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Precision Laser Therapy for Retinoblastoma
Authors:
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,
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 brenda@gallie.ca
Type of article: Review and Expert commentary
Word limit: (/7000)
Tables and Figures: 6 figures and 2 tables.
Financial disclosure: None of the authors has any conflicting interests
Abstract
Introduction–Laser therapy is a cornerstone for control of intraocular
retinoblastoma, after chemotherapy has brought the disease under initial control.
Since first described over 6 decades ago, laser technologies and approaches have
evolved to improve tumor control. Despite its important role, few publications
describe techniques, types of lasers, and modes of delivery for retinoblastoma.
Areas covered–The physical and optical properties of lasers, mechanisms of
action, delivery systems, complications, are described. Hand-held optical coherence
tomography (OCT) detects microscopic retinoblastoma tumors and guides treatment,
achieving precision primary therapy and elimination of recurrences.
Expert commentary–In all the excitement of new therapies to cure intraocular
retinoblastoma, laser treatment always compliments but is rarely mentioned. Hand-
held OCT now adds precision to put laser in the forefront in achieving cure of
retinoblastoma.
Summary
This review discusses laser therapy for intraocular retinoblastoma and highlights the
role of optical coherence tomography in improving laser therapy to precision levels.
Keywords
Retinoblastoma; laser therapy; hand-held optical coherence tomography; precision
medicine; primary tumor detection; early recurrence intervention.
1. Introduction
Retinoblastoma is the most common intraocular malignancy, initiated by mutations
in both copies of the retinoblastoma gene (RB1 gene) [1]. Worldwide, 8000 children
are newly diagnosed annually. Survival approaches 100% if retinoblastoma is
diagnosed and treated while still intraocular, but when retinoblastoma is extraocular,
children have poor survival [1, 2]. The fundamental primary goal of treating cancer is
life salvage, and for retinoblastoma vision salvage is a secondary goal. Salvage of an
eye without visual potential may be dangerous since unrecognized recurrence of the
cancer, can leads to extraocular extension and loss of life [3].
Despite the recent advances and new treatment modalities, the primary 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 [4-6].
Laser is appropriate as primary therapy only for small tumors. Techniques of
laser therapy are rarely described making it difficult to study or learn outside an
apprenticeship situation. Choice of laser wavelength is variable according to
experience and availability. 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 [7, 8].
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 [5, 9].
2. Physics of laser
Einstein 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 [10]. The
acronym LASER represents the underlying fundamental quantum-mechanical
principals involved: Light Amplification by Stimulated Emission of Radiation [11].
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 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 cavity 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 [11].
Lasers are typically categorized by their active medium, which determines the
laser beam wavelength. For all lasers, the wavelength multiplied by the frequency of
oscillation equals the speed of light. Therefore, as the laser 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 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 [12]. All lasers have the
option to control the shot pace or inter-shot interval, according to the experience of
treating ophthalmologist. In general, trainees start with single shots or a longer inter-
shot interval.
3. Types of lasers for retinoblastoma
Xenon arc photocoagulation, first described by Meyer-Schwickerath in 1956, was the
earliest photocoagulation method adopted for treatment of retinoblastoma [13, 14].
Xenon emission is white light, a mixture of wavelengths between 400 and 1600 nm
and results in full-thickness burns without selectively targeting ocular tissues. It is
now replaced by laser photocoagulation for retinoblastoma.
The commonest lasers used for focal therapy in retinoblastoma are 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. While all three lasers
can be delivered with use of an indirect ophthalmoscope, the infrared lasers can also
be applied in a trans-scleral manner, particularly useful for anteriorly located tumors.
The 532 nm and 810 nm lasers can treat tumor by photocoagulation. 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 [12]. Table 1
demonstrates the main differences between the different types of laser in
retinoblastoma.
4. Laser delivery
Retinal laser treatments can be delivered by either binocular indirect ophthalmoscopy
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).
4.1. Laser indirect ophthalmoscopy (LIO).
LIO was first described to treat retinoblastoma in 1992 [15]. LIO 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, the lower the image magnification and the greater the field of view.
The laser spot size on the retina is minimized (with most power) at the focal point, a
specific distance from the indirect ophthalmoscope, and diverges closer and farther
from the focal point. Effect depends on power, relative positions of the headset and
lenses, light scattering by ocular media, and 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. Retinal spot size can be calculated by power of the condensing
aspheric lens multiplied by image plane spot size divided by 60 [16]. However, LIO
requires careful optimization and coordination of the inherent instability of the
patient’s eye, the clinician’s head, and simultaneous foot pedal depression, neck,
hand, wrist and lower back pain among ophthalmologists [17].
4.2. Microscope-mounted delivery system.
Laser may also be delivered through a slit-lamp or operating microscope: the
working 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 [16]. Tilting the contact lens within 15
degrees does not cause significant distortion of the laser spot, as irradiance differs by
maximum 6.8% [18]. 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 [19, 20]. It contains mirrors at 59, 67 and 73 degrees
to aid in visualization and treatment of the periphery [19]. However, photocoagulation
efficiency is reduced in the far periphery, as the laser follows an off-axis, oblique
trajectory. LIO is preferred for peripheral retinal laser treatments as the field of view
is greater than with a microscope-mount.
Also commonly used is the Mainster wide-field (Power +61 D) contact lens,
containing an aspheric lens in contact with the cornea and a convex lens at a fixed
distance [19, 20]. 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. Inverted image lenses may produce smaller anterior than posterior
segment laser beam diameters, 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 [18].
4.3 Trans-scleral laser therapy.
Infrared laser photocoagulation may also be delivered trans-sclerally using an optical
fiber [21, 22]. This technique was first described for the treatment of retinoblastoma in
1998 [23]. in the presence of media opacities. Trans-scleral diode also decreases the
risk of cataract formation by limiting laser transmittance through the lens [23].
5. Laser approaches for retinoblastoma
5.1. Photocoagulation
Photocoagulation is the process by which laser light energy is absorbed by a target
tissue and converted into thermal energy. A 10-20° C temperature rise induces
protein denaturation and subsequent coagulation and necrosis, depending on the
duration and extent of thermal change [13]. Heat generation is influenced by the laser
parameters and optical properties of the absorbing tissue [19]. 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 light in the visible electromagnetic spectrum, (i.e. 532 nm frequency-
doubled Nd:YAG), is largely absorbed by hemoglobin and melanin, half in the RPE
and half in the choroid [19]. Heat is conducted to the neurosensory retina, causing
inner retinal coagulation and focal necrosis, noted ophthalmoscopically as loss of
retinal transparency and a white laser burn. The 532 nm laser is near the absorption
peaks of oxyhemoglobin and deoxyhemoglobin so is taken up by retinal blood
vessels, which is countered by the cooling effect of blood flow, which has greater
velocity than stationary tissues [19]. Confluent laser burns encircling retinoblastoma
tumors may occlude capillaries and large retinal blood vessels, cutting off the tumor
blood supply [15], so photocoagulation is initiated only after systemic or intra-arterial
chemotherapy are completed.
Tumors less than 3 mm elevation (T1a/T1b) [25] may be controlled successfully
by laser without chemotherapy (Figure 1). Larger tumors (T1b/T2) [25] require
chemotherapy to initiate tumor regression, followed by laser encircling
photocoagulation to cut off blood supply and on 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 treatment as plaque
radiotherapy. In larger tumors, encircling laser with consequent obliteration of the
blood supply may lead to loss of tumor cohesiveness and early vitreous seeding
(Figure 3).
“Thermal blooming” is the process by which the photocoagulation zone may
extended beyond the laser spot size particularly with longer duration burns [19]. This
may not be clinically apparent during treatment but contributes to a larger laser scar.
When the tumor becomes white with laser photocoagulation, further penetration of
the light energy to deeper structures is prevented by light scattering [24]. Thus,
repeated laser on the same area will only increase the lateral extent of the laser
application, known as the “shielding effect” [26]. Laser photocoagulation ultimately
leads to gliosis replacing the tumor with variable retinal pigment epithelial
hyperplasia.
Infrared semiconductor diode laser (810 nm) can be used for photocoagulation in
short duration (0.7 – 1.5 seconds). It can be delivered by indirect ophthalmoscopy or
trans-scleral laser delivery. 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 (figure 4). In vitro and in vivo studies
of trans-scleral thermotherapy for choroidal melanoma suggest tumor cell destruction
occurs at a threshold of 60° C, without permanent damage to scleral collagen or
increased risk of retinal tears [27, 28].
5.2. Trans-pupillary thermotherapy
Trans-pupillary thermotherapy (TTT) involves long duration (60 seconds) laser in the
near-infrared spectrum (usually 810 nm diode) with larger spot size and lower power
than photocoagulation [19]. TTT results in deeper tissue penetration (4 mm) since
melanin absorption decreases with increasing laser wavelength. Continuous wave
1064 nm laser penetrates deeper that the 810 nm diode, important in treatment of
thicker tumors [29]. Temperatures of TTT (45 to 60° C) are lower than for
photocoagulation [30]. The endpoint of TTT is faint whitening or graying of the
tumor and visible changes may not be visible at the time of treatment [19, 30].
In 1982, Lagendijk used trans-pupillary thermotherapy (TTT) in two cases of
recurrent retinoblastoma successfully [31]. 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
[32]. 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 [30].
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. Pretreatment with intravenous indocyanine green
(ICG), a chromophore with absorption peak 805 nm complementing the diode 810
nm laser, results in photosensitization and a dose-dependent decrease in the TTT
fluency threshold and irradiance required for treatment [33]. Enhancement of the laser
effect by systemic ICG may lead to regression of tumors that have shown a
suboptimal response to systemic chemotherapy and standard TTT [34-36]. The
optimal timing between ICG injection and TTT has not been determined.
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 [37]. In fact, in a
series of 103 tumors treated with chemothermotherapy, Lumbroso et al. [38] reported
that tumor regression was seen in 96.1%. In this study, TTT was delivered shortly
after an intravenous injection of carboplatin.
5.3 Therapy combining different lasers
Retinoblastoma can be treated with a combination of photocoagulation and
thermotherapy in one 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 [9]. Unfortunately, there is no
randomized clinical trial comparing lasers and technologies to establish evidence
[39].
6. Complications of laser therapy
The most serious complications of laser therapy are usually caused by use of
excessive energy. Therefore treatments start at lower power to titrate to the desired
effect to decrease likelihood of complications. Too small a spot size, too high a
power or too short can induce an iatrogenic rupture of Bruchs’ membrane, which
might be a precursor for choroidal neovascular membrane formation. Intense
photocoagulation may result in full thickness retinal holes which may progress to
rhegmatogenous retinal detachment, or may induce vitreous seeding of
retinoblastoma [40]. OCT is useful to visualize and analyze complications.
Biopsy-proven orbital recurrence of retinoblastoma has been reported following
repeated treatment of a macular recurrence of retinoblastoma with aggressive argon
and diode laser [41]. 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.
Common less serious complications include focal iris atrophy, lenticular
opacification, retinal traction, retinal vascular obstruction and localized serous retinal
detachment [40, 42]. Scars from TTT (810 nm) are recognized to increase in size with
time [43], so using TTT may be suboptimal for tumors located near the fovea and
optic nerve. Chorioretinal scarring with focal scleral bowing is reported following
TTT [44]. Laser is ineffective in areas with any retinal detachment. OCT is useful to
delineate subtle detachments. Laser over the optic nerve can compromise nerve
fibers. The exact tumor relation to the optic nerve can be mapped by OCT to guide
accurate laser treatment near critical structures.
7. Laser guided by optical coherence tomography (OCT)
First reports of OCT focused on the appearance of retinoblastoma and differentiation
from simulating lesions [45, 46]. The hand-held OCT expanded the use to supine
children under anesthetic to image retinoblastoma tumors from diagnosis through
treatments, to eventual stability [47, 48]. OCT visualization facilitates accurate laser
therapy, revealing for example, subclinical invisible tumors [49, 50], subclinical tumor
recurrences within a scar or edge recurrences [9], topographic localization of the
foveal center [9, 51], and differentiating benign white lesions (gliosis, perivascular
sheathing of active retinoblastoma and possible optic nerve involvement) [52]. OCT
can demonstrate intraretinal tumor location (superficial, deep or diffuse infiltrating),
[9], visualize vitreous or subretinal tumor seeds,[9, 53], and determine solid or cavitary
internal architecture of retinoblastoma [54] that might affect therapeutic approach.
With skill and persistence, the hand-held OCT can be used in the mid periphery.[9].
OCT has become crucial in management decisions in retinoblastoma management
[9]. The role of OCT in each examination under anesthetic (EUA) for a child with
retinoblastoma was retrospectively determined to be directive (direct diagnosis,
treatment or follow up) in 94% (293/312) of OCT sessions, or academic. Directive
OCTs were further classified as confirmatory (confirm the pre-OCT clinical
decision) or influential (17%) (changes the pre-OCT clinical decision), highlighting
the importance of OCT in optimal retinoblastoma management.
7.1. Invisible tumors
Invisible tumors (figure 5) are anticipated in children carrying a pathogenic variant of
the RB1 tumor suppressor gene detected either prenatal or postnatal, because they
have a positive parental family history of retinoblastoma [55-57]. These children are
classified now by the 2017 Tumor Node Metastasis Heritability cancer staging for
retinoblastoma to be “H1” even if they do not yet have detectable cancer [5, 25].
Screening for invisible tumors by OCT of the posterior pole of each eye 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 subclinical tumor can be centralized in the OCT scan
and combination of calipers and anatomic landmarks (branching vessels, etc) help to
locate the invisible tumor in the retina for ablation by 532 nm laser. Photocoagulation
with low laser power (100 mW) and short pulse duration (0.5 seconds) is delivered;
gradually increasing power until whitening is noted. Post laser OCT can verify that
the laser burn(s) were in the correct location, including the tiny tumor [9].
7.2. Juxtafoveal tumors
Tumors near the fovea are a challenge to treat with focal therapy and preserve the
foveola. OCT with two OCT macular cube scans (vertical and horizontal) determines
the foveal location to avoid laser to this critical area [9]. Photocoagulation is more
precise than TTT for this sensitive precise work, to preserve vision and avoid scar
migration.[43, 58] Recently, a laser crescent photocoagulation method was described
for perifoveal tumors [Submitted]. The anti-foveal tumor crescent is photocoagulated
using 532 nm laser to obliterate the tumor blood supply that causes central tumor
flattening to be treated in sequential sessions. Additionally, the peripheral anti-foveal
scarring causes a tangential pulling force. This technique was observed to have better
anatomical and visual outcome when the fovea is OCT-detectable at initial laser
session. Furthermore, OCT can detect subtle surrounding exudative retinal
detachment that stops laser treatment initiation.
7.3. Recurrent and residual tumors
OCT can differentiate between gliosis and homogenous potential active tumor
associated with scars [9]. Comparison of OCT of the same area between EUAs can
detect subtle differences (Figure 6), facilitating early, less intensive treatments (laser
power, number of sessions) and improved outcomes. Recurrences on flat retina are
usually treated with photocoagulation with 532 nm laser. However, recurrences over
calcified tumor require longer wavelength photocoagulation. With OCT, laser can be
delivered with precision to specific areas of recurrence instead of the whole scar,
reducing risk of excessive scarring and retinal dragging. When OCT images suggest
stability, observation can be undertaken without danger of tumor growth requiring
increased treatment burden.
7.4. Pre-equatorial tumors
Pre-equatorial tumors can be treated by either photocoagulation or cryotherapy.
Laser therapy is preferred in superior tumors to avoid uveal effusion and exudative
detachment associated with cryotherapy [59, 60]. Shallow tumors may be treated with
532 nm laser photocoagulation for one or two sessions. Elevated pre-equatorial
tumors might require multiple treatments as the laser beam cannot be applied
perpendicular to the tumor with a trans-pupillary approach. In subsequent sessions
with flattening of the tumor, it can be better visualized and treated.
With expertise, peripheral OCT can assess tumor elevation, differentiate scarring
from residual tumors and identify peripheral potential tumor seeding. Laser can be
utilized to surround the tumor with a barrier to retinal detachment prior to
cryotherapy, plaque radiotherapy or pars plana vitrectomy [61]. Laser can be also
used to ablate ischemic or potentially ischemic retina isolated by extensive scar to
protect against neovascularization and subsequent vitreous hemorrhage.
Conclusions
Laser therapy is integral in retinoblastoma tumor control after initial reduction in size
by chemotherapy. However, laser was not been studied in any clinical trial. Improved
tumor visualization and assessment by OCT opens the door to precision laser
treatments of smaller tumors and recurrence, potentially improving cancer outcomes,
reducing invasive procedures, and reducing complications.
Expert Commentary
Laser therapy is a widely available, non-invasive, and relatively safe technique to destroy
residual tumor after chemoreduction (either systemic chemotherapy or IAC). It is a
necessity for posterior pole and superior tumors (especially if partially calcified) where
cryotherapy is not recommended or even contraindicated.
Despite all the recent improvements in retinoblastoma treatment, laser therapy
remains an under-reported cornerstone in tumor control after chemotherapy. Laser
therapy is one of the most frequently available modalities in low-income countries that
cannot afford expensive modalities such as IAC or plaque radiotherapy. The published
literature is deficient in details regarding methods and techniques of laser therapy making
it highly variable between centers, based on the experts’ experience. Variability in
technique and consequently the endpoint of therapy (flat scar versus stable fish flesh like
lesion) need dissemination of proper knowledge and implementation.
There is good opportunity for centers in low-income countries to utilize available
laser machines effectively for retinoblastoma. An effective way of teaching would be
videos in microscope mount laser delivery technique or pre- and post-laser wide-angle
fundus photos in indirect or trans-scleral laser delivery options. Another method would
be preoperative planning of the laser with experts via telemedicine that has proven
effective in decision-making. Laser workshops, conferences and collaborative or
twinning programs between Centers of Excellence may achieve effective utilization of
resources, to improve life, vision and eye salvage in retinoblastoma.
Hand-held OCT has improved our understanding of many aspects in retinoblastoma
diagnosis, treatment and follow-up. OCT is a powerful adjunct tool to laser, identifying
invisible tumors, distinguishing edge recurrences from scar with precise foveal
localization. Despite its cost, the hand-held OCT is important for a Center of Excellence
in retinoblastoma to achieve precision therapy for retinoblastoma. It is recommended to
improve OCT localization by sizing algorithms using calipers, blood vessels and
anatomic landmarks together with improved enhanced depth imaging to assess choroidal
structure for appreciation and differentiation of early tumor invasion versus scarring.
Five year view
Imaging technologies continue to rapidly improve. Soon wide-angle fundus imaging will
be combined with OCT in hand-held units appropriate for children under anaesthetic. In
five years, laser therapy will also be able to be delivered in one tool, guided directly by
fundus image and OCT cross-section to allow quick and accurate laser delivery.
References
1. Dimaras H, Corson TW, Cobrinik D, White A, Zhao J, Munier FL, et al. Retinoblastoma. Nat Rev Dis Primers. 2015;1:15021.2. Kivela T. The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol. 2009;93(9):1129-31.3. Canadian Retinoblastoma S. National Retinoblastoma Strategy Canadian Guidelines for Care: Strategie therapeutique du retinoblastome guide clinique canadien. Can J Ophthalmol. 2009;44 Suppl 2:S1-88.4. Gallie BL, Soliman S. Retinoblastoma. In: Lambert B, Lyons C, editors. Taylor and Hoyt's Paediatric Ophthalmology and Strabismus. 5th Edition ed. Oxford, OX5 1GB, United Kingdom: Elsevier, Ltd.; 2017. p. 424-42.5. Soliman SE, Racher H, Zhang C, MacDonald H, Gallie BL. Genetics and Molecular Diagnostics in Retinoblastoma--An Update. Asia Pac J Ophthalmol (Phila). 2017;6(2):197-207.6. Shields CL, Shields JA, DePotter P, Himelstein BP, Meadows AT. The effect of chemoreduction on retinoblastoma-induced retinal detachment. J Pediatr Ophthalmol Strabismus. 1997;34(3):165-9.7. Yousef YA, Soliman SE, Astudillo PP, Durairaj P, Dimaras H, Chan HS, et al. Intra-arterial Chemotherapy for Retinoblastoma: A Systematic Review. JAMA ophthalmology. 2016;134(6):584-91.8. Scelfo C, Francis JH, Khetan V, Jenkins T, Marr B, Abramson DH, et al. An international survey of classification and treatment choices for group D retinoblastoma. Int J Ophthalmol. 2017;10(6):961-7.9. Soliman SE, VandenHoven C, MacKeen LD, Heon E, Gallie BL. Optical Coherence Tomography-Guided Decisions in Retinoblastoma Management. Ophthalmology. 2017.10. Maiman TH. Stimulated Optical Radiation in Ruby. Nature. 1960;187(4736):493-4.11. Eichhorn M. Laser physics : from principles to practical work in the lab. 1st edition. ed. New York: Springer; 2014. pages cm p.12. Niederer P, Fankhauser F. Theoretical and practical aspects relating to the photothermal therapy of tumors of the retina and choroid: A review. Technol Health Care. 2016;24(5):607-26.13. Krauss JM, Puliafito CA. Lasers in ophthalmology. Lasers Surg Med. 1995;17(2):102-59.14. Abramson DH. The focal treatment of retinoblastoma with emphasis on xenon arc photocoagulation. Acta Ophthalmologica Supplementum. 1989;194:3-63.15. Augsburger JJ, Faulkner CB. Indirect ophthalmoscope argon laser treatment of retinoblastoma. . SO Ophthalmic-Surg. 1992(Sep. 23(9)):P 591-3.16. Friberg TR. Principles of photocoagulation using binocular indirect ophthalmoscope laser delivery systems. Int Ophthalmol Clin. 1990;30(2):89-94.17. Kitzmann AS, Fethke NB, Baratz KH, Zimmerman MB, Hackbarth DJ, Gehrs KM. A survey study of musculoskeletal disorders among eye care physicians compared with family medicine physicians. Ophthalmology. 2012;119(2):213-20.18. Mainster MA, Reichel E, Harrington PG, Erickson PJ, Graham RD. Ophthalmoscopic contact lenses for transpupillary thermotherapy. Semin Ophthalmol. 2001;16(2):60-5.19. Blumenkranz DPaMS. Chapter 39. Retinal Laser Therapy: Biophysical Basis and Applications. In: Ryan SJ, editor. Retina. I. Fifth ed. China: Saunders, Elsevier Inc.; 2013. p. 746-60.20. Mainster MA, Crossman JL, Erickson PJ, Heacock GL. Retinal laser lenses: magnification, spot size, and field of view. Br J Ophthalmol. 1990;74(3):177-9.21. Peyman GA, Naguib KS, Gaasterland D. Trans-scleral application of a semiconductor diode laser. Lasers Surg Med. 1990;10(6):569-75.
22. McHugh DA, Schwartz S, Dowler JG, Ulbig M, Blach RK, Hamilton PA. Diode laser contact transscleral retinal photocoagulation: a clinical study. Br J Ophthalmol. 1995;79(12):1083-7.23. Abramson DH, Servodidio CA, Nissen M. Treatment of retinoblastoma with the transscleral diode laser. Am J Ophthalmol. 1998;126(5):733-5.24. Mainster MA. Wavelength selection in macular photocoagulation. Tissue optics, thermal effects, and laser systems. Ophthalmology. 1986;93(7):952-8.25. Mallipatna A, Gallie BL, Chévez-Barrios P, Lumbroso-Le Rouic L, Chantada GL, Doz F, et al. Retinoblastoma. In: Amin MB, Edge SB, Greene FL, editors. AJCC Cancer Staging Manual. 8th Edition. New York, NY: Springer; 2017. p. 819-31.26. Stefansson E. The therapeutic effects of retinal laser treatment and vitrectomy. A theory based on oxygen and vascular physiology. Acta Ophthalmol Scand. 2001;79(5):435-40.27. Rem AI, Oosterhuis JA, Journee-de Korver HG, van den Berg TJ, Keunen JE. Temperature dependence of thermal damage to the sclera: exploring the heat tolerance of the sclera for transscleral thermotherapy. Exp Eye Res. 2001;72(2):153-62.28. Rem AI, Oosterhuis JA, Journee-de Korver HG, de Wolff-Rouendaal D, Keunen JE. Transscleral thermotherapy: short- and long-term effects of transscleral conductive heating in rabbit eyes. Arch Ophthalmol. 2003;121(4):510-6.29. Rol P, Fankhauser F, Giger H, Durr U, Kwasniewska S. Transpupillar laser phototherapy for retinal and choroidal tumors: a rational approach. Graefes Arch Clin Exp Ophthalmol. 2000;238(3):249-72.30. Abramson DH, Schefler AC. Transpupillary thermotherapy as initial treatment for small intraocular retinoblastoma: technique and predictors of success. Ophthalmology. 2004;111(5):984-91.31. Lagendijk JJ. A microwave heating technique for the hyperthermic treatment of tumours in the eye, especially retinoblastoma. Phys Med Biol. 1982;27(11):1313-24.32. Lumbroso L, Doz F, Levy C, Dendale R, Vedrenne J, Bours D, et al. [Diode laser thermotherapy and chemothermotherapy in the treatment of retinoblastoma]. Journal Francais D Ophtalmologie. 2003;26(2):154-9.33. Peyman GA, Genaidy M, Yoneya S, Men G, Ghahramani F, Kuo PC, et al. Transpupillary thermotherapy threshold parameters: effect of indocyanine green pretreatment. Retina. 2003;23(3):378-86.34. Al-Haddad CE, Abdulaal M, Saab RH, Bashshur ZF. Indocyanine Green-Enhanced Thermotherapy for Retinoblastoma. Ocul Oncol Pathol. 2015;1(2):77-82.35. Hasanreisoglu M, Saktanasate J, Schwendeman R, Shields JA, Shields CL. Indocyanine Green-Enhanced Transpupillary Thermotherapy for Retinoblastoma: Analysis of 42 Tumors. J Pediatr Ophthalmol Strabismus. 2015;52(6):348-54.36. Francis JH, Abramson DH, Brodie SE, Marr BP. Indocyanine green enhanced transpupillary thermotherapy in combination with ophthalmic artery chemosurgery for retinoblastoma. Br J Ophthalmol. 2013;97(2):164-8.37. Inomata M, Kaneko A, Kunimoto T, Saijo N. In vitro thermo- and thermochemo-sensitivity of retinoblastoma cells from surgical specimens. Int J Hyperthermia. 2002;18(1):50-61.38. Lumbroso L, Doz F, Urbieta M, Levy C, Bours D, Asselain B, et al. Chemothermotherapy in the management of retinoblastoma. Ophthalmology. 2002;109(6):1130-6.39. Fabian ID, Johnson KP, Stacey AW, Sagoo MS, Reddy MA. Focal laser treatment in addition to chemotherapy for retinoblastoma. The Cochrane database of systematic reviews. 2017;6:CD012366.40. Hamel P, Heon E, Gallie BL, Budning AS. Focal therapy in the management of retinoblastoma: when to start and when to stop. J AAPOS. 2000;4(6):334-7.41. Jacobsen BH, Berry JL, Jubran R, Kim JW. Orbital Recurrence following Aggressive Laser Treatment for Recurrent Retinoblastoma. Ocul Oncol Pathol. 2015;2(2):76-9.
42. Shields CL, Santos MC, Diniz W, Gunduz K, Mercado G, Cater JR, et al. Thermotherapy for retinoblastoma. Arch Ophthalmol. 1999;117(7):885-93.43. Lee TC, Lee SW, Dinkin MJ, Ober MD, Beaverson KL, Abramson DH. Chorioretinal scar growth after 810-nanometer laser treatment for retinoblastoma. Ophthalmology. 2004;111(5):992-6.44. de Graaf P, Castelijns JA, Moll AC, Imhof SM, Schouten-van Meeteren AY. Atrophic chorioretinal scar and focal scleral bowing following thermochemotherapy with a diode laser for retinoblastoma. Ophthalmic Genet. 2006;27(1):33-5.45. Sony P, Garg SP. Optical coherence tomography in children with retinoblastoma. J Pediatr Ophthalmol Strabismus. 2005;42(3):134; author reply -5.46. Shields CL, Materin MA, Shields JA. Review of optical coherence tomography for intraocular tumors. Curr Opin Ophthalmol. 2005;16(3):141-54.47. Scott AW, Farsiu S, Enyedi LB, Wallace DK, Toth CA. Imaging the infant retina with a hand-held spectral-domain optical coherence tomography device. Am J Ophthalmol. 2009;147(2):364-73 e2.48. Maldonado RS, Izatt JA, Sarin N, Wallace DK, Freedman S, Cotten CM, et al. Optimizing hand-held spectral domain optical coherence tomography imaging for neonates, infants, and children. Invest Ophthalmol Vis Sci. 2010;51(5):2678-85.49. Rootman DB, Gonzalez E, Mallipatna A, Vandenhoven C, Hampton L, Dimaras H, et al. Hand-held high-resolution spectral domain optical coherence tomography in retinoblastoma: clinical and morphologic considerations. Br J Ophthalmol. 2013;97(1):59-65.50. Berry JL, Cobrinik D, Kim JW. Detection and Intraretinal Localization of an 'Invisible' Retinoblastoma Using Optical Coherence Tomography. Ocul Oncol Pathol. 2016;2(3):148-52.51. Hasanreisoglu M, Dolz-Marco R, Ferenczy SR, Shields JA, Shields CL. Spectral Domain Optical Coherence Tomography Reveals Hidden Fovea Beneath Extensive Vitreous Seeding From Retinoblastoma. Retina. 2015;35(7):1486-7.52. Yousef YA, Shroff M, Halliday W, Gallie BL, Heon E. Detection of optic nerve disease in retinoblastoma by use of spectral domain optical coherence tomography. J AAPOS. 2012;16(5):481-3.53. Berry JL, Anulao K, Kim JW. Optical Coherence Tomography Imaging of a Large Spherical Seed in Retinoblastoma. Ophthalmology. 2017;124(8):1208.54. Fuller TS, Alvi RA, Shields CL. Optical Coherence Tomography of Cavitary Retinoblastoma. JAMA ophthalmology. 2016;134(5):e155355.55. Soliman SE, Dimaras H, Khetan V, Gardiner JA, Chan HS, Heon E, et al. Prenatal versus Postnatal Screening for Familial Retinoblastoma. Ophthalmology. 2016;123(12):2610-7.56. Soliman SE, Ulster A, MacDonald H, VandenHoven C, Toi A, Heon E, et al. Psychosocial determinants for treatment decisions in familial retinoblastoma. Ophthalmic Genet. 2017:1-3.57. Soliman SE, ElManhaly M, Dimaras H. Knowledge of genetics in familial retinoblastoma. Ophthalmic Genet. 2016:1-7.58. Fabian ID, Naeem Z, Stacey AW, Chowdhury T, Duncan C, Reddy MA, et al. Long-term Visual Acuity, Strabismus, and Nystagmus Outcomes Following Multimodality Treatment in Group D Retinoblastoma Eyes. Am J Ophthalmol. 2017;179:137-44.59. Anagnoste SR, Scott IU, Murray TG, Kramer D, Toledano S. Rhegmatogenous retinal detachment in retinoblastoma patients undergoing chemoreduction and cryotherapy. Am J Ophthalmol. 2000;129(6):817-9.60. Shields JA, Shields CL, De Potter P. Cryotherapy for retinoblastoma. Int Ophthalmol Clin. 1993;33(3):101-5.61. Zhao J, Li Q, Wu S, Jin L, Ma X, Jin M, et al. Pars Plana Vitrectomy and Endoresection of Refractory Intraocular Retinoblastoma. Ophthalmology. 2017.
Figure Legends:
Table 1: Comparison between lasers in retinoblastoma.
Frequency-doubled Nd-YAG Semiconductor Diode Continuous wave Nd-YAG
Type of laser Green Infrared Far Infrared
Wave length 532 nm 810 nm 1064nm
Delivery Trans-pupillary Trans-pupillary or trans-scleral Trans-pupillary
Mechanism Photocoagulation Photocoagulation or Thermotherapy Thermotherapy
Penetration
Superficial (~2 mm in non-pigmented tumors) [12] limited
by resultant coagulation and shorter wavelength [40].
Deep (4.2 and 5.1mm respectively) primary anatomical site of action is in the choroid. Penetration decreases in necrotic
tumors [12].
ParametersPower: 0.3 – 0.8 W Power: 0.3-1.5 W Power: 1.4 – 3.0 W
Duration: 0.5-0.7 seconds Duration: 0.5-2.5 seconds Duration: 1 second
Clinical endpoint
Increase power by 0.1W increments until tumor/retinal
whitening visible [40]
Slight graying of retina without causing vascular spasm [30, 42]
Table 2. Types of contact and non-contact fundus lenses [15, 18, 19]
Lens TypeMagnification Field of View (°)
Image CharacteristicsImage Laser spot Static Dynamic
Contact Lenses
Goldmann 3-Mirror Universal 0.93X 1.08X 36 74 (15° tilt) Virtual, erect and near
posterior lens capsule
Ocular Mainster Wide Field 0.67X 1.50X 118 127 Real, inverted image in air
Non-Contact Lenses20 D BIO 3.13X 0.32X 46 60
Real, inverted, laterally reversed22 D BIO 2.68X 0.37X 56 73
28 D BIO 2.27X 0.44X 53 69D= Diopter; BIO= Binocular indirect ophthalmoscopy
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