6. 
 
Unresectable paranasal sinus and nasal cavity tumors treated with photon radiation (3D 
conformal or IMRT) +/- chemotherapy have poor outcomes, with MSKCC data revealing 
overall survival of 15% at 5 years, with a 0% local control rate for patients who receive less 
than 65 gray to the primary site 4. In studies of salivary gland tumors, including adenoid cystic 
carcinoma, historic local control rates with radiaton +/- chemotherapy have been 0-43%7-12. 
This is in contrast to recent retrospective data that shows endoscopic or open surgery and 
proton radiation (+/- chemotherapy) in a variety of pathologies in locally advanced tumors, 
yields local control at 1 and 3 years of 92.4% and 82.7%13.  Russo et al recently published 5- 
year local control rates after resection and proton radiation to be 77% for those patients who 
have undergone gross total resection (not synonymous with negative margin surgery—gross 
total resection includes patients with negative margins and microscopically positive 
margins)14. 
 
The suboptimal outcomes related to chemoradiation therapy alone coupled with the promise 
of trimodality therapy using minimally invasive surgery have introduced the idea of 
cytoreductive surgery for advanced disease prior to chemoradiotherapy.  Although these 
cytoreductive interventions can often help with symptoms related to the tumor size, the 
oncologic validity of these approaches have yet to be determined15.  Jansen et al have 
published the only study of the utility of subtotal resection in paranasal sinus cancers and they 
found improved local control and overall survival with debulking and conventional photon 
IMRT16. In a retrospective study by Kawashima et al that did not specifically examine 
cytoreductive surgery, the authors noted that degree of residual tumor burden after skull base 
surgery correlated with patient outcomes17. 
 
In addition to improved local control, cytoreductive surgery may allow for the reduction of 
radiation doses to normal structures, such as the optic nerves, chiasm, carotid arteries, and 
temporal lobes. This could reduce the probability of late cognitive, vascular, and visual 
toxicities.  Historically, convention argued against subtotal surgical resection in these  
patients, as the only option was open surgery with craniotomy and facial incisions; such 
operations often required free flap reconstruction and led to prolonged hospital stays, with 
mortality rates of 5% at the most experienced centers, as well as an overall complication rate 
of 36%, a central nervous system complication rate of 16% (CSF leak, meningitis, 
pneumocephalus), and a wound complication rate of 20% (infection, dehiscence, flap 
necrosis)3. Prolonged recovery in these patients can also potentially lead to delays in adjuvant 
chemoradiotherapy. However, the use of minimally invasive surgical techniques have 
shortened hospital stays, as such procedures obviate the need for external incisions with free 
flap reconstruction and can decrease the risk of CSF leaks and infections. Such reductions in 


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the duration of hospitalization enable the initiation of adjuvant therapy sooner.  Data on the 
national level have demonstrated that those undergoing endoscopic excision of paranasal 
sinus tumors start postoperative radiation (+/- chemotherapy) approximately 20 days earlier 
than those undergoing open craniofacial resection18. In addition, on the national level there is 
no significant difference in the time to starting radiation after diagnosis for those undergoing 
endoscopic surgery plus radiation compared to those not receiving surgery at all18. 
 
The feasibility and oncologic efficacy of near-total resection in unresectable paranasal 
sinus/nasal cavity tumors followed by PBRT and chemotherapy have yet to be studied in any 
prospective fashion. This is in contrast to clival chordomas, which occur in the same anatomic 
region and for which near-total resection coupled with adjuvant chemoradiotherapy has been 
shown to result in better outcomes than nonsurgical or less aggressive surgical treatment 
alone19. The extent of resection of chordoma has been directly correlated to outcomes in a 
meta-analysis20. In other brain and base of skull lesions, the degree of resection as a 
continuous variable is positively associated with survival21,22. Proton beam radiation, which is 
the preferred option for the treatment of skull base and pediatric tumors at many centers, can 
potentially minimize toxicity to adjacent structures to an even greater degree than was 
possible previously. The combination of near-total endoscopic resection, because of its 
reduction in gross disease requiring the highest dose of radiation, and proton radiation, 
because of its ability to spare normal tissue, may lead to significant reductions in treatment- 
related toxicity. 
 
The prior studies including Jansen et al are retrospective assessments of outcome based on 
extent of surgical resection followed by adjuvant treatment, for patients that are presumably 
resectable. Our study is a prospective evaluation of the utility of addition of surgery in patients 
that otherwise may not have received it in order to assess the utility of endoscopic near total 
resection and proton radiation with chemotherapy.  We want to rigorously study in a 
prospective fashion the ability to improve oncologic outcomes for patients with this rare tumor 
type. 
 
3.3 
Characteristics of endoscopic skull base resection 
 
Endoscopic skull base surgery is a widely accepted modality for treatment of both benign and 
malignant lesions of the nasal cavity and the skull base. The goal, as with any oncologic 
surgery, is complete resection of the tumor with negative margins. The use of advanced 
technology has revolutionized surgical management in the paranasal sinuses. Relatively 
recently adopted use of high definition angled endoscopes enable magnified visualization 
which can assist in determining normal and abnormal anatomy. This enables the surgical 
team to ensure resection of all abnormal tissue. In addition, endoscopic resection relies on 
use of intraoperative image guidance, which similarly helps in ensuring safe resection of 
tumor surrounding critical structures. Resection can be tailored intraoperatively  in real time 
based on PET, MRI, or CT scan findings. These technologies greatly assist in optimizing the 
goal of improved local control. 
 
As noted previously, endoscopic excision also provides the potential advantages of obviating 
craniotomy or facial incisions and a more straightforward reconstruction in the presence  of 
undisturbed tissue planes. Open surgical approaches may provide better access to certain 


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areas including soft tissues of the cheek, intraorbital contents, and significant intracranial 
extension, however, an endoscopic resection approach does provide adequate access for 
many patients without an extensive  craniotomy and lateral rhinotomy (facial incision). In 
addition, the adoption of the regional vascularized nasoseptal flap provides a safe way to 
reconstruct large intranasal defects, preventing the need for free flap or other reconstruction. 
Because of the minimally invasive nature of the techniques, patients undergoing endoscopic 
skull base surgery leave the hospital significantly earlier than those undergoing open surgery 
and, consequently, the time to adjuvant treatment is decreased.  In addition, for locally 
advanced lesions, a cytoreductive surgery can potentially decrease the tumor volume prior to 
adjuvant radiation in an anatomic area where a difference of a few millimeters in the radiation 
target area can be critical. 
 
3.4 
Characteristics of Proton Beam Radiation Therapy (PBRT) 
 
Intensity modulated radiation therapy (IMRT), the most commonly used form of photon beam 
radiation therapy in the treatment of HNC, uses multiple x-ray beams to irradiate a tumor 
target, but deposits not insignificant exit dose delivered to normal tissues beyond the 
treatment target. PBRT utilizes multiple beams of directed protons to irradiate a tumor target. 
But in contrast to photons, protons deposit the bulk of their energy at the last few millimeters 
of their range without any significant exit dose23.  Both radiotherapy modalities aim to 
maximize the dose of radiation to the tumor while sparing surrounding normal tissues like the 
oral cavity, salivary glands, larynx, muscles of the head and neck, spinal cord, and brainstem. 
However, given the physical characteristics of protons (i.e. minimal exit dose), PBRT may 
deliver radiation with less accompanying morbidity from damage to surrounding non- 
malignant tissue when compared with IMRT (Figure 1) 24-27. This is especially critical in the 
skull base where damage to adjacent structures such as the brainstem, optic nerves, orbit, 
brain parenychema can have catastrophic consequences.  Indeed, the need to limit dose to 
normal structures often results in some degree of underdosing to paranasal sinus and nasal 
cavity tumors.  Because PBRT dramatically reduces the dose of radiation to normal 
structures, it may allow for a larger proportion of tumor to receive therapeutic radiation doses. 
Indeed, a recently published retrospective study presented evidence that such a benefit leads 
to improved local control compared to photon radiotherapy.28 
 
However, despite these potential advantages to PBRT, it is uncertain as to whether the 
reduction in low and intermediate dose exposure to CNS tissue and consequent ability to 
provide tumoricidal doses to tumor results in a clinically meaningful decrease in toxicities and 
increase in local control. In addition, PBRT has greater intrinsic uncertainties than standard of 
care IMRT, such as the exact range of protons in tissue. Although these uncertainties have 
been mitigated in clinical practice for decades, there remain some unanswered questions, 
and prospective studies are needed to better characterize the impact of radiation dose 
alterations on clinical outcomes. PBRT could result in increased skin toxicity compared to 


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photon-based therapy. 
 
 
 
3.5 
Patient Reported Outcome (PRO) 
 
A patient reported outcome (PRO) is a measurement of a patient’s health status that is 
obtained directly from the patient without interpretation of the patient’s responses by a 
clinician or research associate. The Health and Medicine Division (formerly the Institute of 
Medicine) of the National Academies of Medicine and the Food and Drug Administration 
(FDA) have called for measuring PROs as primary or secondary endpoints of clinical  
trials29,30. Studies have shown that PROs can be more reflective of the patient experience and 
provide more complementary toxicity and symptom data than clinical or Common 
Terminology Criteria of Adverse Events (CTCAE) assessments alone31,32. In this trial, the 
secondary endpoints will be based on clinician-reported CTCAEs as well as patient reported 
outcomes. 
 
Radiotherapy to the head and neck and, more specifically, to the skull base, is associated 
with marked acute and late adverse effects. Acute effects include paranasal sinus crusting 
and bleeding, mucositis, dysphagia, fatigue, dysgeusia, loss of voice, nausea, and fatigue. 
Late effects include xerostomia, dysphagia, trismus, permanent skin changes, neck fibrosis, 
and secondary malignancies. Careful assessment of treatment related morbidity is important, 
as patients who experience significant acute side effects of HNC radiation therapy are 
reported to have a decreased quality of life33-38. Significant deterioration is associated with 
those who report having trismus, xerostomia, dysgeusia, and dental problems. PBRT can 
deliver radiation with reduced dose to nearby normal tissues (e.g., oral cavity, major salivary 
glands, larynx, cochlea, spinal cord, brainstem, and brain), and potentially improve PRO. 
However, research on PRO after proton therapy is scarce. 
 
3.5 IMPACT Testing 
 
IMPACT testing will be done on all patients under IRB protocol #12-245.  All patients will be 
consented to 12-245 and will have a piece of their specimen along with corresponding bloods 
taken perioperatively.   All biospecimen collection and handling will follow the standard 


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procedure for 12-245 patients.  This testing is important for this study, because of the 
extremely rare nature of the disease. As there are a small number of rare pathologies 
assessed in this study, specific questions for IMPACT assessment are challenging a priori.  In 
the future, we will likely couple our IMPACT results with corresponding pathologic specimens. 
3.6 
Summary 
 
The treatment of locally advanced paranasal sinus and skull base tumors is challenging. 
Patients deemed to have unresectable disease have significantly worse outcomes with these 
large-volume tumors, which are typically treated with chemotherapy and radiation; the 
associated toxicities can be significant. Endoscopic near-total resection, when compared with 
open surgery, offers the possibility of tumor debulking with minimal morbidity and shorter 
recovery.  We hypothesize that multimodality treatment involving endoscopic near-total 
resection and adjuvant proton radiotherapy will both minimize toxicity and, most importantly, 
improve local control. A treatment paradigm involving the potential dosimetric advantages of 
postoperative proton treatment as well as minimal morbidity for endoscopic resection has the 
potential to change the treatment approach for patients with these lesions. 
The primary endpoint of this study is to assess the local control for patients with unresectable 
disease, with secondary endpoints of distant metastasis development, disease free survival, 
overall survival, morbidity of treatment, and patient reported outcomes.  Our study may also 
help to standardize treatment algorithms which, at this time, are widely divergent for patients 
with unresectable disease.  If patients in this study demonstrate favorable outcomes, future 
studies could address the feasibility of cytoreductive surgical techniques with adjuvant 
chemotherapy and proton-beam radiation to improve outcomes in patients with “resectable” 
disease. 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a single center, phase II, single-arm trial assessing the efficacy of local control of near- 
total endoscopic resection followed by proton-beam radiation with concurrent chemotherapy  
in unresectable paranasal sinus/nasal cavity tumors. The primary endpoint is local control at 1 
year from the end of treatment with failure defined as progression of disease by > 20% of the 
12 month post treatment MRI  (per RECIST) compared to the post- surgical MRI. If a patient 
dies during treatment, he/she will be counted as a failure. We will secondarily assess 
regional/nodal failure and distant metastases, overall survival, disease specific mortality, and 
progression free survival. Treatment toxicity will be assessed by the Clavien-Dindo 
Classification of Surgical Complications and CTCAE v4.03 as well as PRO measures 
including EORTC HN and SBI39. IMPACT  testing will be performed for all patients undergoing 
treatment for this rare disease. Results of IMPACT testing will be banked for future 
investigation. We will include patients with a variety of histologic diagnoses including 
squamous cell carcinoma (SCC), esthesioneuroblastoma, adenoid cystic carcinoma, and 
adenocarcinoma.. Patients will be included if there is multidisciplinary consensus that the 
primary lesion is not resectable with negative margin surgery without significant morbidity. 
This could include lesions that (1) involve the carotid artery, (2) invade brain parenchyma, (3) 
involve the orbital apex, (4) invade the pterygoid musculature, (5) involve the cavernous 


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sinus, (6) involve the clivus, and/or (7) involve intraconal space. Patients will only be included 
if there is multidisciplinary consensus that at least 80% of the tumor bulk can be removed 
without significant risk of morbidity. There is no cut-off for residual disease. Although  
expected that we will resect >80% of patient’s tumor as discussed pre-operatively, if less than 
this is resected, patient will still proceed with protocol. Patients will be stratified by the 
pathologic diagnosis. 
As this study is going to include patients for which we will be unable to obtain negative 
margins (resections will take place for patients where we can anticipate removal of >80% but 
less than the entirety of the tumor). Our prospective study will be evaluating patients who we 
cannot obtain a negative margin. The inclusion criteria for our study exclude patients with 
resectable disease. R1 resections will be unlikely due to patient selection but will still be 
included if they met the initial inclusion criteria. 
4.3 
Intervention 
 
Patients in this single-arm study will undergo near-total endoscopic resection of skull base 
tumors (≥ 80%) followed by concurrent cisplatin-based chemotherapy with proton-beam 
radiation. 
4.3.1 
Descriptions of PRO Instruments 
 
The PRO instruments and outcomes chosen for the proposed trials are well justified, 
hypothesis-driven, validated, reliable and meaningful to patients. Each instrument is 
described below. We estimate that patient response burden to complete these instruments 
will be approximately 35 minutes. The PRO instruments will be administered to patients 
preoperatively, at timepoints during the radiation and chemotherapy treatment period, and at 
post-treatment follow-up visits. 
 
4.3.2 Standard of care PRO instruments currently implemented 
 
Current standard of care PRO instruments will be used to prospectively collect data from all 
head and neck surgery and radiation therapy patients on this trial. We will use the EORTC HN 
measure and SBI measure. 
 
4.3.3 Study Specific PRO Instruments 
 
4.3.3.1 EORTC QLQ H&N 43 and C30 
 
The European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Head and Neck Module 43 (Appendix 1) is a validated 43-item site-specific 
assessment tool40.The module uses 12 multi-item scales to measure problems with 
swallowing, salivating,senses, speech, social eating, pain, anxiety, body image, teeth, skin, 
shoulder and physical contact . In addition, 7 single-item scales are utilized in assessing 
problems with mouth opening, coughing, , neurology, weight loss,lymphedema and/or a 
wound,and, finally, social contact. All questions are based on a 4-point scale ranging from 
“not at all” to “very much.” 
 
The scoring procedure for the QLQ-H&N43 transforms all of the scale and single-item scores 
to range from 0 to 100.  All QLQ-H&N43 scores are symptom scores, with higher scores 


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representing higher levels of symptomatology/problems.  Internal consistency reliability for the 
multi-item scales was generally acceptable (Cronbach’s alpha ≥ 0.70) in the validation. 
The EORTC QLQ H&N 43 module was designed to be used together with the core 
questionnaire QLQ C30 (Appendix 2), which is an assessment of general well being. 
The EORTC QLQ-C30 (Appendix 2) is a 30-item questionnaire designed to assess the quality 
of life of cancer patients41.  The 30 items of the QLQ-C30 yield both multi-item scale scores 
and single-item scores, for a total of 15 distinct scores.  These include one Global Health 
Status/QoL scale (2 items), five functional scales (Physical Functioning, 5 items; Role 
Functioning, 2 items; Emotional Functioning, 4 items; Cognitive Functioning, 2 items; and 
Social Functioning, 2 items), three symptom scales (Fatigue, 3 items; Nausea and Vomiting, 2 
items; and Pain, 2 items), and six single item symptom scores (Dyspnea, Insomnia, Appetite 
Loss, Constipation, Diarrhea, and Financial Difficulties; all from single items).  The 
questionnaire asks patients to indicate the extent to which they have experienced each of the 
problems “during the past week” on a 4-point Likert-type scale from “Not at all” to “Very 
much”. The 2 exceptions are the 2 items of the Global Health Status/QoL scale, which 
patients are asked to rate on a 7-point scale from “Very poor” to “Excellent”. 
The scoring procedure for the QLQ-C3042 transforms all of the scale and single-item scores to 
range from 0 to 100.  High scores for the Global Health Status/QoL scale represents high  
QoL, high scores for the functional scales represent high/healthy levels of functioning,  but 
high scores for the symptom scales/items represent high levels of symptomatology/problems. 
The instrument has been extensively validated and is widely used in clinical trials.  The multi- 
item scales generally have good internal consistency reliability coefficients. 
 
4.3.3.2 Skull Base Inventory 
 
Skull Base Inventory (Appendix 3) is a 41-item site-specific assessment tool designed to 
assess quality of life in patients with anterior skull base pathology43. The SBI covers 11 
disease-specific domains, including emotional, social, physical, cognitive, family, financial, 
spiritual, endocrine, nasal, neurologic, and visual.  The 41 items are based on a 7-point scale 
ranging from” severe problem” to “no problem”. Each domain is scored out of 100 with lower 
scores associated with poorer quality of life. Items within each domain for which a response 
was recorded were summed and averaged out of 100. A composite score assuming 
equivalent weighting of domains in overall quality of life was created by averaging domain 
scores. Recently, the SBI has been validated and shown to be reliable in assessing disease- 
specific quality of life for patients undergoing both endoscopic and open skull base surgery44. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 Endoscopic Resection 
 
As described previously, endoscopic resection follows the principles of open surgery, with 
emphasis on oncologic considerations. In brief, an endoscope is used and two surgeons 
perform the intervention in a binostril manner. Tumor is generally resected with an emphasis 
on identification of the attachments in the paranasal sinuses, nasal cavity, or skull base. In the 
region of attachment, negative margins are obtained by removing a tissue layer beyond the 
area where the tumor is present. If the tumor has invaded the skull base, the skull base is 
removed and, if necessary, dura is also removed. If the tumor has invaded the orbital wall, 
then the affected bone is removed and, if necessary, periorbital tissue is removed. Margins  
are obtained and mapping can be performed to assist in focusing the adjuvant radiation 
treatment. In cases in which one layer of tissue beyond the tumor is not resectable (e.g., if the 
extratumoral layer is the carotid artery, orbital apex, or other unresectable tissue), tumor is 


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removed only to that layer, if feasible. Use of recently integrated technology, mainly high 
definition straight and angled endoscopes, as well as intraoperative image guidance 
(CT/MRI/PET), have made this surgical technique significantly safer. 
 
5.2 Adjuvant Proton Radiotherapy 
 
Proton therapy treatment will follow the National Cancer Institute’s “Guidelines for the Use of 
Proton Radiation Therapy in NCI-Sponsored Cooperative Group Trials” 
(https://rrp.cancer.gov/content/docs/proton.doc). Proton therapy techniques may include 
passively scattered or scanning or pencil beam technology. 
 
5.3 Cisplatin Chemotherapy 
 
Cisplatin should be administered on day 1 (+/- 3 days) of the start of radiotherapy and then 
every 3 weeks (unless there is a delay for safety concerns such as neutropenia) for a total of 
3 cycles. Treatment can be given over 1 day or split over 2 days.  The chemotherapy will be 
administered per MSKCC guidelines at 100 mg/m2 (dose reductions after the first cycle 
allowed for toxicity). Normal scheduled treatment can be +/- 72 hours from three weeks post 
the prior administration.  Administration entails fluid and anti-emetics as per institution 
standard. Cisplatin should be infused over one hour. Cisplatin can be administered before or 
after radiation is given  but is only started once the radiation program has been initiated. If 
cisplatin treatment in contraindicated after the first cycle of treatment due to toxicity (e.g., 
kidney failure), a change in chemotherapy is allowed after a discussion with the medical 
oncology co-PI. 
5.4 Cisplatin with etoposide chemotherapy 
 
If the final pathology shows SNUC, at the discretion of the treating medical oncologist, the 
patient will receive cisplatin on day 1(+/- 3 days) of the start of radiotherapy and then every 3 
weeks (unless there is a delay for safety concerns) for a total of three cycles. In addition to 
cisplatin at 60 mg/m2 on day 1, the patient will receive etoposide chemotherapy at a dose of 
120 mg/m2 on days 1-3. Normal scheduled treatment can be +/- 72 hours from three weeks 
post the prior administration.  The chemotherapy will be administered per MSKCC guidelines 
(dose reductions after the first cycle allowed for toxicity). Administration entails fluid and anti- 
emetics as per institution standard. Cisplatin can be administered before or after radiation is 
given  but is only started once the radiation program has been initiated. If cisplatin treatment 
in contraindicated after the first cycle of treatment due to toxicity (e.g., kidney failure), a 
change in chemotherapy is allowed after a discussion with the medical oncology co-PI. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
• 
Age greater than or equal to 18 years. 
• 
Histopathologically confirmed diagnosis of one the following cancer types: 
o Squamous cell carcinoma 
o Esthesioneuroblastoma 
o Adenoid cystic carcinoma 
o Adenocarcinoma 


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• 
Paranasal sinus/nasal cavity malignancy is considered unresectable with negative 
margins surgery or resection would be considered excessively morbid. This could 
include lesions with: 
o Carotid involvement 
o Cavernous sinus invasion 
o Brain invasion 
o Orbital apex 
o Intraconal space 
o Pterygoid musculature involvement 
o Invasion of the clivus 
• 
Resection of at least 80% of the volume of the tumor is feasible. Resectability will be 
determined by the surgeon and radiologist after discussion among the  
multidisciplinary team. For patients who have had surgery at an outside institution, the 
same parameters will be thoroughly screened to ensure the patient met the same 
inclusion criteria and resection standards. 
• 
Patients must be a candidate for surgery (as per treating surgeon) and be able to 
tolerate proton radiation and chemotherapy (as per treating radiation oncologist and 
medical oncologist). 
• 
Karnofsky performance status ≥70. 
• 
The subject has organ and marrow function and laboratory values rendering safe 
administration of Cisplatin: 
o The ANC ≥ 1000/mm3 without colony stimulating factor support; 
o Platelets ≥ 100,000/mm3; 
o Hemoglobin ≥ 9 g/dL; 
o Bilirubin ≤ 1.5 
the ULN. For subjects with known Gilbert’s disease, bilirubin ≤ 
3.0 mg/dL; 
o Serum albumin ≥ 2.8 g/dl; 
o Creatinine clearance (CrCl) ≥ 60 mL/min. For creatinine clearance estimation, 
the Cockcroft and Gault equation should be used: 
 
Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72); 
 
Female: Multiply above result by 0.85; 
o ALT and AST ≤ 3.0 
ULN; 
o Serum phosphorus, calcium, magnesium and potassium ≥ LLN. 
• 
No evidence of intercurrent infection. 
• 
Negative pregnancy test for women of childbearing potential (<51 years of age) as per 
institutional policy. 
• 
Patient must be able to read and write in English. 
• 
Patients who intitially meet the histopathological inclusion criteria but surgical 
pathology report shows Sinonasal Undifferentiated  Carcinoma. 
• 
 
6.3 
Subject Exclusion Criteria 
 
• 
Tumor is deemed to be resectable with negative margins by conventional surgical 
standards. 
• 
Patients not able to receive standard-dose cisplatin based on the judgement of the 


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treating medical oncologist. 
• 
Patients with  chronic kidney disease (GFR <60), uncontrolled hypertension, 
congestive heart failure,   pre-existing bone marrow dysfunction, or cytopenias. 
o  Congestive heart failure (CHF): New York Heart Association (NYHA)  Class II- 
IV at the time of screening; 
• 
Concurrent uncontrolled hypertension defined as sustained blood pressure 
(BP) 
> 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal   antihypertensive 
treatment within 7 days of the first dose of study treatment;If severe hearing 
impairment is measured  or if significant neuropathy is reported at baseline the 
treating physician will discuss the risks for further permanent  hearing loss and 
neuropathy with the patient. 
• 
Patients not able to have a MRI (due to pacemaker, claustrophobia, etc.). 
• 
Inability to return to MSKCC for frequent scheduled hydration sessions post- 
chemotherapy. 
• 
Inability  to comply with requirements for cisplatin administration anti-emetic regimens 
post-treatment. 
• 
Patients not able or unwilling to travel for proton therapy. 
• 
Patients with distant metastatic disease. 
• 
Patients with prior radiation to the head and neck. 
 
7.0 
RECRUITMENT PLAN 
 
7.1 
General Recruitment Plan 
 
Patients will be evaluated by an attending physician from the Department of Radiation 
Oncology, the Division of Head and Neck Surgery, Department of Surgery, the Department of 
Neurosurgery, or Department of Medical Oncology, and entered into the study if they are 
appropriate candidates. The attending physician will obtain informed consent from the eligible 
patients. 
The protocol investigator, co-investigator(s), or a member of the treatment team can screen 
medical records of patients with whom they have a therapeutic relationship to identify 
potential research subjects eligible for this study. In addition, protocol investigator, co- 
investigator(s), and research study assistant(s) can screen medical records of patients with 
whom they do not have a therapeutic 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, the research staff, and the patient,  
the patient may be asked to provide certain health information that is necessary for the 
recruitment and enrollment process. The investigator/research staff may also review portions 
of the patient’s 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 whether the patient is 
eligible and to contact the patient regarding study enrollment. If the patient is deemed 
ineligible for the research study, the investigator and/or research study assistant will destroy 
all information collected during the initial conversation and medical records review, except for 
any information that must be maintained for screening log purposes. 


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In most cases, the initial contact with the prospective subject will be conducted either by the 
treatment team, the 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 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). 
After initial contact with the patient, our research team will contact the PROCure or New York 
Proton Center (NYPC) team to initiate financial approval. The financial team at ProCure or 
NYPC will work closely with the patient and their insurance plan to determine his/her financial 
responsibility in regards to proton therapy. The patient will have all appropriate information 
prior to enrolling on the protocol. 
7.2 
Gender/race breakdowns 
 
In selecting patients for this study and the projects proposed in this protocol, we have taken 
due notice of NIH/ADAMHA  policies concerning inclusion of women and minorities in clinical 
research populations. We expect that the study population will be representative of the range 
of paranasal sinus/nasal cavity patients seen at MSKCC. No specific outreach efforts are 
planned. 
7.3 
Target/planned enrollment 
 
The anticipated accrual rate is 1-2 patients per month to meet the accrual goal of 25 patients 
(15 SCC and 10 ACC, esthesio, or Adenocarcinoma).  Based on recent patient treatment 
patterns in the head and neck and radiation oncology services, we estimate that MSK treats 
approximately 20 patients each year who would be eligible for this trial. We do not anticipate 
any difficulties in meeting our accrual goal. 
 
8.0 
PRETREATMENT EVALUATION 
 
All patients will receive the necessary scans and tests according to the standard of care for 
their paranasal/nasal cavity malignancy. 
Table 2 contains all the tests that will be performed within 8 weeks of the start of surgery and 
then chemoradiation. 
 
 
Table 2: PRE-TREATMENT ASSESSMENTS 
Assessments 
Source 
Prior to protocol calendar days 
Consent form signed by patient 
CRC 
1-3 weeksA 
HistoryB 
EMR 
30 days 


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Physical 
EMR 
30 days 
Audiogram 
EMR 
6 weeks 
CBC, CMP, Hepatitis B Core and Surface 
antigen 
EMR 
6 weeks 
Dental Evaluation 
EMR 
6 weeks 
Pregnancy testC 
EMR 
14 days prior to surgery 
Karnofsky performance status 
EMR 
6 weeks 
PET-CT with CT Neck component to 
include IV contrast and MRI of the Nasal 
Cavity/Para-Nasal Sinuses with contrastD 
EMR 
4 weeks 
SBI 
PSA 
6 weeks 
EORTC QLQ C30 & H&N 43 
PSA 
6 weeks 
 
 
A: Patients start treatment within 30 days from time of consent as per institution’s standard 
B: For cisplatin eligibility requirement, a medical history for neuropathy, history of kidney 
disease, diabetes, hypertension, and cardiac disease. 
C: For women of childbearing potential: Pregnancy testing should be performed according to 
institutional standards. 
D: Patients with contrast allergies should be pre-medicated; patients with specific contrast 
contraindications can have contrast administration deferred. 
Abbreviations: CRC (Clinical Research Coordinator);PSA (Patient self-administered with or 
without CRCassistance); EMR (Electronic Medical Record) 
 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
9.2 
Therapy Schema: 
 
 


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9.1:  Endoscopic Resection Treatment Technology 
 
Endoscopic skull base surgery will be performed as per standard of care for any patient with 
tumors of the paranasal sinus and skull base treated at MSK, as described above. For 
patients who have had surgery elsewhere, they will be enrolled as long as standard of care 
parameters per MSKCC were met at the outside institution. Tissue used for IMPACT testing 
will be taken from the main specimen during the operation. For those who have had surgery 
elsewhere, tissue will be requested from the outside institution. The corresponding blood 
required for IMPACT testing will be drawn prior to the surgery. 
9.2. Radiation Therapy 
 
9.2.1 Immobilization  and Simulation 
 
9.2.1.1 Immobilization 
 
Patients will undergo radiation simulation in the supine position using the standard 
thermoplastic mask for immobilization to ensure daily reproducibility of treatments. 
9.2.1.2. Simulation Imaging 
 
Standard simulation CT guidelines from the vertex of the scalp through the tracheal carina, 
encompassing the entire head and neck. 
9.2.2 Definition of Target Volumes and Margins 
 
GTV Gross Primary will include all existing gross disease at the primary site as seen on 
postoperative MRI and simulation CT scan.  The CTV Primary Site will include the 
preoperative gross extent of primary tumor visible by imaging studies (CT, PET, and/or MRI), 
and/or clinical examination along with the postoperative surgical bed; for histologies with high 
risk of neutropic spread, a CTV Nerve will be created to encompass the affected nerve  
tracks. Fusion of preoperative and postoperative MRI to the simulation CT should be 
performed to aide in volume delineation. Irradiation of cervical and retropharyngeal nodal basins 
will be left up to the treating radiation oncologist. For patients in whom the cervical and 
retropharyngeal nodes will be treated, the CTV Node High Risk volume will include nodal basins 
wherein gross nodal was resected; CTV Node Low Risk will include nodal basins in which there 
was no gross nodal disease identified.  If there are suspected grossly involved lymph nodes, a 
volume GTV Gross Node should be created. Skin bolus is acceptable and can be used for 
patients who are at high risk for skin involvement, at the discretion of the treating physician. 
Each CTV will be expanded by 3mm to a planning target volume (PTV), to account for intra- 
fractional patient motion, and inter-fractional setup error. The above are all standard radiation 
oncology treatment planning procedures. 
 
9.2.3 Dose Prescription 
 
PTV Gross Primary = 70 Gy (relative biological effectiveness [RBE]) 
PTV Primary = 60 Gy (RBE) 
PTV Nerve (if applicable) = 54 Gy (RBE) 
PTV Gross Node (if applicable) =70 Gy (RBE) 


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PTV Node High Risk = 54 Gy (RBE) 
PTV Node Low Risk = 51 Gy (RBE). 
9.2.4 Compliance Criteria and Dose-Volume Histogram (DVH) Analysis 
 
Standard of care target coverage will be applied. Target coverage for PBRT should achieve a 
D95 ≥ prescription dose and the PTV D05 ≤ 110% of the prescription dose. 
Organs at risk (OAR), including the parotid glands, submandibular glands, cochleas, oral 
cavity, larynx, esophagus, brachial plexus, brain stem, optic structures, and spinal cord, 
should be contoured according to standard guidelines for standard of care practice. A dose 
volume histogram will be constructed to evaluate target coverage and the doses to the 
surrounding OAR. The following standard of care radiation planning guidelines should be met: 
1) Larynx: 
a. <70 Gy (RBE) maximum point dose 
b. <45 Gy (RBE) mean dose 
2) Esophagus: 
a. <34 Gy (RBE) mean dose to the esophagus 
3) Brachial plexus: 
a. 
<65 Gy (RBE) maximum point dose 
4) Brainstem: 
a. <54 Gy (RBE) maximum point dose 
5) Optic nerves: 
a. <54 Gy (RBE) maximum point dose 
6) Optic chiasm 
a. <54 Gy (RBE) maximum point dose 
7) Spinal cord: 
a. <45 Gy (RBE) maximum point dose to the spinal cord 
8) Oral cavity: 
a. <40 Gy (RBE) mean dose to the oral cavity excluding overlapping PTV 
9) Contralateral parotid 
a. <6 Gy (RBE) mean dose 
10) Contralateral  submandibular 
a. <6 Gy (RBE) mean dose 
 
9.2.5 Treatment Planning Priorities and Instructions 
 
Critical normal structure constraints, specifically, the brain stem, spinal cord, optic structures 
will take priority over coverage of the tumor. This is followed by adherence to brachial plexus, 
larynx, esophagus, oral cavity, contralateral parotid, and contralateral submandibular glands. 
 
9.2.6 Planning 
 
The initial phase of 30 fractions will include all gross (PTV expansions of GTV) and 
microscopic (PTV expansions of CTV) disease volumes.  The final boost of 5 fractions will 
include only gross disease (PTV expansions of GTV). Normally, this course of radiation 
treatment will take 7 weeks to complete. 
Proton therapy will be planned in CMS XIO (Elekta; Stockholm, Sweden) and 
RayStation(Raysearch labs,Stockholm Sweden), and delivered with uniform scanning or 
pencil beam scanning. Physical and biological uncertainties will be evaluated and taken into 
account, and worst- and best-case scenarios with the ranges of uncertainty (2.5% * range + 
2mm) will be evaluated as per standard of care. We expect almost all patients to complete 
therapy. 


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9.2.7 Daily Treatment Localization 
 
Setup accuracy will be confirmed with daily x-ray orthogonal verification of the isocenter 
based on bony anatomy. Verification CT scans will be obtained at Procure or NYPC a 
simulation CT scan. This is all part of the standard of care and will be performed at least once 
in the course of treatment to assess for changes in anatomy and reproducibility, most often in 
the first and/or fourth week of treatment. 
9.3 Cisplatin Chemotherapy 
 
Cisplatin should be administered on days 1-2, 21-22, and 42-43 of radiotherapy at a dose of 
100mg/m2.  The chemotherapy will be administered per MSKCC guidelines at 100 mg/m2 
every three weeks. Normal scheduled treatment can be +/- 48 hours from three weeks post 
the prior administration.  Administratoin entails pre-hydration with 1000 cc of Normal Saline 
(NS) and  mannitol 25% before and after  treatment. Fosaprepitant (150 mg),  palanosetron 
(250 mcg), and decadron  (12 mg)  infusions are used for anti-emetic support before 
treatment. Cisplatin 100 mg/m2 is infused over one hour. Cisplatin can be administered 
before or after radiation is given  but is only started once the radiation program has been 
initiated. 
If the final surgical pathology report shows SNUC, at the discretion of the treating medical 
oncologist, the patient will receive an addition of etoposide chemotherapy to cisplatin 
chemotherapy. The dose of cisplatin will be decresed from 100 mg/m2 to 60 mg/m2. Cisplatin 
should be administered on days 1-2, 21-22 and 42-43 at a dose of 60 mg/m2 and Etoposide 
should be administered at days 1-3, 21-23, and 42-44 at a dose of 120 mg/m2. Infusion rate, 
anti-emetics, hydration will be administered as per institution’s standard or physician’s choice. 
 
The post-chemotherapy administration protocol requires two days of intravenous hydration 
with 1000 cc NS following the day of cisplatin treatment in the chemotherapy suite. 
Dexamethasone 12 mg will be administered  IV/PO on each of these days. 
 
As needed anti-nausea medications will be prescribed for home and include Zofran 8 mg PO 
every 8 hours, Ativan 0.5 mg PO every 6 hours, and Compazine 10 mg every 6 hours. Patient 
will be advised to report any fever of 100.5 or greater or uncontrolled nausea or vomiting  
while at home. 
9.4 Permitted Supportive/ Ancillary Care and Concomitant Medications 
 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol, and documented 
on each site’s source documents as ancillary care or concomitant medication. 
 
9.5 Prohibited Therapies 
 
There are no explicitly prohibited therapies. Patients will be managed according to standard of 
care principles. 
 
9.6 Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections, or until one of the following criteria 
applies: 
• 
Disease progression. 
• 
Intercurrent illness that prevents further administration of treatment. 


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• 
Unacceptable adverse event(s). 
• 
Patient decision to withdraw consent for participation in the study. 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
All patients will be evaluated according to the standard of care for their nasal cavity, 
paranasal sinus, skull base tumor. 
10.1 Evaluation during  concurrent chemo-proton radiotherapy treatment (please see 
Table 3 for details): 
 
• 
Standard weekly treatment evaluations 
• 
Weekly CTCAEv4 toxicity (Appendix 4) and adverse event assessment 
• 
Clavien-Dindo Classification of Surgical Complications (Appendix  5) 
• 
Patient completion of required patient reported outcome assessments including: 
o Study specific PRO instruments: 
 
EORTC QLQ C30 & H&N 43 
 
SBI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations:   MD (medical doctor); PSA (Patient self-administered with or without Research 
Study Assistant assistance); EMR (Electronic Medical Record) 
 
 
10.2 Evaluation during follow up (please see Table 4): 
 
• 
A focused history and physical exam 
• 
Height and weight 
• 
Dental evaluation 
• 
Karnofsky performance status 
Table 3. ASSESSMENTS DURING PROTOCOL TREATMENT 
Assessments 
Source 
During Treatment 
Toxicity and adverse events (CTCAEv4) 
MD 
Weekly throughout RT and at end of RT 
Height and Weight 
EMR 
Postoperatively (pre RT), at week 4 of 
RT(+/- 7 days),  and end of RT (+/- 7 
days) 
Postoperative MRI of the nasal 
cavity/paranasal sinuses 
EMR 
Should be completed 4 weeks post 
surgery (+/- 7 days) 
History and Physical Exam 
EMR 
Safety evaluations during treatment with 
cisplatin involve weekly toxicity checks. 
CBC and CMP 
EMR 
Safety evaluations during treatment with 
cisplatin involve weekly toxicity checks. 
Clavien-Dindo Classification of Surgical 
Complication Assessmemt 
MD 
Postoperative but prior to radiation 
EORTC QLQ C30 & H&N43 
PSA 
Postoperatively (pre RT), at week 4 of 
RT(+/- 7 days),  and end of RT 
(+/- 7 days) 
SBI 
PSA 
Postoperatively (pre RT), at week 4 of 
RT(+/- 7 days), and end of RT 
(+/- 7 days) 


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• 
CTCAEv4 toxicity and adverse event assessment 
• 
Study specific PRO instruments: 
 
EORTC QLQ C30 & H&N43 
 
SBI 
 
Table 4. ASSESSMENTS IN PROTOCOL FOLLOW UP* 
From End of Treatment 
Assessments 
Source 
3 
months 
(+/-2 
weeks) 
6 
months(+/- 
4 weeks) 
12 
months 
(+/-4 
weeks) 
24 months 
(+/-4 
weeks) 
History 
EMR 
X 
X 
X 
X 
Physical 
EMR 
X 
X 
X 
X 
Dental Evaluation 
EMR 
X 
X 
X 
Karnofsky performance 
status 
EMR 
X 
X 
X 
X 
Toxicity and adverse 
events (CTCAEv4) 
MD 
X 
X 
X 
X 
MRI of nasal 
cavity/para-nasal 
sinuses AND PET/CT 
that includes diagnostic 
quality CT of neck. 
EMR 
X 
x 
X 
X 
EORTC QLQ C30/ 
H&N43 
PSA 
X 
X 
X 
X 
SBI 
PSA 
X 
X 
X 
X 
*Additional follow-ups are allowed per standard of care but are not protocol mandated.  The 
patient will not need to fill out these QOL questionnaires at regular cancer follow-up visits 
after the 24-month follow-up visit. 
Abbreviations:   MD (medical doctor); PSA (Patient self-administered with or without Research 
Study Assistant assistance); EMR (Electronic Medical Record) 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
11.1.1 Expected side effects of endoscopic skull base surgery 
 
The expected side effects of endoscopic skull base surgery are managed in a routine fashion 
in the outpatient setting. These include nasal crusting requiring in-office debridements, 
temporary decrease in smell and taste, foul smell and taste, and nasal congestion.  Possible 
complications of endoscopic skull base surgery (with the rates as per the largest series) 
include carotid artery injury (<0.5%), non-life-threatening  epistaxis (2%), postoperative CSF 
leak requiring conservative or operative intervention (5%) 45-48. Corresponding rates among 
the endoscopic skull base surgery team here at MSKCC are 0%, 1.6%, 3.2%. We will use the 
Clavien-Dindo classification of surgical complications, which grades from I-V the morbidity 
related to a specific postoperative complication 39. 
11.1.2 Expected side effects of radiation therapy 


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A list of the adverse events and potential risks associated with radiotherapy of the head and 
neck appear below and will determine whether dose delays and modifications will be made, or 
whether the event requires expedited reporting in addition to routine reporting. 
Radiation side effects are typically divided into those that occur acutely (during radiation and 
up to 3 months after radiation), and those that occur later (>3 months post-radiation). 
11.1.3 Expected side effects of Cisplatin 
 
The side effects of cisplatin include, but are not limited to, nausea, vomiting, decreased white 
blood count (more susceptible to infections), decreased red blood cells (or anemia, with a risk 
of needing a blood transfusion), decreased platelets (making it easier to bleed), fatigue, 
reversible hair loss, electrolyte abnormalities (e.g., hyponatremia, hypokalemia, 
hypomagnesemia), hearing loss, neuropathy, and kidney failure. 
11.1.4 Expected side effects of Cisplatin and etoposide 
 
The side effects of cisplatin plus etoposide include, but are not limited to nausea, vomiting, 
decreased white blood cell count (more susceptible to infections), decreased red blood cells 
(or anemia, with risk of needing blood transfusion), decreased platelets (making it easier to 
bleed), fatigue, hair loss, hearing loss, kidney failure, sores is mouth leading to dysphagia, 
electrolyte abnormalities, neuropathy, fevers, chills, allergic reaction, confusion, difficulty with 
imbalance, cardiovascular event including heart failure, skin rash, liver failure. 
 
 
11.2 Expected Acute Side Effects of Radiation Therapy 
 
Acute toxicity resulting from radiation therapy may include radioepithelitis of pharyngeal 
mucosa, xerostomia, thickened saliva, hypogeusia, dysphagia, hoarseness, nausea, emesis, 
skin irritation, erythema, epilation, weight loss, and fatigue. 
11.3 Expected Late Side Effects of Radiation Therapy 
 
Late toxicity resulting from radiation therapy may include permanent xerostomia, hypogeusia, 
dysphagia, trismus, nasal dryness, serous otitis media, dental decay, esophageal constriction, 
permanent skin changes including telangiectasias, hypothyroidism, ototoxicity (especially if 
concurrent cisplatin is administered), and increased risk for secondary malignancies. 
Osteoradionecrosis may occur in 5% or less of patients, but can be reduced by dental 
evaluation before radiation, as per the standard of care. 
11.4 Toxicity Management 
 
Toxicities will be managed by the treating investigators according to best standard of care to 
ensure optimal supportive care of study participants. 
11.5 Dose Modifications/ Delays 
 
At the discretion of the treating physician, any participant experiencing a grade 3 or higher 
toxicity may have a treatment break until resolution of the toxicity to grade 1 or less. If grade 3 
toxicity persists, requiring a break of more than five consecutive treatments, the participant  
will be taken off protocol therapy per Section 13.0. 


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Cytopenias causing dose delays are not common with every three week dosing schedule and 
growth factors are not used in chemoradiotherapy protocols.  Neutropenia of less than and 
ANC of 1000 and platelts of <100 would trigger a dose delay and re-assessment at 1 week. 
In the case of dose delays,  the final dose of cisplatin may be given up to two weeks after 
completion of radiation therapy.  Elevations in creatinine or BUN will be treated with extra 
sessions of intravenous hydration until the values normalize. Should the creatinine remain 
elevated between 1.4-1.6 mg/dl at the time of a subsequent dose, than cisplatin will either be 
dose reduced to 75 mg/m2 or discontinued. The risks of permanent kidney damage with 
additional cisplatin  will be discussed with the patient prior to further administration. For 
creatinine levels >1.6 further cisplatin will not be administered. Interruption of treatment may 
occur due to holidays, weather closing or machines are down. 
11.6 Adverse Event Reporting 
 
This study will use the Common Terminology Criteria for Adverse Events (CTCAE) version 
v4.03 for adverse event (AE) reporting. After the Informed Consent Document (ICD) is signed, 
study site personnel will record the occurrence and nature of each patient’s pre-existing 
conditions, including clinically significant signs and symptoms of the disease. During the  
study, site personnel will record any change in the pre-existing condition(s), and the 
occurrence and nature of any new adverse events. 
 
Expected events during radiation therapy are: 
• 
Fatigue/malaise 
• 
Weakness 
• 
Nausea 
• 
Mild anorexia 
• 
Oral mucositis 
• 
Radiation dermatitis 
• 
Xerostomia 
• 
Dysphagia 
• 
Tinnitus 
• 
Dysgeusia 
 
General Therapy Related Events: 
• 
Catheter related events (thrombosis, bleeding, infection) 
• 
Hospitalization for the management of any of the above expected events 
 
Reporting Results: 
• 
All AEs related to protocol procedures are reported. All AEs occurring after the patient 
receives the first dose of radiation therapy must be reported in regard to their 
assessment of the potential relatedness of each AE to protocol procedure, studied 
disease state, and/or radiation modality via CRF. If a patient’s radiation treatment is 
discontinued as a result of an AE, personnel must clearly report the circumstances 
and data leading to any such dosage reduction or discontinuation of treatment. 
• 
Events leading to the clinical outcome of death due to disease progression will be 
included as part of the safety and efficacy analyses for this study. 
• 
If a death is considered related to treatment, the death should be reported as a 
Serious Adverse Event and appropriate guidelines followed for SAE reporting. Any 
clinically significant findings from labs, vital sign measurements, and other procedures 
should be reported as well. 


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11.7 Definitions of Adverse Events 
 
11.7.1 Adverse Event (AE) 
 
Defined as any harm or untoward medical occurrence in a research participant who is 
administered a medical product, medical treatment or procedure, even if it does not 
necessarily have a causal relationship with the product, treatment, or procedure. An adverse 
event can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of a medical product, 
medical treatment, or procedure, whether or not considered to be related. Resources 
containing information on AEs include monthly transcripts, assessment forms obtained after 
each clinic visit, and hospital progress and discharge notes. Grade ≥3 adverse events other 
than hematologic toxicities will be recorded, graded, and reported appropriately. 
 
11.7.2 Related or Possibly Related AE 
 
An AE is “related or possibly related to the research procedures” if, in the opinion of the 
principal investigator, it is more likely than not caused by the research procedures. AEs that 
are solely caused by an underlying disease, disorder, or condition of the subject, or by other 
circumstances unrelated to the research are not “related or possibly related”. If there is any 
question whether or not an AE is related or possibly related, Grade 3 or higher AE should be 
reported to the PI and IRB. 
 
11.7.3 Unexpected AE 
 
An AE is “unexpected” when its nature (specificity), severity, or frequency are not 
consistent with (a) the foreseeable risk of adverse events associated with the research 
procedures described in protocol-related documents, such as the IRB-approved research 
protocol, informed consent document, product labeling and package inserts, and; (b) the 
characteristics of the subject population being studied, including the expected natural 
progression of any underlying disease, disorder or condition or any predisposing risk factor 
profile for the adverse event. AEs that do not meet the requirement for expedited reporting will 
be reported to the IRB as part of the annual renewal of the protocol. 
 
11.7.4 Attribution to Therapy 
 
For reporting purposes, attribution is the assessment of the likelihood that an adverse 
event is caused by the research agent, or protocol intervention. The attribution is 
assigned by the principal investigator after considering the clinical information, the 
medical history of the subject, and the past experience with the research agent/intervention. 
 
This is recorded using one of the following four categories: 
• 
Related 
• 
Possibly Related 
• 
Not Related 
• 
Unknown 
 
“Related” events are those which are most certainly caused by the procedures involved in the 
research. 
“Possibly related” events are those which may have been caused by the procedures involved 
in the research. 
 
“Not related” events are those which are due to an underlying disease, disorder, or condition 


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of the subject, or due to other circumstances unrelated to the research or any underlying 
disease, disorder, or condition of the subject. 
 
“Unknown” events are those which have an unclear relationship to the procedures involved in 
the research, either because more information is needed, and will be provided in follow-up, or 
because there is no way to make a determination. 
 
11.8 Follow-up of Adverse Events 
 
All adverse events will be followed up according to Good Clinical Practice. 
 
During Treatment: Throughout the duration of the study, site personnel will track any change 
in the condition(s), the occurrence, and the nature of any AEs, and record the highest grade 
of the adverse event per cycle on the CRF. CTCAE grading will be assigned before each visit 
for any adverse events experienced during the previous visit period. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1 Local Failure 
The main cancer outcome of interest is local failure defined as recurrence of the primary 
paranasal sinus or nasal cavity cancer within the primary disease site at one year from end of 
treatment. Local responses to therapy will be recorded using RECIST 1.1 criteria with the 
baseline comparator MRI being the postoperative/pre-chemoradiotherapy MRI.   Progressive 
disease (PD) per RECIST 1.1 will be defined as a local failure. 
 
12.2 Locoregional Failure 
The cumulative incidence of locoregional failure will be recorded from the end of treatment. 
This will be defined as any progressive disease at the local site or regional/nodal 
(cervical/retropharyngeal) failure. If gross nodes are treated with radiotherapy, a 
regional/nodal failure will be defined using RECIST 1.1 as any progressive disease in a 
treated node.  This will be assessed as per standard of care. 
 
12.3 Distant Metastasis 
Distant metastasis is defined as any distant (below the clavicles) recurrence from the end of 
treatment. 
 
12.4 Progression 
Progression is defined from the end of treatment to first local,regional/nodal or distant 
recurrence event, or death. 
 
12.5 Disease Specific Mortality 
Disease specific mortality is defined from the end of treatment to death from disease.  Deaths 
due to other causes will be regarded as competing risks. 
 
12.6 Overall Survival 
Overall survival is defined from the end of treatment to death from any cause. 


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13.1 
CRITERIAFOR REMOVAL FROM STUDY 
 
If at any time the patient develops locally progressive disease, s/he will be taken off study and 
referred for alternative therapy. If at any time the patient develops unacceptable toxicity, s/he 
will be removed from the study. If at any time the patient dies while on study, s/he will be 
removed from the study. If grade 3 toxicity persists, requiring a break of more than five 
consecutive treatments, the participant will be taken off protocol therapy. We will,  however, 
continue to follow them for the protocol. 
The primary endpoint of which the power calculation is based on number of patients needed 
to observe a difference in local control following surgery then chemoradiation compared to 
historic rates of chemoradiation alone. Patients who are taken off study due to unacceptable 
toxicities will not be replaced as they will be counted as failures towards the primary endpoint. 
Patients who are lost to follow-up do not need to be replaced as they will be counted towards 
failures towards the primary endpoint. The chance of patients lost to follow-up (3 months from 
end of chemoradiation) is extremely low as all patients in our experience will return to see us 
for their first post-treatment follow-up visit.  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 reviewed and determined whether to keep on study  
or not at the discretion of the treating physician. 
A patient has the right to withdraw from the study at any time for any reason without prejudice 
to his/her future medical care by the physician, or at the institution. Should a patient (or a 
patient’s legally authorized representative) decide to withdraw, all efforts will be made to 
complete and report the observations as thoroughly as possible.  A complete final evaluation 
should be made at the time of the patient’s withdrawal. Patients will be removed from one or 
more parts of the study, at the Investigator’s discretion, if one or more of the following events 
occur: 
• 
Significant noncompliance on the part of the patient 
• 
Refusal of the patient to continue treatment or observations 
• 
Decision by the Investigator that termination is in the patient’s best medical interest 
• 
Patient is lost to follow-up 6 months post registration 
 
14.0 
BIOSTATISTICS 
 
A one-stage design will be used for this trial. Of the 25 patients to be enrolled, 15 will be SCC 
patients and the remaining 10 will be ACC, Esthesio, or Adenocarcinoma. Based on historical 
data, current standard non-surgical treatment has a 1-year local failure rate of 40% for SCC 
patients and 65% for ACC, Esthesio or Adenocarcinoma patients. Therefore, a mixed cohort 
of 15 SCC and 10 ACC/Esthesio/Adenocarcinoma patients should have 1-year local failure 
rate of 50% under standard non-surgical treatment4. We expect to decrease such a rate to 
25% using the proposed new treatment. This design depends on a one-arm, one-sided 
binomial test and has a decision rule as follows: If, among the total 25 patients enrolled, we 
have at least 17 patients who are alive, followed and local failure free (or equivalently, at most 
8 patients who are dead, lost to follow up or withdrew from the study, or have local failure)  
one year from the end of the treatment, then we shall declare the proposed treatment strategy 


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worthy of further investigation. Any patient who is taken off study due to unacceptable 
toxicities or lost to follow up, dies or withdraws within one year from the end of treatment will 
be regarded as a local failure. Patients who die during treatment will also be counted as 
failures, though such a probability will be small. This design has a type 1 error rate of 0.05 
and type 2 error rate of 0.15 for testing the hypothesis p>=50% vs p<25%, where p 
represents the 1-year local failure rate. 
 
To assess the complications of minimally invasive endoscopic skull base surgery in patients 
with unresectable disease, we will use Clavien-Dindo classification of surgical complications 
and summarize the grades (I-V) and types. This will be done after surgery but before 
radiation. 
 
To assess acute and long-term toxicity of radiotherapy, we will summarize the CTCAE v4.03 
scores and present descrptive statistics. This will be done weekly throughout RT, at the end 
of RT, and then 3 months after the end of RT for acute toxicities. Long-term toxicities will be 
assessed at 6, 12 and 24 months after the end of RT. 
 
Patient reported outcomes of toxicity due to radiatherapy, EORTC( H&N43 and QLQ C30) 
and SBI, will be summarized and reported at the following time points: After surgery (pre RT), 
week 4 of RT(+/- 7 days),1 week within end of RT, and then at 3, 6, 12 and 24 months after 
the end of RT. 
Specifically, the following subscales for the QLQ will be summarized at each time point. 
 
For EORTC C30, we will look at 15 distinct groupings. These scales are: Global Health 
Status/QoL scale 2 items (29,30); Physical Functioning, 5 items  (1-5); Role Functioning, 2 
items (6,7); Emotional Functioning, 4 items (21-24); Cognitive Functioning, 2 items (20,25); 
Social Functioning, 2 items (26,27); Fatigue, 3 items (10,12,18); Nausea and Vomiting, 2 
items (14,15); Pain, 2 items (9,19); 6-single item symptom scores (Dyspnea (8); Insomnia 
(11); Appetite Loss (13); Constipation (16); Diarrhea (17); and Financial Difficulties (28); all 
from single items). 
For EORTC H&N43, we will look at 19 distinct groupings. Swallowing, 4 items (35, 36,37,38); 
Salivating, 2 items (42,43); Senses, 2 items (44,45); Speech, 5items (47, 55, 56, 57, 58); 
Social eating, 4 items (51, 52, 53, 54); Pain, 4 items (31, 32, 33, 34); Anxiety, 2 items (69, 
70); Body image, 3 items (48,49, 50);Teeth, 3 items (39,40, 73); Skin, 3 items (65,66, 67); 
Shoulder problems, 2 items (62, 63); Physical contact, 2 items (60, 61); 7-Single item 
symptom scores (Mouth opening (41), coughing (46), neurology (72), social contact (59), 
weight low (68), lymphadema (64), problems with wound healing(71)). 
For SBI, we have 11 disease-specific domains/scales: Emotional, 4 items (35,36,37,38); 
Social, 4 items (23,28,29,32); Other Physical, 6 items (8,11,15,18,19,24); Cognitive, 4 items 
(12,13,21,22); Family, 3 items (31,34,40); Financial, 2 items (30,39); Spiritual, 2 items (33,41); 
Endocrine, 4 items (7,25,26,27); Nasal, 4 items (2,3,14,16); Neurologic, 4 items (1,9,10,20); 
Visual, 4 items (4,5,6,17). A composite score assuming equivalent weighting of domains in 
overall quality of life will also be created by averaging domain scores and summarized. 


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Overall survival and progression free survival will be evaluated by Kaplan-Meier method. 
Regional/nodal   progression, distant metastasis progression and disease specific death will 
be evaluated by cumulative incidence function where death without event or not due to 
disease will be classified as a competing risk. We will also report, if feasible, all 1- and 2-year 
rates. 
For the correlative studies, we will collect tissue samples from patients and bank them for 
future investigations. No statistical analyses are planned. 
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 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). 
15.3 
Randomization 
 
This study is not randomized. 
 
16.1 
DATA MANAGEMENT ISSUES 
 
A Clinical Research Coordinator/CRCwill be assigned to the study. The responsibilities of the 
CRC include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordination of the activities 
of the protocol study team. 
The data collected for this study will be entered into our secure clinical research database 
(CRDB). 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 patients’ 
other medical data. 
16.2 
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 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. In addition, there 
are two institutional committees that are responsible for monitoring the activities of our clinical 
trials program. These include: Data and Safety Monitoring Committee (DSMC) for Phase I 


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and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical 
trials, both of which 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. 
16.3 
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 at the MSKCC Intranet at:  
http://mskweb2.mskcc.org/irb/index.html 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
There are no foreseen additional risks to the patients from this study. 
 
Risks of Study Participation: Patients in this study will be receiving the current standard of 
care for their specific disease site. 
Financial Costs to Patients: All diagnostic and therapeutic interventions are accepted as 
routine care of patients/ subjects eligible for this study. 
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 individual subjects. 
Voluntary Nature of 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. 
17.2 
Privacy 
 
MSK’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). 
The consent indicates that individualized  de identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers who have 
received approval from MSK will be allowed to access this information which will not include 
protected health information, such as the participant’s name, except for dates. It is also stated 


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in the Research Authorization that their research data may be shared with other qualified 
researchers. 
17.3 
Serious Adverse Event (SAE) Reporting 
 
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 


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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 
For IND/IDE protocols: 
The SAE report should be completed as per above instructions. If appropriate, the 
report will be forwarded to the FDA by the IND Office 
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 
REFERENCES 
 
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20.0 
APPENDICES 
 
Appendix 1: EORTC QLQ H&N43 
Appendix 2: EORTC QLQ C30 
Appendix 3: Skull Base Inventory 
Appendix 4: CTCAE v4.0 
Appendix 5: Clavien-Dindo Classification