Effectiveness of low-level laser therapy for oral mucositis prevention in patients undergoing chemoradiotherapy for the treatment of head and neck cancer: A systematic review and meta-analysis

Oral Oncology 102 (2020) 104524

Contents lists available at ScienceDirect

Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology

Review

Effectiveness of low-level laser therapy for oral mucositis prevention in patients undergoing chemoradiotherapy for the treatment of head and neck cancer: A systematic review and meta-analysis

T

Vinícius Hallan Souza de Limaa,⁎, Olavo Barbosa de Oliveira-Neto (DDS, MSc, PhD student)b, Pedro Henrique da Hora Sales (DDS, OMFS, MSC student)c, Thiago da Silva Torres (DDS, OMFS, PhD)d, Fernando José Camello de Lima (DDS, PhD)d a

Institute of Health and Biological Sciences (ICBS), Federal University of Alagoas (UFAL), Maceió, Alagoas, Brazil Professor, Department of Anatomy, Biosciences Center (CB), Federal University of Pernambuco (UFPE), Recife, PE, Brazil School of Dentistry, Prothesis and Bucal-facial Surgery Department, Federal University of Pernambuco (UFPE), Recife, Pernambuco, Brazil d Department of Morphology, Human Anatomy Area, Institute of Health and Biological Sciences, Federal University of Alagoas (UFAL), Maceió, Alagoas, Brazil b c

ARTICLE INFO

ABSTRACT

Keywords: Low-level laser therapy Oral mucositis Chemoradiotherapy Head and neck cancer

Oral Mucositis is a frequent and debilitating inflammatory complication in patients with head and neck malignancies and may lead to unplanned treatment interruptions due to intense pain and dysphagia. This systematic review with meta-analysis was performed to determine the effectiveness of low-level laser therapy in preventing oral mucositis in this context. The following databases were searched through September 2018, with last search performed on May 2019, for clinical trials: MEDLINE via PubMed, Cochrane Central, Scopus, Lilacs, ISI Web of Science and SIGLE via Open Grey. From 14,525 records, 4 studies were included in the review and 3 studies were included in meta-analysis. Data from 500 patients (mean age of 53.595 and 54.14 for intervention and control groups, respectively) were analysed. Meta-analysis showed that laser therapy prevents oral mucositis incidence in 28% and 23% of cases during the third and fourth follow-up week, respectively, in comparison to a placebo-treated control group. There was no statistically significant difference the prevention of pain; dysphagia and quality of life were not analysed due to missing. Laser therapy was effective in preventing oral mucositis from the 15th to the 45th days of chemoradiotherapy. However, new primary studies with low risk of bias are needed so a higher scientific evidence can be obtained.

Introduction Oral Mucositis (OM) is a frequent and debilitating inflammatory complication in patients with head and neck malignancies. Severe OM has a 43% incidence in patients undergoing chemoradiotherapy (CRT) for head and neck cancer (HNC) treatment [1–4]. It features a complex pathogenesis that involves microvascular injury, pro-inflammatory cytokines, and host-microbiome interactions, which generates oxidative stress and reactive oxygen species. These cause inflammation in the oral mucosa that is associated to subsequent erosions and opportunistic infections that can occur due to the oral epithelium ulceration or immunodeficiency [2].

The primary morbidity of OM occurs due to intense pain, which is usually caused by ulcerative lesions and can be associated with increasing doses of opioids, which may rapidly develop tolerance [3–4]. OM can also impair oral functions or even lead to poor nutrition, which may reduce quality of life and increase weight loss. In severe cases, it may require the use of a gastrectomy tube or parenteral nutrition [5]. In addition, patients with HNC are also more likely to experience impaired nutrition, which negatively affects tissue healing and infection resistance [6–7]. Non-keratinized tissues are often affected by radiation [4]. Salivary glands are highly sensitive to radiation, showing reduced salivary flow rates [8–9] and progressive inflammatory and degenerative changes in

Abbreviations: OM, oral mucositis; LLLT, low-level laser therapy; HNC, head and neck cancer; OO, oral oncology; RO, radiotherapy and oncology; CRT, chemoradiotherapy ⁎ Corresponding author at: Institute of Health and Biological Sciences (ICBS), Federal University of Alagoas (UFAL), Av. Lourival Melo Mota, S/N – Tabuleiro dos Martins, Maceió, AL 57072-900, Brazil. E-mail address: [email protected] (V.H.S. de Lima). https://doi.org/10.1016/j.oraloncology.2019.104524 Received 17 June 2019; Received in revised form 7 December 2019; Accepted 13 December 2019 1368-8375/ © 2019 Elsevier Ltd. All rights reserved.

Oral Oncology 102 (2020) 104524

V.H.S. de Lima, et al.

Fig. 1. Flow diagram illustrating the study selection process in the systematic review and meta-analysis. Selection process Kappa Index = 99.9%; Eligibility process Kappa Index = 83.3%.

tissue cells [10]. Chemotherapy may also cause xerostomia [11], which may be followed by oral tenderness, pain, and burning sensation within the oral mucosa [12]. Ulcerative mucositis is one of the major limitations to continuous, uninterrupted radiotherapy and concurrent CRT in the management of HNC. It negatively impacts on cancer treatment, and the head and neck region is the most affected site by CRT interruption [13] due to a high residual tumor cells proliferation risk, which may cause recurrence [14]. Currently, OM treatment is based on symptomatic care due to the lack of effective treatments [15–16]. Several studies have shown that low-level laser therapy (LLLT) is effective in preventing OM in patients undergoing CRT for the treatment of HNC [17–21]. By preventing this comorbidity from occurring, a sequence of potentially beneficial tissue reactions linked to cellular homeostasis can be triggered, and, as a result, cellular metabolic rate, collagen fibers, and DNA and RNA synthesis can increase. LLLT can also induce angiogenesis and increase the liberation of growth factors and boost leukocyte activity, which can reduce CRT toxicity [22]. The choice regarding laser parameters often relies on the practitioner’s personal experience, rather than on a previously stablished and scientifically sound guideline [23]. Laser parameters such as wavelength, power, fluency, irradiated area, and frequency of doses

substantially improves complexity in establishing a proper dosimetry [24]. A recent systematic review [24] showed that most used laser parameters are set in the following intervals: 632.8–685 nm (wavelength); 1.8 J/cm2 to 3.0 J/cm2 (fluency); 10–60 mW (power); and 0.8 to 3.0 J (total energy). Thus, this systematic review with meta-analysis was performed to answer the following focused question: what is the effectiveness of the low-level laser in the prevention of oral mucositis in patients undergoing chemoradiotherapy for the treatment of head and neck cancers? Material and methods The present study developed and registered a protocol a priori at the International Prospective Register of Systematic Reviews (PROSPERO – Record: CRD42018108380), available at: http://www.crd.york.ac.uk/ PROSPERO/display_record.php?ID=CRD42018108380). This systematic review with meta-analysis was performed following the PRISMA statement [25]. Eligibility criteria This study included randomized clinical trials regarding the use of low-level laser therapy for oral mucositis prevention in patients 2

Oral Oncology 102 (2020) 104524

3

43 43 43 43 and and and and – Mean values

Sample characteristics and Chemoradiotherapy protocol of included studies. M = Male; F = Female; SD = Standard Deviation; IG = Intervention Group; CG = Control Group; * From Monday to Friday.

125

54–8.5

52.5–10

53.3725

54.3625

–

–

–

–

22 22 22 22 1, 1, 1, 1, Cisplatin Cisplatin Cisplatin Cisplatin 5 days/week* 5 days/week* 5 days/week* 5 days/week* 1.8 2.0 2.0 1.8–2.0 55.70 (±8.60) 52.60 (±12.51) 55.95 (±11.61) 53.2 (±10.3) 53.50 (±6.90) 51.71 (±11.94) 55.18 (±11.70) 53.1 (±9.4) 40–7 48–7 92–18 30–8 42–5 50–5 97–14 27–10 Radiotherapy and Oncology Oral Oncology Radiotherapy and Oncology Radiation Oncology Biol. Phys.

CG

47 55 110 38

Gy/fraction IG IG IG

CG

Patients sex (M-F) Sample size

Antunes et al. [29] Gautam et al. [32] Gautam et al. [30] Gouvêa de Lima et al. [31]

The following characteristics of included studies were collected and divided into an intervention group (IG) and a control group (CG): sample size, mean age, patients’ sex. CRT details were divided in dose per fraction or drug type (for radiotherapy and chemotherapy, respectively) and posology (Table 1). Laser parameters were: Laser type, Wavelength (nm), Laser Fluency (J/cm2 per point), Power (mW), Energy (J per point), Spot size (cm2) and irradiated sites. Data extraction focused on sample characteristics, laser parameters, CRT details, primary and secondary outcomes data. A few laser parameters that were not reported in some studies, were calculated from other reported outcomes using physical equations (Table 2). Data regarding the primary outcome (OM incidence) were extracted and the absence or presence of oral mucositis was defined according to the presence of ulceration in the oral mucosa according to the RTOG Acute Radiation Morbidity Scoring [28]. Criteria score grades from 2 to

Journal

Data extraction

Study and year

Table 1 Summary of sample characteristics and CRT protocol of included studies.

Mean Age (SD)

CG

Radiotherapy protocol

Online searches were performed using Medline via PubMed (1966–2018), Cochrane CENTRAL (up to 2018), Scopus (1996–2018), SIGLE via OpenGrey (1980–2018), Lilacs (1982–2018) and ISI Web of Science (1945–2018). Search strategies were created according to the following MeSH terms: “Head and Neck Neoplasms”, “Drug Therapy”, “Radiotherapy”, “Low-Level Light Therapy”, “Lasers, Semiconductor”, “prevention and control”, ”Stomatitis“, ”Stomatitis, Aphthous“, “Oral Mucositis”. Search strategies were then created specifically for each database using these terms, as follows: Pubmed and Scopus – (((((((”Head and Neck Neoplasms“[Mesh]) AND ”Drug Therapy“[Mesh]) AND ”Radiotherapy“[Mesh]) AND ”Low-Level Light Therapy“[Mesh]) OR ”Lasers, Semiconductor“[Mesh]) AND ”prevention and control“ [Subheading]) AND ”Stomatitis“[Mesh]) OR ”Stomatitis, Aphthous“[Mesh]; Cochrane Central and ISI Web of Science - ((Head and Neck Neoplasms) and (Drug Therapy) and (Radiotherapy) and (Low-Level Laser Therapy) and (Stomatitis) or (Oral Mucositis)); Lilacs – ((Head and Neck Neoplasms) and (Drug Therapy) and (Radiotherapy) and (Low-Level Laser Therapy) and (Stomatitis) or (Oral Mucositis)); SIGLE via OpenGrey – Oral mucositis. The last search was performed on May 2019. A manual reference search was also performed to seek for any potential records that could be considered for inclusion (Fig. 1). Searches were carried out by two independent reviewers (V.H.S.L. and F.J.C.L.), who conducted separately and independently the study selection process. The initial screening was performed by title and abstract reading only. Eligible studies were selected for full text reading. The final decision about study inclusion was obtained by mutual agreement between reviewers. In cases of disagreement, a third experienced reviewer (O.B.O.N.) [26–27] would be consulted for a tiebreaker vote. Kappa index was calculated to determine the inter-reviewer agreement in studies screening (title and abstract), eligibility (full text reading), and risk of bias assessment. The corresponding authors of included papers would be consulted via e-mail if more details on studies were necessary (Fig. 1).

Posology

Study selection

47 55 111 37

Drug type

Chemotherapy protocol

undergoing chemoradiotherapy for head and neck cancer treatment. Exclusion criteria were: Transversal observational studies, case reports, systematic and literature reviews, animal or cellular sample studies; studies that used low-level laser therapy for oral mucositis treatment; inappropriately described intervention papers; studies that performed other treatments that low-level laser therapy only; studies with incomplete follow-up data; studies without sham laser on the control group; and studies that included patients with any systemic comorbidity that could impair the tissue healing process (i.e. diabetes mellitus). There were no exclusions regarding the language of studies.

Application days

V.H.S. de Lima, et al.

Oral Oncology 102 (2020) 104524

V.H.S. de Lima, et al.

Table 2 Summary of laser parameters and outcomes of included studies. Study year

Antunes et al. [29]

Journal

Gouvêa de Lima et al. [31]

Radiotherapy and Oncology Oral Oncology Radiotherapy and Oncology Radiation Oncology Biol. Phys

Mean Values

–

Gautam et al. [32] Gautam et al. [30]

Laser type

Wave length (nm)

Fluency (J/ cm2)

Power (mW)

Energy (J/ dot)

Spot size (cm2)

Grades 0–1 O.M.**

Grades 2–4 O.M.**

Mean Pain Grades (VAS)

IG

CG

IG

CG

IG

CG

InGaAlP

660

4

100

1*

0.24

28

10

19

37

NS

NS

He-Ne He-Ne

632.8 632.8

3.5 3

24 24

3.48* 3*

1 1

8 29

0 3

47 82

55 107

4.26 NS

6.76 NS

GaAlAr

660

2.5

10

0.1*

0.04*

15

12

22

26

NS

NS

–

646.4

3.25

39.5

0.57

Laser properties and outcomes results obtained by full included studies reading and calculus using obtained data. * Data obtained with calculus (E = P·T ; F = E / A ; I = P·A ; E = energy; P = Power; T = Time; A = Area; I = Intensity; F = Fluency). ** Collected in the last week of LLLT. NS = Not Specified; VAS = Visual Analog Scale.

4 were considered as presence of oral mucositis due to the presence of ulceration. Data regarding secondary outcomes (pain, dysphagia, and quality of life) were also collected and were stablished a priori in the study protocol. Pain scales were assessed according to the Visual Analog Scale (VAS), considering grades ≥7 as severe pain (Table 2).

groups, respectively. Primary outcome – Oral mucositis incidence Days 1–7 (1st week): There were no events associated to the first week. Hence, meta-analysis could not be performed for the first week of treatment. Days 8–14 (2nd week): Meta-analysis was performed and showed a non-significant result (P = 0.93). This result indicates that there was no difference regarding laser irradiation to prevent OM grades II–IV (Fig. 2a). Also, there was a high level of heterogeneity for the articles assessed in this period (RR = 0.91, CI = 0.11–7.74, I2 = 88%, P = 0.003). Days 15–21 (3rd week): Meta-analysis was performed and showed a significant result (P < 0.00001). Laser therapy prevented 52% of OM incidence in grades II–IV in this period (Fig. 2b). Also, there was no heterogeneity in this period (RR = 0.48, CI = 0.38–0.60, I2 = 0%, P = 0.91). Days 22–28 (4th week): Meta-analysis was performed and also showed a significant result for this follow-up period (P < 0.00001). Laser therapy prevented 29% of OM incidence in grades II–IV (Fig. 2c). Also, there was no heterogeneity in this period (RR = 0.71, CI = 0.64–0.79, I2 = 0%, P = 0.64). Days 29–35 (5th week): Meta-analysis was performed and showed a significant result for this follow-up period as well (P < 0.00001). Laser therapy prevented 23% of OM incidence in grades II–IV (Figure 2.d). There was no heterogeneity between assessed articles for this follow-up period (RR = 0.77, CI = 0.70–0.85, I2 = 0%, P = 0.40). Days 36–42 (6th week): Meta-analysis was performed and showed a significant result for this follow-up period (P = 0.006). Laser therapy prevented 18% of OM incidence in grades II–IV (Fig. 2e). However, this period showed a moderate (yet non-significant) heterogeneity (RR = 0.82, CI = 0.71–0.94, I2 = 68%, P = 0.08). Days 43–45 (part of the 7th week): This follow-up period showed similar results to the previous week of treatment. Meta-analysis was performed and showed a significant result (P = 0.0006). Laser therapy prevented 19% of OM incidence in grades II–IV (Fig. 2f). However, this period also showed a moderate (yet non-significant) heterogeneity (RR = 0.81, CI = 0.71–0.91, I2 = 56%, P = 0.13).

Risk of bias assessment The risk of bias of included studies was assessed independently by two assessors (V.H.S.L. and F.J.C.L.), and disagreements were also resolved by means of discussion and consensus. In cases of disagreement, a third reviewer would be consulted (O.B.O.N.). The Risk of Bias tool (RoB) of Higgins and Green (2011), developed by the Cochrane Collaboration, was used to assess the randomized clinical trials. According to this tool, the risk of bias was classified as low risk of bias (+), unclear risk of bias (?), or high risk of bias (–) on each of the following items: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias. Data analysis Data were grouped into evidence tables and a descriptive synthesis was made to verify possible variations among studies. Meta-analysis was performed using the randomized effect model, in which the categorical outcomes (OM, pain, dysphagia) were expressed by means of relative risk. The confidence and significance levels were set at, respectively, 95% and 5%. Heterogeneity between studies was calculated using the I2 statistics (Higgins and Green, 2008). Sensitivity analysis was planned by excluding from meta-analysis studies with high risk of bias and by exploring inconsistencies among studies methods, specially LLLT parameters. Meta-analysis was performed using the Review Manager 5.3 software. The Microsoft Excel 2007 software was used to calculate the weighted means regarding age and sex of participants, as well as laser parameters. Results From a total of 14,525 initial records, 4 studies were included for risk of bias assessment (kappa index: 0.99 - very good agreement) [29–32]. From the 4 included studies, only 3 were included in metaanalysis because one study used a laser which power was almost 4 times higher than the power reported in the other included studies (Table 2). Included studies comprised a total of 500 patients (426 male and 74 female). Intervention and control groups had 250 patients, each. Mean age was of 53.595 years and 54.14 years for intervention and control

Secondary outcomes Two articles used similar methodologies to assess the outcome pain between days 42–45 and considered the VAS score ≥7. Hence, these articles were included for meta-analysis regarding this outcome, which showed no difference regarding the use of laser therapy to prevent the incidence of pain (P = 0.31). In addition, meta-analysis showed a high and statistically significant heterogeneity (RR = 0.49, 4

Oral Oncology 102 (2020) 104524

V.H.S. de Lima, et al.

Fig. 2. Forest plot of random effects meta-analysis assessing oral mucositis incidence. (a) Days 8–14; (b) Days 15–21; (c) Days 22–28; (d) Days 29–35; (e) Days 35–42; (f) Days 43–45. M-H: Mantel-Haenzel. CI: Confidence interval. τ: Kendall tau. z: z test. Journal acronyms were used to differentiate articles when author and year are not capable of. Fig. 3. Forest plot of random effects metaanalysis assessing the outcome pain. M-H: Mantel-Haenzel. CI: Confidence interval. Tau2: Kendall tau. z: z test. OO: Oral Oncology.

CI = 0.13–1.92, I2 = 85%, P = 0.009) (Fig. 3). A third article [29] divided IG and CG in different degrees according to the VAS scale (0; 1–2; 3–4; 5–7; 8–10); however, this study could not be included in metaanalysis due to missing data caused by this subdivision.

risk of bias; Gautam [32] (OO) presented 4/7 topics with low risk of bias and 3/7 topics with unclear risk of bias (Figs. 4 and 5) The kappa index showed an inter-reviewer agreement of 0.89 (very good agreement).

Risk of bias assessment

Discussion

No study presented low bias risk in all topics. Antunes [29] and Gautam [30] (RO) showed 5/7 topics with low risk of bias and 2/7 with unclear risk of bias; Gouvêa de Lima [31] presented 5/7 topics with low risk of bias, 1/7 topics with unclear risk of bias and 1/7 topics with high

The effectiveness of the low-level laser in preventing oral mucositis incidence in patients undergoing chemoradiotherapy for the treatment of head and neck cancers was assessed in the present study. Our findings showed that LLLT significantly prevents the incidence of oral 5

Oral Oncology 102 (2020) 104524

V.H.S. de Lima, et al.

convert them to the RTOG scoring criteria. Regarding secondary outcomes, two studies were included for metaanalysis of the outcome pain. Dysphagia and quality of life were not included in meta-analysis due to lack of comparable data, whereas only one study assessed dysphagia [31], and quality of life was measured by different questionnaires in different studies [29,33]. Grades 0–1 were classified as absence of OM or as an acceptable state of health because these scores include patients that do not need analgesics or anti-inflammatory drugs; studies that used other scales were excluded from meta-analysis because other scoring systems do not provide details of the patient condition. In addition, one study [29] was excluded from meta-analysis due to laser power incompatibility (laser power = 100 mW). A study [19] used a laser with 100 mW, which did not prevent oral mucositis and was associated with a decrease in concentrations of Vascular Endothelial Growth Factor, which may reduce angiogenesis in the oral mucosa and, subsequently, reduce its healing capacity. This would lead to a lower ability to prevent OM and not the other way around. Therefore, considering these reasons, this study was excluded from meta-analysis. Other laser parameters (such as spot size) were obtained by calculus, when necessary, to enable data comparison among studies (Table 2). Laser therapy was performed 5 days per week (Monday to Friday) for 45 days, prior to every radiotherapy fraction. Laser therapy was effective in preventing the incidence of OM from the 3 rd week to the 6th week of treatment. The following reductions of new cases of OM were shown: 3rd week (days 15–21) = 52%; 4th week (days 22–28) = 29%; 5th week (days 29–35) = 23%; 6th week (days 36–42) = 18%; and 7th week = 19%. Hence, despite its effectiveness, the preventive factor of laser therapy gradually decreased during follow-up. Laser therapy provided a preventive effect and reduced the incidence of OM, especially in the first weeks of cancer treatment. Therefore, despite the limitations of the present study, it may be suggested that the cumulative effect of cancer therapies make patients more susceptible to OM, which reduces the preventive effectiveness of the Laser. The incidence of severe pain (VAS ≥ 7) presented different results between studies. The study of Gouvêa de Lima [31] showed almost no difference between irradiating or not the oral mucosa, indicating no effectiveness of LLLT. On the other hand, Gautam [32] (OO) showed that LLLT prevents the incidence of severe pain. Included studies presented high heterogeneity, which impaired a solid evidence establishment about the laser in the pain control on OM. Although laser parameters were similar, laser type and spot size measures significantly differed between studies; however, no relationship with pain relief was found. Moreover, meta-analysis also lacked studies with low risk of bias. The use of opioid analgesics was reported on included studies. A total of 56 of 250 patients in IG (22.4%) and 118 of 250 patients in CG (47.2%) needed opioid analgesics, indicating a reduction of approximately 24.8% in its use when LLLT was applied. Gouvêa de Lima et al. [31] was the only study that presented no difference between groups, collaborating with the previous statement of LLLT lack of effectiveness. Risk of bias assessment showed that the included studies did not have high methodological quality, selective reporting and other sources of bias were the main items that increased the risk of bias in included studies. Missing data or incompatible data measurement among some included studies regarding laser parameters and protocols, OM grades, and sample characteristics impaired a robust evidence construction. Therefore, future primary studies should focus in correct these flaws so future systematic reviews can present sound and robust scientific evidence. A previous systematic review[36], in which the preventive effectiveness of LLLT in HNC patients submitted to cancer therapies was assessed and showed a preventive factor of 172%, which differs from our results. This can be explained because the authors analysed studies

Fig. 4. Risk of bias graph with authors judgments about each topic, presented as percentages across all included studies.

Fig. 5. Risk of bias summary with judgments about each item across included studies. (+) = Low risk of bias; (?) = Unclear risk of bias; (−) = High risk of bias; OO = Oral Oncology; RO = Radiotherapy and Oncology.

mucositis from the 3rd to the 7th weeks of treatment. Two of the eligible studies for full-text reading [30,33] presented similar data. We contacted the research group asking for clarifications and, after a thorough assessment, we concluded that both studies presented duplicated data. Hence, the latest study was excluded from the present systematic review. The majority of the included studies did not report any topic regarding surgical procedures that were performed before, during or after chemoradiotherapy, with the exception of one study [29], which excluded patients that could be eligible for a surgical procedure, eliminating this confounding factor. One of the four included studies was not considered for meta-analysis due to the use of a laser with a discrepant power setting and due to the use of a different score of oral mucositis. Three different scoring systems were used to classify oral mucositis in the present study [28,34–35], whereas the most used score was the Toxicity Criteria of the Radiation Therapy Oncology Group (RTOG). Thus, different scoring systems were analyzed as an attempt to 6

Oral Oncology 102 (2020) 104524

V.H.S. de Lima, et al.

with patients undergoing radiotherapy or chemotherapy alone and not both protocols in the same treatment (chemoradiotherapy). If administrated in the same treatment, CRT impacts on OM by worsening its symptoms. Moreover, OM may be more severe in head and neck cancer patients undergoing CRT, appearing earlier in the treatment course and having a longer duration [16]. A systematic review [15] stated and recommended a specific laser wavelength to obtain positive results in radiotherapy patients (623.8 nm); however, was not possible to stablish guidelines for CRT patients due to inconsistences among HNC studies. It’s expected that recommendations regarding laser parameters will be consolidated with new studies in the area, which would facilitate a future meta-analysis. Differences in laser settings, techniques of application, and data measurements can be considered as limitations of the present study. Hence, there is a need to establish a laser settings protocol to maximize OM prevention rates.

[11] [12] [13]

[14] [15]

[16]

[17]

Conclusion Low-level laser therapy was statistically effective in preventing the incidence of oral mucositis. The higher percentage of prevention occurred from 15 to 21 days of follow-up and gradually decreased until the end of the follow-up (days 42–45). Low-level laser therapy was not effective in preventing pain incidence. A robust evidence was not obtained because included studies were assessed as of moderate risk of bias.

[18]

[19]

Funding sources

[20]

This research was funded by the authors and did not receive any specific grant from funding agencies in the public, commercial, or notfor-profit sectors.

[21]

Declaration of Competing Interest

[22]

The authors declared that there is no conflict of interest.

[23]

References [24]

[1] Trotti A, Bellm LA, Epstein JB, Frame D, Fuchs HJ, Gwede CK, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol 2003;66:253–62. https://doi.org/10.1016/S0167-8140(02) 00404-8. [2] Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, et al. Perspectives on cancer therapy-induced mucosal injury. Cancer 2004;100:1995–2025. https://doi.org/10. 1002/cncr.20162. [3] Epstein JB, Miaskowski C. Oral pain in the cancer patient. JNCI Monogr 2019;2019:45–53. https://doi.org/10.1093/jncimonographs/lgz003. [4] Lalla RV, Saunders DP, Peterson DE. Chemotherapy or radiation-induced oral mucositis. Dent Clin North Am 2014;58:341–9. https://doi.org/10.1016/j.cden.2013. 12.005. [5] Duncan GG, Epstein JB, Tu D, El Sayed S, Bezjak A, Ottaway J, et al. Quality of life, mucositis, and xerostomia from radiotherapy for head and neck cancers: a report from the NCIC CTG HN2 randomized trial of an antimicrobial lozenge to prevent mucositis. Head Neck 2005;27:421–8. https://doi.org/10.1002/hed.20162. [6] Elting LS, Keefe DM, Sonis ST, Garden AS, Spijkervet FKL, Barasch A, et al. Patientreported measurements of oral mucositis in head and neck cancer patients treated with radiotherapy with or without chemotherapy: demonstration of increased frequency, severity, resistance to palliation, and impact on quality of life. Cancer 2008;113:2704–13. https://doi.org/10.1002/cncr.23898. [7] Rapoport AP, Miller Watelet LF, Linder T, Eberly S, Raubertas RF, Lipp J, et al. Analysis of factors that correlate with mucositis in recipients of autologous and allogeneic stem-cell transplants. J Clin Oncol 1999;17:2446–53. https://doi.org/10. 1200/jco.1999.17.8.2446. [8] Valdez IH, Atkinson JC, Ship JA, Fox PC. Major salivary gland function in patients with radiation-induced xerostomia: flow rates and sialochemistry. Int J Radiat Oncol Biol Phys 1993;25:41–7. https://doi.org/10.1016/0360-3016(93)90143-J. [9] Moroney LB, Helios J, Ward EC, Crombie J, Burns CL, Yeo SQ, et al. Radiotherapy for cutaneous head and neck cancer and parotid tumours: a prospective investigation of treatment-related acute swallowing and toxicity patterns. Support Care Cancer 2019;27:573–81. https://doi.org/10.1007/s00520-018-4352-5. [10] Henson BS, Inglehart MR, Eisbruch A, Ship JA. Preserved salivary output and xerostomia-related quality of life in head and neck cancer patients receiving

[25] [26]

[27]

[28]

[29]

[30]

[31]

[32] [33]

7

parotid-sparing radiotherapy. Oral Oncol 2001;37:84–93. https://doi.org/10.1016/ S1368-8375(00)00063-4. McDonald E, Marino C. Dry mouth: diagnosing and treating its multiple causes. Geriatrics 1991;46:61–3. Holmes S. Xerostomia: aetiology and management in cancer patients. Support Care Cancer 1998;6:348–55. https://doi.org/10.1007/s005200050176. Bese NS, Hendry J, Jeremic B. Effects of prolongation of overall treatment time due to unplanned interruptions during radiotherapy of different tumor sites and practical methods for compensation. Int J Radiat Oncol Biol Phys 2007;68:654–61. https://doi.org/10.1016/j.ijrobp.2007.03.010. Russo G, Haddad R, Posner M, Machtay M. Radiation treatment breaks and ulcerative mucositis in head and neck cancer. Oncologist 2008;13:886–98. https:// doi.org/10.1634/theoncologist.2008-0024. Oton-Leite AF, Silva GBL, Morais MO, Silva TA, Leles CR, Valadares MC, et al. Effect of low-level laser therapy on chemoradiotherapy-induced oral mucositis and salivary inflammatory mediators in head and neck cancer patients. Lasers Surg Med 2015;47:296–305. https://doi.org/10.1002/lsm.22349. Sroussi HY, Epstein JB, Bensadoun RJ, Saunders DP, Lalla RV, Migliorati CA, et al. Common oral complications of head and neck cancer radiation therapy: mucositis, infections, saliva change, fibrosis, sensory dysfunctions, dental caries, periodontal disease, and osteoradionecrosis. Cancer Med 2017;6:2918–31. https://doi.org/10. 1002/cam4.1221. Antunes HS, Schluckebier LF, Herchenhorn D, Small IA, Araújo CMM, Viégas CMP, et al. Cost-effectiveness of low-level laser therapy (LLLT) in head and neck cancer patients receiving concurrent chemoradiation. Oral Oncol 2016;52:85–90. https:// doi.org/10.1016/j.oraloncology.2015.10.022. Benasso M, Corvò R, Ponzanelli A, Sanguineti G, Ricci I, Pallestrini E, et al. Alternating gemcitabine and cisplatin with gemcitabine and radiation in stage IV squamous cell carcinoma of the head and neck. Ann Oncol 2004;15:646–52. https://doi.org/10.1093/annonc/mdh138. Lopes NNF, Plapler H, Chavantes MC, Lalla RV, Yoshimura EM, Alves MTS. Cyclooxygenase-2 and vascular endothelial growth factor expression in 5-fluorouracil-induced oral mucositis in hamsters: evaluation of two low-intensity laser protocols. Support Care Cancer 2009;17:1409–15. https://doi.org/10.1007/ s00520-009-0603-9. Migliorati C, Hewson I, Lalla RV, Antunes HS, Estilo CL, Hodgson B, et al. Systematic review of laser and other light therapy for the management of oral mucositis in cancer patients. Support Care Cancer 2013;21:333–41. https://doi.org/ 10.1007/s00520-012-1605-6. Bensadoun RJ, Franquin JC, Ciais G, Darcourt V, Schubert MM, Viot M, et al. Lowenergy He/Ne laser in the prevention of radiation-induced mucositis: a multicenter phase III randomized study in patients with head and neck cancer. Support Care Cancer 1999;7:244–52. https://doi.org/10.1007/s005200050256. Zanin T, Zanin F, Carvalhosa AA, De Souza Castro PH, Pacheco MT, Zanin ICJ, et al. Use of 660-nm diode laser in the prevention and treatment of human oral mucositis induced by radiotherapy and chemotherapy. Photomed Laser Surg 2010;28:233–7. https://doi.org/10.1089/pho.2008.2242. Chung H, Dai T, Sharma SK, Huang YY, Carroll JD, Hamblin MR. The nuts and bolts of low-level laser (Light) therapy. Ann Biomed Eng 2012;40:516–33. https://doi. org/10.1007/s10439-011-0454-7. Peralta-Mamani M, da Silva BM, da Silva Pinto AC, Rubira-Bullen IRF, Honório HM, Rubira CMF, et al. Low-level laser therapy dosimetry most used for oral mucositis due to radiotherapy for head and neck cancer: a systematic review. Crit Rev Oncol Hematol 2019;138:14–23. https://doi.org/10.1016/j.critrevonc.2019.03.009. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097. de Lima FJC, de Oliveira Neto OB, Barbosa FT, do Nascimento Galvão AM, Ramos FWS, de Lima CCF, et al. Is there a protocol in experimental skin wounds in rats using low-level diode laser therapy (LLDLT) combining or not red and infrared wavelengths? Systematic review. Lasers Med Sci 2016;31:779–87. https://doi.org/ 10.1007/s10103-016-1893-z. de Oliveira-Neto OB, Barbosa FT, de Sousa-Rodrigues CF, de Lima FJC. Quality assessment of systematic reviews regarding immediate placement of dental implants into infected sites: an overview. J Prosthet Dent 2017;117:601–5. https:// doi.org/10.1016/j.prosdent.2016.09.007. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European organization for research and treatment of cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341–6. https://doi.org/10.1016/ 0360-3016(95)00060-C. Antunes HS, Herchenhorn D, Small IA, Araújo CMM, Viégas CMP, Cabral E, et al. Phase III trial of low-level laser therapy to prevent oral mucositis in head and neck cancer patients treated with concurrent chemoradiation. Radiother Oncol 2013;109:297–302. https://doi.org/10.1016/j.radonc.2013.08.010. Gautam AP, Fernandes DJ, Vidyasagar MS, Maiya AG, Vadhiraja BM. Low level laser therapy for concurrent chemoradiotherapy induced oral mucositis in head and neck cancer patients - A triple blinded randomized controlled trial. Radiother Oncol 2012;104:349–54. https://doi.org/10.1016/j.radonc.2012.06.011. Gouvêa De Lima A, Villar RC, De Castro G, Antequera R, Gil E, Rosalmeida MC, et al. Oral mucositis prevention by low-level laser therapy in head-and-neck cancer patients undergoing concurrent chemoradiotherapy: a phase III randomized study. Int J Radiat Oncol Biol Phys 2012;82:270–5. https://doi.org/10.1016/j.ijrobp. 2010.10.012. Gautam AP, Fernandes DJ, Vidyasagar MS, Maiya GA. Oral Oncol 2012;48:893–7. https://doi.org/10.1016/j.oraloncology.2012.03.008. Gautam AP, Fernandes DJ, Vidyasagar MS, Maiya AG, Nigudgi S. Effect of low-level

Oral Oncology 102 (2020) 104524

V.H.S. de Lima, et al. laser therapy on patient reported measures of oral mucositis and quality of life in head and neck cancer patients receiving chemoradiotherapy – a randomized controlled trial. Support Care Cancer 2013;21:1421–8. https://doi.org/10.1007/ s00520-012-1684-4. [34] Hunter RD. WHO handbook for reporting results of cancer treatment. Int J Radiat Biol 1980;38:481-481. https://doi.org/10.1080/09553008014551861.

[35] Marrow BB. Common toxicity criteria. Encycl Pain 2013:706-706. https://doi.org/ 10.1007/978-3-642-28753-4_200424. [36] Bjordal JM, Bensadoun RJ, Tunèr J, Frigo L, Gjerde K, Lopes-Martins RA. A systematic review with meta-analysis of the effect of low-level laser therapy (LLLT) in cancer therapy-induced oral mucositis. Support Care Cancer 2011;19:1069–77. https://doi.org/10.1007/s00520-011-1202-0.

8