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
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
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
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 on- cotherapy 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 with- in 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 lead- ing to discontinuity or delay in taking chemo or radio cycles. Most importantly it causes de- creased 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 interven- tions. A range of therapeutic modalities for cancer treatment-induced oral mucositis includes:
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 can- cer 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 in- duced 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 systemati- cally evaluate both the prophylactic and therapeutic effects of laser photobiomodulation in pa- tients who might develop or who have developed oral mucositis during chemotherapy or radio- therapy or combined chemo-radiation.
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 can- cer 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 emit- ting 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 review- ing authors were not blinded to authors, institution or journals. All full-text papers that were re- trieved were similarly screened. All the studies which were excluded were recorded with reasons for exclusion.
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 assess- ment 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.
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 re- viewed.
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.,
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 stu- dies 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 in- tensity 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 xeros- tomia, 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 photo- biomodulation 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
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]
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
Type of malignancy and treatment
Sample size (n)
Mean age of partici- pants (years)
Laser Diode parameters
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 chemothera- py
780nm 4 J/cm2 60m
Kuhn et al 2009 Brazil
Leuke- mia,lympho ma,solid tumors CT or HSCT
Test (n) = 9 Con- trol(n)= 12
8.1±3.1 Sham thera- py
5 consecutive days after development of chemo- therapy induced oral mucositis.
830nm 4 J/cm2 100m
Carvalho et al 2011 Brazil
Oral /Oropharynge al neoplasm RT+CT
Test (n) = 35 Con- trol(n)= 35
PBM with 660 nm/
Group 1:Laser PBM with (660 nm/3.
Daily, ﬁve consecutive days per week, starting on the ﬁrst day of radio- therapy (before the radia- tion sessions)
660nm 3.8J/cm2 (Group1) 1.3J/cm2 (Group 2)
5mW 252se c
Gautam et al 2012 India
HNC with oral or oro- pharyngeal involvement CRT
Test (n) = 115 Con- trol(n)=
55.18 ± 11.70
Sham Thera- py
5 sessions/week for 45 days prior to radiothera- py 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)
Kalati et al 2015 Iran
Test (n) = 24 Con- trol(n)= 24
44.5 ± 4.04
Sham thera- py
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
Gautam et al 2015 India
Primary HNC RT
Test (n) = 22 Con- trol(n)= 24
11.70 Sham thera- py
5 fractions/week, total 33 fractions for 6.5 weeks prior to radiothe- rapy at six anatomical sites bilaterally i.e. 12 locations, total dose/session=36 J,
3 J/cm2 24m
Amadori et al 2016 Italy
Hematologic malignan- cies,Solid tumors CT
Test (n) = 62 Con- trol(n)= 61
9.8 ± 3.25
Sham thera- py
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
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 thera- py
Total 12 sessions of Laser therapy were car- ried out. At each ses- sion,post radiation thera- py,laser beam was di- rected on the mucosa, perpendicular to the irradiated surface. The irradiations were per- formed intraorally, avoiding the area of the tumour. The laser was applied at a total of 72 identiﬁed points :12 points were on the buc- cal 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
Legoute et al 2019 France
Advanced HNC CRT
Test (n) = 41 Con- trol(n)= 41
58 (53-65) Sham thera- py
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 occur- rence to day of grade II OM resolution. Inter- val between treatments 1 or 2 days
658nm 4 J/cm2 100m
Table 4: Results of studies selected for review
Author Outcome as- sessed
Method of assessment
Cruz et al 1.Grade of oral mucositis
WHO - NCI-CTC ( Nation- al Cancer Institute - common toxicity criteria)
No significant difference was ob- served 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
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 chemothe- rapy
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 pa- tients 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 pa- tients 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 che- motherapy till 14 weeks compared to control group.
Photobiomodulation was able to decrease the effect of chemothera- py on oral mucositis, xerostomia and pain.
Gautam et al 1.Grade of oral mucositis 2.Pain
2.VAS scale Significant reduction in the inci- dence and duration of severe OM (p=0.016) and severe pain (p=0.023) and weight loss (p=0.004) was ob- served 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 radiothe- rapy. Lesser weight loss, morphine analgesic use and radiation break was observed in laser group.
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 dif- ference 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 muco- sitis in children, while no signifi- cant benefit was noted in reducing OM grade.
Conde et al Grade of oral mucositis
There was significant(p<0.05) in- crease in prevalence of normal mu- cosa (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 sur- vival (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 photobiomodula- tion
photobiomodulation reduced the incidence and severity of mucosi- tis in patients treated with radio- chemotherapy. It was well tole- rated with a good safety profile.
Oncologic therapy has major side effects which include oral mucositis. Literature sug- gests 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 chemo- therapy, radiotherapy, and patients undergoing hematopoietic stem-cell transplantation using pho- tobiomodulation 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).
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 metabol- ism 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 descend- ing 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-
lation was more pronounced among adult population compared to pediatric population. In com- parison 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 prolife- ration rates compared to adults. 80% of the pediatric patients undergoing chemotherapy expe- rience 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 sug- gested 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 radiothe- rapy is helpful as it increases the cell’s capacity to withstand the damage or stress caused by ex- ternal chemo agents or radiation (Chemo protective - Radio Protective). The suggested prophy- laxis 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 cellu- lar 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 ef- fects can also be seen if there is increased production of reactive oxygen species which can re- duce 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 che- motherapy 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 sup- portive 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
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 man- agement 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.
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 stan- dard 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 man- agement of oral mucositis, the evidence should be considered with the heterogeneity of the stu- dies. 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.
1. Alvariño-Martín, C., &Sarrión-Pérez, M. G. (2014). Prevention and treatment of oral mucosi- tis in patients receiving chemotherapy. Journal of clinical and experimental dentistry, 6(1), e74–e80.
2. Amadori, F., Bardellini, E., Conti, G., Pedrini, N., Schumacher, R. F., & Majorana, A. (2016).
Low-level laser therapy for treatment of chemotherapy-induced oral mucositis in childhood: a randomized double-blind controlled study. Lasers in medical science, 31(6), 1231–1236.
3. Arbabi-Kalati, F., Arbabi-Kalati, F., &Moridi, T. (2013). Evaluation of the effect of low level laser on prevention of chemotherapy-induced mucositis. Acta medica Iranica, 51(3), 157–162 4. Bensadoun R. J. (2018). Photobiomodulation or low-level laser therapy in the management of
cancer therapy-induced mucositis, dermatitis and lymphedema. Current opinion in oncol- ogy, 30(4), 226–232.
5. Brown, T. J., & Gupta, A. (2020). Management of Cancer Therapy-Associated Oral Mucosi- tis. JCO oncology practice, 16(3), 103–109.
6. Carvalho, P. A., Jaguar, G. C., Pellizzon, A. C., Prado, J. D., Lopes, R. N., & Alves, F. A.
(2011). Evaluation of low-level laser therapy in the prevention and treatment of radiation- induced mucositis: a double-blind randomized study in head and neck cancer patients. Oral oncology, 47(12), 1176–1181.
7. Chung, H., Dai, T., Sharma, S. K., Huang, Y. Y., Carroll, J. D., & Hamblin, M. R. (2012). The nuts and bolts of low-level laser (light) therapy. Annals of biomedical engineering, 40(2), 516–533.
8. Cronshaw, M., Parker, S., Anagnostaki, E., Mylona, V., Lynch, E., &Grootveld, M. (2020).
Photobiomodulation and Oral Mucositis: A Systematic Review. Dentistry journal, 8(3), 87.
9. Cruz, L. B., Ribeiro, A. S., Rech, A., Rosa, L. G., Castro, C. G., Jr, &Brunetto, A. L. (2007).
Influence of low-energy laser in the prevention of oral mucositis in children with cancer re- ceiving chemotherapy. Pediatric blood & cancer, 48(4), 435–440.
10. de Freitas, L. F., & Hamblin, M. R. (2016). Proposed Mechanisms of Photobiomodulation orLow-Level Light Therapy. IEEE journal of selected topics in quantum electronics : publi- cation of the IEEE Lasers and Electro-optics Society, 22(3), 7000417.
11. de Sousa, M., Kawakubo, M., Ferraresi, C., Kaippert, B., Yoshimura, E. M., & Hamblin, M.
R. (2018). Pain management using photobiomodulation: Mechanisms, location, and repeata- bility quantified by pain threshold and neural biomarkers in mice. Journal of biophoton- ics, 11(7), e201700370.
12. Gautam, A. P., Fernandes, D. J., Vidyasagar, M. S., Maiya, A. G., &Vadhiraja, B. M. (2012).
Low level laser therapy for concurrent chemoradiotherapy induced oral mucositis in head and neck cancer patients - a triple blinded randomized controlled trial. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 104(3), 349–354.
13. Gautam, A. P., Fernandes, D. J., Vidyasagar, M. S., Maiya, A. G., &Guddattu, V. (2015). Low level laser therapy against radiation induced oral mucositis in elderly head and neck cancer patients-a randomized placebo controlled trial. Journal of photochemistry and photobiology.
B, Biology, 144, 51–56.
14. Gussgard, A. M., Hope, A. J., Jokstad, A., Tenenbaum, H., & Wood, R. (2014). Assessment of cancer therapy-induced oral mucositis using a patient-reported oral mucositis experience questionnaire. PloS one, 9(3), e91733.
15. Hahn, T., Zhelnova, E., Sucheston, L., Demidova, I., Savchenko, V., Battiwalla, M., Smiley, S. L., Ambrosone, C. B., & McCarthy, P. L., Jr (2010). A deletion polymorphism in gluta- thione-S-transferase mu (GSTM1) and/or theta (GSTT1) is associated with an increased risk of toxicity after autologous blood and marrow transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplanta- tion, 16(6), 801–808.
16. Higgins, J. P., Altman, D. G., Gøtzsche, P. C., Jüni, P., Moher, D., Oxman, A. D., Savovic, J., Schulz, K. F., Weeks, L., Sterne, J. A., Cochrane Bias Methods Group, & Cochrane Sta- tistical Methods Group (2011). The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ (Clinical research ed.), 343, d5928.
17. Heiskanen, V., & Hamblin, M. R. (2018). Photobiomodulation: lasers vs. light emitting dio- des?. Photochemical & photobiological sciences : Official journal of the European Photo- chemistry Association and the European Society for Photobiology, 17(8), 1003–1017.
18. Jones, J. A., Avritscher, E. B., Cooksley, C. D., Michelet, M., Bekele, B. N., &Elting, L. S.
(2006). Epidemiology of treatment-associated mucosal injury after treatment with newer re- gimens for lymphoma, breast, lung, or colorectal cancer. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 14(6), 505–515.
19. Kuhn, A., Porto, F. A., Miraglia, P., &Brunetto, A. L. (2009). Low-level infrared laser thera- py in chemotherapy-induced oral mucositis: a randomized placebo-controlled trial in child-
ren. Journal of pediatric hematology/oncology, 31(1), 33–37.
20. Legouté, F., Bensadoun, R. J., Seegers, V., Pointreau, Y., Caron, D., Lang, P., Prévost, A., Martin, L., Schick, U., Morvant, B., Capitain, O., Calais, G., &Jadaud, E. (2019). Low-level laser therapy in treatment of chemoradiotherapy-induced mucositis in head and neck cancer:
results of a randomised, triple blind, multicentre phase III trial. Radiation oncology (London, England), 14(1), 83.
21. Lorenzetti, D. L., &Ghali, W. A. (2013). Reference management software for systematic re- views and meta-analyses: an exploration of usage and usability. BMC medical research me- thodology, 13, 141.
22. Mosca, Rodrigo Crespo ., Ong, Adrian A.,Albasha, Omar., Bass, Kathryn.,Arany, Praveen (2019).Photobiomodulation Therapy for Wound Care: A Potent, Noninvasive, Photoceutical Approach, Advances in Skin & Wound Care,32(4),157-167.
23. Marín-Conde, F., Castellanos-Cosano, L., Pachón-Ibañez, J., Serrera-Figallo, M. A., Gu- tiérrez-Pérez, J. L., & Torres-Lagares, D. (2019). Photobiomodulation with low-level laser therapy reduces oral mucositis caused by head and neck radio-chemotherapy: prospective randomized controlled trial. International journal of oral and maxillofacial surgery, 48(7), 917–923.
24. Miller, M. M., Donald, D. V., & Hagemann, T. M. (2012). Prevention and treatment of oral mucositis in children with cancer. The journal of pediatric pharmacology and therapeutics:
JPPT : the official journal of PPAG, 17(4), 340–350.
25. Naidu, M. U., Ramana, G. V., Rani, P. U., Mohan, I. K., Suman, A., & Roy, P. (2004). Che- motherapy-induced and/or radiation therapy-induced oral mucositis--complicating the treat- ment of cancer. Neoplasia (New York, N.Y.), 6(5), 423–431.
26. Pratesi, N., Mangoni, M., Mancini, I., Paiar, F., Simi, L., Livi, L., Cassani, S., Buglione, M., Grisanti, S., Almici, C., Polli, C., Saieva, C., Magrini, S. M., Biti, G., Pazzagli, M., & Orlan- do, C. (2011). Association between single nucleotide polymorphisms in the XRCC1 and RAD51 genes and clinical radiosensitivity in head and neck cancer. Radiotherapy and oncol-
ogy : journal of the European Society for Therapeutic Radiology and Oncology, 99(3), 356–
27. Rodríguez-Caballero, A., Torres-Lagares, D., Robles-García, M., Pachón-Ibáñez, J., González-Padilla, D., & Gutiérrez-Pérez, J. L. (2012). Cancer treatment-induced oral mucosi- tis: a critical review. International journal of oral and maxillofacial surgery, 41(2), 225–238.
28. Sonis S.T. A Comparison and Assessment of Scoring Scales for Mucositis. In: Handbook Oral Mucositis. Chap 6,pp 39-46,2012. Springer Healthcare, Tarporley.
29. Sonis, S. T., Sonis, A. L., & Lieberman, A. (1978). Oral complications in patients receiving treatment for malignancies other than of the head and neck. Journal of the American Dental Association (1939), 97(3), 468–472.
30. Sroussi, H. Y., Epstein, J. B., Bensadoun, R. J., Saunders, D. P., Lalla, R. V., Migliorati, C.
A., Heaivilin, N., &Zumsteg, Z. S. (2017). Common oral complications of head and neck cancer radiation therapy: mucositis, infections, saliva change, fibrosis, sensory dysfunctions, dental caries, periodontal disease, and osteoradionecrosis. Cancer medicine, 6(12), 2918–
31. Trotti, A., Bellm, L. A., Epstein, J. B., Frame, D., Fuchs, H. J., Gwede, C. K., Komaroff, E., Nalysnyk, L., &Zilberberg, M. D. (2003). Mucositis incidence, severity and associated out- comes in patients with head and neck cancer receiving radiotherapy with or without chemo- therapy: a systematic literature review. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 66(3), 253–262.
32. Verdi C. J. (1993). Cancer therapy and oral mucositis. An appraisal of drug prophylax- is. Drug safety, 9(3), 185–195.
33. Villa, A., & Sonis, S. T. (2016). Pharmacotherapy for the management of cancer regimen- related oral mucositis. Expert opinion on pharmacotherapy, 17(13), 1801–1807.
34. Vinesh E., Jeyapriya S M., Kumar M S., Arunachlam M. (2017).Photobiomodulation and oral wound healing.Indian J Multidiscip,7(2),129-34.
35. Vokurka, S., Bystrická, E., Koza, V., Scudlová, J., Pavlicová, V., Valentová, D., Visokaiová,
M., & Misaniová, L. (2006). Higher incidence of chemotherapy induced oral mucositis in fe- males: a supplement of multivariate analysis to a randomized multicentre study. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Can- cer, 14(9), 974–976.
36. Zecha, J. A., Raber-Durlacher, J. E., Nair, R. G., Epstein, J. B., Sonis, S. T., Elad, S., Ham- blin, M. R., Barasch, A., Migliorati, C. A., Milstein, D. M., Genot, M. T., Lansaat, L., van der Brink, R., Arnabat-Dominguez, J., van der Molen, L., Jacobi, I., van Diessen, J., de Lange, J., Smeele, L. E., Schubert, M. M., … Bensadoun, R. J. (2016). Low level laser ther- apy/photobiomodulation in the management of side effects of chemoradiation therapy in head and neck cancer: part 1: mechanisms of action, dosimetric, and safety considera- tions. Supportive care in cancer : official journal of the Multinational Association of Suppor- tive Care in Cancer, 24(6), 2781–2792.
37. Zadik, Y., Arany, P. R., Fregnani, E. R., Bossi, P., Antunes, H. S., Bensadoun, R. J., Gueiros, L. A., Majorana, A., Nair, R. G., Ranna, V., Tissing, W., Vaddi, A., Lubart, R., Migliorati, C.
A., Lalla, R. V., Cheng, K., Elad, S., & Mucositis Study Group of the Multinational Associa- tion of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) (2019). Systematic review of photobiomodulation for the management of oral mucositis in cancer patients and clinical practice guidelines. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 27(10), 3969–3983.
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.