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: David A. Clump, MD, PhD

 
 
Title: 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 
 
 
Version: 12/03/2015 
 
 
Principal Investigator:  
David A. Clump, MD, PhD 
Assistant Professor 
Department of Radiation Oncology 
University of Pittsburgh Cancer Institute  
5230 Centre Avenue 
Pittsburgh, PA 15232 
clumpda2@upmc.edu 
Ph. (412) 623-6720 
Fax (412) 623-6192 
 
 
Co-investigators:  
Dwight Heron, MD 
Brian Karlovits, DO 
Julie Bauman, MD 
James Ohr, DO 
 
 
Statistician: 
Hong Wang, PhD 
 
 
 

 
2 
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 ........................................................................................................................ 10 
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: ..................................................................................................................... 11 
4.2 
Chemotherapy ........................................................................................................................................ 12 
4.3 
Low-Level Laser Therapy ................................................................................................................... 12 
4.4 
Other treatments .................................................................................................................................... 13 
5.0 Follow-up and Assessments ....................................................................................................... 13 
5.1 
Follow up Schedule ................................................................................................................................ 13 
5.2 
Follow-up Assessments ......................................................................................................................... 14 
6.0 Statistical Considerations .......................................................................................................... 16 
6.1 
Primary Endpoints: .............................................................................................................................. 16 
6.2 
Secondary Endpoints: ........................................................................................................................... 16 
6. 3 
Exploratory Endpoints: ...................................................................................................................... 17 
6.4 
Sample Size.............................................................................................................................................. 17 
6.5 
Analysis .................................................................................................................................................... 17 
6.6 
Evaluation of Toxicity .......................................................................................................................... 18 
6.7 
Specific Toxic Outcomes ...................................................................................................................... 18 
6.8 
Other toxic outcomes ............................................................................................................................ 18 
6.9 
Expected accrual rate, accrual duration, and study duration .................................................... 19 
7.0 Adverse Events and Safety Monitoring .................................................................................. 19 
7.1 
Reporting of Serious Treatment Emergent Adverse Events ....................................................... 19 
7.2 
Adverse Event Characteristics ........................................................................................................... 20 
7.3 
Adverse Event reporting ...................................................................................................................... 22 
7.4 
Data Safety Monitoring ..................................................................................................................... 22 
7.5 
Ethics ........................................................................................................................................................ 23 
8.0  Registration Procedures............................................................................................................ 23 
8.1 
General Guidelines ................................................................................................................................ 23 

 
3 
8.2 
Registration Process .............................................................................................................................. 23 
9.0 Protocol Conduct and Guidelines ............................................................................................ 24 
9.1 
Protocol amendments, or changes in study conduct ..................................................................... 24 
9.2 
Publication of results ............................................................................................................................ 24 
9.3 
Ethics and Good Clinical Practice ..................................................................................................... 24 
9.4 
Institutional Review Board/Independent Ethics Committee ...................................................... 24 
9.5 
Informed consent ................................................................................................................................... 24 
9.6 
Declaration of Helsinki ......................................................................................................................... 25 
10.0    References ................................................................................................................................... 26 
 
 
 
 
 
 
 
 

 
4 
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 50 patients at our institution in 12 months after the trial opens.  
 
 
 
 
 
 
 

 
5 
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 

 
6 
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 

 
7 
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]. 

 
8 
Table 1. LLLT trials for oral mucositis prevention 
Reference 
Population 
Methods 
Treatment 
Results 
Comments 
Antunes et al 
Radiother Oncol 2013[11] 
 
 
HNC 
 
(n=94)  
 
Brazil, 2007‐2010  
 
Phase III, 
randomized 
placebo controlled 
trial  
Concurrent Chemoradiotherapy 
(1) Placebo  
(2) LLLT daily prior to each RT fraction  
 
Chemo: cisplatin 100 mg/m2 q3weeks  
RT: 70.2 Gy  
LLLT: InGaAIP, 660 nm, 100mW, 1-4J/cm2 
 
Grade 3‐4 mucositis (WHO): 40.5% vs. 6.4%  
Relative risk: 0.16 (0.05 ‐ 0.5)  
 
Improved QOL for pain, 
swallowing and difficulty with 
eating  
 
Arora et al 
Oral Surg Oral Med Oral 
Pathol Oral Radiol Endod 
2008[13]  
Oral cancer 
 
(n=50)  
 
India, 2005-2006 
 
 
 
Phase III, 
randomized 
controlled trial 
Radiation  
(1) Topical anesthetic, saline washes  
(2) LLLT daily prior to RT  
 
RT: 66 Gy  
LLLT: He‐Ne, 632.8 nm, 10mW, 1.8J/cm2  
Grade 3-4 mucositis (EORTC/RTOG) 53.9% vs. 
18.2% at 3 weeks (p=0.019) 
Functional impairment Scale 
maximum score: 
Oral alimentation not possible: 
31% vs. 0% 
Bensadoun et al 
Support Care Center 
1999[14]  
 
 
HNC 
 
(n=30)  
 
France, 1994-1998 
 
 
Phase III, 
randomized 
placebo controlled 
trial  
Radiation  
(1) Placebo  
(2) LLLT prior to each RT fraction  
 
RT: 65 Gy 
LLLT: He‐Ne, 632.8 nm, 60mW, 2J/cm2 
Grade 3 mucositis (WHO): 35.2% vs. 7.6% (p<0.01)  
 
Severe pain: 23.8% vs. 1.9% (p<0.05) 
 
 
Gautam et al 
Radiother Oncol 2012[16] 
 
 
HNC 
 
(n=221)  
 
India, 2009-2011 
 
 
Phase III, 
randomized 
placebo controlled 
trial  
 
 
Concurrent Chemoradiotherapy 
(1) Sham treatment  
(2) LLLT 5x/week, prior to or following RT  
 
Chemo:  cisplatin 100 mg/m2 q3weeks 
RT: 66 Gy  
LLLT: He‐Ne, 632.8 nm, 24mW, 3J/point  
 
Grade ≥3 mucositis (EORTC/RTOG): 70% vs. 
23.4% (p < 0.0001) 
 
 
 
Pain scores plateaued after 
week 4 in LLLT arm and 
continued to increase in 
placebo arm  
 
Lower dysphagia in LLLT arm 
 
Zanin et al 
Photomed Laser Surg 
2010[18]  
 
 
HNC 
 
(n=72)  
 
Brazil 
 
Phase III, 
randomized 
controlled trial  
 
Concurrent Chemoradiotherapy 
(1) No treatment  
(2) LLLT 2x/week, prior to or following RT  
 
Chemo: cisplatin 70 mg/m2 weekly 
RT:  1.8 Gy daily fractions 
LLLT: He‐Ne, 660 nm, 30mW, 2J/cm2 
 
Mucositis (NCI) significantly lower in LLLT group 
from week 1 to week 4 (p=0.001), but remained 
stable until week 7 (p=0.68) 
LLLT delayed onset of oral 
mucositis 
Lima et al,  
Braz Dent J 2010[17]  
 
 
HNC  
 
(n=25)  
 
Brazil, 2005 
 
Prospective, non-
randomized study 
 
RT ± chemotherapy 
(1) Sucrose and aluminum hydroxide suspension  
(2) LLLT daily prior to each RT fraction  
 
Chemo: cisplatin 100mg/m2 q3weeks  
RT: 40‐70 Gy  
LLLT: 830 nm, 60 mW, 12.4J/cm2  
 
Grade 3 mucositis (OTS Scale) OM 50% vs. 33% 
(p=0.06) 
 
 
Significant decrease in pain 
with LLLT (p=0.036) 
HNC; head and neck cancer. LLLT; low-level laser therapy. RT; Radiation. Gy; Gray. InGaAIP; indium phosphide, gallium and aluminum diode. nm; nanometer. mW; milliwatts. J; Joules. WHO; World Health 
Organization. QOL; Quality of Life. He-Ne; Helium-Neon. EORTC; European Organisation for Research and Treatment of Cancer. RTOG; Radiation Therapy Oncology Group. NCI; National Cancer Institute.  

 
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 and a matched 
pair of control patients from our own institution. 
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.  
 
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 50 patients at our institution in 12 months after the trial opens. 
 

 
10
3.2 
Patient Selection 
 
Inclusion Criteria: 
 
1. Willing and able to understand and sign informed consent form approved by the HRPO. 
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 subjects of child-bearing potential must have a negative pregnancy test prior to 
enrollment.  
 
Exclusion Criteria: 
 
1. Subject 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. Subjects planned to receive altered fractionation radiotherapy or multiple fractions per day 
5. Subject 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. Subject 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. 
 
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 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 

 
11
5. Lost to follow-up 
6. Non-compliance with study treatment 
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 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.  
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 11.3.  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_________ 
 

 
12
 
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_____________ 
 
 
4.2 
Chemotherapy 
 
Prior to treatment, all patients will provide informed written 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 
(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. Patients will be treated extra-orally with a THOR® LED 

 
13
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.  
 
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 11.4). Compliance with therapy will be documented. 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 
 
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 

 
14
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: 
 
 
 
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 

 
15
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 
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 
 
- 
- 
 

 
16
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 
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 
 
 
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.  

 
17
• 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. 
 
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. All patients should be enrolled in 12 months after the trial 
opens. We plan to enroll 50 patients at our institution. 
 
6.5 
Analysis 
 
Primary endpoint 
If 12 or fewer out of the 45 evaluable severe OM events occur, 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 

 
18
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. 
 
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 reconsidering 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: 

 
19
 
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, accrual duration, and study duration 
 
Our anticipated accrual rate at our center is 50 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 Univ. of Pittsburgh 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 drug(s). 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. 
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.  

 
20
  
• 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) 
• 
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 are monitored continuously and have special reporting 
requirements; see protocol section on Serious Adverse Event reporting. 

 
21
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 
• 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 

 
22
• 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 
HRPO Adverse Event reporting 
 
Investigators must report the following to the Univ. of Pittsburgh Human Research Protection Office: 
 
• Internal Adverse Events that are (i) Unexpected, (ii) Related or Possibly Related to the 
Research Intervention, and (iii) serious or otherwise suggests that the research places the 
subject or others at a greater risk of harm (including physical, psychological, economic or 
social harm) than was previously known or recognized. 
• External Adverse Events that are (i) Unexpected; (ii) Related to the Research Intervention 
and (iii) Serious or otherwise suggests that the research places subjects or others at greater 
risk than was previously recognized. 
 
Adverse Events that meet the University HRPO’s reporting requirements must be reported to the HRPO 
office as follows: 
• Internal Adverse Events which are unexpected, fatal or life-threatening, and related or 
possibly Related to the Research Intervention must be reported to the HRPO within 24 hours 
of learning of the event. (Note: It is recognized that the information available during this 24 
hour period may not be sufficient to permit accurate completion of the required adverse 
event reporting forms. However, the HRPO should, at a minimum, be notified of the fatal 
or life-threatening internal adverse event during this time frame, with subsequent followup 
submission of a more detailed written report.) 
• All other internal Adverse Events will be reported to the HRPO within 10 working days of 
the investigator learning of the event. 
• External Adverse Events which are Unexpected, Serious AND suggest that the research 
places subjects or others at greater risk than was previously recognized, and Related to the 
Research Intervention will be reported to the HRPO within 30 working days of their receipt 
by the University/UPMC investigator.  
  
7.4 
Data Safety Monitoring 
 
A data safety monitoring board will meet monthly to evaluate toxicity for this trial.  
  
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 
 
Patients/adverse events will be discussed at these monthly disease center meetings. Unexpected 
serious adverse events will be reported to the HRPO and radiation oncology data safety monitoring 
board (DSMB), and minutes of the monthly disease center meetings will be reviewed at the DSMB 
meetings 
  

 
23
Any clinically significant or unexpected disease or condition that is found during the course of this 
study, will be immediately evaluated by the Principal Investigator and appropriate medical staff and 
then it will be determined how to proceed with the study/ study treatment. 
 
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 the Univ. of Pittsburgh HRPO. 
  
The principal investigator is responsible for informing the Univ. of Pittsburgh HRPO of any 
amendments to the protocol. The protocol must be re-approved by the HRPO annually. Progress 
reports and notifications of serious, unexpected adverse events or drug reactions will be provided to 
the HRPO. 
  
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 at UPMC Shadyside Department of Radiation Oncology, 
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 

 
24
• HIPAA authorization form 
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 HRPO.  
If an immediate change to the protocol is felt to be necessary by the investigator and is implemented 
for safety reasons the HRPO must be informed immediately. Amendments affecting only 
administrative aspects of the study do not require formal protocol amendments or HRPO approval but 
the HRPO must be kept informed of such administrative changes.  
9.2 
Publication of results 
 
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 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, 

 
25
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. 
 
 

 
26
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. 
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. 

 
27
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.