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Photobiomodulation and photodynamic therapy for the treatment of oral

mucositis in patients with cancer

Erika Cristina Pires Marques, Felipe Piccolo Lopes, Ingrid Camargo

Nascimento, Juliana Morelli, Milena Valini Pereira, Vitória Moron
Machado Meiken, Sérgio Luiz Pinheiro

PII: S1572-1000(19)30566-6
DOI: [Link]
Reference: PDPDT 101621

To appear in: Photodiagnosis and Photodynamic Therapy

Received Date: 3 September 2019

Revised Date: 18 November 2019
Accepted Date: 5 December 2019

Please cite this article as: Pires Marques EC, Piccolo Lopes F, Nascimento IC, Morelli J,
Pereira MV, Machado Meiken VM, Pinheiro SL, Photobiomodulation and photodynamic
therapy for the treatment of oral mucositis in patients with cancer, Photodiagnosis and
Photodynamic Therapy (2019), doi: [Link]

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© 2019 Published by Elsevier.

Photobiomodulation and photodynamic therapy for the treatment of

oral mucositis in patients with cancer

Short title: Photobiomodulation for oral mucositis

Erika Cristina Pires Marques,a Felipe Piccolo Lopes,b Ingrid Camargo Nascimento,c

Juliana Morelli,d Milena Valini Pereira,e Vitória Moron Machado Meiken,f Sérgio Luiz

Pinheirog

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a
Department of Restorative Dentistry, Pontifical Catholic University of Campinas

(PUC-Campinas), Campus II, Av. John Boyd Dunlop, s/n, Jardim Ipaussurama, 13034-
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685, Campinas, SP, Brazil. Tel.: +55-19-98271-7626. E-mail:
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erikacristinapires@[Link]
b
Department of Restorative Dentistry, Pontifical Catholic University of Campinas
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(PUC-Campinas), Campus II, Av. John Boyd Dunlop, s/n, Jardim Ipaussurama, 13034-

685, Campinas, SP, Brazil. Tel.: +55-19-99372-5306. E-mail:

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felipepiccolo@[Link]
c
Department of Restorative Dentistry, Pontifical Catholic University of Campinas
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(PUC-Campinas), Campus II, Av. John Boyd Dunlop, s/n, Jardim Ipaussurama, 13034-

685, Campinas, SP, Brazil. Tel.: +55-11-95432-7407. E-mail:

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ingridcamargo.13@[Link]
d
Department of Restorative Dentistry, Pontifical Catholic University of Campinas

(PUC-Campinas), Campus II, Av. John Boyd Dunlop, s/n, Jardim Ipaussurama, 13034-

685, Campinas, SP, Brazil. Tel.: +55-19-99501-7027. E-mail: juh_1995@[Link]

e
Department of Restorative Dentistry, Pontifical Catholic University of Campinas

(PUC-Campinas), Campus II, Av. John Boyd Dunlop, s/n, Jardim Ipaussurama, 13034-

685, Campinas, SP, Brazil. Tel.: +55-19-99120-3933. E-mail:

milena_valini@[Link]
f
Department of Restorative Dentistry, Pontifical Catholic University of Campinas

(PUC-Campinas), Campus II, Av. John Boyd Dunlop, s/n, Jardim Ipaussurama, 13034-

685, Campinas, SP, Brazil. Tel.: +55-19-99359-2017. E-mail:

vm_meiken@[Link]

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g
Pontifical Catholic University of Campinas (PUC-Campinas), Center for Health

Sciences, Postgraduate Program in Health Sciences, Campus II, Av. John Boyd Dunlop,

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s/n, Jardim Ipaussurama, 13034-685, Campinas, SP, Brazil. Tel.: +55-19-99140-5277.

E-mail: slpinho@[Link]
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Corresponding author: Sérgio Luiz Pinheiro, Rua das Quaresmeiras, 54, Residencial
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Jardim das Palmeiras, Bosque 13283-504 - Vinhedo, SP Brazil, slpinho@puc-

[Link], Tel.: +55-19-99140-5277

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Highlights

 Photobiomodulation and photodynamic therapy accelerate oral mucositis

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healing.
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 The maximum mean time to cure oral mucositis was 15 days.

 Photobiomodulation and photodynamic therapy did not cause any adverse

effects.

ABSTRACT
Background: Photobiomodulation therapy (PBM-T) can penetrate soft tissues and exert

analgesic and healing effects, and is thus a promising alternative for prevention and

treatment of oral mucositis (OM). The aim of this study was to evaluate the efficacy of

PBM-T, alone or combined with photodynamic therapy (PDT), for treatment of OM in

cancer patients. Methods: Fifty-six patients were recruited from the Oncology

Department of a teaching hospital. Patients underwent grading of OM and were divided

into two groups (n=28 each): PBM-T and PBM-T + PDT. In the PBM-T group, low-

level laser was applied to 61 points in the oral cavity, once weekly for 4 weeks

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(wavelength 660 nm, power 100 mW, energy density 142 J/cm², spot energy 4 J,

irradiation time 40 seconds). In the PBM-T + PDT group, in addition to PBM-T as

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described above, patients rinsed with 20 mL of photosensitizing mouthwash (curcumin
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1.5 g/L) and the oral cavity was irradiated with a blue (468 nm) LED for 5 min.

Results: Significant reductions in OM grade were observed after application of PBM-T

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or PBM-T + PDT (p<0.0001). PBM-T + PDT resulted in a shorter time to resolution of
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lesions compared to PBM-T alone (p=0.0005). Conclusions: PBM-T, alone or

combined with PDT, can be used for the treatment of OM. PDT + PBM-T in particular

accelerated the OM healing process, reducing time to lesion remission from 15 to 11

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days.

Keywords: stomatitis; photochemotherapy; laser therapy.

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INTRODUCTION
Oral mucositis (OM) is a debilitating complication of high-dose chemotherapy,

radiation therapy to the head and neck, and hematopoietic stem cell transplantation. OM

is an inflammation of the oral mucosa characterized by lesions ranging from local

erythema to extremely painful ulcerations, which usually appear 7 days after the start of

cancer treatment and gradually grow in number and size. The pharyngeal, laryngeal, and
esophageal mucosa are also at risk for mucositis, particularly in patients undergoing

head and neck radiation therapy. The pathogenesis of OM involves the death of basal

epithelial cells due to exposure to the free radicals generated by radiation or

chemotherapy. Free radicals activate cell receptors that stimulate expression of

proinflammatory cytokines and cause tissue injury and cell death, leading to mucosal

lesions. Viral and bacterial pathogens present in the oral microbiota can increase the

severity of these lesions [1]. The mucosal inflammation of OM can cause difficulty in

feeding, swallowing, speech, and hygiene, and the ulcerations of OM can predispose to

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local or systemic infections, which often prevent the patient from continuing cancer

treatment [2-8]. Some prophylactic measures are available to relieve the pain of OM,

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including cryotherapy, chlorhexidine gluconate, oral hygiene, and mouth rinses.
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However, these measures do not act directly on the biological mechanisms involved in

each phase of OM. Photobiomodulation therapy (PBM-T) can penetrate soft tissues and
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exert analgesic and healing effects, and is thus a promising alternative for prevention
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and treatment of OM [1].

PBM-T that uses light sources (laser and LEDs) to relieve pain and

inflammation, exert immunomodulatory effects, and promote wound healing and tissue
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regeneration [9, 10]. Red or infrared light is absorbed by cellular chromophores (atoms

capable of absorbing visible light energy) present in the mitochondria [11] and acts on
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cytochrome c oxidase. As cytochrome c oxidase is stimulated by light, electron

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transport to oxygen molecules is accelerated, leading to increased ATP production.

Simultaneously, PBM-T produces a transient increase in reactive oxygen species, which

then participate in energy production. This increased energy availability culminates in a

series of biochemical and cellular changes, which increase epithelial cell proliferation

and accelerate wound healing [11, 12]. The secondary effects of PBM-T are increased
blood flow, greater oxygen consumption, improved tissue ATP production, increased

antioxidant defenses, activation of transcription factors, and alteration of the expression

pattern of cytokines and growth factors [1]. The PBM-T parameters recommended for

OM in the literature are a wavelength of 633–685 nm or 780–830 nm and a power of

10–150 mW [7, 13-15].

Patients with OM who do not receive PBM-T are likely to experience 50%

more OM lesions [16]. Patients treated with PBM-T have a lower rate of

discontinuation of cancer treatment [3, 14, 17], and clinical trials show improved quality

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of life and increased survival [10, 18]. Furthermore, remission of acute OM lesions

quickly improves the patient’s ability to feed properly [1].

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It is known that patients undergoing cancer treatment are usually
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immunosuppressed, with a greater predisposition to fungal and bacterial infections of

the oral cavity; PDT is an alternative for disinfection of the oral cavity of patients with
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OM. PDT produces singlet oxygen and free radicals that irreversibly damage
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susceptible cellular components of microbial pathogens. The photosensitizer agents

used in PDT are highly selective for microorganisms, with little toxicity to host cells

[19, 20].
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Curcumin, an orange-yellow natural compound, has a wide range of

pharmacological effects and can be used as a photosensitizing agent [21]. Curcumin is

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the main constituent of turmeric powder, extracted from the rhizomes of turmeric, a
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plant used in traditional Indian medicine [1]. It exhibits photodynamic action against

bacteria and fungi, including conventional drug-resistant strains found in the oral cavity,

and has a very broad absorption peak (300 to 500 nm range), with maximum absorption

at the wavelength of 430 nm [22, 23]. Among several forms of OM prevention and

treatment, PBM-T stands out as an effective, low-cost, nontraumatic alternative which

has demonstrated good results. The combination of PBM-T with an antimicrobial

therapy, such as PDT, might speed the OM healing process by promoting disinfection of

the oral cavity [1].

The aim of the present study was to evaluate the effect of PBM-T, alone or

combined with PDT, in the treatment of OM. The null hypothesis was that PBM-T and

PDT would not be effective for the treatment of OM.

MATERIALS AND METHODS

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The present study was approved by the Pontifical Catholic University of

Campinas (PUC-Campinas) Ethics Committee with protocol number 1 823 296.

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Fifty-six patients were selected from the Oncology Department of the PUC-
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Campinas Hospital. Written informed consent was obtained from all patients or their

caregivers.
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Patients were eligible for inclusion if they had OM lesions graded 1 to 4 on the
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WHO classification [5]; had been diagnosed with cancer and started chemotherapy

and/or radiotherapy at the Oncology Department of the hospital; and agreed to

participate in the study.

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Patients were initially assessed according to the severity of OM (Figures 1–4).

Then, they were divided, for convenience, into two experimental groups. Patients with
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extensive tumors, those who were intubated, those who had undergone mandibulectomy
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or glossotomy, and those who otherwise experienced difficulty in using the

photosensitizer mouth rinse were allocated to the PBM-T group; patients who were able

to rinse their oral cavities with the photosensitizer were allocated to the PDT + PBM-T

group (Flowchart 1).

 Flowchart 1. Distribution of participants according to the inclusion and

exclusion criteria.

Patients
evaluated: 158

Patients included: 56
- OM lesions graded 1 to 4;
- Diagnosed with cancer;
- Started chemotherapy and/or radiotherapy;

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- Agreed to participate in the study.

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- Patients with extensive tumors;

PBM-T + PDT (28)

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- Had undergone mandibulectomy or glossotomy;
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- Experienced great difficulty in using the

photosensitizer mouth rinse.

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PBM-T = (28)
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PBM-T group

Low-level laser (DMC, São Carlos, São Paulo, Brazil) was applied at a
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continuous wavelength of 660 nm, output 0.028 cm², power 100 mW, spot energy 4 J,
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energy density 142 J/cm², and irradiation time of 40 seconds per point. PBM-T was

applied to the lips (four points on the upper lip and four on the lower lip), labial

commissure (one point on each side), dorsum of tongue (three points), floor of mouth

(one point on each side), hard palate (three points), soft palate (three points), jugal
mucosa (10 points on each side), and side of tongue (10 points on each side), for a total

of 61 points. The protocol was applied once weekly for 4 weeks.

PDT + PBM-T group

PDT was performed using curcumin mouth rinse (1.5 g/L in distilled water,

adapted from Leite et al. [23]) as the photosensitizer. Patients were instructed to rinse

their oral cavity with 20 mL of the curcumin solution for 5 minutes and discard the

solution. The oral cavity was then irradiated with an UltraLumen SL dental curing light

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(Blue Sand, Brazil) (power 1200 mW, wavelength 468 nm) for 5 minutes (Figure 5).

PBM-T was then performed as described in the previous group.

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After treatment, the severity of OM was assessed and graded by the same
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criteria used for evaluation of OM at baseline. Both groups were followed for 3 months

after the completion of chemotherapy, associate or not radiation therapy.

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The results were analyzed in Biostat 4.0. As the Shapiro–Wilk test rejected the
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assumption of normality, the outcomes of interest (change in OM grade from baseline

and time to resolution of OM lesions) were assessed with the Wilcoxon and Mann–

Whitney U tests. Significance was accepted at 5%.

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RESULTS
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The sample profile is described in Table 1.

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Most patients included in the study had breast neoplasms (28.57% of the PBM-

T group) and head and neck carcinomas (17.86% of the PBM-T group). The PBM-T

group was predominantly female (64.29%), while in the PBM-T + PDT group genders

were uniformly distributed (50% male and 50% female). In descending order of

incidence, the grade of mucositis at baseline in the PBM-T group was I in 46.42%, III in
32.15%, and II in 21.43%; in the PBM-T + PDT group, it was grade III in 42.85% of

patients, grade II in 28.58%, grade I in 17.85%, and grade IV in 10.72%. There were no

patients with grade IV mucositis in the PBM-T group (Table 1).

The proportion of patients receiving chemotherapy and radiation therapy, as

well as the distribution of TNM staging in the PBM-T and PBM-T+PDT groups, are

described in Table 2. All patients in both groups received chemotherapy; 42.10% in the

PBM-T group and 44.44% in the PBM-T+PDT group received radiation as well. There

was no significant between-group difference in TNM staging (p>0.05, Table 2).

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There was a significant reduction in the severity of OM after treatment in both

groups (p<0.0001). There was no significant difference in OM reduction between PBM-

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T alone and PBM-T + PDT (Table 3, Figures 6 and 7). However, PBM-T + PDT
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resulted in a shorter time to resolution of lesions when compared to PBM-T alone

(p=0.0005, Table 4). Total recovery from OM occurred in approximately 15 days with
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PBM-T, whereas in PBM-T + PDT the time to full remission was approximately 11
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days.

In the PBM-T group (n=28), 14 patients had no visible signs, symptoms, or

lesions of OM. Only three patients experienced recurrence of BM after an additional

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cycle of chemotherapy. Five patients died and six were lost to follow-up.

In the PBM-T + PDT group (n=28), 14 patients had no visible signs,

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symptoms, or lesions of OM. Four had recurrent BM: three after an additional cycle of
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chemotherapy and one due to Sjögren's syndrome, an autoimmune disorder

characterized by abnormalities of the lacrimal and salivary glands that leads to

xerostomia and xerophthalmia and can itself cause mucositis. Five patients died and five

were lost to follow-up.

Neither PBM-T nor PDT were associated with any adverse effects.
DISCUSSION

Chemotherapy and radiotherapy remain the mainstay of cancer treatment, but

are often associated with a wide range of adverse effects, including OM. Cisplatin

appears to be particularly associated with increased severity of OM when used in

chemoradiation protocols [14]. Within this context, a number of studies have

investigated the potential benefit of PBM-T for the prevention and treatment of OM [2,

14, 16, 24, 25].

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The present study included all eligible patients treated at the Oncology

Department of a large university hospital and referred for PBM-T for prophylaxis or

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treatment of OM. Accordingly, the study population presented with a wide range of
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neoplasm types. However, there was no heterogeneity in TNM staging between the

PBM-T and PBM-T+PDT groups; 100% of patients received chemotherapy, and little
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under half received adjunctive radiation therapy. The proportion of patients who
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received radiation in addition to chemotherapy was statistically similar in the PBM-T

and PBM-T+PDT groups (42.10% and 44.44%, respectively).

All patients included in this study received PBM-T or PBM-T +PDT since the
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start of chemotherapy, regardless of adjunctive radiation therapy, and laser sessions

were scheduled to coincide with follow-up appointments for chemotherapy and/or

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radiation. Therefore, PBM-T and PBM+PDT for OM were performed concomitantly

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with chemotherapy and radiation in this study.

PBM-T is believed to exert a biphasic effect. The first phase is immediate and

occurs as a result of direct irradiation of cell components, while the second is a delayed

response that occurs after hours or days. Its effects are the result of activation of

endogenous chromophores, light absorption by intercellular water, and several

mediators: growth factors (TGF-β1), pro- and anti-inflammatory cytokines, matrix

metalloproteinases, and small molecules, such as ATP and reactive oxygen species.

These mediators guide cell proliferation, differentiation, angiogenesis, and immune

activation; modulate apoptosis; and improve cell survival, explaining the pain relief and

significant reduction in lesions observed when PBM-T is used to treat OM [1].

In the present study, PBM-T + PDT resulted in a shorter time to repair of OM

lesions when compared to PBM-T alone. Total recovery of OM occurred in

approximately 15 days with PBM-T, versus approximately 11 days with PBM-T + PDT.

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This shorter time to remission with add-on PDT is attributable to its broad-spectrum

antimicrobial activity, mediated by the production of reactive oxygen species that

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damage pathogenic microorganisms.
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The effects of PBM-T at the cellular level increase the availability of ATP,

resulting in fibroblast proliferation and enhanced collagen synthesis, which encourages

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healing with an anti-inflammatory effect and reduces neutrophil infiltration. In this
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sense, our results are consistent with those of several prior studies [11, 16, 24, 26, 27].

Curcumin was used as a photosensitizer in the present study because of its

remarkable additive bactericidal effect. This is mediated by a reduction in the surface

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tension between the photosensitizer and the bacterium, increasing the permeability of

the microbial cell membrane to curcumin; this results in a higher concentration of

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curcumin within the bacterial cell, further enhancing the biomodulator effect of blue
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light [22, 28]. Blue light, in turn, is able to modulate cellular physiology through

interactions with the endogenous cellular redox system, restoring cell homeostasis and

improving cellular functioning and proliferation [12].

 The findings described herein provide additional scientific evidence of the

effectiveness of PBM-T against oral mucositis. This modality should be part of the

therapeutic arsenal for the treatment of cancer patients.

Financial disclosure: This research did not receive any specific grant from funding

agencies in the public, commercial, or not-for-profit sectors.

Conflict of Interest: none.

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FIGURE LEGENDS

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Figure 1. Grade 1 oral mucositis. Erythema is the only visible manifestation.

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Figure 2. Grade 2 oral mucositis. In addition to erythema, an oral ulcer is visible.
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Figure 3. Grade 3 oral mucositis. Several ulcers are visible; the patient is unable to
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tolerate solids.
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Figure 4. Grade 4 oral mucositis. The patient is unable to feed orally.
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Figure 5. Oral cavity being irradiated with blue LED after application of
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photosensitizing mouthwash.
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Figure 6. Before (A) and after (D) PBM-T.

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Figure 7. Before (A) and after (D) PDT + PBM-T.

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TABLES
Table 1. Demographic and clinical profile of the sample.

PBM-T PBM-T + PDT

Variable (n=28) (n=28)

Age, years 26-71 31-81

Sex

Male 10 (35.71%) 14 (50%)

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Female 18 (64.29%) 14 (50%)

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Underlying neoplasm

Rectal adenocarcinoma 1 (3.57%) 2 (7.15%)

Head and neck carcinoma 5 (17.86%)

-p 4 (14.28%)
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Carcinoma of the palate 0 (0%) 1 (3.57%)
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Colon 1 (3.57%) 3 (10.72%)

Face and neck 1 (3.57%) 0 (0%)

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Face + Epiglottis 0 (0%) 1 (3.57%)

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Glottis + larynx 0 (0%) 1 (3.57%)

Hypopharynx + larynx 0 (0%) 1 (3.57%)

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Larynx 1 (3.57%) 1 (3.57%)

Lymphoma 3 (10.72%) 2 (7.15%)

Lymphoma + leukemia 1 (3.57%) 0 (0%)

 PBM-T PBM-T + PDT

Variable (n=28) (n=28)

Breast 8 (28.57%) 4 (14.28%)

Acral melanoma + breast 1 (3.57%) 0 (0%)

Cutaneous melanoma 0 (0%) 1 (3.57%)

Myeloma 1 (3.57%) 0 (0%)

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Neuroectodermal 1 (3.57%) 0 (0%)

Oropharyngeal 1 (3.57%) 2 (7.15%)

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Oropharyngeal + leukemia 0 (0%) 1 (3.57%)

Prostate 2 (7.15%)
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Lung + breast 0 (0%) 1 (3.57%)
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Sarcoma 1 (3.57%) 0 (0%)

Testicular 0 (0%) 1 (3.57%)

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Thyroid 0 (0%) 1 (3.57%)

Grade of OM at baseline*
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I 13 (46.42%) 5 (17.85%)
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II 6 (21.43%) 8 (28.58%)

III 9 (32.15%) 12 (42.85%)

IV 0 (0%) 3 (10.72%)

*Mucositis graded as in Figueiredo et al. [5]

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Table 2. Proportion of patients who received chemotherapy and radiation therapy

in the sample and TNM staging of patients in the PBM-T and PBM-t + PDT

groups.

PBM-T PBM-T + PDT

Variable

Chemotherapy 100% 100%

Radiation therapy 42.10% 44.44%

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Chemotherapy + radiation 42.10% 44.44%

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T1: 5.26% T1: 12%

T2: 21.05% T2: 20%

T3: 42.10%
-p T3: 44% p(MW)=0.4584
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T4: 21.05% T4: 24%

TX: 10.52% TX: 0%

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N0: 15.78% N0: 29.16%

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Tumor stage N1: 31.57% N1: 37.50%

N2: 42.10% N2: 29.16%

p(MW)=0.4173
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N3: 0% N3: 4.16%

NX: 10.52 % NX: 0%

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M0: 75% M0: 80%

p(Md)=0.5000
M1: 16.66% M1: 20%

MX: 8.33% MX: 0%

MW: Mann–Whitney U; Md: median test.

Table 3. Grade of oral mucositis before and after application of PBM-T or PBM-

T + PDT.

PBM-T PBM-T + PDT

n 28 28

Before After Before After

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Md (IQR) 2.00 (2.00)A 0.00 (0.00)B 3.00 (1.00)A 0.00 (0.00)B

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p <0.0001 <0.0001

Grade given as median (Md) and interquartile range (IQR). Different letters indicate
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statistically significant differences. Wilcoxon test, significance accepted at 5%.
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Table 4. Time in days elapsed from application of PBM-T or PBM-T + PDT to

resolution of oral mucositis lesions.

PBM-T PBM-T + PDT

n 28 28 p

Md (IQR) 14.00 (5.25) 10.00 (7.00) 0.0005

Time in days given as median (Md) and interquartile range (IQR). Mann–Whitney U

test, significance accepted at 5%.

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