DENTISTRY GRADE Trabajo Fin de Grado
Course: 2021-2022
Therapeutic Outcomes of Photobiomodulation in Cancer Treatment-induced Oral Mucositis: A
Systematic Review.
Presented by: Wissal Lamdaoui
Tutors: Rebeca Sanchez Martos, Maria Gracia, Fernando Gomez-Ferrer
AKNOWLEDGMENTS
This project would not have been possible without the support of many people. I would like to express my deepest gratitude to Dr. Maria Gracia Sarrion Perez, Dr.
Rebecca Sanchez Martos and Dr. Fernando Gomez Ferrer who read my numerous revisions and helped make some sense of the confusion.
My family deserves endless gratitude: I am grateful for my family’s unequivocal and loving support. I am grateful for my parents whose constant love and support keep me motivated and confident. I owe them all of my accomplishments and success. Deepest thanks to my sibling, who keep me grounded and is always supportive of my adventures.
Lastly, thank you to my partner, I am forever thankful for the unconditional love and support throughout the entire thesis process and every day.
INDEX
1 INTRODUCTION 9
1.1 PHOTOBIOMODULATION 9
1.1.1 DEFINITION 10
1.1.2 MECHANISM OF ACTION 10
1.1.3 LASER TECHNOLOGY IN PHOTOBIOMODULATION 11
1.1.4 LASER DELIVERY PARAMETERS 13
1.1.5 PHOTOBIOMODULATION AND ORAL PATHOLOGY 16
1.2 ORAL MUCOSITIS 16
1.2.1 DEFINITION, PREVALENCE, AND RISK FACTORS 16
1.2.2 ETIOPATHOGENESIS 17
1.2.3 CLINICAL FEATURES 20
1.2.4 SCORING OF ORAL MUCOSITIS 21
1.2.5 MANAGEMENT OF ORAL MUCOSITIS 22
2 RATIONATE, HYPOTHESIS AND OBJECTIVES 23
2.1 RATIONATE 23
2.2 HYPOTHESIS 24
2.3 OBJECTIVES 24
2.3.1 GENERAL OBJECTIVE 24
2.3.2 SPECIFIC OBJECTIVES 24
3 MATERIAL AND METHODS 25
3.1 INCLUSION AND EXCLUSION CRITERIA 25
3.2 SEARCH STRATEGY 25
3.3 SELECTION PROCESS OF THE STUDIES 26
3.4 DATA EXTRACTION AND ANALYSIS 27
3.5 QUALITY OF EVIDENCE EVALUATION AND RISK OF BIAS ASSESSMENT 27
4 RESULTS 28
4.1 SEARCH RESULTS 28
4.2 DESCRIPTION OF STUDY CHARACTERISTICS 29
4.3 RISK OF BIAS AND QUALITY OF EVIDENCE 29
4.4 EFFECTS ON PAIN 30
4.5 EFFECTS ON ORAL MUCOSITIS 30
4.6 EFFECTS ON QUALITY OF LIFE 31
5 DISCUSSION 33
5.1 DISCUSSION OF THE METHODOLOGY 33
5.2 DISCUSSION OF THE RESULTS 36
5.2.1 REDUCTION OF PAIN 36
5.2.2 PREVENT THE EVOLUTION OF ORAL MUCOSITIS 36
5.2.3 QUALITY OF LIFE AFTER TREATING ORAL MUCOSITIS 37
6 CONCLUSION 41
7 BIBLIOGRAPHY 51
8 PAPER 55
9 PRISMA CHECKLIST 2020 74
ABBREVATIONS
AlGaIP: aluminum gallium indium phosphide
CCO: mitochondrial cytochrome C oxidase
CRT: chemoradiotherapy
FDA: food drug administration
GaAs: gallium arsenide
GaAlAs: gallium aluminum arsenide
HeNe: Helium-Neon
LASER: Light Amplification by Stimulated Emission of Radiation
LLLT: low-level laser therapy
LED: Light-Emitting diodes
NIR: near infrarred
NO: nitric oxide
PBM: photobiomodulation
OM: oral mucositis
ABSTRACT
Background: Oral mucositis is a highly prevalent and acute inflammatory side effect in head and neck cancer patients undergoing chemoradiotherapy. This systematic review was performed to analyze the therapeutic efficacy of photobiomodulation (PBM) in managing oral mucositis (OM) that appears in this context.
Material and Methods: The search strategy of the systematic review was conducted according to PRISMA guidelines. The eligibility criteria according to PICO process has been defined as follows: Population (P): adult patients with head and neck cancer; Intervention (I): PBM; Comparison (C): placebo group;
Outcome (O): pain, oral quality of life (QoL), evolution of the grade OM and pain.
The set criteria for inclusion were peer-reviewed articles.
Results: The following database were searched from November 2021 to February 2022, for clinical trials: Pubmed, Scopus and Cochrane. From 296 records, 10 studies were included involving in the systematic review. Data from 759 patients who received chemoradiotherapy were analyzed. These studies used different classifications for oral mucositis (WHO, NCI, RTOF/EORTC), pain (VAS) and quality of life (EORTC QLQ-C30, UW-QOL (v4), FACT-HN). PBM therapy protocol used five different lasers (GaAlAs, InGaAlP, He-Ne, diode laser, red and near-IR LED probe) with wavelengths ranging from 632,8nm to 850nm.
Pain evaluation in was based on the visual analogue scale (VAS) mainly.
Prophylactic PBM was effective as it reduced the incidence of grades 3-4 and reduced the overall mean grade of OM during the chemoradiotherapy course compared to the control group. On the other hand, when PBM was used for treatment purposes, it decreased the mean duration of OM compared to the placebo arm.
Conclusions: PBM reduced the incidence of more severe grade of OM induced by chemoradiotherapy. Also, PBM therapy reduced the mean duration of severe OM, mean pain scores and subsequently improved QoL.
Key words: Oral mucositis, photobiomodulation, laser, low-level laser therapy, head and neck cancer, chemotherapy, radiotherapy.
1 INTRODUCTION
1.1 Photobiomodulation
The therapeutic approach of using light is old as from BC. Back in ancient Egyptian and Hindu civilization, exposure to sunlight (Helio, Chroma, or Phototherapy) was used to achieve physical and emotional wellness. Through the centuries, many studies have been carried out subsequently, but the physician-scientist Niels Ryberg Finsen, founder of modern phototherapy, made history in the 19th century by pioneering the beneficial effects of using red and blue light to cure Lupus vulgaris disease. Subsequently, the introduction of a new tool called LASER (Light Amplification by Stimulated Emission of Radiation) brought innovation to this field in the late 1900s (1).
Photobiomodulation (PBM), formerly known as “low-level laser therapy”
(LLLT) or also cold therapy was brought in for the first time in medicine by Endre Mester in 1967 reporting its stimulatory (wound healing) and inhibitory (pain treatment) effects in biological tissues. Its experiment consisted of implanting a malignant tumor in mice and attempting to cure it applying ruby laser, though Mester observed that instead of healing the tumor, hair growth occurred at a faster rate calling this phenomenon “laser biostimulation” (2). Furthermore, the evolution of laser science demonstrated that on top of coherent radiations and non-coherent radiations (Light-Emitting diodes, LEDs) laser properties’, they do present as well biostimulatory features, which is the reason why LLLT and PBM were adopted in such group of treatment.
Nowadays, when mentioning PBM, it refers to low-power laser therapies since PBM comprises broadband lights, LEDs, and lasers, which all of them establish a wide range of electromagnetic radiations (3).
1.1.1 Definition
PBM technique is defined as being a minimally invasive and drug-free application of visible wavelength (380- 700nm) and near-infrared light (NIR) (700- 950nm) which are more commonly low power coherent radiations and non- coherent LEDs, with a power range comprised between 250-500mW. Also, this group of treatments presents a low level of water absorption with a penetrating property going from 3 to 15mm in hard and soft tissues deepness (1,3).
In general, PBM is described as the manipulation of cellular behavior using light with low energy density applied on injuries or lesions to enhance the healing of both wounds and soft tissues, decrease inflammation processes and provide alleviation of acute and chronic pain. In fact, those processes are based on the principle of energy transfer where photonic energy is applied at a specific range to the tissues, hence modulating biological processes at both intra and extracellular levels. The interaction of low-density energy lights and cells tissues does not provoke any thermal effect, hence calling this laser therapy “cold laser”
or “soft therapy». The most frequently used lasers in PBM count GaAlAs (gallium aluminum arsenide), and GaAs (gallium arsenide), AlGaIP (aluminum gallium indium phosphide), HeNe (Helium-Neon) and GaAs (gallium arsenide) (1,4).
1.1.2 Mechanism of action
The PBM is based on the process whereby the light is absorbed and produces effects on the biological systems. Several lines of evidence suggest that PBM acts on mitochondrial cytochrome C oxidase (CCO), which in turn enhances secondary cell-signaling pathways and results in increasing the levels of ATP, cAMP, and reactive oxygen species (ROS) (2,5). The overall outcome of the mechanism induced by PBM is higher energy metabolism and greater cell viability (4).
In mammalian tissues, it exists three main photoacceptor molecules able to absorb light in the NIR range: hemoglobin, myoglobin, and mitochondrial CCO.
Of these, CCO appears to be the primary photoacceptor involved in energy metabolism and production.
Indeed, there is a growing body of evidence suggesting that PBM might work through the process of photodissociation of nitric oxide (NO) from CCO. In the mitochondria, NO binds to CCO where it competes with oxygen and reduces cell respiration, hence decreasing ATP production. During laser exposure, the correct wavelength and power of light delivered are absorbed by the mitochondrial photoacceptor CCO (6). As a matter of fact, PBM permits the photodissociation of the inhibitory NO from CCO, thus reversing subsequently the mitochondrial inhibition of respiration, increasing ROS and ATP production (2,4). In addition, ROS plays a key role in PBM signaling pathway. Accordingly, it activates the redox-sensitive necrosis transcription factor NF-κB that in turn induces transcription of many gene products that prevent cell apoptosis, stimulate fibroblasts proliferation, migration, collagen synthesis, and modulate angiogenesis and tissue repair (4,6).
Besides, other intracellular stores can photo-release NO, such as nitrosylated hemoglobin and myoglobin leading to downstream cell signaling (2,4,6).
1.1.3 Laser technology in photobiomodulation
Indeed, diversified light sources (lasers, LED) are used when it comes to PBM such as the wavelength, output power, continuous-wave, or pulsed operation modes. Recently, to allow deeper absorption of light by tissues, longer
Near-infrared light
nucleus
Figure 1. Mechanism of action of photobiomodulation. AP-1: activator protein. ATP: Adenosine triple phosphate. cAMP: Cyclic adenosine monophosphate. NF-𝜅B: necrosis factor 𝜅B. NO: nitric oxide. ROS:
Reactive-oxygen species.
wavelength surrounding 800-900nm as well as higher output power reaching up to 100mW (equivalent to 0.1J/s) are admitted regarding therapeutic devices (4).
Regarding the classification of lasers, various features are to be considered such as the coherence of the beam, depth penetration, wavelength, the period of the “on-time” when pulsed, and also their eye damage potential.
Accordingly, the U.S Food Drug Administration (FDA) established a so-called
“laser hazard class” where four main major hazard classes (I to IV) and three subclasses can be found. Following this classification, PBM uses lasers belonging to class III or class IIIB, hence protective eyewear is strictly recommended for both the practitioner and the patient (4).
In general, PBM lasers are to be semiconductor diode lasers within which there are two main types, one is the indium-gallium-aluminum-phosphide (InGaAlP) emitting visible wavelength ranging from 630-680nm, and one is gallium-aluminum-arsenide (GaAlA) emitting invisible wavelength ranging from 750 to 910nm. PBM at low-energy output (<500mW) helps to achieve anti- inflammatory and analgesic effects, wound healing, regeneration of the damaged nervous system, and also enhances osteogenesis (1). The types of lasers used in PBM are classified in Table 1.
An important point to highlight at this point is that in fact, the main limitation of the lasers is their very narrowed bandwidth, which makes it difficult to apply it to larger areas (7). Therefore, PBM light-emitting diodes (LED) is a brand-new technique in the field. The development of the newer-generation LED was funded in 1998 by Harry Whelan at the NASA Space Medicine laboratory. New LEDs do have less divergence, higher and remarkably more stable output powers, and quasimonochromaticity (4,7). LED light emission is based on non-thermal emission of light and its use in PBM and other healthcare applications is well accepted as it can reach up to 23cm into tissues depth and it is relatively less expensive than other laser devices (4,7).
HeNe or InGaAlP
Wavelength 633-660 nm
Pulsed or continuous Most frequently continuous.
Table 1. Lasers in photobiomodulation. GaAlA: gallium-aluminum-arsenide. GaA: gallium arsenide.
HeNe: Helium Neon. InGaAlP: indium-gallium-aluminum-phosphide.
GaA
Wavelength 904 nm
Pulsed or continuous Pulsed
Penetration depth 3-4 cm (dose-dependent)
Therapeutic applications Deep inflammation treatments.
Organic LED is under development and could possibly be introduced in the field of PBM, whereby the emission of light is in response to an electric current (4).
1.1.4 Laser delivery parameters
PBM uses laser wavelengths within the optical therapeutic window at red and NIR (600-1070nm). Though, this concept might now be challenged as improvements in laser wavelengths outside of this range are also available, and are seen to offer various benefits (e.g. uneventful healing after laser ablative soft tissue surgery) (3,4,8).
As a matter of fact, PBM or LLLT use lasers of low power (<100mW,
<0.1J/s) and irradiance up to 5W/𝑐𝑚2. Admittedly, the photonic energy with wavelengths within the optical window is highly absorbed by the chromophores (melanin and hemoglobin), which thereby promotes optimum tissue penetration.
Wavelengths in the range of red light (600-700nm) are used for superficial tissue
Though, it can be mechanically pulsed
Penetration depth 1-2 cm
Therapeutic applications Wound healing, shallow muscles
Benefits On the skin and mucous membranes
Low risk injury to the eye
GaAlA
Wavelength 780-870 nm
Pulsed or continuous Most frequently continuous.
Though, it can be mechanically pulsed
Penetration depth 2-3 cm
Therapeutic applications Wound healing, muscle attachments, oral applications
treatments. Longer wavelengths in NIR ranges, do have higher penetration ability and as a result, are used for deep-seated tissues (3,8).
As lasers have a large therapeutic window, it is essential to set a reasonable power density (mW/𝑐𝑚2) to obtain biological effects. Subsequently, a low energy density cannot be totally compensated by a longer time exposure.
The appropriate energy output is calculated by dividing the energy (J) by the irradiated area (𝑐𝑚2) (9). Evidence strongly advises that the effectiveness of the treatment relies on both energy (radiant exposure) and power density (irradiance) operating at specific thresholds between which PBM is effective (8,10).
Furthermore, the depth of the target treatment area must be considered.
Accordingly, there are some treatment dosages suggested by the scientific community: on gingival tissues, 2 to 3 J/𝑐𝑚2 two or three times a week; on muscles, 4 to 6 J/𝑐𝑚2 two or three times a week; on the tooth, or above the apex (indirectly) 2 to 4 J/𝑐𝑚2 (9,10). Herein, the cumulative effect of PBM must be considered, it refers to the total number of treatments multiplied by the dose administered. The threshold for stimulating tissue response is based on the total cumulative dose in J/𝑐𝑚2. Thus, lower doses lying within the therapeutic range at suitable intervals provide biostimulatory effect and better tissue response. The same total dose administered in one single session at short intervals causes inhibitory effects and additional stress (11).
Besides, evidence suggests that other features must be considered for achieving therapeutic effects: the amount of tissue between the laser probe and the target tissue, and the type of tissue (9). For instance, hemoglobin and skin pigmentation (melanin) possess a high absorption ability of laser light and so need a higher dosage.
The evidence strongly demonstrates that using PBM in a pulsed-wave mode achieves better clinical outcomes since it can reach deeper target tissue (up to 10cm deep) than the continuous wave (CW) light (<1-2cm). Although, PBM has a wide variety of applications, the dosimetry in this field is highly complicated as the choice of parameters is generally practitioner-dependent or experimenter personal preference dependent (8).
Irradiation parameter Unit of measurement
Wavelength Nm Measures in nanometers
(nm) and visible in the range of 400-700nm. It determines which chromophores will absorb the light. Successful clinical trials are achieved using LLLT, which ranges from 660 to 1000nm since there are many peaks of CCO in this interval.
Pulse structure Peak power (W)
Pulse frequency (Hz) Pulse width (s) Duty cycle (%)
In the case of the pulsed beam, the average power is:
peak power (W) x pulse width (s) x pulse frequency (Hz).
Power density o irradiance W/𝑐𝑚2 Calculated as follows: power (W) / area (𝑐𝑚2).
Polarization Linear polarized or circular polarized
Polarized light provided different upshots in comparison to non-polarized light. Light propagation through highly scattering media, such as tissue, scrambles polarization states (12).
Irradiation parameter Unit
Beam area 𝑐𝑚2 Diameter 𝑐𝑚2 x 0.7854
Pi x radius 𝑐𝑚2
Energy J (W) x time (s)
Dose/energy density J/𝑐𝑚2 Power density (W/𝑐𝑚2) x (s) Treatment interval h, days, weeks PBM irradiation required at
least twice a week during a Table 3. Parameters to determine the dose of photobiomodulation therapy.
Table 2. Parameters of photobiomodulation in medicine.
certain amount of time to have clinical significance.
However, there is still a lack of evidence.
Power/output W 1000 mW
1.1.5 Photobiomodulation and oral pathology
According to the basic cellular effects of lasers, the will of reaching a reduction of pain, inflammation, enhancing healing processes with PBM therapy is becoming clear (9,13). Subsequently, PBM has played an influential role oral medicine field in both in vitro and in vivo studies. Oral lichen planus (OLP), recurrent aphthous stomatitis (RAS), oral mucositis (OM) caused by radiation of chemotherapy, xerostomia, bisphosphonate-related osteonecrosis of the jaw (BRONJ) among others are some examples of oral pathologies where PBM has been studied as a therapeutic tool (1). In general, these oral pathologies involve etiopathologic features of immune dysregulation, pain, and inflammation (14).
This systematic review will be focused specifically on oral mucositis induced by cancer treatments.
1.2 Oral mucositis
1.2.1 Definition, prevalence, and risk factors
Oral mucositis (OM) or also called in the literature “mucosal barrier injury”
is characterized by widespread erythema, ulceration, and soreness. It is a condition that involves pain and oral discomfort, ranging from mild to severe, and hence affects severely patients’ nutritional intake and overall comprises quality of life. OM is an ailment that remains the most frequent complication in head-neck cancer patients. It arises from cytotoxic effects of therapies for malignant lesions such as radiotherapy or chemotherapy and hematopoietic stem cell
transplantation (15). OM can also decrease patients’ tolerance to cancer treatment and subsequently threaten the prognosis (15,16).
A high rate of patients under chemotherapy (40%) involving particularly drugs as cisplatin, etoposide, fluorouracil, and melphalan develop OM.
Radiotherapy-induced mucositis affects directly or indirectly the oropharyngeal epithelium, hence 97% of patients undergoing such therapy develop OM (15,16).
OM disorder affects mainly middle-aged persons or older. Besides, it affects both males and females at the same rate (M=F) (15).
Many patient-related variables are related to OM establishment, such as tobacco, alcohol, low leukocytes count, dental restorations, advanced disease and stage, history of mucositis. Strong evidence suggests that nowadays, the rising prevalence of patient-related risk factors consequently influences increase the severity, duration, and mucosal turnover. Besides, treatment and tumor characteristics have also been identified for the development of mucositis (15,17).
1.2.2 Etiopathogenesis
Over the decades, new evidence has been conducted and brought one step ahead in the understanding of the underlying pathogenic mechanism of cancer therapy-induced OM. As a matter of fact, an initial phase of mucositis, identified through histologic investigations, includes a histopathological event that starts at the very beginning of radiotherapy or chemotherapy. Although macroscopic clinical signs of OM do not show up immediately, damage at microscopic levels occurs affecting the submucosal endothelium, which further leads to the collapse of epithelium and ulcerations days later. Along with this, signaling from damaged submucosal cells to the epithelium does regulate epithelial injury (18).
Firstly, the first stage of OM setting is called “initiation” and takes place right immediately after radiotherapy or chemotherapy. When a patient is following a radiation therapy, the initiation of cascade mechanisms is triggered each time the patient receives its radiation dose. However, in patients following
chemotherapy, the initiation of biological cascade is triggered as one time and occurs as a one single event. Initial damage to DNA in submucosal cells and epithelium leads the way to cell apoptosis at a limited scale, thus the damage magnitude at this point is too small to result in clinical manifestations of OM.
During the process, ROS production by chemotherapy drugs cells and tissues DNA affectation, stimulation of macrophages, which in turn generate a regulation pathways cascade (NF-κB and ceramide pathway) (17,18).
Secondly, comes the following event, the primary damage response which results in tissue injury provoked by the biological cascade processes involving ROS release, radiotherapy, chemotherapy, and lethal DNA damage. Once NF- κB is activated, notably by ROS induction pathway, it permits he regulation of gene expression and the release of pro-inflammatory cytokines proteins (TNF, IL-6, IL-1β). Besides, this transcription factor directly modulates the apoptosis in genes of the BCL2 family. Accordingly, NF-κB is the most important transcription factor known to trigger oral mucositis. Radiotherapy and chemotherapy both enhance ceramide synthase and sphingomyelinase which lead to cell apoptosis of submucosal cells through ceramide pathway. Furthermore, the administration of neoplastic therapy also activates matrix metalloproteinase (MMP), which is a group of enzymes that trigger and later break the tissue integrity between epithelium and submucosa leading to further ulceration (17,18).
Then, at this point of the biological mechanism, many damage signals are generated and do come from different sites leading to the signal amplification, which stimulates and amplify tissue injury by means of positive feedback loops.
As NF-κB activates and releases TNF (pro-inflammatory cytokine protein), which in turn TNF activates and releases NF-κB. This results in the amplification of the initial injury by NF-κB and ceramide pathways. The potentiation and magnification of the biological pathway cascade by positive feedback loops induces extend damage response triggered by the neoplastic therapy up to days after its administration (16,17).
Lastly, ulceration of the tissue takes place with the manifestation of important clinical symptoms and is often accompanied by inflammatory cell infiltration. Patients under chemotherapy or radiotherapy do generally present a weak immunity and in this case, they are granulocytopenic. The present ulcerated
epithelium is an entrance gate for bacterial colonization of gram-positive and gram-negative bacteria. Following the colonization, present bacteria take advantage of the situation by up-regulating pro-inflammatory cytokines through macrophages, which in turn enhances tissue destruction. Oral mucositis is characterized by deep, broad, and painful ulceration.
In general, once radiotherapy and chemotherapy administration is fully completed ulcers of oral mucositis start to heal spontaneously within two to three weeks accompanied by a renewal of the epithelium and the local microbial flora (16–18).
Figure 2. Pathophysiology of oral mucositis.
1.2.3 Clinical features
OM is typically characterized by a red and thin lesion on the oral mucosa, evolving from slough to eroded, to eventually become ulcerated. The ulcers on the oral mucosa could be accompanied with bleeding and pain, which interferes with functioning. Usually, the ulcers are covered with a yellow-white fibrin clot impeding sense of taste. All of these features cause general discomfort to immune-compromised patients and constitute a portal entrance to bacteria leading to life-threatening septic complications (15).
1.2.3.1 Radiotherapy-induced oral mucositis
The first signs of radiation-induced oral mucositis are usually characterized by the red aspect of the oral mucosa because of a decreased mucosa thickness and dilatation of the underlying capillaries. Though, prior that erythematous stage, they generally present whitish aspect where patients are either asymptomatic or presenting mild burning sensation to hot food or spices (16,18).
Then, after the erythematous phase, the mucosa is covered by a yellowish white pseudomemebrane made of fibrin clot, which will later erode and break down leading to mucosal ulceration. Beneath the fibrinous pseudomemebrane, epithelial surfaces are exposed and bleed with ease, which is very painful for the patients, impeding their daily oral functions (e.g., chewing, masticating), and further resulting in weight loss (15,16).
1.2.3.2 Chemotherapy-induced oral mucositis
In general, chemotherapy-induced mucositis is less severe and lasts less than in radiation-induced OM (7 to 14 days). Chemotherapy-induced OM is characterized by an erythematous mucosa that will break down leading to further ulcerations. Patients typically experience pain interfering with eating, swallowing, and speaking due to the mucosal ulcerations. Besides, in patients receiving concurrent radiotherapy and chemotherapy, the risk of increasing the severity of OM is greater. Indeed, patients do experience more severe pain and ulceration
of the lesions. Mucosa ulcerations constitute a portal for either bacterial colonization (gram-negative bacteria), virus infections (herpes simplex virus), or fungal infections (candidiasis) and can be occasionally superimposed on OM (16,19). Moreover, severe pain which often comes along OM in chemotherapy- administered patients, impeding oral hygiene and hence affecting gingival and dental structures (16,19).
1.2.4 Scoring of oral mucositis
It exists three most frequently used scales among a variety for grading OM.
The oral toxicity scales most commonly applied are the following: radiotherapy oncology group (RTOG), world health organization (WHO), and national cancer institute common terminology criteria for adverse events (CTCAE). Head and neck patients undertaking radiotherapy or chemotherapy are checked-up once a week, assessing symptoms, oral intakes, and oral mucosa (16).
RTOG WHO CTCAE
Grade 1 Irritation
Mild pain (no need of analgesics)
Mild
Soreness Erythema
Asymptomatic or mild symptoms
Intervention not indicated
Grade 2 Patchy mucositis that might produce an inflammatory
serosangineous discharge
Moderate pain (need of analgesics)
Moderate Erythema Ulcers
Solid diet tolerated
Moderate pain Not interfering with oral intake
Modification of diet
Grade 3 Confluent, fibrinous mucositis
May include severe pain requiring narcotics
Severe Ulcers
Liquid diet only
Severe pain
Interfere with oral pain
Table 4. RTOG, WHO, and CTCAE toxicity scales of OM.
Grade 4 Life-threatening Ulceration Hemorrhages necrosis
Oral alimentation impossible
Death
1.2.5 Management of oral mucositis
The treatment of OM involves many elements that need to be considered such as oral hygiene, oral pain, secondary infections, nutrition intake. As a matter of fact, patients undergoing neoplastic therapy need to be examined once a week, to evaluate the grade of the patient and the evolution of OM (16).
Oral pain management is the most challenging aspect in OM as it is the most important symptom. Systemic analgesics combined to topical gels may be prescribed to control moderate to severe pain (15). Oral pain management will further ease water and food intake and improve patient’s oral care. Benzydamine mouth rinses are prescribed to reduce the severity and pain caused by radiotherapy or chemotherapy-induced OM. Oral gels, “Gelcair” helps to control pain generated by OM as it builds barrier that protects the oral mucosa, which bring comfort and pain relief to the patient. Besides, opiates or corticosteroid may also be prescribed in the same case to speed up healing and prevent infectious complications (15,16). Lidocaine 2% is also recommended in form of mouth washes or topical gels to reduce pain. Photobiomodulation therapy is also used to treat and prevent OM induced by head and neck cancer treatment.
Monitoring microbial colonization and prescribing antifungal or antiviral prophylaxis is key in patient with weak immune system and low neutrophil count.
More general recommendation to radiotherapy or chemotherapy-induced OM involves abundant hydration to keep the oral mucosa humid. If the patient is wearing a removable prosthesis, it is strongly advised to be removed during radiotherapy sessions. Furthermore, antiseptic mouthwashes with chlorhexidine 0.12% help the patient to decrease bacterial loads in the oral cavity and therefore avoid septicemia.
2 RATIONATE, HYPOTHESIS AND OBJECTIVES
2.1 Rationate
The prevalence of OM in head and neck cancer patients treated with chemotherapy and radiotherapy can reach up 100% of cases. OM provoked by theses therapies can cause unbearable mouth discomfort to the patients accompanied with pain, swelling, difficult oral hygiene, and reduced oral intakes.
The mucosa barrier is debilitated, thus leading to local or systemic infections and poor quality of life of these patients. All of these variables affect the treatment of the patient’s neoplasm and could lead to the interruption of such treatments, the decrease of the chemotherapy dosage or radiotherapy, and delay the healing of the lesion.
In general, the management of OM lesions is based on the symptomatology of the patient as there is no gold standard treatment of it. This systematic review discusses the application of PBM as an evolving alternative that is currently being explored in preventing further evolution into more severe grades of OM in patients undergoing oncotherapy. Several studies have emerged and shown that LLLT triggers a cascade of cellular response that eventually enhances angiogenesis, hence wound healing, reduce pain and boost patient’s QoL. Current systematic review reports the power of use and benefits achieved of PBM regarding OM. As a result, PBM is found to be a drug-free and less invasive option that is better accepted by the patients when one takes into account the results obtained.
2.2 Hypothesis
PBM prevents severe grades of OM in patients who have been treated with chemotherapy and radiotherapy and improves patients’ quality of life.
2.3 Objectives
2.3.1 General objective
The general objective of the present systematic review is to analyze the therapeutic efficacy of PBM in managing OM that appears in head and neck patient treated with radiotherapy and chemotherapy.
2.3.2 Specific objectives
To assess the reduction of pain and the duration of OM after the application of PBM in radiotherapy and chemotherapy patients.
To determine the ability of PBM to prevent the evolution of OM into more severe grades.
To analyze the improvement of the quality of life after treating OM with PBM in radiotherapy and chemotherapy patients.
3 MATERIAL AND METHODS
3.1 Inclusion and exclusion criteria
The eligibility criteria according to PICO process has been defined as follows: Population (P): adult patients with head and neck cancer; Intervention (I):
photobiomodulation; Comparison (C): placebo group; Outcome (O): pain, oral quality of life (QoL), evolution of the grade OM.
Subsequently, our research question would be as follows: in head and neck cancer patients undergoing radiotherapy or chemotherapy, does photobiomodulation helps improving the grade of OM as well as pain and quality of life compared to placebo group?
The present systematic review included studies conducted on humans published in English from November 2011 to November 2021. We also included studies if they met the standards of clinical trials and random clinical trial (RCT), with placebo or control group, usual care, patients with OM, patients who undergone radiotherapy or chemotherapy for the treatment of head and neck cancer, together with photobiomodulation for either treatment or prevention of OM.
Exclusion criteria were as follow: animals, children, patients who received stem-cell transplantation, patients with other oral consequences due to radiotherapy or chemotherapy, non-English articles.
3.2 Search strategy
The planning and preparation of the study has followed the protocols established in the PRISMA guidelines for the preparation of systematic reviews.
A search of articles was carried out in the following databases: Scopus, Pubmed, and Cochrane library; between November 2021 and January 2022. The search strategy included the keywords “low-level laser therapy”, and “oral mucositis”. These terms combined with the Boolean operator “AND/OR” to obtain
the articles using the following strategy: ("low-level laser therapy") AND ("oral mucositis").
DATA BASE
SEARCH FILTERS DATE
Pubmed "low-level laser therapy"
AND "oral mucositis"
10 years Randomized clinical trials Clinical trials
30/11/2021
Scopus “Oral mucositis” AND
“low-level laser therapy”
10 years Articles Clinical trials
02/2/22
Cochrane “Oral mucositis” AND
“low-level laser therapy”
10 years English Trials
02/02/2022
3.3 Selection process of the studies
Titles and abstracts from the three databases were downloaded to Zotero software. Zotero was used to import the reference data and to remove duplicate records. Two reviewers (LW, GFF) screened independently titles and abstracts.
Disagreements regarding inclusion were resolved by mutual consensus of both reviewers. Studies that satisfied the eligibility criteria were included through full- text assessment.
3.4 Data extraction and analysis
The following data were obtained from each eligible study: author, year of publication, sample size, type of laser, wavelength, assessment (OM, pain and QoL), OM grades 0-1 and 2-4 in control group (CT) and intervention group (IG), pain grading (VAS) in CG and IG, QoL in CG and IG.
3.5 Quality of evidence evaluation and risk of bias assessment
To assess the overall quality of the evidence, we used the CASPe (Critical Appraisal Skills Program Español) checklist. The CASPe guide for clinical trials is made of eleven questions, three first ones of which are designed to help us to eliminate the less relevant articles. As a matter of fact, if the first three answers are “yes”, then it is worth continuing with the next questions.
4 RESULTS
4.1 Search results
Initially, the data base searches identified a total of 274 articles: PubMed 40 articles, Scopus 124 articles and Cochrane 115 articles., manual search 1 article.
After removing all duplicates with Zotero, a total of 169 articles were retrieved for title and abstract evaluation. At the end of the previous process of selection, 34 articles were identified and evaluated independently for analysis of their full text by two reviewers (figure 3).
Figure 3. Flowchart of the article. Selection process for the systematic review according to PRISMA 2020 guidelines.
4.2 Description of study characteristics
Finally, a total of 10 randomized clinical trials included for the purpose of this systematic review. Overall, a total number of 759 patients were randomly assigned in the included studies. The duration time of PBM was ranging from 10 seconds (20,21,23) to 125-145 seconds (24,25,26). This systematic review includes five types of lasers: GaAlAs (20,21), InGaAlP (22,23), He-Ne (24–27), diode laser (28), red and near-IR LED probe (29). The wavelengths used were:
660nm (20,21,23,28), 685 (22,23), 682,5nm (24–26) and 658nm (27) and 34x660 nm (red) and 35x850nm (near-IR) (29). The energy density used was 2.5J/𝑐𝑚2 (20), 2J/𝑐𝑚2 (22), 3.5J/𝑐𝑚2 (24), 3J/𝑐𝑚2 (25,26), 4J/𝑐𝑚2 (23,27). PBM delivery protocol consisted of 5 consecutive day/week from Monday to Friday going from the first to the last session of chemoradiotherapy. We found that two of them looked at both prevention and treatment of OM lesions (24,26). Four of them looked at exclusively preventing the severity of OM (20,23,29,30). Eventually, four of them aimed to heal OM lesions caused by chemoradiotherapy (21,22,25,27).
4.3 Risk of bias and quality of evidence
The risk of bias is summarized in annex 3 using CASPe guide. CASPe questionnaire for randomized clinical trials is made of 12 questions by which we can either answer by “yes”, “no” or “can’t tell. The first questions help us in the process of screening, hence the articles obtaining a greater number of “yes” to these questions are worth proceeding with the following ones. The results showed that the mean quality levels of the 10 articles were considered to be high with overall risk of bias low.
4.4 Effects on pain
Six included studies (21,23,24,26,27,29) used VAS (visual analog scale) instrument for measuring pain. This tool allows us to measure patients’ perception of pain from 0 to 10, where 0= no pain, 1-3= mild pain, 4-6= moderate pain, 7-9=
severe pain, 10= worst pain possible. Patients in the intervention group experienced less severe pain during the full course of chemoradiotherapy. In fact, in the study of Gautam et al. (24) the mean VAS score of the PBM group was lower (4.36) than the placebo group (6.76). Kauark et al. (29) recorded lower pain score in PBM group of 2.1, which refers to mild pain whereas higher scores of pain were observed in the placebo group (4.5).
4.5 Effects on oral mucositis
Among our included studies four trials (20,22,23,27,28) used WHO grading ranging to 0 to 4 where 0= none, 1= erythema/soreness, 2= ulcer and able to eat, 3= ulcer and limited eating and 4= ulcer with hemorrhage and necrosis. Two studies used NCI (National Cancer Institute Common Toxicity Criteria) (21,29), which ranges from 0 to 5 and where 0= none, 1 (mild)= painless ulcers, erythema or mild soreness in the absence of lesions, 2 (moderate)= painful erythema, oedema or ulcers but eating or swallowing possible, 3 (severe)= painful erythema, oedema or ulcers requiring intravenous hydration, 4 (life-threatening)=
severe ulceration or requiring parenteral or enteral nutrition support or prophylactic intubation and 5= death related to toxicity (31). Three articles used RTOG/EORTC criteria (24–26) which ranges from 0 to 4, where 0= none, 1=
erythema of oral mucosa, 2= patchy mucositis, 3= confluent mucositis and 4=
ulceration, necrosis or hemorrhage.
The groups in the included studies are named: “OM grades 0-2” and “OM grades 3-4”. Each of these categories is subdivided into CG (control group) and IG (intervention group). The effects of PBM on severe grades of OM (grades 3- 4) show favorable results. The literature describes a mean of 19,4% of patients treated with PBM affected by OM severe grades. In the control group (sham laser group), the mean of OM severe grades’ reaches 52,1%. PBM delays the evolution
of OM on to more severe grades. Gautam et al. (24) obtained 70,9% of the patients presenting OM with a grade ranging from 0 to 2 and 29,1% with grade 3-4. Antunes et al. (23) reported 93,6% of participants treated with InGaAlP diode laser with OM grade 0-2, while only 6,4% presented OM grade 3-4.
4.6 Effects on quality of life
In the included studies, various instruments were used to measure QoL of head and neck cancer patients. Two articles (20,23) used EORTC QLQ-C30 instrument to assess QoL. The EORTC QLQ-C30 comprises a functioning scale (e.g., physical, social, cognitive), a global QoL scale and symptoms scale (e.g., nausea, vomiting, fatigue, loss of appetite). Depending on the scale, some require a “yes” or “no” response, whether the other items are scored on a 4 points scale (1= “not at all” and 4= “very much”). The final result is transformed into a 0-100 scale. A high score in the functioning scale and the QoL scale do correspond to a better QoL, on the contrary a high score in the symptoms scale represents a worst QoL. Two included studies (22,29) used University of Washington-quality of life version 4 UW-QOL (v4) questionnaire. UW-QOL (v4) comprises 12 sections (e.g., swallowing, activity, saliva, taste) that are scored in a VAS from 0 to 100 (0= worst score, 100= best score). One article (25) used Functional Assessment of cancer Therapy in Head and Neck patients (FACT-HN) questionnaire to asses QoL of their patients. The latter questionnaire included 27 generic specific (FACT-general) items and 12 head and neck specific items.
FACT-general comprises four categories, which are physical well-being, family/social well-being, emotional well-being, and functional well-being. Higher scores in physical and emotional correspond to poor QoL, whereas higher scores in social and functional correspond to better QoL. In head and neck specific items, higher scores indicate better QoL.
In the study conducted by Djavid et al. (20) using EORTC QLQ-C30, showed that there were no significant difference between the CG and IG in either the functional or symptoms scales after chemoradiotherapy (CG: functioning scale physical: 63±18.1 and symptoms scale: nausea and vomiting: 26.9±12.7;
IG: : functioning scale physical: 53.8±27.5 and symptoms scale: nausea and
H&N35 found that there was no statistical difference between the two arms (CG/IG). Gautam et al. (24). concluded that trans parenteral nutrition (TPN) was required for a shorter period of time in the IG than the CG;
Antunes et al. (23) found better results of QoL in the IG rather than the CG by using EORTC QLQ-C30.
The study of Oton-Leite et al. (22) showed that there is an overall reduction of QoL in both IG and CG, though, QoL scores remain higher in IG. Some domains studied such as, activity or speech were more affected during the baseline-intermediary period in the CG. Pain and saliva where more affected during the baseline-final period in the CG. Kauark et al. (29) also used UW-QOL (v4) questionnaire, found that in the IG, higher scores of general, physical and socio-emotional QoL were obtained compared to the CG.
The study conducted by Gautam et al.in 2013 (25) used the FACT-HN questionnaire and showed a statistical difference between the laser and placebo group. In fact, the IG presented better QoL in their physical and functional well- being (physical: 5.96±3.11, functional: 22.39±1.99) compared to the CG. Also, the IG presented a higher head and neck specific scores which indicates a better QoL.
Martins et al (28) used the PROMS (Patient-reported OM-related Symptoms) scale, which aims to represent the consequences of OM on patient’s QoL. The PROMS questionnaire comprises ten questions about the symptoms of OM. Then the patient indicates the score on a 10cm VAS. Each patient’s score is measured and summed to eventually obtain the PROMS score.
5 DISCUSSION
Oral mucositis is a highly prevalent and painful side effect of cancer chemotherapy and radiotherapy. Our results integrated both preventive and curative outcome of PBM in head and neck cancer patients undergoing CRT. This systematic review showed that the application of prophylactic PBM does reduce the incidence of severe grades of OM in head and neck cancer patients undergoing CRT. The results presented in the systematic review suggest the effectiveness of PBM in treating OM in these patients undergoing cancer therapy.
Indeed, thanks to PBM, a decreased incidence and severity of OM minimize morbidity and improve the comfort patients’ comfort.
5.1 Discussion of the methodology
In general, the risk of bias of the included studies was classified as low (favorable) according to CASPe checklist (using the newly updated version) in the four sections that do constitute the questionnaire designed for randomized clinical trials, which are the following: “is the study design valid for a randomized controlled trial?”, “what the study methodologically sound?”, “what are the results?”, “will the results help locally?”. The percentage of each respective section is the following: 70%, 97.5%, 73% and 90%. In relation with the first section, only 40% of the included studies had a risk of uncertain bias (“can’t tell”) (20, 21, 22, 24) since they did not clarify if all participants who entered the study accounted for at its conclusions. Regarding the second section treating about the methodology used, only one study (27) did not have the study groups similar at the start of the randomized controlled trial since they had fewer number of patients in the end of their experiment. In Legouté et al. (27) study, they started with 97 patients and ended up with 51 patients really treated with PBM over the 5 years since they did not treat mild lesions of OM (<2 grades) in order to focus on more severe grade of mucositis. This heterogeneity or so-called attrition bias, (27) could be related to violation protocol leading to missing data and more exaggerated effects of PBM on OM. Aside from this heterogeneity detected, all of the articles presented a proper blinding of outcome assessors. In the third section, 27% of the studies got answered “can’t tell” which refers to an uncertain
risk of bias. Indeed, some articles (20,21, 23, 25, 26, 27) did not report the precise estimation of the effect of the treatment or others (20, 26) did lack the benefits- risk and the cost of PBM’s part.In the last section of CASPe checklist, the results and conclusion collection in one article (21) could not be applied to our daily practice since PBM therapy was in the end not effective in more severe grade of OM as laser parameters were not suitable for such clinical lesions.
As our systematic review include mainly randomized clinical trials, it leads to the robustness of the results. Although, randomized clinical trials are specifically exposed to the risk of bias either by the authors and investigators when it comes to designing the study sample and selecting the variable or in controlling other elements that may influence the final clinical response.
In 2018, the WALT (World Association for Photobiomodulation Therapy) meeting, members of this association agreed that the optimum dose for curing OM was 5J/𝑐𝑚2 and laser energy delivery ranging from 10 and 150mW/𝑐𝑚2 (32).
besides, in order to avoid phototoxicity caused by hyperthermia, when applying LLLT when managing OM, the energy density should not exceed 6J/𝑐𝑚2.The choice of laser wavelengths applied to reach positive effect in this systematic review, ranged from 632,8nm to 850nm. The range of number of points for the application of laser ranged from 36 to 60 and always avoiding the site of tumor with an optical spot size of 0.24 to 1𝑐𝑚2. Three articles (20,23,28) applied comparable LLLT wavelengths on OM lesions (660nm) and application time (10s for each site) with energy density varying from 2.5J/𝑐𝑚2to 4J/𝑐𝑚2, inferred as suitable when PBM is used for OM prophylactic purposes. The study of Kauark et al. (29) used different parameters of laser therapy as the wavelength employed was 850nm during 60s for each site and indicated promising prophylactic upshots in favor of PBM. The study of Gouvêa et al. (21) had negative results in preventing OM using LLLT. Four other studies (22,24,25,27) reported comparable wavelengths (632,8nm to 685nm) with distinct application times (40s to 145s for each site) and energy density going from 2J/𝑐𝑚2to 4J/𝑐𝑚2, figured as appropriate for using PBM as a curative therapy. Eventually, two other studies (26,28) considered that PBM was effective in preventing and treating severe degrees of OM using He-Ne laser at 632,8nm with an energy density of 3J/𝑐𝑚2
(26) and diode laser at 660 nm with an energy density of 25mW (28). No included study reported any unwanted side effect to PBM; hence, we could assume that it possesses a good safety profile.
Four included studies (22,24,25,27) analyzed the prophylactic outcomes of PBM on OM and reported that the mean duration of OM lesions was reduced compared to the placebo group. Indeed, Gautam et al. (24) in 2012 reported that the mean duration of OM grades 3-4 was significantly lower in the laser group than in the placebo arm. Corroborating the latter results, Gautam et al. (26) found that the mean duration of severe OM in the IG was of 10.5 days and 16.1 days in the CG. The study of Legouté et al. (27) also confirms those data. Accordingly, pain mean duration was also found to be lower in the IG. To strengthen our results, Anschau et al. (30) found that the use of PBM could decrease the resolution time of OM by 4.21 days on average.
Five other studies (20,21,23,28,29), mainly focused on the prophylactic use of PBM. The study of Djavid et al (20) in 2011 reported that PBM significantly decreased the incidence of severe OM. Similarly, Antunes et al. (23) obtained comparable results confirming that PBM drastically reduces the risk of having OM grades 3 or 4 in patients undergoing chemoradiotherapy. However, when comparing the results of Antunes et al. (23) with those of Gouvêa et al. (21) a heterogeneity was detected since 22% of patients showed OM grades 3-4 in the IG and thus PBM was not efficient in its prevention role. This could be explained by the fact that Antunes et al. (23) used a ten times higher power and energy than Gouvêa et al. (23). The systematic review and meta-analysis of Anschau et al.
(30) selected 12 RCTs where PBM stinkingly reduced the severity of OM by 62%
in patients undergoing chemoradiotherapy.
Thus, from evidence, we would suggest that the prophylactic use of PBM reduces the risk of developing higher and more severe grades of OM and when it is used for treatment matters, PBM helps reducing considerably the mean duration of severe OM ulcer lesions.
5.2 Discussion of the results 5.2.1 Reduction of pain
Among the included studies, five (23,24,25,27,29) did address the reduction of pain severity (VAS>7) through the selective inhibition of peripheral pain receptors brought about the application of PBM. Patients were evaluated using the VAS and most studies reported reduction of pain due to the use of PBM.
However, in the study of Gouvêa et al. (21) there was barely any difference between the two arms (CG and IG) as PBM did not help to control pain. Several reasons might be involved for this heterogeneity, first, in this study patients were administered pain killers, second, patients selected already had OM lesions at advanced stages which involves much more intense and severe pain that probably PBM was not strong enough to decrease it.
The use of pain killers was reported on the included articles (21,24,25, 26,27,29). A decreased number of opioid analgesic use in IG than in CG was observed. This could be due to less severe OM experienced by the laser than the sham laser group. Indeed, the analgesic effect in LLLT is gradual, cumulative, and repeated sessions of laser therapy are required to eventually achieve a reduction in central sensitization of pain and amplitude of compound action potentials. Besides, in most of the studies, opioid analgesics supplementation during the course of CRT was less needed in the IG than the CG. Although, Gouvêa et al. (21) was the only study that reported no statistical difference between IG and CG, which is consistent with the fact PBM lacked effectiveness.
Thus, the use of PBM on OM lesions has shown very promising results regarding the management of pain as some authors (23,24,25,27,29) reported a decrease of pain scores using the VAS.
5.2.2 Prevent the evolution of oral mucositis
During laser exposure, under correct LLLT protocols, wavelengths are absorbed by a mitochondrial photoacceptor reversing subsequently the mitochondrial inhibition of respiration and increasing ROS and ATP production.
ROS activates NF-κB transcription factor, that in turn induces transcription of many gene products that prevent cell apoptosis, stimulate fibroblasts
proliferation, migration, collagen synthesis, and modulate angiogenesis and tissue repair (4,6). Heterogeneity was detected in our systematic review because several scoring systems of OM were used that may lead discrepancies between studies. In the evaluation of OM using the WHO scale, Djavid et al. (20), Antunes et al. (23), Legouté et al. (27) and Martins et al. (29), PBM had very efficient result at the end of CRT sessions as it delays the exacerbation of OM towards higher grades. According to RTOG/OERTC grading, used in Gautam et al.in 2012, 2013 and 2015 (24, 25, 26), also showed promising results in regard to PBM as it highlighted its slowing impact on OM severity. The assessment of OM according to the NCI grading of Gouvêa et al. (21) and Kauark et al. (29) showed that PBM was not effective in slowing down the onset of OM and the evolution onto more severe grades. In the study of Gouvêa et al. (21) and Kauark et al. (29), the rate of patients with OM grade 3-4 was very similar to the CG which could be due to the important number of CRT interruptions in the sham-laser group. Other reasons of this heterogeneity would be patients’ characteristics and LLLT parameters.
As a matter of fact, the use of PBM therapy helps in slowing down the process of severe OM progression compared to the sham group. Hence, the application of LLLT restrains the evolution of OM onto more severe and acute grades over time.
5.2.3 Quality of life after treating oral mucositis
The biological pathways of OM may vary to some degree between chemotherapy and radiotherapy. Chemotherapy provokes a more acute OM response since it is administered over a short time systematically.
Chemotherapy-induced OM onset is around fourth and seventh days after the start of the treatment with a peak within two weeks. Radiotherapy targets a specific area of the body and is given in small fraction over weeks of treatment.
Radiotherapy-induced OM is dose-dependent and starts with a cumulative dose of 15Gy around the tenth day of radiation therapy, peak is reached at 30Gy lasting for weeks. Hence, as radiotherapy is administered in a more punctual manner, we can suppose that PBM therapy could be more effective for OM. Although, the
results obtained in this systematic review suggest that PBM is as effective in chemotherapy or radiotherapy.
The properties of PBM offer many benefits in regard to OM and its management. Indeed, PBM has analgesic properties, decreases the inflammation, and helps in reducing the grade severity of OM. All these elements go in favor of better patients’ QoL, with higher food intakes, lower scores of VAS, and less acute exacerbations of OM symptoms. In the included studies, QoL is assessed by means of various instruments.
Chemoradiotherapy is associated with several acute symptoms that negatively affect the QOL of the patient. OM threatens various every-day-life functions such as swallowing, mastication, speech, oral hygiene. Martins et al (28) was the only study to use the PROMS questionnaire and showed, as a matter of fact, that higher PROMS scores were associated with severe OM in the placebo group leading to reduced QoL. At final stages of radiotherapy in PBM group, the correlation coefficients between PROMS and OM severity were low, which could suggest the efficacy of PBM treatment (28). Besides, at the 30th week of radiotherapy in the PBM group, the patients experienced less acute and aggressive symptoms of OM, hence improved QoL compared to the control group. The results obtained clearly suggest the strong role of PBM in preventing the evolution of OM onto more acute stages, thus improving QoL of the patient during cancer treatment. In the study of Oton-Leite et al. (22), the results obtained using UW-QOL (v4) tool inferred that local application of PBM improves QoL and oral functional status. Kauark-Fontes et al (29) also used UW-QOL (v4) questionnaire and reported similar results. The higher scores of social and emotional QoL obtained in the IG could be interpreted by effectiveness of PBM in attenuating OM symptoms. Corroborating our results, Gautam et al. in 2013 (23) also reported the positive impact of LLLT on QoL in patients undergoing head and neck cancer therapy. Indeed, the higher scores of QoL could be explained by the fact that PBM decreases OM acuteness and thus, the patients might experience better oral functions and nutrition. However, heterogeneity was detected in two included studies (20, 21) were the results showed no difference between the placebo and the laser group in terms of QoL. In the study of Djavid et al. (20), the heterogeneity of the results could be due to the low percentage of
patients having OM grade 3-4 (severe) in both IG and CG. The irrelevant results regarding QoL reported in the study of Gouvêa et al. (21) could be explained by the comparable rate of patients in IG and CG experiencing OM severe grades, which could be a reason why similar results in both arms were described.
The evaluation of QoL through the use of different types of questionnaires led us to affirm that PBM helps improving QoL of OM cancer patients. The benefits of PBM in terms of QoL are observed at several levels. Indeed, many aspects of this category of patients undergoing chemoradiotherapy has been improved, such as swallowing, activity, saliva, taste or nausea, vomiting.
Overall, all the results gathered in this present systematic review are consistent with the litterature. In the systematic review and meta-analysis of Peng et al. (31) published in 2020, a total of 30 RCTs were included in order to study therapeutic and prophylactic effect of PBM in patients undergoing chemoradiotherapy. Though this review, the authors found that PBM tremendously reduced the duration of OM compared to the placebo group when it was used for treatment purposes. Moreover, they could conclude that the prophylactic use of PBM prevented the evolution of OM onto more severe grades.
Those findings are; as a matter of fact; identical to ours. Another systematic review and meta-analysis of Bjordal et al. (32) studied the effect of PBM on OM in the same target population and the conclusions were indeed in favor of PBM as they found out that it reduced both the severity and pain duration of OM.
Although the effects of PBM have been already systematically reported and discussed, this systematic review presents limitations. First, the systematic review included studies with different OM scoring systems which made our analysis difficult. Besides, there was also a lack of standardization in QoL evaluation and questionnaires. Finally, differences in laser setting protocol among the included study is also considered as part of the limitations of our study.
Therefore, all these elements obtained in the studies make the reproducibility of the results difficult and the heterogeneity in the methodology also greatly hinders the comparison, thus, our results should be taken with caution. Hence, our findings strongly suggest using standardized classification for grading OM and
QoL, and focusing on PBM protocols for prophylactic and treatment use of PBM in cancer treatment induced OM.
6 CONCLUSION
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.
The use of PBM for treating OM lesions is efficient as our results indicate that PBM therapy reduces the mean duration of severe OM. Our findings do also show that PBM therapy decreases mean pain scores.
PBM is effective in both reducing the grade and duration of OM during the course of chemoradiotherapy in head and neck cancer patients.
Eventually, we can further conclude that the application of PBM accordingly improves QoL of this category of patients since symptoms recover over time of their treatment.
For future research, we advocate to perhaps compare the efficacy of pharmacological agents and PBM. Also, regarding the prophylactic use of PBM, it should be a target to compare PBM therapy at different starting points before the initiation of chemoradiotherapy to avoid unnecessary sessions of PBM
