Low-Level Laser in Treatment of Head and Neck Lymphedema: A Pilot Study
Phase: NA
Conditions: Head and Neck Cancer, Lymphedema, Fibrosis
Sponsor: University of Pennsylvania

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Low-Level Laser in Treatment of Head and Neck Lymphedema: A Pilot Study 
 
 
 
 
Principal Investigator  
 
Jie Deng, PhD, RN, OCN, FAAN 
 
 
 
 
 
Department of Biobehavioral Health Sciences 
 
 
 
 
 
University of Pennsylvania School of Nursing  
215-573-2393 
 
jiedeng@nursing.upenn.edu 
 
 
Co-Investigator  
 
 
Alexander Lin, MD 
Department of Radiation Oncology 
The Hospital of the University of Pennsylvania 
215-662-3198 
 
 
Co-Investigator/Statistician 
 
Alexandra Hanlon, PhD 
Department of Biobehavioral Health Sciences 
University of Pennsylvania School of Nursing  
215-898-4581 
 
 
Co-Investigator  
 
 
John Nicholas Lukens, MD  
Assistant Professor of Radiation Oncology  
Department of Radiation Oncology  
The Hospital of the University of Pennsylvania   
 
 
 

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Table of Contents 
 
Contents 
LIST OF ABBREVIATIONS ......................................................................................................................... IV 
STUDY SUMMARY ...................................................................................................................................... 1 
BACKGROUND AND STUDY RATIONALE ................................................................................................ 2 
1        INTRODUCTION ................................................................................................................................... 2 
1.1 
BACKGROUND AND RELEVANT LITERATURE ..................................................................................... 2 
1.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT .......................................................... 3 
1.2.1 
Nonclinical Data ...................................................................................................................... 3 
1.2.2 
Clinical Data to Date ................................................................................................................ 3 
1.2.3 
Clinical Studies in Children ...................................................................................................... 3 
1.3 
DOSE RATIONALE (IF APPLICABLE) .................................................................................................. 3 
2 
STUDY OBJECTIVES ......................................................................................................................... 3 
2.1 
PRIMARY OBJECTIVE ...................................................................................................................... 3 
2.2 
SECONDARY OBJECTIVE ................................................................................................................. 3 
3 
INVESTIGATIONAL PLAN .................................................................................................................. 3 
3.1 
GENERAL DESIGN .......................................................................................................................... 3 
3.1.1 
Screening Phase ..................................................................................................................... 4 
3.1.2 
Study Intervention Phase and Follow Up Phase ..................................................................... 4 
3.2 
STUDY ENDPOINTS......................................................................................................................... 4 
3.2.1 
Primary Study Endpoints ......................................................................................................... 4 
3.2.2 
Secondary Study Endpoints .................................................................................................... 4 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION ........................................................ 4 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 4 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 4 
4.3 
SUBJECT RECRUITMENT ................................................................................................................. 4 
4.4 
DURATION OF STUDY PARTICIPATION .............................................................................................. 4 
4.5 
TOTAL NUMBER OF SUBJECTS AND SITES........................................................................................ 5 
4.6 
VULNERABLE POPULATIONS ........................................................................................................... 5 
5 
STUDY INTERVENTION (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE, FOOD ETC.) ............... 5 
5.1 
DESCRIPTION ................................................................................................................................. 5 
5.2 
INTERVENTION REGIMEN ................................................................................................................ 5 
5.3 
STORAGE ...................................................................................................................................... 5 
5.4 
PREPARATION AND PACKAGING ...................................................................................................... 5 
5.5 
BLINDING ....................................................................................................................................... 5 
5.6 
SUBJECT COMPLIANCE MONITORING ............................................................................................... 6 
6 
STUDY PROCEDURES AND DATA COLLECTION .......................................................................... 6 
6.1 
SCREENING ................................................................................................................................... 6 
6.2 
STUDY INTERVENTION PHASE ......................................................................................................... 6 
6.2.1 
Visit 1: Baseline Visit ............................................................................................................... 6 
6.2.2 
Visit 2: End of Intervention ...................................................................................................... 6 
6.2.3 
Visit 3: 4 – Week post Intervention .......................................................................................... 6 
6.3 
SUBJECT WITHDRAWAL .................................................................................................................. 6 
7 
STATISTICAL PLAN AND STATISTICAL ANALYSIS ....................................................................... 7 
8 
SAFETY AND ADVERSE EVENTS ..................................................................................................... 7 
8.2 RECORDING OF ADVERSE EVENTS ......................................................................................................... 7 

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8.3 REPORTING OF ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND UNANTICIPATED PROBLEMS TO PENN 
IRB AND ACC ............................................................................................................................................. 8 
8.3.1 Investigator reporting: notifying the study sponsor ...................................................................... 8 
8.4 STOPPING RULES .................................................................................................................................. 8 
8.5 MEDICAL MONITORING........................................................................................................................... 8 
8.5.1 Data and Safety Monitoring Plan ................................................................................................ 8 
9 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING ...................................... 9 
9.1 
CONFIDENTIALITY ........................................................................................................................... 9 
9.2 
DATA COLLECTION AND MANAGEMENT ............................................................................................ 9 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................... 9 
10.1 
STUDY MONITORING PLAN .............................................................................................................. 9 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 10 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 10 
11.1 
RISKS .......................................................................................................................................... 10 
11.2 
BENEFITS .................................................................................................................................... 10 
11.3 
RISK BENEFIT ASSESSMENT ......................................................................................................... 11 
11.4 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION .............................................................. 11 
12 
STUDY FINANCES ............................................................................................................................ 11 
12.1 
FUNDING SOURCE ........................................................................................................................ 11 
12.2 
CONFLICT OF INTEREST ................................................................................................................ 11 
12.3 
SUBJECT PAYMENTS .................................................................................................................... 11 
13 
BENCHMARKS FOR STUDY/PUBLICATION PLAN ....................................................................... 11 
 
 
 
 
 
 
 

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List of Abbreviations 
 
CDT: Complete decongestive therapy 
HNC: Head and neck cancer 
LLLT: Low-level laser therapy 
 
 
 
 
 
 

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Study Summary 
Title 
Low-Level Laser in Treatment of Head and Neck Lymphedema: A Pilot 
Study 
 
Short Title 
Low-level laser therapy in head and neck lymphedema 
Study ID Number 
UPCC12318 
Protocol Number 
Version Date: 06-15-2019  
Phase 
Pilot study  
Methodology 
A single-arm, pre- and post-design clinical trial 
Study Duration 
24 months  
Study Center(s) 
Single-center  
Objectives 
Primary aim: To determine the feasibility of the use of LLLT for HNC survivors 
with lymphedema, specifically to 1) obtain recruitment estimates and determine 
barriers to recruitment; 2) identify barriers to implementation; 3) assess safety; 
and 4) evaluate patient satisfaction. 
Secondary aim: To determine the preliminary efficacy of the use of LLLT on 
the following outcomes: 1) lymphedema progression; 2) symptom burden; and 
3) functional status.  
 
Number of Subjects 
25 subjects expected to be enrolled  
Main Inclusion and 
Exclusion Criteria 
Inclusion criteria: >18 years of age; 2) completion of either postoperative 
radiation or chemoradiation therapy; 3) no evidence of cancer; 4) having head 
and neck external lymphedema; 5) ability to speak and read English; and 6) 
able to provide informed consent. 
Patients will be excluded if they have any of the following medical conditions 
that would prohibit the safe implementation of LLLT: pregnancy; 
photosensitivity; chronic inflammatory diseases; venous thrombosis; history of 
severe trauma; medication that affects body fluid and electrolyte balance; use 
of high doses of non-steroidal anti-inflammatory drugs; or pre-existing skin 
rash, ulceration, open wound in the treatment area; and allergic and other 
systemic skin diseases.  
Investigational 
device 
For Device include 
the planned use 
RianCorp LTU-904 Low-level laser therapy unit 
  
Duration of 
administration (if 
applicable) 
6 weeks 
Safety Evaluations  
Common Terminology Criteria for Adverse Events (CTCAE version 4.03) will 
be used to document adverse events of the clinical trial 
Data 
and 
Safety 
Monitoring Plan  
PI Deng will be responsible for monitoring the data quality and the ongoing 
safety of subjects.  
 
 

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BACKGROUND AND STUDY RATIONALE 
This study will be conducted in full accordance all applicable University of Pennsylvania Research Policies 
and Procedures and all applicable Federal and state laws and regulations including the use of a medical 
device (i.e., RianCorp LTU-904).  
1        Introduction 
Current standard of care for head and neck lymphedema treatment provided by therapists is short-
term in nature (usually up to 4-12 weeks); however, lymphedema is a chronic condition and often worsens 
over time. Therefore, alternative treatment modalities need to be investigated for effective and long-term 
management of lymphedema and associated late fibrosis in the head and neck cancer (HNC) population. 
1.1 
Background and Relevant Literature  
There has been an increase in the incidence of head and neck cancer (HNC) largely related to the 
epidemic of human papillomavirus (HPV) associated disease.1,2 HPV- associated HNC occurs in younger 
and middle-aged patients; cure rates in this population are markedly higher compared to other HNC 
groups.3,4 This contributes to more than half a million HNC survivors in the U.S. today.5 Regardless of 
cause, patients with locally advanced HNC are usually treated with aggressive multi-modality regimens.6 
These regimens often lead to numerous long-term toxicities. One common but under-treated late effect of 
treatment is damage to lymphatic structures and soft tissues resulting in lymphedema.7,8 Animal studies 
indicate that lymphedema is associated with chronic inflammation leading to fibrosis.9,10 Our work was the 
first to assess lymphedema in HNC patients in a systematic manner.7,11 We demonstrated a prevalence 
rate of 75% in HNC survivors.7 We confirmed that lymphedema occurs both externally (e.g., face and neck) 
and internally (e.g., pharynx and larynx).7,12 Subsequent work demonstrated that external lymphedema 
resulted in a decreased range of motion in the jaw, neck and shoulders.13 Internal swelling was found to 
cause substantial impact on critical functions (e.g., swallowing, speaking, and breathing).13,14 Psychological 
effects (e.g., body image disturbance) were also correlated with lymphedema.13,15-17 Finally, lymphedema 
has the potential to negatively impact HNC survivors’ ability to function in both home and work 
environments, resulting in both emotional and financial burden for these individuals, their families, and the 
healthcare system.11,18 
 
Current standard of care for treatment of lymphedema is complete decongestive therapy (CDT), which 
consists of 4 main parts: manual lymphatic drainage, compression (bandaging or garments), exercise, and 
skin care. 10,19,21,22 These treatments are expensive, time-consuming and labor-intensive. CDT provided by 
therapists is short-term in nature (usually up to 4-12 weeks); however, lymphedema is a chronic condition 
and often worsens over time.10,19 Therefore, alternative treatment modalities need to be investigated for 
effective and long-term management of lymphedema and associated late fibrosis in the HNC population.  
 
Among many alternative treatment options, low level laser therapy (LLLT) is a promising, noninvasive 
modality for treatment of lymphedema. LLLT, also named photobiomodulation therapy (PBMT), has had a 
place in general medicine for more than 40 years.24 It has been used as a treatment option to stimulate 
wound healing and reduce inflammation, edema, and pain.24 The U.S. Food and Drug Administration (FDA) 
accepted it as a treatment approach for breast cancer-related upper extremity lymphedema (BCRL) in 
2006.24 One recent systematic review evaluating 7 randomized clinical trials (RCT) concluded that available 
evidence supports LLLT in the management of BCRL, with clinically meaningful reductions in lymphedema-
related swelling and symptom burden (e.g., pain).25 Compared to other treatment modalities, LLLT is a 
noninvasive modality, repeatable, easily performed in outpatient setting, and without any known long-term 
side effects. To our knowledge, the current proposal is the first study investigating the use of LLLT in the 
treatment of head and neck lymphedema. The goal of this proposed research is to determine the feasibility 
and preliminary efficacy of the use of LLLT on facial/neck swelling and fibrotic changes, symptom burden, 
and neck mobility in HNC survivors with lymphedema through a pilot study.  

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1.2 
Name and Description of the Investigational Product  
We will use a RianCorp LTU-904, FDA-approved, Class I laser device in this study. The device will be used 
by the study lymphedema therapist, Joy Cohen, who has had more than 20 years of experience treating 
individuals with lymphedema.   
1.2.1 
Nonclinical Data 
Findings from nonclinical data indicate that LLLT stimulates lymphatic vessels and lymphocytes, as well as 
increases local fluid circulation.27,28  
1.2.2 
Clinical Data to Date 
Currently, only cases studies indicate the potential value of use of LLLT for treating head and neck 
lymphedema.29,30 No large prospective clinical trials are available to evaluate prophylactic and/or 
therapeutic use of LLLT for lymphedema in HNC patients. However, a large body of evidence is available 
in supporting the safety and efficacy of LLLT for management of lymphedema in breast cancer patients. 
For instance, since 1995, the use of LLLT has been investigated in the treatment of breast cancer-related 
lymphedema (BCRL).31 A meta-analysis of 9 studies (7 of them were RCTs) provided evidence that LLLT 
alone or combined with other treatments was able to reduce the arm swelling and pain in women with 
BCRL.31 LLLT does not increase the risk on cellulitis, a known side effect in patients with arm 
lymphedema.31 A recent systematic review also suggested the use of LLLT for treating the following 
conditions in the breast cancer population: oral mucositis, radiodermatitis, chemotherapy-induced 
peripheral neuropathy, and osteonecrosis of the jaw.24 In another recent systematic review, the authors 
concluded that LLLT may have potential applications in the management of a broad range of side effects 
(e.g., lymphedema/fibrosis) of chemo-radiation therapy in patients with HNC.32, 33 
1.2.3 
Clinical Studies in Children  
Not applicable 
1.3 
Dose Rationale (if applicable)  
We propose that participants will receive LLLT twice a week for 6 weeks (12 sessions). This regimen was 
developed based on the evidence from literature.  
2 
Study Objectives 
The goal of this proposed research is to evaluate the effect of LLLT on facial/neck swelling and fibrotic 
changes, symptom burden, and neck mobility in HNC survivors with lymphedema through a pilot study. 
2.1 
Primary Objective 
• 
To determine the feasibility of the use of LLLT for HNC survivors with lymphedema. 
2.2 
Secondary Objective 
• 
To determine the preliminary efficacy of the use of LLLT for HNC survivors with lymphedema.  
3 
Investigational Plan  
3.1 
General Design 
We will conduct a single-arm, pre-and post-design clinical trial. Outcome measures include: 1) feasibility 
(barriers to implementation, safety, and satisfaction) of the proposed intervention [Primary aim]; and 2) 
preliminary efficacy (lymphedema progression, symptom burden, and functional status) of the proposed 
intervention [Secondary aim]. Study assessments will take place at baseline, immediately after end of the 
intervention, and 4-week post-intervention.  
 

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3.1.1 
Screening Phase 
We will recruit a minimum of 6 participants per month. The volume of HNC patients at Penn’s Clinic is 
sufficient to complete this trial without additional sites. The following recruitment procedures will be used: 
screening at HNC clinics and attendance at Head and Neck tumor board and case conferences. All direct 
patient recruitment activities will be conducted at the Penn HNC clinics where private rooms are available 
to be used for conducting clinical research projects.  
3.1.2 
Study Intervention Phase and Follow Up Phase  
After completion of the baseline measures, participants will be scheduled for LLLT. The LLLT includes 
receiving LLLT twice a week for 6 weeks (12 sessions) (LLLT protocol developed based on the literature 
review34-41). After completion of the 12-session LLLT, participants will be given a) contact information and 
instructions to call for problems and b) a calendar outlining dates for 4-week follow-up data collection.  
3.2 
Study Endpoints  
3.2.1 
Primary Study Endpoints 
The primary endpoint will be the feasibility of LLLT in HNC patients, including recruitment estimates, barriers 
to recruitment, and barriers to implementation, safety, as well as patient satisfaction. 
3.2.2 
Secondary Study Endpoints 
The secondary study endpoint will be the potential efficacy of LLLT in HNC patients, including lymphedema 
progression, symptom burden, and functional status. 
4 
Study Population and Duration of Participation  
4.1 
Inclusion Criteria 
• 
>18 years of age  
• 
Completion of either postoperative radiation or chemoradiation therapy 
• 
No evidence of cancer 
• 
Having head and neck external lymphedema 
• 
Ability to speak and read English 
• 
Able to provide informed consent 
4.2 
Exclusion Criteria 
   
Patients will be excluded if they have any of the following medical conditions that would prohibit the safe 
implementation of LLLT: pregnancy; photosensitivity; chronic inflammatory diseases; venous thrombosis; 
history of severe trauma; medication that affects body fluid and electrolyte balance; use of high doses of 
non-steroidal anti-inflammatory drugs; or pre-existing skin rash, ulceration, open wound in the treatment 
area; and allergic and other systemic skin diseases. In addition, patients will be excluded if they are in 
active physical therapy and/or lymphedema therapy. 
4.3 
Subject Recruitment  
The following recruitment procedures will be used: screening at HNC clinics and attendance at Head and 
Neck tumor board and case conferences. All direct patient recruitment activities will be conducted at the 
Penn HNC clinics where private rooms are available to be used for conducting clinical research projects.  
4.4 
Duration of Study Participation 
The duration of the study subjects’ participation will be 10 weeks, including screening, study intervention 
phase (6 weeks) and follow up time period (up to 4 weeks).  

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4.5 
Total Number of Subjects and Sites  
Total number of subjects: 25 
Single-site study: Subjects will be enrolled at Penn only.   
4.6 
Vulnerable Populations 
Not applicable.  
5 
Study Intervention (Study drug, device, biologic, vaccine, food etc.) 
5.1 
Description 
The LTU-904 is a Class I laser device, which is a low output laser in the infrared wavelength (904nm) and 
no safety glasses are required as there is no risk of eye damage as defined by the standards set by the 
international Electrotechnical Commission.  
5.2 
Intervention Regimen 
The LTU-904 will be used in the study. The following laser parameters commonly used in the literature 
will be used in the study: 5mW output; 904nm wavelength in pulsed mode; dosage (energy density) of 
1.5J/cm2. For this pilot study, all the study participants will receive the same treatment regimen, including 
the same dose, therapy sessions, and treatment spots. 
 
Participants will undergo the following procedures at each study visit. First, they will be asked to lie on a 
massage table. Then, the study lymphedema therapist will place a small laser device head directly on the 
skin of either left side or right side of the participant’s face and neck, i.e., the side with the swelling and the 
tough/tight tissues. A total of 14 ~25 spots on the face and neck will be treated. The spots includes: maxillary 
prominence (1 spot), mandible (2 points), pre auricular (1 point), submental (3 points), sternocleidomastoid 
muscle (3 points), supraclavicular area (2 points), and scalene muscle (2 points). Each spot will be treated 
for about 60 seconds. Each study visit will take approximately 25-30 minutes. Prior to low-level laser 
therapy, participants will receive 5 minutes of simple manual lymphatic drainage (MLD) to the head and 
neck region that followed the international standards. 
 
 
5.3 
Storage 
Study Device Storage, Delivery and Management: The LTU-904 will be purchased from RianCorp directly. 
The device will be shipped to the PI directly. The LTU-904 unit comes with a carry case that ensures the 
unit is stored safely. Both the PI Deng and the study lymphedema therapist (Joy Cohen) will be trained by 
an expert from RianCorp directly regarding how to store, dispense, and manage the device appropriately 
prior to subject enrollment or conducting research activity. The study lymphedema therapist will be 
responsible for storing, dispensing, and managing the laser device. The study lymphedema therapist will 
evaluate and monitor the LTU-904 unit regularly to ensure its normal function and prepare it for 
administration to subjects. The study lymphedema therapist will make sure the LTU-904 is stored properly 
after use of the device each time. The study lymphedema therapist will report the failed device to the PI 
Deng. The PI Deng will return the failed device to the manufacturer. The PI Deng will monitor the storage, 
delivery, and management of the laser device throughout the study. 
5.4 
Preparation and Packaging 
The study lymphedema therapist (Joy Cohen) will properly prepare the LTU-904 unit for administration to 
subjects. Ms. Joy Cohen will make sure the LTU-904 is stored properly after use of the device each time. 
5.5 
Blinding 
Not applicable.    

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5.6 
Subject Compliance Monitoring 
The participants are encouraged to be compliant with the scheduled visits. The reasons for non-compliance 
with the study scheduled visits will be documented and potential underlying barriers will be explored.  
6 
Study Procedures and Data Collection  
 
6.1 
Screening  
The screening will be conducted by a trained staff member. Individuals who are interested in this research 
will be screened for eligibility for being in the study. A Screening Checklist will be used to ensure that eligible 
participants are enrolled in the study. A Recruitment Log will be used during the recruitment. 
6.2 
Study Intervention Phase 
6.2.1 
Visit 1: Baseline Visit   
The following procedures and data collection will take place at study visit 1. 
• 
Demographic Form 
• 
Physical Exam for completing HN-LEF Grading Criteria 
• 
Digital photographs of face and neck 
• 
Modified Patterson Scale 
• 
Symptom burden assessments (LSIDS-H&N and NDI) 
• 
Functional status (neck range of motion) 
 
In addition, the following variables will be abstracted from the medical chart with participants’ permission.  
 
• 
HNC Disease and treatment information (HNC Clinical Form) 
• 
Lymphedema and fibrosis diagnosis and treatment information (LEF Treatment Form) 
6.2.2 
Visit 2: End of Intervention  
The following procedures and data collection will take place at study visit 2. 
• 
Physical Exam for completing HN-LEF Grading Criteria 
• 
Digital photographs of face and neck 
• 
Modified Patterson Scale 
• 
Symptom burden assessments (LSIDS-H&N and NDI) 
• 
Functional status (neck range of motion) 
6.2.3 
Visit 3: 4 – Week post Intervention 
The following procedures and data collection will take place at study visit 3. 
• 
Physical Exam for completing HN-LEF Grading Criteria 
• 
Digital photographs of face and neck 
• 
Modified Patterson Scale 
• 
Symptom burden assessments (LSIDS-H&N and NDI) 
• 
Functional status (neck range of motion) 
6.3 
Subject Withdrawal  
Subjects may withdraw from the study at any time without impact to their care. They may be discontinued 
from the study at the discretion of PI Deng, due to lost follow-up or adverse events. Subjects may also be 
withdrawn by PI Deng from the study given safety consideration. 

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7 
Statistical Plan and Statistical Analysis 
While this study is a preliminary study of efficacy and effect sizes, a maximum alpha level of 0.05 will be 
used for the statistical tests.  
 
Statistical analysis for primary aim (feasibility of the intervention): Descriptive statistical and graphical 
methods will summarize the rates of participation (recruited vs. consented), log data (e.g., sessions 
completed), completion of assessments throughout the study, adverse events (safety) and satisfaction data 
within both groups. It is expected that ≥ 80% of participants will complete the study activities, and ≥ 80% 
will report acceptable levels of satisfaction with the interventions, thereby demonstrating feasibility of the 
interventions proposed in this research.  
 
For the secondary objective, change from baseline value will be computed for each outcome variable at 
each follow-up timepoint. The analysis of changes over time relies on mixed-effects modeling, which 
accounts for correlation among subjects’ repeated measures using a compound symmetry covariance 
matrix. Results will be reported as model-based mean change ± standard error.  
8 
Safety and Adverse Events 
 
8.1 Safety Monitoring 
The following strategies will be in place to monitor safety of participants during the course of the study. 
 
During the course of this study, study staff will observe for any adverse side effects or events when 
interacting with participants and be trained to report these to the PI's immediately. Common Terminology 
Criteria for Adverse Events (CTCAE version 4.03) will be used to document adverse events of the trial. All 
the staff members who are involved in this study will be trained how to use CTCAE version 4.03.  
 
In addition, participants in this study will be screened against the inclusion and exclusion criteria. 
Participants will be educated regarding signs and symptoms related to adverse events (e.g., sudden 
increase in swelling) requiring urgent or emergent medical care.    
8.2 Recording of Adverse Events 
Each contact with the subject, the trained staff will seek information on adverse events by specific 
questioning and, as appropriate, by examination. Information on all adverse events will be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document. 
 
All adverse events occurring during the study period will be recorded.  The clinical course of each event will 
be followed until resolution, stabilization, or until it has been determined that the study intervention or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
will be followed up to determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study intervention or study participation will be 
recorded and reported immediately. 
 
All adverse events will be reviewed by Drs. Deng and Lin, any contributing factors will be reviewed, and 
strategies to prevent further complications will be developed and implemented. Dr. Deng will meet with 
study staff monthly to evaluate any other safety concerns. Adverse events will be reported to the Penn IRB 
within the window required by the IRB. If study staff identify the following unanticipated problems related to 
the research (e.g., infection in the treated area, sudden increase in swelling), which occur during the study, 
Drs. Deng, Lin, and study lymphedema therapists will be notified immediately. Patients will be referred and 
received appropriate and timely therapy. Drs. Deng and Lin will determine if participants with adverse 
events or any unexpected issues will remain on the study based on safety consideration. Drs. Deng and 
Lin as well as the study lymphedema therapist will evaluate the relationship of each adverse event to the 
study procedures. PI Deng and Co-I Lin will be responsible for making the determination of the relationship 

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of the adverse event to the study procedures (e.g., definitely related, probably related, possible related, 
unlikely or unrelated). 
 
8.3 Reporting of Adverse Events, Adverse Device Effects and Unanticipated Problems to Penn IRB 
and ACC 
 
PI Deng and the study team will conform to the adverse event reporting timelines and formats, per the Penn 
IRB reporting requirements and Abramson Cancer Center reporting guidelines. 
 
The following information will be included at the time of the initial report: 
• 
Study identifier 
• 
Study site  
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study intervention was discontinued 
• 
The reason why the event is classified as adverse 
events 
• 
Investigator assessment of the association 
between the event and study intervention 
 
Additionally all other events (unanticipated problems, adverse reactions, unanticipated adverse device 
effects and subject complaints) will be recorded and reported with respect to Penn policies as described in 
the Penn Manual.  
 
8.3.1 Investigator reporting: notifying the study sponsor 
Not applicable. The study has no external sponsor.  
8.4 Stopping Rules  
We do not anticipate significant adverse events. Given no safety data available in the population under 
study, the research may involve risks that are currently unforeseeable. If any one event is identified that 
may have caused any type of harm to a participant, study recruitment and associated study activities will 
be immediately halted until the study team reviews the event and determines if any study procedures need 
to be revised. Study recruitment and associated study activities will only resume after review of study 
protocol has been completed and any recommended revisions made as advised by both the study team 
and the Penn IRB.  
8.5 Medical Monitoring 
PI Deng will be responsible for overseeing the safety of the study. In addition, Co-I Lin (study physician) 
and Ms. Joy Cohen (study lymphedema therapist) will be involved in medical monitoring.   
8.5.1 Data and Safety Monitoring Plan 
The data and safety monitoring plan will adhere to policy guidance and standards set by the Penn IRB. The 
PI Deng will be responsible for monitoring the entire study.  
 
Data Management: 1) Self-reported questionnaires will be completed by participants using a tablet to enter 
their responses into REDCap. The research assistant will review participants’ completeness for each 
questionnaire. If participants prefer or if there are technical difficulties, hard copy forms will be used. All hard 
copy data will be double-entered into REDCap, checked for discrepancies, and reconciled with hard copy 
forms. All forms will be stored in a secured cabinet. 2) Phyiscal examination data collected by the study staff 
will be entered by the research assistant into REDCap. These data will also be double-entered, checked for 
discrepancies, and reconciled with the hard copy form. 3) Imaging data (digital photos) will be deidentified 
(white out eyes) and only scoring data will transfer out to REDCap. Data from various sources will be 
integrated into the study databases by the Data Specialist. All data will be coded without any identifiable 
information. The PI Deng and the data specialist will monitor and ensure that all data are timely entered into 

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the databases and all protocol specifics are met. PI Deng will monitor all databases monthly and maintain a 
master table that links participants to ID number in a password-protected database on a secure server 
throughout the study and after close of study. 
 
Monitoring by the PI: PI Deng, with assistance from the Co-I Lin, the study lymphedema therapist (Joy 
Cohen), and other study staff members, will monitor all the study activities to ensure safety of participants 
and integrity of the data collection and management. The research team will meet monthly to discuss 
recruitment, retention, study progress, and any safety concerns. Any potential issues related to the study 
activities will be discussed and addressed appropriately and timely. Participants will be educated regarding 
signs and symptoms related to adverse events requiring urgent or emergent medical care. All adverse events 
will be documented using CTCAE criteria, reviewed by Drs. Deng and Lin. Any contributing factors will be 
reviewed. Strategies to prevent further complications will be developed and implemented. Although adverse 
events are highly unlikely, should they develop, they will be reported to the Penn IRB, within the required 
time window.  
9 
Study Administration, Data Handling and Record Keeping 
9.1 
Confidentiality 
All the study data will be stored in a secured network drive managed by University of Pennsylvania School 
of Nursing IT staff member. All participants will be assigned a study ID number (e.g., 100). Numbers will be 
assigned by trained study staff. It is important and necessary for the study team to know participants names 
in order to communicate with them during the study. This information will be maintained in a participant 
tracking database that is not stored on the hard drive, accessible only to the study team members through 
a password protected computer and link to a Penn School of Nursing server that is accessible only the 
study team. The name column will be deleted at the end of the study. 
9.2 
Data Collection and Management  
Data collection will be conducted by a trained staff member at a private room at the Abramson Cancer 
Center (ACC) HNC clinics (participant recruitment and baseline data collection). The following procedure 
will be utilized to protect the privacy of the research participant. All data will be coded and filed without any 
name or other identifiable information. Self-reported questionnaires will be completed by participants using 
an encrypted and secured tablet to enter their responses into REDCap. The research assistant will review 
participants' completeness for each questionnaire. If participants prefer or if there are technical difficulties, 
hard copy forms will be used. All hard copy data will be double-entered into REDCap, checked for 
discrepancies, and reconciled with hard copy forms. All hard copies will be placed in a locking file cabinet. 
Only the study team have access to the file cabinet and electronic database. After the study is concluded, 
the research data will be stored at Penn School of Nursing. 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
Monitoring by the PI: The PI Deng, with assistance from the Co-I Lin, the study lymphedema therapist (Joy 
Cohen), and other study staff members, will monitor all the study activities to ensure safety of participants 
and integrity of the data collection and management. The research team will meet monthly to discuss 
recruitment, retention, study progress, and any safety concerns. Any potential issues related to the study 
activities will be discussed and addressed appropriately and timely. Participants will be educated regarding 
signs and symptoms related to adverse events requiring urgent or emergent medical care. All adverse events 
will be documented using CTCAE criteria, reviewed by Drs. Deng and Lin. Any contributing factors will be 
reviewed. Strategies to prevent further complications will be developed and implemented. Although adverse 
events are highly unlikely, should they develop, they will be reported to the Penn IRB, within the required 
time window.  

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10.2 Auditing and Inspecting 
The PI Deng will permit study-related monitoring, audits, and inspections by the IRB, government regulatory 
bodies, and University compliance and quality assurance groups of all study related documents (e.g., 
source documents, regulatory documents, data collection instruments, study data etc.).   
11 Ethical Considerations 
Although this is an interventional study, foreseeable physical, psychological, financial, legal, or other risks 
from study participation are believed to be minimal. 
11.1 Risks 
1) Physical: No physical risks (e.g., worsening lymphedema or fibrosis) from using LLLT in individuals 
with breast cancer-related lymphedema have been reported in the known current literature review. No 
physical risks from using LLLT were reported in the cases studies conducted in individuals with head 
and neck lymphedema. Subjects will not have any burning sensation, warmth, or any other uncomfortable 
sensations on the sites treated with low-level laser. Currently, there is no safety data in the population 
under study. Thus, we will inform participants of reporting any physical damages they have during the 
course of the study.  
2) Psychological: There are no known psychological risks associated with LLLT.  
3) Financial: The LLLT will be provided free of charge. Patients may incur expense of gas when driving 
to the Penn Clinic.  
4) Legal: There are no known legal risks.  
5) Other: There may be risks that are unknown at this time. 
Our planned protections from the above-noted risks are as follows:  
1) Physical: Currently, there are no known potential physical risks for being in this study. Given no safety 
data available in the population under study, the research may involve risks that are currently 
unforeseeable. To minimize any potential physical risks, the following will be done: a) Participants will be 
given the study contact phone numbers and emails to ask any questions or to report any unexpected 
problems if the problems are directly related to the study activities; b) if study staff identify any unanticipated 
problems, Drs. Deng, Lin, and study lymphedema therapist (Joy Cohen) will be notified immediately. 
Appropriate evaluation and timely therapy will be provided to the participant. Deng, Lin, and study 
lymphedema therapists will determine if participants with significant unanticipated issues will remain on the 
study based on safety consideration; and c) if anyone experience an adverse event directly related to the 
study activities that are done for research, they can get reasonable, immediate, and necessary medical 
care for their adverse events at Penn.  
2) Psychological: If study staff identifies participants with significant distress during the course of the 
study, PI Deng and Co-I Lin will be notified immediately so that appropriate psychological evaluation and 
referrals will be made. Drs. Deng and Lin will determine if participants with significant psychological issues 
will remain on study.  
3) Financial: The LLLT will be provided free of charge. Patients will incur expense of gas when driving to 
the Penn Clinic during study follow-up visits. To offset travel/gas cost, participants will be provided a 
financial token of appreciation for participation in the study.  
4) Legal: There are no known legal risks.  
5) Other: Should the team become aware of any additional risks, participants will be notified and informed 
consents will be modified to reflect the new information. 
11.2 Benefits 
Potential benefits to the individual: Although the potential direct benefit to study participants is unknown, 
individual participants will be exposed to and have increased knowledge about lymphedema and fibrosis. 
Participants may have positive feelings about participation in a research program that may benefit others.  

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Potential benefits to human kind: Possible future benefits for HNC survivors are potentially substantial. If 
we are able to demonstrate that LLLT is safe, feasible and effective in HNC patients, we will be adding to 
the armamentarium of an alternative intervention that can diminish progression of lymphedema and fibrosis, 
decrease symptom burden, increase function, and improve overall quality of life. 
11.3 Risk Benefit Assessment 
Currently, there are no known potential risks for being in this study. Given no safety data available in 
the population under study, the research may involve risks that are currently unforeseeable. 
As noted above, potential benefits are reasonable and substantial. Thus, based on the risk benefit 
assessment, it appears to be acceptable for this research within human subjects. 
11.4 Informed Consent Process / HIPAA Authorization  
Once the study is approved by the Penn IRB and the ACC, the trained study team members will meet with 
potential participants who express interest in the study. Potential study participants will be provided one 
copy of the informed consent to read and review. Study team members will review the study procedures 
and activities with potential participants. The informed consent document will be written in lay language and 
cover all study activities participants will engage in during the study, define the length of time the study will 
be conducted, and provide instructions for participant withdrawal from the study should they choose to do 
so. Study staff will review and, when necessary, read the informed consent document to potential 
participants. Participants will be given ample time and opportunity to ask questions, and all questions will 
be answered by study staff. The consent process will take place in a private location, with a closed door. 
Once participants have had an opportunity to ask questions, those questions have been answered, and 
they indicate an interest in participation, they will be asked to sign a written informed consent document as 
the study staff witnesses. In addition, the participant will be given a copy of informed consent signed by both 
the participant and study staff. We will not seek waivers of the informed consent process. 
12 Study Finances 
12.1 Funding Source 
Not applicable. 
12.2 Conflict of Interest 
All the team members will follow the University of Pennsylvania Policy on Conflicts of Interest Related to 
Research.  
12.3 Subject Payments 
All participants will be provided with a financial token of appreciation that increases slightly the longer they 
are in the study ($15 for baseline, $20 for end of intervention, $20 for 4-week post-intervention, and $25 for 
8-week post-intervention). 
13 Benchmarks for Study/Publication Plan 
The key benchmark for success of this study is to complete recruitment goals and data collection as 
scheduled. The information gathered from this study will provide important data for designing a large clinical 
trial that tests the efficacy of LLLT on lymphedema in the HNC survivors. Additional benchmarks for success 
include: 1) dissemination of preliminary findings at professional conferences and 2) submission of articles 
to peer-reviewed journals.