Clinical trial NCT00592501
Conditions: Nasopharyngeal Carcinoma
Keywords: proton radiation photon radiation 5-FU cisplatin
Sponsor: Massachusetts General Hospital
Start date: 2006-10-01; Completion date: 2019-04-01
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Photon beam radiation is the standard type of radiation used to treat nasopharyngeal carcinoma. Photon beam radiation enters the body and passes through healthy tissue, encounters the tumor and leaves the body through healthy tissue. Proton beam radiation has been shown to have the same effect on tumors as photon beam radiation but it enters the body, passes through healthy tissue, and encounters the tumor but then stops. This means less healthy tissue is affected by proton beam treatment than by photon beam treatment. The purpose of this study is to determine the effectiveness of proton beam radiation in treating nasopharyngeal cancer and reducing the acute and long-term side effects from the treatment. This study will also test to see if the sparing of the healthy tissue can improve quality of life

Detailed description:
* Before beginning study treatment, participants will be asked to fill out a Quality of Life (QOL) questionnaires, a Speech Assessment, a ChemoSensory Questionnaire, a Patient Swallowing Diary, A Swallowing Study, Salivary Tests and a Trismus Assessment. Participants will need to go to the Massachusetts Eye and Ear Infirmary (MEEI) or Massachusetts General Hospital (MGH) for these tests.
* Radiation therapy will be given once a day, five days a week, for seven weeks. This will be given as outpatient care at the Northeast Proton Therapy Center (proton component) and Massachusetts General Hospital (photon component).
* During radiation treatments, participants will receive cisplatin intravenously once every three weeks. This three-week period is called a cycle of treatment.
* After the completion of radiation, participants will receive cisplatin intravenously once every 4 weeks along with fluorouracil as a continuous infusion over 4 days starting on the day cisplatin is given, for three cycles.
* Participants will have a physical exam and blood work drawn weekly to monitor their health.
* An MR/CT scan of the head and neck will be done 2 months after the radiation treatment.
* Follow-up visits will occur once every three months for 2 years, then once every 6 months during years 3-5, then annually. During these follow-up visits, participants will have the following tests and procedures: physical examination; blood work; chest CT scan and CT/MRI of the head and neck will be repeated once every 6 months during the first three years; swallow study; salivary study; QOL questionnaires; speech assessment; ChemoSensory Questionnaire; and Trismus Assessment.

Arms: arm 1: None
Interventions: intervention 1: Proton/Photon Radiotherapy intervention 2: Cisplatin intervention 3: Fluorouracil
Intervention descriptions: intervention 1: Given once a day, five days a week, for seven weeks. intervention 2: Given intravenously once every three weeks during radiation treatment, then once every four weeks for three cycles. intervention 3: Given as continuous infusion over 4 days starting on the day cisplatin is received after radiation therapy.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
STATUS PAGE 
PROTOCOL 05-089 
 
 
Closed To New Accrual 
 
 
Closure Effective Date: 05/22/12 
 
No new subjects may be enrolled in the study as described above. 
Any questions regarding this closure should be directed to the study’s 
Principal Investigator 


Page 1 of 1 
 
Protocol Number: 05-089 
 
Approval Date:  
09/07/06 
(IRB meeting date when protocol/consent  
 approved or conditionally approved) 
 
Activation Date:  
10/02/06 
(Date when protocol open to patient entry) 
 
Approval signatures are on file in the Office for Human Research Studies, tel. 617-632-3029. 
 
 
 
  
Date 
Posted 
Revised Sections 
IRB Approval 
Date 
OHRS 
Version Date 
11/06/06 
Front Sheet replaced due to Amendment #1 
10/31/06 
- 
01/02/07 
Front Sheet replaced due to Amendment # 2  
12/15/06 
- 
03/05/07 
Consent, Protocol & Front Sheet replaced due to 
Amendment #3 
02/01/07 
- 
09/04/07 
Consent Form replaced due to Continuing Review #2 
08/16/07 
- 
06/12/08 
Front Sheet replaced due to Amendment #4 
06/10/08 
- 
06/27/08 
First Page of Protocol and Front Sheet replaced due to 
Amendment #5 
06/26/08 
- 
08/13/08 
Study renewal due to Continuing Review #3 
08/07/08 
- 
12/22/08 
Front Sheet replaced due to Amendment #7 
12/22/08 
-- 
03/02/09 
Front Sheet Replaced due to Amendment #8 
03/02/09 
- 
04/20/09 
Front Sheet Replaced due to Amendment #9 
04/12/09 
- 
05/14/09 
Front Sheet Replaced due to Amendment #10 
05/14/09 
- 
07/31/09 
Study renewal due to Continuing Review #4 
07/23/09 
- 
06/02/10 
Front Sheet Replaced due to Amendment #11 
05/19/10 
- 
07/20/10 
Consent Form replaced due to Continuing Review #5 
07/01/10 
- 
07/11/11 
Consent Form and Front Sheet replaced due to 
Continuing Review #6 
06/16/11 
- 
03/16/12 
Front Sheet Replaced due to Amendment #14 
03/08/12 
- 
03/30/12 
Protocol, Consent Form and Front Sheet replaced due 
to Amendment #13 
02/09/12 
- 
05/31/12 
Permanent Closure due to accrual goal met (effective 
05/22/12) Amendment #15 
05/30/12 
- 
06/18/12 
ON HOLD: All research must stop due to lapsed 
Continuing Review. Study expired 06/16/12. 
N/A 
N/A 
06/20/12 
On Hold removed. Study Renewal/ Consent Form 
footer replaced due to Continuing Review #7 
06/19/12 
N/A 
06/18/13 
Study renewal/Consent Form footer replaced due to 
Continuing Review #9 
06/06/13 
N/A 
06/05/14 
Study renewal/Consent Form footer replaced due to 
Continuing Review #10 
06/05/14 
N/A 
05/29/15 
Study renewal/Consent Form footer replaced due to 
Continuing Review #11 
05/28/15 
N/A 
Date 
Posted 
Revised Sections 
IRB Approval 
Date 
OnCore 
Version Date 
05/26/16 
Study renewal/ Consent Form footer replaced due to 
Continuing Review #12 
05/24/16 
05/26/16 
05/15/17 
Study renewal/ Consent Form footer replaced due to 
Continuing Review #13 
05/11/17 
N/a 
04/06/2018 
Study renewal/Consent Form footer replaced per 
Continuing Review #14 
04/05/2018 
04/06/2018 
04/05/2019 
ON HOLD:  All research must stop due to lapsed 
Continuing Review.  Study approval expired 04/05/2019 
n/a 
n/a 
06/21/2019 
ON HOLD removed:  Study renewal/Consent Form 
removed due to data analysis only per Continuing 
Review #15 
06/21/2019 
n/a 
 


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05-089
A PHASE II STUDY OF PROTON RADIOTHERAPY WITH CHEMOTHERAPY  
FOR NASOPHARYNGEAL CARCINOMA 
Overall Principal Investigator at MGH: 
Annie Chan, M.D. 
Principal Investigator at DFCI/BWH:  
Roy Tishler, M.D. 
 Co-investigators at MGH: 
Judith Adams C.M.D, Paul Busse Ph..D, M.D., John 
Clark M.D., Tessa Goldsmith M.A. CCC/SLP, Norbert 
Liebsch M.D., Minh-Tam Truong M.D., , M.D., Lori 
Wirth, M.D.  
Co-investigators at MEEI: 
Hugh Curtin, M.D., Daniel Deschler, M.D, Derrick 
Lin, M.D., James Rocco M.D. 
Co-investigators at DFCI/BWH: 
Robert Haddad M.D., Charles Norris M.D., 
Co-investigator at NSCC: 
James McIntyre M.D. 
Statistician: 
Beow Yeap Ph.D. 
NCT00592501


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Table of Contents 
 
 
 
 
 
 
 
 
 
 
 
 
PAGE 
 
Table of Contents………………………………………………………………......2 
 
SCHEMA ……………………………………………………………………........4 
 
1.0 
BACKGROUND……………………………………………………………….....5 
 
2.0 
OBJECTIVES………………………………………………………………….....7 
 
3.0 
PATIENT SELECTION……………………………………………………........7 
 
4.0 
PRE-STUDY INVESTIGATIONS ……….……………………………………..8 
 
5.0 
SUBJECT ENROLLMENT……………………………………………………...9 
 
6.0 
TREATMENT PROGRAM……………………………………………………...9 
 
7.0 
TOXICITY MEASUREMENT……………………………………………........23 
 
8.0 
QUALITY-OF-LIFE ASSESSMENT…………………………………………..23 
 
9.0 
DATA COLLECTION ……………………………………. ……………….......25 
 
10.0 
ADVERSE EVENTS REPORTS ……………………………………………….26 
 
11.0 
MODALITY REVIEW .........................................................................................26 
 
12.0 
BIOSTATISCAL ANALYSIS …………………………………………………..26 
 
13.0 
REFERENCE ………………………………………… …………………………28 
 
14.0 
REGULATORY REQUIREMENTS …………………………………………...30 
 
Appendix 
 
I 
Performance Status  
 
II 
Staging System  
III 
EORTC QLQ-C30 version 3  
            IV  
EORTC QLQ-H&N 
 
V 
Tobacco and Alcohol Assessment/Pre-treatment 
 
VI 
Sialometric Form 


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VII 
Physician Dysphagia Log 
 
VIII 
Patient Swallowing Diary 
 
IX 
Videofluoroscopic Swallowing (VFSS) Evaluation 
    
X  
Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE) 
XI 
Speech Assessment/Head and Neck Health Status Assessment Inventory (HNHSAI) 
XII 
ChemoSensory Questionnaire (CSQ) 
XIII 
Trismus Assessment 
XIV 
Audiology Form 


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SCHEMA 
 
A Phase II Study of Proton Radiotherapy with Chemotherapy for 
Nasopharyngeal Carcinoma 
 
 
 
 
 
Combined Proton-Photon Radiotherapy 
Primary site   
 
70 CGE 
Nodal Disease > 2cm  
70 CGE 
Nodal Disease 1 - 2cm 
66 CGE 
Primary subclinical 
 
60 CGE 
High risk nodal region 
60 CGE 
Low risk nodal region  
50 CGE 
 
Chemotherapy 
Cisplatin 100mg/msq d1 (cycle 1), 22 (cycle 2), 43 (cycle 3)  
5-FU 1000mg/msq 96hr  
Cisplatin 80mg/msq  
 
 
 
 
I. Concurrent Radiotherapy and Chemotherapy (Chemoradiation) 
 
RADIOTHERAPY*  Days  1 
 
 
 
 
 
 
54 
 
CISPLATIN**            
X 
 
 
 
 
 
       
 
 
 
 
 
*Administered Monday through Friday, start date may be on a Monday, Tuesday, Wednesday, or 
Thursday 
 
* *Cisplatin infusion to be given every 21 days during RT. First dose to be administered within the first 
three days of the start of radiation. 
 
 
II. Adjuvant Chemotherapy – to begin 3 - 8 weeks after completion of chemoradiation 
 
Day 
 
1     2      3    4       29    30   31   32     57   58   59   60 
Cisplatin 
x                             x                             x 
5-FU     
x      x     x    x        x     x     x     x        x     x     x     x 
 
1.0 
Background and Significance 


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1.1 
Background 
 
 
In the USA and Western Europe, nasopharyngeal carcinoma (NPC) accounts for 
less than 1% of malignancies.  The average incidence increases 80-fold in endemic areas 
such as Southern China.  NPC is a neoplasm that differs from other squamous cell 
carcinomas of the head and neck with regard to epidemiology, histologic features, 
treatment strategies, and treatment response.  Due to the anatomical location, 
nasopharyngeal cancers are considered unresectable.  The conventional treatment 
approach has been radiation.  Local control rates with conventional once daily radiation are 
75% or higher for Stage I and II diseases but decrease to 20 - 70 % for Stage III and IV 
diseases.  For patients with advanced NPC (stage III - IV) treated with radiation alone, the 
5-year survival rates are only 10 - 40% (1 - 7).    
 
The predominant patterns of failure for locally advanced NPC are local recurrence 
and distant metastasis.  In a retrospective analysis of 1301 patients with NPC, 
locoregional recurrence was shown to be an independent prognostic indicator of 
subsequent distant metastases (8).  Achieving local control is therefore important in the 
treatment of nasopharyngeal carcinoma. 
 
1.2 
Combined radiation and chemotherapy is superior to radiotherapy alone  
 
 
The standard of care of treatment in the United States is concurrent 
chemoradiation followed by adjuvant chemotherapy, based on the results of the 
Intergroup study (SWOG/RTOG/ECOG), which showed improved progression-free and 
overall survival with chemoradiation compared with radiation alone (9).  The study 
compared radiotherapy (70 Gy) alone to chemotherapy concurrent with radiotherapy 
followed by adjuvant chemotherapy in patients with nasopharyngeal cancer.  This revealed 
a statistically significant increase in 3-year progression-free survival (69% versus 24%) and 
3-year overall survival (76% versus 46%) in favor of the chemoradiotherapy arm.  Lin et Al 
recently reported increased progression-free and overall survival rates in patients who 
received 2 cycles of continuous cisplatin and fluorouracil chemotherapy during radiotherapy 
compared to radiotherapy alone in patients with locally advanced nasopharyngeal 
carcinoma in endemic areas (10).  Chan et al in a randomized trial of 350 patients, showed 
that patients who received weekly cisplatin of 40 mg/m² during radiation had a prolonged 
progression-free survival compared to patients who received radiation alone (11).  These 
studies suggest that concurrent chemoradiation with or without adjuvant chemotherapy is 
superior to radiotherapy alone in patients with locally advanced NPC in edemic and non-
edemic areas.  
 
1.3 
Rationale of using proton radiotherapy 
 
 
 
In the Intergroup randomized study, only 63% of patients received all three courses 
of concurrent cisplatin and 55% received all three courses of adjuvant chemotherapy.  


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Twenty-eight percent of patients in the radiotherapy alone arm experienced grade 3 and 4 
mucositis compared to 37% in the chemoradiation arm.  Two percent of patients in the 
radiotherapy arm experienced severe (grade 4) mucositis compared to 12% in the 
chemoradiation arm (9).  In the randomized trial of concurrent weekly cisplatin with 
radiotherapy versus radiotherapy alone by Chan et al, the progression-free survival was not 
statistically significant between the two arms (11).  The percentage of patients completing 
at least four cycles of chemotherapy during external radiotherapy was 78%.  This number 
dropped to 60% and 44% for five and six cycles, respectively.  In this study, mucositis 
was the most common reason of discontinuing chemotherapy.  These data suggest that if 
one can reduce acute treatment toxicity from concurrent chemoradiation, one may increase 
treatment compliance and therefore treatment outcome.   
 
 
Because of the anatomic location of the nasopharynx, radiation treatment with 
and without chemotherapy is associated with significant treatment-related toxicity such 
as brain necrosis, audio-visual toxicity, radiation encephalopathy, radiation myelitis, and 
cranial nerve paralysis.  Xerostomia and swallowing dysfunction are also the major 
complaints in patients who have undergone conventional external beam radiation therapy 
to the nasopharynx.  Protons are charged particles, with similar biological effect as X-
rays.  The advantage of protons lies in their physical dose distribution.  Due to the 
defined range of protons (i.e. Bragg peak), dose distribution can be designed that 
conforms more closely to the tumor volume (12).  This superior physical property of 
proton allowed less radiation to the normal surrounding tissues, therefore expected to 
result in decreased acute and late toxicities.   
 
 
The goal of using proton therapy is therefore to: 1) test the hypothesis that 
reduction of radiation dose to normal tissue can reduce acute toxicity and increase 
treatment compliance to the combined modality treatment and 2) to decrease late toxicity 
and improve health related quality-of-life outcomes. 
 
1.4 
Preliminary experience of proton radiotherapy for T4 nasopharyngeal carcinoma   
 
 
 
At the Massachusetts General Hospital, proton beam radiotherapy has been used 
to treat locally advanced nasopharyngeal carcinoma.  Between 1990 and 2002, 17 
patients with newly diagnosed T4 N0-3 nasopharyngeal carcinoma received combined 
conformal proton and photon radiotherapy.  Seventy-one percentage of patients had 
World Health Organization type 2 - 3 histology  The median prescribed dose to the gross 
target volume  was 73.6 Cobalt-Gray-Equivalent (CGE) (range 69 - 76.8).  Eleven 
patients received accelerated hyperfractionated radiotherapy.  Ten patients received 
induction or concurrent chemotherapy.  All patients except one completed the planned 
concurrent radiation and chemotherapy treatments.  With a median follow-up of 43 
months, 1 and 2 patients developed local and systemic failures, respectively. There was 
no neck recurrence. The locoregional control and relapse-free survival rates at 3 years 
were 92% and 79%, respectively.  For patients who received chemotherapy, the 3-year 


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relapse-free survival rate was 91% compared to 50% for those without chemotherapy (p 
= 0.09).  The 3-year overall survival rate was 74%.  For patients who received 
chemotherapy, the 3-year overall survival rate was 91% compared to 40% for those 
without chemotherapy (p = 0.01).  This preliminary experience suggests that combined 
use of chemotherapy with proton radiotherapy results in improved disease-free and 
overall survivals in patients with T4 nasopharyngeal carcinoma (13).  
 
     
 
2.0 
 Objectives 
 
 
2.1 
Primary Objectives  
(1) 
To test the hypothesis that reduction of radiation dose to normal tissue can 
reduce acute toxicity and increase treatment compliance to combined 
 modality treatment.   
(2) 
To assess health related quality-of-life outcomes after proton radiotherapy 
for nasopharyngeal carcinoma using objective measurements and 
validated quality-of-life instruments.   
 
 
2.2 
Secondary Objectives 
 To determine the rate and pattern of locoregional tumor recurrence in patients 
treated with proton beam radiotherapy and concurrent chemotherapy followed by 
adjuvant chemotherapy in patients with Stage II - IVA nasopharyngeal cancer. 
 
 
3.0 
Subject Selection 
3.1 
Patient Eligibility 
3.1.1 
Biopsy proven stage > T2b and/or node positive (American Joint 
Committee on Cancer Sixth Edition, Stage IIB – IVB) non-metastatic, 
squamous cell carcinoma of the nasopharynx, types WHO I - III. 
3.1.2 
No head and neck surgery of the primary tumor or lymph nodes except for 
incisional or excisional biopsies. 
3.1.3 
Zubrod performance status 0 - 1 or Karnofsky 70 or above.  
3.1.4 
All patients must undergo pre-treatment evaluation of tumor extent and 
tumor measurement.  
3.1.5 
Nutritional and general physical condition must be considered compatible 
with the proposed chemoradiation treatment. 
3.1.6 
Signed study-specific informed consent prior to study entry. 
3.1.7 
Patients must have a WBC > 4,000/µl and a platelet count of > 
100,000/µl; patients must have adequate renal function as documented by 
creatinine clearance > 60 ml/min (actual or calculated by the Cockcroft-
Gault method). 
3.1.8 Age 18 or above 
3.1.9 No active alcohol addiction (as assessed by medical caregiver). 


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3.1.10 Women of childbearing potential must have a negative pregnancy test. 
 
 
3.2 
 Exclusion Criteria 
3.2.1 Stage IVC or evidence of distant metastases. 
3.2.2 Previous irradiation for head and neck tumor. 
3.2.3 Patient is on other experimental therapeutic cancer treatment. 
3.2.4 Other malignancy except non-melanoma skin cancer or carcinomas not of 
head and neck  origin and have been controlled for at least 5 years. 
3.2.5 Active untreated infection. 
3.2.6 Major medical or psychiatric illness, which in the investigators’ opinions, 
would interfere with either the completion of therapy and follow-up or 
with full and complete understanding of the risks and potential 
complications of the therapy. 
3.2.7 Prophylactic use of amifostine or pilocarpine is not allowed. 
3.2.8 Pregnant or breast feeding women, or women and men of childbearing 
potential not willing to use adequate contraception while on treatment and 
for at least 3 months thereafter. 
3.2.9 Symptomatic peripheral neuropathy ≥ grade 2 by National Cancer 
Institute Common Toxicity Criteria (CTCAE) 
3.2.10 Symptomatic altered hearing > grade 2 by CTCAE. 
 
 
4.0 
Pre-study Investigations  
 
Each patient must have completed the following studies prior to study entry unless 
otherwise indicated. 
 
4.1 
Complete history and physical exam including weight, height, performance 
status, neurological examination, and vital signs within 14 days of study. 
4.2 
Complete descriptive documentation of the extent of the primary and regional 
disease (if any).  
4.3 
Completion of the following laboratory studies within 14 days of study entry: 
Complete Blood Count (WBC, neutrophils, platelet counts); serum creatinine, 
creatinine clearance, BUN; Chemistry (electrolytes, magnesium, and calcium); 
serum pregnancy test for women of childbearing.  Completion of the following 
laboratory studies within 14 days of study entry: liver function tests including 
AST, bilirubin, alkaline phosphatase. 
4.4 
Completion of the following radiologic studies within 1 month prior to study 
entry: chest X-ray or CT; CT of head and neck with < 2.5 mm contiguous slices 
in immobilization system (with contrast, unless contraindicated); or MRI of 
nasopharynx/base of skull with T1 contrast with gadolinium and T2 sequences 
required unless contraindicated; liver CT or MRI (must be done only in the 


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presence of elevated alkaline phosphatase, AST or bilirubin or other clinical 
indicator); bone scan (only in the presence of elevated alkaline phosphatase or 
other clinical indicator). The use of PET/CT scan is optional but encouraged.  
Treatment planning CT can be used but must be within 21 days of start of 
radiation.  
4.5 
Thyroid function panel. 
4.6 
Audiogram. 
 
 
5.0 
 Pre-treatment Evaluations 
 
5.1 Dental evaluation 
5.2 Nutritional evaluation 
5.3 Tobacco and alcohol assessment 
5.4 Videofloroscopic Swallowing (VFSS) Evaluation 
5.5 Measurement of whole mouth saliva (sialometry) 
5.6 EORTC QLQ C30 and EORTC QLQ H&N 
5.7 Physician dysphagia log 
5.8 Patient swallowing diary 
5.9 Speech Assessment/Head and Neck Health Status Assessment Inventory (HNHSAI) 
5.10 
ChemoSensory Questionnaire (CSQ) 
5.11 
Trismus Assessment 
 
 
Subject Enrollment  
 
 
 
Patients will be registered through the Quality Control Committee (QCC) at the Dana-
Farber Cancer Institute (617-632-3761, fax 617-632-2295) prior to treatment.  Any 
patient not registered to the protocol prior to the initiation of treatment will be ineligible.  
The following information will be provided to the QCC: 
 
 
 
Name and telephone number of primary oncologist 
 
 
Protocol name  
 
 
Patient name, date of birth, and ID number 
 
 
Primary institution 
 
 
Date of initiation of radiotherapy 
 
 
Confirmation of eligibility 
 
 
Copies of consent form with signatures 
 
 
 
6.0 
Treatment Program 
 


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All patients will undergo their radiation planning and radiation treatment at the 
Massachusetts General Hospital (MGH).  Patients may receive chemotherapy at any of 
the participating institutions.   
 
 
6.1 
Treatment Planning, Imaging, and Localization Requirements  
6.1.1 All patients will be immobilized in a custom designed device. 
 
Immobilization device should include neck and shoulder immobilization. 
6.1.2 Treatment planning CT scans (with contrast, unless contraindicated) will 
be required to define gross target volume and clinical target volume.  The 
treatment planning CT scan should be acquired with the patient in the 
same position and using the same immobilization device as for treatment.  
All tissues to be irradiated must be included in the CT scan. CT scan 
thickness should be 25 mm or smaller slices through the region that 
contains the primary target volumes. The regions above and below the 
target volume may be scanned with slice thickness of 0.5 cm.  Treatment 
planning CT must be within 21 days of start of radiation.   
6.1.3 MRI scans (with gadolinium unless contraindicated) are required in 
assisting the delineation of the treatment volume on planning CT scans.  
6.1.4 The GTV, CTV, and normal tissues must be outlined on all CT slices in 
which the structures exist.  GTV and CTV are defined in section 6.2.1. 
 
6.2 
Volume and ICRU Reference Point Definitions  
 
The definition of volumes will be in accordance with the 1993 ICRU Report #50: 
Prescribing, Recording, and Reporting Photon Beam Therapy. 
6.2.1 
The Gross Tumor Volume (GTV) is defined as all known gross disease 
determined from CT, MRI, clinical information, and/or endoscopic 
findings.  Grossly positive lymph nodes are defined as any lymph nodes 
greater than 1 cm or nodes with a necrotic center. 
6.2.2 
The Clinical Target Volume (CTV) is defined as the GTV plus areas that 
are considered to contain potential microscopic disease.  Three different 
CTVs will be defined, namely CTV60 for the tumor in the primary site and 
the high risk nodal regions and CTV50-54 for the low risk nodal regions.  
Please note that there is no set margin between each GTV and its CTV. 


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6.2.3 
The Planning Target Volume (PTV) will provide a margin of 3 mm 
around each CTV (namely PTV70, PTV60, PTV50-54) to compensate for the 
variabilities of treatment set up and internal organ motion.  
 
6.3 
Critical Normal Structures 
 
Critical normal structures, including the brainstem, spinal cord, optic nerves, 
chiasm, retina, eyes, temporal lobes, and frontal lobes should be outlined in all 
cases. 
Parotid 
glands, 
submandibular 
glands, 
oral 
cavity, 
cochleas, 
temporomandibular joints, mandibles, pituitary glands, hypothalamus, and 
lacrimal glands should also be outlined.  
 
 
6.4 
Treatment Planning 
 
The treatment plan used for each patient will be based on an analysis of the 
volumetric dose, including dose-volume histogram (DVH) analyses of the PTV 
and critical normal structures.  
6.4.1  Dose Specifications 
6.4.1.1 The gross primary tumor and lymph node metastasis of greater 
than 2 cm, PTV70, will receive 70 CGE in 35 fractions at 2 CGE 
per fraction.  An additional of boost of 6 CGE in 3 fractions to the 
primary gross tumor volume for patients with large primary 
tumors is at the discretion of the physician. 
6.4.1.2 The lymph node metastasis of 1 - 2 cm, PTV66, will receive 66 
 CGE in 33 fractions at 2 CGE per fraction. 
6.4.1.3 The primary subclinical and the high risk nodal region (PTV60) 
will receive 30 fractions of 2.0 CGE per fraction, total 60 CGE.  
6.4.1.4 The low neck (including) supraclavicular field will be treated with 
conventional AP field or AP/PA fields at the discretion of the 
physician, and will receive  25 - 27 fractions of 2.0 CGE/fraction 
to a total  50 - 54 CGE unless there are gross nodes in which all 
the gross nodes should receive the same dose as the PTV66-70.  
6.4.1.5 PTV70 and PTV60 of the upper field will be treated with a 
combination of proton beam and photon radiation.  The low neck 
will be treated with photon only.   


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6.4.1.6 The prescription dose is the isodose surface that encompasses at 
least 95% of the planning target volume (PTV).  No more than 
20% of any PTV70 will receive > 110% of the prescribed dose.  
No more than 1% of any PTV70 and any PTV60 will receive < 93% 
of the prescribed dose.  No more than 1% or 1 cc of the tissue 
outside the PTVs will receive > 110% of the dose prescribed to 
the PTV70. 
 
Table 1.  Radiation dose summary 
 
Target 
Dose 
Designation 
Primary Gross Disease 
70 CGE 
PTV70 
Nodal Disease > 2cm 
70 CGE 
PTV70 
Nodal Disease 1 - 2cm 
66 CGE 
PTV66 
Primary subclinical 
60 CGE 
PTV60 
High risk nodal region 
60 CGE 
PTV60 
Low neck 
50-54  CGE 
PTV50-54 
 
 
6.4.2 DVH’s must be generated for all critical normal structures and the 
unspecified tissues.   
 
Table 2.  Dose constraints to critical tissues  
 
Normal tissues 
Total dose (CGE) 
Dose per fraction (CGE) 
Brainstem (surface) 
< 60 - 64 
< 2.0  
Brainstem (center) 
<54 
< 2.0 
Spinal Cord (surface) 
< 50 
< 2.0  
Spinal Cord (center)    
< 45 
< 2.0 
Optic nerves 
< 54 - 63 
< 2.0  
Chiasm 
< 54 - 63 
< 2.0  
Retina 
< 45 
< 2.0  
Temporal/frontal lobes 
< 70 
< 2.0 
 


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6.4.3 Other Normal Structures 
 
Parotid glands: Mean dose < 26 CGE (at least one gland), or at least 20 cc 
of the combined volume of both parotid glands will receive < 20 CGE or 
at least 50% of the gland will receive < 30 CGE (should be achieved in at 
least one gland). 
 
 
Table 3.  Dose constraints to normal tissues  
 
Normal tissues 
Total dose (CGE) 
Lacrimal gland 
< 44 
Submandibular glands  
reduce the dose as much as possible 
Cochleas 
 
reduce the dose as much as possible 
Temporomandibular joints 
reduce the dose as much as possible 
Mandible 
reduce the dose as much as possible 
Lens 
reduce the dose as much as possible 
Oral cavity 
reduce the dose as much as possible 
Pituitary 
reduce the dose as much as possible 
Hypothalamus 
reduce the dose as much as possible 
Larynx  
< 45 CGE 
Esophagus 
reduce the dose as much as possible 
Swallowing Structures 
reduce the dose as much as possible 
Mastication Muscles 
reduce the dose as much as possible 
 
 
 
6.4.4 Planning Priorities  
 
 
 
Critical normal structure constraints followed by the prescription goals are 
 
 
 
the most important planning priorities. The priorities in addressing the  
 
 
 
protocol aims and constraints will be in the following order:  
 
1) 
Critical and normal structure constraints 


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2) 
Dose specifications  
3) 
Planning Goals: other normal structures 
 
 
 
6.5 
Chemotherapy 
6.5.1 Cisplatin 
 
6.5.1.1 Mechanism of Action: The dominant mode of action of cisplatin 
appears to be inhibition of the incorporation of DNA precursors, 
although protein and RNA synthesis are also inhibited. Plasma 
levels of cisplatin decay in a biphasic mode with an initial half-life 
of 25 to 49 minutes, and a secondary phase ranging from 58 to 73 
hours. This prolonged phase is due to protein binding which 
exceeds 90% of the radioactivity in the second phase. Urinary 
excretion is incomplete with only 27 to 45% of the radioactivity 
excreted in the first five days. The initial fractions of radioactivity 
are largely unchanged drugs. Although this drug seems to act as an 
alkylating agent, there are data to indicate that its mode and sites of 
action are different from those of nitrogen mustard and the 
standard alkylating agents. 
6.5.1.2 Formulation: Cisplatin is available as a liquid (concentration 1 
mg/ml) in a 100 ml vial. 
6.5.1.3 Preparation:  Aluminum reacts with cisplatin causing precipitation 
formation and loss of potency; therefore, needles or intravenous 
sets containing aluminum parts that may come in contact with the 
drug must not be used for the preparation or administration of 
cisplatin. 
6.5.1.4 Storage:  Cisplatin should be kept at room temperature to avoid 
precipitation.  The solution may be further diluted in a chloride-
containing vehicle such as D5NS, NS, or D51/2NS (precipitate 
occurs in D5W).  Cisplatin has been shown to react with aluminum 
needles, producing a black precipitate within 30 minutes. 
6.5.1.5 Administration: Cisplatin should be given immediately after 
preparation as a slow intravenous infusion. 
6.5.1.6 Adverse Effects: Incidence rates of adverse events associated with 
cisplatin are provided in the product package insert. The following 
events are expected with the administration of cisplatin: 


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6.5.1.7 Nephrotoxicity: Dose-related and cumulative renal insufficiency is 
the major dose-limiting toxicity of cisplatin. Renal toxicity has 
been noted in 28 - 36% of patients treated with a single dose of 50 
mg/m2. It is first noted in the second week after a dose and is 
manifested as elevated BUN, creatinine, and serum uric acid, or as 
a decrease in creatinine clearance. Because renal toxicity becomes 
more prolonged and severe with repeated courses of cisplatin, 
renal function must return to normal before another dose can be 
given. 
6.5.1.8 Ototoxicity: Ototoxicity has been observed in up to 31% of 
patients treated with a single dose of cisplatin 50 mg/m2. It is 
manifested by tinnitus and/or hearing loss in the high frequency 
range.  Deafness has been reported rarely. 
6.5.1.9 Hematologic Toxicity: Myelosuppression occurs in 25 - 30% of 
patients treated with cisplatin. Nadirs in circulating platelets and 
leukocytes occur between Days 18 and 23 with most patients 
recovering by Day 39 or sooner. Thrombocytopenia, anemia, 
neutropenia, and fever are also possible adverse events. The 
occurrence of acute leukemia has been reported rarely in patients 
treated with anthracycline/alkylator combination chemotherapy. 
6.5.1.10 
Gastrointestinal Toxicity: Marked nausea and vomiting 
occur in almost all patients treated with cisplatin. Diarrhea and 
anorexia have also been reported. 
6.5.1.11 
Neurotoxicity: Neurotoxicity, usually characterized by 
peripheral neuropathies, has been reported. Neuropathy usually 
occurs after prolonged therapy (4 to 7 months); however, 
symptoms have been reported after a single dose. Muscle cramps, 
loss of taste, seizures, autonomic neuropathy, dorsal column 
myelopathy, and Lhermitte’s sign have also been reported. 
6.5.1.12 
Ocular Toxicity: Optic neuritis, papilledema, and cerebral 
blindness have been reported infrequently in patients receiving 
standard recommended doses of cisplatin. Blurred vision and 
altered color perception have been reported after the use of 
regimens with higher doses of cisplatin or greater dose frequency 
than those recommended in the package insert.  
6.5.1.13 
Anaphylactic-like Reactions: Anaphylactic-like reactions 
have occasionally been reported in patients previously exposed to 


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cisplatin. Symptoms include facial edema, wheezing, tachycardia, 
and hypotension. 
6.5.1.14 
Hepatotoxicity: Transient elevations in liver enzymes, 
especially SGOT (AST), and bilirubin, have been reported. 
6.5.1.15 
Other Toxicities: Other infrequent toxicities that have been 
reported include cardiac abnormalities, hiccups, elevated serum 
amylase, rash, alopecia, malaise, and asthenia. Rare cases of local 
soft tissue toxicity have occurred.  
6.5.1.16 
Supplier: Commercially available. 
 
6.5.2 Fluorouracil 
6.5.2.1 Mechanism of action: Synthesis of 5-fluorouracil was first 
described by Heidelberger in 1957. 5-FU is considered to act 
primarily as an inhibitor of thymidylate synthetase. 
6.5.2.2 Hepatotoxicity: Transient elevations in liver enzymes, especially 
SGOT (AST), and bilirubin, have been reported. 
6.5.2.3 Formulation: 5-FU is commercially available in a liquid 
(concentration 50 mg/ml) in a 100 ml vial.  It is stable if protected 
from light.  If a precipitate is present, it is to be gently heated to no 
greater than 140°F in a water bath. In aqueous solution it is 
colorless to faint yellow, and is pH adjusted with sodium hydroxide 
to 8.6-9.0. 
6.5.2.4 Preparation: An infusion pump should be used to control the 
infusion flow rate. The volume of diluent is dependent upon the 
particular type of pump used. 
6.5.2.5 Storage: 5-FU should be stored at room temperature and protected 
from light. 
6.5.2.6 Administration: continuous intravenous infusion. 
6.5.2.7 Adverse Effects: Toxicities associated with the systemic 
administration of 5-FU include anorexia, nausea and vomiting, 
stomatitis, mucositis, phlebitis, diarrhea, myelosuppression, 
alopecia, 
rash, 
photosensitivity, 
maculopapular 
eruptions, 
hyperpigmentation, fingernail changes, neurologic symptoms, 


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cerebellar ataxia (rare), and very occasionally angina with 
accompanying EKG changes. “Hand and foot syndrome” has been 
observed in patients receiving continuous infusion 5-FU. 
6.5.2.8 Supplier: Commercially available. 
 
6.5.3 Chemotherapy Dose Schedule  
Three cycles chemotherapy will be given with radiation therapy every 21 days. 
 
Table 4.  Dose schedule for cisplatin given with radiation    
Agent 
Dose 
Route 
 
Interval 
Notes 
Cisplatin 
100 
mg/m2 
I.V. 
 
3 weeks 
(21 days)
 Administered as per institutional 
standard 
 
Three cycles of adjuvant cisplatin and 5-fluorouracil will be administrated after 
radiation therapy. Adjuvant chemotherapy can be given between 3 - 8 weeks after 
the completion of radiation.  If adjuvant chemotherapy is delayed due to treatment 
related toxicities beyond 8 weeks after the completion of radiation, then adjuvant 
chemotherapy will be deferred. 
 
Table 5.  Dose schedule for adjuvant cisplatin and 5-Fluorouracil given after radiation    
Agent 
Dose 
Route
- 
Interval
Notes 
  
  
  
 
  
  
Cisplatin 
80 
mg/m2/day
I.V. 
- 
4 weeks 
(28 days)
 Administered as per 
institutional standard 
5-Fluorouracil 1,000 mg/ 
m2/day  
I.V. 
 
4 weeks 
(28 days)
Mix according to institutional 
guidelines.  Give as a 96 hour 
continuous infusion 
 
Chemotherapy can be administered up to two days early or late if necessary for 
scheduling purposes. 
 


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6.5.4 Cisplatin Administration Guidelines:  
6.5.4.1 Patients will be pre-hydrated with one liter of D5NS and 20 mEq KCl/L 
and MgSO4 (2 gm/L).  An oral equivalent dose of KCl is an acceptable 
option. 
6.5.4.2 Cisplatin in 1000 ml of NS administered as per institutional standard.  
Ensure there is adequate urine output prior to cisplatin infusion.  Mannitol 
of 12.5 gm may be given immediately before the administration of 
cisplatin or it can be given in cisplatin infusion.  Furosemide 10 mg may 
be given as an intravenous bolus before cisplatin infusion.  For adjuvant 
therapy after radiation, the cisplatin dose is 80 mg/m2. 
6.5.4.3 Patients should receive at least 3 liters of fluids over the ensuing 24 hours, 
either parenterally or orally. The anti-emetic regimens will be 
administrated per institutional guidelines.  In general, the antiemetics 
should include a 5-HT3 antagonist (i.e. granisetron 750 mcg IV or 1 - 2 mg 
orally, or ondansetron 8 - 24 mg IV or orally). Additional antiemetics may 
include, but are not limited to, lorazepam, aprepitant, metoclopramide 
and/or prochlorperazine. 
 
6.5.5 5-Fluorouracil Administration Guidelines: 
 Dose: 5-FU dose = 1000 mg/m2/24 hr as a 96 hour continuous infusion on days 1-
4 of each 28 day cycle.A central intravenous line must be in place for those who 
receive the continuous 5-FU infusion as outpatients. 
 
6.5.6 Cisplatin Dose Adjustments  
6.5.6.1 Neutropenia 
Treatment can be delayed for up to 2 weeks until ANC is ≥ 1500/mm3. 
However, if the counts have not recovered in 2 weeks, the patient should 
go off chemotherapy.  Dose reductions for reduced ANC are not based on 
a single nadir count. The ANC must remain < 500/mm3 for > 5 days 
before a dose reduction is made. If the results of the scheduled weekly 
complete blood count documents an ANC of < 500/mm3, repeat counts 
are to be obtained every other day until the ANC recovers to a level of > 
500/mm3.  If chemotherapy must be withheld due to neutropenia, 
complete blood count should be obtained weekly until the counts reach the 
lower limits for treatment as outlined.   


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Table 6.  Cisplatin dose modifications in neutopenia 
 
 
Nadir of last cycle 
 
 
% Dose of cisplatin from 
starting dose 
 
ANC* on day 1 of  
each cycle  < 1500 
ANC* on day 1 of  
each cycle  > 1500 
Febrile neutropenia 
(regardless of duration) 
Hold 
100% 
< 500 for < 5 days 
Hold 
100% 
< 500 for ≥ 5 days 
Hold 
80% 
 
 
* ANC = absolute neutrophil count 
 
ANC must be ≥ 1,500/mm3 on day 1 of each cycle.  Reduce doses only 
for ANC is < 500/mm3 for ≥ 5 days.   
 
6.5.6.2 Thrombocytopenia 
Chemotherapy must not be administered until platelets are > 100,000.  If 
chemotherapy must be withheld due to thrombocytopenia, platelet counts 
should be obtained weekly until the counts reach the lower limits for 
treatment as outlined.  Treatment is based upon the nadir count of the last 
cycle of chemotherapy as follows: 
 
Table 7.  Cisplatin dose modifications in thrombocytopenia 
 
 
Nadir of last cycle 
 
 
% Dose of cisplatin from 
starting dose 
 
Platelets on day 1 of 
each cycle < 100,000 
Platelets on day 1 of each 
cycle > 100,000 
> 50,000 
Hold 
100% 
< 50,000 (1st occurrence) 
Hold 
80% 
< 50,000 (2nd occurrence) 
Hold 
60% 
 
6.5.6.3 Peripheral neuropathy  


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A neurological examination must be performed at least before entry into 
the study and then once every cycle and when the patient goes off 
chemotherapy. In case of symptoms or signs experienced by the patient, 
more frequent examinations should be performed and dose modification 
will be as follows: 
Grade 0 - 1: no change 
 
Grade ≥ 2:  Decrease cisplatin dose by 50%.  Carboplatin at an AUC of 6 
may be substituted for cisplatin 
 
 
6.5.6.4 Otoxicity  
Cisplatin is known to cause high frequency hearing loss.  If grade 1 or 2 
hearing loss occurs, the risk of additional hearing loss versus the potential 
benefit of continuing cisplatin chemotherapy should be made.  If cisplatin 
is to be continued in the presence of grade 1 or 2 hearing loss, the dose of 
cisplatin should be decreased by 50%.  Grade 3 and 4 hearing loss is an 
indication to discontinue the drug.  In case of grade 3 or 4 toxicity, 
carboplatin (at dosage of AUC 6) may be used to replace cisplatin in the 
remaining chemotherapy cycles. The dose of carboplatin AUC 6 will be 
calculated based on the Calvert formula (table 9). 
 
6.5.6.5 Nephrotoxicity 
 
If, despite adequate rehydration, serum creatinine increases to ≥ grade 1 (> 
1.5 x ULN), creatinine clearance should be recalculated before the next 
cycle and subsequent dose reductions will be considered as follows: 
 
 
 
Table 8.  Cisplatin dose modifications in kidney impairment 
 
 
Calculated creatinine 
clearance (ml/min) 
 
 
% Dose of cisplatin from 
starting dose  
≥  60  
 
100% 
< 60 
0% (withhold treatment for a maximum of 2 weeks and repeat 
serum creatinine weekly after additional hydration), then 
 
If *CCl was < 60 mL/min 
and is now:  
 
The percent dose to give is: 
 
> 50 but < 60 
80% 


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≥ 40 and ≤ 50 
50% 
 
< 40 
0% 
* CCl = creatinine clearance  
 
If creatinine clearance recovers, the dose of cisplatin for the following cycle 
should be re-escalated to the previous dose level. 
 
6.5.7 Carboplatin Adminstration and Dose Adjustments  
Carboplatin may be substituted for cisplatin if a patient develops 1) grade 3 or 
higher ototoxicity, 2) grade 2 or higher peripheral neuropathy, or 3) an 
unacceptable cisplatin-associated nausea and vomiting after receiving 1 or 2 doses 
of cisplatin.  In the event of carboplatin-induced ≥ 3 neurotoxicity, carboplatin is 
discontinued. 
 
Carboplatin is available commercially.  It should be stored and reconstituted 
according to standard pharmacy operating procedures. 
 
Carboplatin will be infused over 1 to 2 hours.  Carboplatin dosage (mg) will be 
calculated for a target AUC 6 using the Calvert formula (table 9).  Creatinine 
clearance (CrCl) will be calculated using the Cockroft-Gault equation (table 10).   
 
For females, use 85% of the calculated CrCl value.  The actual body weight in 
kilograms will be utilized in the Cockroft-Gault formula (table 10).  However, if 
the calculated creatinine clearance exceeds an upper limit for creatinine clearance, 
as specified below, then this ceiling value for creatinine clearance, rather than the 
calculated creatinine clearance, will be used in the Calvert formula to calculate the 
dose of carboplatin.  The maximum creatinine for both male and female patients is 
125ml/min. Alternatively, at the treating physician’s discretion, a measured 24-
hour creatinine clearance can be obtained.  In this case, the measured creatinine 
clearance can be used to calculate the carboplatin dose in the Calvert formula 
(table 9). 
 
 
Table 9.  Calvert formula for calculation of carboplatin dosage 
 
 
Dose of carboplatin (mg) = AUC x [CrCl (ml/min) + 
25] 
 
 
 
 


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Table 10.  Cockroft-Gault equation for calculation of creatinine clearance (CrCl) 
 
 
CrCl (ml/min) =            (140 - age) (wt kg)*            
 
[72 x serum creatinine (mg/dl]  
 
 
* For female, the equation needs to be multiplied by 0.85. 
 
 
6.5.7.1 Thrombocytopenia 
Carboplatin must not be administered until platelets are > 100,000/mm3. 
Treatment is based upon the nadir count of the last cycle of chemotherapy 
as follows: 
 
Table 11.  Carboplatin dose modifications in thrombocytopenia 
 
 
Nadir of last cycle 
 
 
Dose of carboplatin 
 
Platelets on day 1 of 
each cycle < 100,000 
Platelets on day 1 of each cycle 
> 100,000 
> 50,000 
Hold 
AUC 5  
< 50,000  
Hold 
AUC 4 
 
6.5.7.2 Neutropenia 
Carboplatin must not be administered until ANC > 1500/mm3.   
 
Table 12.  Carboplatin dose modifications in neutropenia 
Nadir of last cycle 
 
 
Dose of carboplatin 
 
 
ANC on day 1 of each 
cycle < 1500 
ANC on day 1 of each cycle > 
1500 
Febrile neutropenia 
Hold 
AUC 6 
< 500 for < 5 days 
Hold 
AUC 6  
< 500 for > 5 days 
Hold 
AUC 4 


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6.5.8 5-Fluorouracil Dose Adjustments 
 
6.5.8.1 Mucositis 
 
In case of grade 3 mucositis lasting more than 96 hours or grade 4 
mucositis, 5-fluorouracil dose will be reduced by 20% from 1000 to 800 
mg/m2/day.  A mouth rinse should always be allowed.   
 
In case of grade 3 mucositis lasting more than 120 hours as a second 
occurrence or grade 4 mucositis as a second occurrence, the dose of 5-
fluorouracil will be reduced to 800 mg/m2/day for 3 days. 
 
6.5.8.2 Diarrhea 
 
In the case of severe diarrhea, octreotide is recommended.  If the patient 
has a significant diarrhea occurrence again (> 3 loose stools/24 hr), the 
patient should be treated prophylactically in the subsequent cycles with 2 
tablets of loperamide or diphenoxylate in addition to 1 or 2 tablets after 
each loose stool. The maximum daily dose of loperamide is 16mg and 
diphenoxylate is 20mg/day. 
 
For grade 4 diarrhea, or grade 3 diarrhea lasting > 7 days despite the 
prophylactic treatment, 5-fluorouracil will be reduced by 10% per day 
from 1000 mg/m²/day to 900 mg/m²/day for subsequent cycles. 
Appropriate symptomatic treatment with loperamide or diphenoxylate 
hydrochloride with atropine sulfate should be given. 
 
If despite these measures, grade 4 diarrhea or grade 3 diarrhea lasting > 7 
days occurs again, the dose of 5-fluorouracil will be reduced 20% from 
1000 mg/m²/day to 800 mg/m²/day in the subsequent cycle. 
 
6.5.8.3 Hematologic 
 
 
 
 
For grade 2 or higher hematologic toxicities, 5-fluorouracil dose will be 
reduced by 20% from 1000 to 800 mg/m2/day.  For grade 2 or higher 
hematologic toxicities as a second occurrence, 5-fluorouracil dose will be 
reduced from 800 to 640 mg/m2/day. 
 
 
6.5.8.4 Skin 
 


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In case of rash including hand-foot syndrome or moist desquamation of 
grade 3 lasting > 7 days or grade 4, the dose of 5-fluorouracil will be 
reduced by 20% from 1000 mg/m²/day to 800 mg/m²/day in the 
subsequent cycle. 
 
6.5.8.5 Cardiac 
 
Patients without prior history of angina, who develop angina that appears 
to be temporarily related to the infusion of 5-FU, must have the drug 
infusion stopped and the 5-FU permanently discontinued. 
 
 
6.6 
Neck Dissection 
 
A neck dissection should be considered if a palpable or worrisome radiographic 
abnormality persists in the neck eight weeks after radiotherapy ends.  
 
 
7.0 
Toxicity Measurement 
 
 
 
Toxicities will be graded according to the Common Terminology Criteria for 
Adverse Events, Version 3.0 (CTCAE) (Appendix XI). 
 
 
8.0 
Quality of Life Assessment 
 
 
In patients with head and neck carcinoma, both the disease and its treatment often 
significantly impact daily functions and activities such as eating, speaking, and 
socializing.  Radiotherapy, particularly combined with chemotherapy, is associated with 
severe mucositis, sticky saliva, pain, dry mouth, hoarseness, fatigue, skin irritation, and 
difficulties in swallowing and tasting.  Many of these symptoms can persist years after 
completion of treatment.  Dental problems such as radiation caries could develop.  Many 
of these side effects are the results of photon irradiation to the normal tissues, such as the 
major salivary glands, adjacent to the tumor. 
 
 
 
Proton beam radiation has very distinctive physical properties.  The beams can be 
modulated so that the beam stops at the distal edge of the target, resulting in little or no 
exit dose.  This superior dose distribution, when compared to photons, allows high dose 
conformality and uniform dose distribution around the target and much lower integral 
dose to the non-target normal tissue.  The impact of proton beam irradiation in the health-
related quality of life (QOL) of the head and neck cancer patients has not been studied.   
 
 


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8.1 
Self-assessment of quality-of-life 
 
 
 The validated 35-item EORTC-QLQ-H&N questionnaire along with the EORTC 
QLQ-C30 which measures general quality of life will be used (Appendix IV and 
V).  These self-administrated questionnaires will be given pre-radiation treatment, 
at approximately 1.5, 3, 6, 12, and 24 months post-treatment. 
 
Patients who are found to have serious concerns in quality of life at any time point 
will be referred to the appropriate sources accordingly.  For patients with severe 
mucositis and pharyngitis, pain medications will be prescribed.  Patients with 
difficulty swallowing or speech dysfunction will be evaluated by speech and 
swallowing specialists.  Patients who have difficulty maintaining their weights 
will be referred to the nutritional service; gastrostomy tube for feeding will be 
placed if indicated.  Patients with dental problems will be evaluated by the dental 
service.  For patients with difficulties with body image and social interactions, 
they will be offered to meet with a social worker to discuss their problems.  
Psychiatric evaluation will be referred if indicated. 
 
 
8.2 
Objective assessment of swallowing function 
 
Improved locoregional control of advanced head and neck cancer has been 
reported using concurrent radiotherapy and chemotherapy.  Concurrent 
chemoradiation can result in increased acute and long-term dysphagia compared 
with radiation alone.  Late dyshpagia and fibrosis are major factors limiting the 
intensity of therapeutic regimens for head and neck cancer.   
Videofluoroscopic swallowing study (VFSS) (Appendix X) will be used to 
evaluate swallowing function.  VFSS is a validated method of objective 
assessment of swallowing, allowing viewing and recording of the structures and 
dynamics of the swallowing process.  Each subject will be asked to swallow 
multiple trials of various food consistencies in varying amounts. The consistencies 
included thin liquid barium (diluted with water) followed with non-diluted 
barium, followed with a puree, soft food (fruit mixed with barium), and a solid 
(shortbread cookie) coated with barium. The examinations are recorded, and 
analysis of the three phases of swallowing - oral, pharyngeal, and esophageal – is 
subsequently completed. Assessment will be focused on bolus manipulation and 
control and bolus passage, including cohesion, motility, and timing.   
Evaluation of swallowing function will be performed pre-therapy and at 
approximately 3, 12, and 24 months after therapy.   
 


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8.3 
Objective assessment of xerostomia 
 
Sialometry will be performed before initiation of the first radiation fraction, and at 
approximately 3, 6, 12, and 24 months after the completion of radiation. 
 
8.3.1 Unstimulated Whole Saliva:  Patients should refrain from eating, drinking 
or dental hygiene for at least 60 minutes before collection. During 
collections, patients should be seated and instructed to minimize orofacial 
movements and not to attempt to influence salivary flow (such as by 
sucking or swallowing).  Just before the collection, the patient should be 
instructed to swallow.  He/she should then be instructed to allow saliva to 
accumulate in the floor of mouth for 60 seconds without swallowing. The 
accumulated saliva should be collected into a pre-weighted container. The 
patient should repeat this procedure four more times for a total collection 
time of five minutes. Subjects should be instructed not to swallow during 
the entire collection procedure. 
8.3.2 Stimulated Whole Saliva: After the collection of unstimulated saliva, 
patients will have 2% citrate solution applied with cotton tipped 
applicators to the lateral tongue bilaterally five times over a two minute 
period (0, 30, 60, 90, and 120 seconds).  The mouth should then be 
emptied of retained citrate solution.  Saliva should then be collected for 
five minutes, using the same method as for unstimulated saliva. 
 
 
8.4      Speech Assessment/Head and Neck Health Status Assessment Inventory 
(HNHSAI) 
Patient self-assessment of speech outcome is an important element in quality-of-
life measurements after chemoradiation.  Speech assessment questionnaires are 
from the Head and neck health status assessment inventory (HNHSAI) (14).  Nine 
functional and five attitudinal speech items will be used. The patients’ responses 
to the HNHSAI will be recorded so that the lowest value of 1 represents the most 
impaired function and the highest value of 5 represents normal or optimal 
function.  “Not applicable” responses are considered appropriate.  If the patient 
responded to the query about problems talking at work with the “not applicable” 
response (i.e. “I’m not currently employed”), the response will be treated as 
missing.  The speech assessment will be conducted within 14 days of initiation of 
radiation treatment and at 1.5, 3, 6, 12, and 24 months after treatment completion. 
 
 
8.5  
ChemoSensory Questionnaire (CSQ) 
Treatments for head and neck cancer commonly results in smell and taste 
dysfunction which then can lead to quality-of-life changes.  Smell and taste 
dysfunction can also have a major negative impact on patients’ nutrition status.  


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The Chemosensory Questionnaire (CSQ) developed by Goldberg et al (15) will be 
used.  Four questions each on smell and taste will be used.  A minimum score of 4 
and a maximum of 20 for the smell scale and taste scale are possible with a higher 
score indicating better function.  If there is a single missing score in a single 
section, the average of the three remaining scores is used for the missing value.  If 
two questions are missing in a single section, then the survey section is invalid.  
The chemosensory assessment will be conducted within 14 days of initiation of 
radiation treatment and at 1.5, 3, 6, 12, and 24 months after treatment completion. 
 
 
8.6 
Trismus Assessment 
Trismus or restricted mouth opening is a very common side effect after 
conventional radiation therapy for nasopharyngeal carcinoma.  Radiotherapy 
involving the structures of the temporomandibular joint or muscles of mastication 
could result in trimus.  The degree of trismus will be measured by serial changes 
of the maximal inter-incisal distance in the vertical opening, right lateral, and left 
lateral jaw movements.  The trismus assessment will be conducted within 14 days 
of initiation of radiation treatment and at 1.5, 3, 6, 12, and 24 months after 
treatment completion. 
 
 
8.7 
Patient Swallowing Diary 
Besides the objective assessment of swallowing function by the videofluoroscopic 
measurements, patient self-assessment of swallowing function is also important.  
Subjective swallowing dysfunction has been shown to be common after 
conventional radiation therapy for nasopharyngeal carcinoma (16).  In the patient 
swallowing diary, patients will be ask about their swallowing function with solids 
and liquids before radiation begins, each day during radiation treatment, and at 
1.5, 3, 6, 12, and 24 months after treatment completion. 
 
 
9.0 
Data Collection 
 
Table 13.  Evaluations before, during, and after chemoradiation 
 
 
Pre-
study 
(timing 
before 
study entry) 
 
Pre-
treatment 
During 
chemoradiati
onb 
During 
chemotherapy 
alone 
Follow-upc 
History & 
physical 
14 days  
 
X 
X 
X 
Disease 
8 weeks 
 
 
 
X 


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documentation 
(*EUA) 
Dental evaluation 
 
6 months 
 
 
 
Tobacco and 
alcohol 
assessment 
 
14 days 
 
 
 
Nutritional 
evaluation 
 
1 month 
 
 
 
Patient 
swallowing diary 
 
14 days 
X 
 
1.5, 3, 12, 24 
monthsi 
CBC/platelets 
14 days  
 
X 
Xh 
X 
Chemistry (alkaline 
phosphatasea, AST, 
ALT, bilirubin, BUN, 
serum creatinine, 
creatinine clearance 
(if indicated), 
electrolytes (Na, K, 
Mg, Cl), calcium, 
protein, albumin, 
urinalysis (if 
indicated) 
14 days  
 
X 
(Weekly for BUN 
and creatinine.  
Every 3 weeks 
for the others)  
X 
(Every 3 weeks) 
 
β-HCG for 
females at risk for 
pregnancy 
14 days 
 
 
 
 
 
Thyroid function 
panel (TSH, T3, 
T4) 
 
14 days  
 
 
 
Xl 
Chest X-ray or CT 
1 month 
 
 
 
Xd 
CT/MRI of H&N 
1 month 
 
 
 
Xd 
PET/CTf 
 
1 month 
 
 
X 
Toxicity 
evaluation 
 
 
X 
Xe 
X 
Swallow study 
 
21 days 
 
 
3, 12, 24 
monthsi 
Salivary study 
 
21 days 
 
 
3, 6, 12, 24 
monthsi 
 
Speech 
assessment 
(HNHSAI) 
 
 
14 days 
 
 
1.5, 3, 6, 12, 
24 monthsi 
Subjective QOL 
 
14 days 
 
 
1.5, 3, 6, 12, 
24 monthsi 
Physician 
dysphagia log 
 
14 days 
 
 
1.5, 3, 6, 12, 
24 monthsi 


Version 2.0  
Date: 6.21.2011 
-  
 
29
Audiogram 
6 weeks  
 
 
 
Xg 
Chemosensory 
questionnaire 
(CSQ) 
 
14 days 
 
 
1.5,3,6,12,24 
monthsi 
Trismus 
assessment 
 
14 days 
 
 
1.5,3,6,12,24 
monthsi 
 
* EUA = examination under anesthesia 
X denotes the type of evaluation that needs to be performed during the study period. 
a. 
Liver CT or MRI must be done in presence of elevated alkaline phosphatase, 
AST, or bilirubin or other clinical indicator; bone scan must be done in presence 
of elevated alkaline phosphatase or other clinical indicator. 
b.  
Weekly during radiotherapy. 
c.  
Follow-up will be performed after radiation and then every 3 (+/-3 weeks) months 
during the first two years; every 6 (+/- 3 months) months during years 3 - 5; then 
annually (+/- 6 months).  After year 5, patients are encouraged to continue with 
the follow-up appointments and studies annually (+/- 6 months).  All follow-up 
appointments and studies may be performed at non-participating institutions with 
results sent to the participating institutions for review. 
d.  
These tests will be performed at least every 6 months (+/- 3 months) during the 
first 3 years; the first CT/MRI of nasopharynx will be performed at approximately 
2 months after radiation. 
e. 
Prior to each cycle. 
f.  
PET/CT is optional but encouraged.   It will be performed prior to treatment (must 
be ≤ 21 days prior to study entry), at approximately 2 months after radiation, and 
every 6 months during the first 3 years. 
g.  
Yearly (+/- 6 months) or clinically indicated.  Once patients have reached the 24-
month follow-up time point, patients are encouraged but not required to perform 
these studies at their annual (+/- 6 months) follow-up appointments. 
h. 
Every three weeks, or more frequently as clinically indicated.  CBC/platelets must 
be drawn before treatment, either on day 1 of each cycle or no more than 72 hours 
in advance of each cycle. 
i. 
The 1.5 month studies will be performed at 1.5 (+/- 1) month after radiation, 3-
month studies will be performed at 3 months (+/- 6 weeks), the 6-month studies 
will be performed at 6 (+/- 3) months, the 12-month studies will be performed at 6 
(+/- 3 months), and the 24-month studies will be performed at 24 (+/- 6) months.  
Once patients have reached the 24-month follow-up time point, Patients are 
encouraged but not required to perform these studies at their annual (+/- 6 
months) follow-up appointments. 
 
 
 
 
10.0 
Adverse Events Reports 


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30
 
Adverse events resulting from unanticipated treatment toxicity that is life threatening or 
fatal will be reported to the IRB within 10 working days. 
 
 
11.0 
Modality Review 
 
 
Local Recurrence 
Local recurrence is defined as: evidence of tumor growth/regrowth in any 
direction beyond that present on the pre-treatment imaging studies or the 
appearance of tumor in tissues previously scored as sites of sub-clinical disease.  
The imaging studies are to be comparable in technical factors. Site of failure will 
be related to treatment volumes PTV1, 2, and 3. 
 
Nodal Recurrence 
 Recurrence in regional draining lymph nodes 
 
 
Compliance to therapy 
 Defined as the number of courses of concurrent and adjuvant chemotherapy received, 
as well as the time required to complete the radiotherapy. 
 
Distant Recurrence 
Defined as appearance of tumor at sites beyond regional nodal and marginal sites. 
 
Progression-Free and Overall Survival 
Measured from the date of registration to the date of progressive disease or death. 
 
  
12.0 
Biostatistical Considerations 
 
 
 
The rationale of using protons in the combined modality treatment of locally 
advanced nasopharyngeal carcinoma is the potential to improve patient outcome if the 
treatment compliance were improved by reducing acute toxicity.  In particular, better 
tolerance of systemic chemotherapy is expected with the greater degree of normal tissue 
sparing by the proton beam.  Only 55% of the patients on the Intergroup Study completed 
all 3 concurrent and 3 adjuvant cycles of chemotherapy (9), using the same regimen as in 
the present protocol.  A sample size of 25 patients will provide 80% power to determine 
an increase in the chemotherapy completion rate to at least 77% at a one-sided 
significance level of 6%.  The error rates correspond to a decision rule that requires a 
minimum of 18 patients to complete all 6 cycles of protocol-indicated chemotherapy.  
 
 
 
Mucositis was the most common reason for discontinuing chemotherapy in the 
Intergroup study, with 37% of patients experiencing grade 3 or 4 events on the 
chemoradiation arm.  If grade 3 or 4 mucositis were observed among no more than 5 of 
the 25 patients treated by proton radiotherapy, 80% power will be available to detect a 
decrease in the rate to 16%.  The decision rule is associated with a one-sided significance 


Version 2.0  
Date: 6.21.2011 
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31
level of 6% under the null hypothesis assuming no difference from the Intergroup data.  
In general, 25 patients will provide 90% confidence interval widths that are no more than 
35% for estimating the rate of acute and late effects. As all other toxicities are expected 
to be less common than mucositis, interval widths will be much narrower in practice. 
 
 
 
A secondary objective will investigate the rate and pattern of loco-regional 
recurrence.  In addition to progression-free survival, the rate of loco-regional failure first 
will be estimated by allowing for competing risks due to distant failure and death from 
other causes.  The subgroup sample size will be limited for each of the T1-T2 and T3-T4 
tumor categories, especially as the patient distribution cannot be projected definitively 
for the accrual of only 25 patients with a rare cancer.  Thus the goal will be mainly to 
show the null hypothesis cannot be rejected, that is, the local control rate in tumor 
subgroups will not be lower than that observed using conventional radiotherapy in 
combined modality treatment.  The accrual goal of 25 patients is anticipated to be 
reached in about 3 years.  The referral pattern of tumor stage to proton treatment 
suggests the expected accrual distribution will be approximately 6 patients with T1 - 
2 tumors and 18 patients with T3 - 4 tumors. Assuming the local-regional control rate 
was 70% for T1-T2 tumors at 3 years based on conventional radiotherapy regimens, the 
probability is 7% for at least 4 of 6 patients to have experienced local-
regional failure within 3 years. If the local-regional control rate of T3 - 4 tumors using 
protons were the same as the historical 50% rate using conventional radiotherapy, the 
probability is 5% for 13 or more of 18 patients to have failed locally or in the regional 
lymph nodes.  


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32
13.0  References 
 
1. 
Chu A, Flynn MB, Achino E, et al. Irradiation of nasopharyngeal carcinoma: 
Correlations with treatment factors and stage. Int J Radiat Oncol Biol Phys 
1984;10:2241–2249. 
 
2. 
Hoppe RT, Goffinet DR, Bagshaw MA. Carcinoma of the nasopharynx: Eighteen 
years’ experience with megavoltage radiation therapy. Cancer 1976;37:2605–
2612. 
 
3. 
Mesic JB, Fletcher GH, Goepfert H. Megavoltage irradiation of epithelial tumors 
of the nasopharynx. Int J Radiat Oncol Biol Phys 1981;7:447–453. 
 
4. 
Sanguineti G, Geara F, Garden A, et al. Carcinoma of the nasopharynx treated by 
radiotherapy alone: Determinants of local and regional control. Int J Radiat Oncol 
Biol Phys 1997;37:983–996. 
 
5. 
Bailet JW, Mark RJ, Abemayor E, et al. Nasopharyngeal carcinoma: Treatment 
results with primary radiation therapy.  Laryngoscope 1992;102:965–972. 
 
6. 
Vikram B, Strong EW, Manolatos S, et al. Improved survival in carcinoma of the 
nasopharynx. Head Neck Surg 1984;7:123–128. 
 
7. 
Wang CC. Carcinoma of the nasopharynx. In: Wang CC, editor. Radiation 
therapy for head and neck neoplasms: 3rd ed.  Wiley-Liss Publishers; 1997. p. 
257–280. 
 
8. 
Kwong D, Sham J, Choy D: The effect of loco-regional control on distant 
metastatic dissemination in carcinoma of the nasopharynx: An analysis of 1301 
patients. Int J Radiat Oncol Biol Phys 1994;30:1029–1036. 
 
9. 
Al-Sarraf M, LeBlanc M, Giri PGS, et al.  Chemoradiotherapy versus 
radiotherapy in patients with advanced nasopharyngeal cancer: Phase III 
randomized Intergroup Study 0099. J Clin Oncol 1998;16:1310–1317. 
 
10. 
Lin JC, Jan JS, Hsu CY, et al.  Phase III study of concurrent chemoradiotherapy 
versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect 
on overall and progression-free survival.  J Clin Oncol. 2003;21:631–637. 
 
11. 
Chan AT, Teo PM, Ngan RK, et al.  Concurrent chemotherapy-radiotherapy 
compared with radiotherapy alone in locoregionally advanced nasopharyngeal 
carcinoma: progression-free survival analysis of a phase III randomized trial.  J 
Clin Oncol. 2002;20:2038–2044. 


Version 2.0  
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-  
 
33
 
12. 
Suit HD.  Protons to replace photons in external beam radiation therapy? Clin 
Oncol (R Coll Radiol). 2003;15:S29–31. 
 
13. 
Chan AW, Liebsch LJ, Deschler DG, et al.  Proton radiotherapy for T4 
nasopharyngeal carcinoma.  American Society of Clinical Oncology 40th Annual 
Meeting 2004; New Orleans, Louisiana. 
 
14. 
Karnell LH, Funk GF, Tomblin JB, et al. Quality of life measurements of speech 
in the head and neck cancer patient population. Head and Neck. 1999;21:229-238. 
 
15. 
Goldberg AN, Shea JA, Deems DA, et al.  A chemosensory Questionnaire for 
patients treated for cancer of the head and neck. Laryngoscope. 2005;115:2077-
2086. 
 
16.   Ku PK, Yuen EH, Cheung DM, et al.  Early swallowing problems in a cohort of 
patients with nasopharyngeal carcinoma: Symptomatology and videofluoroscopic 
findings.  Laryngoscope. 2007;117(1):142-6. 
 
 
 


Version 2.0  
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34
14.0 
Regulatory Requirements 
 
14.1 
Declaration of Helsinki 
 
 The PI will ensure that this study will be conducted in full conformity with the 
current version of the declaration of Helsinki and with U.S. FDA requirements. 
 
14.2 
Informed Consent 
 The PI and Co-PIs will obtain witnessed informed consent of the patients (or 
patients’ parents or guardians if appropriate) after adequate explanation of the 
aims, methods, anticipated benefits and potential hazards of the study to the 
patient (or patients’ parents or guardians if appropriate).  The patient will be given 
a copy of the informed consent which is stamped ‘Patients Reference Copy’.  The 
original signed copy informed consent will be retained in the patient’s radiation 
oncology record. 
 
14.3 
Patient Confidentiality 
 
 
The investigators will ensure that patient anonymity is maintained. 


Version 2.0  
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35
APPENDIX I - PERFORMANCE STATUS 
 
 
KARNOFSKY PERFORMANCE SCALE (KPS) 
 
100 
Normal; no complaints; no evidence of disease 
90  
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some sign or symptoms of disease 
70  
Cares for self; unable to carry on normal activity or do active work 
60  
Requires occasional assistance, but is able to care for most personal needs 
50 
Requires considerable assistance and frequent medical care 
40  
Disabled; requires special care and assistance 
30  
Severely disabled; hospitalization is indicated, although death not imminent 
20  
Very sick; hospitalization necessary; active support treatment is necessary 
10  
Moribund; fatal processes progressing rapidly 
0  
Dead 
 
 
ZUBROD PERFORMANCE SCALE (ZPS) 
 
0  
Fully active, able to carry on all predisease activities without restriction 
(Karnofsky 90 - 100). 
1  
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature. For example, light housework, office work 
(Karnofsky 70 - 80). 
2  
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours (Karnofsky 50-60). 
3  
Capable of only limited self-care, confined to bed or chair 50% or more of waking 
hours (Karnofsky 30 - 40). 
4  
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair (Karnofsky 10 - 20). 


Version 2.0  
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36
APPENDIX II - STAGING SYSTEM 
NASOPHARYNX, AJCC STAGING, 6th Edition, 2002 
 
 
Definition of TNM 
 
Primary Tumor (T) 
TX 
Primary tumor cannot be assessed 
T0  
No evidence of primary tumor 
Tis  
Carcinoma in situ 
 
Nasopharynx 
T1 
Tumor confined to the nasopharynx 
T2 
Tumor extends to soft tissues  
T2a 
tumor extends to the oropharynx and/or nasal cavity without parapharyngeal 
extension* 
T2b 
any tumor with parapharyngeal extension* 
T3 
Tumor invades bony structures and/or paranasal sinuses 
T4 
Tumor with intracranial extension and/or involvement of cranial nerves, infratemporal 
fossa, orbit, or masticator space 
 
*Note: Parapharyngeal extension denotes posterolateral infiltration of tumor beyond the 
pharyngobasilar fascia. 
 
Regional Lymph Nodes (N) 
NX 
Regional lymph node metastasis 
N0 
No regional lymph node metastasis 
N1 
Unilateral metastasis in lymph node (s), 6 cm or less in greatest dimension, above the 
supraclavicular fossa* 
N2 
Bilateral metastasis in lymph node (s), 6 cm or less in greatest dimension, above the 
supraclavicular fossa* 
N3 
Metastasis in a lymph node (s) *, greater than 6 cm and/or to supraclavicular fossa 
N3a  
greater than 6 cm in dimension 
N3b  extension to the supraclavicular fossa** 
 
*Note: Midline nodes are considered ipsilateral notes 
 
**Note: Supraclavicular zone or fossa is relevant to the staging of nasopharyngeal carcinoma 
and is the triangular region originally described by Ho.  It is defined by three points: (1) the 
superior margin of the sternal end of the clavicle, (2) the superior margin of the lateral end of the 
clavicle, (3) the point where the neck meets the shoulder (see figure below).  Note this would 


Version 2.0  
Date: 6.21.2011 
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37
include caudal portions of Levels IV and V.  All cases with lymph nodes (whole or part) in the 
fossa are considered N3b. 
 
Stage Grouping: Nasopharynx 
 
Stage 0  
Tis  
 
N0  
 
M0 
Stage I  
T1  
 
N0  
 
M0 
Stage IIA  
T2a  
 
N0  
 
M0 
Stage IIB  
T1  
 
N1  
 
M0 
T2  
 
N1 
 
M0 
T2a  
 
N1  
 
M0 
T2b  
 
N0  
 
M0 
T2b  
 
N1  
 
M0 
Stage III  
T1  
 
N2  
 
M0 
T2a  
 
N2  
 
M0 
T2b  
 
N2  
 
N0 
T3  
 
N0  
 
M0 
T3  
 
N1 
 
M0 
T3  
 
N2  
 
M0 
Stage IVA  
T4  
 
N0  
 
M0 
T4  
 
N1  
 
M0 
T4  
 
N2  
 
M0 
Stage IVB  
Any T   
N3  
 
M0 
Stage IVC  
Any T   
Any N  
M1 

ICF_001.pdf: 
 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 1 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
PROTOCOL TITLE: A Phase II Study of Proton Radiotherapy with Chemotherapy 
for Nasopharyngeal Carcinoma  
DFHCC PRINCIPAL  RESEARCH   DOCTOR  /  INSTITUTION: Annie Chan MD/MGH   
DFHCC SITE-RESPONSIBLE RESEARCH DOCTOR(S) / INSTITUTION(S): Roy Tishler 
MD/DFCI   
 
A. INTRODUCTION 
We are inviting you to take part in a research study. Research is a way of gaining new 
knowledge. If you decide to take part, you will be known as a “participant” rather than a 
“patient”. This is a research study of a different type of radiation therapy called proton 
beam radiotherapy.  
 
You are being asked to take part in this study because you have nasopharyngeal cancer.   
Nasopharyngeal cancer is usually treated with concurrent (meaning at the same time) 
chemotherapy and radiation therapy followed by an additional course of chemotherapy 
alone. 
 
The type of radiation normally given to treat your tumor uses a photon beam.  This study 
involves the use of a different type of radiation using a proton beam to deliver your 
treatment.  In this study you will receive both the photon and proton beam radiation.  
Most of the radiation will be delivered using proton beam.  A portion of the treatment 
will be delivered using photon as to provide the best optimal radiation dose distribution 
and delivery. 
 
About 25 people will take part in this study throughout the Dana-Farber/Harvard Cancer 
Center (DF/HCC). 
 
This consent form will give you the information you will need to understand why this 
study is being done and why you are being invited to participate. It will also describe 
what you need to do to participate and any possible risks, inconveniences or discomforts 
that you may have while participating.  If you decide to participate, you will be asked to 
sign this form and it will be a record of your agreement to participate.  You will be given 
a copy of this form. 
 
NCT00592501


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 2 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
If you do sign this consent form, you will first need to be evaluated by the study doctors 
to see if you can be in the study.  This is called screening. The study has eligibility 
requirements that must be met.   
 
If the screening tests show you can be in the study, you will be able to start on the study 
treatment.  If the study doctor feels the results of these tests show that you cannot be in 
the study, you will not be able to start on study treatment. This is done for safety reasons. 
 
We encourage you to take some time to think this over and to discuss it with your family, 
friends and doctor.  We also encourage you to ask questions now and at any time. 
 
 
B. WHY IS THIS STUDY BEING DONE? 
 
The standard treatment for your type of cancer is concurrent chemotherapy and photon 
radiation therapy followed by additional chemotherapy alone.  If you choose to 
participate in this study, you will be given concurrent chemotherapy using cisplatin 
combined with proton-photon beam radiation.  This will be followed by an additional 
course of chemotherapy using cisplatin and 5-fluorouracil.  The use of combined proton 
and photon instead with photon alone will be investigated in this study. 
 
Photon beam radiation is the standard type of radiation used to treat your type of cancer.  
Photon beam radiation enters the body and passes through healthy tissue, encounters the 
tumor, and then leaves the body through healthy tissue.  In this study, we use combined 
proton beam and photon radiation therapy to treat your tumor.  Most of the radiation will 
be delivered using proton beam.  Proton beam radiation has been shown to have the same 
effect on tumors as photon beam radiation, but has some other advantages.  When using 
proton beam radiation, it enters the body, passes through healthy tissue, and encounters 
the tumor, but then stops.  This means that less healthy tissue is affected by proton beam 
treatment than by photon beam treatment and that more of the energy of radiation goes 
right into the tumor.  
 
The reason that proton beam radiation is not used more widely is that it is only available 
at a few hospitals around the world. 
 
The purpose of this study is to determine the effectiveness of proton beam radiation in 
treating your cancer and reducing the acute and long-term side effects from your 
treatment.  This study will also test to see if the sparing of the healthy tissue can improve 
your quality of life after radiation treatment.   


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 3 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
 
C. WHAT OTHER OPTIONS ARE THERE? 
Taking part in this study is voluntary and you may choose not to participate.  Other 
treatments that may be considered for your condition include the following:  
• Concurrent chemotherapy and radiation therapy using photon beam such as 
conventional photon radiation or intensity modulated photon radiation. 
• Concurrent chemotherapy and radiation therapy using photon beam followed by 
additional chemotherapy 
• Radiation therapy alone using either photon and or proton beam techniques 
• Induction chemotherapy followed by radiation therapy with or without concurrent 
chemotherapy 
• Chemotherapy alone 
• Investigational treatments that may be available to you  
• Comfort care, also called palliative care.  This type of care may help to reduce 
pain, tiredness, appetite problems and other problems caused by the cancer.  It 
does not treat the cancer directly, but instead tries to treat the symptoms. 
 
Your doctor can tell you more about your condition and the possible benefits of the 
different available treatments.  Please discuss these and other options with your study 
doctor. 
 
D. WHAT IS INVOLVED IN THE STUDY? 
After signing this consent form, and before you begin the study, you will need to have the 
following tests or procedures to find out if you can be in the study.  These tests and 
procedures are part of regular cancer care and may be done even if you don’t join the 
study.  If you have had some of these tests or procedures recently, they may not have to 
be repeated.  This will be up to your study doctor.   
 
Standard procedures that are part of regular cancer care that will be done even if you are 
not a part of this study: 
 
• Medical History and Physical Examination 
• Routine blood tests, approximately 1- 2 –teaspoons of blood will be taken.   
• Chest CAT scan 


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 4 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
• Endoscopic evaluation (fiberoptic endoscopic examination).  This requires a 
scope be passed through your nose to examine your nasopharynx (the upper part 
of the throat behind the nose) and other sites of the head and neck area.  
• Dental and nutritional evaluation 
• A hearing test called an audiogram 
• PET scan, if your study doctor thinks it is necessary 
• MRI and CAT scan of the head and neck 
• CT scan of the liver, if your study doctor thinks it is necessary 
• Bone scan if your study doctor thinks it is necessary 
 
If these tests show that you are eligible to participate in the study, you will begin the 
study treatment.  If the tests show that you do not meet the eligibility criteria, you will not 
be able to participate in the study. 
 
Before you begin the study treatment, you will be asked to fill out Quality of life (QOL) 
questionnaires, a Speech Assessment, a ChemoSensory Questionnaire, a Patient 
Swallowing Diary, a Swallowing Study, Salivary Tests, and a Trismus Assessment.  
 
You will need to go to the Massachusetts Eye and Ear Infirmary (MEEI) or 
Massachusetts General Hospital to have the swallow and saliva tests done.  
 
• Quality of Life Questionnaire- You will be asked to fill out four questionnaires. 
Two of the questionnaires contain questions about your general health, your 
symptoms, well-being, and concerns related to your cancer. If the study doctors 
think that you are not doing well emotionally, they will recommend that you meet 
with a mental health professional.  The study doctors will give you the 
information you need to set up a time to meet with someone to help you. Another 
questionnaire is about tobacco and alcohol use and the last one is about any 
difficulty you may have with swallowing.   
 
• Swallow Study- You will be asked to swallow multiple samples of various food 
consistencies in varying amounts. The consistencies included thin liquid barium 
(diluted with water) followed with non-diluted barium, followed with a puree, soft 
food (fruit mixed with barium), and a solid (shortbread cookie) coated with 
barium. 
 
• Saliva Study: Unstimulated Saliva- You should refrain from eating, drinking or 
dental hygiene (brushing your teeth or using mouthwash) for at least 60 minutes 
before this procedure.  During this procedure, you will be seated and instructed to 


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 5 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
minimize facial movements and not to attempt to influence salivary flow (such as 
sucking or swallowing). Just before the collection, you will be instructed to 
swallow.  You will then be asked to allow saliva to accumulate in the floor of 
your mouth for 60 seconds without swallowing. 
 
The saliva will be collected; you will be instructed not to swallow during the entire 
collection procedure.  
 
• Saliva Study: Stimulated Saliva- After the collection of unstimulated saliva, you 
will have 2% citrate solution applied with a cotton tipped applicators to the both 
sides of your tongue for five times over a two minute period (0, 30, 60, 90 and 
120 seconds).  Saliva will then be collected for five minutes, using the same 
method as for unstimulated saliva. 
 
• Speech Assessment 
You will be asked to fill out a speech assessment questionnaire.  Nine functional 
and five attitudinal speech items will be asked.  You will assess your speech on a 
scale of 5 to 1 and 1 represents the most impaired function and the highest value 
of 5 represents normal or optimal function. 
 
• ChemoSensory Questionnaire (CSQ) 
You will be asked to fill out a questionnaire on smell and taste.  Four questions on 
smell and taste will be used respectively.  A minimum score of 4 and a maximum 
of 20 for the smell scale and taste scale are possible with a higher score indicating 
better function.   
 
• Trimus Assessment 
In order to assess your ability to open your mouth after treatment, serial 
measurements of the maximum distance you can move your jaws will be taken 
between before radiation treatment and at certain time points after radiation. 
 
• Patient Swallowing Diary  
You will be asked to fill out a questionnaire about your swallowing function 
before radiation treatment, each day during radiation treatment, and at certain 
time points after radiation.  The questionnaire consists of five questions that 
measure your ability to swallow solids or liquids. 
 
 
 


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 6 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
Study Treatment  
 
SCHEMA 
 
I. Concurrent Radiotherapy and Chemotherapy (Chemoradiation) 
 
RADIOTHERAPY*  Days  1 
 
 
 
 
 
 
54 
 
CISPLATIN**            
X 
 
 
 
 
 
       
 
 
 
 
 
*Administered Monday through Friday, start date may be on a Monday, Tuesday,Wednesday or 
Thursday. 
 
* *Cisplatin infusion to be given every 21 days during RT. First dose to be administered within 
the first three days of the start of radiation. 
 
 
II. Adjuvant Chemotherapy – to begin 3-8 weeks after completion of chemoradiation 
 
Day 
 
1     2      3    4       29    30   31   32     57   58   59   60 
Cisplatin 
x                             x                             x 
5-FU     
x      x     x    x        x     x     x     x        x     x     x     x 
 
Radiation therapy will be given once a day, five days a week, for seven weeks.   This will 
be given as part of outpatient care at the Francis H. Burr Proton Therapy Center (proton 
component of the treatment) and The Massachusetts General Hospital (photon component 
of the treatment).   
  
The Francis H. Burr Proton Therapy Center and the Massachusetts Eye and Ear Infirmary 
are located next to the Massachusetts General Hospital. 
 
You will also receive chemotherapy during and after your radiation treatments at the 
Massachusetts General Hospital or other sites of the Dana-Farber/Harvard Cancer Center. 
 
During your radiation treatments, you will receive the chemotherapy drug cisplatin in 
your vein.  This drug will be given once every 3 weeks starting at the time of radiation. 
This 3-week period is called a cycle of treatment, you will receive 3 cycles of cisplatin..  
Both before you receive the cisplatin and after you receive the cisplatin, you will receive 
additional fluids in your vein, and you may also be given additional fluids by mouth.  The 
length of stay to receive chemotherapy is at least eight hours.   


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 7 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
 
When you complete your radiation treatments, you will again receive cisplatin same as 
above, for three cycles. This will be done once every 4 weeks., Another drug will also be 
given called fluorouricil or 5-FU following the cisplatin.  The 5-FU will be given by 
continuous infusion in your vein over 4 days starting on the day you receive the cisplatin.  
A venous access device and an ambulatory pump will be used to deliver the continuous 
5FU infusion. 
In general, this can be done as an outpatient at your institution. However, depending on a 
number of factors, the chemotherapy treatments may require admission to the hospital.  
 
 
Tests and procedures you will have while you are on this study.  
 
During your radiation and chemotherapy treatment, you will have physical examinations 
and blood (about 1-2 teaspoons) will be drawn weekly to monitor your health. The 
weekly blood draws will continue during your chemotherapy treatments that you receive 
after radiation.  
 
An MR/CT scan of the head and neck will be done 2 months after the radiation treatment.   
 
After the study treatment has ended we would like you to come for follow up visits for 
the rest of your life.  These visits will occur once every 3 months for 2 years, then once 
every 6 months during years 3-5, then annually at the Massachusetts General Hospital. 
 
During these follow up visits, you will have the following tests and procedures: 
 
• Physical examination 
• Blood will be drawn (about 1-2 teaspoons) for routine testing.  
• A chest CT scan and the CT/MRI of the head and neck will be repeated once 
every 6 months during the first 3 years you are on this study. 
• Swallow study - 3, 12, and 24 months after study treatment has ended. 
• Salivary study - 3, 6, 12, and 24 months after study treatment has ended. 
• QOL questionnaires 1.5, 3, 6, 12, and 24 months after study treatment.ended.  
• The swallowing diary (a questionnaire that describes your swallowing ability and 
your symptoms during swallowing) will be filled out each day during radiation 
treatment, then approximately 1.5, 3, 6, 12 and 24 months after study treatment 
has ended. 
• Speech Assessment 1.5, 3, 6, 12, and 24 months after treatment completion  
• ChemoSensory Questionnaire  1.5, 3, 6, 12, and 24 months after treatment 
completion  


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 8 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
• Trismus Assessment 1.5, 3, 6, 12, and 24 months after treatment completion  
Any of the tests and procedures can be done more frequently if your study doctor thinks 
they are needed.  
 
E. HOW LONG WILL I BE IN THE STUDY? 
You will receive study treatment for about 5 months. The follow up visits occur 
occasionally for the rest of your life. 
 
F. WHAT ARE THE RISKS OR DISCOMFORTS OF THE STUDY? 
Proton beam therapy may be less effective in treating your cancer than conventional 
photon beam therapy.  However, previous experience treating participants with head and 
neck tumors and other types of tumors with proton beam therapy, has shown no 
decreased effectiveness compared to photon beam therapy.  
 
While on this study, you are at risk for the side effects described below.  You should 
discuss these with your doctor.  There may also be other side effects that we cannot 
predict. You may receive medications to make side effects less serious and 
uncomfortable.  These side effects generally go away days or weeks after radiation 
therapy has stopped, but in some cases, side effects can be permanent and may require 
treatments.  A risk to taking part in this study is that the treatment you receive may not be 
effective in helping to treat your disease.  You may also experience side effects 
undergoing proton beam radiation that does not provide you with any health-related 
benefits.  Other less common or unexpected side effects may also develop and may be 
irreversible.  During your therapy, you will be monitored closely for potential side 
effects. You are expected to report to the study doctor(s) any adverse sign(s) or 
symptom(s), which may develop while you are on this study. 
 
For your safety, please tell the study doctor about all of your present and past diseases 
and allergies that you are aware of. It is also important that you tell the study doctor about 
any prescription and/or over-the-counter drugs, herbal preparations and nutritional 
supplements that you are taking.  All chemotherapy drugs have side effects, which can be 
anything from mild and reversible to severe, long-lasting and possibly life threatening.  
You need to tell your study doctor or a member of the study team immediately if you 
experience any bad side effects.   
 
As with most types of chemotherapy, the drugs used in this study have the potential to 
affect healthy cells in your body as well as cancerous ones. The healthy cells most often 


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 9 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
affected are blood cells that help to fight infection (white blood cells), blood cells that 
help the blood clot (platelets), and blood cells that carry oxygen in your body (red blood 
cells).   
 
When chemotherapy drugs cause a decrease in these blood cells, it is called bone marrow 
suppression.  While you are undergoing chemotherapy, your blood cell levels will be 
monitored closely. If any of the following occur, notify your nurse immediately: 
 
 A fever of 100.5 or above.   
 
This could be a sign of an infection.  If you have a low white blood cell 
count, this can be serious or life threatening. Admission to the hospital and 
antibiotic therapy may become necessary. 
 
 Low energy or shortness of breath. 
 
This could be a sign of anemia.  If this becomes severe, you may need to 
come into the clinic or hospital to have a transfusion of red blood cells.   
 
 Tendency for bleeding not to stop or bruising easily. 
 
This could be a sign that your platelets are low.  This could be serious or 
life threatening.  You may need to come into the clinic or hospital for a 
transfusion of platelets. 
 
Another risk of chemotherapy drugs is to have blood clots form that can lead to swelling 
in the legs and arms.  These clots may travel to the lungs causing shortness of breath or to 
the brain causing a stroke.  This may become serious and life threatening.  
 
Other common side effects include nausea, vomiting, and loss of appetite.  You may also 
experience loose stools or diarrhea.  It is important to increase your fluid intake if 
diarrhea occurs.  
 
While on this study, you may experience the additional side effects listed below. 
Everyone in the study will be watched carefully for any side effects. However, doctors 
don’t know all the side effects that may happen.  Side effects may be mild or very 
serious.  Some side effects may go away after you stop the study treatment.  
 


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 10 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
The study doctors may give you some medicine that will help with some side effects.  
Some side effects can be long lasting and may never go away and may be fatal. You 
should talk to your study doctor about any side effects that you have.   
During the research study, you will be notified of newly discovered side effects or 
significant findings, which may affect your health or willingness to participate.  You may 
be asked to sign a new consent form that shows that you have been informed of new 
information relating to this research study. 
  
Risks Associated with Radiation Therapy 
 
Very likely (meaning more than 50 % chance this will happen) 
 
• Fatigue 
• Hair loss at the treatment area most likely permanent 
• Redness and irritation of skin within the treatment area 
• Difficulty, pain, or burning sensation when swallowing 
• Dry mouth that remains after treatment 
• Mouth sores 
• Nausea and/or vomiting 
• Loss of appetite and/or taste 
• Skin in treatment area may remain permanently dry  
 
If you have these symptoms you should report them to your study doctor who will 
determine if they are related to the radiation treatments or to infection.  If radiation is the 
cause, the symptoms are usually temporary and relieved with medication.  With dietary 
care and medication for pain, you should be able to eat soft or liquid food and complete 
the study treatment. 
 
Less likely (meaning between 10% to 50% this will happen)  
 
• Voice hoarseness may remain after treatment  
• Thyroid gland dysfunction requiring thyroid hormone pills in the future. Without 
the hormone pills you could experience weight gain, cold intolerance, and fatigue.  
 
 
 


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 11 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
Less likely, but serious  
 
• Injury to the brain that may cause neurological symptoms such as headache, 
seizures, or speech dysfunction.  May require medical or surgical treatments.  
• Injury to the pituitary gland requiring hormonal treatments. Without hormonal 
replacement, you could experience weight gain, infertility, or decreased growth.  
• Injury to the eye structures that may lead to visual impairment. 
• Injury to the jaw or tissue of the neck that may need to jaw or neck stiffness.  
• Irritation of the spinal cord that could result in numbness/tingling or very rarely 
paralysis. 
• Second cancer that could be benign or malignant  
 
Risks Associated with Cisplatin 
 
Very likely (meaning more than 50 % chance this will happen)  
 
• Decrease in blood counts which can lead to a risk of infection and bleeding  
• Loss of appetite and/or taste; metallic taste in your mouth 
• Nausea and/or vomiting  
• Fatigue 
• Hearing loss or ringing in the ears 
• Numbness or tingling in the hands or feet  
 
Less likely (meaning between 10%-50% chance this will happen)  
 
• Muscle cramps or spasm 
• Loss of coordination 
• Involuntary movements or shaking 
• Rash 
• Loss of hair which is temporary 
 
Less likely, but serious 
 
• Loss of muscle or nerve function, which may cause weakness or numbness in 
your hands and feet 
• Facial swelling that could cause airway obstruction  


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 12 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
• Decreasing ability of the kidneys to handle the body’s waste, which may be 
permanent  
• Allergic reactions, which can cause difficulty in breathing, fast heartbeat, and 
sweating 
• Abnormally high levels of enzymes produced by the liver meaning that your liver 
is not functioning properly and can cause fatigue, and jaundice (yellowing of the 
skin and eyes). Although this is usually mild and reversible, this can be serious or 
life threatening. 
• Other cancer called acute leukemia (cancer of blood and bone marrow). 
 
 
Risks Associated with 5-FU (5-Fluorouracil) 
 
Very likely (meaning more than 50% chance this will happen)  
 
• Decrease in blood counts, which can lead to a risk of infection and bleeding  
• Loss of appetite  
• Nausea and/or vomiting  
• Diarrhea with cramping or bleeding 
• Skin rash 
• Fatigue 
• Headaches 
• Hair loss, which is temporary 
• Mouth sores 
• Sore throat 
 
Less likely (meaning between 10% to 50% chance this will happen) 
 
• Confusion 
• Inflammation of the fingers and toes 
• Increased sensitivity to sunlight 
• Darkening of the skin, nails, or veins 
• Loss of coordination or balance 
• Inflammation of the veins that may lead to clots or stroke  
 
 
Less likely, but serious 
 
• Damage to the heart that causes chest pain and lead to a heart attack  


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 13 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
 
Risks associated with MRI 
 
MRIs use powerful magnets to make images. Therefore, persons with metal implants, 
such as surgical clips or pacemakers should not have an MRI.  However, there are no 
known health risks associated with this exposure.  People who feel uncomfortable in 
confined spaces (claustrophobia) may feel uncomfortable in the narrow cylinder.  The 
MRI makes loud banging noises as it takes images. Earplugs can be used to reduce the 
noises. The MRI can be stopped at any time at your request. 
 
Risks associated with CT/PET scan 
 
The radiation associated with these diagnostic x-ray studies will not adversely affect the 
treatment of your disease.   
 
Risks associated with blood drawing 
 
You may experience some discomfort, bruising and/or bleeding at the site of the needle 
insertion. Occasionally, some people experience dizziness or feel faint. In rare instances, 
infection may develop at the site of the needle insertion.  
 
Reproductive risks 
 
Because the drugs and radiation in this study can affect an unborn baby, you should not 
become pregnant or father a baby while on this study.  You should also not nurse your 
baby while on this study.  If you are pregnant, you will not be enrolled in this study. Both 
men and women of reproductive potential must agree to use appropriate methods of birth 
control throughout their participation in this study. 
 
Non-physical risks  
 
Because of side effects or the time required for tests and clinic visits while you are on this 
study, you may be unable to keep up with your normal daily activities such as running 
errands or going to work. 
 
 
 


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 14 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
G. WHAT ARE THE BENEFITS OF THE STUDY? 
Taking part in this study may or may not make your health better.  We hope the 
information learned from this study will help doctors learn more about proton therapy as 
a treatment for nasopharyngeal cancer in the future.   
 
H. CAN I STOP BEING IN THE STUDY AND WHAT ARE MY RIGHTS? 
 
Yes.  Taking part in this study is your choice. You can stop at any time.  Tell the study 
doctor if you are thinking about stopping or decide to stop.  He or she will tell you how to 
stop.  Leaving the study will not affect your medical care.  You can still get your medical 
care from your hospital or doctor.  We will provide you with any new information that 
may affect your willingness to continue to take part in this study.   
 
It is important to tell the study doctor if you are thinking about stopping so any risks from 
the radiation therapy and chemotherapy can be evaluated by your doctor.  In some cases, 
the abrupt stopping of a drug can have risks in itself, so it is important to discuss stopping 
with the study doctor.  Another reason to tell your doctor that you are thinking about 
stopping is to discuss what follow-up care and testing could be most helpful for you. 
 
If you do change your mind about taking part in this study, please let us know.  You have 
the right to withdraw your permission for the use of your study information. This 
information will be removed unless we have already used it or if it becomes important for 
us to have a record of the people who start the study, not just those who finish it. If you 
decide to withdraw this permission, you must do so in writing by contacting the 
researchers listed as the Study Contact.  Once you withdraw from the study, we will not 
collect new information about you.  
 
The study doctor or the study sponsor may decide to remove you from this study without 
your permission for many reasons: 
 
• If you do not follow the study requirements 
• If the study procedures are found to be unsafe  
• If the study procedures are found to be ineffective 
• If you experience severe side effects  
 
If you are removed from the study, the study doctor will explain to you why you were 
removed.  The study doctor and research team will help arrange for your continued care.  


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 15 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
I. WILL I BE PAID TO TAKE PART IN THIS RESEARCH STUDY? 
You will not be paid to take part in this research study. 
 
J. WHAT ARE THE COSTS? 
Taking part in this study may lead to added costs to you or your insurance company.  
Please ask you doctor about any expected added costs or insurance problems. 
 
You or your insurance company will be charged for all the procedures, tests, and 
treatments that are being done in this study.  You may be responsible for any co-
payments and deductibles that are standard for your insurance company. 
 
If you have any questions about your insurance coverage or the items you might be 
required to pay for, please call financial services for information.  The contact 
information for financial services: 
 
• Dana Farber Cancer Institute: 617-632-3455  
• Massachusetts General Hospital: 617-726-2191   
• Brigham and Women’s Hospital: 617-732-5524 or 617-732-7485 
 
The National Cancer Institute provides an online resource to help people participating in 
cancer clinical trials understand which services their insurance company is required by 
law to pay.  This can be found at the website below. 
 
http://www.cancer.gov/clinicaltrials/learning/insurance-coverage  
 
You will receive no payment for taking part in this study. 
 
K. WHAT HAPPENS IF I AM INJURED OR SICK BECAUSE I TOOK PART IN THIS 
STUDY? 
 
We will offer you the care needed to treat injuries directly resulting from taking part in 
this research.  We may bill your insurance company or other third parties, if appropriate, 
for the costs of the care you get for the injury, but you may also be responsible for some 
of them. 
 


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 16 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
There are no plans for  Dana-Farber Cancer Institute (DFCI), Massachusetts General 
Hospital (MGH), or Brigham & Women’s Hospital (BWH) to pay you or give you other 
compensation for the injury.  You do not give up your legal rights by signing this form. 
 
If you think you have been injured as a result of taking part in this research study, tell the 
person in charge of this research study as soon as possible.  The research doctor’s name 
and phone number are listed in this consent form. 
 
L. WHO IS FUNDING THIS STUDY? 
 
The National Cancer Institute (NCI) is funding this research study.  This means that the 
Dana-Farber/Harvard Cancer Center is receiving payments form the NCI to support the 
activities that are required to conduct the study.   
 
 
M. WHAT ABOUT CONFIDENTIALITY? 
We will take measures to protect the privacy and security of all your personal 
information, but we cannot guarantee complete confidentiality of study data.  
 
Medical information created by this study may become part of your hospital medical 
record. Information that does not become part of your medical record will be stored in 
your study file. Study files are coded and not labeled with your name.  The code linking 
your name to the file will be kept in a safe location.  
 
Information contained in your records is used by study staff and in some cases it will be 
shared with the sponsor of the study.  If your information is being shared with the 
sponsor, no information that could identify you will be given to the sponsor.  
Occasionally, a sponsor representative may come to the study site to review your study 
files. This person will never take any information that can identify you back to the 
sponsor. There may be times when we are required by law to share your information. In 
those cases, we do not need your permission.  
 
The results of this study may be published.  You will not be identified in any publication 
without your permission. 
 
 
 


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 17 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
N. WHO DO I CONTACT IF I HAVE QUESTIONS ABOUT THE STUDY? 
 
You are encouraged to ask questions about the study or your role as a participant at any 
time. 
 
For questions about the study or research-related injury, contact: 
 
MGH     Annie Chan MD (617-726-4212) 
DFCI     Roy Tishler MD (617-632-2148)  
 
24-hour contact: MGH: 617-724-1159 
 
For questions about your rights as a research participant, please contact a representative 
from the Office for Human Research Studies (OHRS) at DFCI (617) 632-3029. This can 
include questions about your participation in the study, concerns about the study, a 
research related injury, or if you feel/felt under any pressure to enroll in this study or to 
continue to participate in this study.  
 
O. PRIVACY OF PROTECTED HEALTH INFORMATION 
 
Federal law requires Dana Farber/Harvard Cancer Center (DF/HCC) and its affiliated 
researchers, health care providers, and physician network to protect the privacy of 
information that identifies you and relates to your past, present, and future physical and 
mental health and conditions (“protected health information”).  If you enroll in the 
research described in this consent form, your “protected health information” will be used 
and shared with others as explained below. 
 
A. What protected health information about me will be used or shared with 
others during this research? 
 
• Existing medical records 
 
• New health information created from study-related tests, procedures, 
visits, and/or questionnaires 
 
B. Why will protected information about me be used or shared with others? 
 
The main reasons include: 


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 18 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
A. To conduct and oversee the research described earlier in this form 
B. To ensure the research meets legal, institutional, and accreditation 
requirements 
C. To conduct public health activities including reporting of adverse events 
or situations where you or others may be at risk of harm 
D. Other reasons may include for treatment, payment, or health care 
operations.  For example, some medical information produced by this 
study may become part of your hospital medical record because the 
information may be necessary for your medical care. In order to provide 
you with routine care, other people at the hospital may need to review the 
health information we put into your record.   
 
This would include such people as your regular doctors and nurses and the 
hospital’s billing department.   You will also be given a notice for use and 
sharing of protected health information. 
 
C. Who will use or share protected health information about me? 
 
E. DF/HCC and its affiliated researchers and entities participating in the 
research will use and share your protected health information.  In addition, 
the DF/HCC review board that oversees the research at DF/HCC and its 
affiliated staff who have a need to access this information to carry out 
their responsibilities (for example, oversight, quality improvement, and 
billing) will be able to use and share your protected health information. 
 
D. With whom outside of DF/HCC may my protected health information be 
shared? 
 
All reasonable efforts will be made to protect the confidentiality of your 
protected health information.  We may however, need to share this 
information with the following people or groups so they can carry out their 
duties related to this study: 
 
• Outside individuals or entities that have a need to access this information 
to perform functions on behalf of DF/HCC and its affiliates, for example 
data storage companies, insurers, or legal advisors) 
• The sponsor(s) of the study, NCI, its subcontractors, and its agents: Other 
researchers and medical centers participating in this research, if applicable 


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
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                                                    Supercedes Version Dated: 02-04 
 
Page 19 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
• Federal Agencies such as the Department of Health and Human Services 
(DHHS), the Food and Drug Administration (FDA), the National Institutes 
of Health, and/or the Office for Human Research Protections (NIH/OHRP  
• Hospital accrediting agencies 
 
Those who receive your protected health information may share it if they are 
required to do so by law. They may not be required to obey the federal privacy 
rules that the hospital and researchers must follow and may share your 
information with others without your permission.  
 
The results of this study may be published in a medical book or journal or 
used for teaching purposes.  However, neither your name nor other identifiers 
will be used in any publication or teaching material without your specific 
permission. 
 
E. For how long will protected health information about me be used or shared 
with others? 
 
F. If you sign this form, we will collect your health information until the end 
of the research.  We may collect some information from your medical 
records even after your direct participation in the research project ends. 
Research information may be analyzed and re-analyzed in light of 
scientific and medical advances, or reviewed for quality assurance, 
oversight or other purposes. 
 
G. We can only use your protected health information again if a special 
committee in the hospital (the IRB) gives us permission.  This committee 
may ask us to talk to you again before doing the research.  However, the 
committee may also let us do the research without talking to you again if 
we keep your health information confidential. 
 
F. Statement of privacy rights: 
 
H. You have the right to withdraw your permission for the use of your 
information at anytime. We will not be able to withdraw all the 
information that already has been used or shared with others to carry out 
related activities such as oversight, or to ensure quality of the study. If you 
withdraw your permission, you must do so in writing by contacting the 
researcher listed as the Study Contact. 


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 20 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
I. You have the right to choose not to sign this form.  If you decide not to 
sign this form, you cannot participate in this research study.  However, 
refusing to sign will not affect your present or future care and will not 
cause any penalty or loss of benefits to which you are otherwise entitled.   
J. You have the right to request access to your protected health information 
that is used or shared during this research and that is related to your 
treatment or payment for your treatment, but you may access this 
information only after the study is completed.  To request this information, 
please contact the researcher listed under Study Contacts on the consent 
form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 21 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
O. DOCUMENTATION OF CONSENT 
 
My signature below indicates: 
• I have had enough time to read the consent and think about participating in 
this study; 
• I have had all of my questions answered to my satisfaction; 
• I am willing to participate in this study; 
• I have been told that my participation is voluntary and I can withdraw at any 
time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Participant 
 
 
 
Date 
or Legally Authorized Representative   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relationship of Legally Authorized Representative to Participant   
 
 


 
Research Consent Form 
 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BWH/CH/DFCI/MGH/Partners Network Affiliates 
OPRS 11-04 
                                                    Supercedes Version Dated: 02-04 
 
Page 22 of 22 
DFCI IRB Protocol Number:  05-089 
Date DFCI  IRB Approved this Consent Form:      February 9, 2012 
Date Posted for Use:             March 30, 2012 
Date DFCI  IRB Approval Expires:               June 15, 2012 
OHRS Version Date: 03/07/2012 
 
Adult Participants 
 
To be completed by person obtaining consent: 
 
The consent discussion was initiated on   
 (date). 
 
Signature of individual obtaining consent:  
 
 
Printed name of above:  
 
 
 
Date:  
 
 
 A copy of this signed consent form will be given to the participant or legally authorized representative, 
or, where the participant is a minor, the participant’s parent or legal guardian. 
For Adult Participants 
 1)  The participant is an adult and provided consent to participate. 
 
 1a)  Participant (or legally authorized representative) is a non-English speaker and 
 
signed the translated Short Form in lieu of English consent document: 
 
As someone who understands both English and the language spoken by the participant, I 
interpreted and/or witnessed, in the participant’s language, the researcher’s presentation of the 
English consent form.  The participant was given the opportunity to ask questions.  
Signature of Interpreter/Witness:  
 
Printed Name of Interpreter/Witness:  
 
Date:  
 
 
 
 1b)  Participant is illiterate 
 
The consent form was read to the participant who was given the opportunity  
 
to ask 
questions.  
Signature of Witness:  
 
Printed Name of Witness:  
 
Date:  
 
 2)  The participant is an adult who lacks capacity to provide consent and his/her legally authorized 
representative: 
 2a) gave permission for the adult participant to participate  
 2b) did not give permission for the adult participant to participate