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Laser Therapy for Retinoblastoma in the Era of Optical Coherence Tomography

Authors:

Sameh Soliman1-2 , Stephanie Kletke1 , Kelsey Roelofs3 , Cynthia VandenHoven1 , Leslie Mckeen1 ,

Brenda Gallie1 .

Authors’ affiliations:

1 Department of Ophthalmology and Visual Sciences, Hospital for Sick children, Toronto,

Ontario, Canada.

2 Department of Ophthalmology, Faculty of Medicine, University of Alexandria, Egypt.

3 Department 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 brenda@gallie.ca

Type of article: Review

Word limit:

Tables and Figures:

Keywords:

Abstract

Introduction: The past several decades have seen vast advancements in the treatment paradigm

for retinoblastomaNew approaches to retinoblastoma have ., and the use of Focal laser therapy is

certainly no exceptionconsistently a cornerstone for disease control, after chemotherapy has

brought the disease under control, but not cured. .T While the first description of focal laser

therapy for retinoblastoma dates towas over 6 decades ago;, technologies and approaches several

improvements in protocols have occurred over the past two decades have evolved to that have

greatly improved our ability to achieve local tumor control. Despite its important role in disease

control, It was observed that the published literature is deficient little is published regarding laser

therapy techniques, types, and mode of delivery and even its role in disease control.

Areas covered: the literature search undertaken.????In thisWe review the physical and optical

properties of lasers are briefly discussed, and the various mechanisms of action, delivery

systems, and potential complications, and the new role of optical coherence tomography (OCT)

in to guided treatment decisions and management detection of sub-clinical“microscopic” tumors

are discussed. the literature search undertaken.????

Expert commentary:

BG to do

Key issues

Introduction

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 and

treated while still intraocular, while but when retinoblastoma is extraocular, 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, and for

retinoblastoma with vision salvage is a secondary goal. Salvage of an eye without visual

potential may be a dangerous goal since that can lead to unrecognized recurrence of the cancer,

can leads to 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.[5, 6]

Laser therapy for retinoblastoma is a topic rarely addressed in publications. Laser is rarely

utilizedappropriate as a primary therapy except inonly for 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 wave length 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.

Body

1. PHYSICS 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]

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.

2. 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.

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 The 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.

3. 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 is

minimized (with most power) because the laser beamat the focuses at some focal point, a specific

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 torequires careful

optimization and coordination of the inherent instability of the patient’s eye, and the clinician’s

head, particularly withand simultaneous foot pedal depression, .[14] The positional requirements

and relatively long treatment durations associated with LBIO laser deliverywhich contribute to

higher prevalence of self-reported neck, hand, wrist and lower back pain amongst

ophthalmologists.[15]

3.2: Microscope-mounted delivery system.

This systemIt connects the Laser may also be delivered 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 and treatment 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.

Also nother commonly used contact lens is the Mainster wide-field (Power +61 D) , contact lens,

which containings an aspheric lens in contact with the cornea and a convex lens at some a 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,

while the Goldmann three-mirror which has the highest on-axis 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)

DiodeInfra-red laser photocoagulation may also be delivered via a trans-sclerally approach using

an optical fiber.optic 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 andand for treating tumors in the presence of media

opacities. Trans-scleral deliverydiode also decreases the risk of cataract formation by limiting

laser transmittance through the pupillens.[21]

[4.] 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]

Laser lights in the visible electromagnetic spectrum, such as the(ie 532 -nm frequency-doubled

Nd:YAG), are is 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, noted ophthalmoscopically as.

This leads to loss of retinal transparency and the a white laser response notedburn

ophthalmoscopically. The 532 -nm laser is near the absorption peaks of oxyhemoglobin and

deoxyhemoglobin so is taken up by also destroys the retinal blood supply vessels, which is

countered by 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 may occlude capillaries and large retinal blood vessels, cutting off the

tumor blood supply, and other feeder vessels may require supplementary treatment.[13] so This

explains why it is preferred not to start photocoagulation is initiated only before after systemic or

intra-arterial chemotherapy completionare completed, in order to preserve the delivery of

chemotherapy to the tumorumor-delivery uninterrupted.

Tumors less than 3 mm elevation may be successfully controlled by laser without chemotherapy.

Larger tumors require first chemotherapy to initiate tumor regression, followed by laser In larger

tumors, encircling photocoagulation to cut off blood supply and o n subsequent treatments, 4–6

weeks apart, laser photocoagulation is applied directly to the tumor (Figure 2). Tumors that are

too large for laser therapy 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 lLaser is preferred over

encircling laser alone. (Figure 2)

“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 leads to gliosis replacing the tumor withleads to scarring, gliosis and

variable RPE retinal pigment eplithelial hyperplasia.

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 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 exceedspenetrates deeper that

that forthe 810 nm diode, and 532 nm lasers, which is important when consideringin treatment

of thicker tumors.[25] Resultant Temperatures of TTT (45 to 60 o C) 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.[17, 26] This is dependent on fundus pigmentation and laser parameters.

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. [27-

29]Pretreatment with intravenous indocyanine green (ICG), a chromophore with an absorption

peak (805 nm) complementing the diode 810 nm 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 laser effect by with systemic ICG may lead to

regression of tumors withthat have shown a suboptimal response to systemic chemotherapy and

standard TTT.[28-30] The optimal timing between ICG injection and TTT has not been full

elucidateddetermined.

(FA and ICG enhanced TTT, STEPHANIE)

Complications of TTT reported following treatment of retinoblastoma include chorioretinal

scarring with focal scleral bowing.[23]

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

comparedcomparing lasers and technologies mechanisms to set establish evidence to use any.

[31]

4.[5.] COMPLICATIONS OF LASER THERAPY:

The most serious complications caused byof laser therapy are often usually caused by use of

excessive energy. Therefore, and as such, starting your treatments start at a lower power and to

titrateing to the desired effect to decreases the likelihood of complications. In cases where

tooToo small a spot size, too high a power or too short a duration is usedcan induce, an

iatrogenic rupture of Bruchs’ membrane, which may occur. This might act asbe a precursor for

choroidal neovascular membrane formation. Additionally, Intense photocoagulation may result

in full thickness retinal holes which may progress to rhegmatogenous retinal detachment, or may

. In retinoblastoma, this can result in induce vitreous seeding of retinoblastoma.[32] OCT can

help inis useful to visualize and analyze ing and following these complications.

Although rare, Biopsy-proven orbital recurrence of retinoblastoma has been reported following

successful repeated treatment of a macular recurrence of retinoblastoma 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]

Additional Common less serious 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 shownare recognized to

increase in size with time after treatment for retinoblastomaretinoblastoma [35] and as such, one

must be cautiousso may be in using this laser for tumors l suboptimal for tumors located near the

fovea and optic nerve. Other cComplications of TTT reported following treatment of

retinoblastoma include cChorioretinal scarring with focal scleral bowing is reported following

TTT.[36]

Laser is ineffective in should be avoided over areas with any retinal detachment whether high or

shallow. OCT is useful to delineatecan help diagnose subtle detachments. Laser over the optic

nerve can compromise nerve fibers vitality and should be avoided. The exact tumor relation to

the optic nerve can be mapped by OCT and to is thus considered during treatment planningguide

accurate laser treatment near critical structures.

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%.[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)

[6.] LASER GUIDED BY OPTICAL COHERENCE TOMOGRAPHY (OCT) IN

RETINOBLASTOMA:

First reports of OCT was introduced to retinoblastoma in the early 2000s. The first few reports

focused on describing howthe appearance of retinoblastoma appears and how toand

differentiation e it from other simulating tumorslesions.[45, 46] Introduction ofThe hand held

OCT expanded the use tohelped examining supine children under anesthetic allowing imaging of

moreto image retinoblastoma tumors from diagnosis through treatments, to eventual stability.at

different phases of their active treatment from diagnosis to stability.{Scott, 2009

#13722;Maldonado, 2010 #13713} This allowedOCT visualization facilitates accurate of a

multitude of situations that can affect and guide laser therapy, revealing for example, as

subclinical invisible tumors,{Rootman, 2013 #10244;Berry, 2016 #13759} subclinical tumor

recurrences either within a previous scar or edge recurrences,{Soliman, 2017 #15422}

topographic localization of the foveal center,{Hasanreisoglu, 2015 #13211;Soliman, 2017

#15422} and differentiatingng benign whitish white lesions (such as gliosis, and perivascular

sheathing from of active retinoblastoma and possible optic nerve involvement).[52] OCT can

demonstrate intraretinal tumor location (within the retina whether superficial, deep or diffuse

infiltrating) retinoblastoma,.[7] OCT can visualize vitreous or subretinal tumor seeds, either

vitreous or subretinal.[7, 53] It can alsoand determine the solid or cavitary internal architecture

of retinoblastoma whether solid or cavitary[54] that might affect the therapeuticy approach

(Figure 2X). Despite very difficultWith skill and persistence, the handheld OCT can be used to

in examine the mid periphery. but highly dependent on the expertise of the photography

specialist.[7]

OCT has become crucially influenced in our management decisions in retinoblastoma

management.{Soliman, 2017 #17193} In a recent research, The role of OCT in each examination

under anesthetic (EUA) session for a child with retinoblastoma was retrospectively classified

determined to be into directive (direct diagnosis, treatment or follow up) in 94% (293/312) of

OCT and sessions, or academicacademic sessions. Directive OCTs was found in 94% (293/312)

OCT sessions. Directive OCTs were further classified into as confirmatory (if they confirm the

pre-OCT clinical decision) or influential (17%) (if they influence change ing the pre-OCT

clinical decision), . It was found that 17% of directive OCTs were influential highlighting the

importance of OCT in the optimal retinoblastoma management.

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.

668.1. INVISIBLE TUMORS:

Invisible tumors can beare anticipated in children with carrying a pathogenic variant of the

positive RB1 tumor suppressor gene variant either detected either prenatal or postnatal, because

they have a positive parental family history of retinoblastoma. These children are classified now

by the 2017 Tumor Node Metastasis Heritablity cancer staging for retinoblastoma to be “H1”

even if they do not yet have detectable cancer. or a child with other clinical tumors (in H1

children). The ideal procedure to Sscreening for invisible tumors is by OCT mapping of the

posterior pole of each eye especially in the first 6–9 months of age can reveal. tiny spheres of

altered density in the inner nuclear layer of the retina. Once detected, the the subclinical tumor

should becan be centralized in the OCT scan and combination of c. Calipers and anatomic

landmarks especially (branching vessels, etc) and its branching can be used to help locating to

locate the invisible tumor in the retinal retina for ablation by 532 nm laserimage.

Photocoagulation with low laser power (100 mW) and short pulse duration (0.5 seconds) is

delivered, to gradually increasinge power until whitening is noted. Post laser OCT can verify that

the laser burn(s) were in the correct location, including the tiny tumor treatment where the tumor

swells with increase reflectiveness and back shadowing. (Figure 3).

68.2. JUXTAFOVEAL TUMORS:

Tumors around near the fovea are a treatment challenge to treat with focal therapy and preserve

the foveolaal center. Classical laser treatment will eventually destroy the fovea as the resultant

scar is usually greater than the tumor size. OCT localizesOCT with two OCT macular cube

scans (vertical and horizontal) localizes the foveal center by obtaining two OCT macular cube

scans (vertical and horizontal) to precisely determines the foveal location , to avoidto avoid laser

application to this critical area. Photocoagulation is more precise than TTT for this sensitive

precise work, 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.

68.3: RECURRENT AND RESIDUAL TUMORS:

OCT can detect subclinical tumor edge recurrences. OCT can differentiate between gliosis tumor

calcification and homogenous potential active tumor associated with scars. Comparison between

of successive OCT scans of the same area between EUAs can detect subtle tumor

recurrencedifferences . (Figure 4), facilitating early, less intensive This potentiate less

treatments (burden regarding laser power, number of sessions) and improved final outcomes.

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.

Whiteish treatment scars previously posed a clinical challenge to determine distinguish whether

it is a tumorresidual or recurrennt tumor and gliosis. residual, recurrence or a fibrosis. This was

usually managed either byWith OCT, more laser treatment can be delivered with precision to

specific areas of recurrence instead of the whole scar, reducing risk of excessive scarring and

retinal draggingwith the possibility of more scarring and traction. When OCT images suggest

stability, o or observation can be undertaken without the potential danger of tumor growth

requiring more increased 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 uveal effusion and exudative detachment associated

potential with cryotherapy associated uveal effusion and exudative detachment. Flat Shallow pre-

equatorial tumors are usuallymay be treated with 532 nm laser photocoagulation for one or two

sessions. More Elevated pre-equatorial tumors might require multiple laser treatments as the

laser beam is not able to apply perpendicular to the tumor cannot be treated equally as the inward

curve of the tumor cannot be thoroughly painted with a trans-pupillary laserapproach. In

subsequent sessions with more outward flattening of the tumor, the inward curvetumor can be

better visualized and treated.

Despite challengingWith expertise, peripheral OCT can assess tumor elevation, differentiate

scarring from residual tumors and identify peripheral potential tumor seeding (Figure 5). In

certain tumors, Llaser can be utilized as an initial belt like treatment to surrounding the tumor

with a barrier to retinal detachment as a preparatory step prior to cryotherapy, or plaque

radiotherapy or pars plana vitrectomy.{Zhao, 2017 #20057} Peripheral Laser can be also used to

ablate for potential ischemic or potentially ischemic retina peripheral isolated by to an extensive

tumor scar to prevent protect againstdevelopment of neovascularization and probable subsequent

vitreous hemorrhage. As a general rule, a smaller spot size is required in peripheral lesions to

prevent iris injury.

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 retinoblastoma tumor control after initial reduction

in size by chemotherapy size reduction. In spite of this factHowever, lLaser was never

properlynot been studied in any clinical triala randomized controlled fashion to set evidence.

Improved tumor visualization and assessment Introduction ofby OCT improved tumor

visualization and assessment improvingopens the door to precision our laser strategies treatments

of smaller tumors and recurrence, potentially improving cancer outcomes, reducing invasive

procedures, and and minimizingreducing complications.

Expert Commentary

I would include something related to the future of OCT guided laser.

BG will do next.

Five year view

Imaging technology are continuing to rapidly improve. Soon wide-angle fundus imaging will be

combined with There is huge advance in Imaging technology that will allow incorporation of

fundus imaging and OCT in hand-held units appropriate for children under anaesthetic. Perhaps

in five years, laser therapy will also be able to be delivered in on tool, guided directly by both

fundus image and OCT cross-section to allow quick and accurate laser delivery. the

incorporation of Laser therapy within this machine is expected to follow to facilitate better

aiming and improve the reproducibility of Laser techniques.

References

1. Dimaras, H., et al., Retinoblastoma. Nat Rev Dis Primers, 2015. 1: p. 15021.2. Kivela, T., The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an

issue of birth and death. Br J Ophthalmol, 2009. 93(9): p. 1129-31.3. Gallie, B.L. and S. Soliman, Retinoblastoma, in Taylor and Hoyt's Paediatric Ophthalmology and

Strabismus, B. Lambert and C. Lyons, Editors. 2017, Elsevier, Ltd.: Oxford, OX5 1GB, United Kingdom. p. 424-442.

4. Soliman, S.E., et al., Genetics and Molecular Diagnostics in Retinoblastoma--An Update. Asia Pac J Ophthalmol (Phila), 2017. 6(2): p. 197-207.

5. Yousef, Y.A., et al., Intra-arterial Chemotherapy for Retinoblastoma: A Systematic Review. JAMA Ophthalmol, 2016.

6. Scelfo, C., et al., An international survey of classification and treatment choices for group D retinoblastoma. Int J Ophthalmol, 2017. 10(6): p. 961-967.

7. Soliman, S.E., et al., Optical Coherence Tomography-Guided Decisions in Retinoblastoma Management. Ophthalmology, 2017.

8. Maiman, T.H., Stimulated Optical Radiation in Ruby. Nature, 1960. 187(4736): p. 493-494.9. Eichhorn, M., Laser physics : from principles to practical work in the lab. 1st edition. ed.

Graduate texts in physics. 2014, New York: Springer. pages cm.10. Niederer, P. and F. Fankhauser, Theoretical and practical aspects relating to the photothermal

therapy of tumors of the retina and choroid: A review. Technol Health Care, 2016. 24(5): p. 607-26.

11. Krauss, J.M. and C.A. Puliafito, Lasers in ophthalmology. Lasers Surg Med, 1995. 17(2): p. 102-59.12. Abramson, D.H., The focal treatment of retinoblastoma with emphasis on xenon arc

photocoagulation. Acta Ophthalmol Suppl, 1989. 194: p. 3-63.13. Augsburger, J.J. and C.B. Faulkner, Indirect ophthalmoscope argon laser treatment of

retinoblastoma. Ophthalmic Surg, 1992. 23(9): p. 591-3.14. Friberg, T.R., Principles of photocoagulation using binocular indirect ophthalmoscope laser

delivery systems. Int Ophthalmol Clin, 1990. 30(2): p. 89-94.15. Kitzmann, A.S., et al., A survey study of musculoskeletal disorders among eye care physicians

compared with family medicine physicians. Ophthalmology, 2012. 119(2): p. 213-20.16. Mainster, M.A., et al., Ophthalmoscopic contact lenses for transpupillary thermotherapy. Semin

Ophthalmol, 2001. 16(2): p. 60-5.17. Blumenkranz, D.P.a.M.S., Chapter 39. Retinal Laser Therapy: Biophysical Basis and Applications,

in Retina, S.J. Ryan, Editor. 2013, Saunders, Elsevier Inc.: China. p. 746-760.18. Mainster, M.A., et al., Retinal laser lenses: magnification, spot size, and field of view. Br J

Ophthalmol, 1990. 74(3): p. 177-9.19. Peyman, G.A., K.S. Naguib, and D. Gaasterland, Trans-scleral application of a semiconductor

diode laser. Lasers Surg Med, 1990. 10(6): p. 569-75.20. McHugh, D.A., et al., Diode laser contact transscleral retinal photocoagulation: a clinical study.

Br J Ophthalmol, 1995. 79(12): p. 1083-7.21. Abramson, D.H., C.A. Servodidio, and M. Nissen, Treatment of retinoblastoma with the

transscleral diode laser. Am J Ophthalmol, 1998. 126(5): p. 733-5.22. Rem, A.I., et al., Temperature dependence of thermal damage to the sclera: exploring the heat

tolerance of the sclera for transscleral thermotherapy. Exp Eye Res, 2001. 72(2): p. 153-62.23. Rem, A.I., et al., Transscleral thermotherapy: short- and long-term effects of transscleral

conductive heating in rabbit eyes. Arch Ophthalmol, 2003. 121(4): p. 510-6.

24. Mainster, M.A., Wavelength selection in macular photocoagulation. Tissue optics, thermal effects, and laser systems. Ophthalmology, 1986. 93(7): p. 952-8.

25. Rol, P., et al., Transpupillar laser phototherapy for retinal and choroidal tumors: a rational approach. Graefes Arch Clin Exp Ophthalmol, 2000. 238(3): p. 249-72.

26. Abramson, D.H. and A.C. Schefler, Transpupillary thermotherapy as initial treatment for small intraocular retinoblastoma: technique and predictors of success. Ophthalmology, 2004. 111(5): p. 984-91.

27. Peyman, G.A., et al., Transpupillary thermotherapy threshold parameters: effect of indocyanine green pretreatment. Retina, 2003. 23(3): p. 378-86.

28. Al-Haddad, C.E., et al., Indocyanine Green-Enhanced Thermotherapy for Retinoblastoma. Ocul Oncol Pathol, 2015. 1(2): p. 77-82.

29. Hasanreisoglu, M., et al., Indocyanine Green-Enhanced Transpupillary Thermotherapy for Retinoblastoma: Analysis of 42 Tumors. J Pediatr Ophthalmol Strabismus, 2015. 52(6): p. 348-54.

30. Francis, J.H., et al., Indocyanine green enhanced transpupillary thermotherapy in combination with ophthalmic artery chemosurgery for retinoblastoma. Br J Ophthalmol, 2013. 97(2): p. 164-8.

31. Fabian, I.D., et al., Focal laser treatment in addition to chemotherapy for retinoblastoma. Cochrane Database Syst Rev, 2017. 6: p. CD012366.

32. Hamel, P., et al., Focal therapy in the management of retinoblastoma: when to start and when to stop. J AAPOS, 2000. 4(6): p. 334-7.

33. Jacobsen, B.H., et al., Orbital Recurrence following Aggressive Laser Treatment for Recurrent Retinoblastoma. Ocul Oncol Pathol, 2015. 2(2): p. 76-9.

34. Shields, C.L., et al., Thermotherapy for retinoblastoma. Arch Ophthalmol, 1999. 117(7): p. 885-93.

35. Lee, T.C., et al., Chorioretinal scar growth after 810-nanometer laser treatment for retinoblastoma. Ophthalmology, 2004. 111(5): p. 992-6.

36. de Graaf, P., et al., Atrophic chorioretinal scar and focal scleral bowing following thermochemotherapy with a diode laser for retinoblastoma. Ophthalmic Genet, 2006. 27(1): p. 33-5.

37. Meyer-Schwickerath, G., [New Methods for the Treatment of Intraocular Tumors]. Munch Med Wochenschr, 1964. 106: p. 1974-6.

38. Shields, J.A. and J.J. Augsburger, Current approaches to the diagnosis and management of retinoblastoma. Surv Ophthalmol, 1981. 25(6): p. 347-372.

39. Shields, J.A., The expanding role of laser photocoagulation for intraocular tumors. The 1993 H. Christian Zweng Memorial Lecture. Retina, 1994. 14(4): p. 310-22.

40. Lagendijk, J.J., A microwave heating technique for the hyperthermic treatment of tumours in the eye, especially retinoblastoma. Phys Med Biol, 1982. 27(11): p. 1313-24.

41. Lumbroso, L., et al., [Diode laser thermotherapy and chemothermotherapy in the treatment of retinoblastoma]. J Fr Ophtalmol, 2003. 26(2): p. 154-9.

42. Shields, C.L., et al., Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma [see comments]. Ophthalmology, 1997. 104(12): p. 2101-11.

43. Inomata, M., et al., In vitro thermo- and thermochemo-sensitivity of retinoblastoma cells from surgical specimens. Int J Hyperthermia, 2002. 18(1): p. 50-61.

44. Lumbroso, L., et al., Chemothermotherapy in the management of retinoblastoma. Ophthalmology, 2002. 109(6): p. 1130-6.

45. Sony, P. and S.P. Garg, Optical coherence tomography in children with retinoblastoma. J Pediatr Ophthalmol Strabismus, 2005. 42(3): p. 134; author reply 134-5.

46. Shields, C.L., M.A. Materin, and J.A. Shields, Review of optical coherence tomography for intraocular tumors. Curr Opin Ophthalmol, 2005. 16(3): p. 141-54.

47. Scott, A.W., et al., Imaging the infant retina with a hand-held spectral-domain optical coherence tomography device. Am J Ophthalmol, 2009. 147(2): p. 364-373 e2.

48. Maldonado, R.S., et al., Optimizing hand-held spectral domain optical coherence tomography imaging for neonates, infants, and children. Invest Ophthalmol Vis Sci, 2010. 51(5): p. 2678-85.

49. Rootman, D.B., et al., Hand-held high-resolution spectral domain optical coherence tomography in retinoblastoma: clinical and morphologic considerations. Br J Ophthalmol, 2013. 97(1): p. 59-65.

50. Berry, J.L., D. Cobrinik, and J.W. Kim, Detection and Intraretinal Localization of an 'Invisible' Retinoblastoma Using Optical Coherence Tomography. Ocul Oncol Pathol, 2016. 2(3): p. 148-52.

51. Hasanreisoglu, M., et al., Spectral Domain Optical Coherence Tomography Reveals Hidden Fovea Beneath Extensive Vitreous Seeding From Retinoblastoma. Retina, 2015. 35(7): p. 1486-7.

52. Yousef, Y.A., et al., Detection of optic nerve disease in retinoblastoma by use of spectral domain optical coherence tomography. J AAPOS, 2012. 16(5): p. 481-3.

53. Berry, J.L., K. Anulao, and J.W. Kim, Optical Coherence Tomography Imaging of a Large Spherical Seed in Retinoblastoma. Ophthalmology, 2017. 124(8): p. 1208.

54. Fuller, T.S., R.A. Alvi, and C.L. Shields, Optical Coherence Tomography of Cavitary Retinoblastoma. JAMA Ophthalmol, 2016. 134(5): p. e155355.

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

Magnificatio

n

Laser Spot

Magnificatio

n

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 ContactReal, inverted

image in air

20 D BIO 3.13X 0.32X 46 60Non-

contact

Real, inverted,

laterally

reversed

Pan-retinal

2.2 BIO2.68X 0.37X 56 73

Non-

contact

Real, inverted,

laterally

reversed

28 D BIO 2.27X 0.44X 53 69Non-

contact

Real, inverted,

laterally

reversed

D= Diopter; BIO= Binocular indirect ophthalmoscopy