Laser Therapy for Retinoblastoma in the Era of Optical Ccoherence Ttomography

Authors:

Sameh Soliman, Stephanie Kletke, Kelsey Roelofs, Cynthia VandenHoven, Leslie Mckeen,

Brenda Gallie

Type of article: Review

Word limit:

Tables and Figures:

Keywords:

Abstraarct

Key issues

Introduction (SAMEH)

On RB incidence and genetics (1 paragraph)

Very general paragraph on management of RB

Why laser therapy needs revisiting?

Retinoblastoma is the most common pediatric intraocular malignancy that occur secondary to

mutations in both copies of the retinoblastoma gene (RB1 gene).[1] Worldwide, approximately

8000 new patients present. Survival is very high approaching 100% if retinoblastoma presented

while still intraocular.[1, 2] The mainstay of therapy is tumor size reduction via chemotherapy

cycles (either systemic, intrarterial or periocular chemotherapy) followed by focal therapy in the

form of laser or cryotherapy according to tumor location and size. Chemotherapy is never

sufficient alone to control tumor without focal consolidation.[3, 4] Despite that, the role of laser

therapy is frequently undermined while presenting outcomes of recent treatment modalities as

intraarterial and intravitreal chemotherapy.[5, 6]

Optical coherence tomography (OCT) has revolutionized our perspective of variable retinal

disorders including retinoblastoma by allowing more detailed anatomical evaluation of the

retinal layers and tumor architecture. OCT allowed visualizing subclinical new tumors and tumor

recurrences. It differentiated tumor from gliosis during scar evaluation. It allowed better

perception of important anatomic landmarks as the fovea and optic nerve. [4, 7]

In the current review, the authors will review the role of different lasers in management of

retinoblastoma. They will elaborate on OCT guided laser therapy precision.

Body

[1.] PHYSICS OF LASERPhysics of laser: including sources and definition of laser

parameters. (KELSEY)

Although Einstein initially postulated the concept behind the stimulated emission process

upon which lasers are based in 1917, it was not until 1960 that T.H. Maiman performed the first

experimental demonstration of a ruby(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 whichpump, 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 monochromiatic (one color), coherent (in-phase) and

collimated (light waves aligned). Mirrors at either end of the resonance cavity reflect photos

traveling parallel to the cavities axis whichaxis, 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 what determines the laser

wavelength. Broad categories of lasers include solid state, gas, excimer, dye and semiconductor.

Semiconductor lasers used in ophthalmology include the diode laser used to perform

transpupillary thermotherapy (TTT) (810nm) and solid-state lasers such as the neodymium

(Nd):YAG (yttrium-aluminum-garnet) (1064nm). Frequency doubling of the Nd:YAG results in

a halving of the wavelength, producing the green (532nm) laser.

The power of a laser is expressed in watts (W) which), 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 laser machines has 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 single shots or a

longer inter-shot interval. Semiconductor lasers used in ophthalmology include the diode laser

used to perform transpupillary thermotherapy (TTT) (810nm) and solid-state lasers such as the

neodymium (Nd):YAG (yttrium-aluminum-garnet) (1064nm). Frequency doubling of the

Nd:YAG results in a halving of the wavelength, producing the green (532nm) laser.

[2.] Types of laser: 532, 810 and 1064.TYPES OF LASERS FOR

RETINOBLASTOMA: (KELSEY)

The commonest lasers used for focal therapy in retinoblastoma include the green (532nm)

frequency doubled Nd:YAG neodymium (Nd):YAG (yttrium-aluminum-garnet), the 1064nm

continuous wave Nd:YAG laser and the 810nm semiconductor infrared indirect or transcleral

diode laser. While all three lasers can be deliverddelivered with use of an indirect

ophthalmoscope, the 810nm diode laser can also be applied in a trans-scleral manner which can

be particularly useful for anteriorlymanner, which can be particularly useful for anteriorly,

located tumors. Of the three, the green 532nm laser has the most superficial depth of penetration

as it works by a photocoagulative manner whichmanner, which serves to limit tissue penetration.

This contrasts with both the 810nm and 1064nm lasers which act primarily by raising choroidal

temperature (hyperthermia and thus called thermotherapy) in a subthresholdsub-threshold

manner. Table 1 demonstrates the main differences between the different types of laser in

retinoblastoma.

[3.] Laser Delivery TechniquesLASER DELIVERY: (STEPHANIE)

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).

Laser indirect ophthalmoscopy was first described to treat retinoblastoma in 1992.[11] BIO

combined with scleral depression is the most 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 of the focal point. It therefore depends on the power, relative positions of the headset

and BIO lenses, amount of light scattering by ocular media, as well as 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.[12] The retinal spot size can be calculated by (Power of the condensing

aspheric lens x Image plane spot size) / 60.[12] BIO is preferred for peripheral retinal laser

treatments as the field of view is greater than with microscope-mounted laser. However, caution

must be exercised as BIO 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.

[12] Owing to the technique of Laser delivery and the relatively long treatment, the treating

physician neck is at risk of ligamentous injury and cervical disc prolapse.

A microscope-mounted delivery system connects the laser with the slit-lamp or operating

microscope. While the working distance for BIO 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.[12] Tilting

the contact lens within 15 degrees does not cause significant distortion of the laser spot, as

irradiance differs by maximum 6.8%.[13] 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.[14, 15] It contains mirrors at 59, 67 and 73 degrees to aid in

visualization of the periphery.[14] However, photocoagulation efficiency is reduced in the far

periphery, as the laser follows an off-axis, oblique trajectory. 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.[14, 15] 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.[13]

Table 2. Types of contact and non-contact fundus lenses [14, 16, 17]

Image Magnificatio

n

Laser Spot Magnificatio

n

Static Field of View (°)

Dynamic Field of View (°)

Contact or Non-contact

Image Characteristics

Goldmann Three-Mirror

Universal

0.93X 1.08X 3674

(with 15° tilt)

Contact

Virtual, erect image located near posterior lens capsule

Ocular Mainster

Wide Field0.67X 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

[4.] Mechanisms of Laser: Photocoagulation versus ThermotherapyMECHANISMS OF

LASER THERAPY: (STEPHANIE)

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.[16] Heat generation is influenced by the laser parameters and optical properties

of the absorbing tissue.[14] 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.[17]

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.[14] Heat is then conducted to the neurosensory retina, causing inner retinal

coagulation and focal increase in necrotic cells. 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.[14] Confluent laser burns encircling

retinoblastoma tumors occlude large retinal blood vessels and other feeder vessels may require

supplementary treatment.[11] In larger tumors, encircling photocoagulation may lead to earlier

tumor seeding into the vitreous secondary to obliteration of blood supply and starting tumor

necrosis and loss of tumor compactness. (Figure 1)

“Thermal blooming” is the process by which the photocoagulation zone may be extended

beyond the laser spot size with longer durations.[14] This may not be clinically apparent during

treatment and is one factor contributing to increased size of the laser scar post-operatively. When

a whitish response to the laser is noted, further penetration of the light energy to deeper

structures is prevented by light scattering.[17] Thus, retreatments only increase the lateral extent

of the laser application, known as the “shielding effect”. Laser photocoagulation ultimately leads

to scarring, gliosis and variable RPE hyperplasia.

4.2. TRANS-PUPILLARY THERMOTHERAPY: (TTT)

TTT has also been applied to retinal tumors to achieve localized tissue apoptosis. It involves

continuous 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.[14] This 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 for 810-nm diode and 532-nm lasers, which is important when

considering treatment of thicker tumors.[18] Resultant temperature rises are lower than for

classic photocoagulation (45 to 60 degrees Celsius).[19] The endpoint of TTT is faint whitening

or graying of the tumor and prominent laser changes may not be visible at the time of treatment.

[14, 19] This is dependent on fundus pigmentation and laser parameters. Complications of TTT

reported following treatment of retinoblastoma include chorioretinal scarring with focal scleral

bowing.[20]

4.3 SEQUENTIAL LASER THERAPY:

Certain tumors especially large central juxtafoveal and perifoveal tumors might necessitate

combination of both photocoagulation and thermotherapy in successive or sequential treatments.

The tumor border and periphery are treated with 532 nm Laser. 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.[21]

[5.] Techniques of laser (encircling Vs tumor painting Vs both) (SAMEH)

[6.] OCT introduction in RB (Benefits) (SAMEH)OPTICAL COHERENCE

TOMOGRAPHY 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.[22, 23] 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.[24, 25] This allowed

visualization of a multitude of situations that can affect and guide laser therapy as

subclinical invisible tumors,[26, 27] subclinical tumor recurrences either within a

previous scar or edge recurrences,[7] topographic localization of foveal center,[7, 28]

differentiating whitish lesions such as gliosis and perivascular sheathing from active

retinoblastoma and possible optic nerve involvement.[29] 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, 30] It can also

determine the internal architecture of retinoblastoma whether solid or cavitary[31] that

might affect our therapy approach. (Figure 2) Despite very difficult, OCT can be used to

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

specialist.[7]

1.[7.] Potential OCT guided laser tips (SAMEH)

a. Laser for invisible tumors

b. Laser for JF and PF tumors

c. Laser for recurrences

d. OCT mapping for tumor activity

2.[8.] Laser in special circumstances in RB: (SAMEH, BRENDA)

a. Peripheral tumors

b. Ischemic areas

c. Superior tumors

d. Associated retinal detachment

e. Isolated large vitreous seed

3.[9.] Complications of Laser Therapy (KELSEY)

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. 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] Additional complications can include focal iris atrophy, lenticular

opacification, retinal traction, retinal vascular obstruction and localized serous retinal

detachment.[32, 33] Additionally, scars from TTT (810nm) have been shown to increase in

size after treatment for retinoblastoma[34] and as such, one must be cautious in using this

laser for tumors located near the fovea and optic nerve.

4.[10.] Contraindications of Laser therapy (SAMEH, BRENDA)

Conclusions

Expert Commentary

Five year view

References

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25. 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.

26. 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.

27. 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.

28. 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.

29. 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.

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Table 1: Comparison between Lasers in retinoblastoma.

Type of laser

Green532nm

Diode810nm

Continuous wave 1064nm

Frequency-doubled Nd-YAGSolid State

Semi-conductor Nd-YAGSolid 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 WDuration: 0.3-0.4 seconds

Power: 0.3-1.5 WDuration: 0.5 – 1.5 seconds

Power: 1.4 – 3.0 WDuration: 1 second

Clinical endpoint

Increase power by 0.1W increments until tumor/retinal whitening visible[32]

Slight graying of retina without causing vascular spasm [19, 33]

Table 2. Types of contact and non-contact fundus lenses [11, 13, 14]

Image Magnificatio

n

Laser Spot Magnificatio

n

Static Field of View (°)

Dynamic Field of View (°)

Contact or Non-contact

Image Characteristics

Goldmann Three3-Mirror

Universal

0.93X 1.08X 3674

(with 15° tilt)

Contact

Virtual, erect image located near posterior lens capsule

Ocular Mainster

Wide Field0.67X 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

Define