Utilization of Photobiomodulation for the Prevention and Treatment of Oral Mucositis

Abstract

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). Photobiomodulation (PBM) has been found to be feasible with significant efficacy in preventing the progression of oral mucositis in adult patients undergoing HCT. The purpose of this study was to determine the feasibility and efficacy of PBM in pediatric oncology patients undergoing HCT. Method: Forty children and adolescents admitted to the transplant unit for an allogeneic HCT for acute lymphoblastic leukemia or acute myeloid leukemia were treated daily at six sites until day + 20 or engraftment. Results: There were 1,035 patient encounters, with successful treatment of four or more sites during 979 patient encounters for a feasibility 93.3% CI [0.926, 0.039]. We had estimated a meaningful effect size of 20% for PBM and estimated 51% of patients treated with PBM would have at least one day or more of Grade 3 mucositis. The rate of patients who received PBM and developed Grade 3 mucositis was 20% CI [0.091, 0.356]. Patients treated with PBM had fewer days of hospitalization (p = .009) and less severe mucositis in comparison to the matched control group (p = .03). Conclusion: PBM is feasible and effective in preventing and treating oral mucositis and is now supported by the Children's Oncology Group for prevention and treatment of oral mucositis in patients undergoing an allogeneic HCT or receiving head/neck radiation.

Introduction

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 HCT (Bellm et al., 2000). The incidence of HCT 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 (Rubenstein et al., 2004; Sonis et al., 2004). Oral mucositis is a progressive process that begins shortly after the administration of high-dose chemotherapy, with DNA strand breaks resulting in direct cellular injury of the basal epithelium and submucosa (Rubenstein et al., 2004). Additionally, mucositis represents local tissue reactions including damage from reactive oxygen species (ROS), inflammatory cytokines, and damage to submucosal connective tissues and vasculature. Stages of oral mucositis include mucosal burning, erythema, and edema with progression to ulceration. Ulceration occurs most commonly on the nonkeratinized mucosa of the mouth floor, tongue, buccal mucosa, and soft palate (Sonis et al., 2004). Oral mucositis is most noted several days after completion of chemotherapy with a peak in severity between 6 and 12 days posttransplant (Sandmaier et al., 2007).

Oral ulcerations are painful, may become infected, bleed, and impact nutritional intake. Together these factors increase the need for parenteral nutrition, and 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. During HCT, a one-point increase in peak mucositis grade has been associated with a 2.1-fold increase in the 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 the risk of mortality within the first 100 days (Sonis et al., 2001). A recent systematic review describes cost attributable to mucositis in the HCT setting to range up to $299, 214 including days of hospitalization (Rodrigues-Oliveira et al., 2021).

For adults, oral mucositis prevention guidelines support the use of basic oral care, anti-inflammatory agents (mouthwashes), cryotherapy, intravenous growth factors (KGF-1), glutamine, and honey (Elad et al., 2020). In 2014, The Multinational Association of Supportive Care in Cancer and International Society for Oral Oncology (MASCC/ISOO) mucositis guidelines recommended photobiomodulation (PBM) for prevention of mucositis for patients undergoing HCT, after numerous studies reported benefits of PBM (Lalla et al., 2014). The 2020 recommendation by the MASCC/ISOO upgraded the suggestion of PBM to a recommendation for adults with head and neck cancers receiving radiation with and without chemotherapy (Elad et al., 2020).

In a 2017 pediatric oral mucositis guideline review, a weak recommendation was given for the implementation of PBM therapy in pediatrics due to the need for specialized equipment, training, and an unknown feasibility in the ability to deliver the therapy in clinical care (Sung et al., 2017). This guideline did however recognize the benefit of PBM therapy in pediatrics. Until recently, there have been few guidelines that recommend implementation of PBM in the pediatric setting. In 2021, the pediatric oral mucositis guideline review made an endorsement with a strong recommendation for implementation of PBM in pediatric patients with cancer and those undergoing an HCT (Patel et al., 2021). This clinical practice guideline, developed by the Pediatric Oncology Group of Ontario, was endorsed by the Children's Oncology Group (COG) Supportive Care Guideline Committee in December 2021 (https://childrensoncologygroup.org/cog-supportive-care-endorsed-guidelines).

Mechanism of PBM

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 absorption of energy by intracellular organelles and molecules; however, the amount and specifics of energy absorption are dependent upon wavelength and rate of energy delivery (Schubert et al., 2007). 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. This process inhibits mitochondrial respiration and significantly increases production of ROS or 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 light-emitting diodes [LEDs]), 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 (Dompe et al., 2020).

Barriers to PBM Implementation

While PBM has been recognized as an intervention for the prevention and treatment of oral mucositis, few cancer centers have implemented the practice. The lack of implementation is secondary to barriers of cost associated with the purchase of equipment, training, and infrastructure to sustain an ongoing program. Another barrier is the inconsistency in treatment protocols, specifically when to start PBM and when it is safe to discontinue. An adult study began treatment on day 1 of conditioning and continued until day 2 post progenitor cell infusion (Schubert et al., 2007). Three pediatric studies were reviewed for initiation of PBM, with two studies beginning PBM on day 1 of conditioning (Soto et al., 2015; Treister et al., 2016) and the third study initiating PBM after the completion of conditioning (Eduardo et al., 2015). Two studies continued PBM until engraftment (Eduardo et al., 2015; Soto et al., 2015) and the third continued until day +20 after cell infusion (Treister et al., 2016). To implement a sustainable PBM program for the prevention and treatment of oral mucositis, barriers must be addressed including the treatment protocol (initiation of PBM and day of completion), training, and measurement of feasibility and efficacy.

The aim of this study was to determine the feasibility and efficacy of PBM in the prevention and treatment of Grade 3 oral mucositis in patients undergoing HCT. The secondary aim was to compare clinical manifestations (grade and duration of oral mucositis) associated with the development of oral mucositis between those treated with daily PBM and a matched control.

Method

From February 2020 to May 2021, children and adolescents admitted to the transplant unit for an allogeneic HCT for acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) were eligible for enrollment in the study. The study was conducted in a free-standing pediatric oncology academic setting. Due to COVID-19 restrictions, the study was closed to accrual for seven months. Eligible patients not treated due to study hold were matched as comparative controls. The study was approved by the institutional review board. Consent was obtained from all patients aged 18 years and older or parents of patients <18 years. Assent was obtained from children according to institutional policy. Demographic, disease-related, and clinical variables were collected on patients treated with PBM and controls and included age, sex, race, diagnosis, and conditioning regimen.

Participants received PBM therapy daily, beginning on the 1st day of conditioning and continuing until engraftment (ANC ≥ 500 for two consecutive days) or day +20. PBM was delivered via the THOR Model LX2 M™ unit (THOR Photomedicine Ltd, Chesham, UK) and delivered through the application of the LED Cluster Probe externally to the right and left buccal cheek, submandibular, left/right cervical region. An intraoral application was administered with the lollipop probe. Each light application was timed for 60 s. Therapy was delivered by study staff who attended an in-person training and practice session with THOR staff.

Mucositis was graded daily according to the Common Toxicity Criteria for Adverse Events (CTACE) 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. This instrument was utilized for the study, as this was the instrument used for mucositis documentation among the comparison controls. The grade of mucositis for those treated with PBM agreed with the CTACE database rating for mucositis, assuring reliability between patients treated with PBM and controls. All participants received the standard mouth care regimen prescribed for HCT patients, consisting of soft brushing and alkaline saline swish and spit three times a day. Participants were excluded if they became acutely ill or missed more than four consecutive days of treatment.

Feasibility was assessed according to the number of successful treatments administered divided by the total number of attempted treatments, providing the percentage of successful treatments administered (Treister et al., 2016). Daily treatment included the described six sites of PBM application, with application documented as receiving all six applications, partial treatment (at least one to five sites), or no treatment. A successful treatment was defined a priori as PBM successfully administered to four or more sites. The collected data was summarized for total days on protocol, days treatment was received, and the number of treatments received at each site. Criteria for feasibility were set at 75% of successful treatments.

A retrospective review from June 2015 to May 2019 identified 93 allogeneic transplant patients with similar conditions, and 66 (71%) of them developed Grade 3 oral mucositis (Donohoe et al., 2018). With an estimated clinically meaningful effect size (the magnitude of the PBM therapy reducing Grade 3 mucositis) of 20% for PBM, the estimated percentage of patients who would receive PBM and develop Grade 3 oral mucositis was set at 51%. The test statistic of Chang et al. (1999) was used to establish the effect size, and the magnitude of PBM therapy reducing Grade 3 mucositis.

Statistical Analysis

Descriptive statistics (counts, percentages, mean, median, standard deviation, and interquartile range) and confidence interval were calculated for the percentage of successful treatment administered, total days on the protocol, days treatment was received, cumulative dose, and the number of treatments received at each site.

The count, percentage, and confidence interval were calculated for allogeneic HCT patients who received PBM and developed Grade 3 mucositis. Whether the percentage was significantly different from the historical rate was accessed by the monitoring rule. The null hypothesis was p ₀= .71; the alternative hypothesis was p ₁= .51; the type-I err or rate = .05 and power .8 was used. The attained type-I error rate and power were .048 and .813, respectively. An interim analysis was conducted after 40 evaluable patients received PBM.

Descriptive statistics compared the demographic characteristics between the PBM group and the control without PBM. A paired t test was used to determine differences in duration of mucositis (number of days) of Grades 1 and 2 mucositis between groups, and two sample t tests to determine differences in duration of mucositis for Grade 3. Weighted averages were also computed for each grade of mucositis, this average considers the varying degrees of importance of the number of days in each grade. Within each grade, patients were ranked against each other by the days of mucositis duration. Each patient is then given three rankings for each grade of mucositis, with a weighted average of each ranking. Wilcoxon rank sum compared the rankings between the PBM treated and control without PBM. Wilcoxon signed-rank test for paired data compared the median number of hospital days between the PBM-treated and controls without PBM.

Results

All potentially eligible patients were enrolled with no patient/parent refusals. For the primary aim, an interim analysis was conducted after the enrollment of 40 eligible patients, mean 10.9 years of age [range 4 months–22 years], 52.5% male, and 67.5% primary diagnosis of AML. There were 1,035 patient encounters, with successful treatment of four or more sites during 979 patient encounters for a feasibility of 93.3% CI [0.926, 0.039]. We had estimated a meaningful effect size of 20% for PBM and estimated 51% of patients treated with PBM would have at least one day or more of Grade 3 oral mucositis. The rate of patients who received PBM and developed Grade 3 mucositis was 20% CI [0.091, 0.356]. Eight patients developed Grade 3 mucositis for an average of 2.4 days [range 1–5 days]. The study met the criteria for feasibility and efficacy and was close to accrual.

Patients treated with PBM were compared to untreated controls and found to have no differences in age, sex, or primary diagnosis (Table 1). There was no difference in patient race or conditioning regimens between those treated with PBM and untreated controls. There was a significant difference in duration of Grades 1 to 2 mucositis between the PBM treated (M 5.5 ± 4.1 days) as compared to the control group (8.8 ± 6.9 days; p = .002). Grade 3 mucositis duration was shorter in the PBM treated (M 0.48 ± 1.15 days), but was not statistically significant when compared to the controls (M 1.15 ± 2.2 days; p = .09; Table 2). The PBM treated, and control groups were compared for total days of hospitalization, with the PBM treated group mean of 32.4 (6.4 SD) days of hospitalization compared to the control group mean of 40.2 (15.7 SD) days of hospitalization (p = .009).

Table 1.

Demographics of PBM Treated and Controls (N = 80)

	PBM treated (n = 40)		Controls (n = 40)		p
	M	SD	M	SD
Age	10.9	5.8	9.9	5.3	.424
	n	%	n	%
Sex
Female	19	47.5	18	45.0	1.000
Male	21	52.5	22	55.0
Primary disease
ALL	13	32.5	17	42.5	.352
AML	27	67.5	23	57.5

Note. PBM = photobiomodulation; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia.

Table 2.

Duration of Grade 1/2 and Grade 3 Mucositis

Duration	PBM treated (n = 40)				Control (n = 40)
	M	SD	Median	Range	M	SD	Median	Range	p
Grade 1/2	5.58	4.13	6.00	0−13	8.88	6.92	7.00	0–29	.002
Grade 3	2.40	1.50	2.00	1–5	3.80	2.40	4.00	1–8	.141

Note. PBM = photobiomodulation.

The weighted average of those treated with PBM was ranked and compared to the ranking of controls. When compared to patients treated with PBM, controls had significantly more severe mucositis than the patients treated with PBM (p = .03; Figure 1).

Figure 1.

Weighted average severity of mucositis in control compared to photobiomodulation (PBM) treated.

Discussion

We found the use of PBM to be feasible and effective in preventing and treating oral mucositis in patients undergoing HCT. Furthermore, since the initiation of our study, COG has included PBM in the treatment guides for mucositis in patients undergoing HCT and those receiving head and neck radiation (https://childrensoncologygroup.org/cog-supportive-care-endorsed-guidelines).

Our study has limitations, as the primary study aim was to detect the difference in the rate of Grade 3 mucositis compared to previously published data. However, the study was not powered for a difference in the duration of Grade 3 mucositis between those treated with PBM and untreated controls. Barriers to the delivery of PBM therapy have been described as cost for specialized equipment and an infrastructure for program sup port (Schubert et al., 2007; Sung et al., 2017). Thus, limiting the implementation of PBM as a patient service.

Clinical Implications

It is important that services for the delivery of PBM be implemented as clinical care for patients at risk for mucositis, and nurses can play an integral role in the delivery of this supportive care. To assure the PBM therapy is delivered according to our standard operating procedure, a PBM therapy service is now in place. For a referral to the light service team, a PBM therapy order has been built into EPIC, and the treatment is documented daily. The treatment protocol is an approved nursing policy, along with the standard operating procedure. This model of service will assure sustainability, which has been a major barrier to implementation. The service is comprised of a nurse who delivers the therapy (Monday–Friday), with therapy initiated on day one of conditioning until engraftment for all patients undergoing HCT, gene therapy for sickle cell, and autologous transplant for neuroblastoma. Patients with head/neck tumors are treated daily prior to radiation and are then treated on day one through count recovery during subsequent chemotherapy courses. Solid tumors, specifically Ewing's sarcoma, rhabdomyosarcoma, and osteosarcoma are treated as described for prevention of mucositis. The integration of PBM therapy into standard of care has been strongly supported by nursing and institutional administration. The PBM therapy program received the 2022 Clinical Practice Improvement.

Conclusion

PBM is effective in the prevention and treatment of oral mucositis. However, barriers at the institutional level must be addressed. These include the institutional investment in purchase of the PBM unit and application probes, as well as daily supplies. If feasible, designated staff should be assigned to administration of PBM, thus assuring consistency in practice and care of the PBM units. Future research should explore potential changes in the patient's oral microbiome during treatment with PBM and potential reduction in central line infections.