Photobiomodulation therapy on chemo- and radiotherapy induced oral conditions: an umbrella review.

Текст сохранён. Часть иллюстраций пока доступна только в первоисточнике; загрузка будет проверена повторно.

Introduction

Characterized as a debilitating condition of the oral epithelium, oral mucositis (OM) is one of the most common toxic side effects of chemo- and radiotherapy, affecting up to 90% of patients undergoing these treatments [ 1 , 2 ]. OM results in extremely painful erythematous/ulcerative lesions on non-keratinised mucosa, such as the tongue, buccal mucosa, oropharynx, and lips, which can prevent oral intake. Not only does it have a negative impact on the patient’s quality of life, but in cases of severe OM there is an increased risk of local and systemic infection and, a reduction or delay in antineoplastic treatment, which may have a worrying impact on prognosis, and an increase in the cost of patient management. [ 3 – 5 ].

Furthermore, OM is associated with increased mortality in patients undergoing haematopoietic cell transplantation (HCT) (also known as haematopoietic stem cell transplantation). Despite its potentially devastating consequences, OM remains a significant challenge for patients undergoing cancer therapy, and therefore the management of OM is critical to the well-being of oncology patients. [ 4 , 6 ].

Several interventions are currently available to prevent, relieve or alleviate the symptoms of OM, but their effectiveness remains uncertain. Basic oral care, anti-inflammatory agents, analgesics, photobiomodulation (PBM) and cryotherapy are the most common options [ 7 ]. PBM, also known as Low Level Laser Therapy (LLLT), is a non-invasive and non-thermal treatment that involves the application of low-level light sources of a specific wavelength to injured areas over a period of time to promote tissue repair and reduce inflammation and pain [ 8 , 9 ]. The mechanism remains unclear, but evidence suggests that PBM acts on mitochondrial cytochrome C oxidase (CCO), which activates secondary signalling pathways leading to increased levels of ATP, cAMP and reactive oxygen species (ROS), promoting tissue regeneration [ 8 , 9 ].

PBM has extensive applications in the prevention and treatment of OM in cancer patients undergoing various treatments. PBM is effective in preventing and treating OM in patients undergoing cancer treatment, such as high-dose chemotherapy for haematopoietic stem cell transplantation (HSCT) and radiotherapy for head and neck (H&N) cancer without concurrent chemotherapy (CT) [ 7 ]. In a recent guideline update, prevention of OM with intraoral PBM therapy was recommended in patients undergoing HSCT or in patients receiving H&N radiotherapy with or without CT [ 10 ].

Although many studies have evaluated the efficacy of PBM in the prevention and treatment of OM in cancer patients, the quality of these studies is variable and there is no consensus on laser parameters such as wavelength, power, amount and rate of energy delivered to the tissue, and time [ 7 , 11 ]. Another explanation for ambiguous recommendations is the wide variety of protocols that can be applied, which exacerbates the lack of agreement on laser parameters and leads to different outcomes [ 12 ].

Therefore, we conducted an umbrella review to assess the level of evidence from systematic reviews (SRs) and meta-analysis that have examined PBMs the effect on the prevention and treatment of OM in patients undergoing CT and/or radiotherapy. Our objective was to offer an extensive overview of the current evidence and to pinpoint crucial elements that warrant enhancement in future investigations.

Materials and methods

We report this umbrella review upon the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline updated in 2020 [ 13 ]. The review protocol was approved a priori by all authors. The protocol was defined and discussed a priori with all authors and registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the following reference: CRD42023484013.

The review question was: “What is the level of evidence for the efficacy of PBM for chemo- and or/radiotherapy induced OM?”

The following PICO(S) statements were specified: Population (P) - cancer patients undergoing chemo- and/or radiotherapy with OM; Intervention (I) - PBM; Comparison (C) - placebo or related therapy; Outcome (O) - level of methodological and meta-analytic evidence of SRs; Setting (S) - SRs with or without meta-analysis.

2.1. Eligibility criteria

The following eligibility criteria were considered in the selection process: (1) the study must be a systematic review or a meta-analysis, (2) the data must be sourced from human studies, and (3) the study must examine the effectiveness of PBM in addressing chemo- and/or radiotherapy oral conditions. No restrictions on publication year or language were imposed.

2.2. Information sources search

Seven electronic databases were searched: Medline (via PubMed), Web of Science, EMBASE (The Excerpta Medica Database), LILACS (Latin-American scientific literature in health sciences), Cochrane Database of Systematic Reviews, CINAHL, and TRIP (Turning Research Into Practise). Grey literature was searched on https://opengrey.eu/ . We merged keywords and subject headings in accordance with the thesaurus of each database and applied exploded subject headings, with the following syntax: (chemotherapy-induced OR chemotherapy) AND laser.

2.3. Study selection

IR and JB independently screened the titles and abstracts of the research papers. The level of agreement between the reviewers was assessed using kappa statistics. Any paper identified as potentially eligible by either reviewer was ordered for full-text review, which was also independently screened by the reviewers. Any disagreements that arose were resolved by discussion with a third reviewer, CZ.

2.4. Data extraction process and data items

Two researchers, IR and JB independently extracted authors and year of publication, objective/focal question, databases searched, number of studies included, type of studies included, main outcomes and main conclusions. Disagreements were resolved by discussion with a third reviewer, CZ.

2.5. Methodological quality appraisal

Two researchers (IR and JB) used the Assessing the Measurement Tool to Assess Systematic Reviews (AMSTAR 2) to evaluate the methodological quality of the reviews included in the present study. The AMSTAR 2 tool is a 16-item assessment that determines the overall confidence in the results of the review [ 14 ]. The quality of the SRs was rated based on the AMSTAR guidelines as follows: High quality meant “Zero or one non-critical weakness,” Moderate quality meant “More than one non-critical weakness,” Low quality meant “One critical flaw with or without non-critical weaknesses,” and Critically Low quality meant “More than one critical flaw with or without non-critical weaknesses.” The AMSTAR 2 online tool ( https://amstar.ca/Amstar_Checklist.php , accessed in November 2023) was used to calculate the AMSTAR quality rate for each study.

2.6. Strength and validity of meta-analytic estimates

Data were processed and managed using Excel from MS Office 365. To assess the strength of meta-analytic estimates, according to Papadimitrou et al. [ 15 ], four levels of evidence have been defined: strong, very suggestive, suggestive and weak. [ 15 , 16 ] (Table 1 ):

Table 1 Categorization of meta-analytical estimates Evidence Conditions Strong ● > 1000 cases included in the meta-analysis * ● p-value ≤ 10 −6 [ 17 – 19 ]; ● I 2 < 50%; ● Null value was excluded by the 95% prediction interval; ● No evidence of small study effects or excess significance bias. Highly Suggestive ● > 1000 cases included in the meta-analysis * ● p-value ≤ 10 −6 [ 17 – 19 ] ● Largest study in the meta-analysis was statistically significant Suggestive ● > 1000 cases included in the meta-analysis * ● p-value ≤ 10 −6 [ 17 – 19 ] Weak ● None of the above conditions were verified * Based on a threshold that ensured 80% power for hazard ratios ≥ 1.20 (α = 0.05) [ 15 ]

The fail-safe number (FSN) for statistically significant meta-analysis was then determined using Rosenberg’s FSN method [ 20 ]. Subsequently, the median and range were calculated for each evidence grade (strong, highly suggestive, suggestive, and weak). If the FSN is small in comparison to the actual number of studies, it suggests that the results derived from the observed studies are not reliable due to publication bias, specifically the type of bias assumed by the method (i.e., a set of studies with null results is missing).

2.7. Overlap

Overlaps are identified as fundamental in well-done surveys, and this can be done comprehensively using the Corrected Covered Area (CCA) method. [ 21 ]. For this reason, we estimated CCA as percentages and categorised as per Pieper et al. [ 21 ]: 0–5 indicates low overlap, 6–10 moderate overlap, 11–15 high overlap, and > 15 very high overlap. A pairwise CCA grid was built in Microsoft Excel to identify which combinations of paired reviews had the highest overlap [ 21 ].

Results

3.1. Study selection

After a search of databases, a total of 1201 articles were retrieved for our search. Following removal of duplicates ( n = 141), a total of 1060 records were screened for eligibility criteria using titles and abstracts, and 984 were excluded after title and/or abstract screening. Of the 76 articles assessed for eligibility for full paper review, 55 were excluded, with reasons for exclusion detailed in Supplementary Data 1. A final number of 21 SRs [ 12 , 22 – 42 ] were therefore included in the qualitative synthesis. The PRISMA diagram is shown in Fig. 1 .

Fig. 1 PRISMA flowchart. Flow diagram visually summarising the screening and selection processes, and the numbers of articles recorded at each different stage

3.2. Studies characteristics

Overall, these SRs were mainly produced in Brazil ( n = 8) [ 12 , 23 , 25 , 27 , 31 , 36 , 42 ], China ( n = 2) [ 26 , 34 ] and the United Kingdom ( n = 2) [ 33 , 37 ], with contributions from groups in Canada [ 24 ], Iran [ 28 ], Israel [ 29 ], Indonesia [ 39 ], Malaysia [ 35 ], Norway [ 22 ], Singapore [ 40 ], Spain [ 38 ] and Syria [ 41 ] (Table 2 ). The populations included in the SRs were adults and children, with five reviews evaluating both. The type of cancer was heterogeneous, some studies didn’t specify the type of cancer, while others included more than one, such as head and neck and haematological cancers. The majority followed the PRISMA ( n = 14) [ 24 – 27 , 30 , 31 , 33 , 35 – 41 ].

In terms of risk of bias (RoB), the Cochrane ROB tool ( n = 9) [ 24 , 26 , 27 , 30 , 33 , 37 , 39 , 40 , 42 ], the Jadad scale ( n = 4) [ 22 , 23 , 28 , 34 ], the Cochrane ROB2 tool ( n = 4) [ 31 , 35 , 36 , 41 ], the PEDro scale ( n = 1) [ 25 ] and the Critical Appraisal Skills Program Español (CASPe) checklist ( n = 1) [ 38 ] were used, although one was not reported [ 12 ] and another was not assessed [ 29 ].

3.3. Methodological quality

When analysing the inter-rater reliability of the AMSTAR 2, good agreement was found (Cohen kappa score = 0.82; 95% confidence interval (CI): 0.78–0.86). None of the SRs were of high or moderate methodological quality. The majority were of critically low quality ( n = 15, 71.4%) and only 28.5% were of low quality (Table 3 ). The included meta-analyses predominantly failed to report the sources of funding for the studies included in the review ( n = 21, 95.5%), to explain the selection of study designs for inclusion in the review ( n = 20, 90.9%), to provide a list of excluded studies and the reasons for the exclusions ( n = 19, 86. 4%), to consider RoB in individual studies when interpreting and discussing the results of the review ( n = 14, 63.6%), to use a comprehensive literature search strategy ( n = 13, 59.1%), and to assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis ( n = 13, 86.7%, considering that 7 SRs did not perform meta-analysis).

3.4 Meta-analytic estimates of strength, validity and overlap

Of the 21 SRs, 15 conducted meta-analysis (71.4.1%) [ 22 – 28 , 30 , 31 , 34 – 37 , 40 , 42 ]. A total of 40 meta-analytic estimates were obtained and analysed. Overall, 27 meta-analyses used ratio measures (16 risk ratio and 11 odds ratio) and 13 difference measures (7 standardised mean difference [ 22 , 26 , 40 ] and 6 mean difference [ 22 , 26 – 28 , 36 ]). About 87.5% of the meta-analyses were significant ( n = 33), but only one meta-analysis had a strength of “highly suggestive” [ 34 ], while the rest were classified as “weak”. The highly suggestive meta-analysis included 1190 participants, while the median number of participants in the meta-analysis classified as weak was 258 (ranging from 55 to 1035).

Analysing the overlap values, the covered area was 12.14% and the corrected covered area was 7.75%, indicating moderate overlap. We then examined the pairwise CCA grid to determine which combinations of paired reviews had the highest overlap (Fig. 2 ). Overall, the level of overlap between SRs was not significant, with only 4 having very high overlap and one having high overlap. Fig. 2 Overlap diagram in percentage (%) according to each included SR and year (Green cells indicate low overlap, yellow cells indicate moderate overlap, orange cells indicate high overlap and red cells indicate very high overlap)

Among the meta-analyses with weak evidence, the FSN was higher than the number of studies included in 20.0% of the meta-analyses ( n = 8), which means that the statistical significance of the summary estimates is very unlikely to change if more studies are added in the future.

Table 2 Characteristics of the included systematic reviews Authors, Year and Country Population Cancer type(s) Studies ( n ) Guideline / Guidance Risk of Bias tool Search period Main conclusions Funding Bjordal et al. (2011) [ 22 ] (Norway) Children and adults NR 11 Quorum Jadad scale 1997–2009 Doses of 1–6 J per point of LLLT prevents OM occurrences and reduces severity, pain, and duration of OM ulcers. NR Migliorati et al. (2013) [ 12 ] (Brazil) NR Head and neck cancer patients undergoing HSCT 24 NR NR before 31 Dec 2010 Protocols vary greatly. LLLT has the potential in the prevention and treatment of OM and associated pain. Conclusions cannot be applied separately for each of the individual laser devices. NR He et al. (2018) [ 26 ] (China) < 23 years old Any childhood cancer or going through HSCT 8 PRISMA Cochrane ROB tool 2007–2017 Prophylactic LLLT reduces OM, severe OM and the average severity of OM. Shanghai Municipal Education Commission Gaoyuan Nursing Grant Support and the Shanghai Supporting and Training Funds for Young Teachers in University Carneiro-Neto et al. (2016) [ 25 ] (Brazil) 22–94 years old Head and Neck 6 PRISMA PEDro Scale Jan 2010 - May 2015 Diode Laser LLLT is safe. NR Redman et al. (2022) [ 37 ] (United Kingdom) < 18 years old Different childhood cancer types 14 PRISMA Cochrane ROB tool From inception until 28 Jun 2020 LLLT is a safe therapy in adults and children and may reduce OM and associated pain. Protocols vary greatly. None Al-Rudayni et al. (2021) [ 35 ] (Malaysia) NR NR 6 PRISMA and Cochrane Handbook Cochrane ROB2 tool From inception until 07 Jun 2020 PBM is effective in chemotherapy-induced OM. International Medical University Sánchez-Martos et al. (2023) [ 38 ] (Spain) Adults Head and neck cancer 10 PRISMA CASPe Nov 2021 - Feb 2022 PBM therapy is effective in preventing the incidence of OM since our findings show that the prophylactic use of PBM decreases the risk of severe OM grades. None Anschau et al. (2019) [ 27 ] (Brazil) Adults and children NR 5 PRISMA Cochrane ROB tool 1992–2017 Moderate evidence that LLLT is effective in resolving OM lesions in adult patients undergoing cancer therapy. Not enough evidence to point out effectiveness in the curative treatment of OM in children. Hospitalar Conceição Group de Oliveira et al. (2021) [ 36 ] (Brazil) < 18 years old to 81 years old Lymphatic and breast cancer 5 PRISMA and EQUATOR Cochrane ROB2 tool Feb1990 - May 2020 Photodynamic therapy alone and combined with low-level light therapy show promising results for the treatment of OM. More randomized clinical trials need to be carried out. CAPES & FAPESP (grants 2021/01191-0, 2020/07110-0, 2018/18440-0, 2018/23015-7 and 2019/08375-0) and by CNPq (grant number 313473/2019-6) Mazhari et al. (2019) [ 28 ] (Iran) < 18 years old NR 4 NR Jadad scale Jan 2006 – Dec 2017 Laser treatment can be used as a supportive treatment for OM caused by chemotherapy. However, it is expensive and requires technology and special training. Mashhad University of Medical Sciences (Iran) de Lima et al. (2020) [ 30 ] (Brazil) Adults Head and neck cancer 4 PRISMA Cochrane ROB tool 1945–2018 LLLT was effective in preventing the incidence of OM, but was not effective in preventing pain incidence. None Campos et al. (2020) [ 31 ] (Brazil) NR Head and neck cancer 13 PRISMA Cochrane ROB2 tool 2007–2018 Laser therapy is efficient and cost-effective in comparison with the placebo group. NR Cronshaw et al. (2020) [ 33 ] (United Kingdom) NR NR 29 PRISMA Cochrane ROB tool Jan 1995 - Dec 2019 PBM is safe and effective to mitigate OM. There is a lack of optimised clinical protocols. None Zadik et al. (2019) [ 43 ] (Israel) NR hematological and head and neck 56 (only referenced 53 studies) NR Not evaluated Jan 1st of 2011 – Jun 30th of 2016 More well-designed randomized controlled trials, including pediatric patient populations and patients treated with chemotherapy, are needed to clarify the promising potential of PBM in the management of OM in cancer patients. None Danwiek et al. (2023) [ 39 ] (Indonesia) Adults NR 47 (only referenced 43 studies) PRISMA Cochrane ROB and JBI Tools Before Jun 2021 LLLT is most effective in reducing OM degree and associated pain. NR Peng et al. (2020) [ 34 ] (China) Children and adults hematological and head and neck 29 NR Jadad scale 1946 - Dec 2018 Prophylactic LLLT is effective in preventing OM, reducing severity duration. Need to determine the optimal setting for LLLT. Sichuan University Post-Doctoral Research and Development Fund (grant No. 19 XJ0008) Figueiredo et al. (2013) [ 23 ] (Brazil) NR hematological, head and neck and osteossarcoma 12 NR Jadad scale 1997–2011 Laser therapy is effective, especially with OM 3 grade or higher NR Oberoi et al. (2014) [ 24 ] (Canada) Children and adults hematological, head and neck, breast cancer, multiple myeloma 18 PRISMA Cochrane ROB tool 1946- Feb 2014 Prophylactic LLLT reduces severe OM and pain. None Chan et al. (2023) [ 40 ] (SIngapore) Adults Hematological 18 PRISMA Cochrane ROB tool NR Both PBM and OC were effective nonpharmacological OM prophylaxis and analgesia among chemo- conditioned HSCT patients, without significant difference in effectiveness. NR Khalil et al. (2023) [ 41 ] (Syria) Children and adults Leukemia, lymphoma solid tumors, breast cancer and solid tumors 6 PRISMA ROB2 Until Mar 2023 PBM effectively prevents OM when applied to healthy tissue. Damascus University Cruz et al. (2023) [ 42 ] (Brazil) Children and adults Leukemia, Lymphoma, solid tumors, HSCT, oropharynx, hematological, Digestive and colon cancer 6 Cochrane Handbook Cochrane ROB tool Until Sep 2021 PBM significantly reduces the severity and pain in OM NR NR Not reported, PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses, HSCT Hematopoietic stem cell transplantation, LLLT low-level laser therapy, CASPe Critical Appraisal Skills Program Español, ROB Risk of bias, OM Oral mucositis, PBM Photobiomodulation, OC Oral cryotherapy

Table 3 Methodological quality assessment using AMSTAR2 Study Overall Score 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Bjordal et al. (2011) [ 22 ] Critically Low Y PY N Y N N N N Y/Y Y Y/Y N N N N Y Migliorati et al. (2013) [ 12 ] Critically Low N N N N Y Y N N N/N N NA NA N NA NA N Figueiredo et al. (2013) [ 23 ] Critically Low Y Y N PY Y Y N PY Y/Y N Y/Y N N N N Y Oberoi et al. (2014) [ 24 ] Low Y PY N PY Y Y N PY Y/Y N N/N N N N N Y Carneiro-Neto et al. (2016) [ 25 ] Critically Low Y PY N N Y Y N PY Y/Y N Y/Y Y N N N Y He et al. (2018) [ 26 ] Low Y PY N PY Y Y N N Y/Y N Y/Y Y Y Y Y Y Anschau et al. (2019) [ 27 ] Low Y Y N PY Y Y Y PY Y/Y N N/N N Y Y Y Y Mazhari et al. (2019) [ 28 ] Critically Low Y PY N N Y Y N Y Y/Y N Y/Y N N N N Y Zadik et al. (2019) Critically Low Y N N N Y Y N PY N/N N NA NA N NA NA Y de Lima et al. (2020) [ 30 ] Low Y Y N Y Y N Y PY Y/Y N N/N N N N N Y Campos et al. (2020) [ 31 ] Critically Low Y Y N N N N N PY Y/Y N N/N N Y Y Y Y Cronshaw et al. (2020) [ 33 ] Critically Low Y N N N N N N N Y/Y N NA NA N NA NA Y Peng et al. (2020) [ 34 ] Critically Low Y PY N N Y Y N PY Y/Y N N/N N N N N Y Al-Rudayni et al. (2021) [ 35 ] Critically Low Y Y Y N Y Y Y N Y/Y N Y/Y N Y Y Y Y de Oliveira et al. (2021) [ 36 ] Critically Low Y PY N N Y Y N Y Y/Y N Y/Y N Y Y Y Y Redman et al. (2022) [ 37 ] Low Y PY N PY Y Y N N Y/Y N Y/Y N Y Y Y Y Sánchez-Martos et al. (2023) [ 38 ] Critically Low Y PY Y N Y Y N N Y/Y N NA NA N NA NA Y Danwiek et al. (2023) [ 39 ] Critically Low Y PY N N Y Y N N Y/Y N NA NA N NA NA Y Chan et al. (2023) [ 40 ] Critically Low Y Y N PY Y Y N PY Y/Y N N/N N Y Y Y Y Khalil et al. (2023) [ 41 ] Low Y PY N PY Y Y N N Y/Y N NA NA N NA NA Y Cruz et al. (2023) [ 42 ] Critically Low Y PY N N Y Y N PY Y/Y N N/N N Y Y Y Y 1 – PICO elements; 2 – Review methods established a priori; 3 – Selection of the study designs explained; 4 – comprehensive literature search strategy; 5 – study selection in duplicate; 6 – data extraction in duplicate; 7 – List of excluded studies with justification; 8 – Adequate included study details description; 9 – Satisfactory technique for assessing the risk of bias; 10 – Sources of funding for the studies included reported; 11 – Appropriate methods for meta-analysis; 12 - Impact of risk of bias in meta-analysis; 13 – Account for risk of bias when interpreting/ discussing the results of the review; 14 – Satisfactory explanation for, and discussion of, any heterogeneity; 15 – Adequate investigation of publication bias; 16 – Conflict of interest and funding statements Y Yes, PY Partial Yes, N No, NA Not applicable

Discussion

Summary of main findings

This is the first umbrella review to comprehensively evaluate the level evidence of SRs of PBMs effect on the prevention and treatment of OM in patients undergoing CT and/or radiotherapy. We identify 21 SRs suggesting key factors that can inform and improve future research on the effect of PBM on patients with OM secondary to chemo- and radiotherapy. Although a significant number of SRs were included, both the methodological and meta-analytic domains show low consistency and validity, respectively.

AMSTAR 2, overlapping and meta-analytic appraisal

The AMSTAR tool has been designed to critically assess the quality of SRs, taking into account their critical and non-critical weaknesses [ 14 ]. Of the 16 domains evaluated in AMSTAR 2, domains 3 (Did the review authors explain their selection of study designs for inclusion in the review? ), 7 (Did the review authors provide a list of excluded studies and justify the exclusions? ) and 10 (Did the review authors report the sources of funding for the studies included in the review? ) were not addressed in more than 85% of the included SRs. Regarding domain 3, 90.5% of the SRs didn’t specify the followed search strategy, with the included studies and justifications [ 14 ]. Concerning domain 7, 85.7% of the SRs didn’t provide a list of excluded items with the corresponding reasons, thus increasing bias. [ 14 ]. in domain 10, 95.2% of the included trials did not report the source of funding, which is of great concern, as reporting the source of funding is important because commercially funded trials are known to be more likely to produce results in favour of the sponsoring product than independently funded trials [ 14 ]. Given the limitations and potential biases present in these studies, the validity and reliability of their findings may be called into question.

The overlap interpretation also showed worrying results due to low percentiles (Fig. 2 ). A large number of SRs are published each year and duplication of reviews on similar topics is common, and overlap may occur if they include one or more identical primary studies, such as RCTs [ 21 ]. Hence, it was expected that reviews published in the same year would have a high overlap, since they would have included the same studies, however, this isn’t in line with our findings. For example, two SRs, Zadik et al. (2019) and Cronshaw et al. (2020), had an overlap of 19.7%, which was the higher value obtained, while de Lima et al. (2020) and Heiskanen et al. (2020) had an overlap of 0.0%, as mentioned above. This leads us to believe that there might be a lack of consistency in the search strategy, which we also came across in the AMSTAR assessment.

The meta-analytic results go in line with the scarcity of quality evidence. Regarding the number of participants, only one study included more than 1000 participants, being the only “Highly suggestive” [ 34 ] whereas the remaining had a median number of 258 participants and were classified as “Weak”. This concern suggests that RCTs are failing in terms of numbers of participants and that their conclusions are not robust. Another important aspect to consider is the potential for bias in heterogeneity statistics, also due to small meta-analysis. It’s important to assess the homogeneity and heterogeneity of a trial because we can predict whether or not the effect of a particular treatment will be similar when applied to new people [ 44 ]. However heterogeneity is difficult to predict, especially in small meta-analyses [ 44 ] as presented in our results. Hence, larger studies of intervention, as RCTs, need to be conducted to have more predictable and reliable results.

Implications for practice and research

The findings of the analysis reveal considerable disparities in the quality of evidence, as the bulk of the studies incorporated were assessed as critically low and low. The results of this study align with those of a recent umbrella review [ 45 ], and raise doubts about the methodological proficiency of the groups responsible for the SRs and the quality of their review procedures.

Although the included studies have concluded that PBM is effective in reducing pain and severe OM, this can be questioned by the low quality of the included studies as we have identified. This is a major concern not only in clinical practice, where there’s a lack of robust evidence to support treatment outcomes, but also in research, where existing SRs are not rigorous, and the methodology is unreliable.

PBMs have been suggested by several authors to have a long-term carcinogenic effect, although long-term follow-up studies of patients treated with PBMs for OM prevention have not shown an increase in cancer recurrence. [ 10 , 29 , 46 – 48 ]. Hence, it’s crucial that the clinician informs the patient of the potential risks of PBM.

In addition, many of the included SRs mention the absence of guidelines and the need to define laser parameters [ 24 , 29 , 33 , 34 , 36 , 37 , 42 ]. RCTs are conducted according to their own protocol and do not have standardised parameters, which increases the variability of results. There is therefore an urgent need for more high-quality evidence that follows the latest guidelines and works to improve them so that patients receive the safest and most effective treatment.

Strengths and limitations

This umbrella review followed a strict protocol and the most recent tools available to evaluate the quality evidence of the included studies enhancing the trustworthiness of our findings.

There are limitations to this umbrella review that are worth mentioning. The fact that an overview synthesizes the results and conclusions of SRs, it does not provide an analysis of the primary studies included, preventing any conclusion regarding primary data. Yet, upon examining the meta-analytical strength, two significant constraints hinder the attainment of higher validity ranks: the low number of participants (< 1000 participants) and the bias potential of heterogeneity statistic due to small meta-analyses [ 44 ]. As such, the number of studies available contain still a very low number to provide more robust meta-analytical consistency and for this reason, this umbrella review support the need for larger studies of intervention, preferably randomized trials.

Conclusion

The level of evidence for the efficacy of PBM in chemo- and radiotherapy-induced oral conditions is constituted by SRs with inconsistent methodological quality, and the meta-analytical strength of which is low. This umbrella review underscores the salient aspects that warrant improvement in subsequent primary and secondary research pertaining to this subject matter.

Supplementary Information

Supplementary Material 1.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

The authors declare that no financial support was received for the research, authorship, and/or publication of this article.

Clinical trial number

Not applicable.

Authors’ contributions

Inês Rodrigues: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Writing - original draft; Writing - review & editing. Vanessa Machado: Methodology; Resources; Software; Writing - original draft; Writing - review & editing. Luísa Bandeira Lopes: Writing - review & editing. Pedro Trancoso: Writing - review & editing. António Mano Azul: Writing - review & editing. José João Mendes: Supervision, Writing- Reviewing and Editing. Carlos Zagalo: Supervision, Writing- Reviewing and Editing. João Botelho: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Resources; Software; Supervision; Validation; Writing - original draft; Writing - review & editing.

Funding

This research received no external funding.

Availability of data and materials

All data and materials are fully displayed in the manuscript or the studies included in this systematic review.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

References

1. Elad S Yarom N Zadik Y Kuten-Shorrer M Sonis ST The broadening scope of oral mucositis and oral ulcerative mucosal toxicities of anticancer therapies CA Cancer J Clin 2022 72 57 77 10.3322/caac.21704 34714553 Elad S, Yarom N, Zadik Y, Kuten-Shorrer M, Sonis ST. The broadening scope of oral mucositis and oral ulcerative mucosal toxicities of anticancer therapies. CA Cancer J Clin. 2022;72:57–77. 10.3322/caac.21704. 34714553 10.3322/caac.21704

2. Brown TJ Gupta A Management of Cancer Therapy-Associated oral mucositis JCO Oncol Pract 2020 16 103 9 10.1200/JOP.19.00652 32048926 Brown TJ, Gupta A. Management of Cancer Therapy-Associated oral mucositis. JCO Oncol Pract. 2020;16:103–9. 10.1200/JOP.19.00652. 32048926 10.1200/JOP.19.00652

3. Elting LS Cooksley C Chambers M Cantor SB Manzullo E Rubenstein EB The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis Cancer 2003 98 1531 9 10.1002/cncr.11671 14508842 Elting LS, Cooksley C, Chambers M, Cantor SB, Manzullo E, Rubenstein EB. The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer. 2003;98:1531–9. 10.1002/cncr.11671. 14508842 10.1002/cncr.11671

4. Pulito C Cristaudo A Porta CL Zapperi S Blandino G Morrone A Oral mucositis: the hidden side of cancer therapy J Exp Clin Cancer Res 2020 39 210 10.1186/s13046-020-01715-7 33028357 PMC7542970 Pulito C, Cristaudo A, Porta CL, Zapperi S, Blandino G, Morrone A, et al. Oral mucositis: the hidden side of cancer therapy. J Exp Clin Cancer Res. 2020;39:210. 10.1186/s13046-020-01715-7. 33028357 10.1186/s13046-020-01715-7 PMC7542970

5. Villa A Sonis ST Pharmacotherapy for the management of cancer regimen-related oral mucositis Expert Opin Pharmacother 2016 17 1801 7 10.1080/14656566.2016.1217993 27477002 Villa A, Sonis ST. Pharmacotherapy for the management of cancer regimen-related oral mucositis. Expert Opin Pharmacother. 2016;17:1801–7. 10.1080/14656566.2016.1217993. 27477002 10.1080/14656566.2016.1217993

6. Bruno JS Al-Qadami GH Laheij AMGA Bossi P Fregnani ER Wardill HR From pathogenesis to intervention: the importance of the Microbiome in oral Mucositis Int J Mol Sci 2023 24 8274 10.3390/ijms24098274 37175980 PMC10179181 Bruno JS, Al-Qadami GH, Laheij AMGA, Bossi P, Fregnani ER, Wardill HR. From pathogenesis to intervention: the importance of the Microbiome in oral Mucositis. Int J Mol Sci. 2023;24:8274. 10.3390/ijms24098274. 37175980 10.3390/ijms24098274 PMC10179181

7. Lalla RV Bowen J Barasch A Elting L Epstein J Keefe DM MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy Cancer 2014 120 1453 61 10.1002/cncr.28592 24615748 PMC4164022 Lalla RV, Bowen J, Barasch A, Elting L, Epstein J, Keefe DM, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2014;120:1453–61. 10.1002/cncr.28592. 24615748 10.1002/cncr.28592 PMC4164022

8. de Freitas LF Hamblin MR Proposed mechanisms of Photobiomodulation or Low-Level Light Therapy IEEE J Sel Top Quantum Electron Publ IEEE Lasers Electro-Opt Soc 2016 22 7000417 10.1109/JSTQE.2016.2561201 PMC5215870 28070154 de Freitas LF, Hamblin MR. Proposed mechanisms of Photobiomodulation or Low-Level Light Therapy. IEEE J Sel Top Quantum Electron Publ IEEE Lasers Electro-Opt Soc. 2016;22:7000417. 10.1109/JSTQE.2016.2561201. 10.1109/JSTQE.2016.2561201 PMC5215870 28070154

9. Courtois E Bouleftour W Guy J-B Louati S Bensadoun R-J Rodriguez-Lafrasse C Mechanisms of PhotoBioModulation (PBM) focused on oral mucositis prevention and treatment: a scoping review BMC Oral Health 2021 21 220 10.1186/s12903-021-01574-4 33926421 PMC8086292 Courtois E, Bouleftour W, Guy J-B, Louati S, Bensadoun R-J, Rodriguez-Lafrasse C, et al. Mechanisms of PhotoBioModulation (PBM) focused on oral mucositis prevention and treatment: a scoping review. BMC Oral Health. 2021;21:220. 10.1186/s12903-021-01574-4. 33926421 10.1186/s12903-021-01574-4 PMC8086292

10. Elad S Cheng KKF Lalla RV Yarom N Hong C Logan RM MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy Cancer 2020 126 4423 31 10.1002/cncr.33100 32786044 PMC7540329 Elad S, Cheng KKF, Lalla RV, Yarom N, Hong C, Logan RM, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2020;126:4423–31. 10.1002/cncr.33100. 32786044 10.1002/cncr.33100 PMC7540329

11. Schubert MM Eduardo FP Guthrie KA Franquin J-C Bensadoun R-JJ Migliorati CA A phase III randomized double-blind placebo-controlled clinical trial to determine the efficacy of low level laser therapy for the prevention of oral mucositis in patients undergoing hematopoietic cell transplantation Support Care Cancer 2007 15 1145 54 10.1007/s00520-007-0238-7 17393191 Schubert MM, Eduardo FP, Guthrie KA, Franquin J-C, Bensadoun R-JJ, Migliorati CA, et al. A phase III randomized double-blind placebo-controlled clinical trial to determine the efficacy of low level laser therapy for the prevention of oral mucositis in patients undergoing hematopoietic cell transplantation. Support Care Cancer. 2007;15:1145–54. 10.1007/s00520-007-0238-7. 17393191 10.1007/s00520-007-0238-7

12. Migliorati C, Hewson I, Lalla RV, Antunes HS, Estilo CL, For the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO), 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. 10.1007/s00520-012-1605-6. 10.1007/s00520-012-1605-6 23001179

13. Page MJ McKenzie JE Bossuyt PM Boutron I Hoffmann TC Mulrow CD The PRISMA 2020 statement: an updated guideline for reporting systematic reviews Syst Rev 2021 10 89 10.1186/s13643-021-01626-4 33781348 PMC8008539 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev. 2021;10:89. 10.1186/s13643-021-01626-4. 33781348 10.1186/s13643-021-01626-4 PMC8008539

14. Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;j4008. 10.1136/bmj.j4008. 10.1136/bmj.j4008 PMC5833365 28935701

15. Papadimitriou N Markozannes G Kanellopoulou A Critselis E Alhardan S Karafousia V An umbrella review of the evidence associating diet and cancer risk at 11 anatomical sites Nat Commun 2021 12 4579 10.1038/s41467-021-24861-8 34321471 PMC8319326 Papadimitriou N, Markozannes G, Kanellopoulou A, Critselis E, Alhardan S, Karafousia V, et al. An umbrella review of the evidence associating diet and cancer risk at 11 anatomical sites. Nat Commun. 2021;12:4579. 10.1038/s41467-021-24861-8. 34321471 10.1038/s41467-021-24861-8 PMC8319326

16. Bellou V Belbasis L Tzoulaki I Evangelou E Risk factors for type 2 diabetes mellitus: an exposure-wide umbrella review of meta-analyses PLoS ONE 2018 13 e0194127 10.1371/journal.pone.0194127 29558518 PMC5860745 Bellou V, Belbasis L, Tzoulaki I, Evangelou E. Risk factors for type 2 diabetes mellitus: an exposure-wide umbrella review of meta-analyses. PLoS ONE. 2018;13:e0194127. 10.1371/journal.pone.0194127. 29558518 10.1371/journal.pone.0194127 PMC5860745

17. Ioannidis JPA Tarone R McLaughlin JK The false-positive to false-negative ratio in epidemiologic studies Epidemiology 2011 22 450 6 10.1097/EDE.0b013e31821b506e 21490505 Ioannidis JPA, Tarone R, McLaughlin JK. The false-positive to false-negative ratio in epidemiologic studies. Epidemiology. 2011;22:450–6. 10.1097/EDE.0b013e31821b506e. 21490505 10.1097/EDE.0b013e31821b506e

18. Johnson VE Revised standards for statistical evidence Proc Natl Acad Sci 2013 110 19313 7 10.1073/pnas.1313476110 24218581 PMC3845140 Johnson VE. Revised standards for statistical evidence. Proc Natl Acad Sci. 2013;110:19313–7. 10.1073/pnas.1313476110. 24218581 10.1073/pnas.1313476110 PMC3845140

19. Sterne JAC Sifting the evidence—what’s wrong with significance tests? Another comment on the role of statistical methods BMJ 2001 322 226 31 10.1136/bmj.322.7280.226 11159626 PMC1119478 Sterne JAC. Sifting the evidence—what’s wrong with significance tests? Another comment on the role of statistical methods. BMJ. 2001;322:226–31. 10.1136/bmj.322.7280.226. 11159626 10.1136/bmj.322.7280.226 PMC1119478

20. Rosenberg MS The file-drawer problem revisited: a general weighted method for calculating fail-safe numbers in meta-analysis Evol Int J Org Evol 2005 59 464 8 15807430 Rosenberg MS. The file-drawer problem revisited: a general weighted method for calculating fail-safe numbers in meta-analysis. Evol Int J Org Evol. 2005;59:464–8. 15807430

21. Lunny C Pieper D Thabet P Kanji S Managing overlap of primary study results across systematic reviews: practical considerations for authors of overviews of reviews BMC Med Res Methodol 2021 21 140 10.1186/s12874-021-01269-y 34233615 PMC8265144 Lunny C, Pieper D, Thabet P, Kanji S. Managing overlap of primary study results across systematic reviews: practical considerations for authors of overviews of reviews. BMC Med Res Methodol. 2021;21:140. 10.1186/s12874-021-01269-y. 34233615 10.1186/s12874-021-01269-y PMC8265144

22. Bjordal JM Bensadoun R-J 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 10.1007/s00520-011-1202-0 21660670 Bjordal JM, Bensadoun R-J, 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. 10.1007/s00520-011-1202-0. 21660670 10.1007/s00520-011-1202-0

23. Figueiredo ALP Lins L Cattony AC Falcão AFP Laser terapia no controle da mucosite oral: um estudo de metanálise Rev Assoc Médica Bras 2013 59 467 74 10.1016/j.ramb.2013.08.003 24119379 Figueiredo ALP, Lins L, Cattony AC, Falcão AFP. Laser terapia no controle da mucosite oral: um estudo de metanálise. Rev Assoc Médica Bras. 2013;59:467–74. 10.1016/j.ramb.2013.08.003. 10.1016/j.ramb.2013.08.003 24119379

24. Oberoi S Zamperlini–Netto G Beyene J Treister NS Sung L Effect of prophylactic low level laser therapy on oral mucositis: a systematic review and Meta-analysis PLoS ONE 2014 9 e107418 10.1371/journal.pone.0107418 25198431 PMC4157876 Oberoi S, Zamperlini–Netto G, Beyene J, Treister NS, Sung L. Effect of prophylactic low level laser therapy on oral mucositis: a systematic review and Meta-analysis. PLoS ONE. 2014;9:e107418. 10.1371/journal.pone.0107418. 25198431 10.1371/journal.pone.0107418 PMC4157876

25. Carneiro-Neto J, de-Menezes J, Moura L, Massucato E, de-Andrade C. Protocols for management of oral complications of chemotherapy and/or radiotherapy for oral cancer: systematic review and meta-analysis current. Med Oral Patol Oral Cir Bucal. 2016;0(0). 10.4317/medoral.21314. 10.4317/medoral.21314 PMC5217492 27918734

26. He M Zhang B Shen N Wu N Sun J A systematic review and meta-analysis of the effect of low-level laser therapy (LLLT) on chemotherapy-induced oral mucositis in pediatric and young patients Eur J Pediatr 2018 177 7 17 10.1007/s00431-017-3043-4 29128883 He M, Zhang B, Shen N, Wu N, Sun J. A systematic review and meta-analysis of the effect of low-level laser therapy (LLLT) on chemotherapy-induced oral mucositis in pediatric and young patients. Eur J Pediatr. 2018;177:7–17. 10.1007/s00431-017-3043-4. 29128883 10.1007/s00431-017-3043-4

27. Anschau F Webster J Capra MEZ De Azeredo Da Silva ALF Stein AT Efficacy of low-level laser for treatment of cancer oral mucositis: a systematic review and meta-analysis Lasers Med Sci 2019 34 1053 62 10.1007/s10103-019-02722-7 30729351 Anschau F, Webster J, Capra MEZ, De Azeredo Da Silva ALF, Stein AT. Efficacy of low-level laser for treatment of cancer oral mucositis: a systematic review and meta-analysis. Lasers Med Sci. 2019;34:1053–62. 10.1007/s10103-019-02722-7. 30729351 10.1007/s10103-019-02722-7

28. Mazhari F Shirazi AS Shabzendehdar M Management of oral mucositis in pediatric patients receiving cancer therapy: a systematic review and meta-analysis Pediatr Blood Cancer 2019 66 e27403 10.1002/pbc.27403 30421549 Mazhari F, Shirazi AS, Shabzendehdar M. Management of oral mucositis in pediatric patients receiving cancer therapy: a systematic review and meta-analysis. Pediatr Blood Cancer. 2019;66:e27403. 10.1002/pbc.27403. 30421549 10.1002/pbc.27403

29. On behalf of The Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) Zadik Y Arany PR Fregnani ER Bossi P Antunes HS Systematic review of photobiomodulation for the management of oral mucositis in cancer patients and clinical practice guidelines Support Care Cancer 2019 27 3969 83 10.1007/s00520-019-04890-2 31286228 On behalf of The Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO), Zadik Y, Arany PR, Fregnani ER, Bossi P, Antunes HS, et al. Systematic review of photobiomodulation for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer. 2019;27:3969–83. 10.1007/s00520-019-04890-2. 31286228 10.1007/s00520-019-04890-2

30. De Lima VHS De Oliveira-Neto OB Da Hora Sales PH Da Silva Torres T De Lima FJC 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 Oncol 2020 102 104524 10.1016/j.oraloncology.2019.104524 32062592 De Lima VHS, De Oliveira-Neto OB, Da Hora Sales PH, Da Silva Torres T, De Lima FJC. 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 Oncol. 2020;102:104524. 10.1016/j.oraloncology.2019.104524. 32062592 10.1016/j.oraloncology.2019.104524

31. Campos TM Do Prado Tavares Silva CA Sobral APT Sobral SS Rodrigues MFSD Bussadori SK Photobiomodulation in oral mucositis in patients with head and neck cancer: a systematic review and meta-analysis followed by a cost-effectiveness analysis Support Care Cancer 2020 28 5649 59 10.1007/s00520-020-05613-8 32666214 Campos TM, Do Prado Tavares Silva CA, Sobral APT, Sobral SS, Rodrigues MFSD, Bussadori SK, et al. Photobiomodulation in oral mucositis in patients with head and neck cancer: a systematic review and meta-analysis followed by a cost-effectiveness analysis. Support Care Cancer. 2020;28:5649–59. 10.1007/s00520-020-05613-8. 32666214 10.1007/s00520-020-05613-8

32. Heiskanen V Zadik Y Elad S Photobiomodulation Therapy for Cancer Treatment-related salivary gland dysfunction: a systematic review Photobiomodulation Photomed Laser Surg 2020 38 340 7 10.1089/photob.2019.4767 32109187 Heiskanen V, Zadik Y, Elad S. Photobiomodulation Therapy for Cancer Treatment-related salivary gland dysfunction: a systematic review. Photobiomodulation Photomed Laser Surg. 2020;38:340–7. 10.1089/photob.2019.4767. 10.1089/photob.2019.4767 32109187

33. Cronshaw M Parker S Anagnostaki E Mylona V Lynch E Grootveld M Photobiomodulation and oral mucositis: a systematic review Dent J 2020 8 87 10.3390/dj8030087 PMC7559189 32764305 Cronshaw M, Parker S, Anagnostaki E, Mylona V, Lynch E, Grootveld M. Photobiomodulation and oral mucositis: a systematic review. Dent J. 2020;8:87. 10.3390/dj8030087. 10.3390/dj8030087 PMC7559189 32764305

34. Peng J Shi Y Wang J Wang F Dan H Xu H Low-level laser therapy in the prevention and treatment of oral mucositis: a systematic review and meta-analysis Oral Surg Oral Med Oral Pathol Oral Radiol 2020 130 387 e3979 10.1016/j.oooo.2020.05.014 32624448 Peng J, Shi Y, Wang J, Wang F, Dan H, Xu H, et al. Low-level laser therapy in the prevention and treatment of oral mucositis: a systematic review and meta-analysis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2020;130:387–e3979. 10.1016/j.oooo.2020.05.014. 32624448 10.1016/j.oooo.2020.05.014

35. Al-Rudayni AHM Gopinath D Maharajan MK Veettil SK Menon RK Efficacy of Photobiomodulation in the treatment of Cancer Chemotherapy-Induced oral mucositis: a Meta-analysis with Trial Sequential Analysis Int J Environ Res Public Health 2021 18 7418 10.3390/ijerph18147418 34299869 PMC8307997 Al-Rudayni AHM, Gopinath D, Maharajan MK, Veettil SK, Menon RK. Efficacy of Photobiomodulation in the treatment of Cancer Chemotherapy-Induced oral mucositis: a Meta-analysis with Trial Sequential Analysis. Int J Environ Res Public Health. 2021;18:7418. 10.3390/ijerph18147418. 34299869 10.3390/ijerph18147418 PMC8307997

36. De Oliveira AB Ferrisse TM Basso FG Fontana CR Giro EMA Brighenti FL A systematic review and meta-analysis of the effect of photodynamic therapy for the treatment of oral mucositis Photodiagnosis Photodyn Ther 2021 34 102316 10.1016/j.pdpdt.2021.102316 33940208 De Oliveira AB, Ferrisse TM, Basso FG, Fontana CR, Giro EMA, Brighenti FL. A systematic review and meta-analysis of the effect of photodynamic therapy for the treatment of oral mucositis. Photodiagnosis Photodyn Ther. 2021;34:102316. 10.1016/j.pdpdt.2021.102316. 33940208 10.1016/j.pdpdt.2021.102316

37. Redman MG Harris K Phillips BS Low-level laser therapy for oral mucositis in children with cancer Arch Dis Child 2022 107 128 33 10.1136/archdischild-2020-321216 34230010 Redman MG, Harris K, Phillips BS. Low-level laser therapy for oral mucositis in children with cancer. Arch Dis Child. 2022;107:128–33. 10.1136/archdischild-2020-321216. 34230010 10.1136/archdischild-2020-321216

38. Sánchez-Martos R, Lamdaoui W, Arias-Herrera S. Therapeutic outcomes of Photobiomodulation in Cancer Treatment-induced oral mucositis: a systematic review. J Clin Exp Dent. 2023;e749–59. 10.4317/jced.60710. 10.4317/jced.60710 PMC10550082 37799759

39. Danwiek J, Amtha R, Gunardi I. Management of oral mucositis: a systematic review. Minerva Dent Oral Sci. 2023;72. 10.23736/S2724-6329.23.04695-8. 10.23736/S2724-6329.23.04695-8 37066889

40. Chan X Tay L Yap SJ Wu VX Klainin-Yobas P Effectiveness of photobiomodulation and oral cryotherapy on oral Mucositis among patients undergoing Chemotherapy Conditioning prior to hematological stem cell transplantation Semin Oncol Nurs 2023 39 151405 10.1016/j.soncn.2023.151405 36935333 Chan X, Tay L, Yap SJ, Wu VX, Klainin-Yobas P. Effectiveness of photobiomodulation and oral cryotherapy on oral Mucositis among patients undergoing Chemotherapy Conditioning prior to hematological stem cell transplantation. Semin Oncol Nurs. 2023;39:151405. 10.1016/j.soncn.2023.151405. 36935333 10.1016/j.soncn.2023.151405

41. Khalil M Hamadah O Saifo M Preconditioning with Photobiomodulation as an effective method in preventing Chemotherapy-Induced oral mucositis: a systematic review Photobiomodulation Photomed Laser Surg 2023 41 597 607 10.1089/photob.2023.0075 37976239 Khalil M, Hamadah O, Saifo M. Preconditioning with Photobiomodulation as an effective method in preventing Chemotherapy-Induced oral mucositis: a systematic review. Photobiomodulation Photomed Laser Surg. 2023;41:597–607. 10.1089/photob.2023.0075. 10.1089/photob.2023.0075 37976239

42. Cruz AR Minicucci EM Betini M Almeida-Lopes L Tieghi Neto V Cataneo AJM Efficacy of photobiomodulation in the treatment of oral mucositis in patients undergoing antineoplastic therapy: systematic review and meta-analysis Support Care Cancer 2023 31 645 10.1007/s00520-023-08105-7 37853254 Cruz AR, Minicucci EM, Betini M, Almeida-Lopes L, Tieghi Neto V, Cataneo AJM. Efficacy of photobiomodulation in the treatment of oral mucositis in patients undergoing antineoplastic therapy: systematic review and meta-analysis. Support Care Cancer. 2023;31:645. 10.1007/s00520-023-08105-7. 37853254 10.1007/s00520-023-08105-7

43. Zadik Y, Arany PR, Fregnani ER, et al. Systematic review of photobiomodulation for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer. 2019;27(10):3969–83. 10.1007/s00520-019-04890-2. 10.1007/s00520-019-04890-2 31286228

44. Von Hippel PT The heterogeneity statistic I2 can be biased in small meta-analyses BMC Med Res Methodol 2015 15 35 10.1186/s12874-015-0024-z 25880989 PMC4410499 Von Hippel PT. The heterogeneity statistic I2 can be biased in small meta-analyses. BMC Med Res Methodol. 2015;15:35. 10.1186/s12874-015-0024-z. 25880989 10.1186/s12874-015-0024-z PMC4410499

45. Botelho J Mascarenhas P Viana J Proença L Orlandi M Leira Y An umbrella review of the evidence linking oral health and systemic health: from the prevalence to clinical and circulating markers Dentistry Oral Med 2022 10.1101/2022.04.11.22273715 PMC9734115 36494387 Botelho J, Mascarenhas P, Viana J, Proença L, Orlandi M, Leira Y, et al. An umbrella review of the evidence linking oral health and systemic health: from the prevalence to clinical and circulating markers. Dentistry Oral Med. 2022. 10.1101/2022.04.11.22273715.

46. On behalf of the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) Bowen JM Gibson RJ Coller JK Blijlevens N Bossi P Systematic review of agents for the management of cancer treatment-related gastrointestinal mucositis and clinical practice guidelines Support Care Cancer 2019 27 4011 22 10.1007/s00520-019-04892-0 31286233 On behalf of the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO), Bowen JM, Gibson RJ, Coller JK, Blijlevens N, Bossi P, et al. Systematic review of agents for the management of cancer treatment-related gastrointestinal mucositis and clinical practice guidelines. Support Care Cancer. 2019;27:4011–22. 10.1007/s00520-019-04892-0. 31286233 10.1007/s00520-019-04892-0

47. Antunes HS Herchenhorn D Small IA Araújo CMM Viégas CMP De Assis Ramos G Long-term survival of a randomized phase III trial of head and neck cancer patients receiving concurrent chemoradiation therapy with or without low-level laser therapy (LLLT) to prevent oral mucositis Oral Oncol 2017 71 11 5 10.1016/j.oraloncology.2017.05.018 28688677 Antunes HS, Herchenhorn D, Small IA, Araújo CMM, Viégas CMP, De Assis Ramos G, et al. Long-term survival of a randomized phase III trial of head and neck cancer patients receiving concurrent chemoradiation therapy with or without low-level laser therapy (LLLT) to prevent oral mucositis. Oral Oncol. 2017;71:11–5. 10.1016/j.oraloncology.2017.05.018. 28688677 10.1016/j.oraloncology.2017.05.018

48. Brandão TB Morais-Faria K Ribeiro ACP Rivera C Salvajoli JV Lopes MA Locally advanced oral squamous cell carcinoma patients treated with photobiomodulation for prevention of oral mucositis: retrospective outcomes and safety analyses Support Care Cancer 2018 26 2417 23 10.1007/s00520-018-4046-z 29423682 Brandão TB, Morais-Faria K, Ribeiro ACP, Rivera C, Salvajoli JV, Lopes MA, et al. Locally advanced oral squamous cell carcinoma patients treated with photobiomodulation for prevention of oral mucositis: retrospective outcomes and safety analyses. Support Care Cancer. 2018;26:2417–23. 10.1007/s00520-018-4046-z. 29423682 10.1007/s00520-018-4046-z