View of Efficacy of LASER Photobiomodulation in the Management of Cancer Treatment Induced Oral Mucositis: A Systematic Review

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Efficacy of LASER Photobiomodulation in the Management of Cancer Treatment Induced Oral Mucositis: A Systematic Review

Babita Prasad ^1*, Soumya. SV ², Puja C Yavagal ³, Chandrashekar Yavagal ⁴, Sachin B Mangalekar ⁵, Amit Ashok Basannavar ⁶

1International College for Light Medicine and Laser Surgery (India Chapter)

2Dr.MGR Medical University, Christian Medical College,Tamil Nadu, India

3Rajiv Gandhi University of Health Sciences, Bapuji Dental College and Hospital, Karnataka, India

4Rajiv Gandhi University of Health Sciences, Maratha Mandal’s N.G.H. Institute of Dental Sciences and Research Centre, Karnataka, India

5Bharti Vidyapeeth (Deemed to be University) Dental College and Hospital, Maharashtra, India

6Bharti Vidyapeeth (Deemed to be University) Dental College and Hospital, Maharashtra, India

*[email protected] , author 2 [email protected], author 3 pujacya- [email protected], author 4 [email protected], author 5 [email protected], author 6

[email protected]

ABSTRACT

Oral mucositis is one of the most severe side effects of cancer treatment. Photobiomodu- lation therapy is a novel supportive therapy to prevent and manage cancer treatment induced oral mucositis. This review aimed at the assessment of efficacy of Laser photobiomodulation therapy in preventing and managing cancer treatment induced oral mucositis. Methods: An extensive electronic search for in vivo randomized controlled trials via Medline (via PubMed) and The Cochrane Controlled Clinical Trials Register databases from 2007 -2019 was done using MESH terms “stomatitis”, “oral mucositis”, “low-level light therapy”, “light therapy” and “clinical trial”.

Articles were retrieved and exported to Mendeley Desktop 1.13.3 software. Results: In total, 9 articles were selected for review out of 164 articles retrieved from the search and remaining were

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excluded based on the eligibility criteria. All studies except one demonstrated better pain relief and healing with laser photobiomodulation therapy compared to control group (sham therapy) Conclusion: Photobiomodulation therapy can serve as an effective preventive and therapeutic modality to manage cancer treatment induced oral mucositis.

Keywords: Stomatitis; Oral mucositis; Low-level laser therapy; Radiotherapy; Chemotherapy

Introduction

Oral mucositis is the most common, painful debilitating side effect of non-surgical oncotherapy. Around 30–40% of cancer patients treated with chemotherapy develop mucositis and this rises to almost 90% for head and neck cancer (HNC) patients treated with radio and chemotherapy (Villa & Sonis, 2016). The development and severity of mucositis depends on oncotherapy regimen, doses, number of cycles and patients’ characteristics. Some of the known risk factors for mucositis are old age, female gender, high bodyweight, compromised drug clearance conditions and genetic susceptibility (Jones et al.,2006) (Sonis et al.,1978) (Pratesi et al.,2011).

Oral mucositis starts within 7 days of onset of radiotherapy and after chemotherapy it starts within a day. The difficulty level of performing the daily chores is very high in people suffering from oral mucositis since it is associated with pain, burning sensation, and bleeding. Oral mucositis causes taste alterations, burning sensation, dysphagia, nutrition deprivation, secondary fungal, bacterial infections and altered speech. The symptoms contribute to compromised treatment leading to discontinuity or delay in taking chemo or radio cycles. Most importantly it causes decreased quality of life of cancer patients. Therefore, good supportive care is necessary to treat oral mucositis (Pratesi et al.,2011) (Hahn et al.,2010).

Management of oral mucositis has been largely palliative although targeted therapeutic interventions have been developed. The Mucositis Study Group of the Multinational Association for Supportive Care in Cancer and the International Society of Oral Oncology (MASCC/ISOO) has developed clinical practice guidelines for the management of mucositis. According to the guidelines, management of oral mucositis comprises of: nutritional support, pain control, oral de- contamination, palliation of dry mouth, management of oral bleeding and therapeutic interventions. A range of therapeutic modalities for cancer treatment-induced oral mucositis includes:

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cryotherapy with ice cubes, growth factors like recombinant human keratinocyte growth factor- 1,human keratinocyte growth factor-2 and human fibroblast growth factor-2; Antiinflammatory agents like Benzydamine hydrochloride and L-glutamine; Antioxidants like Amifostine and N- acetylcysteine; Immune regulators Dusquetide, SGX942 and natural agents like turmeric (Cur- cuma longa), essential oils of manuka (Leptospermum scoparium) and kanuka (Kunzeaericoides).

However, there are no clear guidelines of managing cancer treatment induced side effects which are usually physically intolerable and mentally unacceptable. Oral care is often ignored over cancer therapy (Verdi,1993) (Rodríguez-Caballero et al.,2011) (Trotti et al.,2003) (Brown & Gup- ta,2020) (Alvariño-Martín, C., & Sarrión-Pérez, M. G,2014) (Zadik et al.,2019).

Laser photobiomodulation (PBM) is a novel therapy used for treating oncotherapy induced oral mucositis. In 2004, the expert panels of the Multinational Association of Supportive Care in Cancer (MASCC) and the International Society for Oral Oncology (ISOO) considered low level laser therapy, after reviewing literature published from 1966 to May 2002, as a possible option in the management of cancer treatment induced oral mucositis with a level II of evidence and a grade B of recommendation (Zadik et al.,2019). PBM which was previously known as Low Level Laser Therapy (LLLT) is the application of red and near infra-red light(600nm-1000nm) over injuries or lesions to improve wound and soft tissue healing, reduce inflammation and to give relief to both acute and chronic pain. Photobiomodulation devices typically deliver light at 10mW - 500mW power (0.01 -> 0.01 Watts). The power density typically ranges from 0.005W/Cm² -> 5 W/Cm². It is non-invasive, pain free and safe therapy with no associated ad- verse effects. Many systematic reviews and meta analysis studies which have summarised the efficacy of laser photobiomodulation have included studies done using different types of lasers predominantly focusing on treatment of mucositis rather than prevention of mucositis (Chung et al.,2012) (de Freitas & Hamblin 2016). Thus, this systematic review was planned To systematically evaluate both the prophylactic and therapeutic effects of laser photobiomodulation in patients who might develop or who have developed oral mucositis during chemotherapy or radiotherapy or combined chemo-radiation.

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Literature Review Literature retrieval

An extensive electronic search was made on two data bases namely Medline (via PubMed) and The Cochrane Controlled Clinical Trials Register from 2007 -2019 using MESH terms and Boolean operators as shown in Table 1. Hand searching was performed in the relevant journals. Reference lists of the retrieved were also checked. No restrictions on the language or date of publication were applied during the search.

Criteria for article selection:

Research question framed was “What is the efficacy of laser photobiomodulation in the management of cancer therapy induced oral mucositis?”. Articles were retrieved based on PICOS criteria: (Table 2)

Criteria for inclusion of studies

1. Low-level laser of red and infrared wavelength diode lasers used for the treatment of cancer therapy induced oral mucositis.

2. In -vivo randomised controlled trials

3. Outcome measures were pain relief, reduced inflammation and wound healing assessed through visual analogue scale and histological examination of oral mucositis lesions.

Criteria for exclusion of studies

1. Review articles, letters to editor, editorials, observational studies, commentaries, in-vitro and animal studies.

2. Studies which used other than diodes lasers for photobiomodulation such as Light emitting diodes,CO2 lasers, Nd: YAG lasers, etc. for treatment of oral mucositis

Each study was reviewed by four authors independently and any difference of opinion was resolved by reaching a consensus and if necessary, resolved by a fifth reviewer. The reviewing authors were not blinded to authors, institution or journals. All full-text papers that were retrieved were similarly screened. All the studies which were excluded were recorded with reasons for exclusion.

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Data extraction and management

Data and quality information was extracted and fed into Revmann 5.3 software (Lorenzetti & Ghali, 2013). The year of publication and country of origin were recorded. Inclu- sion/exclusion criteria were specified and a detailed description of interventions was given. All outcomes were reported in trials at different intervals.

Assessment of risk of bias in included studies

The studies were assessed for risk of bias by using the Cochrane risk of the bias assessment tool (Higgins et al.,2011). The domains assessed for each included study were: sequence generation, allocation concealment, blinding of outcome assessment, completeness of outcome data, risk of selective outcome reporting, risk of other potential sources of bias. A description of the risk of bias domains was tabulated for each included trial, along with a judgment of no risk (procedure followed) and unclear (not mentioned) risk of bias, using the Revman 5.3 review manager software.

Results

The search strategy yielded a total of 164 articles. (Figure 1) Post removal of duplicates, articles were retrieved, and their materials and methods were scanned and reviewed for PICOS criteria and eligibility criteria. This yielded a total of 9 articles which were systematically reviewed.

Characteristics of the studies: Studies included in systematic review were reported in India, Italy, France, Spain, Iran and Brazil. All the studies followed an in-vivo, randomized controlled design. All studies compared photobiomodulation with sham treatment except the study by Car- valho et al where the control group was also given PBM therapy with different dosage compared to the test group (Carvalho et al., 2011). The Laser parameters, mode of application, and duration of therapy used in the studies varied and are listed in Table 3. Majority of the studies identiﬁed and included in this review used visible red wavelengths within the 632.5–660 nmrange (Carval- ho et al., 2011) (Gautam et al., 2012) (Gautam et al., 2015) (Kalati et al., 2015) (Legoute et al., 2019). In addition, other studies used wavelengths within the range of 780–970nm (Cruz et al.,

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2007) (Kuhn et al.,2009) (Amadori et al.,2016) (Conde et al.,2018). Majority of the studies used a small optical spot size of only 0.04 cm² with a probe in contact with or near-contact to the target tissues. The number of points of application for these studies varied from 15 to 80, with a de- clared ﬂuence at each point of 1 to 83 J/cm², and an irradiance of 0.024 to 13.8 W/cm². Few studies were done among paediatric patients (Cruz et al., 2007) (Kuhn et al.,2009) (Amadori et al.,2016) and the rest were among adults. Outcome measures assessed across different studies were grading of oral mucositis, pain, use of analgesics, dysphagia, xerostomia, quality of life, breaks in radiotherapy and chemotherapy cycles and recurrence of mucositis. Majority of studies used WHO - NCI-CTC ( National Cancer Institute -common toxicity criteria) scale followed by Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organiza- tion for Research and Treatment of Cancer (EORTC) scale for grading of mucositis (Sroussiet al.,2017) (Soni S,2012) (Gussgaurd et al.,2014).

Outcome of studies: All studies except study by Cruz et al,2007 demonstrated beneficial effect of Laser photobiomodulation in decreasing the severity of oral mucositis (Kuhn et al., 2009) (Amadori et al.,2016) (Conde et al.,2018) (Carvalho et al., 2011) (Gautam et al.,2012) (Gautam et al., 2015) (Kalati et al.,2015) (Legoute et al.,2019). In few studies there was decrease in the intensity of pain associated with mucositis with photobiomodulation therapy (Kuhn et al.,2009) (Amadori et al.,2016) (Conde et al.,2018)(Carvalho et al.,2011) (Gautam et al.,2012) (Gautam et al., 2015) (Kalati et al.,2015) (Legoute et al.,2019). Few studies demonstrated decreased xerostomia, improved quality of life, decreased dysphagia, less use of morphine analgesic, lesser breaks in radio-chemo cycles and decreased recurrence of oral mucositis associated with photobiomodulation therapy (Gautam et al.,2012) (Gautam et al., 2015) (Amadori et al.,2016). Risk of bias was unclear in majority of the studies. (Figure 2)

Table 1 -Search strategy of studies

Database Search strategy Articles

retrieved

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PubMed "Stomatitis"[MeSH Terms] OR "stomatitis"[All Fields] OR ("oral"[All Fields] AND "mucositis"[All Fields]) OR "oral mucositis"[All Fields]) AND ("low-level light therapy"[MeSH Terms] OR ("low-level"[All Fields] AND "light"[All Fields] AND "therapy"[All Fields]) OR "low- level light therapy"[All Fields] OR ("low"[All Fields] AND "level"[All Fields] AND "laser"[All Fields] AND "therapy"[All Fields]) OR "low level laser therapy"[All Fields]) AND Clinical Trial[ptyp]

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Cochrane Oral mucositis and laser therapy, light therapy 111

Table 2-PICOS format (Population, Intervention, Control, Study design) to identify studies pertaining to research question search strategy of studies

Population Patients suffering from cancer therapy induced oral mucositis

Intervention Laser photobiomodulation for Cancer therapy induced oral mucositis Control Patients receiving placebo, local or systemic analgesics

Outcome Analgesia, wound healing, decreased inflammation Study design Randomized controlled trials

Table 3-Characteristics of studies selected for review

Author /Year/

Country

Type of malignancy and treatment

Sample size (n)

Mean age of partici- pants (years)

Control group

Test Group

Therapy Duration

Laser Diode parameters

Wave- length

Energy Density

Pow- er

Time

Cruz et al 2007 Brazil

Leuke- mia,lympho ma,solid tumors HSCT

Test (n) = 29 Con- trol(n)= 31

8.7 ±4.3 No therapy Laser PBM

5 consecutive days from initiation of chemotherapy

780nm 4 J/cm2 60m

W

66sec

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Kuhn et al 2009 Brazil

Leuke- mia,lympho ma,solid tumors CT or HSCT

8.1±3.1 Sham therapy

Laser PBM

5 consecutive days after development of chemotherapy induced oral mucositis.

830nm 4 J/cm2 100m

W

40sec

Carvalho et al 2011 Brazil

Oral /Oropharynge al neoplasm RT+CT

G1:56.2±

14.5 G2:58.1±

10.1

Group 2:

PBM with 660 nm/

/1.3 J/c/cm2/

Group 1:Laser PBM with (660 nm/3.

8 J/cm2

Daily, ﬁve consecutive days per week, starting on the ﬁrst day of radiotherapy (before the radiation sessions)

660nm 3.8J/cm2 (Group1) 1.3J/cm2 (Group 2)

15m W

5mW 252se c

260se c

Gautam et al 2012 India

HNC with oral or oro- pharyngeal involvement CRT

Test (n) = 115 Con- trol(n)=

124

55.18 ± 11.70

Sham Thera- py

Laser PBM

5 sessions/week for 45 days prior to radiotherapy at six anatomical sites in the oral cavity (buccal mucosa, lateral and ventral tongue, labial mucosa, ﬂoor of the mouth, and palate ex- cluding cancer site)

632.8n m

3J/cm2 24m

W

125se c

Kalati et al 2015 Iran

HNC CT

44.5 ± 4.04

Sham therapy

Laser PBM

One session prior to every chemotherapy session. Each session 10 spots

in oral cavity were irradiated: two spots on the cheeks, two on the tongue, two on the floor of the mouth, one on the soft palate and one on the hard palate

630nm 5 J/cm2 30m

W

166 sec

Gautam et al 2015 India

Primary HNC RT

55.18 ±

11.70 Sham therapy

Laser PBM

5 fractions/week, total 33 fractions for 6.5 weeks prior to radiotherapy at six anatomical sites bilaterally i.e. 12 locations, total dose/session=36 J,

632.8n m

3 J/cm2 24m

W

125 sec

Amadori et al 2016 Italy

Hematologic malignancies,Solid tumors CT

9.8 ± 3.25

Sham therapy

Laser PBM

Laser therapy started on day 1 of the diagnosis of OM and continued for another 3 consecutive days (4 days in total).

Laser irradiated at the sites of OM (buccal mucosa, lip mucosa, tongue, floor of mouth and soft palate)

830nm 4.5 J/cm2 150m W

30 sec

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Conde et al 2018 Spain

Squamous cell carcino- ma oral/orophary ngeal CRT

Test (n) = 18 Con- trol(n)=18

60.89±9.9 Sham therapy

Laser PBM

Total 12 sessions of Laser therapy were car- ried out. At each session,post radiation therapy,laser beam was di- rected on the mucosa, perpendicular to the irradiated surface. The irradiations were performed intraorally, avoiding the area of the tumour. The laser was applied at a total of 72 identiﬁed points :12 points were on the buccal mucosa (right and left), eight on the mucosa of the upper and lower lip, 12 on the hard palate, four on the soft palate, 12 on the lingual surface of the tongue, 10 on the left and right lateral edges of the tongue, eight on the ventral surface of the tongue, four on the ﬂoor of the mouth, and one on each labial commissures.

940nm 4.5J/cm2 500m W

9sec

Legoute et al 2019 France

Advanced HNC CRT

58 (53-65) Sham therapy

Laser

PBM All anatomic sites with moderate or severe OM (OMS scale grade ≥ 2) were treated daily after radiotherapy session, 1 session / day, 5 times / week from day of grade II OM occurrence to day of grade II OM resolution. Inter- val between treatments 1 or 2 days

658nm 4 J/cm2 100m

W

40sec

Table 4: Results of studies selected for review

Author Outcome as- sessed

Method of assessment

Results Summary

Cruz et al 1.Grade of oral mucositis

WHO - NCI-CTC ( Nation- al Cancer Institute - common toxicity criteria)

No significant difference was observed between groups concerning the grades of mucositis on day 8 (P

= 0.234) or on day 15 (P = 0.208).

No evidence of benefit of Laser PBM

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Kuhn et al 1.Grade of oral mucositis

WHO – NCI-CTC Scale

Mean duration of oral mucositis post therapy was

5.8±2 days in laser group and 8.9±2.4 days in control group (p=0.004).

Photobiomodulation with LLLT reduced the severity of mucositis in patients treated with chemotherapy

Carvalho et al

1.Grade of oral mucositis 2.Pain

1.WHO- NCI-CTC Scale

2.visual analog scale (VAS) Post therapy, patients in Group 1 presented mucositis(grade 2) at mean time of 13.5 days (range 6–

26 days) while in Group 2 at mean time of 9.8 days (range 4–

14 days)( p = 0.005). Group 2 patients presented a higher mucositis grade than Group 1 at weeks 2 (p = 0.019), 3 (p = 0.005) and 4 (p = 0.003) for WHO scale and weeks 2 (p = 0.009) and 4 (p = 0.013) for NCI scale. The patients in Group 1 reported lower pain levels (p = 0.004)

Photobiomodulation with LLLT was effective in control of the intensity of mucositis and in the pain related to the mucositis in patients treated with radio- chemo- therapy.

Gautam et al 1.Grade of oral mucositis 2.Pain 3.Dysphagia

1.Toxicity criteria of the Radiation Therapy Oncolo- gy Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) scale 2.Visual analogue scale 3.Functional Impairment Scale

There was significant reduction in incidence of severe oral mucositis (F=16.64, df=8876, p<0.0001) and its associated pain (F=25.06, df=8876, p<0.0001), dysphagia (F=20.17, df=8876, p<0.0001) and opioid analgesics use (p<0.0001) in laser than placebo group patients.

Photobiomodulationdecreased the incidence of chemoradiotherapy induced severe oral mucositis and its associated pain, dysphagia and opioid analgesics use

Kalati et al 1.Grade of oral mucositis 2.Pain 3.Xerostomia

1.WHO- NCI-CTC Scale 2.visual analog scale (VAS) 3.LENT SOMA scale

Photobiomodulation significantly reduced, mucositis intensity (p<0.001), Xerostomia(p<0.001) and pain (p<0.001) at 2 weeks post chemotherapy till 14 weeks compared to control group.

Photobiomodulation was able to decrease the effect of chemotherapy on oral mucositis, xerostomia and pain.

Gautam et al 1.Grade of oral mucositis 2.Pain

1.EORTC Scale

2.VAS scale Significant reduction in the incidence and duration of severe OM (p=0.016) and severe pain (p=0.023) and weight loss (p=0.004) was observed in laser than placebo group.

No difference was found for enteral feeding use (p=0.667) between two groups.

Photobiomodulationdecreased the severity of oral mucositis and oral pain in elderly Head and neck cancer patients receiving radiotherapy. Lesser weight loss, morphine analgesic use and radiation break was observed in laser group.

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Amadori et al

Grade of oral mucositis

1.WHO- NCI-CTC Scale

The difference in the decline of OM grading between the two groups was not statistically significant (p = 0.07). A statistically significant difference in pain reduction between two groups both at T1 and at T2 (p <

0.005) was observed.

Photobiomodulation demonstrated efficacy in reducing pain due to chemotherapy-induced oral mucositis in children, while no significant benefit was noted in reducing OM grade.

Conde et al Grade of oral mucositis

RTOG/EORTC Scale

There was significant(p<0.05) increase in prevalence of normal mucosa (grade 0 mucositis) in laser group (72.7%) compared to control group (20%)

Photobiomodulation reduces the incidence and severity

of mucositis in patients treated with radio- chemotherapy.

Legoute et al 1.Grade of oral mucositis 2.Pain 3.Quality of life 4.Recurrence of mucositis

1.WHO- NCI-CTC Scale 2.visual analog scale (VAS) 3.“EORTC QLQ-H&N35 questionnaire

4. Recurrence-Free Surviv- al (RFS), and Overall survival (OS)

Acute oral mucositis (grade ≥ 3) was observed in 54.8 % of the active laser group versus 43.9%

in the control group (modified intend to treat, p =0.32). Median time before occurrence of OM ≥ grade 3 in half of the patients was 8 weeks in active laser group vs. 9 weeks in control group. .95%

of patients exhibited a very good tolerance of laser photobiomodulation

photobiomodulation reduced the incidence and severity of mucositis in patients treated with radio- chemotherapy. It was well tolerated with a good safety profile.

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Discussions

Oncologic therapy has major side effects which include oral mucositis. Literature suggests there are many treatment modalities to control oral mucositis but so far no effective therapy has been found. Standard guidelines are needed to manage oral mucositis. This systematic review analysed the efficacy of laser photobiomodulation as a possible supportive therapy to prevent and treat oral mucositis. Majority of the studies in this systematic review demonstrated decrease in the severity of oral mucositis and pain associated with head and neck cancer treated with chemotherapy, radiotherapy, and patients undergoing hematopoietic stem-cell transplantation using photobiomodulation therapy (Kuhn et al.,2009) (Amadori et al.,2016) (Conde et al.,2018) (Carvalho

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et al.,2011) (Gautam et al.,2012) (Gautam et al., 2015) (Kalati et al.,2015) (Legoute et al.,2019).

The mechanism of photobiomodulation starts with the transfer of photonic energy to a cellular target, which subsequently affects intra-cellular organelle metabolism. This takes place in the mi- tochondria, which respond to the absorption of red to near-infra-red (IR) wavelengths of light by an increase in activity of the electron transport respiratory chain thereby resulting in an increase in the production of ATP and nitric oxide along with some changes beneficial to cellular metabolism like selective uptake of pro-inflammatory cytokines and an inhibition of COX-2 activity, per- fusion of tissues with oxygenated blood, increased production of pro-collagen and growth factors, increase in cellular motility and rate of division, reduction in nociception and selective inhibitory effects on axonal transmission. Photobiomodulation can influence cytoplasmic reactive oxygen species (ROS) levels and enhance immune response at the target site. In this process, endorphins and enkephalins are released which block membrane depolarization that prevents nerve impulse transmission. (Heiskanen & Hamblin, 2018).

Few studies in the review demonstrated improved analgesia with PBM (Kuhn et al., 2009) (Amadori et al., 2016) (Conde et al.,2018) (Carvalho et al.,2011) (Gautam et al.,2012) (Gautam et al., 2015) (Kalati et al.,2015) (Legoute et al.,2019). The light energy of wavelength range 600- 1000nm gets absorbed by the tissues which modulates the descending pain pathway with the help of natural endogenous analgesics which causes partial or selective pain inhibition at the synaptic pathway between neurons of the descending pathway and neurons of the ascending pathway. The mechanism also leads to blocking of the ascending pain pathway and stimulation of the descending pain pathway which increases the release of natural endogenous analgesics like serotonin, beta-endorphin which reduces pain or even block nociception. Many studies suggested that the light which is having deeper tissue penetration provides a better analgesic effect. (Sousa et al.,2018) (de Freitas & Hamblin,2016).Majority of studies showed improved and faster healing of mucositis lesions. The cellular mechanism of action for wound healing occurs in the second phase where the light gets absorbed by the tissues, and activates the coagulation pathway and stimulates platelet aggregation which leads to proliferation and degranulation of mast cells. This causes stimulation of cytokine and growth factors which initiates proliferation of keratinocytes and fibroblast leading to neovascularization and angiogenesis leading to reepithelization, repair, and regeneration. (Moscaet al.,2019) (Sousa et al.,2018). The beneficial effect of photobiomodu-

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lation was more pronounced among adult population compared to pediatric population. In comparison to adults, the development of mucositis is quite severe in young patients. The incidence and severity of mucositis are higher in pediatric patients as there is rapid cell division and proliferation rates compared to adults. 80% of the pediatric patients undergoing chemotherapy experience oral mucositis although the incidence differs depending upon the type of malignancy and treatment regimen. (Miller et al.,2012) (Naidu et al.,2004) Vokurka et al suggested that, gender could be an independent risk factor and predictor for oral mucositis in high-dose chemotherapy settings. Females appear to be more susceptible to mucositis post-chemotherapy compared to males (Vokurka et al.,2006).

Recent MASCC (Multinational Association of Supportive Care in Cancer) protocol suggested that prophylaxis can help in preventing the severity and occurrence of oral mucositis in patients undergoing cancer therapy. The treatment of cells and tissues before chemo or radiotherapy is helpful as it increases the cell’s capacity to withstand the damage or stress caused by external chemo agents or radiation (Chemo protective - Radio Protective). The suggested prophylaxis dosage of PBM ranges from 2-8J/cm2, as it is the dose-related response which is biphasic where lower energy is associated with stimulation and higher energy is related to pain inhibition.

The cells become more resilient to the chemotherapeutic drugs or the radiation used. At the cellular level when cells are pretreated with the light there is an optimal enhancement of the electron transport chain which accelerates the aerobic metabolism. The aerobic metabolism enhances the optimal production of ATP and Nitric oxide which makes the cells more resilient to stress caused by external chemotherapeutic drugs or radiation. Also, the survival of the cell is enhanced by ac- tivation of the cellular protective mechanisms induced by light. However, some downstream effects can also be seen if there is increased production of reactive oxygen species which can reduce the production of ATP by causing decoupling of the electron transport chain (Cronshaw et al.,2020) (Zadik et al.,2019).

According to the NICE guidelines, intraoral photobiomodulation before radiation or chemotherapy is suggested as Standard of care in HSCT (hematopoietic stem cell transplantation) patients who need high dose chemotherapy with or without full body irradiation. As per the supportive evidence, the beneficial wavelength ranges between 630 to 660 nm (red part of the elec- tromagnetic spectrum). Two protocols are suggested - one using 632.8nm wavelength of light on

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18 sites at a distance less than a centimetre, daily from the start day of HSCT till its’ cessation.

The second protocol suggests the use of 650nm wavelength of light on 54-70 sites in contact mode, daily from the start day of HSCT till 7-13days post-HSCT. Extra-oral PBM for the management of oral mucositis is also reported to have a beneficial effect (Zadik et al.,2019)

Studies by Zecha JA et al (2016), Bensadoun RJ et al (2018) and Zadik Y et al (2019) have suggested dosimetric clinical practice and safety considerations for photobiomodulation therapy in preventing and managing cancer treatment induced oral mucositis.

Conclusion

Photobiomodulation seems to be a novel, safe, well tolerated therapy for management of cancer treatment induced oral mucositis. There was heterogeneity in the parameters presented by various studies included in this review. More systematic reviews involving trials based on standard protocols of photobiomodulation may clarify its promising potential in the management of cancer treatment induced oral mucositis.

Limitations and Recommendations

Although majority of studies in the review showed beneficial effects of PBM for management of oral mucositis, the evidence should be considered with the heterogeneity of the studies. As oral mucositis development and severity depends upon various factors like the type of malignancy, chemo drug used, dose, type of radiation, chemo –radio cycles, frequency, duration, age, sex, etc. evidence related to studies standardised for confounding factors and effect modifi- ers need to be considered. Multi centric trials, with longer follow-up period should be designed.

This may enable in formulating a standard dosimetry protocol and clinical practice guidelines for photobiomodulation therapy.

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Abbreviations: PBMT- Photobiomodulation therapy, LLLT – Low-Level Light Therapy,

HSCT- Hematopoietic Stem Cell Transplant, HNC- Head & Neck Cancer, RCT- Randomized Controlled Trials, OM- Oral Mucositis, CRT- Chemo Radiotherapy, RT-Radiotherapy, CT- Chemotherapy, RTOG- Radiation Therapy Oncology Group, EORTC -the European Organi- zation for Research and Treatment of Cancer NCI-CTC National Cancer Institute -common toxicity criteria, MASCC -Multinational Association of Supportive Care in Cancer ,ATP Adenosine Tri-Phosphate, ISOO International Society for Oral Oncology, VAS Visual Ana- log Scale and ROS Reactive Oxygen Species.