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Photobiomodulation or low-level laser therapy in the management of cancer

therapy-induced mucositis, dermatitis and lymphedema

Article in Current Opinion in Oncology · May 2018

DOI: 10.1097/CCO.0000000000000452

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REVIEW

CURRENT
OPINION Photobiomodulation or low-level laser therapy in
the management of cancer therapy-induced
mucositis, dermatitis and lymphedema
AQ1 René-Jean Bensadoun

Purpose or review
There is a large body of evidence supporting the efficacy of low-level laser therapy (LLLT) also known as
PhotoBioModulation (PBM) when used for the prevention and/or treatment of oral mucositis in patients
undergoing radiotherapy for head and neck cancer, or high-dose chemotherapy regimens. This review
aims at giving the state of the art of this technique in this indication.
Recent findings
Recent advances in LLLT/PBM technology, together with a better understanding of mechanisms involved
and dosimetric parameters may lead to the management of a broader range of complications associated
with cancer treatment. This could enhance patient adherence to cancer therapy, and improve quality of life
and treatment outcomes.
Summary
The article discusses LLLT/PBM mechanisms of action, dosimetry, and safety, and aims to identify some
cancer treatment side-effects for which LLLT/PBM may prove to be effective (oral mucositis, radiation
dermatitis, lymphedema). In addition, LLLT/PBM parameters for each of these complications are suggested
and future research directions are discussed.
Keywords
lymphedema, oral mucositis, PBM/LLLT, radiation dermatitis

INTRODUCTION site. Although the complex biological mechanisms

Low-level laser (or light) therapy (LLLT), now better underlying the therapeutic effects of LLLT/PBM
described as PhotoBioModulation (PBM), has been have not been completely elucidated and may vary
consistently shown in laboratory studies to have among different cell types and tissue states (healthy
distinct biological effects, and has a dose-dependent versus stressed or hypoxic), laboratory and clinical
mechanism of action at the cellular level [1–3]. studies suggest that LLLT/PBM significantly reduces
Since the introduction of LLLT/PBM in 1967, over inflammation and prevents fibrosis. Moreover,
400 randomized, double-blind (some placebo- LLLT/PBM, when delivered appropriately, reduces
controlled) clinical trials have been published for pain and improves optimal function of the whole
multiple applications [4–6]. The first clinical appli- organism. In addition, in-vivo studies show that
cation of LLLT/PBM was for the enhancement of LLLT/PBM is neuroprotective and may benefit
wound healing [7]. A meta-analysis including ani- neurodegenerative diseases and neurotrauma.
mal and human studies concluded that LLLT/PBM Current data suggest that LLLT/PBM acts predomi-
was an effective tool for accelerating wound repair nantly on cytochrome c oxidase in the mitochon-
and tissue regeneration [7]. It has been shown that drial respiratory chain by facilitating electron
LLLT/PBM influences different phases of wound transport resulting in an increased transmembrane
healing including: the inflammatory phase, in
which immune cells migrate to the site of tissue Centre de Haute Energie Nice, France AQ2
injury; the proliferative phase, which includes Correspondence to René-Jean Bensadoun, MD, Centre de Haute Ener-
stimulation of fibroblasts and macrophages as well gie, 10 Bd Pasteur, 06000 – Nice, France. Tel: ++33 4 93 53 87 10; AQ3
as other repair components; and the remodeling e-mail: [email protected]
phase, consisting of collagen deposition and Curr Opin Oncol 2018, 30:000–000
rebuilding of the extracellular matrix at the wound DOI:10.1097/CCO.0000000000000452

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treated for head and neck cancer (HNC) [11,12]. For AQ4
KEY POINTS example, in an animal model of oral mucositis it was
 A very enthusiastic new development of PBM use in demonstrated that LLLT/PBM decreased COX-2
cancer-therapy-induced side-effects. expression and decreased the number of neutrophils
in the inflammatory infiltrate. Moreover, in the
 A huge progress in the definition of PBM modalities of chronic sequelae of (chemo)radiotherapy an exces-
action and treatment parameters.
sive fibroblastic response is hypothesized to be
 The emergence of clinical guidelines in many situations, related to acute oxidative injury, with resulting cell
firsts being the use of PBM in the prevention of oral damage, ischemia, and an ongoing inflammatory
mucositis and radiation dermatitis. response resulting in fibrosis [11–13].
The critical difference between normal wound
healing and fibrosis development appears to be that
in fibrosis, signaling pathways escape normal cellu-
proton gradient that drives ATP production. ATP is lar regulation. The reduction of fibrosis could be
the universal energy source in living cells and is mediated by the beneficial effects of LLLT/PBM on
essential for all biological reactions; even a small the oxidant/antioxidant balance down regulation of
increase in ATP levels can enhance the bioavailabil- the profibrotic transforming growth factor-b and
ity to power the functions of cellular metabolism. In inhibition of excessive fibroblast proliferation.
addition, the absorption of red or near-infrared The efficacy of LLLT/PBM in both acute and
(NIR) light may cause a short, transient burst of chronic conditions and affected tissues has been
reactive oxygen species that are followed by an shown to be promising in the majority of studies,
adaptive reduction in oxidative stress. although not all have yielded positive outcomes.
Although the information above raises ques- These divergent results may be attributed to factors
tions about possible undesirable effects of LLLT/ including dosimetry. It has been observed that
BPM on tumor progression and response to anti- increasing the overall dose of LLLT/PBM may have
cancer treatment [8,9], some other observations a counter-productive effect compared to the benefit
suggest that LLLT/BPM might favorably impact obtained with lower doses [1,13,14].
&
tumor behavior [10 ].
Virtually all conditions modulated by LLLT/
PBM (e.g., ulceration, inflammation, edema, pain, Low-level laser therapy/PhotoBioModulation
fibrosis, neurological, and muscular injury) are parameters [1,6,13–15]
thought to be involved in the pathogenesis of (che- The LLLT/PBM parameters (summarized in Table 1, AQ5
mo)radiotherapy-induced complications in patients
&
from [10 ]) are usually within the red and NIR

Table 1. Low-level laser therapy/PhotoBioModulation parameters

Category Parameter Unit Explanation

Irradiation Wavelength nm Light is packets of electromagnetic energy called photons that sometimes behave like
parameters particles but also have a wave-like property. Wavelength determines which
chromophores will absorb the light. Light is visible in the 400–700 nm range. The
energy of each photo is greater at short wavelengths than longer wavelengths;
e.g., red light is 2 eV per photon and blue light is 3 eV.
Power W The number of photons per second. The higher the power the more photons emitted every
second.
Beam area cm2 The surface area of the beam on the patient. Also known as spot size. This is not always
easy to determine because laser beams are usually more intense in the middle then
fade toward the edge (Gaussian distribution) so it is hard to define where the exact
edge of the beam is without special instruments. Many research authors do not report
this parameter, let alone report it correctly.
Aperture size cm2 The area of the light source tip. This is not necessarily identical to the beam area. The
difference between the aperture size and beam area will be determined by the beam
divergence and distance of the light source tip from the tissue.
Irradiance (power W cm2 Power (W)  beam area (cm2). More irradiance could allow less treatment time,
density, or however many studies have shown that if the irradiance is too high, treatment can be
intensity) less effective even if the same total dose is delivered. The treatment guidelines suggest
the well tolerated and effective irradiance ranges.

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Adapted with permission [10 ].

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wavelength range of 6001000 nanometers (nm), the other required laser parameters according to
with a power density of between 5150 mW per cm2 evidence gathered in a systematic way for each
and are typically applied for 30 to 60s per point. indication is a prerequisite for the successful use
The therapeutic effect is typically dictated by of this technique. Without standardization in beam
the energy density measured in joules (J) per cm2. measurement, dose calculation, and the correct
AQ6 Experimental evidence can be found in the litera- reporting of these parameters, studies will not be
ture for parameters as widely divergent as 0.1–12 J reproducible, and outcomes will not be consistent. A
per cm2. Laser systems used include helium–neon, common misconception is that wavelength and
gallium–aluminum, neodymium-doped yttrium– energy (in J) or energy density (J/cm2) are all that
aluminum–garnet, gallium–aluminum–arsenide is necessary to replicate a successful treatment, and
diode, indium–gallium–aluminum– phosphorus, that it does not matter what the original power,
and nonthermal, nonablative carbon dioxide lasers. power density, and duration of application were.
The PBM effects on the exposed tissues depend upon Tables 1 and 2 (from 10) provide a checklist
the cell type, redox state of the cell, irradiation to help researchers understand and report all the
parameters (wavelength, power density), and time necessary parameters for a reproducible scientific
of exposure [1,13,14,15]. A biphasic dose–response study. In addition, it is not uncommon to find dis-
has been shown in several studies, which underlines crepancies between the specifications provided by a
that there are optimal irradiation and dose param- device manufacturer and the actual performance of
eters, although these will vary depending upon the the device. Thus, device maintenance, including
depth of the disease below the mucosal or skin power measurements, should be carried out regularly
surface. One must remember that doses lower than during research trials and also in clinical practice.
the optimal value may have a reduced effect, Although clinical data on PBM use in cancer
whereas doses higher than optimal can have nega- patients appear to be reassuring, the crucial factor
tive therapeutic outcomes. For LLLT/PBM to be is to insure treatment safety. It is important to note
effective, the irradiation parameters—including that PBM is a nonthermal process and any signifi-
the energy delivered, power density, pulse structure, cant tissue heating should be explicitly avoided. We
delivery to the appropriate anatomical location, and suggest that clinicians use the lowest PBM dose that
appropriate treatment timing and repetition—need is clinically effective, and use all recommended
to be within the biostimulatory dose windows. This safety measures. It is also suggested that until we
has been shown by studies which demonstrate neg- have more specific data on tumor effects, direct
ative effects where dose depends on energy dose exposure of the tumor site during PBM treatment
level alone. Titrating adequate doses and defining be avoided.

Table 2. Low-level laser therapy/PhotoBioModulation parameters (ctnd)

Category Parameter Unit Explanation

Irradiation (Radiant) energy J Power (W)  time (s). More power could mean less treatment time
parameters however many studies have shown that too much power is less
(ctnd) effective even if the same total energy is delivered. The treatment
guidelines suggest the well tolerated and effective energy ranges.
Time s How long each treatment is applied at each location.
Dosage (fluence J cm2 Energy (J)  beam area (cm2)  time (s). Different outcomes can be
or energy density) obtained if the total dosage is delivered with high energy and short
time or low energy and long time.
Operating mode Continuous The continuity of the production of the output beam may be continuous or
wave pulsed pulsed. There are several types of pulsed beam.
Pulse structure s The durations of the pulse being on or off.
Treatment Physical relationship Applicable when there is more than one way to approach the organ. For
parameters to the organ example, intraoral device versus extraoral device.
Timing Time of treatments per day/week and the total number of treatments.
Treatment schedule The frequency of treatments per day/week and the total number of
treatments.
Anatomical location The anatomical site that was exposed to the light beam. If multiple
locations were treated, all need to be described.

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Adapted with permission [10 ].

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Oral mucositis [1–5,15–20] &

patients treated with RT for HNC [25 ]. Evidence was
oral mucositis affects virtually all patients undergo- derived from high-quality studies using specific
ing CRT for advanced HNC, and the majority of LLLT/PBM parameters and the study group noted
hematopoietic stem cell transplantation (HSCT) and that there remains a need to identify optimal LLLT/
&
high-dose CT regimens [21–24,25 ,26]. Clinically, PBM parameters, including energy density, ideal
the manifestations of oral mucositis form a contin- timing of laser application, variations in cancer type
uum, with erythematous mucosal changes when and cancer treatment regimens. Based on this evi- AQ7
mild and ulcerative lesions that expose the submu- dence and on our experience, we propose the fol-
cosa in its severe form [11,12,21]. Its detrimental lowing regimen for the management of oral
effects on quality of life and functional status are mucositis (and mucositis affecting the oropharynx):
significant and often interfere with the cancer treat- a wavelength of 633–685 or 780–830 nm; a power
ment regimen, both on the patient level and in output of between 10 and 150 mW; an energy den-
terms of cost. The current understanding of oral sity of 2–3 J per cm2 and no more than 6 J per cm2
mucositis is largely based on animal models, which on the tissue surface treated; a frequency of 2–3
have shown the multifactorial nature of the condi- times a week up to daily; and successive applications
tion and have implicated a cascade of interrelated on single spots on a lesion rather than a scanning
events in multiple tissue regions. These observations motion over the entire lesion. Extra-orally adminis-
combine into the five-phase model of oral mucosi- tered LLLT/PBM may be effective for the manage-
tis, based on the sequence of events following cyto- ment of oral mucositis of the buccal mucosa,
toxic treatment [11]. The formation of excessive vestibule, and inner epithelial surfaces of the lips.
reactive oxygen species and activation of NF-kB This could be applied in combination with an intra-
&

are the key factors in its pathobiology. Subsequent oral device (see Fig. 1 [27 ]).
studies have implicated microvascular injury, the The suggested energy density (1–6 J/cm2) does
&

formation of proinflammatory cytokines, host– not exclude other settings [28 ]. It is recommended
microbiome interactions and extracellular matrix to avoid the tumor site and to follow good clinical
alterations in oral mucositis pathogenesis. In addi- practice. As research advances, more specific recom-
tion, epidermal growth factor receptor (EGFR) mendations in this new and exciting field will
inhibitors and tyrosine kinase receptor inhibitors become available.
administered as single drug or combined with
CRT may enhance oral mucositis or cause additional Radiation dermatitis [7,29–35]
symptoms. Effective management options for oral Radiation dermatitis occurs in the majority of
mucositis are still scarce, and pain control is often patients with loco-regionally advanced HNC treated
inadequate. A Cochrane meta-analysis [4] and a with RT. The pathobiology of acute radiation der-
systematic review and meta-analysis from 2011 on matitis is complex and partially overlaps that of oral
11 randomized control trials [1] (RCTs) in HNC mucositis. Irradiation of the skin leads to direct
patients treated with CT and/or RT concluded that tissue injury and inflammatory cell recruitment,
there was consistent evidence that LLLT/PBM leading to damage to epidermal basal cells, endo-
applied with doses of 1–6 J per point reduced oral thelial cells, and vascular components. Radiation-
mucositis prevalence, severity and duration, and induced generation of free radicals causing DNA
associated pain [1–5,17–20]. Another meta-analysis injury and release of inflammatory cytokines (in
including RCTs in various cancer treatment settings particular IL-1 and IL-6) lead to clinical changes
showed that LLLT/PBM reduced oral mucositis risk such as erythema, oedema, and possible ulceration.
and decreased its severity and duration. The efficacy Late RT-induced changes in the skin are character-
appeared to be similar for red (630–670 nm) and NIR ized by the disappearance of follicular structures, an
(780–830 nm) light, although the optimal doses increase in collagen and damage to elastic fibers in
seemed to vary between these wavelengths. Simi- the dermis, and a fragile epidermal covering. Trans-
larly, a systematic review and meta-analysis includ- forming growth factor-b is considered to play a
ing 18 RCTs reported that prophylactic LLLT/PBM central role in mediating RT-induced tissue fibrosis.
reduced severe oral mucositis and associated pain in The total radiation dose, dose per fraction, overall
patients treated for HNC or undergoing HSCT. The treatment time, beam type and energy, surface area
Clinical Practice Guidelines of the Multinational of the skin exposed to radiation, use of combined
Association of Supportive Care in Cancer and Inter- CRT with or without targeted therapies, and indi-
national Society for Oral Oncology mucositis study vidual risk factors, all contribute to the severity of
group found evidence for LLLT/PBM prevention of skin reactions. The severity of acute reactions has
oral mucositis in patients undergoing HSCT, and been shown to predict late effects. Radiation

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FIGURE 1. Oral mucositis: proposed PBM treatment parameters. PBM, PhotoBioModulation. Adapted with permission [27 ]. &

dermatitis impacts adversely on cosmesis and func- of radiation dermatitis in patients with breast can-
tion, particularly in patients with secondarily cer, but these results could not be reproduced,
infected irradiated skin, and reduces quality of life. although important parameters such as irradiation
Patients with squamous cell carcinoma of the time and size of area treated were not reported.
head and neck treated with an EGFR inhibitor may Promising results have been reported for LLLT laser
develop an acneiform skin rash in addition to radi- treatment at a NIR wavelength (970 nm) in patients
&
ation dermatitis [10 ]. Based on the effects of LLLT/ with EGFR inhibitor-induced facial rash.
PBM on the epidermis and dermis (reduced inflam-
mation and improved wound healing), and on the
shared similarities in pathobiology with oral muco- Lymphedema [36–40]
sitis, it seems reasonable to assume that LLLT/PBM Lymphedema as a consequence of cancer treatment
may reduce the severity and/or prevalence of radia- is apparent in breast cancer and HNC. In the case of
tion dermatitis (Fig. 2). HNC, it has been one of the neglected late effects,
Multiwavelength LLLT/ PBM ameliorated the although these complications may be reduced with
development of late radiation damage to the skin intensity modulated RT. In HNC patients, lymph-
in an animal model. LED treatment immediately edema may develop externally, on the face and
after intensity modulated RT reduced the incidence neck, and/or internally involving the larynx and

FIGURE 2. Radiation dermatitis: proposed PBM treatment parameters. PBM, PhotoBioModulation. Adapted with permission [27 ].
&

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FIGURE 3. Head and neck lymphedema: proposed PBM treatment parameters. PBM, PhotoBioModulation. Adapted with
permission [27 ].
&

pharynx. External lymphedema may have a pro- lymphedema, and elicits several potentially benefi-
found effect on body image, whereas internal cial effects, including reduction of inflammation
lymphedema may interfere with breathing, contrib- and pain, promotion of tissue repair, reduction of
ute to dysphagia and trismus, and may affect speech. fibrosis, and protection and regeneration of nerves.
Lymphedema has been reported in high numbers in Therefore, there is a clear motivation for the appli-
HNC, for example, a single center study on 81 HNC cation of LLLT/PBM to treat a broad range of acute
patients reported 75% incidence with 10% external, and chronic complications associated with RT or
39% internal, and 51% experiencing both types of CRT in cancer patients. Complementary RCTs
lymphedema. Individuals with pharyngeal carci- should be conducted to assess the feasibility and
noma were at highest risk. Chronic lymphedema efficacy of LLLT/PBM for prophylactic and therapeu-
that develops later (2–6 months after) may resolve tic management of the treatment complications of
& &
spontaneously in some patients, but not in all. The cancer therapy [41 ,42 ].
pathobiology of lymphedema consists of an initia-
tion where disruption of lymphatic structures Acknowledgements
occurs by surgery or RT, resulting in the accumula- None.
tion of lymph fluid in the interstitial tissues. This
leads to infiltration of inflammatory cells, and, Financial support and sponsorship
because of the lymphatic dysfunction, cytokines
None.
and chemokines remain in the tissue and recruit
additional inflammatory cells from the circulation.
This ongoing vicious inflammatory response results Conflicts of interest
in additional soft tissue damage and fibrosis, which There are no conflicts of interest.
further adversely affects lymphatic function. In
breast cancer patients, LLLT has been identified as
a potential treatment for postmastectomy lymph- REFERENCES AND RECOMMENDED
edema, as it stimulates lymphangiogenesis, enhan- READING
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ces lymphatic motility, and reduces lymphostatic been highlighted as:
fibrosis. Patients received additional benefits from & of special interest
&& of outstanding interest

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