Enhancing Vision and visual potential for perifoveal
retinoblastoma using after optical coherence tomographic guided
sequential laser photocoagulation Comment by Sameh Soliman:
Reviewer 1the title (and précis) suggests that the OCT-guided laser
allows for enhanced outcomes in eyes with perifoveal tumors. This
is misleading. If the authors wish to prove this statement, it
would be advisable to have two comparison groups: one without OCT
guidance and one with OCT guidance.
Sameh E. Soliman, MD,1,2 * Cynthia VandenHoven, BAA, CRA,1
Leslie D. MacKeen, BSc,1 Brenda L. Gallie, MD, FRCSC.1,3-5
Authors affiliations
1 Department of Ophthalmology and Vision Sciences, Hospital for
Sick Children, Toronto, Canada.
2 Department of Ophthalmology, Faculty of Medicine, University
of Alexandria, Alexandria, Egypt.
3 Department of Ophthalmology & Vision Sciences, Faculty of
Medicine, University of Toronto, Toronto, Ontario, Canada.
4 Departments of Molecular Genetics and Medical Biophysics,
Faculty of Medicine, University of Toronto, Toronto, Ontario,
Canada.
5 Division of Visual Sciences, Toronto Western Research
Institute, Toronto, Ontario, Canada.
*Corresponding author: Sameh E. Soliman, 555 University Avenue,
room 7265, Toronto, ON, M5G 1X8. [email protected]
Running head: Visual potential in perifoveal retinoblastoma
Word count: 2609/2500 words
Numbers of figures and tables: 3 figures and 2 tables and 2
online only figures
Key Words: retinoblastoma, optical coherence tomography, laser,
cancer
At a glance (33/35)
Precise OCT-guided sequential laser photocoagulation, guided by
OCT, achieved enhanced good vision and visual potential in eyes
with perifoveal retinoblastoma, and better outcomes (anatomical
vision potential, visual acuity, and no recurrences) with
juxtafoveal than foveolaral tumors. Comment by Sameh Soliman:
Reviewer 1the title (and précis) suggests that the OCT-guided laser
allows for enhanced outcomes in eyes with perifoveal tumors. This
is misleading. If the authors wish to prove this statement, it
would be advisable to have two comparison groups: one without OCT
guidance and one with OCT guidance.
Abstract: (250/250)
Background/Aims: To assess tumor control, vision and anatomical
visual potential in eyes with perifoveal retinoblastoma treated by
sequential photocoagulation from the anti-foveal tumor edge inwards
toward the fovea, avoiding direct treatment near the fovea.
Patients were ; monitored for tumor control, foveal and perifoveal
anatomy at each treatment session by optical coherence tomography
(OCT),; and treated for amblyopia when the other eye had better
vision.
Methods: All eyes between 1/1/2011 and 31/5/2017 with perifoveal
retinoblastoma treated with laser therapy after chemotherapy
between 1/1/2011 and 31/5/2017 post-chemotherapy for juxtafoveal
(no underlying tumorfovea clear of tumor but and <<3000 µm
from tumor edge) or foveolaral retinoblastoma (has underlying tumor
underlying fovea) were retrospectively reviewed for tumor control
without recurrence,; anatomical success (foveal pit preservation
and/or restoration with ≥500 µm perifoveal retina free of tumor and
scar),; and functional success (acceptable (>0.1 decimal) or
good (>0.3 decimal) visual acuity (VA)).
Results: Twenty-two eyes (14 juxtafoveal, 8 foveolar al tumors)
of 20 patients (19 bilateral, 1 familial and 11 females) were
included. No jJuxtafoveal tumors had tumor recurrence and 13/14
showed foveal pit preservation (13/14), with ≥500 µm (mean 595 µm)
of perifoveal retina tumor free (13/14, mean 595 µm), no tumor
recurrences. Foveolaral tumors had significant worse anatomical
outcomes: failure to restore foveal pit or perifoveal retina (8/8,
p=0.001) and more tumor recurrences (5/8, p=0.001). Functional
success with acceptable VA was achieved in 12/14 juxtafoveal and
5/8 foveal tumors eyes (p=0.01). Amblyopia therapy data were
insufficient to evaluate impact on VA.
Conclusions: Anatomical visual potential and functional vision
were better in juxtafoveal than foveolaral retinoblastoma treated
with foveal-sparing laser photocoagulation guided by OCT. The role
of amblyopia therapy requires a prospective study.
IntroductionComment by Sameh Soliman: Reviewer 1: There is
nothing original about these results. A perifoveal tumor would
require laser to the foveal, in contrast to a juxtafoveal tumor
that may spare part of the foveal. It is not clear that we need a
study or a manuscript to prove what is obvious from logic or what
has been previously published: i.e. that a tumor involving the
fovea and therefore laser to the fovea would have worse structural
and functional outcomes. The authors even state this themselves,
“Some eyes with juxtafoveal tumors had better visual outcomes than
those with foveal tumors. This is expected, as there is more tumor
involvement of the foveal center in foveal tumors.”
Retinoblastoma management has recently evolved to include
precision diagnostic and therapeutic tools including molecular
diagnosis,1 optical coherence tomography (OCT),2 intravitreal
chemotherapy3,4 and intra-arterial chemotherapy (IAC),5,6 resulting
in increased eye salvage and potential for vision.
Chemoreduction (systemic or IAC) for macular retinoblastoma is
rarely sufficient to the cancer. Frequently, consolidation laser
therapy is required to control residual tumor but risks deleterious
effect on vision.7,8 Cryotherapy and plaque radiotherapy are less
practical options for visual preservation.9,10 Enhancing visual
potential relies on achieving the best possible anatomical and
functional outcome. Visual potential depends on tumor relation to
the fovea and optic nerve, tumor regression pattern after
chemotherapy (systemic or intra-arterial), resultant post-laser
scarring, and status of other eye and early amblyopia therapy if
the other eye has better vision. ADDIN EN.CITE
Watts200220500205002050017Watts, P.Westall, C.Colpa, L.MacKeen,
L.Abdolell, M.Gallie, B.Heon, E.Department of Ophthalmology, The
Hospital for Sick Children, Toronto, Ontario, Canada.
[email protected] results in children treated for
macular retinoblastomaEye (Lond)Eye
(Lond)75-801612002/03/27Amblyopia/etiology/physiopathology/*therapyBandagesChild,
PreschoolFemaleFollow-Up StudiesHumansInfantInfant, Newborn*Macula
LuteaMalePatient ComplianceRecovery of FunctionRetinal
Neoplasms/complications/*therapyRetinoblastoma/complications/*therapyRetrospective
StudiesSensory DeprivationVisual Acuity2002Jan0950-222X
(Print)0950-222X
(Linking)11913894https://www.ncbi.nlm.nih.gov/pubmed/1191389410.1038/sj.eye.67000707
Chemoreduction alters the relation of fovea (the anatomic
central pit) and foveola (the central macular region containing
only cone cells) to tumor, depending on the tumor epicenter and
regression pattern.11 A tumor close to or involving the foveola is
often described as perifoveal. Laser treatment to perifoveal tumors
risks foveal destruction or post-laser scarring. OCT improves
topographic localization of the fovea.2,12
We hypothesized that avoiding direct laser treatment to the
foveolar edge of perifoveal tumors might enhance vision and visual
potential but still achieve tumor control by cutting off the tumor
blood supply. In Toronto, a fovea-sparing laser photocoagulation
technique was utilized for many years. In the current study we
reviewed vision, anatomical visual potential, and tumor control in
eyes with perifoveal retinoblastoma treated with fovea-sparing
laser photocoagulation with OCT guidance.
In the current study we reviewed vision, anatomical visual
potential, and tumor control in eyes with residual perifoveal tumor
after systemic or intra-arterial chemotherapy, treated by
fovea-sparing laser photocoagulation guided by OCT of the foveal
and perifoveal areas, and early amblyopia therapy.
MethodsStudy Design
This study reports a retrospective, single-institution,
interventionaland interventional case series. The records of all
eyes with residual perifoveal retinoblastoma after systemic or
intra-arterial chemotherapy, treated with foveal-sparing laser
photocoagulation between 1/1/2011 and 31/5/2017 at The Hospital for
Sick Children (SickKids), Toronto, Ontario, Canada were reviewed.
This study was approved by Institutional Research Ethics board and
follows the Declaration of Helsinki guidelines.
Eligibility
Eyes with residual active or fish-flesh perifoveal tumors after
chemotherapy were classified as (1) juxtafoveal if the fovea was
adjacent to the tumor <3000 µm from tumor edge at initial laser
session by OCT and, (2) foveolar if the fovea overlay tumor on OCT
and involved <4 quadrants of a 2 disc-diameter (DD) circle
centered over the foveolar yellow luteal pigment (Supplemental
figure 1). All tumors that extended beyond the 2 DD circle, or were
>3000 µm from the foveola by OCT (extra-foveal tumors) were
excluded because of the anticipated poor and good visual outcomes
respectively. All included eyes had OCT imaging including central
tumor and retina at initial treatment session.
Foveal-sparing laser photocoagulation
After tumor a good response to systemic or intra-arterial
chemotherapychemoreduction, 532 nm, 810nm and/or 1064 nm OCT-guided
laser photocoagulation of tumor was performed under general
anesthetic in sequential sessions 3-5 weeks apart, aiming to
preserve the anatomic fovea for preservation for maximal to
optimize visual potential (supplemental Figure 1). OCT identified
and documented the fovea to design the foveal sparing laser
crescent (Supplemental Figure 2).12
Initially, a crescent-shaped outer tumor boundary avoiding the
fovea and including the adjacent retina was photocoagulated using
532 nm laser. This crescent spares the foveal edge whether
juxtafoveal or foveolar tumor. On subsequent sessions, a slightly
smaller inner crescent shaped tumor area, was photocoagulated using
either 532 (<1 mm height) or 810 (for >2mm 1mm height) nm
laser. TAt first, the innermost tumor (towardclose to the fovea)
was avoided. In sequential sessions, if OCT documented >1500 µm
emergence of perifoveal retina between tumor and foveal pit, the
tumor was ttreated according to tumor height avoiding the adjacent
perifoveal retina.
In Subsequent sessions, OCT determined residual tumor height to
determine type of laser to use. OCT identified areas of residual or
recurrent tumor that were localized via OCT software calipers.
Post-laser OCT ensured accuracy of laser treatment (Supplemental
Figure 2).12
EligibilityEyes with active or fish-flesh regressed tumors
involving the foveal center (foveola) after chemotherapy were
classified as (1) juxtafoveal if the foveola was clear of tumor and
<3000 µm from tumor edge at initial laser session by OCT, (2)
foveal if the foveola couldn’t be identified or had underlying
tumor. Foveal tumors were eligible if tumor involvement was < 4
quadrants of a 2 disc-diameter (DD) circle centered over the yellow
luteal pigment (Supplemental figure 2). All perifoveal tumors that
involved and extended beyond the 2 DD circle circumference, and
tumors that were >3000 µm from the foveola by OCT (extra-foveal
tumors) were excluded because of the anticipated poor and good
visual outcomes respectively. All included eyes had OCT imaging
including central tumor and retina at initial treatment session.
Data Collection
The data collected included presenting age, laterality,
International Intraocular Retinoblastoma Classification (IIRC),13 ,
pre-laser chemotherapy protocol, tumor regression patterns
(predominantly-calcific versus predominantly fish-flesh
regression), foveal OCT vertical and/or horizontal scans performed
at initial laser treatment and last follow-up, laser parameters and
complications, total active treatment duration (time from diagnosis
until last treatment) and available data regarding amblyopia
therapy. The eye cancer stage was retrospectively defined using 8th
edition TNMH (Tumor, Node, Metastasis and Heritability) cancer
staging.14
OCT Parameters
Handheld OCT (Bioptoegen) was utilized in SickKids from 2010.15
Macular scans performed prior to initial laser treatment and at
last follow-up were evaluated for, (1) foveola fovea
identification, (2) foveolaral thickness (normal versus atrophic),
(3) mean foveaola-tumor distance (uninvolved perifoveal retina
between foveaola and nearest tumor/scar) using the OCT software by
two independent reviewers (authors SS and CV)), (4) preservation of
the photoreceptor inner segment-outer segment (IS-OS) junction
preservation, and (5) secondary macular changes (cysts, atrophy,
retinoschisis, traction or detachment). Comment by Sameh Soliman:
Reviewer 1: The authors write that Oct was performed, “prior to
initial laser treatment and at last follow-up”. This implies that
OCTs were not performed at each laser visit. Therefore, it is
unclear how the laser treatments were “OCT guided”. Please clarify.
In fact, there is little content in the article that supports the
assertion that the laser is OCT-guided. There is no description of
the OCT-guidance in the methods (only that an OCT was done prior to
any treatment… but how does that guide subsequent laser
treatments”).
OutcomesEnhanced Vvisual potential was evaluated .by, (1) Tumor
control was defined as absence of tumor regrowth at the non-treated
foveolaral area and/or recurrences requiring non-focal therapy;.
edge recurrences controlled by focal therapy were not considered
failureFocal therapy-controlled edge recurrences were not
considered failure. (2) Anatomical success was scored as
preservation/restoration of the foveal pit and ≥500 µm of tumor-
and or scar-free perifoveal retina. (3) Functional success was
determined by visual acuity (VA) acceptable (VA( ≥ 1.0 logMAR, 0.1
decimal or, 20/200 Snellen) or good (VA ≥ 0.5 logMAR, 0.3 decimal
or, 20/60 Snellen) at last follow-up. A child was legally blind if
VA was ≤1.0 logMAR or 0.1 decimal in the best vision eye. Vision
was measured using age-appropriate methods: Cardiff cards at 1
meter or matching Lea symbols at 3 meters for young children (<3
years), and Snellen chart at 20 feet for older children. Visual
acuity was documented as logMAR, decimal or Snellen equivalent,
subsequently converted to logMAR.
Statistical analysis
Basic descriptive statistics were calculated using Microsoft
Excel 2013. Mean, standard deviation, range (minimum and maximum)
and median were used to describe quantitative data. Qualitative
data was stated by number and percentNumber and percent stated
qualitative data. Statistical tests used included student T-Test,
Chi Square Test, Fisher Exact Test, Mann Whitney Test and Mood’s
Median Test. Significance of results was judged at the 5%
level.
ResultsDemographic data: (Table 1)
Twenty-two eyes of 20 children with retinoblastoma (19
bilateral) were included. The mean presenting age was 9 months
(range 3-22). IIRC13 eye classification were Groups B (10), C (7)
and D (5). By TNMH 8th Ed,14 11 eyes were cT1b, 8 were cT2a and 3
were cT2b. The foveolaa was involved in all included eyes at
presentation; , and 5 eyes had the only the central tumor only
while 17 eyes had additional smaller peripheral tumors. All
children had an RB1 germline mutation (H1) except the unilaterally
affected child. All children received systemic chemotherapy with
vincristine, carboplatin and etoposide (mean 4 cycles, range 1-6),
three eyes received additional IAC (1, 2 and 3 sessions) and two
eyes received 3 and 4 periocular injections of topotecan. After
chemoreduction and prior to laser therapy, 14 eyes had tumors with
predominantly fish-flesh regression and 8 eyes had tumors with
predominantly calcific regression. Three eyes had tumor cavitary
changes (1 cavity/tumor).
Initial OCT Assessment (before first laser session)
After completion of chemotherapy, Fourteen14 eyes of 13 children
had juxtafoveal tumor (10/14 with fish-flesh regression, 1/14
cavitary changes) and 8 eyes of 8 children had foveolaral tumor
(4/8 with fish-flesh regression, 2/8 cavitary changes). One child
had one eye with juxtafoveal and another the other eye with
foveolaral tumor. The foveal pits Eyes in eyes with juxtafoveal
tumors showed were a foveal pit at mean distance 960±818 µm (mean,
standard deviation; µm (range 160–2782 µm) from the nearest tumor
edge. The foveal pit in eyes with, while 3 eyes (3/8) with
foveolaral tumor had a detectable foveal pit that overlaid tumor
(3/8) or r. No foveal pit could not be identified in 5/8 eyes with
foveolaral tumors (Table 2, Figures 1 and 2).
Laser Therapy
The 14 juxtafoveal tumors Fourteen eyes with juxtafoveal tumors
were treated with 532 nm laser photocoagulation (median 6, range
1-9) sessions;, 12/14 eyes tumors had received subsequent
additional 810 nm laser photocoagulation (median 2, range 1-5);.
One one eye tumor received had a one additional treatment with 1064
nm laser hyperthermia. The median active treatment duration spanned
8.6 months (range 5-14 months).
The Eight eyes with8 foveolaral tumors were treated with 532 nm
laser photocoagulation (median 6, range 4-10 sessions);, 7/8 eyes
tumors received had additional 810 nm laser photocoagulation
(median 2, range 1-7 sessions) and 2/8 eyes tumors received had
1064 nm laser hyperthermia. The median active treatment duration
spanned 9, (range 6-19) months. One eye developed vitreous
hemorrhage after a 1064 nm laser , which resolvedsession.
Final OCT Assessment: (Table 2)
With juxtafoveal tumors, foveal pit preservation was observed in
13/14 eyes; in one eye, the, with a flattened fovea was flattened
by in one eye due to an epiretinal membrane (ERM) (Figure 3).
Twelve eyes had normal within normal central foveal foveolar
thickness ; and two eyes had an atrophic foveolaa. Post treatment
the OCT measurement of foveaola-tumor distance (Figure 3) was a
mean 1547±670 (mean±standard deviation), range 414–2679 µm; with
mean perifoveal distance gained of was 587±546 (mean±standard
deviation), range -115–1557 µm. Thirteen eyes maintained intact
perifoveal retina ≥ 500 µm (p=0.03). Five eyes (36%) showedhad a
preserved subfoveolaal IS-OS junction; while 9/14 eyes (64%)
showedhad cystic changes and/or retinoschisis in the
perifovealfoveolar retinal layers. Five eyes showed a foveolarn ERM
(Figures 1 and 3).Comment by Gallie Brenda: Comparing what?
Foveal Foveolar tTumorss remained had under the subfoveolaal
tumor remnants in 7/8 eyes with and an ERM in one eye. Two out of
three eyes with an apparent pretreatment foveal pit overlying the
tumor retained the foveal pit. Four eyes showed cystic changes and
retinoschisis in adjacent retina.
Outcomes: (Table 2)
Follow-up for eyeswas the same for with juxtafoveal tumors (was
median 2.52.8; (range 1.41.9–6.97.4) years),, and andfor eyes with
foveolaral tumors, (median 2.12.5; (range 1.38–3.18) years). All
juxtafoveal tumors were controlled without recurrences. Tumor
regrowth was evident in 5/8 eyes with foveolaral tumors (one with
cavitary changes, Figure 2b) that were controlled with additional
laser treatments 3/5 eyes; 2/8 eyes (Figure 2) required additional
IAC and one eye required plaque radiotherapy (I125, 40 Gy to apex).
One eye had hemorrhage subsequent to 1064 nm laser that
spontaneously cleared after 4 months revealing tumor recurrence;
the eye was enucleated after IAC and plaque radiotherapy failed to
control tumor; histopathology revealed no high-risk features. Tumor
recurrence with foveolaral tumors was significantly more frequent
than with juxtafoveal tumors (p=0.001). Tumor recurrence was not
related to presence of cavitary changes (p=0.6).
Vision assessment was possible in 2021/22 eyes and was not
possible in two eyes with foveal tumors, one due to young age and
one due to (one eye was enucleated)ion.
VA was median 0.3 LogMAR (0.5 decimal, (20/40) in eyes with
juxtafoveal tumors and 0.88 LogMAR (0.13 decimal, (20/160) in eyes
with foveolaral tumors. Acceptable and (≥1.0 logMAR) or good (≥0.5
logMAR)good VA was observed in respectively 12/14 and 8/14 eyes
with juxtafoveal tumors and 5/6 and 0/6 eyes with foveolaral tumors
(p=0.21 and 0.001 respectively). Good vision was observed in all
eyes with preserved sub-foveal IS-OS junction (p=0.03). Type of
tumor regression after chemotherapy did not affect VA with
juxtafoveal tumors (p=0.28). Good vision was significantly observed
in eyes with no sub-foveal tumor at first laser treatment
(p=0.001), preserved sub-foveolaral IS-OS junction (p=0.03) and
poor VA in fellow eyes (p=0.001). while Secondary retinal changes
(retinoschisis or ERM) were not significantly associated with VA
<0.5 logMAR 0.3 (p=0.9, juxtafoveal and 0.7,
respectivelyfovealar)
None of the 8 eyes with foveolaral tumors were considered an
anatomical success. In comparison, 12/14 eyes with juxtafoveal
tumors retained within normal foveal pit appearance within normal
and ≥ 500 µm of perifoveal retina, free of both tumor and treatment
related pathology. Nine eyes showed perifoveal retinal cystic
changes and/or retinoschisis (4 with good VA) and 5 eyes showed an
ERM (4 with good VA) (Figures 1 and 3). One child (1/13) with
juxtafoveal tumor and 4/8 children with foveolaral tumors were
legally blind (p=0.03).
Amblyopia therapy
Amblyopia occlusion therapy was not offered to the children with
poor vision or enucleated other eyes (9 patients with juxtafoveal
tumors and 4 patients with foveolaral tumors). Records of the 7
children who underwent amblyopia therapy were insufficient to
extract accurate data regarding timing of initiation, duration of
occlusion, type of patching, frequency or VA changes.
Discussion
Retinoblastoma (International Intraocular Retinoblastoma
Classification (IIRC)13 groups B/C/D or T1b/T2a/T2b, 8th edition
TNMH classification),14 size reduction is achieved by chemotherapy
(systemic or IAC) is commonly followed by laser consolidation to
achieve stable tumor control.1,16,17 The use of OCT to accurately
locate the fovea and provide topographic macular assessment enabled
refined focal therapy consolidation after chemotherapy.2
Classical laser treatment to perifoveal retinoblastoma decreases
visual outcome due to either direct foveal destruction or secondary
laser scar migration.18 We developed a sequential fovea-sparing
laser technique2 for central tumors with a tumor- free area within
a 2DD circle centered over the fovea. The initial anti-foveal laser
barrier is hypothesized to block with the tumor blood supply
resulting in tumor death and shrinkage, assuming that the foveal
avascular zone would not contribute blood supply to the nearby
tumor. Additionally, The resultant scarring might also creates a
tangential anti-foveal pulling force that might mobilize pulls the
tumor further away from the fovea. This technique was sufficient to
control juxtafoveal tumors without recurrences. Recurrences were
significant in subfoveal foveolar tumors suggesting a dual blood
supply to the tumor across the horizontal meridian. (Figure
3)Comment by Gallie Brenda: Or foveolar???
The retinoblastoma literature is deficient in describing
reproducible laser techniques that are therefore highly dependent
on physician experience and laser availability. As a result, we
cannot be sure thatWe can not find literature on this technique
approach to macular retinoblastoma. is not utilized by other
treatment centers. A recent literature review noted that no
randomized clinical trials were everhave been conducted to show the
technique or efficacy of laser therapy with for retinoblastoma.19
No comparative study of thermotherapy versus photocoagulation has
been reported. However, laser therapy plays a pivotal role in
consolidation therapy after chemotherapy for retinoblastoma.10
Gombos et al20 suggested that systemic chemotherapy was sufficient
to control 84 % (26/31 macular tumors) of their included eyes.
However, they excluded from their sample any eye that required
additional focal or external beam therapy or had short follow up
less than a year, but did not present the number of excluded eyes,
which might represent selection bias. This work was in the early
era where systemic chemotherapy was still being evaluated.
We show that OCT guides the potential for success of laser by
accurately locating the foveal center (juxtafoveal vs. foveal
foveola tumor) and the foveaola-tumor distance. During sequential
laser sessions, OCT determined retinal changes associated with
laser therapy such as sub-retinal exudates and macular
intra-retinal and sub-retinal edema. OCT surveillance of the foveal
region delineated flat scars that needed no more treatment and
facilitated timely detection of subclinical (otherwise invisible)
tumor recurrences. OCT differentiates between gliosis and tumor
recurrence, preventinged unnecessary treatment of inactive
lesions.2 However, the hand-held OCT does not have built-in
functionality to map macular thickness; we recorded as a surrogate
for macular health, preservation of the photoreceptor IS-OS
junction. OCT can identify cavitary changes in tumors and their
changes after treatments.21 We sequentially photocoagulated
non-cavitary parts of the tumor until the cavity collapsed. Despite
recent publications22,23 suggesting stability of cavitary tumors
after chemotherapy, the present series showed progression of
cavitary retinoblastoma in one eye that was treatment resistant and
required enucleation (Figure 2).
In comparison to normal foveal parameters,24,25 few OCT
parameters have been described in macular retinoblastoma.26,27 In
the current study, OCT documented anatomical restoration of >
500 µm of perifoveal retina adjacent to tumor. This distance is a
well-known cut-off to define clinically significant macular edema
in diseases affecting central vision28,29 and large macular
holes.30 We considered perifoveal restoration of > 500 µm of
apparently normal retina as anatomical success, since anticipating
that the greater the free tumor-foveola distance, the better the
anticipated vision.31 We anticipate that OCT measures this distance
more accurately than clinical measurement or fundus photos
calipers.
Chawla et al.32 studied the effect of trans-pupillary
thermotherapy (TTT, long duration heating of tumor) in central
IIRC13 Group B eyes (both macular and extra macular tumor) and
found that the post treatment VA (median 6/60) was worse than
pretreatment VA, especially with macular tumors. TTT has been shown
to be a significant risk factor for VA worse than 20/200 in IIRC13
Group D eyes after chemotherapy.31 The central tumors tended to
regress in a fish-flesh pattern, similar to our observations
(Figures 1 and 2). Schefler et al.8 evaluated the role of
repetitive TTT whole tumor laser photocoagulation in IIRC13 group B
macular tumors (IIRC ADDIN EN.CITE
Murphree2005136361363613636017Murphree, A. L.Intraocular
retinoblastoma: the case for a new group
classificationOphthalmology Clinics of North AmericaOphthalmol Clin
North AmOphthalmology clinics of North America41-5318200513 group
B) and found that 14/33 44 (4232%) patients eyes could be examined
for VA; and 9 patients had with macular foveal tumors (laterality
not determined) with had VA mean 20/120 and median 20/200 (VA
calculated from the published data). In our the present series,
treated with OCT-guided laser, median VA was 0.5 decimal (20/40)
with juxtafoveal tumors and 0.13 decimal (20/160) with foveolaral
tumors despite including more advanced IIRC ADDIN EN.CITE
Murphree2005136361363613636017Murphree, A. L.Intraocular
retinoblastoma: the case for a new group
classificationOphthalmology Clinics of North AmericaOphthalmol Clin
North AmOphthalmology clinics of North America41-531820058 Groups C
and D eyes. We attribute the our better VA in our study mainly due
to the accuracy of OCT-guided laser photocoagulation avoiding
direct foveolar laser and resulting in less scar migration than
TTT, which was found to be a significant risk factor for VA worse
than 20/200 in IIRC ADDIN EN.CITE
Murphree2005136361363613636017Murphree, A. L.Intraocular
retinoblastoma: the case for a new group
classificationOphthalmology Clinics of North AmericaOphthalmol Clin
North AmOphthalmology clinics of North America41-5318200513 Group D
eyes after chemotherapy.31
Visual acuity with age appropriate assessment was used as a
functional success indicator. In young agechildren, VA assessment
is challenging due to difficult cooperation and, amblyopia
development, and therefore is often missing in reporting outcomes
of treatment modalities in retinoblastoma.5 Despite observed
anatomical success, functional outcomes depended on other variables
and the status of the other eye. Moreover, anatomical failure was
not equivalent to poor visual acuity. Watts et al.11 found that
part time occlusion therapy improved vision in 80% of children with
macular retinoblastoma and a better vision other eye, followed for
a median of 2 years with acceptable VA (>1.0 LogMAR or better)
in 75% of eyes. Some eyes with juxtafoveal tumors had better visual
outcomes than those with foveolaral tumors. This is expected, as
there is more tumor involvement of the foveal center in foveal
tumors.
In summary, achieving good vision is possible in juxtafoveal
retinoblastoma using OCT-guided sequential fovea-sparing laser
photocoagulation. However, multiple factors31 are responsible for
the final visual outcome such as type of tumor regression, relation
of calcification to the foveal center, early amblyopia therapy,
tumor-foveola distance, status of the other eye and final foveal
architecture.. In the current study, for children with a better
vision other eye, it was not possible to draw significant
correlations with any of these factors due to small sample size and
incomplete documentation of details of amblyopia therapy. Treatment
complications including vascular occlusions and choroidal ischemia
after IAC might also contribute to poor vision.5,33,34
In the current study, it was not possible to draw significant
correlations with any of these factors due to small sample size and
incomplete documentation of details of amblyopia therapy. ThisThe
present study is also limited by the small sample size,
non-comparative and retrospective nature and with relative short
termshort-term follow- up for visionual acuity. A long-term
prospective study is recommended to better assess the laser
effectiveness,effectiveness, mainly in juxtafoveal tumors with
comparative arm with non-OCT guided laser therapy . Although
difficult to initiate, and a comparative study of photocoagulation
versus thermotherapy TTT is important to determine effectiveness in
tumor control and vision outcome would be ideal but difficult to
initiate.
Conclusions
Achieving good vision is possible in juxtafoveal retinoblastoma
using OCT-guided sequential fovea-sparing laser photocoagulation.
Foveal tumors may require more size reduction by chemotherapy than
tumors away from the foveal before starting laser therapy in order
to improve vision outcome.
Acknowledgements/DisclosuresAuthors acknowledge Dr. Francine
Yang, M.D. who reviewed the visual acuity assessments.Authors’
contributions
Concept and design: Soliman, Gallie
Data collection: Soliman, VandenHoven, MacKeen.
Figure construction: Soliman, VandenHoven, MacKeen
Analysis and interpretation: Soliman, Gallie.
Critical review: Soliman, VandenHoven, MacKeen, Gallie
Overall responsibility: Soliman, VandenHoven, MacKeen,
Gallie
Conflict of Interest Disclosures: All authors have completed and
submitted the ICMJE Form for Disclosure of Potential Conflicts of
Interest. Dr Gallie reported being an unpaid medical director of
Impact Genetics. No other disclosures were reported.
Financial Support: None
References
1.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.
2.Soliman SE, VandenHoven C, MacKeen LD, Heon E, Gallie BL.
Optical Coherence Tomography-Guided Decisions in Retinoblastoma
Management. Ophthalmology. 2017.
3.Munier FL, Soliman S, Moulin AP, Gaillard MC, Balmer A,
Beck-Popovic M. Profiling safety of intravitreal injections for
retinoblastoma using an anti-reflux procedure and sterilisation of
the needle track. Br J Ophthalmol. 2012;96(8):1084-1087.
4.Munier FL, Gaillard MC, Balmer A, et al. Intravitreal
chemotherapy for vitreous disease in retinoblastoma revisited: from
prohibition to conditional indications. Br J Ophthalmol.
2012;96(8):1078-1083.
5.Yousef YA, Soliman SE, Astudillo PP, et al. Intra-arterial
Chemotherapy for Retinoblastoma: A Systematic Review. JAMA
ophthalmology. 2016;134(6):584-591.
6.Gobin YP, Dunkel IJ, Marr BP, Brodie SE, Abramson DH.
Intra-arterial chemotherapy for the management of retinoblastoma:
four-year experience. Arch Ophthalmol. 2011;129(6):732-737.
7.National Retinoblastoma Strategy Canadian Guidelines for Care
/ Stratégie thérapeutique du rétinoblastome guide clinique
canadien. Can J Ophthalmol. 2009;44(Supp 2):S1-88.
8.Schefler AC, Cicciarelli N, Feuer W, Toledano S, Murray TG.
Macular retinoblastoma: evaluation of tumor control, local
complications, and visual outcomes for eyes treated with
chemotherapy and repetitive foveal laser ablation. Ophthalmology.
2007;114(1):162-169.
9.Shields CL, Mashayekhi A, Cater J, et al. Macular
retinoblastoma managed with chemoreduction: analysis of tumor
control with or without adjuvant thermotherapy in 68 tumors. Arch
Ophthalmol. 2005;123(6):765-773.
10.Chawla B, Jain A, Azad R. Conservative treatment modalities
in retinoblastoma. Indian Journal Of Ophthalmology.
2013;61(9):479-485.
11.Watts P, Westall C, Colpa L, et al. Visual results in
children treated for macular retinoblastoma. Eye (Lond).
2002;16(1):75-80.
12.Soliman S, Kletke S, Roelofs K, VandenHoven C, McKeen L,
Gallie B. Precision laser therapy for retinoblastoma. Expert review
of ophthalmology. 2018:1-11.
13.Murphree AL. Intraocular retinoblastoma: the case for a new
group classification. Ophthalmology clinics of North America.
2005;18:41-53.
14.Mallipatna A, Gallie BL, Chévez-Barrios P, et al.
Retinoblastoma. In: Amin MB, Edge SB, Greene FL, eds. AJCC Cancer
Staging Manual. Vol 8th Edition. New York, NY: Springer;
2017:819-831.
15.Rootman DB, Gonzalez E, Mallipatna A, 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.
16.Liu Y, Zhang X, Liu F, Wang KL. Clinical efficacy and
prognostic factors of chemoreduction combined with topical
treatment for advanced intraocular retinoblastoma. Asian Pacific
journal of cancer prevention : APJCP. 2014;15(18):7805-7809.
17.Gallie BL, Soliman S. Retinoblastoma. In: Lambert B, Lyons C,
eds. Taylor and Hoyt's Paediatric Ophthalmology and Strabismus. 5th
Edition ed. Oxford, OX5 1GB, United Kingdom: Elsevier, Ltd.;
2017:424-442.
18.Houston SK, Wykoff CC, Berrocal AM, Hess DJ, Murray TG.
Lasers for the treatment of intraocular tumors. Lasers Med Sci.
2013;28(3):1025-1034.
19.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.
20.Gombos DS, Kelly A, Coen PG, Kingston JE, Hungerford JL.
Retinoblastoma treated with primary chemotherapy alone: the
significance of tumour size, location, and age. Br J Ophthalmol.
2002;86(1):80-83.
21.Fuller TS, Alvi RA, Shields CL. Optical Coherence Tomography
of Cavitary Retinoblastoma. JAMA ophthalmology.
2016;134(5):e155355.
22.Chaudhry S, Onadim Z, Sagoo MS, Reddy MA. THE RECOGNITION OF
CAVITARY RETINOBLASTOMA TUMORS: Implications for Management and
Genetic Analysis. Retina. 2017.
23.Rojanaporn D, Kaliki S, Bianciotto CG, Iturralde JC, Say EA,
Shields CL. Intravenous chemoreduction or intra-arterial
chemotherapy for cavitary retinoblastoma: long-term results. Arch
Ophthalmol. 2012;130(5):585-590.
24.Thomas MG, Kumar A, Mohammad S, et al. Structural grading of
foveal hypoplasia using spectral-domain optical coherence
tomography a predictor of visual acuity? Ophthalmology.
2011;118(8):1653-1660.
25.Noval S, Freedman SF, Asrani S, El-Dairi MA. Incidence of
fovea plana in normal children. J AAPOS. 2014;18(5):471-475.
26.Cao C, Markovitz M, Ferenczy S, Shields CL. Hand-held
spectral-domain optical coherence tomography of small macular
retinoblastoma in infants before and after chemotherapy. J Pediatr
Ophthalmol Strabismus. 2014;51(4):230-234.
27.Samara WA, Pointdujour-Lim R, Say EA, Shields CL. Foveal
microanatomy documented by SD-OCT following treatment of advanced
retinoblastoma. J AAPOS. 2015;19(4):368-372.
28.Polito A, Del Borrello M, Polini G, Furlan F, Isola M,
Bandello F. Diurnal variation in clinically significant diabetic
macular edema measured by the Stratus OCT. Retina.
2006;26(1):14-20.
29.Sims LM, Stoessel K, Thompson JT, Hirsch J. Assessment of
visual-field changes before and after focal photocoagulation for
clinically significant diabetic macular edema. Ophthalmologica.
1990;200(3):133-141.
30.Michalewska Z, Michalewski J, Adelman RA, Nawrocki J.
Inverted internal limiting membrane flap technique for large
macular holes. Ophthalmology. 2010;117(10):2018-2025.
31.Fabian ID, Naeem Z, Stacey AW, et al. Long-term Visual
Acuity, Strabismus, and Nystagmus Outcomes Following Multimodality
Treatment in Group D Retinoblastoma Eyes. Am J Ophthalmol.
2017;179:137-144.
32.Chawla B, Jain A, Seth R, et al. Clinical outcome and
regression patterns of retinoblastoma treated with systemic
chemoreduction and focal therapy: A prospective study. Indian
Journal Of Ophthalmology. 2016;64(7):524-529.
33.Munier FL, Beck-Popovic M, Balmer A, Gaillard MC, Bovey E,
Binaghi S. Occurrence of sectoral choroidal occlusive vasculopathy
and retinal arteriolar embolization after superselective ophthalmic
artery chemotherapy for advanced intraocular retinoblastoma.
Retina. 2011;31(3):566-573.
34.Tsimpida M, Thompson DA, Liasis A, et al. Visual outcomes
following intraophthalmic artery melphalan for patients with
refractory retinoblastoma and age appropriate vision. Br J
Ophthalmol. 2013;97(11):1464-1470.
Figure Legends
Figure 1. Anatomical outcome of fovea-sparing laser
photocoagulation with juxtafoveal tumors. Yellow box: (a) eye with
fish-flesh regressed juxtafoveal tumor (upper row) after 4 cycles
of systemic chemotherapy; OCT (green line) showed preserved foveal
pit (yellow arrow) without underlying tumor; (b) after laser (lower
row), fish- flesh regressed tumor was replaced by flat scarring
except where calcified. The foveola tumor distance (red line)
increased post laser. Red box: (c) juxtafoveal tumor (d)
successfully managed with preserved foveal pit and increased
foveola tumor distance.
Figure 2. Recurrences in fovea-sparing laser photocoagulation of
foveolaral tumors. (Yellow box, above) (a) pPre- laser eye with a
fish-flesh regressed foveal tumor with foveal center (yellow arrow)
over tumor on vertical and horizontal OCT scans; the 2 DD circle
indicated perifoveal retina free of tumor and potential good visual
outcome. (b) After SLC: tumor scarring and flattening in the upper
half but regrowth in the lower half (middle column); regrowth
easily perceived in relation to the three vessels crossing over the
tumor (*). (c) Recurrence treated with 4 cycles of IAC and more
laser; tumor reduction achieved with preserved fovea, reduced
subretinal tumor, retinoschisis (OCT). (Red box, below) (d) Foveal
tumor treated with laser shows (e, f) recurrence (X) in that failed
IAC and plaque irradiation; the eye was enucleated with refractory
tumor. Tumor cavitary change can be seen (#) before recurrence.
Figure 3. Secondary macular changes after fovea-sparing laser
photocoagulation treatment. (a-c) Retinoschisis was the most common
secondary change were perifoveal retinal layers showed
retinoschisis in both juxtafoveal (a-b) and foveolaral tumors (c).
Other changes included (d) foveal atrophy and (e) loss of foveal
contour secondary to epiretinal membrane. Loss of the photoreceptor
inner segment outer segment (IS-OS) junction was noted in 64% of
juxtafoveal tumors (a, b and d) while 36% showed preserved IS-OS
junction (e). (f) Regressed tumor with overlying preserved fovea
(yellow arrowhead) and retinal layers that show retinoschisis and
minimal sub retinal fluid. The final visual acuity in these eyes
was 0.1, 0.4, 0.25, 0.16, 0.5 and 0.05 decimal respectively.
Online only figure LegendsComment by Gallie Brenda: CHECK, I
THINK YOU PUT THE LEGEND ON THE PAGE OF THE eFIGURE s…(and here in
text) then you submit the eFigures as pdf, while the real figures
for publication are high level TIFF images…….
eFigure 1. Inclusion and Exclusions. Included eyes with
perifoveal tumors had (a) juxtafoveal tumor (yellow box)
encroaching on the fovea with preserved foveal pit (yellow arrow)
with subretinal tumor on OCT; (b) foveolar tumor (blue box)
encroaching the fovea with preserved foveal pit & underlying
tumor (b1) or loss of foveal pit (b2) on OCT. Excluded eyes had
(c1-2) foveal tumor (green box) without potential for visual
salvage, due to total involvement of a 2 DD circle circumference
centered over the fovea; or (d) extra-foveal tumor (red box) with
excellent potential visual outcome due to non-involvement of 2 DD
central circle.Sequential fovea-sparing laser photocoagulation. (a)
Initial (yellow box)tumor and 532 nm laser photocoagulation from
crescent-shaped anti-foveal edge (C1) including outer tumor
boundary with the adjacent retina; smaller crescent shaped tumor
area (C2) moving closer to the fovea, photocoagulated using 810 nm
laser; fovea was avoided. (b) Subsequent (green box) scarring of
outer boundary noted photocoagulation (C1 and C2) repeated with
smaller crescents, (c) until either a flat scar or totally
calcified lesion or a combination was reached (blue box); OCT
(green line) shows preserved foveal pit (yellow arrow) without
underlying tumor with retinoschisis between retinal layers
overlying the calcific tumor.
eFigure 2. Sequential fovea-sparing laser photocoagulation. (a,
yellow box) Initial tumor and 532 nm laser photocoagulation from
crescent-shaped anti-foveal edge (c1) including outer tumor
boundary with the adjacent retina; smaller crescent shaped tumor
area (c2) moving closer to the fovea, photocoagulated using 810 nm
laser; fovea was avoided. (b) Subsequent (green box) scarring of
outer boundary noted photocoagulation (C1 and C2) repeated with
smaller crescents, (c) until either a flat scar or totally
calcified lesion or a combination was reached (blue box); OCT
(green line) shows preserved foveal pit (yellow arrow) without
underlying tumor with retinoschisis between retinal layers
overlying the calcific tumor. d) OCT guided detection of invisible
residual tumor (arrows), OCT caliper (dashed red line) helps
localization of the tumor for indirect laser delivery. After
initial photocoagulation, OCT shows incomplete laser treatment to
the tumor clearly demarcated in the center (*1) by difference in
reflectivity of the tumor. After laser reapplication, OCT can show
complete laser treatment (*2).Inclusion and Exclusions. Included
eyes had (a) juxtafoveal tumor (yellow box) encroaching on the
fovea with preserved foveal pit (yellow arrow) without subretinal
tumor on OCT; (b) perifoveal tumor (blue box) encroaching the fovea
with preserved foveal pit & underlying tumor (b1) or loss of
foveal pit (b2) on OCT. Excluded eyes had (c1-2) foveal tumor
(green box) without potential for visual salvage, due to total
involvement of a 2 DD circle circumference centered over the fovea;
or (d) extra-foveal tumor (red box) with excellent potential visual
outcome due to non-involvement of 2 DD central circle.
Table 1: Demographic characteristics of the eligible
patients/eyes
Demographics
Juxtafoveal tumors (n)
Foveal tumors (n)
Total
PATIENTS
13
8
20*
Age (months)
mean ± SD
9 ± 5
9 ± 5
9 ± 5
range
3-22
5-18
3-22
Gender
female
7
5
11*
male
6
3
9
laterality
Bilateral
12
8
19*
Unilateral
1^
0
1
Germline status
germline
12
8
19*
Non germline
1^
0
1
Systemic Chemotherapy
13
8
20*
EYES
14
8
22
Stage at diagnosis (IIRC/TNMH)
B/T1b
8
2
10
C/T1b
1
0
1
C/T2a
3
1
4
C/T2b
0
2
2
D/T2a
1
3
4
D/T2b
1
0
1
Adjuvant treatments
IAC
1
2
3
POT
2
0
2
Tumor regression
Calcific
4
4
8
Fish-flesh
10
4
14
*One child had one eye with juxtafoveal tumor and the other with
perifoveal tumor; ^ same child; SD: standard deviation; IAC,
intraarterial chemotherapy; POT, periocular chemotherapy; IIRC,
international intraocular retinoblastoma classification;8 TNMH, 8th
edition Cancer Staging Retinoblastoma.9
Table 2: Optical coherence tomography parameters before and
after laser therapy with primary and secondary outcomes
OCT Parameters
Juxtafoveal tumors
Foveal tumors
Significance (p)
PRE-TREATMENT
Foveal pit
14
3
0.001*
No foveal pit
0
5
Tumor underlying center
0
8
0.001*
Tumor foveola distance (µm)
mean± SD
960 ± 818
n/a
n/a
range
216 - 2782
median
667
≥ 500
4/7
POST-TREATMENT
Normal fovea pit
13
0
0.005*
Flat foveal pit
1
3
No foveal pit
0
5
Tumor underlying center
0
7
0.001*
Tumor foveola distance (µm)
mean± SD
1547 ± 670
n/a
n/a
range
414-2679
median
1672
≥ 500
13/14 (93%)
0.03*£
PRE-POST RESTORATION
mean± SD
587 ± 546
n/a
n/a
range
-115 to 1557
median
592
Preserved IS-OS junction
5
0
0.05
Secondary changes
Retinoschisis
9
4
0.5
ERM
5
1^
n/a
Atrophy
2
n/a
n/a
OUTCOMES
Complication
0
1(VH)
0.18
Tumor recurrence
0 (0%)
5 (63%)
0.001*
Eye salvage
14 (100%)
7 (88%)
0.18
Anatomical Success
≥ 500µm AND preserved/restored fovea
12 (86%)
0 (0%)
0.001*
Vision
Evaluable
14 (100%)
6 (75%)
0.05*
Acceptable (≥ 0.1 decimal)
11 (86%)
5 (63%)
0.46
Good (≥ 0.3 decimal)
8 (57%)
0 (0%)
0.01*
Legally blind (≤ 0.1 better eye)
1 (8%)
4 (50%)
0.03*
* Statistically significant; ^ detected pretreatment; £ pre and
post treatment significance; IS-OS, inner segment outer segment
junction; SD: standard deviation; n/a, not applicable; ERM,
epiretinal membrane; VH, vitreous hemorrhage.
1