A Phase II Prospective Trial of Low-Level Laser Therapy for Prevention of Oral Mucositis in Patients Receiving Chemotherapy and Radiation for Head and Neck Cancer
Phase: NA
Conditions: Mucositis
Sponsor: Barbara Ann Karmanos Cancer Institute

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Title: 2015-170: A Phase II Prospective Trial of Low-Level Laser Therapy for Prevention of 
Oral Mucositis in Patients Receiving Chemotherapy and Radiation for Head and Neck Cancer 
Study Center: 
Karmanos Cancer Center 
4100 John R 
Detroit, Michigan 48201 
Principal Investigator:  
Harry Kim, M.D. 
Associate Professor and Service Chief 
Division of Radiation Oncology 
Department of Oncology 
Barbara A. Karmanos Cancer Center 
Wayne State University School of Medicine 
4201 St Antoine UHC-1D 
Detroit MI 48201 
kimh@karmanos.org  
Phone: 313-576-9543 
Fax: 313-576-9625 
Co-investigators:  
Mark Zaki, MD 
Resident, Radiation Oncology  
Karmanos Cancer Center  
Wayne State University School of Medicine 
4201 St Antoine UHC-1D 
Detroit MI 48201 
mazaki@med.wayne.edu  
Phone: 313-576-9632 
Fax: 313-576-9625 
Pam Laszewski RN, OCN 
Clinical Leader, Radiation Oncology 
Karmanos Cancer Center 
4100 John R 
Mail code: GE00R0 
Detroit, MI 48201 
laszewsk@karmanos.org 
Phone: 313-576-9563 
Fax: 313-576-9639 
Statistician: 
Greg Dyson, PhD 
Biostatistician 
Assistant Professor, Biostatistics Core 
Karmanos Cancer Institute 
Wayne State University 
dysong@karmanos.org 
Phone: 313-576-8654 
Study Coordinator: 
Ted Chaperon 
Study Coordinator 
Karmanos Cancer Institute 
Clinical Trials Office 
4100 John R Mailcode: GE00CT 
Detroit, MI 48201 
Phone: (313) 576-9383 
Fax: (313) 576-8364 
Current Version Date: 
07/20/2016 
Previous Version Dates: 
12/03/2015 
04/12/2016 
NCT02723604

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Table of Contents 
Study Schema  ........................................................................................................................................... 4 
1.0 Objectives: ....................................................................................................................................... 5 
1.1 
Primary Objective .................................................................................................................................... 5 
1.2 
Secondary Objectives  ............................................................................................................................... 5 
2.0 Introduction .................................................................................................................................... 5 
2.1 
Disease Overview  ...................................................................................................................................... 5 
2.2 
Product Background  ................................................................................................................................ 6 
2.3 
Product Mechanism of Action  ............................................................................................................... 6 
2.4 
Product Efficacy  ........................................................................................................................................ 7 
Table 1. LLLT trials for oral mucositis prevention .............................................................................................. 8 
2.5 
Product Safety  ........................................................................................................................................... 9 
2.6 
Rationale for the Study  ........................................................................................................................... 9 
3.0 Selection and Withdrawal of Subjects
 ...................................................................................... 9 
3.1 
Study Design  .............................................................................................................................................. 9 
3.2 
Patient Selection  ..................................................................................................................................... 10 
3.3 
Withdrawal of Subjects  ........................................................................................................................ 11 
4.0 Treatment Methods  ..................................................................................................................... 11 
4.1 
Radiation Treatment  ............................................................................................................................. 11 
4.1.1 
Definition of Target Volumes: ................................................................................................................... 11 
4.1.2 
Definition of Organs at Risk: ..................................................................................................................... 12 
4.2 
Chemotherapy ........................................................................................................................................ 13 
4.3 
Low-Level Laser Therapy  ................................................................................................................... 13 
4.4 
Other treatments  .................................................................................................................................... 14 
5.0 Follow-up and Assessments  ....................................................................................................... 14 
5.1 
Follow up Schedule  ................................................................................................................................ 14 
5.2 
Follow-up Assessments  ......................................................................................................................... 14 
6.0 Statistical Considerations  .......................................................................................................... 17 
6.1 
Primary Endpoints:  .............................................................................................................................. 17 
6.2 
Secondary Endpoints:  ........................................................................................................................... 17 
6. 3  
Exploratory Endpoints:  ...................................................................................................................... 18 
6.4 
Sample Size  .............................................................................................................................................. 18 
6.5 
Analysis .................................................................................................................................................... 18 
6.6 
Evaluation of Toxicity ........................................................................................................................... 19 
6.7 
Specific Toxic Outcomes  ...................................................................................................................... 19 
6.8 
Other toxic outcomes  ............................................................................................................................ 19 
6.9 
Expected accrual rate, accrual duration, and study duration
 .................................................... 20 
7.0 Adverse Events and Safety Monitoring
 .................................................................................. 20 
7.1 
Reporting of Serious Treatment Emergent Adverse Events
 ....................................................... 20 
7.2 
Adverse Event Characteristics  ........................................................................................................... 21 
7.3 
WSU HIC Adverse Event reporting
 .................................................................................................. 23 
7.4 
Data Safety Monitoring ..................................................................................................................... 24 
7.5 
Ethics ........................................................................................................................................................ 25 
8.0  
Registration Procedures ............................................................................................................ 25 
8.1 
General Guidelines  ................................................................................................................................ 25 

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8.2 
Registration Process  .............................................................................................................................. 25 
9.0 Protocol Conduct and Guidelines  ............................................................................................ 26 
9.1 
Protocol amendments, or changes in study conduct 
..................................................................... 26 
9.2 
Publication of results  ............................................................................................................................ 26 
9.3 
Ethics and Good Clinical Practice
 ..................................................................................................... 26 
9.4 
Institutional Review Board/Independent Ethics Committee
 ...................................................... 26 
9.5 
Informed consent  ................................................................................................................................... 26 
9.6 
Declaration of Helsinki  ......................................................................................................................... 27 
10.0 References
 ................................................................................................................................... 28 
11.0 Appendix ..................................................................................................................................... 30 
11.1 
Karnofsky Performance Scale  .......................................................................................................... 31 
11.2 
Weekly Toxicity Scoring Sheet  ......................................................................................................... 32 
11.3 
LLLT Treatment Record Form  ....................................................................................................... 33 
11.4 
Table 2. Consensus Contouring Guidelines for Organs at Risk
 .............................................. 38 
11.5 
Table 3. OAR dose parameters to be recorded
 ............................................................................ 40 
11.6 
FACT-G (Version 4)  ........................................................................................................................... 41 
11.7 
FACT-H&N (Version 4)  .................................................................................................................... 43 
11.8 
Oral Mucositis Daily Questionnaire  ............................................................................................... 44 
11.9 Data and Safety Monitoring Report
 ................................................................................................ 45 
11.10 Study Calendar ……………………………………………………………………………………………………….47 
      
 
 
 
 
 
 
 
 
 

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Study Schema 
 
A phase II, single-arm trial to examine the efficacy of prophylactic low-level laser therapy 
(LLLT) to reduce the incidence of oral mucositis and adverse events in patients receiving 
combined modality therapy consisting of chemotherapy and radiation therapy for head and neck 
cancer. 
 
Patients meeting the eligibility criteria will be enrolled to receive prophylactic LLLT in addition 
to standard of care measures for oral mucositis or other toxicity of therapy. The radiation and 
chemotherapy dose, schedule, modality, technique, and any required adjustments will not be 
influenced by this protocol and will follow standard existing institutional practices.  
 
Patients will receive LLLT three times per week concurrently with chemoradiotherapy. LLLT 
may be delivered either immediately prior to or after the patient’s daily fraction of radiotherapy. 
Patients will be treated extra-orally with a THOR® LED cluster for one minute along the buccal 
mucosa on each side and intraorally for one minute to the tongue and soft palate. During each 
LLLT treatment session a thorough oral exam will be performed to identify any areas of 
mucositis. If the patient should develop intraoral lesions they will be targeted directly with the 
intraoral probe for one minute to each site of mucositis. The laser settings to be used are as 
follows: frequency 2.5 Hz; wavelength 660 nm; and power 75 mW, for an energy of 4.5 J.  
 
Patients will be evaluated prior to therapy, weekly during therapy, two weeks after the 
completion of therapy, and three months after the completion of therapy. During each 
assessment, the following toxicities will be assessed: pain, mucositis, dysphagia, xerostomia, 
dysgeusia, dermatitis, trismus, and quality of life.   
 
Previous studies indicate that approximately 40% of patients will experience severe mucositis 
with radiation and concurrent chemotherapy. The hypothesis in this trial is that the addition of 
LLLT to this treatment regimen will decrease the rate of severe acute OM to 20%. We plan to 
enroll 25 patients at our institution in 12 months after the trial opens. The same protocol will be 
opened separately at the University of Pittsburgh Medical Center (UPMC), where an additional 
25 patients will be enrolled. A Data Use Agreement will allow combination of the data for a total 
of 50 patients to be analyzed.  
 
 
 
 
 
 
 

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1.0 Objectives: 
 
1.1 
Primary Objective 
 
Our primary objective is to determine the ability of low-level laser therapy (LLLT) to 
reduce the rates of severe oral mucositis in patients receiving radiation with concurrent 
chemotherapy for head and neck cancer (HNC).  
 
1.2 
Secondary Objectives 
 
1. To establish the time to onset of severe oral mucositis following the initiation of 
radiotherapy with LLLT.  
2. To determine the incidence of pain, dysphagia, xerostomia, dysgeusia, trismus, 
radiodermatitis, and OM-related QOL (via FACT-H&N score) with LLLT.   
3. To evaluate the mean cumulative radiation dose at time of onset of severe oral 
mucositis with LLLT. 
4. Determine the duration of oral mucositis.  
5. Record the amount of narcotic analgesia use during treatment. 
6. Evaluate the number of breaks in chemoradiotherapy with LLLT use.  
7. Determine the proportion of patients who require feeding tube placement during 
treatment.  
2.0 Introduction 
 
2.1 
Disease Overview 
 
Combined modality therapy with chemotherapy and radiation is a commonly employed 
treatment approach for patients with various types of HNC [1]. Despite the overall safety 
and efficacy of this treatment modality, side effects exist, including acute 
chemoradiation-induced pain, dermatitis, xerostomia, dysgeusia, dysphagia, 
odynophagia, and oral mucositis. In fact, a majority of patients treated with this modality 
will experience some degree of oral mucositis (OM) [2]. OM can affect many oral 
functions including mastication and swallowing which may lead to dehydration, renal 
failure and necessitate the placement and use of a feeding tube and negatively impact and 
patient’s quality of life (QOL). Severe OM can also predispose a patient to increased risk 
of infections requiring hospitalization and increased cost of treatment [3]. The severity of 
these reactions can be so severe that patients who experience treatment-related mucositis 
are less likely to complete the planned course of therapy without unplanned interruptions 
in therapy. Previous studies provide evidence that unplanned breaks in radiotherapy for 
HNC result in worse tumor control [4]. Furthermore, adverse events can increase the cost 
of healthcare by resulting in preventable hospital admissions for intravenous hydration 
and nutritional support and procedures including feeding tube placement. In fact, OM has 

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been shown to be associated with an incremental cost of $1,700 - $6,000 per patient, 
depending on the grade [5].  
 
Despite multiple clinical trials, no single treatment has been proven to be effective in 
substantially reducing incidence or severity of chemoradiation induced oral mucositis.  
The current standard practice for the management of OM is symptom management and 
supportive care with narcotic pain medications and anesthetic mouth rinses and 
nutritional support with supplementation either by mouth or feeding tube.  
 
2.2 
Product Background 
 
Photomedicine utilizing low level laser (or “light” as light emitting diode sources are 
increasingly being used in place of lasers) therapy (LLLT) has been investigated as a 
novel therapeutic approach since the 1960s. LLLT is a safe, low-intensity form of light 
therapy. LLLT employs visible (generally red) or near-infrared light generated from a 
laser or light emitting diode (LED) [6]. Therapy with LLLT has been shown to relieve 
pain, reduce inflammation, and improve tissue repair. LLLT does not function through 
ablative or thermal mechanisms, but rather a photochemical effect comparable to 
photosynthesis in plants whereby the light is absorbed and exerts a chemical change [6].  
 
LLLT was first completely limited to treatment with laser sources, such as the helium 
neon (HeNe) or indium phosphide, gallium and aluminum diode (InGaAIP) lasers. The 
non-coherent light produced by light emitting diode (LED) devices has the same 
biological properties and clinical effectiveness as coherent light produced by lasers, with 
the advantages of LED technology being that it is significantly less expensive and can be 
arranged in arrays permitting greater surface area exposure and subsequent shorter 
overall treatment times. Furthermore, LED-based LLLT applied extraorally has good 
penetration through skin and soft tissue to the oral mucosa [7] 
 
2.3 
Product Mechanism of Action 
 
The mechanism of action no LLLT is rooted in photochemistrisy. Light photons must be 
absorbed by molecular photoacceptors or chromophores for photochemistry to occur [8]. 
The cellular mechanism of LLLT has been attributed to the absorption of monochromatic 
visible and near infrared (NIR) radiation by the cellular respiratory chain [9]. 
Phototherapy is characterized by its ability to induce photobiological processes in cells. 
Mitochondria play a crucial role in cellular metabolism and the generation of energy in 
the form of adenosine triphosphate (ATP) through oxidative phosphorylation. 
Mitochondria have been studied as the main target of phototherapy. Cytochrome c 
oxidase is the proposed photoacceptor for the red-NIR light range in mammalian cells, as 
absorption spectra for light were found to be similar to the absorption spectra of 
cytochrome c oxidase [10]. LLLT to isolated mitochondria increased ATP synthesis, 
RNA and protein synthesis, and enhanced synthesis of NADH and ATP [6]. In stressed 
tissues, mitochondria make nitric oxide that competes with oxygen in the oxidative 
phosphorylation chain. This in turn decreases ATP synthesis and can increase production 

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of reactive oxygen species (ROS), which are small molecules that are highly reactive 
with proteins, nucleic acids, and lipids. ROS are potentially harmful to intracellular 
elements and their formation triggers cellular sensors that can engage signaling pathways 
involved in gene transcription (such as nuclear factor κB (NF-κB). While the exact 
mechanism of action is unknown, LLLT has been shown to interact with cytochrome c 
oxidase in mitochondria to release nitric oxide, facilitating oxidative phosphorylation. 
This increases ATP production and stimulates downstream signals to produce 
antioxidants and growth factors for cellular repair and proliferation. As a result, LLLT 
has been shown to decrease pain and inflammation and promote wound healing and 
tissue repair.  
 
2.4 
Product Efficacy 
 
LLLT is a non-invasive technique which has been examined for the prevention and 
treatment of radiotherapy-induced OM. Multiple randomized trials have shown a 
reduction in the rates of OM and pain with the use of LLLT [11-20]. A list of trials 
examining the impact of LLLT for OM prevention in patients with HNC is given in table 
1.  
 
Furthermore, a systematic review and meta-analysis of eleven randomized placebo-
controlled trials of LLLT use during chemotherapy or radiation therapy in HNC patients 
was performed [21]. This found a relative risk for developing OM was significantly 
(p=0.02) reduced after LLLT compared with placebo. The number of days with OM 
grade 2 or worse was also significantly reduced after LLLT to 4.38 days less than 
placebo. Likewise, OM severity was reduced after LLLT compared with placebo. All 
studies in this meta-analysis recorded possible adverse effects of LLLT therapy, but there 
were no differences from treatment with placebo. Evidence from these small, randomized 
controlled trials shows a significant reduction in incidence and severity of OM for HNC 
patients.   
 
Additionally, the Multinational Association of Supportive Care in Cancer and 
International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for 
Mucositis recommends in favor of LLLT for the prevention of OM in patients receiving 
high-dose chemotherapy for hematopoietic stem cell transplants with or without total 
body irradiation and a suggestion for LLLT in the prevention of OM in patients receiving 
RT for HNC [22]. No guideline was issued for patients receiving concurrent 
chemotherapy and radiation therapy for HNC due to lack of high-level evidence. The 
European Society for Medical Oncology (ESMO) clinical practice guidelines for the 
management of oral and gastrointestinal mucositis also advises the use of LLLT to reduce 
the incidence of oral mucositis and its associated pain, in patients receiving high-dose 
chemotherapy or chemoradiotherapy before hematopoietic stem cell transplant [23]. 

V ersi o n D at e: 0 7/ 2 0/ 2 0 1 6  
8
T a ble 1. L L L T tri als f or or al m uc ositis pre ve nti o n  
Refere nce
 P o p ul ati o n
 
Met h o ds
 
Tre at me nt
 
Res ults
 
C o m me nts
 
A nt u nes et al 
Ra di ot her O nc ol 2 0 1 3[ 1 1] 
 
 
H N C 
 
( n = 9 4)  
 
Brazil, 2 0 0 7
2 0 1 0  
 
P hase III, 
ra n d o mize d 
place b o c o ntr olle d 
trial  
C o nc urre nt C he m ora di ot hera p y 
( 1) Place b o˜  
( 2) L L L T dail y pri or t o eac h R T fracti o n  
 
C he m o: cis plati n 1 0 0 m g/ m 2 q 3 wee ks  
R T: 7 0. 2 G y  
L L L T: I n Ga AI P, 6 6 0 n m, 1 0 0 m W, 1- 4J/c m 2 
 
Gra de 3
4 m uc ositis ( W H O): 4 0. 5 % vs. 6. 4 %  
Relati ve ris k: 0. 1 6 ( 0. 0 5 
 0. 5)  
 
I m pr o ve d Q O L f or pai n, 
s wall o wi n g a n d diffic ult y wit h 
eati n g  
 
Ar ora et al 
Oral S ur g Oral Me d Oral 
Pat h ol Oral Ra di ol E n d o d 
2 0 0 8[ 1 3]  
Oral c a ncer 
 
( n = 5 0)  
 
I n dia, 2 0 0 5- 2 0 0 6 
 
 
 
P hase III, 
ra n d o mize d 
c o ntr olle d trial  
Ra diati o n  
( 1) T o pical a nest hetic, sali ne was hes˜ 
( 2) L L L T dail y pri or t o R T  
 
R T: 6 6 G y  
L L L T: He
Ne, 6 3 2. 8 n m, 1 0 m W, 1. 8J/c m 2  
Gra de 3- 4 m u c ositis ( E O R T C/ R T O G) 5 3. 9 % vs. 
1 8. 2 % at 3 wee ks ( p = 0. 0 1 9) 
F u ncti o nal i m pair me nt Scale 
ma xi m u m sc ore: 
Oral ali me ntati o n n ot p ossi ble: 
3 1 % vs. 0 %  
Be nsa d o u n et al 
S u p p ort Care Ce nter 
1 9 9 9[ 1 4]  
 
 
H N C 
 
( n = 3 0)  
 
Fra nce, 1 9 9 4- 1 9 9 8 
 
 
P hase III, 
ra n d o mize d 
place b o c o ntr olle d 
trial  
Ra diati o n  
( 1) Place b o˜  
( 2) L L L T pri or t o eac h R T fracti o n  
 
R T: 6 5 G y 
L L L T: He
Ne, 6 3 2. 8 n m, 6 0 m W, 2J/c m 2 
Gra de 3 m u c ositis ( W H O): 3 5. 2 % vs. 7. 6 % ( p < 0. 0 1)  
 
Se vere pai n: 2 3. 8 % vs. 1. 9 % ( p < 0. 0 5) 
 
 
Ga uta m et al 
Ra di ot her O nc ol 2 0 1 2[ 1 6] 
 
 
H N C 
 
( n = 2 2 1)  
 
I n dia, 2 0 0 9- 2 0 1 1 
 
 
P hase III, 
ra n d o mize d 
place b o c o ntr olle d 
trial  
 
 
C o nc urre nt C he m ora di ot hera p y 
( 1) S ha m treat me nt˜  
( 2) L L L T 5 x/ wee k, pri or t o or f oll o wi n g R T  
 
C he m o:  cis plati n 1 0 0 m g/ m 2 q 3 wee ks 
R T: 6 6 G y  
L L L T: He
Ne, 6 3 2. 8 n m, 2 4 m W, 3J/ p oi nt  
 
Gra de ≥3 m uc ositis ( E O R T C/ R T O G): 7 0 % vs. 
2 3. 4 % ( p < 0. 0 0 0 1) 
 
 
 
Pai n sc ores platea u e d after 
wee k 4 i n L L L T ar m a n d 
c o nti n ue d t o i ncrease i n 
place b o ar m  
 
L o wer d ys p ha gia i n L L L T ar m 
 
Za ni n et al 
P h ot o me d Laser S ur g 
2 0 1 0[ 1 8]  
 
 
H N C 
 
( n = 7 2)  
 
Brazil 
 
P hase III, 
ra n d o mize d 
c o ntr olle d trial  
 
C o nc urre nt C he m ora di ot hera p y 
( 1) N o treat me nt˜  
( 2) L L L T 2 x/ wee k, pri or t o or f oll o wi n g R T  
 
C he m o: cis plati n˜ 7 0  m g/ m 2 wee kl y 
R T:  1. 8 G y dail y fracti o ns 
L L L T: He
Ne, 6 6 0 n m, 3 0 m W, 2J/c m 2 
 
M uc ositis ( N CI) si g nifica n tl y l o wer i n L L L T gr o u p 
fr o m wee k 1 t o wee k 4 ( p = 0. 0 0 1), b ut re mai ne d 
sta ble u ntil wee k 7 ( p = 0. 6 8) 
L L L T dela ye d o nset of oral 
m u c ositis 
Li ma et al,  
Braz De nt J 2 0 1 0[ 1 7]  
 
 
H N C  
 
( n = 2 5)  
 
Brazil, 2 0 0 5  
 
Pr os pecti ve, n o n-
ra n d o mize d st u d y 
 
R T ± c he m ot hera p y 
( 1) S ucr ose a n d al u mi n u m h y dr o xi de s us pe nsi o n˜  
( 2) L L L T dail y pri or t o eac h R T fracti o n  
 
C he m o: cis plati n 1 0 0 m g/ m 2 q 3 wee ks  
R T: 4 0
7 0 G y  
L L L T: 8 3 0 n m, 6 0 m W, 1 2. 4J/c m 2  
 
Gra de 3 m u c ositis ( O T S Scale) O M 5 0 % vs. 3 3 % 
( p = 0. 0 6) 
 
 
Si g nifica nt decrease i n pai n 
wit h L L L T ( p = 0. 0 3 6)  
H N C; hea d a n d nec k ca ncer. L L L T; l o w-le vel laser t hera p y. R T; Ra diati o n. G y; Gra y. I n Ga AI P; i n di u m p h os p hi de, galli u m a n d al u mi n u m di o de. n m; na n o meter. m W; milli watts. J; J o ules. W H O; W orl d Healt h 
Or ga nizati o n. Q O L; Q ualit y of Life. He- Ne;  Heli u m- Ne o n. E O R T C; E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca n cer. R T O G; Ra diati o n T hera p y O nc ol o g y Gr o u p. N CI; Nati o nal Ca ncer I nstit ute.  

Version Date: 07/20/2016 
9
2.5 
Product Safety 
 
Lasers used for LLLT are categorized as Class 3b. Class 3b lasers emit 5mW to 500mW lasers, 
with some emitting infrared light below 5mW. A class 3b laser may be hazardous under direct 
and specular viewing conditions, but is not a fire hazard. The patient and LLLT operator require 
use of protective eyewear. The LLLT system is equipped with a key switch and a safety 
interlock. The THOR® Laser system (THOR Photomedicine Ltd, Chesham, UK) that will be 
used to deliver LLLT in this protocol is an FDA-approved medical device (510(K) number 
K030226).  
 
There has been no reported toxicity in any of the studies of LLLT for the prevention and/ or 
management of oral mucositis. In the limited number of studies evaluating extraoral LLLT, there 
has similarly been no reported cutaneous or oral toxicity. 
 
2.6 
Rationale for the Study 
 
Previous phase III trials conducted in other countries, primarily Brazil [11], France [14], and 
India [16], have shown a significant improvement in OM with LLLT. However, no U.S. trials 
have been reported. The rationale for this phase II trial is to validate the results from 
international trials in a U.S. cohort of patients. Therefore, our goal is to evaluate the efficacy of 
LLLT in reducing treatment related toxicities including OM, pain, xerostomia, dysgeusia, and 
dysphagia and improving OM-related QOL in patients undergoing radiation with chemotherapy 
for HNC.  To accomplish our goal, we propose a prospective, single-arm, phase II trial with the 
aim of improving health-care quality and reducing the incidence of treatment-related toxicity as 
compared to historical controls. The same protocol will be opened separately at the University of 
Pittsburgh Medical Center (UPMC). A Data Use Agreement will allow for a combination of the 
data from both centers to be analyzed.   
3.0 Selection and Withdrawal of Subjects 
 
3.1 
Study Design 
 
This is a phase II prospective, single-arm, open label trial testing the efficacy of LLLT in 
prevention of oral mucositis for HNC patients treated with chemoradiotherapy. Primary 
endpoints are the incidence of severe (assessed separately as CTCAE v. 4.0 grade 3-5 or WHO 
grade 3-4) OM in patients receiving a cumulative radiation dose of at least 5000 cGy. Secondary 
endpoints include the time onset to severe OM, mean cumulative radiation dose at the time of 
OM, duration of OM, the incidence of pain, dysphagia, xerostomia, dysgeusia, trismus, 
radiodermatitis, and QOL.  
 
All toxicities will be graded by NCI CTCAE v. 4.0. In addition, oral mucositis will also be 
graded by WHO mucositis grading scale. Dysphagia will also be graded by a dietary assessment. 
Trismus will be assessed by measurments of the interincisal distance. QOL will be measured by 
the FACT-H&N assessment.  

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10 
 
Previous studies (detailed in Section 2.2, Table 1) indicate that approximately 40% of patients 
will experience severe OM with radiation and concurrent chemotherapy. The hypothesis in this 
trial is that the addition of LLLT to this treatment regimen will decrease the rate of severe acute 
OM to 20%. We plan to enroll 25 patients at our institution in 12 months after the trial opens. 
The same protocol will be opened separately at the University of Pittsburgh Medical Center 
(UPMC), where an additional 25 patients will be enrolled. A Data Use Agreement will allow 
combination of the data for a total of 50 patients to be analyzed. 
 
3.2 
Patient Selection 
 
Inclusion Criteria: 
 
1. Willing and able to understand and sign informed consent form approved by the IRB. 
2. Males or females greater than or equal to 18 years old.  
3. Biopsy-proven HNC including cancers of the nasopharynx, oropharynx, larynx, 
hypopharynx, or HNC of unknown primary origin amenable to therapy with radiation and 
concurrent chemotherapy.  
4. Patients who are planned to receive definitive or adjuvant radiotherapy with concurrent 
platinum-based chemotherapy. 
5. Patients whose clinical treatment plans include a continuous course of external beam 
radiotherapy by intensity-modulated radiation therapy (IMRT) and/or image-guided radiation 
therapy (IGRT), given as a cumulative dose of 5000 – 7000 cGy in single daily fractions of 
180 - 200 cGy, combined with a concurrent course of weekly or tri-weekly cisplatin or 
carboplatin chemotherapy. 
6. Karnofsky performance status score >60. 
7. Female patients  of child-bearing potential must have a negative pregnancy test prior to 
enrollment.  
 
Exclusion Criteria: 
 
1. Patient has evidence of current mucositis, mucosal ulceration, or unhealed surgical wounds 
from surgical resection or biopsy. 
2. Prior radiation to the head and neck.  
3. Patients with gross tumor involvement of the oral cavity or oral mucosa.  
4. Patient planned to receive altered fractionation radiotherapy or multiple fractions per day 
5. Patient is using a pre-existing feeding tube for nutritional support at the time of study entry.  
6. Women who are pregnant or breast-feeding.  
7.  Patient plans to receive concurrent chemotherapy, other than the regimens specified in the 
inclusion criteria. 
8. Patients who have chronic immunosuppression or are on current immunosuppressive 
therapies.  
9. Patients who have a contraindication to radiation therapy.  
10. Patients enrolled on another investigational trial for oral mucositis prevention.  
11. Life expectancy of less than 3 months.  
12. Unable or unwilling to adhere to study-specified procedures. 
 

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11 
3.3 
Withdrawal of Subjects 
 
Any subject, having previously provided informed consent to participate in the protocol, is free 
to withdraw from the study at any time for any reason without prejudice to their future medical 
care by the physician or at the study site. The Investigator or Sponsor may also withdraw the 
subject at any time in the interest of subject safety. The primary reason for withdrawal must be 
recorded.  
 
Subject participation may be terminated prior to completion of the clinical study for any of the 
following reasons:  
 
1. Unacceptable toxicity 
2. Death 
3. Lack of efficacy 
4. Withdrawal by subject 
5. Lost to follow-up 
6. Non-compliance with study treatment (Subjects who miss >20% of planned LLLT 
treatments will be considered non-compliant with the protocol) 
7. Study physician decision in the best interest of subject safety 
8. Pregnancy 
9. Major protocol deviation that can affect the safety or efficacy of study population 
10. Study terminated 
11. Other 
4.0 Treatment Methods 
 
4.1 
Radiation Treatment 
 
Prior to treatment, all patients will provide informed written consent for radiation therapy as per 
existing institutional policy. All patients will undergo a computed tomography (CT) simulation 
for treatment planning. Radiation therapy will be delivered with an intensity modulated radiation 
therapy (IMRT) technique and/or image-guided radiation therapy (IGRT). The prescribed course 
of radiotherapy will not be altered based on this study. Radiotherapy will be delivered 5 days per 
week, Monday – Friday with one radiation treatment given per day. The planned cumulative 
dose of radiation will be determined by the treating physician and will range from 5000 – 7000 
cGy in 180 - 200 cGy daily fractions over the course of 5-7 weeks. This treatment is not part of 
the research protocol. 
 
4.1.1 Definition of Target Volumes: 
 
Target volumes will be outlined per institutional practice and not modified based on this 
protocol. Target volumes are defined as the following: 
Gross Tumor Volume (GTV) represents the region judged to contain gross primary tumor or 
involved node(s) based on clinical and endoscopic examinations, CT scan, and, when applicable, 
other imaging techniques.  

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12 
Clinical Target Volume (CTV) is defined as the GTV plus areas considered at risk for containing 
microscopic disease delineated by the treating physician. The CTV margins can be narrower 
when GTV is in the proximity of the spinal cord or critical normal tissues.  
Planning Target Volume (PTV) represents an additional margin around the CTV to compensate 
for the variability of treatment set up and internal organ motion.   
 
4.1.2 Definition of Organs at Risk: 
 
CT-based planning will be used to identify the target volumes and organs at risk (OARs). OARs 
will be contoured according to the DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, 
NCRI, NRG Oncology, and TROG consensus guidelines [24] which are included in table 2 
which is provided in appendix 11.4.  The dose parameters given to OARs will be recorded (table 
3). Dose limits to OARs will be determined by institutional practice and specific dose-constraints 
will not be required on this protocol. The following radiation doses will be recorded.  
 
Table 3. Dose parameters to OARs to be recorded 
 
 
 
Brainstem 
 
 
Maximum Dose_________ 
 
Spinal Cord 
 
 
Maximum Dose_________ 
 
Right Parotid 
 
 
Mean Dose_____________ 
V30Gy_________________ 
Left Parotid 
 
 
Mean Dose_____________ 
V30Gy_________________ 
Parotids (bilateral) 
 
 
D20cc_________________ 
 
Submandibular Gland 
 
Mean Dose_____________ 
 
Extended Oral Cavity 
 
Maximum Dose_________ 
Mean Dose_____________ 
Lips 
 
 
Maximum Dose_________ 
Mean Dose_____________ 
Buccal Mucosa 
 
 
Maximum Dose_________ 
Mean Dose_____________ 
Mandible 
 
 
Maximum Dose_________ 
 
Pharyngeal Constrictors 
 
Mean Dose_____________ 
 

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13 
 
4.2 
Chemotherapy 
 
Prior to treatment, all patients will provide informed written consent for chemotherapy as per 
existing institutional policy. The prescribed course of chemotherapy will be determined by the 
managing medical oncologist per institutional practices and will not be altered based on this 
study. The frequency and dose of chemotherapy will be recorded for each patient on the trial. 
This treatment is not part of the research protocol. 
 
4.3 
Low-Level Laser Therapy 
 
Treatment will be administered on an outpatient basis. While there are no expected toxicities, 
potential adverse events will be monitored per Section 7 (Adverse Events and Safety 
Monitoring). No investigational agents or therapies for the prevention of oral mucositis other 
than those described in this protocol may be administered.  
 
LLLT will be delivered with the THOR® Laser system (THOR Photomedicine Ltd, Chesham, 
UK). LLLT will begin on the first or second day of radiotherapy and be delivered three times per 
week (e.g. Monday, Wednesday, and Friday) until the completion of radiotherapy. A trained 
radiation oncology nurse or physician will deliver treatment. LLLT may be delivered either 
immediately prior to or after the patient’s daily fraction of radiotherapy. If it is determined that a 
break in radiotherapy is required for clinical reasons, LLLT will also be held. Patients will be 
treated extra-orally with a THOR® LED cluster for one minute along the cheek to treat the 
buccal mucosa on each side and intraorally for one minute to the tongue and soft palate. During 
each LLLT treatment session a thorough oral exam will be performed to identify any areas of 
mucositis. If the patient should develop intraoral lesions they will be targeted directly with the 
intraoral probe for one minute to each site of mucositis.  
 
The laser settings to be used are as follows: frequency 2.5 Hz; wavelength 660 nm; and power 75 
mW. The dose per anatomic site treated will be 4.5 J/cm2. No dose modifications for the LLLT 
will be made.  
 
The extra-oral probe will be cleaned before and after each use. Prior to each use, the intraoral 
probe will be covered with a protective dental sleeve. Patients and laser operator will wear 
THOR® laser safety glasses for the duration of laser therapy.  
 
Treatment dates and sites will be recorded for each patient on the LLLT Treatment Record Form 
given in the appendix (appendix 11.3). Compliance with therapy will be documented. Subjects 
who miss >20% of planned LLLT treatments will be considered non-compliant with the 
protocol. For each treatment session, the dose will be set (timer on control unit) and the patient 
will be positioned comfortably a chair. The LLLT device will be for a minimum of 3 exposures:  
  
1. Right cheek  
2. Left cheek  
3. Tongue/Soft palate 
 

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14 
The treatment per site will take 60 seconds, for a minimum treatment time of three minutes. If 
any areas of mucositis are evident on examination at the time of LLLT treatment, each area will 
be targeted with an intraoral probe for an additional 60 seconds.  
  
There will be no pre- or post-treatment measures/precautions.  
 
4.4 
Other treatments 
 
Subjects that develop symptomatic mucositis will be managed as necessary according to standard 
standard of care hospital protocol for oral mucositis in addition to LLLT. This may include 
topical creams, pain medications, anesthetic mouth rinses, mouth coatings, and nutritional 
support with supplementation either by mouth or feeding tube, without the use of specific 
investigational, restricted agents. No standard treatment will be denied to a patient on this 
protocol.  
5.0 Follow-up and Assessments 
 
5.1 
Follow up Schedule 
 
A general history & physical by a radiation oncologist and/or medical oncologist must be done 
within 8 weeks prior to registration. Patients will be evaluated for protocol eligibility at the time 
of initial consultation. At the time of initial evaluation, baseline assessments will be performed. 
During the course of treatment, each patient will be seen by the supervising physician in clinic 
for an on-treatment evaluation at least once per week (or at an interval of once per five radiation 
treatments).  Follow-up appointments will be scheduled for two weeks and three months after the 
completion of therapy.  
 
Table 4. Study Calendar Overview 
Screening 
Baseline 
Treatment Period 
Follow-up 
Period 
Assessments 
LLLT Dosing 
Day -1 to 
Day -28  
 
Study Day 0 
Weekly 
 
Last day of 
treatment 
3x/week 
concomitant with 
chemoradiation 
Two weeks 
 
Three months 
 
5.2 
Follow-up Assessments 
 
During each assessment, the following toxicities will be assessed: pain, OM, dysphagia, 
xerostomia, dysgeusia, dermatitis, trismus, and QOL.   
 
Mouth pain and throat pain severity will be assessed weekly using a standard 0-10 scale. A 
record of the amount of analgesic medications required will be required at each visit.  
 
A diet assessment will be performed at weekly on-treatment assessments as follows: 

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15 
Diet Assessment 
Diet 1: 
Diet 2: 
Diet 3: 
What has the subject been 
able to eat within the past 24 
hours (mark only one) 
If the subject has been unable to eat Solid food, 
mark all the reason(s) why (mark all that apply) 
Based solely on how the 
mouth feels, what does the 
subject feel (s)he could try to 
eat if (s)he did not have to 
swallow (mark only one) 
☐Solids 
☐Nausea/Vomiting 
☐Oral discomfort 
☐Solids 
☐Liquids 
☐Loss of appetite 
☐Dry mouth 
☐Liquids 
☐Nothing by Mouth 
☐Throat discomfort 
☐No teeth 
☐Nothing by Mouth 
 
If Solids is marked above, 
proceed to next section. 
☐Difficulty Swallowing 
☐Other__________________________________ 
 
If Liquids or Nothing by 
Mouth is marked about 
continue to “Diet 2”. 
If Oral discomfort  is marked above, proceed to 
the next section. 
 
If Oral discomfort  is NOT marked above, 
proceed to “Diet 3”.  
 
OM will be assessed using the NCI CTCAE version 4.0 [25] as follows: 
Adverse 
Event 
Grade 
 
1 
2 
3 
4 
5 
Oral 
Mucositis 
Asymptomatic or 
mild symptoms; 
intervention not 
indicated 
 
Moderate pain; not 
interfering with oral 
intake; modified 
diet indicated 
 
Severe pain; 
interfering 
with oral 
intake 
 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
 
Death 
 
 
OM will also be assessed using the World Health Organization (WHO) grading scale [26]:  
WHO Oral Mucositis Grade 
 
Grade 0 (None) 
None 
Grade 1 (Mild) 
Oral soreness/erythema 
Grade 2 (Moderate) 
Oral soreness/erythema, ulcers, can tolerate solid foods 
Grade 3 (Severe) 
Oral soreness/erythema, ulcers, liquid diet only 
Grade 4 (Life-threatening) 
Oral alimentation is not possible 
 
Patient-reported OM outcomes will be assessed using the Oral Mucositis Daily Questionnaire 
(OMDQ) [27] 
 
Oral Mucositis Daily Questionnaire 
2. During the PAST 24 HOURS how much MOUTH AND THROAT SORENESS DID YOU HAVE? (Circle  
one number) 
 
0 
1 
2 
3 
4 
No soreness 
A little soreness 
Moderate soreness 
Quite a lot of 
soreness 
Extreme soreness 
 
 
 
 
 
 
3. During the PAST 24 HOURS how much did MOUTH AND THROAT SORENESS limit you in each of the 
following activities: 
 
 
Not limited 
Limited a little 
Limited some 
Limited a lot 
Unable to do 
a. Swallowing 
0 
1 
2 
3 
4 

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16 
b. Drinking 
0 
1 
2 
3 
4 
c. Eating 
0 
1 
2 
3 
4 
d. Talking 
0 
1 
2 
3 
4 
e. Sleeping 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
4. On a scale of 0 to 10, how would you rate your OVERALL MOUTH AND THROAT SORENESS during 
the PAST 24 HOURS? (Please circle the most appropriate number) 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
Worst possible 
 
*Questions 2 through 4 of OMDQ adapted from Elting et al, 2008 [27] 
 
 
Dysphagia will be assessed using the NCI CTCAE version 4.0 [25] as follows: 
Adverse 
Event 
Grade 
 
1 
2 
3 
4 
5 
Dysphagia 
Symptomatic, 
able to eat 
regular diet 
 
Symptomatic and 
altered 
eating/swallowing 
 
Severely altered 
eating/swallowing; 
tube feeding or TPN 
or hospitalization 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
Xerostomia will be assessed using the NCI CTCAE version 4.0 [25] as follows: 
Adverse 
Event 
Grade 
 
1 
2 
3 
4 
5 
Dry Mouth 
Symptomatic (e.g., 
dry or thick saliva) 
without significant 
dietary alteration; 
unstimulated saliva 
flow >0.2 ml/min 
 
Moderate symptoms; 
oral intake alterations 
(e.g., copious water, 
other lubricants, diet 
limited to purees and/or 
soft, moist foods); 
unstimulated saliva 0.1 
to 0.2 ml/min 
Inability to 
adequately 
aliment orally; 
tube feeding or 
TPN indicated; 
unstimulated 
saliva 
 
- 
- 
 
Dysgeusia will be assessed using the NCI CTCAE version 4.0 [25] as follows: 
Adverse 
Event 
Grade 
 
1 
2 
3 
4 
5 
Dysgeusia 
Altered taste but no 
change in diet 
 
Altered taste with change in 
diet (e.g., oral supplements); 
noxious or unpleasant taste; 
loss of taste 
- 
 
- 
- 
 
Dermatitis will be assessed using the NCI CTCAE version 4.0 [25] as follows: 
Adverse 
Event 
Grade 
 
1 
2 
3 
4 
5 
Dermatitis 
radiation 
Faint erythema 
or dry 
desquamation  
Moderate to brisk 
erythema; patchy 
moist desquamation, 
mostly confined to 
Moist 
desquamation in 
areas other than 
skin folds and 
Life-threatening 
consequences; 
skin necrosis or 
ulceration of full 
Death 

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skin folds and 
creases; moderate 
edema 
creases; bleeding 
induced by 
minor trauma or 
abrasion 
 
thickness dermis; 
spontaneous 
bleeding from 
involved site; skin 
graft indicated 
 
 
Trismus 
The interincisal distance will be measured in millimeters at the patient’s maximum comfortable 
extent of mouth opening. Measurements will be taken at baseline, the last day of treatment, two-
week follow-up, and 3 month follow-up appointments.  
Quality of Life 
QOL will be assessed at the time of enrollment prior to initiation of treatment, on the last day of 
treatment, and on the last day of study participation, 3 months after completion of radiation. This 
will be assessed using the Functional Assessment of Cancer Therapy: General (FACT-G) version 
4 (Appendix 11.7).  
 
QOL as related to head and neck cancer will be assessed at each follow-up appointment using the 
FACT – H&N version 4 (Appendix 11.8). 
6.0 Statistical Considerations 
6.1 
Primary Endpoints: 
 
 
The incidence of severe (WHO grade 3-4) oral mucositis in patients treated to a 
cumulative radiation dose of at least 5000 cGy.  
 
The incidence of severe (CTCAE v. 4.0 grade 3-5) oral mucositis in patients treated to a 
cumulative radiation dose of at least 5000 cGy.  
 
6.2 
Secondary Endpoints: 
 
 
Time to onset of severe (CTCAE v. 4.0 grade 3-4) oral mucositis following the initiation 
of radiotherapy.  
 
Mean cumulative radiation dose at time of onset of severe (CTCAE v. 4.0 grade 3-4) oral 
mucositis. 
 
Duration of oral mucositis.  
 
The incidence of pain.   
 
The incidence of dysphagia (CTCAE v. 4.0 and via diet assessment). 
 
The incidence of xerostomia (CTCAE v. 4.0). 
 
The incidence of dysgeusia (CTCAE v. 4.0). 
 
The incidence of trismus (Measurement of interincisal distance). 
 
The incidence of radiodermatitis (CTCAE v. 4.0).  
 
Evaluation of OM-related QOL (via FACT-H&N score).   
 
Incidence of any grade oral mucositis in patients treated to a cumulative radiation dose of 
at least 5000 cGy. 

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18 
6. 3 
Exploratory Endpoints: 
 
 
Proportion of patients with severe (CTCAE v. 4.0 grade 3-4) oral mucositis by 5000 and 
7000 cGy.  
 
Proportion of patients with severe (CTCAE v. 4.0 grade 3-4) oral mucositis by schedule 
of chemotherapy given (weekly versus Q 3 weeks). 
 
Time to reach planned dose of radiation therapy.  
 
Amount of narcotic analgesia use during treatment. 
 
Assessments of breaks in treatment defined as one of the following:  
o 
Missing at least 1 chemotherapy treatment; 
o 
Dose reduction in planned cisplatin administration; OR  
o 
3 consecutive days of no RT secondary to mucositis. ˜ 
 
Proportion of patients who require feeding tube placement during treatment (excluding 
patients who received a prophylactic feeding tube prior to the initiation of therapy).  
 
Percent change in body weight during the course of treatment. 
 
6.4 
Sample Size 
 
Previous studies (detailed in Section 2.2, Table 1) indicate that approximately 40% of patients 
will experience severe OM with radiation and concurrent chemotherapy. The hypothesis in this 
trial is that the addition of LLLT to this treatment regimen will decrease the rate of severe acute 
OM to 20%. A sample size of 45 yields 90% power to detect a difference of 0.20 using an exact 
one-sided binomial test with a Type I error of 0.05. A total of 50 patients are required to ensure 
that there are at least 45 compliant with the treatment schedule. Subjects who miss >20% of 
planned LLLT treatments will be considered non-compliant with the protocol. All patients 
should be enrolled in 12 months after the trial opens. We plan to enroll 25 patients at our 
institution. The same protocol will be opened separately at the University of Pittsburgh Medical 
Center (UPMC), where an additional 25 patients will be enrolled. A Data Use Agreement will 
allow combination of the data for a total of 50 patients to be analyzed. 
 
6.5 
Analysis 
 
Primary endpoint 
If 12 or fewer out of the 45 evaluable severe OM events occur (WHO grade 3-4 or CTCAE v. 
4.0 grade 3-5 oral mucositis), we will reject the null hypothesis that the occurrence of severe OM 
is 0.4 with the addition of LLLT therapy. Point and 90% confidence intervals (using Wilson’s 
method) will also be estimated to describe the primary endpoint. 
 
Secondary endpoints 
Descriptive statistics (point and exact 90% confidence interval estimates from the resultant 
Kaplan-Meier curve) will be generated for the time-to-severe OM and duration of severe OM 
endpoints. Point and 90% confidence intervals (using Wilson’s method) will also be estimated to 
describe the binary endpoints. Continuous endpoints will be described by 90% confidence 
intervals using the t-distribution. 
 
 

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19 
Exploratory endpoints 
Similar descriptive analyses as described in the above paragraph will be used for the binary, 
time-to-event and continuous endpoints. 
 
6.6 
Evaluation of Toxicity 
 
All registered patients will be evaluated for toxicity probably related to the treatment. There have 
been no reported toxicities directly attributed to intraoral or extraoral LLLT. No systemic 
toxicities (e.g fever, nausea, fatigue) are anticipated or have been reported in association with 
oral LLLT. No specific toxicity is expected attributable to LLLT due to the addition of LLLT in 
patients receiving radiation with concurrent chemotherapy. Toxicity data will be collected at 
least weekly during the course of treatment to ensure the validity of this claim.  
 
6.7 
Specific Toxic Outcomes 
 
No toxicities or dose-limiting toxicities have been reported in association with LLLT in the 
biomedical literature. Specifically with respect to LLLT for the prevention and/or management 
of oral mucositis, no toxicities or DLTs have been reported. Any toxicities arising would be 
anticipated to be localized to the exposed tissues. These would include undesignated 
skin/mucosal changes, such as localized skin erythema, mucosal swelling (not typically 
associated with mucositis) or unanticipated sensory changes. Of note, oral mucositis may 
develop despite LLLT and will not be considered a treatment-related toxicity. 
 
We will closely monitor the following outcomes: grade 3 oral dysesthesia (burning/tingling 
sensation in the distribution exposed to LLLT), grade 3 or 4 oral mucosal swelling not 
attributable to mucositis (GI Disorders, other, specify), Grade 3 erythema and/or pain of the skin 
(in the distribution exposed to LLLT),visual loss, blurred vision, retinal tear or detachment, 
uveitis, or other eye disorders. If 2 or more patients out of the first 10 (or fewer) treated in the 
phase II portion of the study develop a grade III (using the CTCAE guidelines) or higher toxicity 
in any of these categories that are probably or definitely related to the LLLT treatment received 
within the first 2 weeks after the completion of treatment, we would recommend revisiting the 
study for safety reasons. Adjudication is necessary to ensure that we judge this study based on 
adverse events that are specific to LLLT therapy and not any other therapy that the patient 
happens to receive. We will continue to monitor these specific toxic outcomes throughout the 
course of the trial, in a sliding window fashion.  
 
6.8 
Other toxic outcomes 
 
Data on other toxic side effects (excluding those detailed in the previous paragraph) that patients 
may experience will also be collected. We have chosen a safety threshold of 0.25 to monitor 
other toxic side effects. We would recommend termination of the phase II portion of the study 
for safety reasons if there were X many occurrences of grade 3 or higher toxicity (using the 
CTCAE guidelines) among the first N (or fewer) patients treated, as it would result in an upper 
confidence limit greater than 0.25: 
 

Version Date: 07/20/2016 
20 
N 
X 
p 
UCL 
8 
1 
0.125 0.255 
13 
2 
0.154 0.256 
18 
3 
0.167 0.253 
22 
4 
0.181 0.261 
27 
5 
0.185 0.256 
32 
6 
0.188 0.252 
36 
7 
0.194 0.256 
41 
8 
0.185 0.252 
 
In the above table, N = the number of patients treated; X = the cumulative number of patients 
with a grade 3 or higher toxicity currently observed; p = the observed toxicity rate; and UCL = 
the exact 1-sided upper 80% confidence limit for p, using Wilson's method without a continuity 
correction. After treating 41 patients, the potential toxicity risk of this regimen should be well 
defined, and thereafter the possible need for termination of the study based on toxicity should be 
minimal. 
6.9 
Expected accrual rate, accrua
l duration, and study duration 
 
Our anticipated accrual rate at our center is 25 patients per year. The accrual rate per year at 
UPMC will also be 25 patients per year. Thus, it should take approximately 1 year to accrue the 
maximum 50 patients needed for the data analysis. Allowing for 2 weeks of follow-up to obtain 
the primary endpoint on the last patient enrolled and 4 months to assemble, analyze and interpret 
the data the total study duration is projected to be at most 1.5 years. 
 
7.0 Adverse Events and Safety Monitoring 
 
There have been no reported toxicities directly attributed to oral LLLT for the prevention/ 
management of mucositis. Any toxicity would be expected to be localized to the region exposed 
(e.g. erythema of the skin, hyperalgesia). We do not anticipate treatment-related toxicity. LLLT 
has never been demonstrated to exacerbate or potentiate mucositis. Regardless, subjects will be 
followed carefully for any possible toxicity. Adverse event (AE) monitoring and reporting is a 
routine part of every clinical trial. These will be followed per WSU IRB requirements.  
 
7.1 
Reporting of Serious Treatment Emergent Adverse Events 
 
An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-
existing) undesirable sign(s), symptom(s), or medical condition(s) occurring after signing the 
informed consent even if the event is not considered to be related to the study intervention. 
Please refer to the adverse event section of the protocol for the protocol-specific definitions of 
study drug and study treatment. 
 
The descriptions and grading scales found in the revised NCI CTCAE version 4.0 will be utilized 
for AE reporting.  All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 

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If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, or grades 1 - 4, will be used. Adverse event monitoring should be continued 
for at least 3 months following the last LLLT treatment. 
 
• ‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting purposes 
only.  
  
• Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 
Adverse events (but not serious adverse events) occurring before starting study treatment but 
after signing the informed consent form will be recorded as part of the medical history or current 
medical condition. Abnormal laboratory values or test results constitute adverse events only if 
they induce clinical signs or symptoms, are considered clinically significant or require therapy 
(e.g., any hematologic abnormality that requires transfusion or cytokine treatment); and should 
be recorded on the Adverse Events Case Report Form (CRF) under the signs, symptoms or 
diagnosis associated with them. In addition, isolated abnormal laboratory values that are 
considered clinically significant (e.g., cause study discontinuation or constitutes in and of itself a 
Serious Adverse Event) should be recorded on the Adverse Events CRF. SAEs occurring after 
signing the Informed Consent are recorded on the Adverse Event CRF. 
 
7.2 
Adverse Event Characteristics 
 
The occurrence of adverse events should be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
 
1. 
The severity grade (CTCAE grade 1-4) 
2. 
Its relationship to each study treatment (suspected/not suspected) 
3. 
Its duration (start and end dates or if continuing at final exam) 
4. 
Action taken (no action taken/temporarily interrupted; study treatment permanently 
discontinued due to this adverse event; concomitant medication taken; non-drug therapy 
given; hospitalization/prolonged hospitalization) 
5. 
Whether it is serious, where a serious adverse event (SAE) is defined as one which: 
• 
Is fatal or life-threatening 
• 
Results in persistent or significant disability/incapacity 
• 
Constitutes a congenital anomaly/birth defect 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
unless hospitalization is for: 
• 
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 

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22 
• 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the informed 
consent 
• 
Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• 
Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• 
Is medically significant, i.e., defined as an event that jeopardizes the patient or 
may require medical or surgical intervention to prevent one of the outcomes listed 
above 
Unlike routine safety assessments, SAEs a
re monitored continuously and have special 
reporting requirements; see protocol sect
ion on Serious Adverse Event reporting. 
All adverse events should be treated appropriately. Once an adverse event is detected, it should 
be followed until its resolution, an assessment should be made at each visit (or more frequently, 
if necessary) of any changes in its severity, its suspected relationship to the study treatment, any 
of the interventions required to treat it, and its outcome. 
Information about all serious adverse events will be collected and recorded. A serious adverse 
event is an undesirable sign, symptom or medical condition which: 
 
is fatal or life-threatening 
 
results in persistent or significant disability/incapacity 
 
constitutes a congenital anomaly/birth defect 
 
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
 
elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
 
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
 
social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
 
is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
 
Events not considered to be serious adverse events are hospitalizations for the routine 
treatment or monitoring of the studied indication, not associated with any deterioration in 
condition. 
 
Sores in the mouth and throat that are likely to interfere with swallowing 
 
Temporary hair loss (of the face/chin/neck) 
 
Tanning, redness, or blistering or peeling of skin in treatment area 
 
Loss of teeth, or cavities in teeth, if strict dental care is not followed 
 
Hardness and tightness of the skin and muscles of the head and neck 
 
Dryness of the mouth or altered taste that may be permanent  
 
Loss of appetite 

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23 
 
Weight loss which may necessitate the placement of a temporary feeding tube 
 
Nausea and/or vomiting 
 
Weakness 
 
Hearing loss, ringing of the ears 
 
Numbness of the fingers and toes 
 
Lower blood counts with risk of infection or bleeding 
 
Anemia 
 
Loss of taste 
 
Muscle cramps 
 
Loss of coordination 
 
Involuntary movement 
 
Restlessness 
 
Treatment, which was elective or pre-planned, for a pre-existing condition that did 
not worsen 
 
Treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of serious given above and not resulting in hospital admission. 
 
7.3 
WSU IRB Adverse Event reporting 
 
All adverse event reporting will be done in compliance with the Wayne State Institutional 
Review Board as follows: 
 
A. Death or Life Threatening Adverse Reaction or Unexpected Event:  
If a death or immediately life-threatening Adverse Reaction/Unexpected Event occurs, it must be 
reported to the IRB office within three (3) business days of the PI becoming aware, even if the 
information in the report is incomplete. As more information is forthcoming, one or more 
additional reports should be filed with the IRB. The initial report of the Adverse Reaction or 
Unexpected Event and follow-up reports should be filed using the IRB Adverse Reaction and 
Unexpected Event Form.  
 
B. Serious Adverse Reaction or Unexpected Event:  
If a Serious Adverse Reaction/Unexpected Event occurs (one that necessitates or prolongs 
hospitalization, results in a permanent or significant disability or congenital anomaly, or is 
judged to be serious by the principal investigator), and is unexpected, (not listed in the consent 
form) it must be reported to the IRB within five (5) business days of the PI becoming aware. If 
the Serious Adverse Event is listed in the consent form but a relationship to the study 
intervention/activity cannot be ruled out by the PI, it must be reported to the IRB within five 
(5) business days. If the information is incomplete on the initial filing, follow-up reporting is 
required. The IRB Adverse Reaction and Unexpected Event Form should be used in all reports 
pertaining to these reactions/events.  
 
C. Non-Serious (Moderate or Minor) Adverse Reaction or Unexpected Event:  
If a non-serious Adverse Reaction occurs that is unexpected (not listed in the informed consent), 
it must be reported to the IRB within ten (10) business days of awareness, unless the Principal 
Investigator can rule out the relationshi
p to the study agent or intervention. If a non-serious 
Adverse Reaction occurs that is expected (listed in the informed consent), but is more frequent, 

Version Date: 07/20/2016 
24 
more intense or longer lasting that expected, or requires medical treatment, it must be reported to 
the IRB within ten (10) business days. If the reaction that is listed in the consent form occurs as 
described in the informed consent, it does not need to be reported to the IRB. 
 
If an Unexpected Event occurs, it must be reported to the IRB  within ten (10) business days of 
the awareness by the Principal Investigator. The Adverse Reaction/ Unexpected Event Form 
should be used for these submissions.  
 
D. Possibly-Related Adverse Reactions/ Unexpected Events 
In the rare case where a sponsor requires that a non-reportable (i.e., possibly related) Adverse 
Reaction/ Unexpected Event be reported to the IRB, an amendment should be submitted by the 
PI requesting that the non-reportable safety report be appended to the IRB file. It remains the 
primary responsibility of the WSU PI, the study sponsor, and any associated DSMB to identify 
trends that might require the event to be elevated to definitely or probably related status.  
If a trend is identified that elevates the Adverse Reaction to definitely or probably related status, 
an Adverse Reaction/ Unexpected Event Form should be completed, along with an amendment 
for consent form changes, if needed, and submitted to the IRB.  
  
7.4 
Data Safety Monitoring 
 
All charts to be reviewed and data recorded and analyzed using federal and institutional HIPAA 
guidelines. The data will be housed in a password-protected database that will be accessible only 
to the primary investigator. 
 
Scheduled meetings will be held monthly or more frequently depending on the activity of the 
protocol.  These meetings will include the protocol investigators and supporting staff involved 
with the conduct of the protocol. 
  
During these meetings the investigators will discuss: 
 
Safety of protocol participants (adverse events and reporting) 
 
Validity and integrity of the data (data completeness on case report forms and complete 
source documentation) 
 
Enrollment rate relative to expectation of target accrual, (eligible and ineligible 
participants) 
 
Retention of participants, adherence to the protocol and protocol violations 
 
Protocol amendments 
  
Completed Data and Safety Monitoring Reports of these regular investigator meetings will be 
kept on file in the office of the Clinical Trials Core (see form in appendix 11.10). The data 
manager assigned to the clinical trial will be responsible for completing the report form.  The 
completed reports will be reviewed and signed off by the Principle Investigator (PI) or by one of 
the Co-PI’s in the absence of the PI.  The signed off forms will then be forwarded to the 
Director, Clinical Trials Core for review of completeness and processing with the Data and 
Safety Monitoring Committee. 
  
The Barbara Ann Karmanos Cancer Institute, Data and Safety Monitoring Committee will meet 
on a monthly basis to review the prior month Serious Adverse Event forms and Data and Safety 
Monitoring study specific reports that have been filed. 

Version Date: 07/20/2016 
25 
7.5 
Ethics 
 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements. 
  
The final study protocol, including the final version of the Written Informed Consent Form, must 
be approved in writing by Wayne State University IRB or the IRB of the respective institution. 
  
The principal investigator is responsible for informing the Wayne State University IRB of any 
amendments to the protocol. The protocol must be re-approved by the IRB annually. Progress 
reports and notifications of serious, unexpected adverse events or drug reactions will be provided 
to the IRB. 
  
The principal investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study. Subjects must also 
be notified that they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. In 
accordance with the Health Information Portability and Accountability Act (HIPAA), the Written 
Informed Consent Form must include a subject authorization to release medical information to 
any agency, or Institutional Review Board access to subject’s medical information that includes 
all hospital records relevant to the study, including subjects’ medical history. 
  
The principal investigator must store the original, signed Written Informed Consent Form. A 
copy of the signed Written Informed Consent Form must be given to the subject. 
8.0 Registration Procedures 
8.1 
General Guidelines 
 
Eligible patients will be entered on the study centrally at the clinical trials office of the Karmanos 
Cancer Center/Wayne State University, by the Study Coordinator. 
At the time of registration: 
 
Patients must have signed an informed consent form prior to registration. 
 
Confirm that all required pre-study requirements are completed as per the study 
calendar. 
 
Collect demographic information on the patient including age, gender, smoking 
history, alcohol history, tumor stage, histology, prior therapy. 
   
8.2 
Registration Process 
 
To register a patient, the following documents should be completed and faxed or e-mailed to the 
Study Coordinator: 
• Signed patient consent form 
• HIPAA authorization form 

Version Date: 07/20/2016 
26 
9.0 Protocol Conduct and Guidelines 
9.1 
Protocol amendments, or changes in study conduct 
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed and approved. Amendments significantly affecting the safety 
of subjects, the scope of the investigation or the scientific quality of the study require additional 
approval by the IRB.  
If an immediate change to the protocol is felt to be necessary by the investigator and is 
implemented for safety reasons the IRB at the center must be informed immediately. 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB approval but the IRB must be kept informed of such administrative changes.  
9.2 
Publication of results 
 
Data from the results of this study will be combined with the data from the results of the  same 
protocol submitted at the University of Pittsburgh Medical Center and will be published together 
in one collective report. The results of this study will be presented in abstract form in an 
international medical conference forum and published in a peer-reviewed  journal.   
9.3 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described in: 
 
 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. Directive 
91/507/EEC, The Rules Governing Medicinal Products in the European Community. 
 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations). 
 
Declaration of Helsinki and amendments, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects). 
 
The investigator agrees to adhere to the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice that it conforms to. 
9.4 
Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB).  
9.5 
Informed consent 
The investigator must explain to each subject (or legally authorized representative) the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time 

Version Date: 07/20/2016 
27 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the subject’s legally appointed 
representative, if witnessed by a person not involved in the study, mentioning that the patient 
could not read or sign the documents. No patient can enter the study before his/her informed 
consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by the 
investigator with it for IRB/IEC/REB approval. 
9.6 
Declaration of Helsinki 
The investigator will conduct the trial in accordance with the principles of the Declaration of 
Helsinki. Copies of the Declaration of Helsinki and amendments will be provided upon request 
or can be accessed via the website of the World Medical Association at 
http://www.wma.net/e/policy/17-c_e.html. 
 
 

Version Date: 07/20/2016 
28 
10.0 References 
 
1. 
Pfister, D.G., et al., Head and Neck Cancers, Version 1.2015. J Natl Compr Canc Netw, 2015. 
13(7): p. 847‐56. 
2. 
Trotti, A., et al., Mucositis incidence, severity and associated outcomes in patients with head 
and neck cancer receiving radiotherapy with or without chemotherapy: a systematic 
literature review. Radiother Oncol, 2003. 66(3): p. 253‐62. 
3. 
Cheng, K.K., et al., Severe oral mucositis associated with cancer therapy: impact on oral 
functional status and quality of life. Support Care Cancer, 2010. 18(11): p. 1477‐85. 
4. 
Groome, P.A., et al., Compromised local control due to treatment interruptions and late 
treatment breaks in early glottic cancer: Population‐based outcomes study supporting need 
for intensified treatment schedules. Int J Radiat Oncol Biol Phys, 2006. 64(4): p. 1002‐12. 
5. 
Elting, L.S., et al., Risk, outcomes, and costs of radiation‐induced oral mucositis among 
patients with head‐and‐neck malignancies. Int J Radiat Oncol Biol Phys, 2007. 68(4): p. 
1110‐20. 
6. 
Huang, Y.Y., et al., Biphasic dose response in low level light therapy ‐ an update. Dose 
Response, 2011. 9(4): p. 602‐18. 
7. 
Kim, W.S. and R.G. Calderhead, Is light‐emitting diode phototherapy (LED‐LLLT) really 
effective? Laser Ther, 2011. 20(3): p. 205‐15. 
8. 
Sutherland, J.C., Biological effects of polychromatic light. Photochem Photobiol, 2002. 76(2): 
p. 164‐70. 
9. 
Karu, T., Laser biostimulation: a photobiological phenomenon. J Photochem Photobiol B, 
1989. 3(4): p. 638‐40. 
10. 
Karu, T.I. and S.F. Kolyakov, Exact action spectra for cellular responses relevant to 
phototherapy. Photomed Laser Surg, 2005. 23(4): p. 355‐61. 
11. 
Antunes, H.S., et al., Phase III trial of low‐level laser therapy to prevent oral mucositis in head 
and neck cancer patients treated with concurrent chemoradiation. Radiother Oncol, 2013. 
109(2): p. 297‐302. 
12. 
Arun Maiya, G., M.S. Sagar, and D. Fernandes, Effect of low level helium‐neon (He‐Ne) laser 
therapy in the prevention & treatment of radiation induced mucositis in head & neck cancer 
patients. Indian J Med Res, 2006. 124(4): p. 399‐402. 
13. 
Arora, H., et al., Efficacy of He‐Ne Laser in the prevention and treatment of radiotherapy‐
induced oral mucositis in oral cancer patients. Oral Surg Oral Med Oral Pathol Oral Radiol 
Endod, 2008. 105(2): p. 180‐6, 186 e1. 
14. 
Bensadoun, R.J., et al., Low‐energy He/Ne laser in the prevention of radiation‐induced 
mucositis. A multicenter phase III randomized study in patients with head and neck cancer. 
Support Care Cancer, 1999. 7(4): p. 244‐52. 
15. 
Gautam, A.P., et al., Low level laser therapy against radiation induced oral mucositis in elderly 
head and neck cancer patients‐a randomized placebo controlled trial. J Photochem Photobiol 
B, 2015. 144: p. 51‐6. 
16. 
Gautam, A.P., et al., Low level laser therapy for concurrent chemoradiotherapy induced oral 
mucositis in head and neck cancer patients ‐ a triple blinded randomized controlled trial. 
Radiother Oncol, 2012. 104(3): p. 349‐54. 
17. 
Lima, A.G., et al., Efficacy of low‐level laser therapy and aluminum hydroxide in patients with 
chemotherapy and radiotherapy‐induced oral mucositis. Braz Dent J, 2010. 21(3): p. 186‐92. 

Version Date: 07/20/2016 
29 
18. 
Zanin, T., et al., Use of 660‐nm diode laser in the prevention and treatment of human oral 
mucositis induced by radiotherapy and chemotherapy. Photomed Laser Surg, 2010. 28(2): p. 
233‐7. 
19. 
Carvalho, P.A., et al., Evaluation of low‐level laser therapy in the prevention and treatment of 
radiation‐induced mucositis: a double‐blind randomized study in head and neck cancer 
patients. Oral Oncol, 2011. 47(12): p. 1176‐81. 
20. 
Oton‐Leite, A.F., et al., Effect of intraoral low‐level laser therapy on quality of life of patients 
with head and neck cancer undergoing radiotherapy. Head Neck, 2012. 34(3): p. 398‐404. 
21. 
Bjordal, J.M., et al., A systematic review with meta‐analysis of the effect of low‐level laser 
therapy (LLLT) in cancer therapy‐induced oral mucositis. Support Care Cancer, 2011. 19(8): 
p. 1069‐77. 
22. 
Lalla, R.V., et al., MASCC/ISOO clinical practice guidelines for the management of mucositis 
secondary to cancer therapy. Cancer, 2014. 120(10): p. 1453‐61. 
23. 
Peterson, D.E., et al., Management of oral and gastrointestinal mucositis: ESMO Clinical 
Practice Guidelines. Ann Oncol, 2011. 22 Suppl 6: p. vi78‐84. 
24. 
Brouwer, C.L., et al., CT‐based delineation of organs at risk in the head and neck region: 
DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus 
guidelines. Radiother Oncol, 2015. 117(1): p. 83‐90. 
25. 
Institute, N.C., Common Terminology Criteria for Adverse Events v4.0 in NIH publication # 09‐
7473, N. NCI, DHHS. , Editor. 
26. 
Organization, W.H., WHO handbook for reporting results of cancer treatment. 1979: Geneva : 
World Health Organization. 
27. 
Elting, L.S., et al., Patient‐reported measurements of oral mucositis in head and neck cancer 
patients treated with radiotherapy with or without chemotherapy: demonstration of 
increased frequency, severity, resistance to palliation, and impact on quality of life. Cancer, 
2008. 113(10): p. 2704‐13. 
 
 
 

Version Date: 07/20/2016 
30 
11.0 Appendix 
 
11.1 
Karnofsky Performance Scale 
11.2 
Weekly Toxicity Scoring Sheet 
11.3 
LLLT Treatment Record Form 
11.4 
Table 2. Consensus Contouring Guidelines for Organs at Risk 
11.5 
Table 3. OAR dose parameters to be recorded 
11.6 
FACT-G 
11.7 
FACT-H&N 
11.8 
Oral Mucositis Daily Questionnaire (OMDQ) 
11.9 
Data and Safety Monitoring Report 
11.10   Study Calendar 
 
 

Version Date: 07/20/2016 
31 
 
11.1 Karnofsky Performance Scale 
 
 
KARNOFSKY PERFORMANCE SCALE 
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

Version Date: 07/20/2016 
32 
11.2 Weekly Toxicity Scoring Sheet 
 
Protocol ID______________ 
Subject number_______________ 
Assessment date_________________ 
Radiation dose_____________ 
 
Assessment type: 
☐Baseline 
☐Weekly  
☐Last Treatment 
☐Follow-up 
 
Mouth Pain (0-10) _________ 
Throat Pain (0-10) _________ 
PEG tube (Y / N) 
Alcohol use (Y / N) 
Smoking (Y / N) 
Weight_________kg 
 
Analgesics (medications and dose)__________________________________________________________________________________________ 
 
Diet Assessment 
Diet 1: 
Diet 2: 
Diet 3: 
What has the subject been able to eat 
within the past 24 hours (mark only one) 
If the subject has been unable to eat Solid food, mark 
all the reason(s) why (mark all that apply) 
Based solely on how the mouth feels, what does 
the subject feel (s)he could try to eat if (s)he did 
not have to swallow (mark only one) 
☐Solids 
☐Nausea/Vomiting 
☐Oral discomfort 
☐Solids 
☐Liquids 
☐Loss of appetite 
☐Dry mouth 
☐Liquids 
☐Nothing by Mouth 
☐Throat discomfort 
☐No teeth 
☐Nothing by Mouth 
 
If Solids is marked above, proceed to next 
section. 
☐Difficulty Swallowing 
☐Other__________________________________ 
 
If Liquids or Nothing by Mouth  is 
marked about continue to “Diet 2”. 
If Oral discomfort is marked above, proceed to the 
next section. 
 
If Oral discomfort is NOT marked above, proceed to 
“Diet 3”.  
 
WHO Oral Mucositis Grade 
Grade 0 (None) 
None 
Grade 1 (Mild) 
Oral soreness/erythema 
Grade 2 (Moderate) 
Oral soreness/erythema, ulcers, can tolerate solid foods 
Grade 3 (Severe) 
Oral soreness/erythema, ulcers, liquid diet only 
Grade 4 (Life-threatening) 
Oral alimentation is not possible 
 
Adverse Event 
Grade 
 
1 
2 
3 
4 
5 
Oral Mucositis 
Asymptomatic or mild 
symptoms; intervention 
not indicated 
 
Moderate pain; not 
interfering with oral intake; 
modified diet indicated 
Severe pain; interfering 
with oral intake 
 
Life-threatening 
consequences; urgent 
intervention indicated 
 
Death 
 
Adverse Event 
Grade 
 
1 
2 
3 
4 
5 
Dysphagia 
Symptomatic, able 
to eat regular diet 
 
Symptomatic and altered 
eating/swallowing 
 
Severely altered 
eating/swallowing; tube feeding or 
TPN or hospitalization indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
 
Adverse Event 
Grade 
 
1 
2 
3 
4 
5 
Dry Mouth 
Symptomatic (e.g., dry or thick 
saliva) without significant 
dietary alteration; unstimulated 
saliva flow >0.2 ml/min 
 
Moderate symptoms; oral intake 
alterations (e.g., copious water, other 
lubricants, diet limited to purees and/or 
soft, moist foods); unstimulated saliva 0.1 
to 0.2 ml/min 
Inability to adequately 
aliment orally; tube 
feeding or TPN indicated; 
unstimulated saliva 
 
- 
- 
 
Adverse Event 
Grade 
 
1 
2 
3 
4 
5 
Dysgeusia 
Altered taste but no change in diet 
 
Altered taste with change in diet (e.g., oral supplements); 
noxious or unpleasant taste; loss of taste 
- 
 
- 
- 
 
Adverse Event 
Grade 
 
1 
2 
3 
4 
5 
Dermatitis 
radiation 
Faint erythema or 
dry desquamation  
Moderate to brisk erythema; 
patchy moist desquamation, 
mostly confined to skin folds 
and creases; moderate edema 
Moist desquamation in 
areas other than skin 
folds and creases; 
bleeding induced by 
minor trauma or abrasion 
Life-threatening consequences; 
skin necrosis or ulceration of full 
thickness dermis; spontaneous 
bleeding from involved site; skin 
graft indicated 
Death 
 
Signature________________________________

Version Date: 07/20/2016 
33 
11.3 LLLT Treatment Record Form 
Subject ID:_______________ 
Radiation start date_________  
Monday (Date____________) 
Wednesday (Date___________) 
Friday (Date____________) 
Notes: 
 
 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
 
 
Week 1 
Right buccal mucosa* 
 
 
 
 
 
 
 
 
 
Left buccal mucosa* 
 
 
 
 
 
 
 
 
 
Ventral tongue* 
 
 
 
 
 
 
 
 
 
Upper lip 
 
 
 
 
 
 
 
 
 
Lower lip 
 
 
 
 
 
 
 
 
 
Right tongue 
 
 
 
 
 
 
 
 
 
Left tongue 
 
 
 
 
 
 
 
 
 
Hard Palate 
 
 
 
 
 
 
 
 
 
Soft palate 
 
 
 
 
 
 
 
 
 
Floor of mouth 
 
 
 
 
 
 
 
 
 
Other sites: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Monday (Date____________) 
Wednesday (Date___________) 
Friday (Date____________) 
Notes: 
 
 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
 
Week 2 
Right buccal mucosa* 
 
 
 
 
 
 
 
 
 
Left buccal mucosa* 
 
 
 
 
 
 
 
 
 
Ventral tongue* 
 
 
 
 
 
 
 
 
 
Upper lip 
 
 
 
 
 
 
 
 
 
Lower lip 
 
 
 
 
 
 
 
 
 
Right tongue 
 
 
 
 
 
 
 
 
 
Left tongue 
 
 
 
 
 
 
 
 
 
Hard Palate 
 
 
 
 
 
 
 
 
 
Soft palate 
 
 
 
 
 
 
 
 
 
Floor of mouth 
 
 
 
 
 
 
 
 
 
Other sites: 
 
 
 
 
 
 
 
 
 
 
 
*Required treatment area (other areas treated if symptomatic) 
†1 minute /  2.5Hz 
Signature_________________________________ 

Version Date: 07/20/2016 
34 
11.3 LLLT Treatment Record Form 
Subject ID:_______________ 
 
Monday (Date____________) 
Wednesday (Date___________) 
Friday (Date____________) 
Notes: 
 
 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
 
 
Week 3 
Right buccal mucosa* 
 
 
 
 
 
 
 
 
 
Left buccal mucosa* 
 
 
 
 
 
 
 
 
 
Ventral tongue* 
 
 
 
 
 
 
 
 
 
Upper lip 
 
 
 
 
 
 
 
 
 
Lower lip 
 
 
 
 
 
 
 
 
 
Right tongue 
 
 
 
 
 
 
 
 
 
Left tongue 
 
 
 
 
 
 
 
 
 
Hard Palate 
 
 
 
 
 
 
 
 
 
Soft palate 
 
 
 
 
 
 
 
 
 
Floor of mouth 
 
 
 
 
 
 
 
 
 
Other sites: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Monday (Date____________) 
Wednesday (Date___________) 
Friday (Date____________) 
Notes: 
 
 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
 
Week 4 
Right buccal mucosa* 
 
 
 
 
 
 
 
 
 
Left buccal mucosa* 
 
 
 
 
 
 
 
 
 
Ventral tongue* 
 
 
 
 
 
 
 
 
 
Upper lip 
 
 
 
 
 
 
 
 
 
Lower lip 
 
 
 
 
 
 
 
 
 
Right tongue 
 
 
 
 
 
 
 
 
 
Left tongue 
 
 
 
 
 
 
 
 
 
Hard Palate 
 
 
 
 
 
 
 
 
 
Soft palate 
 
 
 
 
 
 
 
 
 
Floor of mouth 
 
 
 
 
 
 
 
 
 
Other sites: 
 
 
 
 
 
 
 
 
 
 
 
*Required treatment area (other areas treated if symptomatic) 
†1 minute /  2.5Hz 
 
Signature_________________________________ 

Version Date: 07/20/2016 
35 
 
11.3 LLLT Treatment Record Form 
Subject ID:_______________ 
 
Monday (Date____________) 
Wednesday (Date___________) 
Friday (Date____________) 
Notes: 
 
 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
 
 
Week 5 
Right buccal mucosa* 
 
 
 
 
 
 
 
 
 
Left buccal mucosa* 
 
 
 
 
 
 
 
 
 
Ventral tongue* 
 
 
 
 
 
 
 
 
 
Upper lip 
 
 
 
 
 
 
 
 
 
Lower lip 
 
 
 
 
 
 
 
 
 
Right tongue 
 
 
 
 
 
 
 
 
 
Left tongue 
 
 
 
 
 
 
 
 
 
Hard Palate 
 
 
 
 
 
 
 
 
 
Soft palate 
 
 
 
 
 
 
 
 
 
Floor of mouth 
 
 
 
 
 
 
 
 
 
Other sites: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Monday (Date____________) 
Wednesday (Date___________) 
Friday (Date____________) 
Notes: 
 
 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
 
Week 6 
Right buccal mucosa* 
 
 
 
 
 
 
 
 
 
Left buccal mucosa* 
 
 
 
 
 
 
 
 
 
Ventral tongue* 
 
 
 
 
 
 
 
 
 
Upper lip 
 
 
 
 
 
 
 
 
 
Lower lip 
 
 
 
 
 
 
 
 
 
Right tongue 
 
 
 
 
 
 
 
 
 
Left tongue 
 
 
 
 
 
 
 
 
 
Hard Palate 
 
 
 
 
 
 
 
 
 
Soft palate 
 
 
 
 
 
 
 
 
 
Floor of mouth 
 
 
 
 
 
 
 
 
 
Other sites: 
 
 
 
 
 
 
 
 
 
 
 
*Required treatment area (other areas treated if symptomatic) 
†1 minute /  2.5Hz 
Signature_________________________________ 

Version Date: 07/20/2016 
36 
 
11.3 LLLT Treatment Record Form 
Subject ID:_______________ 
 
Monday (Date____________) 
Wednesday (Date___________) 
Friday (Date____________) 
Notes: 
 
 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
 
 
Week 7 
Right buccal mucosa* 
 
 
 
 
 
 
 
 
 
Left buccal mucosa* 
 
 
 
 
 
 
 
 
 
Ventral tongue* 
 
 
 
 
 
 
 
 
 
Upper lip 
 
 
 
 
 
 
 
 
 
Lower lip 
 
 
 
 
 
 
 
 
 
Right tongue 
 
 
 
 
 
 
 
 
 
Left tongue 
 
 
 
 
 
 
 
 
 
Hard Palate 
 
 
 
 
 
 
 
 
 
Soft palate 
 
 
 
 
 
 
 
 
 
Floor of mouth 
 
 
 
 
 
 
 
 
 
Other sites: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Monday (Date____________) 
Wednesday (Date___________) 
Friday (Date____________) 
Notes: 
 
 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
 
Week 8 
Right buccal mucosa* 
 
 
 
 
 
 
 
 
 
Left buccal mucosa* 
 
 
 
 
 
 
 
 
 
Ventral tongue* 
 
 
 
 
 
 
 
 
 
Upper lip 
 
 
 
 
 
 
 
 
 
Lower lip 
 
 
 
 
 
 
 
 
 
Right tongue 
 
 
 
 
 
 
 
 
 
Left tongue 
 
 
 
 
 
 
 
 
 
Hard Palate 
 
 
 
 
 
 
 
 
 
Soft palate 
 
 
 
 
 
 
 
 
 
Floor of mouth 
 
 
 
 
 
 
 
 
 
Other sites: 
 
 
 
 
 
 
 
 
 
 
 
*Required treatment area (other areas treated if symptomatic) 
†1 minute /  2.5Hz 
Signature_________________________________ 

Version Date: 07/20/2016 
37 
 
11.3 LLLT Treatment Record Form 
Subject ID:_______________ 
 
Monday (Date____________) 
Wednesday (Date___________) 
Friday (Date____________) 
Notes: 
 
 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
 
 
Week 9 
Right buccal mucosa* 
 
 
 
 
 
 
 
 
 
Left buccal mucosa* 
 
 
 
 
 
 
 
 
 
Ventral tongue* 
 
 
 
 
 
 
 
 
 
Upper lip 
 
 
 
 
 
 
 
 
 
Lower lip 
 
 
 
 
 
 
 
 
 
Right tongue 
 
 
 
 
 
 
 
 
 
Left tongue 
 
 
 
 
 
 
 
 
 
Hard Palate 
 
 
 
 
 
 
 
 
 
Soft palate 
 
 
 
 
 
 
 
 
 
Floor of mouth 
 
 
 
 
 
 
 
 
 
Other sites: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Monday (Date____________) 
Wednesday (Date___________) 
Friday (Date____________) 
Notes: 
 
 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
Mucositis 
(Y/N) 
Treated Area 
(Y/N) 
Treated Area 
Settings†: 
(Y/N) 
 
Week 10 
Right buccal mucosa* 
 
 
 
 
 
 
 
 
 
Left buccal mucosa* 
 
 
 
 
 
 
 
 
 
Ventral tongue* 
 
 
 
 
 
 
 
 
 
Upper lip 
 
 
 
 
 
 
 
 
 
Lower lip 
 
 
 
 
 
 
 
 
 
Right tongue 
 
 
 
 
 
 
 
 
 
Left tongue 
 
 
 
 
 
 
 
 
 
Hard Palate 
 
 
 
 
 
 
 
 
 
Soft palate 
 
 
 
 
 
 
 
 
 
Floor of mouth 
 
 
 
 
 
 
 
 
 
Other sites: 
 
 
 
 
 
 
 
 
 
 
 
*Required treatment area (other areas treated if symptomatic) 
†1 minute /  2.5Hz 
Signature_________________________________ 

Version Date: 07/20/2016 
38 
 
11.4 Table 2. Consensus Contouring 
Guidelines for Organs at Risk 
 
Organ at Risk 
Remarks 
Anatomic Boundaries 
Cranial 
Caudal 
Anterior 
Posterior 
Lateral 
Medial 
Required 
Parotid gland 
Include carotid 
artery, 
retromandibular vein 
and extracranial 
facial nerve.  
External auditory 
canal, mastoid 
process  
Post. part submandibular 
space  
Masseter m., post. 
border mandibular 
bone, med. and lat. 
pterygoid m.  
 
Ant. belly 
sternocleidomastoid 
m., lat. side post. 
belly of the digastric 
m. (posterior- medial)  
 
Subcutaneous fat, 
platysma  
 
Post. belly of the 
digastric m., styloid 
process, 
parapharyngeal space  
 
Submandibular 
gland 
 
Med. pterygoid m., 
mylohyoid m.  
 
Fatty tissue  
 
Lat. Surface 
mylohyoid m., 
hyoglossus m.  
 
Parapharyngeal 
space, 
sternocleidomastoid 
m.  
 
Med. surface med. 
pterygoid m., med. 
surface mandibular 
bone, platysma  
 
Lat. surface 
mylohyoid m., 
hyoglossus m., 
superior and middle 
pharyngeal 
constrictor m., 
anterior belly of the 
digastric m. 
Extended oral 
cavity 
Posterior to mandible 
and maxilla, no inner 
surface of the lips  
Hard palate mucosa 
and mucosal 
reflections near the 
maxilla  
The base of tongue 
mucosa and hyoid 
posteriorly and the 
mylohyoid m. and ant. 
belly of the digastric m. 
anteriorly  
Inner surface of the 
mandible and maxilla  
 
Post. borders of soft 
palate, uvula, and 
more inferiorly the 
base of tongue  
 
Inner surface of the 
mandible and maxilla  
 
 
Lips 
 
Hard palate (lateral), 
anterior nasal spine 
(at the midline)  
 
Lower edge teeth 
sockets, cranial edge 
mandibular body  
 
Outer surface of the 
skin  
 
Mandibular body, 
teeth, tongue, air (if 
present)  
 
Depressor anguli oris 
m., buccinator m., 
levator anguli oris 
m./risorius m. 
Buccinator  
 
Buccal mucosa 
 
Bottom of maxillary 
sinus  
Upper edge teeth sockets  
Lips, teeth  
 
Med. pterygoid m.  
 
Buccal fat  
 
Outer surface of the 
mandible and 
maxilla, oral 
cavity/base of 
tongue/soft pallate  
Pharyngeal 
constrictor 
muscle 
Thickness ~3 mm  
 
Caudal tips of 
pterygoid plates  
 
Caudal edge of arytenoid 
cartilages  
 
Superior: hamulus of 
pterygoid plate; 
mandibula; base of 
tongue; pharyngeal 
lumen. Middle: base 
of tongue; hyoid. 
Inferior: soft tissue of 
Prevertebral muscle  
 
Superior: medial 
pterygoid muscle. 
Middle: greater horn 
of hyoid bone. 
Inferior: superior 
horn of thyroid 
 

Version Date: 07/20/2016 
39 
supraglottic/glottic 
larynx  
 
cartilage  
 
Optional 
 
Supraglottic 
larynx 
 
Tip of epiglottis  
 
Cranial edge of arytenoid 
cartilages  
 
Hyoid bone, pre-
epiglottic space, 
thyroid cartilage  
Inferior PCM, 
pharyngeal lumen  
 
Thyroid cartilage  
 
Pharyngeal lumen 
(lumen excluded)  
 
Glottic area 
 
Cranial edge of 
arytenoid cartilages  
Caudal edge of ant. part 
of thyroid cartilage  
 
Cricoid, anterior 
border arytenoids  
 
 
Crico-
pharyngeal inlet 
 
Caudal edge of 
arytenoid cartilages  
 
1 cm caudal to the lower 
edge of the cricoid 
cartilage  
Tracheal lumen  
 
Vertebral body  
 
 
 
Cervical 
esophagus 
 
1 cm caudal to the 
lower edge of the 
cricoid cartilage  
Caudal edge of C7  
 
 
 
 
Brachial plexus 
If the brachial plexus 
is wrapped around 
the vascular bundle 
on the most inferior 
slices, the vascular 
structure is included 
in the contour 
Cranial border of C5, 
vertebral body  
 
Cranial border of T3, 
vertebral body  
Post. border of: 
anterior scalene m., 
subclavian artery, 
axillary vein  
 
Ant. border of: 
middle scalene m., 
seratus anterior m., 
subscapularis m.  
Lat. border of: ant. 
and middle scalene 
m., pectoralis major, 
teres major  
 
Intervertebral 
foramen (bony 
vertebral body), lat. 
border of 1st rib  
 
Organs at risk with specification of anatomic boundaries. Ant. = anterior, post. = posterior, lat. = lateral, med. = medial, m. = muscle.  
Table adapted from: 
Brouwer CL et al. CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, 
NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines. Radiother Oncol (2015). [24] 
 

Version Date: 07/20/2016 
40 
11.5 Table 3. OAR dose pa
rameters to be recorded 
 
 
 
 
Brainstem 
 
 
Maximum Dose_________ 
 
Spinal Cord 
 
 
Maximum Dose_________ 
 
Right Parotid 
 
 
Mean Dose_____________ 
V30Gy_________________ 
Left Parotid 
 
 
Mean Dose_____________ 
V30Gy_________________ 
Parotids (bilateral) 
 
 
D20cc_________________ 
 
Submandibular Gland 
 
Mean Dose_____________ 
 
Extended Oral Cavity 
 
Maximum Dose_________ 
Mean Dose_____________ 
Lips 
 
 
Maximum Dose_________ 
Mean Dose_____________ 
Buccal Mucosa 
 
 
Maximum Dose_________ 
Mean Dose_____________ 
Mandible 
 
 
Maximum Dose_________ 
 
Pharyngeal Constrictors 
 
Mean Dose_____________ 
 
 
 

Version Date: 07/20/2016 
41 
11.6 FACT-G (Version 4) 
 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to 
indicate your response as it
 applies to the past 7 days. 
 
 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of energy .......................................................
0 
1 
2 
3 
4 
GP2 
I have nausea ......................................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family .........................................
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain ..........................................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment .........................
0 
1 
2 
3 
4 
GP6 
I feel ill ...............................................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ........................................
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GS1 
I feel close to my friends ....................................................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ............................
0 
1 
2 
3 
4 
GS3 
I get support from my friends .............................................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness ....................................
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness ..................................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) ..............................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life ............................................
0 
1 
2 
3 
4 

Version Date: 07/20/2016 
42 
FACT-G (Version 4) 
 
Please circle or mark one number per line to indica
te your response as it applies to the past 7 
days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GE1 
I feel sad ..............................................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness ..........
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness ..................
0 
1 
2 
3 
4 
GE4 
I feel nervous .......................................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying .............................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse ............................
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) ..........................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling .....................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life ..........................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness ...................................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ...............................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ......................
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now ..............
0 
1 
2 
3 
4 
 
 
 
 
 
 

Version Date: 07/20/2016 
43 
11.7 FACT-H&N (Version 4) 
 
Please circle or mark one number per line to indica
te your response as it applies to the past 7 
days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
H&N1 
I am able to eat the foods that I like ....................................
0 
1 
2 
3 
4 
H&N2 
My mouth is dry ..................................................................
0 
1 
2 
3 
4 
H&N3 
I have trouble breathing ......................................................
0 
1 
2 
3 
4 
H&N4 
My voice has its usual quality and strength ........................
0 
1 
2 
3 
4 
H&N5 
I am able to eat as much food as I want ..............................
0 
1 
2 
3 
4 
H&N6 
I am unhappy with how my face and neck look ..................
0 
1 
2 
3 
4 
H&N7 
I can swallow naturally and easily ......................................
0 
1 
2 
3 
4 
H&N8 
I smoke cigarettes or other tobacco products ......................
0 
1 
2 
3 
4 
H&N9 
I drink alcohol (e.g. beer, wine, etc.)...................................
0 
1 
2 
3 
4 
H&N 
10 
I am able to communicate with others ................................
0 
1 
2 
3 
4 
H&N 
11 
I can eat solid foods .............................................................
0 
1 
2 
3 
4 
H&N 
12 
I have pain in my mouth, throat or neck .............................
0 
1 
2 
3 
4 
  
  
 
 

Version Date: 07/20/2016 
44 
11.8 Oral Mucositis Daily Questionnaire 
 
2. During the PAST 24 HOURS how much MOUTH AND THROAT SORENESS DID YOU HAVE? (Circle one 
number) 
 
0 
1 
2 
3 
4 
No soreness 
A little soreness 
Moderate soreness 
Quite a lot of 
soreness 
Extreme soreness 
 
 
 
 
 
 
3. During the PAST 24 HOURS how much did MOUTH AND THROAT SORENESS limit you in each of the 
following activities: 
 
 
Not limited 
Limited a little 
Limited some 
Limited a lot 
Unable to do 
a. Swallowing 
0 
1 
2 
3 
4 
b. Drinking 
0 
1 
2 
3 
4 
c. Eating 
0 
1 
2 
3 
4 
d. Talking 
0 
1 
2 
3 
4 
e. Sleeping 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
4. On a scale of 0 to 10, how would you rate your OVERALL MOUTH AND THROAT SORENESS during the 
PAST 24 HOURS? (Please circle the most appropriate number) 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
Worst 
possible 
 
*Questions 2 through 4 of OMDQ adapted from Elting et al, 2008 [27] 
 
 
 

V ersi o n D at e: 0 7/ 2 0/ 2 0 1 6  
4 5 
1 1. 9  D at a  a n d  S afet y  M o nit ori n g Re p ort 
 
B ar b ar a A n n K A R M A N O S C a ncer I nstit ute: Pr ot oc ol S pecific D at a a n d S afet y M o nit ori n g Re p ort 
P R O T O C O L #: 
   
 
R E P O R T D A T E: 
     
                                                                                       
P R O T O C O L TI T L E 
  
 
A T T E N D A N C E 
  
  
 
  
  
 
  
 
 
  
 
 
P R O T O C O L A C TI VI T Y SI N C E L A S T R E P O R T 
Accr ual G oal: 
Eli gi ble: 
 
T otal n u m ber of A E’s t o date:  
Accr ual t o Date: 
 I neli gi ble 
( pr o vi de reas o n):  
Accr ual Si nce  
Last M o nt hl y  
Re p ort: 
 
S pecificall y f or P hase I Trial &/ or D ose Escalati n g Trials: 
D ose Le vel 
Accr u al 
  1 
  
  2 
 
  3 
 
Rec or d all Gra de 3, 4, a n d 5 A d vers e E ve nts ( A E).  Gr o u p b y cate g or y of A E.  rec or d t he date O F t he 
occ urre nce, attri b uti o n a n d if  re p orta ble t o t he I R B.    S ha de t he r o ws of t he A E’s t hat ha ve occ urre d f or 
t his Re p ort.  attac h t he HI C U P re p ort f or m f or t hese re p orta ble e ve nts t hat occ urre d o n t his re p ort. 
Pt. I D # 
Cate g or y a n d  t y pe of a d verse 
reacti o n 
 
Date of 
Occ urre nce 
Gra de 1  Attri b uti o n2 
Re p orta ble t o I R B 
( Y/ N) 
Yes wit h date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Gra de: 1- Mil d, 2- M o derate, 3- Se ve re, 4- Life-t hreate ni n g, or 5- Deat h. 
2. Attri b uti o n: 1- u nrelate d, 2 - u nli kel y, 3 - p ossi bl y, 4 - pr o babl y, or 5 - defi nitel y   
 
O F F T R E A T M E N T ˜  Pr o vi de re as o n [ pr o gressi o n, de at h, t o xicit y, c o m plete d t her a p y, etc]. 
  
 
P R O T O C O L VI O L A TI O N S 
 De vi ati o ns fr o m pr ot ocol tre at me nt, m o nit ori n g, or st u d y c ale n d ar. 
  
 
P R O T O C O L A M E N D M E N T S 
 I ncl u de d ate s u b mitte d t o re g ul at ory b o dies a n d d ate a p pr o ve d. 

Version Date: 07/20/2016 
46 
  
 
OTHER COMMENTS 
 
 
 
Investigator Signature: 
 
Data Manager 
Signature: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Version Date: 07/20/2016 
47 
11.10 Study Calendar 
  
Treatment (low‐level laser therapy) 
Follow Up (low‐level laser therapy) 
  
Pre‐Study 
Treatment Period 
Last Day of Treatment 
Follow Up Period 
  
Screening ‐28 to ‐1  Baseline Day 0  Weekly Visit  Visits 3x/week  Last Day of Treatment 
Follow Up Week 2  Follow Up Month 3 
Medical History 
X 
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
Physical Exam 
X 
  
  
  
  
  
  
Assessment of Oral 
Mucositis (WHO) 
  
X 
X 
  
X 
X 
X 
Chemotherapy [1; AN] 
  
  
  
  
X 
  
  
Organs at Risk Review 
(OAR) [2; AN] 
  
  
  
  
X 
  
  
Radiation Therapy [3; 
AN] 
  
  
  
  
X 
  
  
Dietary Assessment 
  
X 
X 
  
X 
X 
X 
Mouth Pain, Throat 
Pain, PEG Tube, Alcohol 
use, Smoking, Weight 
  
X 
X 
  
X 
X 
X 
FACT‐G 
  
X 
X 
  
X 
X 
X 
Oral Mucositis Daily 
Questionnaire  
 
X 
X 
 
X 
X 
X 
FACT‐H&N 
  
X 
X 
  
X 
X 
X 
Low‐level Laser 
Therapy (LLLT) 
Treatment Record Form 
  
  
X 
X 
  
  
  
Trismus Assessment 
  
X 
  
  
X 
X 
X 
Adverse Events: CTCAE 
(oral mucositis, 
dysphagia, xerostomia, 
dysgeusia, and 
dermatitis) 
  
X 
X 
  
X 
X 
X 
Concomitant 
Medications (for 
analgesia & mucositis) 
  
X 
X 
  
X 
X 
X 

Version Date: 07/20/2016 
48 
Calendar Foot Notes 
1. The prescribed course of chemotherapy will be determined by the managing medical oncologist per institutional practices and will not be altered based on 
this study. 
2. Dose limits to OARs will be determined by institutional practice and specific dose‐constraints will not be required on this protocol. 
3. Radiation therapy will be delivered with an intensity modulated radiation therapy (IMRT) technique and/or image‐guided radiation therapy (IGRT). The 
prescribed course of radiotherapy will not be altered based on this study. Radiotherapy will be delivered 5 days per week, Monday ‐ Friday with one radiation 
treatment given per day. The planned cumulative dose of radiation will be determined by the treating physician and will range from 5000 ‐ 7000 cGy in 180 ‐ 200 
cGy daily fractions over the course of 5‐7 weeks. This treatment is not part of the research protocol. 
AN. As Needed