Laser Therapy for Retinoblastoma in the Era of Optical Coherence
Tomography
Authors:Comment by Sameh Soliman: Authors’ names and
affiliation: Including address, academic qualifications and
job titles of all authors, as well as telephone number and email
address of the author for correspondence on a separate cover sheet
as the peer reviewers will be blinded to the authors’ identity.
Please note that only the address of the first author of the
article will appear on Medline/PubMed, not necessarily the
corresponding author.
Sameh Soliman1-2, Stephanie Kletke1, Kelsey Roelofs3, Cynthia
VandenHoven1, Leslie Mckeen1, Brenda Gallie1.
Authors’ affiliations:
1Department of Ophthalmology and Visual Sciences, Hospital for
Sick children, Toronto, Ontario, Canada.
2Department of Ophthalmology, Faculty of Medicine, University of
Alexandria, Egypt.
3Department of Ophthalmology, Alberta children hospital,
University of Calgary, Alberta, Canada
Corresponding author:
Dr. Brenda Gallie at the Department of Ophthalmology and Vision
Sciences, the Hospital for Sick Children, 555 University Avenue,
Toronto, ON M5G 1X8, Canada, or at [email protected]
Type of article: Review
Word limit: Comment by Sameh Soliman: The word limit for Reviews
is 7,000 words (not including figures, tables or references).
Tables and Figures: Comment by Sameh Soliman: Figures and
Tables: Up to 5 figures and 5 tables are permitted.
Keywords: Comment by Sameh Soliman: Keywords: A brief list
of keywords, in alphabetical order, is required to assist indexers
in cross-referencing. The keywords will encompass the therapeutic
area, mechanism(s) of action, key compounds and so on.
AbstractComment by Sameh Soliman: Structured abstract (maximum
200 words): The aim of the abstract is to draw in the
interested reader and provide an accurate reflection of the content
of the paper. We therefore request the following structure is
followed for full-length review articles:Introduction: Authors are
required to describe the significance of the topic under
discussion.Areas covered: Authors are required to describe the
research discussed and the literature search undertaken.Expert
commentary: The author’s expert view on the current status of the
field under discussion.References must not be included in the
abstract.
Introduction: The past several decades have seen vast
advancements in the treatments paradigm for retinoblastoma., and
the use of Focal laser therapy is certainly no
exceptionconsistently a cornerstone for disease control, but
techniques have not been extensively described. T While the first
description of focal laser therapy for retinoblastoma dates towas
over 6 decades ago, with technologies and approaches several
improvements in protocols have occurred over the past two decades
evolving with the intention to that have greatly improved our
ability to achieve local tumor control. It was observed that the
published literature is deficient regarding laser therapy
techniques, types, mode of delivery and even its role in disease
control.
Areas covered: In this review the physical and optical
properties of lasers are briefly discussed, and the various
mechanisms of action, delivery systems and potential complications,
optical coherence tomography (OCT) guided treatment decisions and
management of sub-clinical tumors are discussed. the literature
search undertaken.????
Expert commentary:
Key issuesComment by Sameh Soliman: Key issuesAn executive
summary of the authors’ main points (bulleted) is very useful for
time-constrained readers requiring a rapidly accessible
overview.
Introduction Comment by Sameh Soliman: Body of the
article:Introduction: Incorporating basic background information on
the area under review.Body: Body of the review paper covering the
subject under review, using numbered subsections.Conclusion: The
conclusion for all articles should contain a brief summary of the
data presented in the article. Please note that this section is
meant to be distinct from, and appear before the ‘Expert opinion’
section.
Retinoblastoma is the most common intraocular malignancy that is
initiated by mutations in both copies of the retinoblastoma gene
(RB1 gene).[1] Worldwide, approximately 8000 children are newly
diagnosed annually. Survival approaches 100% if retinoblastoma is
diagnosed while still intraocular, while children with extraocular
retinoblastoma have poor survival.[1, 2] Treatment strategies vary
according to presentation but the fundamental primary goal of
treating cancer is life salvage, with vision salvage a secondary
goal. Salvage of an eye without visual potential may be a dangerous
goal that can lead to unrecognized recurrence of the cancer,
extraocular extension and loss of life.
With Despite the recent advances and new treatment modalities in
retinoblastoma management, the main primarystay of therapy for
intraocular retinoblastoma remains tumor size reduction by
chemotherapy (systemic, intra-arterial or periocular) followed by
focal therapy with laser, cryotherapy, plaque radiotherapy and/or
intravitreal chemotherapy, according to tumor location and size.
Chemotherapy without focal consolidation is rarely sufficient to
control retinoblastoma.[3, 4] However, the role of laser therapy in
achieving tumor control is commonly unmentioned in presentation of
outcomes of treatment modalities such as intra-arterial and
intravitreal chemotherapy.
Laser therapy for retinoblastoma is a topic rarely addressed in
publications. Laser is rarely utilized as a primary therapy except
in small tumors. Techniques of laser therapy are rarely described
making it difficult to study or learn outside an apprenticeship
situation. Choice of the type of Laser is highly variable according
to experience and availability without a consensus. Furthermore,
the role of Laser in achieving primary or recurrent tumor control
is unmentioned or even neglected in reporting or comparing outcomes
of recent treatments as intra-arterial chemotherapy (IAC) or
Intravitreal chemotherapy (IViC) giving the reader the false
impression of insignificant role of Laser.[5, 6] techniques of
laser therapy are rarely described making it difficult to study or
learn outside an apprenticeship situation.
Optical coherence tomography (OCT) has revolutionized our
perspective of variable retinal disorders including retinoblastoma
by allowing detailed anatomical evaluation of the retinal layers
and tumor architecture. OCT visualizes subclinical new tumors and
tumor recurrences, differentiates tumor from gliosis during scar
evaluation, and improves perception of important anatomic landmarks
for vision such as the fovea and optic nerve.[4, 7]
We now review the role of different lasers in management of
retinoblastoma and describe OCT guided laser therapy to achieve
precision in tumor control and visual outcome.
BodyPHYSICS OF LASER:
Although Einstein initially postulated the concept behind the
stimulated emission process upon which lasers are based in 1917,
but it was not until 1960 that T.H. Maiman performed the first
experimental demonstration of a ruby (Cr3+AL2O3) solid state
laser.[8] In fact, The acronym LASER represents the underlying
fundamental quantum-mechanical principals involved: Light
Amplification by Stimulated Emission of Radiation.[9] All lasers
require a pump, an active medium and an optical resonance cavity.
Energy is introduced into the system by the pump, which excites
electrons to move from a lower to higher energy orbit. As these
electrons to return to their ground state, they emit photons, all
of which will be of the same wavelength resulting in light that is
monochromatic (one color), coherent (in-phase) and collimated
(light waves aligned). Mirrors at either end of the resonance
cavity reflect photons traveling parallel to the cavityie’s axis,
which then stimulate more electrons, resulting in amplification of
photon emission. Eventually photons exit the laser cavity through
the partially reflective mirror into the laser delivery
system.[9]Comment by Gallie Brenda: What is the correct format for
refs?? Check carefully if the ref number comes before or after the
.
Lasers are typically categorized by their active medium, as this
is whatwhich determines the laser beam wavelength. For all lasers,
tThe wavelength multiplied by the frequency of oscillation for all
lasers equals the speed of light. Therefore, as the lasers
wavelength increases its frequency decreases proportionally and
vice versa. Additionally, Planck’s law (E=h) states that the energy
(E) of a photon is a product of Planck’s constant (h=6.626 x 10-34
m2kg/s) multiplied by the frequency (). As such, lasers with low
wavelengths (and high frequency) impart high energy, and those with
high wavelengths (and low frequency) are less powerful. Broad
categories of lasers include solid state, gas, excimer, dye and
semiconductor.
The power of a laser is expressed in watts (W), which is the
amount of energy in joules (J) per unit time (J/sec). Power density
takes into account both the power (W) and the area over which it is
distributed (W/cm2). It is important to note that if spot size is
halved, the power density is quadrupled, and that if the amount of
energy (J) remains constant, decreasing the duration will increase
the power (W) delivered. Longer pulse duration increases the risk
that heat waves will extend beyond the optical laser spot, thus
damaging surrounding normal tissue.[10] All lasers machines have
the option to control the shot pace or inter-shot interval,
according to the experience of treating ophthalmologist. In
general, trainees are better to start by with single shots or a
longer inter-shot interval.
TYPES OF LASERS FOR RETINOBLASTOMA:
Xenon arc photocoagulation, first described by
Meyer-Schwickerath in 1956, was one of the earliest
photocoagulation methods adopted for treatment of
retinoblastoma.[11, 12] Xenon emission is white light, consists ofa
mixture of wavelengths between 400 and 1600 -nm and results in
full-thickness burns without selectively targeting ocular tissues.
It has since beenis now replaced by laser photocoagulation for
retinoblastoma. Comment by Gallie Brenda: What else was there? None
I know of…..
The commonest lasers used for focal therapy in retinoblastoma
include are the green (532 nm) frequency doubled neodymium Nd:YAG
(yttrium-aluminum-garnet) by indirect ophthalmoscope, 810 nm
semiconductor infrared indirect or trans-scleral diode laser, and
the 1064 nm far infrared continuous wave Nd:YAG laser and the 810nm
semiconductor infrared indirect or trans-scleral diode laser. While
all three lasers can be delivered with use of an indirect
ophthalmoscope, the 810nm diodeinfrared lasers can also be applied
in a trans-scleral manner, which can be particularly useful for
anteriorly located tumors. and for treating tumors in the presence
of media opacities. Trans-scleral delivery also decreases the risk
of cataract formation by limiting laser transmittance through the
pupil.[13] Of the three, the green 532 nm laser and 810 nm lasers
can treat tumor by photocoagulation. Both 810 nm and 1064 nm lasers
can also treat by raising tumor temperature (hyperthermia, commonly
called trans-pupillary thermotherapy or TTT) in a sub-threshold
manner.[10] Table 1 demonstrates the main differences between the
different types of laser in retinoblastoma.
LASER DELIVERY:
Retinal laser treatments can be delivered by either binocular
indirect ophthalmoscopy (BIO) using non-contact, hand-held lenses
(20 D, pan-retinal 2.2 D or 28 D) or by microscope-mounted laser
with contact lenses (Goldmann Universal Three-Mirror, Ocular
Mainster Wide Field) and a coupling agent (Table 2).
3.1: Laser indirect ophthalmoscopy (LIO).
LIOIt was first described to treat retinoblastoma in 1992.[13]
LBIO combined with manipulation of eye position with a scleral
depressor is the ideal laser delivery technique for children under
general anesthesia. The higher the power of the condensing lens
utilized, the lower the image magnification and the greater the
field of view. The laser spot size on the retina varies because the
laser beam focuses at some distance from the indirect
ophthalmoscope, and diverges on either side ofcloser and farther
from the focal point. It thereforeEffect depends on the power,
relative positions of the headset and BIO lenses, amount of light
scattering by ocular media, as well asand the patient’s refractive
error. For instance, a 20 D lens causes a 900 µm image plane spot
to be reduced to 300 µm in an emmetropic eye.[14] The retinal spot
size can be calculated by (ppower of the condensing aspheric lens
multiplied byx iImage plane spot size) divided by/ 60.[14] However,
caution must be exercised as LBIO is less stable than other
delivery systems due to inherent instability of the patient’s eye
and the clinician’s head, particularly with simultaneous foot pedal
depression.[14] The positional requirements and relatively long
treatment durations associated with LBIO laser delivery contribute
to higher prevalence of self-reported neck, hand, wrist and lower
back pain amongst ophthalmologists.[15]Comment by Gallie Brenda:
???
3.2: Microscope-mounted delivery system.
This systemIt connects delivers the laser with through a
slit-lamp or operating microscope. While the working distance for
LBIO is variable, the distance from the microscope to the patient’s
eye is fixed. Therefore, retinal laser spot size is only dictated
by the patient’s refractive error, contact lens and pre-selected
laser spot diameter on the microscope.[14] Tilting the contact lens
within 15 degrees does not cause significant distortion of the
laser spot, as irradiance differs by maximum 6.8%.[16] The
universal Goldmann three-mirror (Power -67 D) has a flat anterior
surface that cancels the optical power of the anterior cornea,
therefore decreasing peripheral aberrations.[17, 18] It contains
mirrors at 59, 67 and 73 degrees to aid in visualization of the
periphery.[17] However, photocoagulation efficiency is reduced in
the far periphery, as the laser follows an off-axis, oblique
trajectory. LBIO is preferred for peripheral retinal laser
treatments as the field of view is greater than with a
microscope-mounted laser. Comment by Gallie Brenda: explain
this?
Another commonly used contact lens is the Mainster wide-field
(Power +61 D), which contains an aspheric lens in contact with the
cornea and a convex lens at some fixed distance.[17, 18] Compared
to the Goldmann three-mirror which has the highest on-axis
resolution, the Mainster lens has improved field of view at the
expense of poorer resolution.[16] Inverted image lenses may produce
smaller anterior than posterior segment laser beam diameters, thus
leading to higher irradiance in the anterior segment. Injury to the
cornea and lens have been reported during retinal photocoagulation
with inverted image lenses, particularly in the presence of high
power settings and ocular media opacities.[16]
3.3: Trans-scleral laser therapy. (STEPHANIE)Comment by Gallie
Brenda: Are there any current paper on this for retinoblastoma?We
used to occasionally do this but not in many years.
Infra-red laser photocoagulation may also be delivered via a
trans-scleral approach using a fiberoptic probe.[19, 20] This
technique was first described for the treatment of retinoblastoma
in 1998.[21] Direct visualization of a red laser aiming beam
through the wall of the globe confirms the treatment area, with the
main outcome being whitening of the tumor and surrounding retina.
In vitro and in vivo studies of trans-scleral thermotherapy for
choroidal melanoma suggest tumor cell destruction occurs at a
threshold of 60 degrees Celsius, without permanent damage to
scleral collagen or increased risk of retinal tears.[22, 23] Given
the precise nature of delivery and effective scleral transmission,
trans-scleral diode is useful for treatment of anteriorly located
retinoblastoma tumors and in the presence of media opacities.
Trans-scleral diode also decreases the risk of cataract formation
by limiting laser transmittance through the pupil.[21]
MECHANISMS OF LASER THERAPYAPPRAOCHES FOR RETINOBLASTOMA: 4.1.
PHOTOCOAGULATION:
Photocoagulation is the process by which laser light energy is
absorbed by a target tissue and converted into thermal energy. A
10-20 degree Celsius temperature rise induces protein denaturation
and subsequent coagulation and necrosis, depending on the duration
and extent of thermal change.[11] Heat generation is influenced by
the laser parameters and optical properties of the absorbing
tissue.[17] Absorption characteristics are dictated by
tissue-specific chromophores, such as melanin in the retinal
pigment epithelium (RPE) and choroidal melanocytes, hemoglobin in
blood vessels, xanthophyll in the inner and outer plexiform layers,
lipofuscin and photoreceptor pigments.[24]
Lasers in the visible electromagnetic spectrum, such as the 532
-nm frequency-doubled Nd:YAG, are largely absorbed by hemoglobin
and melanin, approximately half in the RPE and half in the
choroid.[17] Heat is then conducted to the neurosensory retina,
causing inner retinal coagulation and focal increase in necrotic
cellsnecrosis. This leads to loss of retinal transparency and the
white laser response noted ophthalmoscopically. The 532 -nm laser
also destroys the retinal blood supply as the wavelength is near to
the absorption peaks of oxyhemoglobin and deoxyhemoglobin. However,
this requires more energy due to the cooling effect of blood flow,
which has greater velocity than stationary tissues.[17] Confluent
laser burns encircling retinoblastoma tumors occlude large retinal
blood vessels and other feeder vessels may require supplementary
treatment.[13] Since the initial laser treatments cut off the tumor
blood supply, This explains why it is preferred not to start
photocoagulation is initiated only before after systemic or
intra-arterial chemotherapy completionare completed to preserve the
chemotherapy tumor-delivery uninterrupted.
Eyes with tumors less than 3 mm elevation may be successfully
controlled by laser without chemotherapy. Larger tumors require
first chemotherapy, followed by first laser In larger tumors,
encircling photocoagulation to cut off blood supply and initiate
tumor regression. On subsequent treatments, four to six weeks
apart, laser photocoagulation will be applied directly to the tumor
(Figure 2). Tumors that are too large for laser therapy only may
not be controlled, and require other modalities of
treatmentespecially without chemotherapy, may sometimes lead to
failure of tumor control or earlier vitreous seeding secondary to
obliteration of tumor blood supply, with resultant tumor necrosis
and loss of tumor compactness (Figure 1). In our experience,
combined tumor encircling and painting by Laser is preferred over
encircling laser alone. (Figure 2) Comment by Sameh Soliman:
Combined approachComment by Sameh Gaballah: FIGURE 1 include tumors
with encircling photocoagulation. Leslie.Comment by Sameh Soliman:
Combined approach
“Thermal blooming” is the process by which the photocoagulation
zone may be extended beyond the laser spot size particularly with
with longer duration burns.[17] This may not be clinically apparent
during treatment and is one factorbut contributesing to increased a
larger size of the laser scar post-operatively. When the tumor
becomes white with laser photocoagulation, fa whitish response to
the laser is noted, further penetration of the light energy to
deeper structures is prevented by light scattering.[24] Thus,
repeated laser treatments on the same area will only increase the
lateral extent of the laser application, known as the “shielding
effect”. Laser photocoagulation ultimately replaces the tumor with
leads to scarring, gliosis and variable RPE retinal pigment
eplithelial hyperplasia.Comment by Gallie Brenda: Reference????
4.2. TRANS-PUPILLARY THERMOTHERAPY:
Trans-pupillary thermotherapy (TTT) has also been applied to
retinal tumors to achieve localized tissue apoptosis. It involves
continuous long duration (60 seconds) laser application treatment
in the near-infrared spectrum (800-1064 nm), usually 810 -nm diode,
for longer durations (60 seconds) and with larger spot size and
lower power than photocoagulation.[17] This TTT results in deeper
tissue penetration (4 mm) since melanin absorption decreases with
increasing laser wavelength. The penetration depth of continuous
wave 1064 nm laser thus exceeds that forthe 810 nm diode and 532 nm
lasers, which is important when considering treatment of thicker
tumors.[25] Resultant temperatures (45 to 60 oC) rises are lower
than for classic photocoagulation (45 to 60 degrees Celsius).[26]
The endpoint of TTT is faint whitening or graying of the tumor and
prominent visible laser changes may not be visible at the time of
treatment, dependent on fundus pigmentation and laser
parameters.[17, 26] This is dependent on fundus pigmentation and
laser parameters. Comment by Gallie Brenda: check the ref style: if
superscript will be after the punctuation, if number in brackets
will ve before the punctuation
Standard TTT may be insufficient to treat large, thick tumors or
lesions associated with significant chorioretinal atrophy.
Furthermore, while TTT requires inherent lesion pigmentation to
achieve an adequate response, retinoblastoma is characteristically
non-pigmented. ADDIN EN.CITE ADDIN EN.CITE.DATA [27-29]Pretreatment
with intravenous indocyanine green (ICG), a chromophore with
absorption peak 805 nm, complementing the diode laser emission of
810 nm, results in photosensitization and a dose-dependent decrease
in the TTT fluence threshold and irradiance required for
treatment.[27] Enhancement of the effect with systemic ICG may lead
to regression of tumors that have shown a suboptimal response to
systemic chemotherapy and standard TTT.[28-30] The optimal timing
between ICG and TTT has not been full elucidated.
(FA and ICG enhanced TTT, STEPHANIE)
Complications of TTT reported following treatment of
retinoblastoma include chorioretinal scarring with focal scleral
bowing.[23] Comment by Gallie Brenda: more papers on the dragging
of retina and shifting of scara?
4.3 SEQUENTIAL LASER THERAPY COMBINING DIFFERENT LASERS:
Certain tumors especially large central juxtafoveal and
perifoveal tumorsRetinoblastoma might can be treated with a
necessitate combination of both photocoagulation and thermotherapy
in successive one or sequential treatments. The tumor border and
periphery are treated with 532 nm lLaser. A longer wavelength laser
is used to treat the elevated center either in the same or
sequential session.[7] Unfortunately, there is no randomized
clinical trial that compared laser mechanisms to set evidence to
use any.[31] Comment by Sameh Soliman: ADD our sequential and the
Pakistani paper here
COMPLICATIONS OF LASER THERAPY:
The most serious complications caused by laser therapy are often
caused by use of excessive energy, and as such, starting your
treatment at a lower power and titrating to the desired effect
decreases the likelihood of complications. In cases where too small
a spot size, too high a power or too short a duration is used, an
iatrogenic rupture of Bruchs’ membrane may occur. This might act as
precursor for choroidal neovascular membrane formation.
Additionally, intense photocoagulation may result in full thickness
retinal holes which may progress to rhegmatogenous retinal
detachment. In retinoblastoma, this can result in vitreous
seeding.[32] OCT can help in visualizing and following these
complications.
Although rare, biopsy-proven orbital recurrence of
retinoblastoma has been reported following successful treatment of
a macular recurrence with aggressive argon and diode laser.[33] In
this case, MRI demonstrated a large intraconal mass contiguous with
the sclera, and B-scan ultrasound confirmed scleral thinning at the
recurrence site. The orbital recurrence was felt to result from
tumor seeding of the orbit at a site of focal scleral thinning
within an atrophic chorioretinal scar, following multiple intense
laser treatments.[33]Comment by Sameh Soliman: Brenda, do you want
to include a figure regarding SMW?
Additional complications can include focal iris atrophy,
lenticular opacification, retinal traction, retinal vascular
obstruction and localized serous retinal detachment.[32, 34]
Additionally, scars from TTT (810 nm) have been shown to increase
in size after treatment for retinoblastomaretinoblastoma [35] and
as such, one must be cautious in using this laser for tumors
located near the fovea and optic nerve. Other complications of TTT
reported following treatment of retinoblastoma include
chorioretinal scarring with focal scleral bowing.[36]
Laser should be avoided over areas with retinal detachment
whether high or shallow. OCT can help diagnose subtle detachments.
Laser over the optic nerve can compromise nerve fiber vitality and
should be avoided. The exact tumor relation to the optic nerve can
be mapped by OCT and is thus considered during treatment
planning.
PUBLISHED EVIDENCE ON LASER IN RETINOBLASTOMA:
Meyer-Schwickerath reported the results first introduced the
idea of xenon photocoagulation into the management paradigm for
retinoblastoma in 1955 and subsequently reported their results in
1964. [37] Although laser therapy for retinoblastoma has been used
for several decades[37, 38] it wasn’t until the 1980’s and 1990’s
that the role for focal laser therapy in the management of
retinoblastoma became widely popularized.[39] In 1982 Lagendijk
used trans-pupillary thermotherapy (TTT) in two cases of recurrent
retinoblastoma successfully.[40] Subsequently, a relatively large
study by Lumbroso et al reported their outcomes in 239 children
using TTT delivered with a diode laser through an operating
microscope and found that when this was combined with chemotherapy
excellent local tumor control and eye preservation was
achieved.[41] Other groups similarly concluded that while
chemoreduction alone may not be adequate at achieving complete
tumor control, chemoreduction in combination with adjuvant
treatment (including laser photocoagulation, thermotherapy,
cryotherapy and radiation) resulted in good retinal tumor control,
even in eyes with advanced disease.[42]
As the use of laser therapy in the management of retinoblastoma
gained traction, several clinicians investigated this potentially
synergistic role between thermotherapy and chemotherapy. This
treatment algorithm was termed chemothermotherapy and was based on
the hypothesis that the delivery of heat facilitates the cellular
uptake of certain chemotherapeutic agents.[43] In fact, in a series
of 103 tumors treated with chemothermotherapy, Lumbroso et al[44]
reported that tumor regression was seen in 96.1%. ADDIN EN.CITE
Lumbroso20024690[46]4690469017Lumbroso, L.Doz, F.Urbieta, M.Levy,
C.Bours, D.Asselain, B.Vedrenne, J.Zucker, J. M.Desjardins,
L.Department of Ophthalmology, Institut Curie, Paris,
France.Chemothermotherapy in the management of
retinoblastomaOphthalmologyOphthalmology1130-61096Antineoplastic
Agents/*therapeutic useCarboplatin/*therapeutic useChild,
PreschoolCombined Modality TherapyFemaleFollow-Up
StudiesHumanHyperthermia, Induced/*methodsInfantInfant,
NewbornMaleRemission InductionRetinal
Neoplasms/pathology/*therapyRetinoblastoma/pathology/*therapySalvage
TherapyTreatment
Outcome2002Jun12045055http://www.aaojournal.org/cgi/content/full/109/6/1130http://www.aaojournal.org/cgi/content/abstract/109/6/1130http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12045055[46]
In this study, TTT was delivered shortly after an intravenous
injection of carboplatin.
Predictors for success of focal laser photocoagulation and
thermotherapy have also been identified. Abramson et al. concluded
that tumors <1.5 disc diameters in base diameter can be
successfully treated with TTT alone, with nearly two thirds (64%)
of tumors only requiring one session.[26] Alternative laser
techniques have also been described, including the use of the
532-nm laser which has been shown to effectively treat small
(<2mm in height, <4 disc diameter) tumors. [32] Depending on
the tumor location, the clinician may prefer one laser type over
the other. For instance, while TTT using the 810-nm diode laser is
effective, the scar that is created can increase in size after
treatment [35] and therefore when applying laser near vital macular
structures some prefer laser photocoagulation (532-nm laser).
Similarly, trans-scleral diode laser may be the preferred modality
for small anteriorly located retinoblastomas.[21] Although a
variety of potential complications as discussed above have been
noted, the majority of these can be avoided by using the minimal
effective laser power.[32] It is important to note however that
despite the use of laser focal therapy being a mainstay in the
treatment of retinoblastoma, there have been no randomized
controlled trials evaluating the effect of systemic chemotherapy
with versus without laser therapy for post-equatorial
retinoblastoma.[31]
NEW PAPERS ON LASER AND VISUAL OUTCOME: (KELSEY)Comment by Sameh
Soliman: Fabian, Am J Ophthalmol. 2017 Jul;179:137-144.
OPTICAL COHERENCE TOMOGRAPHY (OCT) IN RETINOBLASTOMA:
OCT was introduced to retinoblastoma in the early 2000s. The
first few reports focused on describing how retinoblastoma appears
and how to differentiate it from other simulating tumors.[45, 46]
Introduction of hand held OCT helped examining supine children
under anesthetic allowing imaging of more retinoblastoma tumors at
different phases of their active treatment from diagnosis to
stability.[47, 48] This allowed visualization of a multitude of
situations that can affect and guide laser therapy as subclinical
invisible tumors,[49, 50] subclinical tumor recurrences either
within a previous scar or edge recurrences,[7] topographic
localization of foveal center,[7, 51] differentiating whitish
lesions such as gliosis and perivascular sheathing from active
retinoblastoma and possible optic nerve involvement.[52] OCT can
demonstrate tumor location within the retina whether superficial,
deep or diffuse infiltrating retinoblastoma.[7] OCT can visualize
tumor seeds either vitreous or subretinal.[7, 53] It can also
determine the internal architecture of retinoblastoma whether solid
or cavitary[54] that might affect the therapy approach (Figure 2X).
Despite very difficult, OCT can be used to examine the mid
periphery but highly dependent on the expertise of the photography
specialist.[7] Comment by Sameh Gaballah: Include an image of every
point mentioned in the paragraph.
OCT has crucially influenced our management decisions in
retinoblastoma management. In a recent research, the role of OCT in
each examination under anesthetic (EUA) session for a child with
retinoblastoma was retrospectively classified into directive
(direct diagnosis, treatment or follow up) and academic sessions.
Directive OCTs was found in 94% (293/312) OCT sessions. Directive
OCTs were further classified into confirmatory (if they confirm the
pre-OCT clinical decision) or influential (if they influence
changing the pre-OCT clinical decision). It was found that 17% of
directive OCTs were influential highlighting the importance of OCT
in the armamentarium of evaluation during an EUA.
THE FUTURE: OPTICAL COHERENCE TOMOGRAPHY GUIDED LASER:
Currently, OCT is an essential tool in diagnosis, planning and
monitoring of laser therapy in certain scenarios in
retinoblastoma.
68.1. INVISIBLE TUMORS:
Invisible tumors can be anticipated in children with positive
RB1 variant either detected prenatal or postnatal, positive
parental family history of retinoblastoma or a child with other
clinical tumors (in H1 children). The ideal procedure to screen for
invisible tumors is OCT mapping of the posterior pole especially in
the first 6 months of age. Once detected, the subclinical tumor
should be centralized in the OCT scan. Calipers and anatomic
landmarks especially vessels and its branching can be used to help
locating the invisible tumor in the retinal image. Photocoagulation
with low laser power (100 mW) and short pulse duration (0.5
seconds) is delivered, to gradually increase power until whitening
is noted. Post laser OCT can verify treatment where the tumor
swells with increase reflectiveness and back shadowing. (Figure 3)
Comment by Sameh Soliman: VV images (leslie)
68.2. JUXTAFOVEAL TUMORS:
Tumors around the fovea are a treatment challenge to preserve
the foveal center. Classical laser treatment will eventually
destroy the fovea as the resultant scar is usually greater than the
tumor size. OCT localizesOCT localizes the foveal center by
obtaining two OCT macular cube scans (vertical and horizontal) to
precisely determine the foveal location, to avoidto avoid laser
application to this critical area. Photocoagulation is superior to
TTT in posterior pole tumors to preserve vision and avoid scar
migration. Recently an OCT guided sequential laser crescent
photocoagulation method was described for juxtafoveal tumors
avoiding the fovea. The antifoveal tumor crescent is
photocoagulated using 532 nm laser to obliterate the blood supply
to the tumor. This will flatten the tumor center that will be
treated in sequential sessions. Additionally, the peripheral
scarring causes a tangential anti-foveal force pulling tumor away
from the fovea. (Figure 3) This technique was described to have
better anatomical and visual outcome in juxtafoveal tumors where
the fovea is OCT detectable at initial laser session. Furthermore,
OCT can detect subtle surrounding exudative retinal detachment that
might stop us from initiating laser treatment. Comment by Gallie
Brenda: Ref???Fabian paper
68.3: RECURRENT AND RESIDUAL TUMORS:
OCT can detect subclinical tumor edge recurrences. OCT can
differentiate between tumor calcification and homogenous potential
active tumor. Comparison between successive OCT scans of the same
area can detect subtle tumor recurrence. (Figure 4) This potentiate
less treatment burden regarding laser power, number of sessions and
final outcome. Recurrences on flat retina are usually treated with
photocoagulation with 532 nm laser. However, recurrences over
calcified tumor require longer wavelength photocoagulation and even
TTT.
Whitish treatment scars previously posed a clinical challenge to
determine whether it is a tumor residual, recurrence or a fibrosis.
This was usually managed either by more laser treatment with the
possibility of more scarring and traction or observation with the
potential danger of tumor growth requiring more treatment burden.
OCT helped visualizing the layers of this scars differentiating
between these conditions guiding the diagnosis and subsequent
treatment choice. OCT directed repeating laser treatment to
specific areas with recurrence instead of the whole scar thus
reducing potential extensive scarring and retinal dragging.
68.4. PRE-EQUATORIAL TUMORS:
Pre-equatorial tumors can be treated by either photocoagulation
or cryotherapy. Laser therapy is usually preferred in superior
tumors to avoid potential cryotherapy associated uveal effusion and
exudative detachment. Flat pre-equatorial tumors are usually
treated with 532 nm laser photocoagulation for one or two sessions.
More elevated tumors might require multiple laser treatments as the
tumor cannot be treated equally as the inward curve of the tumor
cannot be thoroughly painted with trans-pupillary laser. In
subsequent sessions with more outward flattening of the tumor, the
inward curve can be better visualized and treated.
Despite challenging, peripheral OCT can assess tumor elevation,
differentiate scarring from residual tumors and identify peripheral
potential tumor seeding (Figure 5). In certain tumors, laser can be
utilized as an initial belt like treatment surrounding the tumor as
a preparatory step prior to cryotherapy or plaque radiotherapy.
Peripheral laser can be also used for potential ischemic retina
peripheral to an extensive tumor scar to prevent development of
neovascularization and probable subsequent vitreous hemorrhage. As
a general rule, a smaller spot size is required in peripheral
lesions to prevent iris injury. Comment by Sameh Soliman: Discuss
with Brenda. ?? AD
FUTURE PRESPECTIVE: (can be written in the 5 year view)
OCT and wide field imaging in one unit??
Conclusions
Laser therapy in retinoblastoma is integral in tumor control
after initial chemotherapy size reduction. In spite of this fact,
Laser was never properly studied in a randomized controlled fashion
to set evidence. Introduction of OCT improved tumor visualization
and assessment improving our laser strategies and minimizing
complications.
Expert CommentaryComment by Sameh Soliman: Expert
Commentary: 500-1000 words (included in overall word count).To
distinguish the articles published in the Expert Review series,
authors must provide an additional section entitled ‘Expert
Commentary’. This section affords authors the opportunity to
provide their interpretation of the data presented in the article
and discuss the developments that are likely to be important in the
future, and the avenues of research likely to become exciting as
further studies yield more detailed results. The intention is to go
beyond a conclusion and should not simply summarise the paper.
Authors should answer the following:What are the key weaknesses in
clinical management so far?What potential does further research
hold? What is the ultimate goal in this field?What research or
knowledge is needed to achieve this goal and what is the biggest
challenge in this goal being achieved?Is there any particular area
of the research you are finding of interest at present?Please note
that ‘opinions’ are encouraged in the Expert commentary section,
and, as such, referees are asked to keep this in mind when peer
reviewing the manuscript.
I would include something related to the future of OCT guided
laser.
Five year viewComment by Sameh Soliman: Five-year viewAuthors
are challenged to include a speculative viewpoint on how the field
will have evolved five years from the point at which the
review was written.
There is huge advance in imaging technology that will allow
incorporation of fundus imaging and OCT. the incorporation of Laser
therapy within this machine is expected to follow to facilitate
better aiming and improve the reproducibility of Laser
techniques.
ReferencesComment by Sameh Soliman: References: A maximum
of 100 references is suggested. Ensure that all key work relevant
to the topic under discussion is cited in the text and listed in
the bibliography. Reference to unpublished data should be kept to a
minimum and authors must obtain a signed letter of permission from
cited persons to use unpublished results or personal communications
in the manuscript.Annotated bibliography: Important references
should be highlighted with a one/two star system and brief
annotations should be given (see the journal’s Instructions for
Authors page for examples and for a more detailed description
of our referencing style).
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Table 1: Comparison between lasers in retinoblastoma.
Type of laser
Green
532nm
Diode
810nm
Continuous wave 1064nm
Frequency-doubled Nd-YAG
Solid State
Semi-conductor
Nd-YAG
Solid State
Common delivery method
Indirect
Indirect or transcleral
Indirect
Mechanism of action
Retinal photocoagulation results in tumor apoptosis
Acts in a subthreshold manner to raising choroidal temperature.
Causing minimal thermal damage to the RPE and overlying retina
Depth of penetration
Superficial: limited by the resultant coagulation [32] and by
nature of shorter wavelength. Estimated to penetrate ~2 mm in
non-pigmented tumors such as retinoblastoma.[10]
Deep: primary anatomical site of action is in the choroid. Diode
and Nd:YAG lasers are estimated to penetrate 4.2 and 5.1mm
respectively. Penetration depth decreases in necrotic
tumors.[10]
Parameters
Power: 0.3 – 0.8 W
Duration: 0.3-0.4 seconds
Power: 0.3-1.5 W
Duration: 0.5 – 1.5 seconds
Power: 1.4 – 3.0 W
Duration: 1 second
Clinical endpoint
Increase power by 0.1W increments until tumor/retinal whitening
visible[32]
Slight graying of retina without causing vascular spasm [26,
34]
Table 2. Types of contact and non-contact fundus lenses [13, 16,
17]
Lens Type
Image Magnification
Laser Spot Magnification
Static Field of View (°)
Dynamic Field of View (°)
Contact or Non-contact
Image Characteristics
Goldmann 3-Mirror Universal
0.93X
1.08X
36
74
(with 15° tilt)
Contact
Virtual, erect image located near posterior lens capsule
Ocular Mainster Wide Field
0.67X
1.50X
118
127
Contact
Real, inverted image in air
20 D BIO
3.13X
0.32X
46
60
Non-contact
Real, inverted, laterally reversed
Pan-retinal 2.2 BIO
2.68X
0.37X
56
73
Non-contact
Real, inverted, laterally reversed
28 D BIO
2.27X
0.44X
53
69
Non-contact
Real, inverted, laterally reversed
D= Diopter; BIO= Binocular indirect ophthalmoscopy