Utilization of Low Level Laser Therapy for Radiation Induced Dermatitis in Patients With Head and Neck Squamous Cell Carcinoma
Phase: NA
Conditions: Radiation Dermatitis
Sponsor: Heath Skinner

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PROTOCOL TITLE: Utilization of Low Level Laser Therapy (LLLT) 
for Radiation-Induced Dermatitis in Patients with 
Head and Neck Squamous Cell Carcinoma 
(HNSCC) 
 
PRINCIPAL INVESTIGATOR: 
David Weksberg, MD, PhD 
 
VERSION DATE: 
12DEC2022 
 
CLINICALTRIALS.GOV REGISTRATION: NCT02384434 
 
 
 
 

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Table of Contents 
1.0 
Study Summary ........................................................................................................ 3 
2.0 
Objectives ................................................................................................................ 4 
3.0 
Background .............................................................................................................. 4 
4.0 
Study Endpoint......................................................................................................... 6 
5.0 
Study Intervention/Investigational Agent ................................................................ 6 
6.0 
Procedures Involved................................................................................................. 7 
7.0 
Study Timelines ....................................................................................................... 8 
8.0 
Inclusion and Exclusion Criteria .............................................................................. 8 
9.0 
Withdrawal of Subjects ............................................................................................ 8 
10.0 Risks to Subjects ...................................................................................................... 9 
11.0 Potential Benefits to Subjects ................................................................................ 10 
12.0 Data Management .................................................................................................. 10 
13.0 Provisions to Monitor the Data to Ensure the Safety of Subjects .......................... 10 
 
 
 

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1.0 
Study Summary 
 
Study Title 
Utilization of Low Level Laser Therapy (LLLT) for 
Radiation-Induced Dermatitis in Patients with Head and 
Neck Squamous Cell Carcinoma (HNSCC) 
Study Design 
Single-arm, Phase I/II 
Primary  
Objective/Endpoint 
Assess the safety and efficacy of low level laser therapy 
(LLLT) in mitigating radiation-induced dermatitis in patients 
undergoing radiation therapy for head and neck squamous 
cell carcinoma (HNSCC) 
 
Endpoint: Documented Grade 3 or higher Adverse Events as 
per CTCAE v4.0  
Secondary 
Objective(s)/Endpoints 
assessment of patient-reported quality of life data, pain 
parameters and dermatologic quality of life responses 
 
Endpoints: 
• quality of life data measured using the University of 
Washington Quality of Life Questionnaire (UW-QOL)  
• pain parameters assessed using Brief Pain Inventory (BPI) 
• dermatologic quality of life responses measured using the 
Dermatology Life Quality Index (DLQI) 
Research 
Intervention(s)/ 
Investigational 
Agent(s)  
THOR Laser system 
IND/IDE #  
N/A 
Study Population 
patients with histologically proven squamous cell carcinoma 
of the oral cavity, oropharynx, hypopharynx or larynx who 
are candidates for either definitive or adjuvant therapy 
consisting of a chemotherapy regimen and concurrent 
radiation therap 
Sample Size 
75 planned  
Study Duration for 
individual participants 
15 months 
 
 

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2.0 
Objectives 
2.1 The study aims to assess the safety and efficacy of the utilization of 
low level laser therapy to mitigate radiation-induced dermatitis in 
patients undergoing definitive or adjuvant radiation therapy with 
head and neck squamous cell carcinoma. 
2.2 The hypothesis is that low level laser therapy given prior to and 
during the course of treatment will decrease the rate of grade III 
dermatitis, a common finding seen in patients undergoing radiation 
therapy with head and neck squamous cell carcinoma. An additional 
goal of low level laser therapy is to increase wound healing. 
3.0 
Background 
3.1 
There are approximately 43,000 cases of head and neck squamous 
cell carcinoma (HNSCC) diagnosed annually in the United States of which 
approximately two-thirds will present with locally-advanced disease 
(Stage III or IV). For these patients, traditional treatment options including 
surgical resection and adjuvant radiotherapy have been largely supplanted 
by non-operative approaches. The success of non-operative approaches 
has been made possible through both refinement of radiotherapy (RT) 
techniques as well as an increased understanding of the biology of the 
disease and the subsequent introduction of targeted agents including 
cetuximab, an inhibitor of the epidermal growth factor (EGFR) 
(Kabolizadeh et al, 2012). 
Much has been learned about the biology of HNSCC including the role of 
EGFR. This receptor is expressed at high levels in the majority of 
HNSCC. Furthermore, pre-clinical data indicate that it is intimately 
associated with the malignant phenotype of HNSCC. EGFR activation in 
response to its ligand results in phosphorylation of its intracytoplasmic 
tyrosine kinase domain, leading to a cascade of signal transduction within 
the cell and ultimately alternations in DNA synthesis, cell proliferation, 
anti-apoptosis, and transcription of growth factors such as pro-angiogenic 
molecules. Blockade of this pathway serves as an effective anti-neoplastic 
as well as radiosensitization strategy. 
The anti-neoplastic properties and radiosensitization of EGFR blockade 
was proven in a landmark randomized trial in patients with locally-
advanced, non-operative HNSCC in which patients were randomized to 
RT alone or RT with weekly cetuximab (Bonner JA, et al., 2010). The 
investigators found that locoregional control and survival were 
significantly improved with cetuximab. Specifically, the 3-year rate for 
freedom from local-regional progression and overall survival were 47% 
and 55% for RT with cetuximab compared with 34% and 45% for RT 
alone. The relative reduction in the risk of local-regional progression and 
death were 32% (p=0.005) and 26% (p=0.03), respectively (Bonner JA, et 
al., 2010). Interestingly, improved outcomes were associated with the 

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development a drug-induced acne-like rash, a common side effect of this 
class of medications. 
In this respect, cetuximab appears to have a different toxicity profile than 
that of traditional chemotherapy such as cisplatin. The most commonly 
reported side effect is the development of skin reactions including 
macular, papular, and pustular rashes, xerosis, fissures, telangiectasias, 
and hyperpigmentation of the hair and nails (Bernier et al., 2008). The 
most frequent of these reactions is an acne-like rash that predominately 
appears in areas rich in sebaceous glands. The acne-like rash comprises 
itchy erythematous follicular papules that evolve into pustules. Other 
presentations include diffuse erythema with follicular papulopustules and 
telangiectasia, a seborrhoeic dermatitis-like rash or, occasionally, an 
edematous facial erythema. In the absence of radiation, the acne-like rash 
can be seen within a few days of the initiation of treatment and peaks 2–3 
weeks after starting therapy (Bernier et al., 2008). 
The effect on the skin during the combination of cetuximab and radiation 
is of considerable interest, as it might require special care to reduce 
symptoms and severity. It appears that radiation may delay the onset of the 
cetuximab-induced rash as it typically appears within irradiated fields 3–5 
weeks after initiation of treatment (Bernier et al., 2008). There appears to 
be no obvious relationship between the severity of cetuximab-associated 
acne-like rash outside irradiated fields and the severity of radiation 
dermatitis. The aforementioned Phase III trial (Bonner JA et al., 2010) 
revealed no statistically significantly increase in the incidence or severity 
of radiation dermatitis compared with radiotherapy alone. The incidence 
of grade 3 radiation dermatitis was 18% with RT alone and 23% with RT 
with cetuximab (p = 0.27). There was a slight increase in the median 
duration of radiation dermatitis in the cetuximab arm (11.1 weeks) 
compared with the RT-alone arm (9.4 weeks). 
While the majority of skin reactions seen with cetuximab are grade 1 or 2 
(80%), there is certainly an effect on quality of life (QoL) as well as 
treatment continuity. A survey of EGFR inhibitor use by oncologists 
found that 76% of clinicians interrupted treatment due to skin toxicity and 
32% discontinued therapy altogether (Boone et al., 2006). However, its 
prevalence presents an opportunity to explore novel modes of symptom 
reduction as well as to assess modalities that may improve pain and 
patient-reported quality of life (PR-QoL). Currently, the most utilized 
treatments include anti-inflammatory agents, antibiotics, antihistamines, 
and saline compresses (Bernier et al., 2008). A potential novel strategy to 
influence both the cetuximab as well as radiation-induced dermatitis is the 
implementation of low level laser light therapy (LLLT). 
3.2 
LLLT is potentially effective in wound healing by producing an 
anti-inflammatory response by promoting cellular metabolism and 
increasing circulation and lymphatic flow. The mechanism of action may 
be related to a decrease in interstitial edema and an increase in the healing 

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process. Its clinical utility in reducing oral mucositis was assessed 
prospectively and was recently discussed in a Cochrane review (Clarkson 
et al., 2010; Guatuam AP et al., 2012; Migliorati et al., 2013). Here, LLLT 
showed a reduction in severe mucositis when compared with the sham 
procedure (risk ratio: 5.28, 95% confidence interval: 2.30 to 12.13). While 
these studies support an improvement in oral mucositis with LLLT, the 
clinical experience addressing an improvement in cetuximab-induced 
rashes and radiation-dermatitis is limited. An Italian case series (Gobbo et 
al., 2011) reported that in 4 patients with metastatic colorectal cancer and 
two patients with HNSCC, LLLT reduced cetuximab-related skin 
toxicities. Here, patients were treated with two 8-minute long consecutive 
sessions/day over a 4-day treatment. Patients were evaluated weekly for 
up to 3 weeks and after 180 days. Follow-up evaluations including a 
questionnaire about the onset and progression of the acneiform rash and 
visual analog scales were reported. The authors reported that after the 
fourth session of LLLT, the patients showed a decrease in both cetuximab-
related toxicity and visual analog scales, up to complete regression of the 
lesions in all treated areas (Gobbo et al., 2011). No adverse effects from 
treatment were reported. These findings suggest that LLLT may be an 
effective way of managing cetuximab- and radiation-induced skin 
toxicities. Herein we propose a pilot study to assess the efficacy of LLLT 
to mitigate and ameliorate the acneiform-rash, radiation dermatitis, and 
pain while assessing its impact on PR-QoL measures. 
 
4.0 
Study Endpoints 
4.1 Primary Endpoint: The primary endpoint is to characterize the rate of 
any Grade 3 or higher Adverse Events as per CTCAE v4.0 
(Common Terminology Criteria for Adverse Events). 
4.2 Secondary Endpoints:  Several patient reported QOL metrics will be 
collected as secondary endpoints.  
• quality of life data measured using the University of 
Washington Quality of Life Questionnaire (UW-QOL)  
• pain parameters assessed using Brief Pain Inventory (BPI) 
• dermatologic quality of life responses measured using the 
Dermatology Life Quality Index (DLQI) 
5.0 
Study Intervention/Investigational Agent 
 
THOR Laser system: MASCC/ISOO Clinical Practice Guidelines for mucositis (May 
2014) recommend LLLT to prevent oral mucositis. In addition, the following studies 
have indicated that LLLT in the setting of RT alone or chemo‐RT, appears to confer a 
benefit in reducing the rates of mucositis when compared to placebo or supportive care 
and is suggested for the prophylaxis of mucositis: -Phase III trial of low-level laser 

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therapy to prevent oral mucositis in head and neck cancer patients treated with concurrent 
chemoradiation. -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. -Effect of low level helium-neon (He-Ne) laser therapy in the prevention & 
treatment of radiation induced mucositis in head & neck cancer patients. -Efficacy of He-
Ne Laser in the prevention and treatment of radiotherapy-induced oral mucositis in oral 
cancer patients. -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. Low level laser therapy for concurrent chemoradiotherapy induced oral mucositis 
in head and neck cancer patients - a triple blinded randomized controlled trial. -Oral 
mucositis prevention by low-level laser therapy in head-and-neck cancer patients 
undergoing concurrent chemoradiotherapy: a phase III randomized study. -Use of 660-
nm diode laser in the prevention and treatment of human oral mucositis induced by 
radiotherapy and chemotherapy. -Efficacy of low-level laser therapy and aluminum 
hydroxide in patients with chemotherapy and radiotherapy-induced oral mucositis. -Laser 
phototherapy as topical prophylaxis against head and neck cancer radiotherapy-induced 
oral mucositis: comparison between low and high/low power lasers. 
 
6.0 
Procedures Involved 
6.1 Screening / Pre-treatment: 
• Medical history 
• Physical examination, including Karnofsky Performance 
Status and vital signs. 
• Signed informed consent 
• Subject body weight and height 
• Quality of Life Assessments (UW QoL, BPI, DLQI) 
6.2 Evaluation during Treatment 
• Patients will be treated with the 69 diode LED cluster 
probe. The wavelength utilized are both 660 nm and 850 
nm. The average power density is 100 mW/cm2 and the 
spot size is 0.2 cm2. Treatment time is 60 seconds to each 
site. There are a minimum of nine treatment sites: (1) left 
forehead, (2) right forehead, (3) left upper cheek/malar 
region, (4) right upper cheek/malar region, (5) right lower 
cheek / trigeminal nerve mandibular division distribution, 
(6) left lower cheek / trigeminal nerve mandibular division 
distribution, (7) submental region, (8) left neck, (9) right 
neck. Patients will be pretreated with a minimum of 3 
sessions over 7 days before starting radiotherapy. Patients 
will receive LLLT at least twice the week prior to initiation 
of radiation and then at least three times per week during 
the course of radiation treatment. 

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• Adverse Event Assessment (Grading of skin toxicity and 
mucositis by patient) 
• Completion of patient reported DLQI during treatment 
week 5 and at end of treatment 
6.3 
Evaluation following Treatment 
• Patients will be seen in follow-up at least every three 
months in the first year following completion of treatment. 
o Observer reported mucositis and skin reaction every 
three months for one year 
o Patient reported QoL assessments (UQ QoL, BPI, 
DLQI) every three months for one year 
7.0 
Study Timelines 
• 
The expected duration of an individual subject’s participation 
is approximately 15 months. 
8.0 
Inclusion and Exclusion Criteria 
8.1 Inclusion Criteria: 
• Male or female patients ≥ 18 years of age 
• Karnofsky performance status > 70 
• Histologic proof of squamous cell carcinoma of the oral 
cavity, oropharynx, hypopharynx, or larynx 
• No prior radiotherapy to the head and neck region. 
• No previous systemic chemotherapy or targeted therapy 
• Must be aware of the neoplastic nature of his/her disease 
and willingly provide written, informed consent after being 
informed of the procedure to be followed, the nature of the 
therapy, alternatives, potential benefits, side-effects, risks 
and discomforts. 
• Patients using standard therapies for cetuximab-induced 
acne-form rash will be included. 
8.2 Exclusion Criteria: 
• Evidence of distant metastasis on upright chest x-ray 
(CXR), computed tomography (CT) or other staging studies 
• Any co-morbidity or condition of sufficient severity to limit 
full compliance with the protocol per assessment by the 
investigator 
• Concurrent serious infection 
• Continued use of Niacin 
9.0 
Withdrawal of Subjects 

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9.1 
Patients are to discontinue therapy in the event of: 
• Disease progression 
• Development of a serious medical illness 
• Evidence of dose-limiting toxicity 
• Major protocol violation 
• Discretion of the principal investigator 
9.2 
Patients may withdraw from study participation voluntarily. 
10.0 Risks to Subjects 
10.1 There are few risks associated with low-level laser therapy. This 
treatment is non-invasive and uses a cold laser output. Infrequently, 
eye damage has occurred with prolonged visual contact with the 
laser. Further, patients using concomitant supplemental niacin may 
experience, facial flushing. 
10.2 Although no reported grade 3 or greater toxicities for LLLT have 
been published, patients will be closely monitored by a certified 
nurse prior to each delivery. Patients will be instructed to seek 
alternatives to niacin if taking this medication at the time of 
enrollment to the study. Additionally, eye protection is provided to 
all patients and staff present in the examination room during delivery 
of LLLT to prevent any eye damage. Significant mucositis from 
radiation is expected. Appropriate supportive care will be provided 
including analgesia, local therapies, and potentially low level laser 
therapy. Patients will be monitored weekly by the treating physicians 
to appropriately manage and record potential toxicities. Patients 
developing dermatologic adverse events will be monitored for the 
development of inflammatory or infectious sequelae. Supportive 
therapies other than the investigational intervention may include the 
following: 
• Antibiotics: The benefit of routine antibiotics in 
uncomplicated (uninfected) rash is unclear. Some clinicians 
have used oral minocycline (Minocin), mupirocin 
(Bactroban), or topical clindamycin (Cleocin). Rash 
complicated by cellulitis should be treated with appropriate 
antibiotics based on clinical judgment or microbial 
sensitivity analysis. 
• Antihistamines: Benadryl or Atarax may be helpful to 
control itching. 
• Topical Steroids: The benefit of topical steroids is unclear. 
• Retinoids: No data to support use. Use is not advised. 

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• Benzoyl peroxide: Should NOT be used--may aggravate 
rash. 
• Makeup: Rash can be covered with makeup; this should not 
make it worse (use a dermatologist-approved cover-up, 
e.g., Dermablend, or any other type of foundation). 
Remove makeup with a skin-friendly liquid cleanser, e.g., 
Neutrogena, Dove, or Ivory 
• Skin Cleansing Liqui-Gel. 
• Moisturizers: Use emollients to prevent and alleviate the 
skin dryness, e.g., Neutrogena Norwegian Formula Hand 
Cream or Vaseline Intensive Care Advanced Healing 
Lotion. 
• Sunlight: It is recommended that patients wear sunscreen 
and hats and limit sun exposure during treatment as 
sunlight can exacerbate any skin reactions that may occur. 
• Over-the-counter medications: Over-the-counter acne 
vulgaris medications (e.g., benzoyl peroxide) are not 
advised. This rash is not like acne vulgaris and these 
treatments could make it worse. 
11.0 Potential Benefits to Subjects 
11.1 Taking part in this study may or may not make the subject's health 
better. While doctors hope that this study treatment will be more 
useful against cancer compared to the usual treatment, there is no 
proof of this yet. We do know that the information from this study 
will help doctors learn more about this drug as a treatment for 
cancer. This information could help future cancer patients. 
12.0 Data Management 
12.1 This prospective observational study seeks to describe the toxicities 
of patients undergoing this intervention.  Rates of Grade 3 CTCAE 
toxicities will be documented, along with PR-QOL secondary 
endpoints, and will be compared to historical reports of toxicity in 
the literature. 
13.0 Provisions to Monitor the Data to Ensure the Safety of Subjects 
13.1 Data will be monitored internally by the research manager. Any 
considerable deviations or concerns are to be addressed with the 
research manager and the principal investigator. 
Expected adverse events from each intervention (radiotherapy and 
LLLT) are listed in the research protocol and are to be managed 
accordingly. For all adverse events, sufficient information should be 
obtained by the investigator to determine the causality, (i.e., study 

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drug or other illness). The investigator is required to assess causality 
and indicate that assessment on the CRF. Follow-up of the adverse 
event, after the date of therapy discontinuation, is required if the 
adverse event or its sequelae persist. Follow-up is required until the 
event or its sequelae resolve or stabilize at a level acceptable to the 
investigator. Adverse events that continue, or emerge within 30 days, 
after the patient’s discontinuation or completion of the study will be 
followed until the events resolve, are considered stable, or can be 
ascribed to causes other than study treatment. 
All serious AE meeting criteria for reporting will be reported per the 
University of Pittsburgh Institutional Review Board’s policies. In the 
event of such adverse event, the investigator must report the event(s) 
via phone within 24 hours and a written report filed within 24 hours 
to the Principal Investigator. 
 
14.0 Statistical Considerations 
14.1 Study Design/Endpoints 
This is a phase I/II clinical trial aiming to assess the safety and 
efficacy of low level laser therapy (LLLT) in mitigating radiation-
induced dermatitis in patients undergoing radiation therapy for head 
and neck squamous cell carcinoma (HNSCC). The primary endpoint 
is documented Grade 3 or higher Adverse Events as per CTCAE 
v4.0. The secondary objectives are the assessment of patient-
reported quality of life data, pain parameters and dermatologic 
quality of life responses. The secondary endpoints are: 
• Quality of life data measured using the University of Washington 
Quality of Life Questionnaire (UW-QOL)  
• Pain parameters assessed using Brief Pain Inventory (BPI) 
• Dermatologic quality of life responses measured using the 
Dermatology Life Quality Index (DLQI)aimed at the evaluation of 
the safety and clinical activity of tiragolumab in combination with 
atezolizumab, carboplatin, and pemetrexed in the 1st line treatment 
of non-squamous NSCLC patients with untreated brain metastases. 
 
14.2. Statistical Analysis Plan 
14.2.1 
Analysis of the Primary Endpoint 
The main goal of this study is to descriptively estimate grade 3 or 
higher adverse events as per CTCAE v4.0. The frequency and 
percentage will be calculated along with its exact 95% CI.  
All patients who enroll in the study, and received at least 1 dose of 
the study treatment are evaluable for safety analysis. As per NCI 

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CTCAE Version 5, the term toxicity is defined as adverse events that 
are classified as either possibly, probably, or definitely related to 
study treatment. The maximum grade for each type of toxicity will 
be recorded for each patient, and frequency tables will be reviewed 
to determine toxicity patterns. The incidence of treatment-emergent 
AEs and SAEs will be summarized by system organ class and/or 
preferred term, severity, and relationship to study treatment 
determined. 
14.2.2 
Analysis of Secondary Endpoints 
University of Washington Quality of Life questionnaire (UW-QOL): 
The UW-QOL consists of 12 single question domains focusing on 
current patient health and quality of life within the past 7 days. These 
domains have between 3 and 6 response options that are scaled 
evenly from 0 (worst) to 100 (best) according to the hierarchy of 
response. The domains are pain, appearance, activity, recreation, 
swallowing, chewing, speech, shoulder, taste, saliva, mood and 
anxiety; patient choice of up to three of these domains that have been 
the most important to them. There are also three global questions, 
one about how the patient feel relative to before they developed their 
cancer, one about their health-related QOL and one about their 
overall QOL. In regard to their overall QOL, patients are asked to 
consider not only physical & mental health, but also many other 
factors, such as family, friends, spirituality or personal leisure 
activities that were important to their enjoyment of life.  
Brief Pain Inventory (BPI): The BPI allows patients to rate the 
severity of their pain and the degree to which their pain interferes 
with common dimensions of feeling and function.  
Dermatology Life Quality Index (DLQI): The DLQI is a ten-
question questionnaire designed to measure the health-related quality 
of life of adult patients suffering from a skin disease. Each question 
is scored from 0 to 3, giving a possible score range from 0 (meaning 
no impact of skin disease on quality of life) to 30 (meaning 
maximum impact on quality of life).  
For all these QoL measures, descriptive statistics (mean, SD, 
median, and inter-quartile range) will be primarily used to 
summarize the scored scales at each scheduled assessment time 
point. Additionally, change from baseline in the domain scores at the 
time of each assessment will be summarized. Patients with an 
evaluable baseline score and at least one evaluable post baseline 
score during the treatment period will be included in the change from 
baseline analyses. Mixed effect model for repeated measures 
(MMRM) will be used to examine the change of Qol measures with 
time and treatment.  
 

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14.3. Sample Size/Accrual Rate 
As stated in Section 14.2, the main goal of this descriptive study is 
not for hypothesis testing. We plan to accrue 75 patients. With this 
sample size, the exact 95% CI for the grade 3 AE has a maximum 
width of 24%. For example, if the observed rate is 15/75 (20%), then 
the 95% CI will be (12%, 31%) . The following is a table for the CI. 
Observed 
proportion of 
grade 3 AE 
Exact 95% CI 
for the grade 3 
AE rate 
5/75 (7%) 
(2%, 15%) 
10/75 (13%) 
(7%, 23%) 
15/75 (20%) 
(12%, 31%) 
20/75 (27%) 
(17%, 38%) 
25/75 (33%) 
(23%, 45%) 
30/75 (40%) 
(29%, 52%)