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Mitigation of Cancer Therapy Side-Effects with Light
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DOI: 10.1088/978-1-6817-4075-1
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Section 1. Photobiomodulation and low level laser therapy

LLLT/PBM has been consistently shown in laboratory studies to have distinct
biological effects, and has a dose-dependent mechanism of action at the cellular
level. Since the introduction of LLLT/PBM in 1967, over 400 randomized, double-
blind (some placebo-controlled) clinical trials have been published for multiple
applications. The first clinical application of LLLT/PBM was for the enhancement
of wound healing. A meta-analysis including animal and human studies concluded
that LLLT/PBM was an effective tool for accelerating wound repair and tissue
regeneration. It has been shown that LLLT/PBM influences different phases of
wound healing including: (i) the inflammatory phase, in which immune cells migrate
to the site of tissue injury; (ii) the proliferative phase, which includes stimulation of
fibroblasts and macrophages as well as other repair components; and (iii) the
remodelling phase, consisting of collagen deposition and rebuilding of the extra-
cellular matrix at the wound site.
Although the complex biological mechanisms underlying the therapeutic effects
of LLLT/PBM have not been completely elucidated and may vary among different
cell types and tissue states (healthy versus stressed or hypoxic), laboratory and
clinical studies suggest that LLLT/PBM significantly reduces inflammation and
prevents fibrosis. Moreover, LLLT/PBM, when delivered appropriately, reduces
pain and improves optimal function of the whole organism. In addition, in vivo
studies show that LLLT/PBM is neuroprotective and may benefit neurodegenerative
diseases and neurotrauma.
Current data suggest that LLLT/PBM acts predominantly on cytochrome c
oxidase (CcO) in the mitochondrial respiratory chain by facilitating electron trans-
port resulting in an increased transmembrane proton gradient that drives adenosine
triphosphate (ATP) production. ATP is the universal energy source in living cells
and is essential for all biological reactions; even a small increase in ATP levels can
enhance the bioavailability to power the functions of cellular metabolism. In
addition, the absorption of red or near-infrared (NIR) light may cause a short,
transient burst of reactive oxygen species (ROS) that are followed by an adaptive
reduction in oxidative stress.
doi:10.1088/978-1-6817-4075-1ch1 1 ª Morgan & Claypool Publishers 2016

A low concentration of ROS activates many cellular processes, since ROS

activates transcription factors including nuclear factor kappa B (NF-κB), resulting
in the upregulation of stimulatory and protective genes. These genes generate
growth factors belonging to the fibroblast growth factor family, cytokines, and
chemokines that are involved in tissue repair.
In hypoxic or otherwise stressed cells, mitochondria produce nitric oxide (mtNO),
which binds to CcO and displaces oxygen. This binding results in inhibition of
cellular respiration, decreased ATP production and increased oxidative stress (a state
that develops when the levels of ROS exceed the defence mechanisms), leading to the
activation of intracellular signalling pathways, including several transcription
factors. These include the redox factor-1 (Ref-1), activator protein-1 (AP-1),
NF-κB, p53, activating transcription factor/cAMP-response element-binding protein
(ATF/CREB), hypoxia-inducible factor (HIF)-1 and HIF-like factor. These tran-
scription factors induce down-stream production of both inflammatory mediators,
such as tumour necrosis factor-alpha (TNF-α), Interleukin (IL)-1 and IL-6, cyclo-
oxygenase (COX)-2 and prostaglandin E2 (PGE-2), and anti-inflammatory mediators
(TGF-β, IL10). There is evidence suggesting that when LLLT/PBM is administered
with appropriate parameters to stressed cells, NO is dissociated from its competitive
binding to CcO, ATP production is increased, and the balance between pro- and
antioxidant mediators is restored, resulting in a reduction of oxidative stress. For
example, LLLT/PBM has been shown to attenuate the production of ROS by human
neutrophils. LLLT/PBM reduced ROS in an animal model of traumatic tissue injury;
whereas in a model of acute lung inflammation LLLT/PBM was found to reduce the
generation of TNF-α and to increase IL-10, an anti-inflammatory cytokine. In
addition, NO is a potent vasodilator and can increase the blood-supply to the
illuminated tissue. LLLT-mediated vascular regulation increases tissue oxygenation
and also allows for greater traffic of immune cells. These two effects may contribute to
the promotion of wound repair and regeneration.
Analgesic effects are probably induced by additional mechanisms rather than by
the increased ATP/reduced oxidative stress model. LLLT/PBM with a relatively
high power density (>300 (milliwatts) mW cm−2), when absorbed by nociceptors,
has an inhibitory effect on A and C neuronal pain fibres. This slows the neural
conduction velocity, reduces amplitude of compound action potentials and sup-
presses neurogenic inflammation.
Virtually all conditions modulated by LLLT/PBM (e.g. ulceration, inflammation,
oedema, pain, fibrosis, neurological and muscular injury) are thought to be involved
in the pathogenesis of (chemo)radiotherapy ((C)RT)-induced complications in
patients treated for head and neck cancer (HNC). For example, in an animal model
of oral mucositis (OM) it was demonstrated that LLLT/PBM decreased COX-2
expression and decreased the number of neutrophils in the inflammatory infiltrate.
Moreover, in the chronic sequelae of (C)RT an excessive fibroblastic response is
hypothesized to be related to acute oxidative injury, with resulting cell damage,
ischemia, and an ongoing inflammatory response resulting in fibrosis. The critical
2
difference between normal wound healing and fibrosis development appears to be

that in fibrosis, signalling pathways escape normal cellular regulation. The reduction
of fibrosis could be mediated by the beneficial effects of LLLT/PBM on the oxidant/
antioxidant balance down-regulation of the profibrotic transforming growth factor-
beta (TGF-β) and inhibition of excessive fibroblast proliferation.
The efficacy of LLLT/PBM in both acute and chronic conditions and affected
tissues has been shown to be promising in the majority of studies, although not all
have yielded positive outcomes. These divergent results may be attributed to factors
including dosimetry. It has been observed that increasing the overall dose of LLLT/
PBM may have a counter-productive effect compared to the benefit obtained with
lower doses
LLLT/PBM parameters
The LLLT/PBM parameters (summarized in table 1.1) are usually within the red
and NIR wavelength range of 600−1000 nanometres (nm), with a power density of
between 5−150 mW cm−2 and are typically applied for 30–60 s per point. The
therapeutic effect is typically dictated by the energy density measured in joules (J)
cm−2. Experimental evidence can be found in the literature for parameters as widely
divergent as 0.1–12 J cm−2. Laser systems used include helium–neon (HeNe),
gallium–aluminium (GaAl), neodymium-doped yttrium–aluminium–garnet (Nd:
YAG), gallium–aluminium–arsenide (GaAlAs) diode, indium–gallium–aluminium–
phosphorus (InGaAlP), and non-thermal, non-ablative carbon dioxide (CO2) lasers.
The PBM effects on the exposed tissues depend upon the cell type, redox state
of the cell, irradiation parameters (wavelength, power density) and time of
exposure. A biphasic dose response has been shown in several studies, which
underlines that there are optimal irradiation and dose parameters, although these
will vary depending upon the depth of the pathology below the mucosal or skin
surface. One must remember that doses lower than the optimal value may have a
reduced effect, while doses higher than optimal can have negative therapeutic
outcomes.
For LLLT/PBM to be effective, the irradiation parameters—including the energy
delivered, power density, pulse structure, delivery to the appropriate anatomical
location, and appropriate treatment timing and repetition—need to be within the
biostimulatory dose windows. This has been shown by studies which demonstrate
negative effects where dose depends on energy dose level alone. Titrating adequate
doses and defining the other required laser parameters according to evidence
gathered in a systematic way for each indication is a prerequisite for the successful
use of this technique. Without standardization in beam measurement, dose
calculation, and the correct reporting of these parameters, studies will not be
reproducible, and outcomes will not be consistent. A common misconception is
that wavelength and energy (in J) or energy density (J cm−2) are all that is
necessary in order to replicate a successful treatment, and that it does not matter
what the original power, power density, and duration of application were.
3
Table 1.1. LLLT parameters.
Category Parameter Unit Explanation
Irradiation Wavelength Nanometre (nm) Light is packets of electromagnetic energy called photons
parameters that sometimes behave like 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 photon is greater at
short wavelengths than longer wavelengths; e.g. red light is
∼2 electronvolts (eV) per photon and blue light is ∼3 eV.
Power Watt (W) The number of photons per second. The higher the power
the more photons emitted every second.
Beam area Centimetre squared The surface area of the beam on the patient. Also known as
(cm2) spot size. This is not always easy to determine because laser
beams are usually more intense in the middle then fade
4
towards 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 Centimetre squared The area of the light source tip. This is not necessarily
(cm2) 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 Watts per Power (W) ÷ beam area (cm2). More irradiance could allow
density, or intensity) centimetre squared less treatment time, however many studies have shown that
(W cm−2) if the irradiance is too high, treatment can be less effective
even if the same total dose is delivered. The treatment
guidelines suggest the safe and effective irradiance ranges.
(Radiant) Energy Joules (J) Power (W) × time (s). More power could mean less
treatment time however many studies have shown that too
much power is less effective even if the same total energy is
delivered. The treatment guidelines suggest the safe and
effective energy ranges.
Time Second (s) How long each treatment is applied at each location.
Dosage (fluence or Joules per Energy (J) ÷ beam area (cm2), or power (W) ÷ beam area
energy density) centimetre squared (cm2) × time (s). Different outcomes can be obtained if the
(J cm−2) total dosage is delivered with high energy and short time or
low energy and long time.
Operating mode Continuous wave The continuity of the production of the output beam may be
(CW), pulsed continuous or pulsed. There are several types of pulsed
beam.
5
Pulse structure Second(s) The durations of the pulse being on or off.
Treatment Physical relationship Applicable when there is more than one way to approach the
parameters to the organ organ. For example, intra-oral device versus extra-oral
device.
Timing Time of the treatment session relative to the cancer
treatment.
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.
Table 1.1 provides a checklist to help researchers understand and report all the
necessary parameters for a reproducible scientific study. In addition, it is not
uncommon to find discrepancies between the specifications provided by a device
manufacturer and the actual performance of the device. Thus, device maintenance,
including power measurements, should be carried out regularly during research
trials and also in clinical practice.
Section 2. Dermatitis
Radiation dermatitis occurs in the majority of patients with loco-regionally
advanced HNC treated with RT.
The pathobiology of acute radiation dermatitis is complex and partially overlaps
that of OM. Irradiation of the skin leads to direct tissue injury and inflammatory cell
recruitment, leading to damage to epidermal basal cells, endothelial cells and
vascular components. Radiation-induced generation of free radicals causing DNA
injury and release of inflammatory cytokines (in particular IL-1 and IL-6) lead to
clinical changes such as erythema, oedema and possible ulceration. Late RT-induced
changes in the skin are characterized by the disappearance of follicular structures, an
increase in collagen and damage to elastic fibres in the dermis, and a fragile
epidermal covering. TGF-β is considered to play a central role in mediating RT-
induced tissue fibrosis.
The total radiation dose, dose per fraction, overall treatment time, beam type and
energy, surface area of the skin exposed to radiation, use of combined CRT with or
without targeted therapies, and individual risk factors, all contribute to the severity
of skin reactions. The severity of acute reactions has been shown to predict late
effects. Radiation dermatitis impacts adversely on cosmesis and function, partic-
ularly in patients with secondarily infected irradiated skin, and reduces quality of life
(QoL).
Table 1.2. Radiation dermatitis treatment parameters.
Radiation Prophylactic: Start Extra-oral: Red Extra-oral: Extra-oral:

dermatitis daily PBM treatment laser diode cluster, Prophylactic: Cutaneous
at the initiation of 630–680 nm, 2 J cm−2 for surfaces on the
RT, or with a grade 1 20–150 mW cm−2 laser diode radiation field
radiation dermatitis or Mixed red and panel. 3 J cm−2 where dermatitis
Therapeutic: IR LED cluster for extra oral is anticipated
Continue treatment 20–80 mW cm−2 LED cluster (often
at least 3 times a Therapeutic: At erythematous
week until symptoms least 4 J cm−2 after RT)
improve
6
Patients with squamous cell carcinoma (SCC) of the head and neck treated with
an epidermal growth factor receptor (EGFR)-inhibitor may develop an acneiform
skin rash in addition to radiation dermatitis.
Based on the effects of LLLT/PBM on the epidermis and dermis (reduced
inflammation and improved wound healing), and on the shared similarities in
pathobiology with OM, it seems reasonable to assume that LLLT/PBM may reduce
the severity and/or prevalence of radiation dermatitis. Multi-wavelength LLLT/
PBM ameliorated the development of late radiation damage to the skin in an animal
model. LED treatment immediately after intensity modulated RT (IMRT) reduced
the incidence of radiation dermatitis in patients with breast cancer, but these results
could not be reproduced, although important parameters such as irradiation time
and size of area treated were not reported. Promising results have been reported for
LLLT laser treatment at a NIR wavelength (970 nm) in patients with EGFR
inhibitor-induced facial rash.
Section 3. Lymphedema
Lymphedema as a consequence of cancer treatment is apparent in breast cancer and
HNC. In the case of HNC, it has been one of the neglected late effects, although
these complications may be reduced with IMRT. In HNC patients, lymphedema
may develop externally, on the face and neck, and/or internally involving the larynx
and pharynx. External lymphedema may have a profound effect on body image,
whereas internal lymphedema may interfere with breathing, contribute to dysphagia
and trismus, and may affect speech.
Lymphedema has been reported in high numbers in HNC, for example, a single
centre study on 81 HNC patients reported 75% incidence with 10% external, 39%
internal and 51% experiencing both types of lymphedema. Individuals with
pharyngeal carcinoma were at highest risk. Chronic lymphedema that develops
later (2–6 months after) may resolve spontaneously in some patients, but not
in all.
The pathobiology of lymphedema consists of an initiation where disruption of
lymphatic structures occurs by surgery or RT, resulting in the accumulation of
lymph fluid in the interstitial tissues. This leads to infiltration of inflammatory cells
Table 1.3. Head and neck lymphedema treatment parameters.
Head and Therapeutic: Extra-oral: IR Extra-oral: Extra-oral: Treat

neck Continue laser diodes or 3 J cm2 laser edematous area
lymphedema treatment at LED cluster diodes or LED over the neck or
least 2 or 3 750–830 nm cluster surgical site if any,
times a week 20–80 mW cm−2 also targeting
until symptoms regional lymphatic
improve chain
7
and, because of the lymphatic dysfunction, cytokines and chemokines remain in the
tissue and recruit additional inflammatory cells from the circulation. This ongoing
vicious inflammatory response results in additional soft tissue damage and fibrosis,
which further adversely affects lymphatic function.
In breast cancer patients, LLLT has been identified as a potential treatment for
post-mastectomy lymphedema, as it stimulates lymphangiogenesis, enhances lym-
phatic motility, and reduces lymphostatic fibrosis. Patients received additional
benefits from LLLT/PBM when used in conjunction with standard lymphedema
treatment. Systematic reviews found evidence suggesting that LLLT/PBM reduced
limb volume in patients with lymphedema following treatment for breast cancer.
Future research is needed comparing LLLT/PBM to standard practices to establish
the duration of laser application, number of treatment sessions, energy settings,
power density and dose, using longer follow-up.
Section 4. Mucositis
OM affects virtually all patients undergoing CRT for advanced HNC, and the
majority of haematopoietic stem cell transplantation (HSCT) and high dose CT
regimens. Clinically, the manifestations of OM form a continuum, with erythem-
atous mucosal changes when mild and ulcerative lesions that expose the submucosa
in its severe form. Its detrimental effects on QoL and functional status are significant
and often interfere with the cancer treatment regimen, both on the patient level and
in terms of cost.
The current understanding of OM is largely based on animal models, which have
shown the multifactorial nature of the condition and have implicated a cascade of
interrelated events in multiple tissue regions. These observations combine into the
five-phase model of OM, based on the sequence of events following cytotoxic
treatment. The formation of excessive ROS and activation of NF-κB are the key
factors in its pathobiology. Subsequent studies have implicated microvascular
injury, the formation of proinflammatory cytokines, host–microbiome interactions
and extracellular matrix alterations in OM pathogenesis. In addition, EGFR
inhibitors and tyrosine kinase receptor inhibitors (TKIs) administered as single
drug or combined with CRT may enhance OM or cause additional symptoms.
Effective management options for OM are still scarce, and pain control is often
inadequate.
A Cochrane meta-analysis and a systematic review and meta-analysis from
2011 on 11 randomised control trials (RCTs) in HNC patients treated with CT
and/or RT concluded that there was consistent evidence that LLLT/PBM applied
with doses of 1–6 J per point reduced OM prevalence, severity and duration,
and associated pain. Another meta-analysis including RCTs in various cancer
treatment settings showed that LLLT/PBM reduced OM risk and decreased its
severity and duration. The efficacy appeared to be similar for red (630–670 nm)
and NIR (780–830 nm) light, although the optimal doses seemed to vary between
8
Table 1.4. Mucositis treatment parameters
PBM device
Treatment characteristics and Therapeutic PBM
Complication Treatment protocol area application dose Optional target tissues
Oral Prophylactic: Extra-oral: IR Extra-oral: 3 J cm−2 Extra-oral: Lips,

Mucositis Chemotherapy: Protocols vary. LED cluster or IR LED cluster cutaneous surface
Start PBM treatment at first day of mixed red and IR Intra-oral: corresponding to the
CT or prior to therapy and LED cluster Prophylactic: 2 J per buccal mucosae, bilateral
continue during all courses of 20–80 mW cm−2 point cervical lymphatic chain
chemotherapy Intra-oral: Intra-oral:
Therapeutic: 4 J per
Radiotherapy: Start PBM treatment 630–830 nm point until the whole Prophylactic: treat each of
the first day of RT or prior to RT 20–80 mW area involved is the at risk mucosal
and continue during all days of RT covered (2 J for surfaces
(no requirement regarding the prophylactic use) Therapeutic: sites vary,
9
timing of PBM sessions, before or depending upon the site of
after RT session) mucositis
Therapeutic: Continue treatment at
least 3 times a week until symptoms
improve
Daily treatment is recommended in
case of severe mucositis
these wavelengths. Similarly, a systematic review and meta-analysis including 18

RCTs reported that prophylactic LLLT/PBM reduced severe OM and associated
pain in patients treated for HNC or undergoing HSCT. The Clinical Practice
Guidelines of the Multinational Association of Supportive Care in Cancer and
International Society for Oral Oncology (MASCC/ISOO) Mucositis Study Group
found evidence for LLLT/PBM prevention of OM in patients undergoing HSCT,
and patients treated with RT for HNC. Evidence was derived from high quality
studies using specific LLLT/PBM parameters and the study group noted that there
remains a need to identify optimal LLLT/PBM parameters, including energy
density, ideal timing of laser application, variations in cancer type and cancer
treatment regimens.
Based on this evidence and on our experience, we propose the following regimen
for the management of OM (and mucositis affecting the oropharynx): a wavelength
of 633–685 nm or 780–830 nm; a power output of between 10 and 150 mW; an
energy density of 2–3 J cm−2 and no more than 6 J cm−2 on the tissue surface treated;
a frequency of 2–3 times a week up to daily; and successive applications on single
spots on a lesion rather than a scanning motion over the entire lesion. Extra-orally
administered LLLT/PBM may be effective for the management of OM of the buccal
mucosa, vestibule and inner epithelial surfaces of the lips. This could be applied in
combination with an intra-oral device (see table 1.4).
Section 5. Salivary gland—hyposalivation

Another significant complication of RT to the head and neck region is hyposaliva-
tion, and its related complaint of xerostomia (subjective oral dryness). For all head
and neck radiation regimens pooled, the weighted prevalence of xerostomia was
found to be 6% before treatment, 93% during irradiation, and a slightly lower
prevalence from one month to more than two years post-treatment. Saliva plays an
important role in maintaining mucosal integrity, promoting oral wound healing,
taste perception, formation of food bolus, initiation of food ingestion, swallowing
and speech. Alterations in the oral microbiota, reduced oral clearance, changes in
salival composition such as decreased buffer capacity, pH, immunoglobulin con-
centrations, defensins and dietary changes may increase the risk for mucosal
infections and rapidly progressing dental demineralization and caries. A substantial
decrease in salivary function has a significant impact on QoL, and results in an
increased burden of long-term oral health care.
Irradiation of the salivary glands results in loss of gland function, beginning early
in the course of RT and has been shown to induce apoptosis in parotid glands in a
dose-dependent manner. There can be a modest improvement in xerostomia a few
months after RT suggesting that an adaptation or compensatory function of
non-irradiated salivary glands or a recovery of some of the function occurs.
However, most patients have persisting oral dryness for the rest of their life, even
when 3D conformal RT is used. With IMRT preserving more of the major salivary
10
Table 1.5. Hyposalivation treatment parameters.
Hyposalivation Prophylactic: Extra-oral: IR laser Extra-oral: Extra-oral: Major

and xerostomia Radiotherapy: Start diodes or LED cluster Prophylactic: 3 J cm−2 salivary glands,
PBM treatment the 750–830 nm laser diodes or LED bilaterally (parotid,
first day of RT and 20–80 mW cm−2 cluster sublingual and
continue daily with Intra-oral: Intra-oral: submandibular)
radiation (no 630–680 nm Prophylactic: 3 J cm−2 Intra-oral: Total of 6
11
requirement regarding 20–150 mW per point points (3 each side)
the timing of PBM targeting major
sessions, before or salivary glands and
after RT session) minor salivary glands
(on vestibular side, in
the rear of salivary
ducts)
glands, long-term oral dryness may be reduced, but a significant proportion of

patients may still experience xerostomia.
The literature on LLLT/PBM for the management of hyposalivation is limited.
In a study involving a variety of non-cancer patients with xerostomia, LLLT/PBM
was applied daily: extra-orally to the parotid and submandibular glands and intra-
orally on the sublingual glands. A gradual increase in the stimulated salivary flow
was found after LLLT/PBM as compared to controls and similar reports have been
documented from non-cancer patients with xerostomia. Animal studies have
shown an increase in the number of ductal epithelial cell mitoses, and protein
synthesis in submandibular glands following LLLT/PBM. Similarly, there are
reports of increased salivary flow rate and amylase activity in rat parotid glands.
LLLT/PBM given concurrently with RT could prevent hyposalivation and
xerostomia and had an impact on the composition of saliva. Less severe
xerostomia was also reported following prophylactic LLLT/PBM in HSCT
recipients and in a small RCT in HNC patients treated with RT, and increased
salivary flow was observed in LLLT/PBM-treated patients when compared to
controls.
These results point to the application of LLLT/PBM for the prevention of
hyposalivation and xerostomia; potentially LLLT may also show efficacy for the
treatment of hyposalivation when there is any residual function following current
RT modalities (the parameters are suggested in table 1.5).
Section 6. Dysphagia
Dysphagia and odynophagia (painful swallowing) are common in HNC patients,
particularly in those suffering from oral, oropharyngeal, laryngeal and oesophageal
cancers, and those treated with RT or CRT. Dysphagia can be acute or chronic, due
to anatomical, mechanical or neurological changes, affecting any structure from the
lips to the gastric cardia. Around 60% of patients are reported to have dysphagia
following CRT, of which 45% had severe dysphagia at a median of 17 months post-
treatment. It has been observed that chronic dysphagia is unlikely to resolve over
time.
Dysphagia associated with CRT has a complex pathogenesis, involving acute
inflammation, oedema, and fibrosis, with neurological and structural alterations
and muscular injury resulting in generalized weakness and a lack of muscle
coordination while swallowing. Excessive fibrosis results in a loss of elasticity
that may contribute to chronic dysphagia. Furthermore, hyposalivation may
contribute to dysphagia following CRT. Duration of total parenteral nutrition
(TPN) or nasogastric tube feeding, and resultant reduced swallowing, may affect
the ability to return to a safe, normal oral intake and the subsequent inactivity may
lead to atrophy of the muscles aiding in the process of swallowing. Dysphagia
negatively affects QoL and may predispose sufferers to aspiration and life-threat-
ening pulmonary complications.
12
Table 1.6. Dysphagia treatment parameters.
Dysphagia Prophylactic: Extra-oral: Lateral Extra-oral: IR laser Extra-oral: Extra-oral: Midline

Radiotherapy: Start treatment the first and ventral pharynx diodes or LED Prophylactic: neck and lateral
day of RT and continue all days of and larynx cluster 750–830 nm 3 J cm−2 laser neck anterior to
radiation (no requirement regarding the Intraoral: Soft 20–80 mW cm−2 diodes or sternocleidomastoid
timing of laser sessions, before or after palate, oropharynx Intra-oral: LED cluster muscle
radiation session) 630–680 nm Intra-oral: Intra-oral: Bilaterally,
13
Therapeutic: Continue treatment at least 20–150 mW Prophylactic: four points to soft
3 times a week until symptoms improve 3 J per point palate and onto
oropharynx
IMRT has emerged as an effective technique to deliver the full radiation dose to
the tumour and regions at risk, while reducing the exposure of surrounding healthy
tissues. Identified dysphagia and aspiration risk structures (DARS) are susceptible to
damage during IMRT. In particular, damage to the tongue base, pharyngeal
constrictors, the larynx, and the autonomic neural plexus was found to be crucial
in the development of post-RT dysphagia. Studies confirmed that reducing the
radiation dose to DARS decreases the dysphagia risk, but dysphagia remains a
significant clinical problem.
The potential role of LLLT/PBM in the prevention and treatment of dysphagia
requires further investigation. One study reported a lower incidence of severe OM
and mucositis affecting the throat (contributing to acute dysphagia) when six
predetermined oral sites were exposed to LLLT/PBM prior to and during RT. In
this study, dysphagia was scored indirectly by assessing the need for TPN. Given
the ability of LLLT/PBM to prevent and ameliorate inflammation and pain
associated with OM, and the potential to control exuberant fibrosis, LLLT/PBM
delivered to the DARSs may have a potential role in the management of acute and
chronic dysphagia. The parameters for LLLT/PBM for dysphagia are suggested in
table 1.6.
Section 7. Dysgeusia
Altered taste (dysgeusia) is complex and includes difficulties with smell and touch
resulting in reduced food interest, affecting appetite and QoL. Taste is one of the five
senses and interacts with smell, touch and other physiological cues to affect the
wider perception of flavour. Taste function is the perception derived when food
molecules stimulate the taste receptors of the tongue, the soft palate and the
oropharyngeal region to perceive basic taste qualities (sweet, sour, salty, bitter
and umami), measured via standardized methods.
The prevalence of dysgeusia is estimated to be 66.5% following RT alone, and
76.0% after CRT; approximately 15% of patients continued to experience dysgeusia
after treatment and it is known that the severity of taste alterations assessed by
patients was correlated with the cumulative RT dose.
Table 1.7. Dysgeusia treatment parameters.
Dysgeusia Therapeutic: Continue Intra-oral: Intra-oral: Intra-oral:

treatment from the day 630–680 nm Dorsal and A total of ten
the patient complains of 20–150 mW lateral points on the
taste alterations, at least tongue at dorsum of the
2 or 3 times a week until 3 J cm−2 tongue
symptoms improve
14
The mechanisms of dysgeusia during cancer therapy are not well understood.
However, it is believed that CT and RT cause dysgeusia by destroying rapidly
dividing taste bud cells and olfactory receptor cells. Direct neurologic toxicity may
also be involved, as taste recovery lags behind epithelial recovery and may continue
indefinitely. Hyposalivation may also make a significant contribution. The presence
of the anterior part of the tongue in the radiation field may be predictive for taste
disturbances.
Altered taste significantly affects overall QoL and may lead to energy and
nutrient deficiencies and related complications and weight loss. Management
options to decrease the prevalence and severity of taste problems are inadequate.
A pilot study reported that LLLT/PBM administered to taste buds may
ameliorate psychogenic/neurological burning mouth symptoms including taste
alterations but, to our knowledge, there are no published studies on LLLT/PBM
for the management of taste problems in cancer patients. Hence, we feel that studies
on the efficacy of LLLT/PBM for the management of dysgeusia in patients treated
for HNC should be performed and the proposed potential LLLT/PBM parameters
are provided in table 1.7.
Section 8. Voice alterations

Voice and speech are important communication tools and form part of a person’s
identity and personality. Voice quality mainly depends on the movement and
characteristics of the vocal cords, and speech on the resonance characteristics of
the vocal tract. Speech is based on the volitional coordinated movements of the
articulator structures and can be affected by any alteration in muscle or tissue
properties of these structures. Although voice and speech dysfunctions significantly
affect QoL, these complications have received little attention and are likely under-
reported in efforts to preserve organ function after cancer therapy.
Currently, there is insufficient information on the prevalence of speech and voice
dysfunction in advanced HNC patients treated with CRT. Prospective studies are
needed, including baseline measurements and standardized multi-dimensional
assessment of functional aspects of voice and speech.
The aetiology of voice and speech problems resembles that of dysphagia and may
include neuromuscular weakness as a result of tumour invasion. CRT-induced voice
and/or speech dysfunction can result from mucositis of the soft palate and laryngeal
soft tissues, fibrosis or vocal fold atrophy, oedema and atrophy of laryngeal and
pharyngeal tissues and altered saliva or hyposalivation.
IMRT, designed to spare anatomical structures that are involved with voice and/
or speech functions, may well prevent long-term functional impairment and aid
early speech rehabilitation.
We are not aware of any studies on the effect of LLLT/PBM on the quality of
speech and voice in HNC patients, but LLLT/PBM may preserve function of the
anatomical structures involved directly, and could have indirect benefits by
decreasing the incidence of hyposalivation.
15
Table 1.8. Voice alteration treatment parameters.
Voice/speech Therapeutic: Intra-oral: Intra-oral: 3 J cm−2 Intra-oral: Towards the anterior

alterations Continue treatment 780–830 nm per point oropharynx over the dorsum of tongue
(due to local from the day patient 50–200 mW Extra-oral: on larynx (avoid gag reflex, do not touch any soft
inflammation) complains of area, wavelength tissues including dorsal tongue). Patient
difficulty speaking, at 750–830 nm may gently close the mouth during the
16
least 2 or 3 times a IR laser diodes or procedure to reduce gag reflex
week even if LED cluster
symptoms are not 20–80 mW/cm2
improving
dramatically
Section 9. Trismus
Trismus is a restriction or reduced opening of the jaws, due to local infection, tissue
fibrosis, pain upon mouth opening, tonic contraction of the muscles of mastication,
or a tumour. Trismus has been defined variously as a mouth opening of less than 40
or less than 20 mm, whereas less restrictive classifications also have been used.
The weighted prevalence of trismus is estimated to be 25% following conventional
RT, 5% following IMRT and 31% for CRT. Patients may have limitations in jaw
opening associated with tumour invasion of the masticatory muscles or the
temporomandibular joint, or may develop trismus following RT to these structures.
Cumulative radiation doses above 60 Gy are most likely to cause trismus, but the
inclusion of the lateral pterygoid muscles in the high dose fields appears to be the
most decisive factor. Trismus can be an acute symptom during treatment/RT and
typically develops 3–6 months post RT, and frequently becomes a lifelong problem.
Studies have demonstrated that fibrosis is an important initial event in RT-
induced trismus. Additionally, there may be scar tissue from surgery, nerve damage,
or a combination of these factors. Mandibular hypomobility ultimately results in
muscle contraction and potentially temporomandibular joint dysfunction.
Trismus and orofacial pain interfering with function may have significant health
implications including reduced nutritional intake, difficulty speaking, compromised
oral health and poor QoL. Aside from avoiding RT to the masticatory structures,
early interventions are indicated to prevent or minimize trismus
LLLT/PBM to prevent or reduce the severity of RT-induced trismus in HNC
patients has not been reported. The potential of LLLT/PBM to reduce fibrosis and
to promote muscle regeneration forms the main rationale for a potential clinical
benefit. LLLT/PBM parameters are proposed in table 1.9.
Section 10. Osteoradionecrosis

Soft tissue necrosis and/or osteoradionecrosis (ORN) may occur as a consequence of
RT. ORN is a process of radiation-induced vascular occlusion leading to loss of
osteocytes and bone necrosis following RT. The incidence of ORN has declined with
proper pre-treatment dental care and advances in RT. In conventional RT,
mandibular ORN prevalence ranges from 5%–15%, but with the advent of IMRT
less than 5% of patients are affected.
The pathogenesis of ORN is not completely understood. It has been proposed
that ORN occurs following a radiation-induced fibroatrophic process, including free
radical formation, endothelial dysfunction, inflammation, microvascular thrombo-
sis, remodelling, and finally bone and tissue necrosis. Common triggers of necrosis
are inflammatory dental disease, trauma to soft tissue, and dental surgical proce-
dures in sites of high dose radiation exposure to bone. Removing of diseased teeth
after RT is considered a critical risk factor for ORN, but the lesion can also emerge
due to periodontal disease, trauma or even spontaneously. Prevention of ORN is
mainly based on extractions of compromised teeth before RT and adequate dental
care during and following cancer therapy.
17
Table 1.9. Trismus treatment parameters. TMJ = temporomandibular joint.
Trismus Prophylactic: Extra-oral: IR laser Extra-oral: 3–6 J cm−2 Extra-oral: Bilaterally over the
Radiotherapy: Apply PBM on diodes or LED laser diodes or LED temporalis muscle, TMJ, masseter
pterygoid/TMJ region, at least 3 cluster 750–830 nm cluster muscle. buccinator muscle
times a week, when high dose 20–80 mW cm−2 Intra-oral: Intra-oral: Bilaterally, point over
RT is given in that region Intra-oral: 3 J per point the region of pterygoids/
(oropharyngeal and 630–680 nm pterygomandibular raphae (may
nasopharyngeal carcinoma 20–200 mW be difficultclinically) and other
for example). muscles of mastication
Therapeutic: Continue treatment
from the day of diagnosis at least
2 or 3 times a week
18
Table 1.10. Osteoradionecrosis treatment parameters.
Osteonecrosis Therapeutic: Continue Extra-oral: IR Extra-oral: Intra-oral: Five or more points

treatment at least 2 or 3 laser diodes or 6 J cm−2 laser (1 cm apart) along lingual and
times a week until LED duster diodes or LED buccal aspects of maxilla and/or
symptoms improve 750–830 nm cluster mandible depending on site and size
Daily treatment is 20–80 mW cm−2 Intra-oral: of region affected

recommended Intra-oral: 6 J per point
Combination with other 630–680 nm
medical/surgical treatment 20–200 mW
approaches may be needed.
Bevacizumab, an antibody that blocks vascular endothelial growth factor may

induce jaw osteonecrosis, possibly as a result of tissue ischemia. Bevacizumab may
impair wound healing and can cause osteonecrosis exposed through an oral
mucosal. Sunitinib, a TKI that blocks several pathways central to angiogenesis
and tumour cell proliferation, has also been associated with osteonecrosis of the jaw.
LLLT/PBM had a biostimulation effect on irradiated rat bone when applied
before and during RT. However, an in vivo study found that LLLT/PBM was not
able to reverse RT-induced bone damage. To our knowledge there are no clinical
studies on the effects of LLLT/PBM for RT-induced jaw osteonecrosis. There are
several reports on a benefit from LLLT/PBM in the management of bisphosphonate-
related osteonecrosis of the jaw (BRONJ) and a proposed prophylactic protocol
including LLLT/PBM for reducing BRONJ incidence following tooth extractions.
In vivo study on rodent wound healing model found evidence that both laser and
LED were capable of stimulating angiogenesis. These findings point to a possible
role of LLLT/PBM in the management of jaw osteonecrosis induced by RT or
angiogenesis inhibitors. We propose LLLT/PBM parameters for future clinical trials
in table 1.10.
Section 11. Safety concerns

As with any device used in medicine, safety checks are paramount for LLLT/PBM,
in particular if it is to be used as a ‘prescribable’ therapy for cancer patients. In the
past three decades of LLLT/PBM use in the management of OM in cancer patients,
no significant adverse effects have been reported. However, the hypothesis that
LLLT/PBM has an effect on tumour cells, or protects them from cytotoxic
treatment, has been proposed. This section will review what is known to the
scientific community so far and what needs to be done to test the above hypotheses.
It is unlikely that LLLT/PBM has carcinogenic effects in normal cells. The
non-ionizing wavelengths of the red and NIR spectrum used in LLLT/PBM are far
longer than the safety limit of 320 nm for DNA damage. No signs of malignant
transformation in non-malignant epithelial cells and fibroblasts were observed
following exposure to LLLT/PBM with a wavelength of 660 nm, 350 mW for
15 min during three consecutive days. In addition, no malignant transformation of
normal breast epithelial cells was detected in an in vitro study comparing the effects
of different doses and wavelengths of LLLT/PBM during multiple exposures.
There are no data to suggest that LLLT/PBM may protect cancer cells against the
cytotoxic effects of RT or CT. We know that, in vitro, LLLT/PBM on RT-induced
cytotoxicity in normal and leukemic cells enhances the radiation-induced killing
of the malignant cells after LLLT/PBM exposure. Also a pro-apoptotic effect of
LLLT/PBM in oral SCC cells has been found, with no anti-apoptotic effects that
might promote tumour cell resistance to cancer therapy. Increased apoptosis of
human osteosarcoma cells was also induced by the administration of NIR (810 nm,
continuous wave, 20 mW cm−2, 1.5 J cm−2) prior to NPe6-mediated photodynamic
therapy, as a result of increased cellular ATP and a higher uptake of the photo-
sensitiser. LLLT/PBM increased the loco-regional blood flow that contributed to
19
better local oxygenation, and hypothesized that LLLT/PBM applied shortly before
cancer treatment might enhance the effect of ionizing RT and local CT.
Most of the effects of LLLT/PBM on cell proliferation and differentiation have
been investigated in vitro using malignant cell lines, which have generated conflicting
data across a range of different tumour cell lines and LLLT/PBM parameters. For
example, (i) proliferation of laryngeal carcinoma cells after 809 nm GaAIAs laser
irradiation at energy densities between 1.96 and 7.84 J cm−2 and (ii) increased cell
proliferation of HEp2 carcinoma cells after LLLT/PBM exposure at different
wavelengths (685 and 830 nm) and doses. In a study comparing LLLT/PBM
administered to normal osteoblasts and to osteosarcoma cells with a range of
different wavelengths and doses, only 10 J cm−2 from an 830 nm laser was able to
enhance osteoblast proliferation, whereas energy densities of 1, 5 and 10 J cm−2 from
a 780 nm laser decreased proliferation. Osteosarcoma cells were unaffected by
830 nm laser irradiation, whereas a 670 nm laser had a mild proliferative effect. An
in vitro study compared the effects of different doses of LLLT/PBM at various
wavelengths on human breast carcinoma and melanoma cell lines, and found that
doses of LLLT/PBM increased breast carcinoma cell proliferation, multiple expo-
sures had either no effect or showed negative dose response relationships. LLLT/
PBM (wavelength = 660 nm) administered in low doses (1 J cm−2) increased the
in vitro proliferation and invasive potential of tongue SCC cells. Similarly, another
in vitro study suggested that LLLT/PBM (660 or 780 nm, 40 mW, 2.05, 3.07 or
6.15 J cm−2) may stimulate oral dysplastic and oral cancer cells by modulating the
Akt/mTOR/CyclinD1 signalling pathway to produce more aggressive behaviour.
In contrast, a decreased mitotic rate was found in gingival SCC after LLLT/PBM
at 805 nm and energy density of 4 and 20 J cm−2, whereas no effect on cell
proliferation or protein expression of osteosarcoma cells was found when LLLT/
PBM was administered with a wavelength of 830 nm. LLLT/PBM (808 nm; 5.85
and 7.8 J cm−2) had an inhibitory effect on the proliferation of a human hepatoma
cells line. Glioblastoma/astrocytoma cells exhibited a slightly decreased mitotic rate
after LLLT/PBM at 805 nm and 5–20 J cm−2. Similarly, 808 nm laser irradiation
with an energy density of more than 5 J cm−2 inhibited cell proliferation of
glioblastoma cells in vitro. Moreover, observed growth inhibition of cancer cell
lines occurred at relatively high cumulative LLLT doses. This in fact led to a
proposal that, LLLT/PBM may have therapeutic potential in lung cancer. LLLT/
PBM administered at a dose of 150 J cm−2 appeared to be safe, with only minor
effects on B16F10 melanoma cell proliferation in vitro, and had no significant effect
on tumour growth in vivo. Only a high power density (2.5 W cm−2) combined with a
very high dose of 1050 J cm−2 could induce melanoma tumour growth in vivo.
LLLT/PBM (660 nm, 30 mW, 424 mW cm−2, 56.4 J cm−2, 133 s, 4 J) applied to
chemically induced oral SCC in hamster cheek pouch tissue, increased the growth
and severity of the SCC. However, the results were different in a mouse model used
to study the effects of LLLT/PBM on multiple UV-induced skin tumours. The
experimental mice received full body 670 nm LLLT/PBM delivered twice a day at
5 J cm−2 for 37 days, whereas controls received sham LLLT/PBM. No enhanced
tumour growth was observed: there was a small but significant reduction in tumour
20
area in the LLLT/PBM group, potentially related to a local photodynamic effect or

LLLT/PBM-induced antitumor immune activity. Similar results were reported in an
animal study showing that small tumours exposed to LLLT/PBM receded and
completely disappeared.
It was hypothesized that upregulation of ATP signalling by LLLT/PBM
promoted apoptosis, as well as differentiation of tumour cells, thereby slowing
down tumour proliferation.
The results from these studies suggest that different tumour cells have distinct
responses to specific LLLT/PBM parameters and doses. In part, these differences
may also be explained by variations in the cellular microenvironment, since these
have been shown to affect cellular signal transduction pathways to LLLT/PBM
exposure. The microenvironment of tumour cells varies among in vitro studies and
differs significantly from that found in animal models. Moreover, this difference
implies that the potential of LLLT/PBM to enhance proliferation of tumour cells
in vitro does not necessarily translate into harmful effects of LLLT/PBM in cancer
patients.
A clinical study reported no differences in cancer recurrence rates for patients
receiving LLLT/PBM for lymphedema following breast cancer treatment, compared
to controls. A recent RCT in which LLLT/PBM was administered for prevention of
OM during CRT in HNC patients (diagnosed with SCC of the nasopharynx,
oropharynx and hypopharynx), reported that at a median follow-up of 18 months
(range 10–48 months), patients treated with LLLT/PBM had better loco-regional
disease control and improved progression-free or overall survival.
Current evidence suggests that LLLT/PBM in the red or NIR spectrum with an
energy density of 1–6 J cm−2 is safe and effective, hence it should not be withheld, in
particular from HNC patients. Nevertheless, as robust evidence for the lack of
malignant cell protection or enhancement of tumour growth has not been published,
vigilance remains warranted. Further investigations using animal models and long
term follow-up (and retrospective analysis) clinical investigations should be con-
ducted to confirm the effects of LLLT/PBM on oncology outcomes and to obtain
more insight into dose relationships and the mechanisms of host–tumour responses
to LLLT/PBM.
A recent review has identified several biological pathways and molecules involved
in the above, in particular for PBM over an area where the tumour has been,
resected such as in the case of HNC. While many clinical follow-ups and laboratory
studies are warranted in streamlining dose parameters, there are no reported cases of
PBM as a source of reactivation of tumour cells in the literature
Section 12. Conclusion and future directions

Acute and chronic complications induced by RT and CRT in patients with HNC
represent a significant clinical challenge. There are similarities with respect to
pathophysiology across different complications, and patients may suffer from
multiple concurrent and interrelated problems. There is anecdotal evidence suggest-
ing that the inflammation associated with acute complications is a harbinger for
21
chronic complications. This observation suggests that preventive approaches start-

ing before, and in the early phases of treatment with RT and CRT, may reduce not
only the risk of developing acute problems, but may also have an impact on the risk
for late complications.
PBM has shown effectiveness in the management of OM, and elicits several
potentially beneficial effects, including reduction of inflammation and pain, promo-
tion of tissue repair, reduction of fibrosis, and protection and regeneration of nerves.
Therefore, there is a clear motivation for the application of PBM to treat a broad
range of acute and chronic complications associated with RT or CRT in HNC
patients and other cancer patients including HSC. RCTs should be conducted to
assess the feasibility and efficacy of PBM for prophylactic and therapeutic manage-
ment of the head and neck complications of cancer therapy.
We hope that this book will serve as the basis for establishing a platform for
facilitating future collaborations among clinicians and researchers, which will then
create firm scientific evidence for the use of PBM in patients with HNC. PBM
protocols should be administered using suitable parameters for the anatomic
structures at risk. The parameters (including the wavelengths) we have proposed are
largely based on evidence derived from studies using PBM for the management of OM
(typically 633–685 nm or 780–830 nm). However, trials directed to other (non-head
and neck) indications for the use of PBM suggest that a broader range of wavelengths
(590–1064 nm) has efficacy for healing and for reducing inflammation and pain.
Future investigations should be conducted to better define optimal PBM parameters
for each of the complications of HNC treatment. In addition, the ideal timing and
frequency of PBM administration should be determined, as well as how long PBM
should be continued following the completion of cancer treatment. PBM parameters
should be reported in detail (as discussed in section 1). Validated outcome measures
must be identified and employed to assess the effect of prophylaxis and therapy, from
the time of diagnosis through active treatment and survival.
With regard to HNC, bearing in mind the reasonable safety and potential
benefits, one must be cautious when considering the possibility of residual tumours
within the site of PBM. While the reported results of in vitro studies of PBM on
malignant cells vary, and clinical reports have shown little or no adverse reactions,
there is a paucity of robust data regarding potential protection and promotion of
tumours. Studies should also be directed toward the potential beneficial effects of
PBM by enhancing the efficacy of (C)RT or immunologic antitumor reactivity. It is
thus imperative that further investigations be aimed at obtaining more insight into
the mechanisms of the host–tumour responses to PBM and to elucidating the effects
of PBM on oncology treatment outcomes.
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Mitigation of Cancer Therapy Side-Effects with Light

Book · October 2016

RENE-JEAN BENSADOUN Raj G Nair

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Section 1. Photobiomodulation and low level laser therapy

doi:10.1088/978-1-6817-4075-1ch1 1 ª Morgan & Claypool Publishers 2016

A low concentration of ROS activates many cellular processes, since ROS

difference between normal wound healing and ﬁbrosis development appears to be

Category Parameter Unit Explanation

divergence and distance of the light source tip from the

Table 1.2. Radiation dermatitis treatment parameters.

Radiation Prophylactic: Start Extra-oral: Red Extra-oral: Extra-oral:

Table 1.3. Head and neck lymphedema treatment parameters.

Head and Therapeutic: Extra-oral: IR Extra-oral: Extra-oral: Treat

Oral Prophylactic: Extra-oral: IR Extra-oral: 3 J cm−2 Extra-oral: Lips,

these wavelengths. Similarly, a systematic review and meta-analysis including 18

Section 5. Salivary gland—hyposalivation

Hyposalivation Prophylactic: Extra-oral: IR laser Extra-oral: Extra-oral: Major

glands, long-term oral dryness may be reduced, but a signiﬁcant proportion of

Dysphagia Prophylactic: Extra-oral: Lateral Extra-oral: IR laser Extra-oral: Extra-oral: Midline

Table 1.7. Dysgeusia treatment parameters.

Dysgeusia Therapeutic: Continue Intra-oral: Intra-oral: Intra-oral:

Section 8. Voice alterations

Voice/speech Therapeutic: Intra-oral: Intra-oral: 3 J cm−2 Intra-oral: Towards the anterior

Section 10. Osteoradionecrosis

Osteonecrosis Therapeutic: Continue Extra-oral: IR Extra-oral: Intra-oral: Five or more points

Daily treatment is 20–80 mW cm−2 Intra-oral: of region affected

Bevacizumab, an antibody that blocks vascular endothelial growth factor may

Section 11. Safety concerns

area in the LLLT/PBM group, potentially related to a local photodynamic effect or

Section 12. Conclusion and future directions

chronic complications. This observation suggests that preventive approaches start-

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Langendijk J A, Doornaert P, Rietveld D H, Verdonck-de Leeuw I M, Leemans C R and Slotman

Roe J W et al 2010 Swallowing outcomes following Intensity Modulated Radiation Therapy

Simoes A, de Campos L, de Souza D N, de Matos J A, Freitas P M and Nicolau J 2010 Laser

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