Support Care Cancer

DOI 10.1007/s00520-016-3153-y

REVIEW ARTICLE

Low-level laser therapy/photobiomodulation in the management

of side effects of chemoradiation therapy in head and neck cancer:
part 2: proposed applications and treatment protocols
Judith A. E. M. Zecha 1 & Judith E. Raber-Durlacher 1,2 & Raj G. Nair 3 & Joel B. Epstein 4,5 &
Sharon Elad 6 & Michael R. Hamblin 7,8,9 & Andrei Barasch 10 & Cesar A. Migliorati 11 &
Dan M. J. Milstein 1 & Marie-Thérèse Genot 12 & Liset Lansaat 13 & Ron van der Brink 5 &
Josep Arnabat-Dominguez 15 & Lisette van der Molen 13 & Irene Jacobi 13 &
Judi van Diessen 14 & Jan de Lange 1 & Ludi E. Smeele 1,13 & Mark M. Schubert 16 &
René-Jean Bensadoun 17

Received: 2 August 2015 / Accepted: 7 March 2016

# Springer-Verlag Berlin Heidelberg 2016

Abstract nology, together with a better understanding of mechanisms

Purpose There is a large body of evidence supporting the involved and dosimetric parameters may lead to the manage-
efficacy of low-level laser therapy (LLLT), more recently ment of a broader range of complications associated with
termed photobiomodulation (PBM) for the management of HNC treatment. This could enhance patient adherence to can-
oral mucositis (OM) in patients undergoing radiotherapy for cer therapy, and improve quality of life and treatment out-
head and neck cancer (HNC). Recent advances in PBM tech- comes. The mechanisms of action, dosimetric, and safety

* René-Jean Bensadoun Liset Lansaat

renejean.bensadoun@che-nice.com l.lansaat@nki.nl
Judith A. E. M. Zecha Ron van der Brink
j.zecha@amc.uva.nl RVanderbrink@coh.org
Judith E. Raber-Durlacher Josep Arnabat-Dominguez
j.e.raberdurlacher@amc.uva.nl joseparnabat@ub.edu
Raj G. Nair Lisette van der Molen
r.nair@griffith.edu.au l.vd.molen@nki.nl
Joel B. Epstein Irene Jacobi
joel.epstein@cshs.org i.jacobi@nki.nl
Sharon Elad Judi van Diessen
SElad@URMC.Rochester.edu j.v.diessen@nki.nl
Michael R. Hamblin Jan de Lange
hamblin@helix.mgh.harvard.edu j.delange@amc.uva.nl
Andrei Barasch Ludi E. Smeele
barasaff@cs.com l.smeele@nki.nl
Cesar A. Migliorati Mark M. Schubert
migliorati@uthsc.edu mschuber@seattlecca.org
Dan M. J. Milstein
D.M.Milstein@amc.uva.nl 1
Department of Oral and Maxillofacial Surgery, Academic Medical
Marie-Thérèse Genot Center, University of Amsterdam, Meibergdreef 9, 1105, AZ
mtgenot@skynet.be Amsterdam, The Netherlands
 Support Care Cancer

considerations for PBM have been reviewed in part 1. Keywords Low-level laser therapy . Low-level light therapy .
Part 2 discusses the head and neck treatment side effects Photobiomodulation . Mucositis . Orofacial complications .
for which PBM may prove to be effective. In addition, Chemotherapy . Radiation therapy . Head and neck cancer .
PBM parameters for each of these complications are sug- LLLT . PBM
gested and future research directions are discussed.
Methods Narrative review and presentation of PBM parame-
ters are based on current evidence and expert opinion. Introduction
Results PBM may have potential applications in the manage-
ment of a broad range of side effects of (chemo)radiation Nearly all patients with advanced head and neck cancer
therapy (CRT) in patients being treated for HNC. For OM (HNC) suffer orofacial, oropharyngeal, and neck complica-
management, optimal PBM parameters identified were as fol- tions from treatment with radiation therapy (RT) or chemora-
lows: wavelength, typically between 633 and 685 nm or 780– diotherapy (CRT) [1].
830 nm; energy density, laser or light-emitting diode (LED) The severity of complications varies depending upon the type
output between 10 and 150 mW; dose, 2–3 J (J/cm2), and no and site of the tumor, mode and intensity of therapies involved,
more than 6 J/cm2 on the tissue surface treated; treatment and individual patient characteristics. Nevertheless, in most pa-
schedule, two to three times a week up to daily; emission tients, complications are associated with significant morbidity
type, pulsed (<100 Hz); and route of delivery, intraorally and mortality resulting in increased use of health-care resources
and/or transcutaneously. To facilitate further studies, we pro- and may compromise patient adherence to cancer therapy proto-
pose potentially effective PBM parameters for prophylactic cols resulting in suboptimal outcomes. Most patients develop
and therapeutic use in supportive care for dermatitis, dyspha- multiple complications, which result in a significant burden of
gia, dry mouth, dysgeusia, trismus, necrosis, lymphedema, illness with negative impact on quality of life (QoL) [1–5].
and voice/speech alterations. Supportive care addressing these complications must con-
Conclusion PBM may have a role in supportive care for a tinue from initial diagnosis of HNC, through treatment and
broad range of complications associated with the treatment survival. However, many interventions have limitations and
of HNC with CRT. The suggested PBM irradiation and dosi- are primarily palliative in nature [6].
metric parameters, which are potentially effective for these Among the presently available supportive care measures,
complications, are intended to provide guidance for well- the use of photobiostimulation (PBM) has shown significant
designed future studies. It is imperative that such studies in- promise. PBM refers to various light energies such as low-
clude elucidating the effects of PBM on oncology treatment level laser therapy (LLLT) and light-emitting diode (LED) and
outcomes. visible light (see part 1).

2 10
Department of Medical Dental Interaction and Department of Division of Oncology, Weill Cornell Medical Center, New York, NY,
Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), USA
University of Amsterdam and VU University, P.O. Box 22660 1100 11
Department of Diagnostic Sciences and Oral Medicine, Director of
DD, Amsterdam, the Netherlands
Oral Medicine, College of Dentistry, University of Tennessee Health
3
Oral Medicine Oral Pathology and Human Diseases, Menzies Health Science Center, 875 Union Ave. Suite N231, Memphis, TN 38163,
Institute Queensland and Oral Medicine Consultant, Department of USA
Haematology and Oncology/Cancer Services, Gold Coast University 12
Laser Therapy Unit, Institut Jules Bordet, Centre des Tumeurs de
Hospital, Queensland Health, Queensland, Australia
l’Université Libre de Bruxelles, Brussels, Belgium
4
Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai 13
Antoni van Leeuwenhoek Department of Head and Neck Oncology
Medical Center, Los Angeles, CA 90048, USA
and Surgery, Netherlands Cancer Institute, Amsterdam, the
5
Division of Otolaryngology and Head and Neck Surgery, City of Netherlands
Hope, Duarte, CA 91010, USA 14
Antoni van Leeuwenhoek Department of Radiation Oncology,
6
Division of Oral Medicine, Eastman Institute for Oral Health, and Amsterdam, Netherlands Cancer Institute, Amsterdam, the
Wilmot Cancer Center, University of Rochester Medical Center, Netherlands
Rochester, NY 14620, USA 15
Department of Oral Surgery, Faculty of Dentistry, University of
7
Wellman Center for Photomedicine, Massachusetts General Hospital, Barcelona, Barcelona, Spain
Boston, MA 02114, USA 16
Seattle Cancer Care Alliance (SCCA), Oral Medicine, 825 Eastlake
8
Department of Dermatology, Harvard Medical School, Ave E Ste G6900, Seattle, WA 98109, USA
Boston, MA 02115, USA 17
World Association for Laser Therapy (WALT) Scientific
9
Harvard-MIT Division of Health Science and Technology, Secretary, Centre de Haute Energie (CHE), 10 Bd Pasteur,
Cambridge, MA 02139, USA 06000 Nice, France
Support Care Cancer

Systematic reviews have suggested efficacy of PBM for The current understanding of the pathogenesis of OM is
oral mucositis (OM) management in myeloablative hemato- largely based on animal models, which document the multi-
poietic stem cell transplant (HSCT) recipients and in HNC factorial nature of this inflammatory condition and have im-
patients [7–12]. However, recent advances in PBM applica- plicated a cascade of interrelated events in multiple tissue
tion and PBM devices, together with a better understanding of compartments. These observations lead to the five-phase
the pathobiology of HNC treatment-induced complications, model of OM, based on the sequence of events following
may lead to a broader range of indications for PBM in the cytotoxic treatment [13]. Inflammation induced by the forma-
management of these problems. tion of excessive reactive oxygen species (ROS) and activa-
A task force consisting of an international multidisci- tion of nuclear factor kappa B (NF-κB) are the key factors in
plinary panel of clinicians and researchers with expertise its pathobiology [14]. Subsequent studies implicated micro-
in the area of supportive care in cancer and/or PBM vascular injury, formation of proinflammatory cytokines,
clinical application and dosimetry was formed. The mis- host–microbiome interactions, and extracellular matrix alter-
sion of this group is to identify potential indications for ations in mucositis pathogenesis [15]. In addition, epidermal
PBM in the management of side effects of cancer ther- growth factor receptor (EGFR) inhibitors and tyrosine kinase
apy, design of PBM study protocols, identify validated receptor inhibitors (TKI) administered as single drugs or com-
outcome measures, and test the efficacy and safety of bined with CRT may enhance OM or cause additional symp-
proposed protocols for the management of complications toms [16, 17]. Effective management options for OM are lim-
related to cancer therapy. ited [18], and pain control is typically inadequate [2].
Part 1 of this review addressed mechanisms of action, do- A Cochrane meta-analysis concluded that PBM may pre-
simetric, and safety considerations. This paper (part 2) dis- vent severe OM [7]. A systematic review and meta-analysis of
cusses the following: (i) selected oral, oropharyngeal, facial, 11 randomized controlled trials (RCTs) in HNC patients treat-
and neck complications of treatment for HNC, in which PBM ed with (chemo)radiation therapy concluded that there was
may have potential for prophylaxis and/or treatment; (ii) PBM consistent evidence that PBM applied with doses of 1–6 J
parameters for prophylaxis and therapy to mitigate these com- per point reduced OM prevalence, severity, and duration,
plications based on current evidence and knowledge; and (iii) and its associated pain [9]. Another meta-analysis including
directions of future research related to the use of PBM in RCTs in various cancer treatment settings showed that PBM
HNC. reduced OM risk and decreased its severity and duration [10].
The efficacy appeared to be similar for red [630–670 nm] and
NIR (780–830 nm) light, although the optimal doses may vary
between these wavelengths. Similarly, a systematic review
PBM for the management of orofacial and neck
and meta-analysis including 18 RCTs reported that prophylac-
complications of cancer therapy
tic PBM reduced severe OM and associated pain in patients
treated for HNC or undergoing HSCT [12]. The Clinical
The following paragraphs summarize selected acute and
Practice Guidelines of the Multinational Association of
chronic complications associated with HNC therapy and the
Supportive Care in Cancer and International Society for Oral
literature relevant to the use of PBM for the management of
Oncology (MASCC/ISOO) Mucositis Study Group found ev-
these complications.
idence to recommend PBM for the prevention of OM in
For each of these complication, we propose prophylactic
HSCT recipients conditioned with high-dose chemotherapy,
and therapeutic PBM protocols based on evidence derived
with or without total body irradiation, and to suggest a role for
from the literature and expert opinion (Table 1). These proto-
patients treated with RT for HNC [11, 18]. Evidence was
cols are intended to provide clinical guidance and to serve as a
derived from high-quality studies using specific PBM param-
starting point for continuing research. Please see part 1 of this
eters, and the authors noted that there remains a need to iden-
review for discussion of mechanism of action and of safety of
tify optimal PBM parameters per cancer treatment modality.
PBM.
Based on this evidence and on our experience, we propose
the following regimen for the management of OM and muco-
Oral mucositis sitis affecting the oropharynx: wavelength of 633–685 or 780–
830 nm; power output of between 10 and 150mW; energy
Oral mucositis affects virtually all patients undergoing CRT density 2–3 J/cm2, and no more than 6 J/cm2 on the tissue
for HNC. Clinically, the manifestations of OM form a contin- surface treated; administered two to three times a week up to
uum, with erythematous mucosal changes when mild, and, daily; and using successive intraoral applications on single
ulcerative lesions that expose the submucosa when severe. spots on the mucosa, rather than a scanning motion over the
The detrimental effects of OM upon QoL and functional status entire mucosal surface. The upper safety limit was set as a
are significant [2]. precaution since no clinical data defining a safe upper limit
 Support Care Cancer

Table 1 Suggested photobiomodulation regimens for prevention and/or treatment of cancer therapy-induced morbidity in head and neck cancer
patients
Complicaon Treatment protocol** Treatment area PBM Device Therapeuc PBM Dose Oponal target ssues
Characteriscs and
applicaon
Oral Mucosis Prophylacc: Extra-oral: Extra-oral: Extra-oral:
Chemotherapy: Protocols vary. Infrared (IR) LED cluster 3 J/cm2 IR LED cluster Lips, cutaneous surface
Start PBM treatment at first day or corresponding to the buccal
of CT or prior to therapy and Mixed Red and IR LED Intra-oral: mucosae, bilateral cervical
connue during all courses of cluster 20mW/cm2 - Prophylacc: 2 J per point lymphac chain*
chemotherapy 80mW/cm2 Therapeuc: 4 J per point
unl the whole area
Radiotherapy: start PBM Intra-oral: involved is covered Intra-oral:
treatment the first day of RT or 630 - 830nm (2 J for prophylacc use) Prophylacc: treat each of the
prior to RT and connue during all 20mW - 80mW at risk mucosal surfaces *
days of RT (no requirement Therapeuc: sites vary,
regarding the ming of PBM depending upon the site of
sessions, before of aer RT mucosis
session)

Therapeuc:
Connue treatment at least 3
mes a week unl symptoms
improve
Daily treatment is recommended
in case of severe mucosis
Radiaon Prophylacc: Extra-oral: Extra-oral: Extra-oral:
dermas Start daily PBM treatment at the Red laser diodes cluster, Prophylacc: 2 J/cm2 for Cutaneous surfaces on the
iniaon of RT, or with a grade 1 630-680 nm, laser diodes panel, radiaon field where dermas
radiaon dermas 20-150 mW/cm2 3 J/cm2 for extra oral LED is ancipated (oen
or Cluster erythematous aer RT)
Therapeuc: Mixed Red and IR LED
Connue treatment at least 3 cluster 20mW/cm2 - Therapeuc:
mes a week unl symptoms 80mW/cm2 At least 4 J/cm2
improve

Dysphagia Prophylacc: Extra-oral: Extra-oral: Extra-oral: Extra-oral:

Radiotherapy: start treatment the Lateral and ventral IR laser diodes or LED Prophylacc: 3 J/cm2 laser Midline neck and lateral neck
first day of radiotherapy and pharynx and larynx cluster diodes or LED cluster anterior to sternocleidomastoid
connue all days of radiaon (no 750- 830 nm muscle
requirement regarding the Intraoral: 20mW/cm2 - 80mW/cm2 Intra-oral:
meing of laser sessions, before Soft palate, oropharynx Prophylacc: 3 J per point Intra-oral:
of aer radiaon session) Intra-oral: Bilaterally, 4 points to so
630 - 680nm palate and onto oropharynx
Therapeuc: 20mW - 150mW
Connue treatment at least 3
mes a week unl symptoms
improve
Hyposalivaon Prophylacc: Extra-oral: Extra-oral: Extra-oral:
and xerostomia Radiotherapy: start PBM IR laser diodes or LED Prophylacc: 3 J/cm2 laser Major salivary glands,
treatment the first day of RT and cluster diodes or LED cluster bilaterally (parod, sublingual
connue daily with radiaon (no 750- 830 nm and submandibular)*
requirement regarding the ming 20mW/cm2 - 80mW/cm2 Intra-oral:
of PBM sessions, before of aer Prophylacc: 3 J/cm2 per Intra-oral:
RT session) Intra-oral: point Total of 6 points (3 each side)
630 - 680nm targeng major salivary glands
20mW - 150mW and minor salivary glands (on
vesbular side, in the rear of
salivary ducts)

Dysgeusia Therapeuc: Intra-oral: Intra-oral: Intra-oral:

Connue treatment from the day 630 - 680nm Dorsal and lateral tongue at A total of 10 points on the
the paent complains of taste 20mW - 150mW 3 J/cm2 dorsum of the tongue
alteraons, at least 2 or 3 mes a
week unl symptoms improve**
Support Care Cancer

Table 1 (continued)
Trismus Prophylacc: Extra-oral: Extra-oral: Extra-oral:
Radiotherapy: Apply PBM on IR laser diodes or LED 3-6 J/cm2 laser diodes or LED Bilaterally over the temporalis
pterygoid/TMJ region, at least 3 cluster cluster muscle, TMJ, masseter muscle,
mes a week, when high dose RT 750- 830 nm buccinator muscle *
is given in that region 20mW/cm2 - 80mW/cm2 Intra-oral:
(oropharyngeal and 3 J per point Intra-oral:
nasopharyngeal carcinoma for Intra-oral: Bilaterally, point over the
example). 630 - 680nm region of
20mW - 200mW pterygoids/pterygomandibular
Therapeuc: raphae (may be difficult
Connue treatment from the day clinically) and other muscles of
of diagnosis at least 2 or 3 mes a mascaon *
week

Osteonecrosis Therapeuc: Extra-oral: Extra-oral: Intra-oral:

Connue treatment at least 2 or 3 IR laser diodes or LED 6 J/cm2 laser diodes or LED 5 or more points (1 cm apart)
mes a week unl symptoms cluster cluster along lingual and buccal aspects
improve 750- 830 nm of maxilla and / or mandible
20mW/cm2 - 80mW/cm2 Intra-oral: depending on site and size of
Daily treatment is recommended 6 J per point region affected *
Combinaon with other Intra-oral:
medical/surgical treatment 630 - 680nm
approaches may be needed. 20mW - 200mW

Head and neck Therapeuc: Extra-oral: Extra-oral: Extra-oral:

lymphedema Connue treatment at least 2 or 3 IR laser diodes or LED 3 J/cm2 laser diodes or LED Treat edematous area over the
mes a week unl symptoms cluster cluster neck or surgical site if any, also
improve 750- 830 nm targeng regional lymphac
20mW/cm2 - 80mW/cm2 chain*

Voice/speech Therapeuc: Intra-oral: Intra-oral: Intra-oral:

alteraons (due Connue treatment from the day 780nm - 830nm 3 J/cm2per point Towards the anterior
to local paent complains of difficulty 50mW - 200mW oropharynx over the dorsum of
inflammaon) speaking, at least 2 or 3 mes a Extra-oral : on larynx area, tongue (avoid gag reflex, do not
week even if symptoms are not wavelength 750-830 nm touch any so ssues including
improving dramacally** IR laser diodes or LED cluster dorsal tongue). Paent may
20mW/cm2 - 80mW/cm2 gently close the mouth during
the procedure to reduce gag
reflex

These protocols are based on evidence derived from the literature (mainly derived from mucositis studies) and expert opinion and are intended to provide
clinical guidance and to serve as a starting point for research. LED cluster probe dose has been expressed in J/cm2, and single point laser dose has been
expressed in joules per point. For LED cluster probes, treatment time (s) = dose (J/cm2) / power density (W/cm2). For single-point laser probes, treatment
time (s) = dose (J) / laser power (W)

are currently available. Emission type, continuous or pulsed skin leads to direct tissue injury and inflammatory cell
(<100 Hz) as low-frequency pulsed light may be superior to recruitment, involving damage to epidermal basal cells
continuous wave light for wound healing or the prevention of and connective tissue including endothelial cells and vas-
injury. Extraorally administered PBM may be effective for the cular components [19]. Radiation-induced generation of
management of OM of the buccal mucosa, vestibule, and in- free radicals induces DNA injury and release of inflamma-
ner epithelial surfaces of the lips which could be applied in tory cytokines [mainly interleukin (IL)-1 and IL-6] [20,
combination with an intraoral device. 21]. This process leads to the development of erythema,
edema, and possible ulceration. Late RT-induced changes
Dermatitis involving skin are characterized by the loss of follicular
structures, an increase in collagen and damage to elastic
Radiation dermatitis occurs in the majority of patients with fibers in the dermis, and a fragile epidermal covering [22].
locoregionally advanced HNC treated with RT. Transforming growth factor beta (TGF-β) is considered to
The pathobiology of acute radiation dermatitis is com- play a central role in mediating RT-induced tissue fibrosis
plex and partially overlaps that of OM. Irradiation of the [23–25].
 Support Care Cancer

The severity of skin reactions is dependent on the total IMRT and more recently volumetric-modulated arc therapy
radiation dose, the dose per fraction, the overall treatment (VMAT) have emerged as an effective technique to deliver the
time, beam type and energy, the surface area of the skin ex- full radiation dose to the tumor and regions at risk while re-
posed to radiation, the use of combined chemoradiotherapy ducing exposure of surrounding healthy tissues. Eisbruch and
with or without targeted therapies, and individual risk factors coworkers [45] identified dysphagia/aspiration-related struc-
[20]. The severity of acute reactions has been shown to predict tures (DARS) as susceptible to damage during IMRT. In par-
late effects. Radiation dermatitis impacts adversely on ticular, damage to the tongue base, pharyngeal constrictors,
cosmesis and function and reduces QoL, especially in patients the larynx, and the autonomic neural plexus was found to be
who develop secondarily infected dermatitis [19]. crucial in the development of post-RT dysphagia. Studies con-
Patients with head and neck squamous cell carcinoma firmed that reducing the radiation dose to DARS decreases
(HNSCC) treated with an epithelial growth factor receptor dysphagia risk [46–49]
(EGFR) inhibitor may develop an acneiform skin rash in ad- In addition, preventive swallowing exercises in the pre-
dition to radiation dermatitis [17, 22]. treatment setting had promising results on preserving
Based on the effects of PBM on the epidermis and dermis (pharyngeal) swallowing function [48–50].
(reduced inflammation and improved wound healing), and on One study reported a lower incidence of severe OM and
the shared similarities in pathobiology with OM, it seems mucositis affecting the throat (contributing to acute dyspha-
reasonable to assume that PBM may reduce the prevalence gia) when six predetermined oral sites were exposed to PBM
and/or severity of radiation dermatitis [26–28]. prior to and during RT [51]. In this study, dysphagia was
A study in pigs suggested that multiwavelength PBM ame- scored indirectly by assessing the need for TPN. Given the
liorated the development of late radiation damage to the skin ability of PBM to prevent and ameliorate inflammation and
[29]. DeLand et al. [30] reported that LED treatments imme- pain associated with OM, and potential to control exuberant
diately after intensity-modulated radiation therapy (IMRT) re- fibrosis [52], PBM delivered to the DARS structures may
duced the incidence of radiation dermatitis in patients with have a potential role in the management of acute and chronic
breast cancer. However, Fife et al. [31] were not able to repro- dysphagia. This requires further investigation.
duce these results, although unfortunately, they did not specify
important parameters such as irradiation time and size of area Hyposalivation and xerostomia
treated.
A case series report described promising results for PBM Another significant complication of RT to the head and neck
treatment at a NIR wavelength (970 nm) in patients with region is hyposalivation, and its related complaint of
EGFR inhibitor-induced facial rash [32]. xerostomia (subjective oral dryness). For all head and neck
radiation regimens pooled, nearly all patients suffered from
Dysphagia xerostomia as a result of RT [53].
Irradiation of the salivary glands results in loss of gland
Acute and chronic dysphagia and odynophagia are common function, beginning early in the course of RT [54] and has
in HNC patients, due to cancer following oropharyngeal/ been shown to induce apoptosis in parotid glands in a dose-
laryngeal surgery and in those treated with RT or CRT [33, dependent manner. This process is p53-dependent [55].
34]. Dysphagia can be due to anatomical, mechanical, or neu- Saliva plays an important role in maintaining mucosal in-
rological changes affecting any structure from the lips to the tegrity, promoting oral wound healing, taste perception, for-
gastric cardia [35]. mation of food bolus, initiation of food ingestion, swallowing,
Dysphagia associated with RT or CRT has a complex path- and speech [56]. Alterations in the oral microbiome, reduced
ogenesis, involving acute inflammation, edema, and fibrosis, oral clearance, changes in saliva composition (e.g., decreased
with consequent neurological and muscular injury that may buffer capacity, pH, immunoglobulin concentrations,
result in generalized weakness and a lack of muscle coordina- defensins), and dietary changes may increase the risk for mu-
tion while swallowing [34, 36, 37]. Excessive fibrosis results cosal infections and rapidly progressing dental demineraliza-
in a loss of elasticity that may contribute to chronic dysphagia tion and caries [57]. A substantial decrease in salivary func-
[38, 39]. In addition, hyposalivation may contribute to dys- tion has a significant impact on QoL and results in an in-
phagia following RT [3]. Moreover, the duration of total par- creased burden of long-term dental care and nutrition [58–60].
enteral nutrition (TPN) or tube feeding and resulting reduced There can be a modest improvement in xerostomia a few
swallowing may affect the ability to return to safe, normal oral months after RT, suggesting that an adaptation or compensa-
intake, since inactivity will cause atrophy of the swallowing tory function of nonirradiated salivary glands or recovery of
muscles [40, 41]. Dysphagia negatively affects QoL [3, 42] some of the function occurs. However, most patients have
and may predispose to aspiration and life-threatening pulmo- persisting oral dryness for the rest of their life, even when
nary complications [43, 44]. 3D conformal radiotherapy and IMRT is used. With IMRT
Support Care Cancer

preserving more of the major salivary glands, long-term oral may also be involved, as taste recovery lags epithelial recov-
dryness may be reduced, but a significant proportion of pa- ery and may continue indefinitely [75]. Hyposalivation may
tients still experience xerostomia [61]. also have a significant contribution. The presence of the ante-
The literature on PBM for the management of rior part of the tongue in the radiation field may be predictive
hyposalivation is limited. In a study involving a variety of of taste disturbances [76].
noncancer patients with xerostomia, PBM was applied daily: Altered taste significantly affects overall QoL and may lead
extraorally to the parotid and submandibular glands and to energy and nutrient deficiencies and related complications
intraorally on the sublingual glands. A gradual increase in that may lead to weight loss [3, 73]. Management options to
the stimulated salivary flow was found after PBM compared decrease the prevalence and severity of taste problems are
to controls [62]. Similar results in noncancer patients were inadequate [75].
reported by Vidović et al. [63]. Animal studies have shown A pilot study reported that PBM administered to taste buds
an increase in the number of duct epithelial cell mitoses and may ameliorate neurologically mediated burning mouth syn-
stimulation to protein synthesis in submandibular glands fol- drome symptoms including taste alterations [77], but to our
lowing PBM [64, 65]. Similarly, a study reported the use of knowledge, there are no published studies on PBM for the
PBM to increase salivary flow rate and amylase activity in rat management of taste problems in cancer patients. Whether
parotid glands [66]. These authors also performed a study in PBM has any efficacy in the management of dysgeusia in
HNC patients and reported that PBM given concurrently with patients treated for HNC remains to be explored.
RT could prevent hyposalivation and xerostomia and had an
impact on the composition of saliva [67]. Less severe Trismus
xerostomia was also reported following PBM in HSCT recip-
ients [68] and in patients treated with chemotherapy for solid Trismus refers to reduced opening of the jaws that may be
tumors [69]. Increased salivary flow was observed in HNC caused by spasm of the muscles of mastication, fibrosis in
patients treated with RT [70]. A recent study performed in masticatory muscles, and temporomandibular joint disorders,
HNC patients at least 6 months following conventional RT which generally refers to mouth opening of less than 40 or less
found no improvement of hyposalivation and xerostomia, than 20 mm, whereas less restrictive classifications also have
likely due to irreversible acinar atrophy and fibrosis [71]. been used [78].
These results point to the potential use of PBM for preven- The prevalence of trismus is estimated to be 25 % follow-
tion of hyposalivation/xerostomia; it may also show efficacy ing conventional RT, 5 % following IMRT, and 31 % for CRT
for the treatment of hyposalivation when there is residual [79]. Patients may have limitations in jaw opening associated
gland function following current RT modalities. with tumor invasion of the masticatory muscles or the tempo-
romandibular joint, or may develop trismus following RT to
Taste alterations these structures [78, 80]. Cumulative radiation doses above
60 Gy are more likely to cause trismus [81], while the inclu-
Taste is one of the five senses and interacts with smell, touch, sion of the lateral pterygoid muscles in the high-dose fields
and other physiological cues to affect the wider perception of appears to be the most decisive factor [82]. Trismus due to RT,
flavor. Disturbed taste (dysgeusia) is complex and includes typically develops 3–6 months post-RT associated with fibro-
difficulties with smell and touch resulting in reduced food sis and frequently becomes a lifelong problem [80, 83].
interest and affecting appetite and QoL. Taste function is the Studies have demonstrated that fibrosis is an important
perception derived when food molecules stimulate taste recep- initial event in RT-induced trismus. Additionally, there may
tors of the tongue, soft palate, and the oropharyngeal region to be scar tissue from surgery, nerve damage, or a combination of
perceive basic taste qualities (sweet, sour, salty, bitter, and these factors [80]. Mandibular hypomobility ultimately results
umami), which can be measured via standardized methods in muscle contraction and potentially temporomandibular
[72]. joint dysfunction [79].
The prevalence of dysgeusia is estimated to be 66.5 % Trismus and orofacial pain interfering with function may
following RT alone and 76.0 % after CRT; approximately have significant health implications including reduced nutri-
15 % of patients continued to experience dysgeusia after treat- tional intake, difficulty speaking, compromised oral health,
ment [73]. Ohrn and colleagues reported that the severity of and poor QoL [84]. Aside from avoiding RT to the mastica-
taste alterations assessed by patients was correlated with the tory structures, early interventions (e.g., mouth opening exer-
cumulative RT dose [74]. cises) are indicated to prevent or minimize trismus [48, 85,
The mechanisms of dysgeusia during cancer therapy are 86].
not well understood; however, it is believed that CT and RT Concerning muscle spasms following oral surgery, a reduc-
cause dysgeusia by destroying rapidly dividing taste bud cells tion was found in several studies using PBM [87, 88]. To our
and olfactory receptor cells [73]. Direct neurologic toxicity knowledge, PBM to prevent or reduce the severity of RT-
 Support Care Cancer

induced trismus in HNC patients has not been reported. The lymphedema externally, on the face and neck, and/or internal-
evidence for PBM to reduce fibrosis and promote muscle re- ly involving the larynx and pharynx. External lymphedema
generation forms the main rationale for a potential clinical may have a profound effect on appearance and body image
benefit and justifies further study. [106], whereas internal lymphedema may impact breathing,
contribute to dysphagia and trismus, and may affect speech
Soft tissue necrosis and osteoradionecrosis [107].
In a single center study on 81 HNC patients, 75 % had
Soft tissue and/or osteoradionecrosis (ORN) may occur as a lymphedema. Of those, 10 % had external, 39 % had internal,
consequence of RT. ORN is a process of radiation-induced and 51 % had both types of lymphedema [107]. Individuals
vascular occlusion leading to loss of osteocytes and bone ne- with pharyngeal carcinoma were at highest risk [108].
crosis following RT [89]. The incidence of ORN has declined Lymphedema typically develops 2–6 months after the com-
with proper pretreatment dental care and advances in RT; in pletion of RT and may resolve spontaneously in some patients,
conventional RT, mandibular ORN prevalence ranges from 5 but not in all. Assessment and measurement of head and neck
to 15 %. More recently, in the era of IMRT, less than 5 % of lymphedema remains challenging [109].
patients are affected [60, 80, 90]. Lymphedema is initiated by disruption of lymphatic struc-
The pathogenesis of ORN is not completely understood. It tures by surgery, RT or both, resulting in the accumulation of
has been proposed that ORN occurs following a radiation- lymph fluid in the interstitial tissues. This leads to infiltration
induced fibroatrophic process, including free radical forma- of inflammatory cells and, because of the lymphatic dysfunc-
tion, endothelial dysfunction, inflammation, microvascular tion, cytokines and chemokines remain in the tissue and re-
thrombosis, fibrosis and remodeling, and finally bone and cruit additional inflammatory cells from the circulation. This
tissue necrosis [91]. Common triggers of necrosis are inflam- ongoing inflammatory response results in additional soft tis-
matory dental disease, trauma to soft tissue, and dental surgi- sue damage and fibrosis, which further adversely affects lym-
cal procedures in sites of high-dose radiation exposure to phatic function [110].
bone. Dental surgery after RT is considered a critical risk PBM has been identified as a potential treatment for post-
factor for ORN, but ORN can also arise due to periodontal mastectomy lymphedema, as it stimulates
disease, trauma or spontaneously [92–94]. Prevention of ORN lymphangiogenesis, enhances lymphatic motility, and reduces
is mainly based on extractions of compromised teeth before lymphostatic fibrosis [111]. Patients received additional ben-
RT and adequate dental care and prevention during and fol- efits from PBM when used in conjunction with standard
lowing cancer therapy [1, 89]. lymphedema treatment [112]. Systematic reviews found evi-
PBM has a biostimulatory effect on irradiated rat bone dence suggesting that PBM reduced limb volume in patients
when applied before and during RT [95], and similar results with lymphedema following treatment for breast cancer
were reported by El-Maghraby et al. [96]. In contrast, an [113–115]. It was concluded that future research should be
in vivo study found that PBM was not able to reverse RT- performed comparing PBM with standard practices and to
induced bone damage [97]. To our knowledge, there are no establish the duration of light application, number of treatment
clinical studies on the effects of PBM for RT-induced jaw sessions, energy settings, power density, and dose. In addition,
osteonecrosis. However, multiple studies suggested a benefit longer follow-up was considered necessary [114]. Lee and
from PBM in the management of medication-related coworkers proposed that PBM may also have a role in the
osteonecrosis of the jaw (MRONJ) [98–101]. Vescovi et al. management of lymphedema associated with HNC [116].
proposed a prophylactic protocol including PBM for reducing
BRONJ incidence following tooth extractions [102].
Luomanen et al. reported about a successful treatment of a Voice and speech alterations
patient with MRONJ using Nd:YAG laser [103]. A study in
a rodent wound healing model found evidence that both laser Voice and speech are important communication tools and
and LED PBM were capable of stimulating angiogenesis form part of a person’s identity and personality. Voice quality
in vivo [104]. mainly depends on the movement and characteristics of the
The possible role of PBM in the management of RT- vocal cords, and speech on the resonance characteristics of the
induced jaw osteonecrosis deserves further exploration. vocal tract. Speech is based on the volitional coordinated
movements of the articulator structures and can be affected
Head and neck lymphedema by any alteration in muscle or tissue properties of these struc-
tures. Although voice and speech dysfunctions significantly
A commonly neglected late effect in patients treated for HNC affect QoL, these complications have received little attention
is secondary lymphedema [105], although this complication and are likely underreported in efforts to preserve organ func-
may be reduced with IMRT. Patients may develop tion after cancer therapy [117–119].
Support Care Cancer

Currently, there is limited information on the prevalence of likely to affect the anatomic structures at risk. The parameters
speech and voice dysfunction in advanced HNC patients treat- (including the wavelengths) we have proposed are largely
ed with RT or CRT. Prospective studies are needed, including based on evidence derived from studies using PBM for the
baseline measurements and standardized multidimensional as- management of OM (typically 633–685 or 780–830 nm).
sessment of functional aspects of voice and speech [118]. However, trials directed to other (non-head and neck) indica-
The etiology of voice and speech problems resembles that tions for the use of PBM suggest that a broader range of
of dysphagia and may include neuromuscular weakness as a wavelengths (590–1064 nm) has efficacy for healing and for
result of tumor invasion. Dependent on the dose tolerance of reducing inflammation and pain. Future investigations should
the critical organs involved, CRT-induced voice and/or speech be conducted to better define optimal PBM parameters for
dysfunction can result from mucositis of the soft palate, each of the complications of HNC treatment. LED specifics
tongue and laryngeal soft tissues, edema, fibrosis, or atrophy need to be carefully matched to PBM using lasers when con-
of the vocal folds, pharyngeal and oral tissues, and altered sidering LED arrays and using them clinically. In addition, the
saliva or hyposalivation [120–122]. ideal timing and frequency of PBM administration should be
New RT delivery techniques designed to spare these struc- determined, as well as how long PBM should be continued
tures may prevent functional impairment. following the completion of cancer treatment. PBM parame-
A study using an animal model of reflux laryngitis (a con- ters should be reported in detail (discussed in part 1) and
dition including hoarseness, voice fatigue, globus, chronic validated outcome measures must be identified and employed
cough, throat pain, and dysphagia) suggested that the anti- to assess the effect of prophylaxis and therapy, from the time
inflammatory effects of PBM may play in the management of diagnosis through active treatment and survival.
of this condition [123]. Despite the potential benefits and plausible safety of PBM for
We are not aware of any studies on the effect of PBM on the supportive care in HNC patients, vigilance remains warranted.
quality of speech and voice in HNC patients. Since PBM may While the reported results of in vitro studies of PBM on malig-
preserve function of the anatomical structures involved by its nant cells vary, and clinical reports have shown little or no ad-
anti-inflammatory effects and may have indirect benefits by verse reactions, there is a paucity of robust data regarding poten-
stimulating the salivary flow, future studies are warranted. tial protection and promotion of tumor. Studies should be also
directed to the potential beneficial effects of PBM by enhancing
the efficacy of (C)RT or immunologic antitumor reactivity.
Conclusion Investigations on the efficacy of PBM in the management
of side effects of HNC treatment should be conducted. It is
Acute and chronic complications induced by RT and CRT in imperative that such studies include elucidating the effects of
patients with HNC represent a significant clinical challenge [1]. PBM on oncology treatment outcomes.
There are similarities with respect to pathophysiology across
different complications, and patients may suffer from multiple
Compliance with ethical standards
concurrent and interrelated problems [13]. There is anecdotal
evidence suggesting that the inflammation associated with Disclaimer This article is based on a narrative review of existing data
acute complications is a harbinger for chronic complications. and the clinical observations of an international multidisciplinary panel of
This observation suggests that preventive approaches starting clinicians and researchers with expertise in the area of supportive care in
cancer and/or PBM clinical application and dosimetry. This article is
before, and in the early phases of treatment with RT and CRT,
informational in nature. As with all clinical materials, this paper should
may not only reduce the risk for developing acute problems but be used with the clear understanding that continued research and practice
may also have an impact on the risk for late complications. could result in new insights and recommendations. The review reflects
PBM has shown effectiveness in the management of OM the collective opinion and as such does not necessarily represent the
opinion of any individual author. In no event shall the authors be liable
and elicits several potentially beneficial effects, including re-
for any decision made or action taken in reliance on the proposed
duction of inflammation and pain, promotion of tissue repair, protocols.
reduction of fibrosis, and protection and regeneration of
nerves. Therefore, there is a clear motivation for studies on Disclosures Judith A.E.M. Zecha, Andrei Barasch, Sharon Elad,
the application of PBM for the prevention and treatment of a Steven Sonis, Cesar A. Migliorati, Marie-Thérèse Genot, Dan M.J.
Milstein, Liset Lansaat, Irene Jacobi, Judi van Diessen, Jan. de Lange,
broad range of acute and chronic complications associated
Ludi E. Smeele and Mark M. Schubert have no disclosures relevant to this
with RT or CRT in HNC patients. work to report.
The purpose of this article is to serve as a basis for estab- Judith E. Raber-Durlacher, Raj G. Nair, Joel B. Epstein, Ron van der
lishing a platform for facilitating future collaborations among Brink, Josep Arnabat Dominguez, and Rene-Jean Bensadoun have re-
ceived travel expenses and hotel accommodation for the founding meet-
clinicians and researchers, in order to create firm scientific
ing of iGLOB from THOR Photomedicine Ltd., UK. Raj Nair has re-
evidence for the use of PBM in patients with HNC. PBM ceived an honorarium from THOR, UK. Michael R Hamblin was sup-
protocols should be administered using parameters that are ported by US NIH grant R01AI050875.
 Support Care Cancer

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