Prevention of Oral Mucositis in Children and Adolescents Undergoing Hematopoietic Stem Cell Transplant Using Photobiomodulation Therapy
Phase: NA
Conditions: Oral Mucositis
Sponsor: St. Jude Children's Research Hospital

Revision 1.1 dated 12-22-2020
Protocol Document Date: 12-22-2020
St. Jude 
PrOM CTG# - NCT04227340
Initial version, dated: 07-30-19, (IRB Approved: 12-23-19) Activation Date: 01-15-20 
Revision 0.1, dated: 02-03-2020, (IRB Approved: 02-13-2020) Activation Date: 02-18-20 
LOA1, dated: 03-23-2020, (IRB Approved: 03-30-2020)
Amendment 1.0, dated 3-13-2020, (IRB Approved: 5-5-2020) Activation Date: 5-27-20 
LOA2, dated  7-8-2020, (IRB Approved: ) Activation Date:
Revision 1.1, dated: 12-22-2020, (IRB Approved: ) Activation Date: 
PREVENTION OF ORAL MUCOSITIS IN CHILDREN AND ADOLESCENTS 
UNDERGOING HEMATOPOIETIC CELL TRANSPLANT USING 
PHOTOBIOMODULATION THERAPY
Principal Investigator
Belinda Mandrell, PhD, RN 
Division of Nursing Research
Department of Pediatric Medicine
Co-Investigators
Judy Bosi, BS1
Mike Burgess, BSN, RN2
Sarah Daniels, MS6
Robert Cary Daniel, DDS3
Melody Greene, DDS3
Kimberly Holbrook, MSN, RN2
Deena Levine, MD4
Zhaohua Lu, PhD5
Gina Norman, MSN, RN2 
Susan Ogg, MSN, RN1 
Christopher Rowland, DDS4 
Teresa Street, BSN, RN2 
Ashley Swearingen, BSN, 
RN2 Brandon Triplett, MD3
1 Department of Pediatric Medicine, Division of Nursing Research, 2 Nursing, Bone 
Marrow Transplant, 3 Department of Surgery, 4 Department of Oncology, 5Department 
of Biostatistic, 6 Child Life
Collaborating Institutions Co-Investigators: 
Cesar A Migliorati, DDS, PhD 
St. Jude Children's Research Hospital
IRB NUMBER: 19-0225
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Revision 1.1 dated 12-22-2020
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College of Dentistry, University of Florida
St. Jude Children's Research 
Hospital 262 Danny Thomas 
Place
Memphis, Tennessee 38105-3678
Telephone:  (901) 595-3300
St. Jude Children's Research Hospital
IRB NUMBER: 19-0225
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Revision 1.1 dated 12-22-2020
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Protocol MNEMONIC and Title: Prevention/Treatment of Oral Mucositis in 
Children and Adolescents undergoing Hematopoietic Cell Transplant (HCT) using 
Photobiomodulation Therapy (PBM)
Principal Investigator: Belinda Mandrell, PhD, RN
IND Holder: Not Applicable
Brief Overview: Oral mucositis is a significant and common toxicity experienced by 
patients who receive chemotherapy as a preparatory regimen for a hematopoietic cell 
transplant (HCT). Furthermore, oral mucositis has been reported as the single most 
debilitating side effect reported by patients undergoing HCT. The incidence of HCT 
mucositis among adults is estimated to range between 76% and 89%; however, comparisons 
are difficult due to variability in patient ages, treatments and criteria for scoring oral 
mucositis.
The use of intra-oral photobiomodulation (PBM) therapy in adult patients after the 
development of oral mucositis is well documented and now included in the international 
mucositis guidelines, with limited evidence in pediatrics. This study will build evidence for 
the incorporation of extra-oral PBM therapy into daily nursing care of children and 
adolescents undergoing HCT. This intervention has potential in providing evidence for 
efficacy in the prevention and treatment of oral mucositis, the single most debilitating side 
effect reported by patients undergoing HCT.
Patients admitted for an allogeneic hematopoietic cell transplant (HCT) will be eligible to 
receive daily extra-oral and intra/oral PBM beginning on the first morning of conditioning 
chemotherapy and continuing until Day +20 or engraftment (ANC ≥ 500 for two 
consecutive days), at which time treatment will end. Patients admitted for an autologous 
transplant and determined by the transplant team to be at risk for ≥ grade 3 oral mucositis 
will be eligible to receive daily extra-oral/intra oral PBM beginning on the first morning of 
conditioning chemotherapy and continuing until engraftment (ANC ≥ 500 for two 
consecutive days) or until patient is without mucositis (grade 1) for two consecutive days.
Intervention: PBM is defined as the application of coherent or non-coherent light to an 
area of pathology to promote tissue regeneration, reduce inflammation, and relieve pain. 
The biological mechanism of PBM allows intracellular absorption of energy by 
intracellular organelles and molecules; however, the amount and specifics of energy 
absorption is dependent upon the wavelength and rate of energy delivery dependent on the 
power of the device. PBM is FDA approved for tissue damage, pain and inflammation.
There is no age limitation.
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Brief Outline of Treatment Plan: Children, adolescents and young adults admitted for an 
allogeneic HCT and those determined by the transplant team to be at risk for ≥ grade 3 
oral mucositis will be eligible to receive PBM (34 x 660 nm 10 mW, 35 x 850 nm 30 mW; 
1390 mW total power output at an irradiance of 50mW/cm2).The PBM will be 
administered by trained research staff beginning on the first morning of the conditioning 
regimen (plus/minus 2 days) and continue daily until Day +20 or engraftment (event
occurring first) and for allogeneic continue daily until engraftment or until the patient is
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Protocol MNEMONIC and Title: Prevention/Treatment of Oral Mucositis in 
Children and Adolescents undergoing Hematopoietic Cell Transplant (HCT) using 
Photobiomodulation Therapy (PBM)
without grade 1 (no) mucositis for two consecutive days. All patients will receive the 
standard mouth care regimen prescribed for transplant patients. The nurse, advance nurse 
practitioner and physician caring for the patient will grade mucositis daily per the 
Common Toxicity Criteria (version5), and pain will be documented per institutional pain 
assessment scale (0-10). Patient- reported pain, and oral function will be collected daily.
Study Design:
This two-stage design study will assess for development of grade 3 
mucositis during daily PBM treatment.
Sample Size: 66
Data Management: Data management and statistical analysis will be provided by the 
Division of Nursing Research and Biostatistics Department at St. Jude Children’s 
Research Hospital
Human Subjects: The risks to subject are minimal. Retinal irritation is unlikely: 
however, each patient will be issued glasses for eye protection. Patients will be informed 
of this during informed consent discussion. Adverse events will be monitored and 
reported and treated appropriately.
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Contents
1.0 OBJECTIVES ..........................................................................................................................................................1
1.1 Primary Objective ..............................................................................................................................................1
1.2 Secondary Objectives.........................................................................................................................................1
1.3 Exploratory Objective........................................................................................................................................1
2.0 BACKGROUND AND RATIONALE....................................................................................................................2
2.1 Background ........................................................................................................................................................2
2.2 Rationale for Photobiomodulation Therapy.......................................................................................................3
3.0 RESEARCH PARTICIPANT ELIGIBILITY CRITERIA AND STUDY ENROLLMENT..................................8
3.1 Inclusion Criteria................................................................................................................................................8
3.2 Exclusion Criteria ..............................................................................................................................................8
3.3 Research Participant Recruitment and Screening ..............................................................................................8
3.4 Enrollment on Study at St. Jude.........................................................................................................................9
3.5 Procedures for Study Staff .................................................................................................................................9
4.0 DESIGN AND METHODS...................................................................................................................................10
4.1 Design and Study Overview.............................................................................................................................10
5.0 DRUG/DEVICE/BIOLOGIC AGENT INFORMATION ...................................................................................12
6.0 REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS ......................................................................15
6.1 Pre-Study Evaluations ....................................................................................................................................15
6.2 Response Evaluations During Therapy ..........................................................................................................15
6.3 Off-Study Evaluations....................................................................................................................................16
7.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF-STUDY CRITERIA......................17
       7.1 Off-study criteria.............................................................................................................................................17
8.   SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS ..............................................................17
8.1.Adverse Events (AEs) ....................................................................................................................................17
9.
DATA COLLECTION, STUDY MONITORING, AND CONFIDENTIALITY................................................18
9.1 Data Collection and Confidentiality...............................................................................................................18
9.2 Study Monitoring............................................................................................................................................19
10. STATISTICAL CONSIDERATIONS .................................................................................................................19
11. OBTAINING INFORMED CONSENT...............................................................................................................24
11.1 Consent at Age of Majority ..........................................................................................................................24
11.2 Consent When English is Not the Primary Language ..................................................................................24
12. REFERENCES.......................................................................................................................................................25
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1.0
OBJECTIVES
The use of intra-oral photobiomodulation therapy (PBM) in adult patients, who 
develop therapy related mucositis, is included in the international mucositis 
guidelines, with limited evidence in pediatrics. This intervention has the potential 
of providing additional evidence within the pediatric literature to the benefits of 
PBM in the prevention and treatment of oral mucositis in pediatric patients 
undergoing HCT. The ultimate goal would be incorporation of PBM into daily 
nursing care guidelines for pediatric patients undergoing HCT, thus improving 
outcomes and health-related quality of life.
1.1 Primary Objective
To evaluate feasibility and efficacy of photobiomodulation therapy (PBM) in 
reducing oral mucositis in children and adolescents at risk for grade 3 oral 
mucositis undergoing an allogeneic hematopoietic cell transplant (HCT).
Hypothesis 1: Children and adolescents will receive 75% of the attempted PMB 
treatment and will be less likely to develop grade 3 oral mucositis from the 1st 
day of conditioning to day +20 transplant or engraftment (event occurring first)
1.2 Secondary Objectives
To compare clinical manifestations associated with the development of oral 
mucositis between those treated with daily PBM and a matched control. Clinical 
factors to include: grade and duration or oral mucositis.
Hypothesis 2: Children and adolescents treated with extra-oral PBM will develop 
lower grade mucositis, with shorter mucositis duration (days) than the 
comparison matched control.
1.3 Exploratory Objective
1.
To evaluate efficacy of photobiomodulation therapy in autologous patients at 
risk for grade 3 oral mucositis compared to matched control.
Hypothesis: Children and adolescents treated with PBM will be less 
likely to develop grade 3 mucositis than matched control.
2.   To evaluate utilization of play-based procedural preparation and         
treatment feasibility and parental satisfaction.
Hypothesis: Children and adolescents introduced to low level light therapy 
through play-based procedural preparation will complete treatment at all 
sites compared to those without play-based preparation.
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2.0 BACKGROUND AND RATIONALE
2.1 Background
Oral mucositis is a significant and common toxicity experienced by patients who 
receive high-dose chemotherapy as a preparatory regimen for a hematopoietic 
cell transplant (HCT). Furthermore, oral mucositis has been reported as the single 
most debilitating side effect reported by patients undergoing transplantation.[1] 
The incidence of HCT conditioning mucositis is estimated to range between 76% 
and 89%; however, comparisons are difficult due to variability in patient ages, 
treatments and criteria for scoring oral mucositis.[2, 3]
Oral mucositis is a progressive process that begins shortly after the administration 
of high-dose chemotherapy and results from DNA strand breaks that result in 
direct cellular injury of cells in the basal epithelium and within the submucosa 
resulting in mucosal destruction.[2] Additionally, mucositis represents local 
tissue reactions including damage from reactive oxygen species, inflammatory 
cytokines, and damage to submucosa connective tissues and vasculature. Stages 
of oral mucositis include mucosal burning, erythema, edema with progression to 
ulceration. Ulceration occurs most commonly on the nonkeratinized mucosa of 
the mouth floor, tongue, buccal mucosa and soft palate.[3] Oral mucositis is noted 
several days after completion of chemotherapy with a peak in severity between 6 
and 12 days post-transplant.[4]
Oral ulcerations are painful, may become secondarily infected, bleed and impact 
nutritional intake. Together these factors increase the need for parenteral nutrition, 
opioid administration for pain and predispose the patient to secondary infection 
and bacteremia. The cost of oral mucositis can be excessive due to increased 
utilization of antibiotics, blood products, pain medication and supplemental 
nutrition thus leading to longer hospitalizations. According to Sonis et al.,[5] a 
one point increase in peak mucositis grade in HCT has been associated with a 2.1 
fold increase in risk of significant infection, 2.7 additional days of parenteral 
nutrition, 2.6 additional days of hospitalization, additional hospital cost of
$25,405 and 3.9 fold increase in risk of mortality with the first 100 days. While 
reporting benefit, the literature is limited in describing the efficacy of treatment 
for oral mucositis prevention and treatment among pediatric patients. Most studies 
have reviewed the efficacy of adult HCT oral mucositis interventions, with the 
inclusion of laser therapy recommended in adult oral mucositis guidelines.[2] 
Currently there is insufficient evidence for the application of PBM inclusion into 
oral mucositis guideline in the pediatric oncology population.[6]
This is a nurse led innovation utilizing a novel therapy for the prevention and 
treatment of the single most debilitating side effect reported in patients 
undergoing HCT. This innovative proposal has the potential to change our 
established Nursing Standard of Oral Care Guidelines for children and 
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adolescents undergoing a HCT through planned and coordinated application of
daily PBM with standard oral care. If the PBM is found to reduce the severity and 
duration of oral mucositis, the change in nursing routine with the inclusion of 
nurse delivered PBM will have a direct impact on improving health outcomes 
specifically patient reported pain, decrease in positive blood and oral cultures and 
less days of nutritional support. A decrease in the severity and duration of oral 
mucositis will also have a potential impact on health care cost with a decrease in 
supportive care measures, which may subsequently decrease days of 
hospitalization.
2.2 Rationale for Photobiomodulation Therapy
PBM is defined as the application of coherent light to an area of pathology to 
promote tissue regeneration, reduce inflammation, and relieve pain. The biological 
mechanism of PBM allows intracellular absorption of energy by intracellular 
organelles and molecules; however, the amount and specifics of energy absorption 
is dependent upon laser wavelength and rate of energy delivery dependent on the 
power of the laser.[7] Mitochondria in stressed or ischemic tissues produces 
excessive mitochondrial nitric oxide (mtNO) which binds to cytochrome c oxidase, 
competitively displacing oxygen and consequently reducing ATP, but this 
inhibition of mitochondrial respiration significantly increases production of ROS 
(free radicals). These excess ROS trigger the process of inflammation, cell death 
and subsequently oral mucositis. Light of the correct wavelength (generated by low 
intensity lasers and LED's), when applied to stressed tissues, is absorbed by 
cytochrome c oxidase. The light displaces the mtNO thereby reducing oxidative 
stress and increasing ATP production; this reduces inflammation and increases cell 
metabolism. A recent comprehensive review described the mechanisms of action 
for light therapy and molecular interactions and the implication of cytochrome c 
oxidase as the photo acceptor modulating light therapy.[8]
Figure 1 demonstrates the stages of wound healing and the benefit of light 
stimulation.[8]
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Figure 2 illustrates possible excitatory pathway by which light stimulates the 
electron transport chain to higher functionality[8]
Several studies have evaluated the effect of PBM on prevention and treatment of 
oral mucositis among adult patients undergoing HCT, with encouraging results. [9- 
11] These results prompted a change in the latest update of the Multinational 
Association of Supportive Care in Cancer and International Society of Oral 
Oncology (MASCC/ISOO) mucositis guidelines and now include a new 
recommendation for the use of PBM (34 x 660 nm 10 mW, 35 x 850 nm 30 mW; 
1390 mW total power output at an irradiance of 50mW/cm2), in prevention of adult 
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patients receiving HCT conditioned with high-dose chemotherapy, with or without 
total body irradiation .[12] The guideline also suggested the use of PBM in the 
prevention of oral mucositis in head & neck cancer patients treated with radiation 
therapy without concomitant chemotherapy.
Pediatric Evidence
A recent guideline was published by The Pediatric Oncology Group of Ontario 
(POGO) Mucositis Prevention Guideline Development Group specific to PBM. 
After review of the literature, the group placed high value on the possible reduction 
in mucositis with such intervention with a low risk of harm. While the evidence was 
adequate for potential benefit, the recommendation was weak due to the need for 
specialized equipment, expertise and unknown feasibility to deliver the therapy in 
routine clinical care.[13] This recommendation was taken from a systematic review 
by Oberoi et al, [14] of 18 prophylactic PBM studies. The meta-analysis reported 
PBM significantly reduced the incidence of severe mucositis, overall grade of oral 
mucositis, the incidence of severe pain, overall mean pain scores and use of opioid 
analgesia.
PBM has been evaluated in two small sample studies, as a device to prevent oral 
mucositis in pediatric patients undergoing HCT.[6, 15] The first study treated 9 
patients with PBM directly to the mucositis lesion and 12 control who had received 
a HCT or chemotherapy. The patients were treated for 5 days. Patients were 
evaluated by mucositis duration, with PBM OM duration 5.8 ± 2 days and the 
control 8.9 ± 2.4 days. [15] The second study treated 12 patients four times a week 
with a protocol of combined intraoral and extraoral PBM for an average of 22 days 
and matched to a retrospective group. Mucositis severity was significantly less than 
the control group, and higher (non-significant) oral function than the control. [6] 
Another study reviewed 51 HCT pediatric patients treated with daily PBM and 
found good clinical outcomes with control of mucositis severity and pain 
reduction.[16] This technique was further evaluated with the objective of 
controlling pain associated with oral mucositis in a pediatric transplant population 
with successful outcomes.[17]
Many of the cited studies have delivered PBM intraoral as individual small “spots” 
via a laser probe, specific to oral mucositis sites from the lips to soft palate in a time 
consuming manner and one which may be challenging in pediatric use.[18] A more 
recent approach is use of a larger light-emitting diode (LED) through an extra oral 
approach, treating the oral, oropharyngeal, and esophageal mucosa, with improved 
patient corporation. [19] A recent study evaluated the feasibility of extraoral PBM 
by trained nurses for the prevention of oral mucositis in HCT patients.[20] The 
study enrolled 13 HCT patients 4 years and older. The study did not evaluate 
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efficacy but found the treatment delivery to feasible and well tolerated.
The timing of PBM during therapy is inconsistent across studies. An adult study 
began treatment at day 1 of conditioning and continued until day 2 post progenitor 
cell infusion.[7] Three pediatric studies were reviewed for initiation of PBM, with 
two studies beginning PBM at day 1 of conditioning, [6, 20] and the third study 
initiating PBM after the completion of conditioning.[16] Two studies continued 
PBM until engraftment[6, 16] and the third continued until day 20 after cell 
infusion.[20]
HCT Patient Experience at St. Jude
To better understand our patient experience, we conducted a retrospective review of 
the HCT patient experience and reviewed the medical records of 45 patients. [21] 
Patients were divided into two groups based on mucositis severity (mucositis 
defined as ≥ grade 3 on the Common Terminology Criteria of Adverse Events).
Demographic and clinical data were obtained via electronic medical record review 
and compared between groups.
This retrospective study reviewed transplant admissions between June 2015 and 
May 2016.[21] During this period, 75% of the allogenic transplant patients had ≥ 
grade 3 mucositis with median mucositis onset at Day 3 (range -3 to 9) after 
progenitor cell infusion, median mucositis duration of 11 days, median of 9 days 
from (range 3 to 26) mucositis onset to engraftment and a median of 2 days (range - 
21 to 26) from engraftment to the end of mucositis. All of the 25 patients received 
parenteral nutrition and 96% received pain medications for oral pain. Patients with
≥ grade 3 mucositis were more likely than those with grade 1/2 mucositis to have 
positive blood or oral cultures (p=0.018), to have undergone an allogeneic 
transplant [ 17 of 21 patients (p=0.008)] and had significantly longer 
hospitalizations (p=0.002). However, our review did find a subset of patients 
receiving auto transplant, such as neuroblastoma, to be at risk for high grade 
mucositis.
Our retrospective data revealed the onset of mucositis can be as early as Day -3 
with continuation until engraftment. While studies have variability in timing of 
PBM, these findings support our proposed initiation of therapy to begin on the first 
morning of conditioning until engraftment with an ANC ≥500 for two consecutive 
days. Seventy-five percent of the those with grade 3 mucositis had undergone an 
allogenic transplant and 33% autologous. Therefore, patients undergoing 
autologous transplant and at risk for grade 3 mucositis, as identified by the bone 
marrow transplant clinicians will be included in the exploratory objective.
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To determine sample size, we extended our review of allogenic transplant recipients 
from May 2015 to June 2019. Our review identified 93 first allogeneic transplant 
patients, with 66 (71%) developing grade 3 mucositis during transplant.
Play-Based Procedural Preparation
Child life specialists are psychosocial providers who focus on improving coping 
skills and reducing stress among children and families in medical environments. 
These developmental experts implement play-based interventions to promote 
feelings of control, familiarity, understanding, and predictability in otherwise 
stressful and unfamiliar hospital settings. One such intervention is play-based 
preparation, in which child life specialists use age appropriate language and medical 
play to assess children’s and families’ understanding, to teach new concepts, and to 
determine coping plans that are implemented during procedures (Burns-Nader & 
Hernandez-Reif, 2016). This style of preparation incorporates a familiar concept, 
play, with unfamiliar medical concepts and materials to increase predictability, 
understanding, and expectations to assist children and families’ abilities to cope 
with their hospitalization.[22]
Child life interventions are useful for preparing children in developmentally 
appropriate ways, and they also have an impact on parental satisfaction associated 
with medical experiences. When child life specialists provide psychosocial services 
prior to and during children’s procedures, parents are more satisfied with their 
child’s care and find the child to be more cooperative (Sanchez Cristal, et. al., 
2018). Parents also report a strong appreciation for the respect and compassion 
associated with interventions supported by child life specialists.
Preparing children and families for procedures reduces preprocedural anxiety and 
improves postprocedural emotions of children and families. [23] Although several 
studies demonstrate the positive impact of child life preparation on children’s 
responses to invasive procedures such as needle sticks and surgeries less is known 
about the role of play-based preparation for non-invasive procedures. These non- 
invasive procedures, such as routine physical examinations of blood pressure or 
temperature, can also be unfamiliar and scary for children in the hospital. Low-level 
light therapy (LLLT) for mucositis is a non-invasive and unfamiliar intervention for 
children. Using play to prepare children for this procedure may help clarify its 
importance and their role while also creating space to develop a coping plan. The 
following child life aims will explore the impact of a play-based preparation for 
LLLT on parent satisfaction and feasibility of patient participation.
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3.0 RESEARCH PARTICIPANT ELIGIBILITY CRITERIA AND STUDY 
ENROLLMENT
According to institutional and NIH policy, the study will accession research 
participants regardless of gender and ethnic background. Institutional experience 
confirms broad representation in this regard.
3.1 Inclusion Criteria
3.1.1
No age limitation
3.1.2
To be admitted for an allogeneic hematopoietic cell transplant,
3.1.3
All eligible autologous hematopoietic cell transplant, at risk for 
grade 3 mucositis per transplant service secondary to conditioning 
regimen or previous history of grade 3 mucositis
3.1.4
Dental exam prior to admission, as per preadmission criteria
3.1.5
Willingness of research participant to provide assent/consent and 
parent/ legal guardian/representative to give written informed 
consent.
3.2 Exclusion Criteria
3.2.1
Deemed by transplant team as unable to participate
3.2.2
Known sensitivity to light therapy
3.2.3
Inability or unwillingness of research participant or legal 
guardian/representative to give written informed consent.
3.2.4
CAR-Tcell Protocol
3.3 Research Participant Recruitment and Screening
Potential participants undergoing HCT will be identified in the weekly bone 
marrow pre-admission conference. Each participant being admitted for an 
allogenic transplant and meeting inclusion criteria will be offered PBM therapy. 
The bone marrow transplant clinicians may identify autologous recipient at risk 
for grade 3 mucositis per conditioning regimen or history of high-grade mucositis. 
These participants will be included for the exploratory objective. For all patients 
meeting inclusion criteria, an appointment will be made with the participant and 
family during the HCT evaluation period. The potential participant and parents 
will be approached by a member of the study team who will briefly explain the
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study and respond to any patient/family questions. An educational slide show 
presentation delivered by an ipad will describe the PBM process and mechanism 
(see attached). At that time, the patient and parents will be asked if they wish to 
participate in the study. If they agree, the informed consent/assent document will 
be reviewed and signed. This meeting will take place approximately one week to 
day of admission to in-patient Transplant Service. All patients who meet the 
study criteria will be approached for enrollment.
After low level light therapy consent, participants will be offered the opportunity 
to receive a play-based preparation by a certified child life specialist (CCLS).
Those who elect to receive this child life preparation will be scheduled to meet 
with a trained CCLS prior to admission. The play-based preparation will 
incorporate age and developmentally appropriate explanations of the non-invasive 
procedure and will be adapted to each patient’s psychosocial and cognitive 
developmental needs. To standardize the child life preparation, the following 
components will be included in each of the interventions: hands on manipulation 
of the LLLT equipment (ie. Glasses and light tool), demonstration and return 
demonstration of procedure on a medical doll, and discussion and development of 
coping plan for procedure. The play-based preparation intervention will last 
approximately 30 minutes.
3.4 Enrollment on Study at St. Jude
A member of the study team will confirm potential participant eligibility as 
defined in Section 3.1-3.2, complete and sign the ‘Participant Eligibility 
Checklist’. The Study Team will enter the Eligibility Checklist information into 
the Central enrollment system. Eligibility will be reviewed, and a research 
participant-specific consent form and assent document (where applicable) will be 
generated. The signed consent/assent form must be faxed or emailed to the 
Clinical Trials Operations (CTO) 
 or emailed to 
 in order to complete the enrollment. If you 
have a prospective research enrollment and need assistance releasing your consent 
on a weekend or holiday, please call the Milli helpline (
).
3.5 Procedures for Study Staff
Prior to initiating the study, nursing research staff attended a photobiomodulation 
therapy workshop, under the direction of the Thor laser manufacture. All staff have 
been trained and assessed in extraoral PBM application during the workshop. 
Additionally, the protocol has been written in consultation with Dr.
Migliorati, who has been instrumental in the study of PBM for the prevention of 
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mucositis in adults and was co-author of the international mucositis guidelines 
published in Supportive Care in Cancer.[24] Light therapy is commonly administered 
by dental technicians and a small (n=13) feasibility study found that trained staff 
(nursing) were adequate in administration of PBM. [20] Study staff will also be trained 
in consent processes, data transfer, and plans to monitor intervention integrity and data 
quality.
4. DESIGN AND METHODS
4.1 Design and Study Overview
This study will enroll children and adolescents prior to admission for an 
allogeneic HCT, and those undergoing an autologous transplant at deemed at risk 
for grade 3 oral mucositis. Light therapy will be administered by trained persons 
within Nursing Research Division: Belinda Mandrell, Judy Bosi, Susan Ogg and 
Michele Pritchard. The parent may hold the device in place with assistance from 
the trained persons. Patients will receive extra-oral and intra-oral PBM on the first 
day of conditioning, those undergoing an allogeneic HCT will have treatment 
daily until engraftment or +Day 20 (event occurring first). For those undergoing 
an autologous transplant treatment will continue until engraftment or until the 
patient is without mucositis for two consecutive days. If the patient becomes 
acutely ill during therapy and misses 4 consecutive days of PBM, the data will not 
be evaluated. These patients will be replaced to give 66 evaluable patients for the 
primary objective. Patients in isolation will continue to receive PBM with the 
device covered in plastic and cleaned prior to leaving the isolation holding area.
The PBM will be delivered through application of the LED Cluster Probe 
externally to the right external buccal, left external buccal, mid face with mouth 
open and submandibular and left/right cervical. Patients who develop an oral 
lesion, intra-oral directed therapy will be administered with the dental light probe. 
For patients that can tolerate, an intraoral probe will deliver light directly onto the
oral mucosa, this will then replace the mid face application with mouth open. 
Each laser application will be timed at 60 seconds. [8] The PBM treatment will be 
administered via the THOR Model LX2M unit. All participants will receive the 
standard mouth care regimen prescribed for HCT patients. Observation and 
treatment will begin the first day of conditioning and continue daily until 
engraftment (2 consecutive days of ANC ≥ 500) or Day +20 (which comes first) 
and until mucositis resolution for two consecutive days for the autologous 
transplant.
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Feasibility will be assessed similar to Treister et al [20] through the number of 
successful treatments administered by the total number of attempted treatments, 
providing the percentage of successful treatment administered. Daily treatment 
will include 6 sites of PBM application, with application documented as receiving 
all 6 applications, in part treatment (at least one to five sites) or no treatment. A 
successful treatment is defined as the treatment is successfully administered to 4 
or more sites. Reasons for partial or no treatment will be documented. Criteria for 
feasibility is that the percentage of successful treatments administered exceeds 
75%. The collected data will be summarized for total days on protocol, days 
treatment is received, cumulative dose and the number of treatments received at 
each site.
Table
Summary of Photobiomodulation Therapy Delivered
Case
Days 
on
Days 
receive
d
Total 
cumulati
v e 
dose
Treatme
n t site 
=
Treatme
n t site 
= 
midline
Treatme
n t site 
=
Treatme
n t site 
=
Treatme
nt site 
=
Treatme
n t site 
=
numb
e r
protoc
ol
a
treatme
nt
b
(J/cm2)
c
right 
face
face
left face
left neck midline 
neck
righ
t 
nec
k
aDays on protocol defined as from the first day of hematopoietic cell transplantation 
conditioning through engraftment
bDays received treatment defined as days with treatment during any of the on-protocol days
cCummulative dose define as single treatment dose multiplied by the number of treatment sites 
(up to 6 in total) for each treatment session
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Efficacy will be assessed with assessment of grade 3 mucositis development from 
day 1 of conditioning to Day +20 of transplant or engraftment as a binary 
outcome (yes/no)
Daily observation: The observation of oral mucositis will be conducted by non- 
study staff and conducted as clinical care by the nurse, advanced practice provider 
and/or physician.
Assessment: Each patient or parent proxy will complete the Children’s Mucositis 
Assessment via ipad along with documentation of mucositis grade, duration, days 
of nutrition support, use of narcotics, positive oral and blood cultures.
Each patient will be matched and compared to a previously treated patient. The 
comparison will be matched on primary disease, conditioning regimen, age and 
sex, with comparison of treatment variables of mucositis grade, duration, pain 
medications, days of nutritional support, blood and oral cultures, to day +20 or 
engraftment (depending upon which occurs first).
5.0
DRUG/DEVICE/BIOLOGIC AGENT INFORMATION
The PBM treatment will be administered via the Food and Drug Administration 
(FDA) approved THOR Model LX2M unit (THOR Photomedicine Ltd, 
Chesham, UK). The THOR LX2M is a red and near infrared light emitting diode 
(LED) licensed for management and treatment of inflammation and tissue repair. 
The THOR Model LX2M has a 69 Diode LED Cluster Probe (34 X 660nm 
10mW, 35 X 850nm 30mW: 1390mW total power output) at an irradiance of 
50mW/cm 2 . The unit is portable and can be carried to each patient room.
Cleaning will be according to hospital equipment policy.
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Safety
The PBM poses less risk than that associated with the class IV surgical laser used 
in dentistry. While the potential hazards are ocular, the PBM are class 3B lasers 
and emit divergent beams with the ocular risk diminishing with distance.[25] 
Recommendations include avoiding direct aim of the laser into the eye and the 
use of safety spectacles for use with laser therapy. The safety spectacles will be 
prescribed according to age, with the adjustable Ibis Infant eye protection for 
patients less than 1 year of age and the adjustable kids laser safety googles for the 
young child. Patients, staff, and observers must wear laser safety glasses while 
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PBM is in use. Specific contraindications are listed below:
Contraindications to PBM
Eyes
THOR lasers have divergent beams but are potentially harmful if viewed directly 
from a distance of less than 1.1 meters. Patient, practitioner and observers should 
wear THOR laser safety glasses when the laser is in use.
Relative contraindications / precautions
Cancer
Do not use PBM over any known malignant lesions unless:
1. for pain relief during the terminal stages of the illness, but only with their 
physicians permission.
2. For cancer therapy side effects (e.g. oral mucositis, radiation dermatitis, etc.),
Pregnancy
There is no evidence of harm to an unborn baby however there are no safety tests 
either, so for medical legal reasons we recommend not treating directly over the 
developing fetus. It may be used on the pregnant woman for the treatment of back 
pain etc.
Thyroid
There is no evidence of harm and there is some evidence of benefit for treating 
Hashimoto's thyroiditis with PBM. It is conceivable that a high intensity laser 
treatment direct to the thyroid might (temporarily) stimulate (or inhibit) some 
thyroid activity. The THOR LED treatments are however relatively low intensity 
and far less likely to trigger any adverse events when treating that region of the 
neck.
Tattoo
Treatment over a tattoo with higher irradiance laser may cause pain as the dye 
absorbs the laser energy and gets hot. If treatment is painful remove treatment 
probe from contact and treat ~15mm from surface of skin.
Hair on the head
Treatment on the head and neck with high irradiance laser may cause pain as the 
melanin in the fine superficial hair follicle absorbs a lot of the laser energy. If 
treatment is painful remove treatment probe from contact and treat ~15mm from 
surface of skin.
Very dark skin
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Occasionally some people with very dark skin feel an unpleasant amount of 
heating. If treatment is painful remove treatment probe from contact and treat
~15mm from surface of skin.
Cleaning of Laser Between Patients
All laser heads will be covered with clear disposable dental sleeves that are 
approved for use with the LLLT and in dentistry. At treatment completion the 
sleeves will be discarded and all laser heads, laser box and all cords will be 
cleaned with disinfectant wipes (Sani-Cloth) and allowed to air dry in between 
each patient, per discussion with infectious disease.
6.0 REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS
6.1Pre-Study Evaluations
Each participant will have a pre-transplant dental assessment to assess for caries, 
periodontal disease and mouth ulcerations, as well as pre-transplant oral and nasal 
cultures as per protocol.
6.2 Response Evaluations During Therapy
Parent Satisfaction
After the initial LLLT treatment, a parent-reported satisfaction survey will be 
administered via paper questionnaire. Parent satisfaction will be reported by 
parents on a 5-point Likert scale to questions adapted from a parent satisfaction 
survey used in a study regarding child life services in pediatric imaging [26] 
Parents will be asked to rate their level of satisfaction on 10 items, with 1 = 
Strongly Disagree to 5 = Strongly Agree. An additional marker of “not applicable 
(N/A)” will be available as a response option for parents who respond to the 
survey and did not receive a child life play-based preparation. Higher scores 
indicate higher satisfaction.
Parent Satisfaction Survey Items
1. The procedure was explained using language my child could understand.
2. My child’s emotional needs were met.
3. Staff showed concern for my child’s comfort.
4. I knew what to do to help my child.
5. Staff showed concern for my questions and worries.
6. Staff respected my knowledge of my child.
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7. I am satisfied with the care provided to my child.
8. The child life intervention was helpful for my child’s understanding in the 
procedure.
9. Staff were friendly and helpful.
10. Staff worked together well to care for my child.
Pain and Oral Function Assessment
After the 6-minute laser/ treatment session the child or parent proxy will complete 
the mucositis evaluation scale which includes self-report oral function specific to 
ability to swallow, eat and drink, as well as the patient’s self-reported need for 
medication specific to mouth pain. The evaluation of mucositis can be completed 
in less than 5 minutes and is a validated inventory, Children’s International 
Mucositis Evaluation Scale which has been used for mucositis in pediatric HCT.
[27] The scale has test-retest reliability with r>0.8 for all respondent types. See 
attached. The scale is available in English, Spanish and Portuguese.
The study staff will maintain a treatment log for each participant. Data collected 
will include: days on PBM protocol, days treatment received, total cumulative 
dose defined as single treatment dose multiplied by the number of treatment sites 
(up to 6 in total) for each treatment session.
Mucositis will be graded according to the Common Toxicity Criteria for Adverse 
Events version 5: Grade I patient is asymptomatic or with mild symptoms, no 
intervention, Grade II patient has moderate pain, no interference with oral intake 
and a modified diet, Grade III patient has severe pain, interfering with oral intake, 
Grade IV life-threatening, Grade V death.
In addition to the study staff assessment, the clinical assessment of mucositis and 
pain from the daily APN and physician physical assessment will be collected.
Chart Abstraction
The patient’s age, sex, primary diagnosis, transplant type, conditioning regimen, 
radiation dose, time to engraftment, days of nutritional support, utilization of pain 
medication, and results of positive oral, nasal and blood cultures during 
transplant.
6.3Off-Study Evaluations
1. Patients are off-study on last day (Day +20 or engraftment or absence of mucositis) 
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of PBM administration except for patients undergoing autologous tandem
transplant will discontinue treatment with mucositis resolution and then resume 
light therapy with second transplant. Thus, these patients will remain on study until 
resolution of mucositis after second transplant. Therefore, will not reconsent with 
the second transplant, parents and patient may refuse if desired
7. CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND 
OFF-STUDY CRITERIA
7.1Off-study criteria
7.1.1 Death
7.1.2 Request of the Patient/Parent
7.1.3 Discretion of the Study PI, such as the following

The researcher decides that continuing in the study would be harmful

A treatment is needed that is not allowed on this study

The participant misses > 3 consecutive days of PBM the data cannot 
be used in the study

The participant’s condition gets worse

New information is learned that a better treatment is available, or that 
the study is not in the participant’s best interest

Study evaluations are complete
8.
SAFETY AND ADVERSE EVENT REPORTING 
REQUIREMENTS
8.1. Adverse Events (AEs)
Adverse events will be monitored from the time of first study intervention, Day 1 
of conditioning until Day +20 or engraftment. Participants will be instructed to 
report all AEs during the study and will be assessed for the occurrence of AEs 
throughout the study.
8.2. Definitions
Adverse Event (AE): Any untoward medical occurrence associated in a study 
participant after the first intervention on study. Adverse Events grade 1-4 will be 
graded by the NCI CTC AE version 5.0.
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Serious Adverse Event (SAE): Any adverse event temporally associated with the 
subject’s participation in research that meets any of the following criteria:
* results in death; * is life-threatening (places the subject at immediate risk of 
death from the event as it occurred); * requires inpatient hospitalization or 
prolongation of existing hospitalization; * results in a persistent or significant 
disability/incapacity; * results in a congenital anomaly/birth defect; or * any other 
adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of 
the other outcomes listed in this definition.
8.3. Handling of Adverse Events (AEs) and Deaths
Recording of Adverse Events and Serious Adverse Events: Skin will be 
assessed and recorded daily for erythema or breakdown prior to light application.
Reporting Adverse Events and Serious Adverse Events: The St. Jude PI, upon 
awareness of an event, will determine the seriousness of AEs and ensure that all 
UPs are entered into the electronic submission system (iRIS) within 10 days. All 
(pertinent, as in recording above) AEs, serious or not, will be recorded in a log, 
spreadsheet, or report and submitted to the St. Jude IRB at the time of continuing 
review.
Reporting of Unanticipated Problems (UPs): The St. Jude PI will refer to St. Jude 
Human Research Protection Program (HRPP) Policy 01.720 for specifics on the 
reporting of unanticipated problems to the St. Jude IRB. The St. Jude IRB reports 
UPs to BIMO as per 21 CFR 56. The UP link
follows:
Deaths meeting reporting requirements are to be reported immediately to the St. 
Jude IRB, but in no event later than 48 hours after the investigator first learns of 
the death.
9.
DATA COLLECTION, STUDY MONITORING, AND 
CONFIDENTIALITY
9.1 Data Collection and Confidentiality
All data will be kept confidential and will be maintained in a secure, password 
protected database accessible only by study personnel. Study numbers will be 
assigned to each patient so that the patient’s medical record number will not be 
used as the identifying number. All data will be kept confidential and stored in 
locked files inside locked offices. The site PI, study team, and staff of the 
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CPDMO at SJCRH will have access to the original data forms. Participants may
decline without any negative repercussions whatsoever. Those refusals will be 
documented in the research record and examined for any possible patterns in 
patient/parent demographic variables.
.
9.2 Study Monitoring
This study is considered low risk for monitoring purposes. The Principal 
Investigator (PI) and study team are responsible for ensuring participant eligibility 
and protocol compliance. The study team will hold meetings as needed to review 
case histories or quality summaries on participants and will generate minutes 
which are signed by the PI.
A quality review for form completeness will be performed on the informed 
consent forms of 100% of St. Jude participants by Clinical Trials Operations 
(CTO) personnel.
CTO will review up to 10% of the study participants annually for life status, 
status on study, and the appropriateness of the informed consent and eligibility 
processes. The monitor will annually verify regulatory documentation pertinent to 
the study, all Serious Adverse Event reports, and Age of Majority consenting on 
all study participants. The plan for monitoring may be revised over time, to adapt 
monitoring frequency and/ or intensity to a changing environment when 
appropriate (for example: new safety signals; positive history of compliance; all 
participants are in long term follow-up; or the enrollment period has ended). The 
Monitor will generate a formal report which is shared with the Principal 
Investigator, study team, and the Internal Monitoring Committee (IMC).
Protocol continuing reviews by the Institutional Review Board (IRB) and 
Scientific Review Committee (CT-SRC) will occur at least annually. In addition, 
Unanticipated Problems and/or Serious Adverse Event reports are reviewed by the 
IRB.
10.
STATISTICAL CONSIDERATIONS
10.1 Sample Size
A review from June 2015 to May 2019, identified 93 first allogeneic transplant 
patients with similar conditions, and 66 (71%) of them developed grade 3 or 
above oral mucositis. With an estimated clinically meaningful effect size of 20% 
for PBM, the estimated percentage of patients who will receive PBM and develop 
grade 3 oral mucositis is 51%.
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We will use the two-stage one-arm design with historical controls to monitor both 
efficacy and futility. The complete historical control sample will be used in both 
the interim analysis and final analysis. The test statistic in Chang et al [28] treats 
the historical control sample as if they are the control arm in a two-arm design.
Given the relatively small sample size, we did not use the asymptotic distribution 
of the test statistic. Instead, we used Monte Carlo methods to estimate the 
sampling distribution of the test statistic under null and alternative hypotheses by 
100,000 Monte Carlo data sets. The simulation program is written in R.
The rules of which accommodate both efficacy and futility. The null hypothesis is 
p0=0.71; the alternative hypothesis is p1=0.51; The type-I error rate = 0.05 and 
power 0.8 are used.. The detailed information about the two-stage design is 
shown in the following table. The attained type-I error rate and power are 0.048 
and 0.813, respectively.
Boundary Crossing 
Probability
(Incremental)
Boundari
es
Under H0
Under H1
Efficac
y
Futilit
y
Loo
k 
#
n
Efficac
y
Futilit
y
Efficac
y
Futilit
y
1
40
20
29
0.015
0.508
0.526
0.015
2
66
38
39
0.033
0.444
0.288
0.172
Tota
l
0.048
0.952
0.813
0.187
The expected sample size under null and alternative hypotheses is 56 and 51, 
respectively. In the historical data between July 2015 and May 2016, 24 patients 
received allogeneic HCT. We estimate that study accrual of 66 transplant 
patients will be completed in 31 months after study activation.
10.2 Statistical Analyses
10.2.1 Statistical analysis for the primary objective
To evaluate the feasibility and efficacy of photobiomodulation therapy (PBM) in 
reducing oral mucositis in children and adolescents at risk for grade 3 oral 
mucositis undergoing an allogeneic hematopoietic cell transplant (HCT).
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Hypothesis 1: Children and adolescents will receive 75% of the attempted PMB 
treatment and will be less likely to develop grade 3 oral mucositis from the 1st 
day of conditioning to day +20 of transplant or engraftment.
Descriptive statistics (counts, percentages, mean, median, standard deviation and 
interquartile range) and confidence interval will be calculated for the percentage 
of successful treatment administered, total days on the protocol, days treatment is 
received, cumulative dose and the number of treatments received at each site.
The count, percentage and confidence interval will be calculated for allogeneic 
HCT patients who receive PBM and develop Grade 3 mucositis. Whether the 
percentage of the prospective sample is significantly different from the historical 
rate is accessed by the monitoring rule in Section 10.1.
10.2.2 Statistical analysis for the secondary objective
To compare clinical manifestations associated with the development of oral 
mucositis between those treated with daily PBM and a matched control. Clinical 
factors to include: mucositis grade, duration, and days to engraftment.
Hypothesis 2: Children and adolescents treated with extra-oral PBM will develop 
lower grade mucositis, with shorter mucositis duration (days) than the 
comparison matched control.
Patients enrolled in the PBM study will be matched to a transplant control that 
did not receive PBM by age, sex, primary disease and transplant regimen. For a 
patient receiving PBM, the patients with the same sex, primary disease and 
transplant regime will be used as the candidate pool. The patient in the pool with 
the smallest difference of age is selected as matching. If there is more than one 
patient in the pool that satisfies the smallest difference of age, a reproducible 
random number generator will be used to randomly select one patient out of the 
multiple candidates.
The patient identifier, age, sex, primary disease and transplant regime for the 
patients without PBM in the historical data will be sent to the Biostatisticians 
without the outcome of development of grade 3 mucositis. The patient identifier 
for the selected patients in the historical data will be determined. Then other 
information for these patients will be obtained for analysis.
The two groups will be compared from day 1 of conditioning regimen until 
engraftment (2 consecutive days of an ANC>500) or Day+20.
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The PBM group and the historical group without PBM will be compared on 
mucositis grade, duration of mucositis (number of days) and days from cell 
infusion to engraftment. We will compute the descriptive statistics (mean, 
standard deviation, median, and range) of the duration of mucositis and days to 
engraftment. We will also compute the descriptive statistics (count and 
percentage) of mucositis grade. To compare the clinical variables between the 
PBB and matched control groups, we will use generalized linear model with the 
variables for matching as covariates. The difference will be assessed by two-sided 
Wald tests with type I error rate < 0.05. For the duration of mucositis, the subset 
of patients who developed Grade 3 mucositis will be compared with their match 
control patients with similar methods described above.
10.2.3 Statistical analysis for the exploratory objective
To evaluate efficacy of photobimodulation therapy in autologous patients at 
risk for ≥ grade 3 oral mucositis compared to matched control.
The count, percentage of developing Grade 3 mucositis and its confidence interval 
will be calculated for autologous HCT patients who receive PBM. In the historical 
data between July 2015 and May 2016, 8 neuroblastoma patients who received 
autologous HCT were at risk for grade 3 mucositis. It is expected that – 22 
autologous HCT patients will be treated with PBM. Fisher’s exact test or two- 
sided Wilcoxon rank-sum test with type I error rate < 0.05 is used to compare 
these patients with the patients in the historical data. The matching is based on 
age, sex, primary disease, and conditioning regimen.
To evaluate utilization of play-based procedural preparation and treatment 
feasibility and parental satisfaction.
Descriptive statistics (counts, percentages, mean, median, standard deviation and 
interquartile range) and confidence interval will be calculated for the percentage 
of successful treatment administered, total days on the protocol, days treatment is 
received, cumulative dose and the number of treatments received at each site 
between those who had procedural based preparation and those that did not.
Descriptive statistics (counts, percentages, mean, median,) will describe parental 
satisfaction.
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10.4 Anticipated Completion Dates
Anticipated Primary Completion Date : 35 months after activation
Anticipated Study Analysis Completion Date: 1 year after completion
Anticipated date of reporting: 2 years after completion
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11.
OBTAINING INFORMED CONSENT
The process of informed consent will follow institutional policy. Informed 
consent should be obtained by the principal investigator, Belinda Mandrell, PhD, 
RN, Susan Ogg MSN, RN, Judy Bosi, CRA or Mary Caples CRA, in the presence 
of at least one non-physician witness. Eligible parents will first be approached by 
a member of the study team regarding the study purpose, methods and design 
details. Only with parental permission will the eligible patients be approached 
regarding participating in the study. Both verbal and written assent and consent 
procedures will be completed in a private room and following our institutional 
guidelines. The consent/assent process will be documented in the medical record 
per institutional guidelines. Patients and parents may decline participation 
without any negative repercussions whatsoever. Refusals will be documented in 
the research records and examined for any possible patterns. All patients who 
meet eligibility criteria regardless of gender or minority status are fully eligible to 
participate in this study.  Any adverse effects experienced by participating 
patients during their enrollment on this protocol will be reported to the IRB at 
both sites within 48 hours. At the time of consent, documentation will be made in 
the medical record specific to patient and parental information regarding COVID-
19 risk and distribution of COVID information sheet.
11.1 Consent at Age of Majority
The age of majority in the state of Tennessee is 18 years old. Research 
participants will be reconsented should they become 18 during the study period. 
must be consented at the next clinic visit after their 18th birthday.
11.2 Consent When English is Not the Primary Language
When English is not the patient, parent, or legally authorized representative’s 
primary language, the Social Work department will determine the need for an 
interpreter. This information documented in the participant’s medical record. 
Either a certified interpreter or the telephone interpreter’s service will be used to 
translate the consent information. The process for obtaining an interpreter and for 
the appropriate use of an interpreter is outlined on the Interpreter Services, OHSP, 
and CPDMO websites.
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12. REFERENCES
1.
Bellm, L.A., et al., Patient reports of complications of bone marrow transplantation.
Support Care Cancer, 2000. 8(1): p. 33-9.
2.
Rubenstein, E.B., et al., Clinical practice guidelines for the prevention and treatment of 
cancer therapy-induced oral and gastrointestinal mucositis. Cancer, 2004. 100(9 Suppl): 
p. 2026-46.
3.
Sonis, S., Elting, LS., Keefe, D., et al., Perspectives on cancer therapy-induced mucosal 
injury: pathogenesis, measurement, epidemiology, and consequences for patients. 
Cancer, 2004. 100(9 Suppl)): p. 1995-2025.
4.
Sandmaier, B.M., S. Mackinnon, and R.W. Childs, Reduced intensity conditioning for 
allogeneic hematopoietic cell transplantation: current perspectives. Biol Blood Marrow 
Transplant, 2007. 13(1 Suppl 1): p. 87-97.
5.
Sonis, S., Oster, G., Fuchs, H., et al., Oral mucositis and the clinical and economic 
outcomes of hematooietic stem-cell transplantation. Journal of Clinical Oncology, 2001. 
19(8): p. 2201-2205.
6.
Soto M; Lalla, R., Gouveia, R.V., et al., Pilot study on the efficacy of combined intraoral 
and extraoral low-level laster thearpy for prevention of oral mucositis in pediatric 
patients undergoing hematopoietic stem cell transplantation. Photomedicine and Laser 
Surgery, 2015. 33(11): p. 540-546.
7.
Schubert, M., Eduardo, F., Guthrie, K., et al., A phase III randomized double-blind 
placebo-controlled clinical trial to determine the efficacy of low laser therapy for the 
prevention of oral mucositis in patients undergoing hematopoietic cell transplantation. 
Support Care Cancer, 2007. 10: p. 1145-54.
8.
Prindeze, N.J., L.T. Moffatt, and J.W. Shupp, Mechanisms of action for light therapy: a 
review of molecular interactions. Exp Biol Med (Maywood), 2012. 237(11): p. 1241-8.
9.
Schubert, M.M., et al., A phase III randomized double-blind placebo-controlled clinical 
trial to determine the efficacy of low level laser therapy for the prevention of oral 
mucositis in patients undergoing hematopoietic cell transplantation. Support Care 
Cancer, 2007. 15(10): p. 1145-54.
10.
Antunes, H.S., et al., Low-power laser in the prevention of induced oral mucositis in bone 
marrow transplantation patients: a randomized trial. Blood, 2007. 109(5): p. 2250-5.
11.
Silva, G.B., et al., The prevention of induced oral mucositis with low-level laser therapy 
in bone marrow transplantation patients: a randomized clinical trial. Photomed Laser 
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St. Jude Children's Research Hospital
IRB NUMBER: 19-0225
IRB APPROVAL DATE: 01/28/2021