Enhancing Assessing Vision and visual potential for perifoveal retinoblastoma using after optical coherence tomographic guided sequential laser photocoagulation 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. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Transcript
Enhancing Assessing Vision and visual potential for perifoveal
retinoblastoma using after optical coherence tomographic guided
sequential laser photocoagulation
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
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
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Sameh Soliman, 05/22/18,
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.
At a glance (33/35)
Precise OCT-guided sequential laser photocoagulation, guided by OCT, achieved enhanced good vision
and probable visual potential in eyes with perifoveal retinoblastoma, and better outcomes (anatomical
vision potential, visual acuity, and no recurrences) with juxtafoveal than foveolaral tumors.
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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
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.
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Introduction
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) is essential for macular retinoblastoma and is rarely sufficient to
control the cancer. solely except in certain tumors if calcific regression occurs. Frequently, consolidation
laser therapy is required to control residual tumor but might haverisks deleterious effect on vision.7,8
Cryotherapy and plaque radiotherapy are notless practical options to control macular tumors 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.7
Chemoreduction of macular retinoblastoma tumors alters the relation of fovea (the anatomic central
pit) and foveola (the central macular region containing only cone cells) to -tumor, relation depending on
the tumor epicenter location and tumor regression pattern.11 The The foveal center (foveola) may remain
involved within the tumor ortumor or fortunately become uninvolved. A tumor When the foveola is
nearclose to or involving the foveola a tumor edge whether involved by tumor or not, this tumor is often
described as perifoveal. Laser treatment to perifoveal tumors is challenging to avoidrisks foveal
destruction by laser or post-laser scarring. OCT improvesd topographic localization of the fovea.2,12
Enhancing visual potential relies on achieving the best possible anatomical and functional outcome.
We hypothesized that avoiding direct laser treatment to the edge adjacent to the foveolar tumor edge of
perifoveal tumors(regardless of its involvement by tumor) might enhance vision and visual potential but
still achieve tumor control by cutting off the tumor blood supplyby achieving the best possible anatomical
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Sameh Soliman, 05/17/18,
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.”
and functional outcome. In Toronto, a fovea-sparing laser photocoagulation technique was utilized for
many years. and 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. after utilizing this technique
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.
Methods
Study 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 chemo-regressed perifoveal tumors after chemotherapy
involving the foveal center (foveola) after chemotherapy were classified as (1) juxtafoveal if the foveaola
was adjacent to the tumor <3000 µm from tumor edge at initial laser session by OCT was clear of tumor
and <3000 µm from tumor edge at initial laser session by OCT, (2) foveolar if the foveaa isoverlay
clinically atoverlying the tumor on OCT and edge (identified by the yellow luteal pigment) and foveola is
either OCT-identified or not and overlying tumor edge. Foveal tumors were eligible ifwith tumor
involvedment was < 4 quadrants of a 2 disc-diameter (DD) circle centered over the foveolar the yellow
luteal pigment (Supplemental figure 1). All tumors that involved and extended beyond the 2 DD circle
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Gallie Brenda, 06/09/18,
What do you mean here? All 4 quadrants? Or overall bigger than 2DD?I would delete this statement. Also repeated in legend of supplemental fig 1
circumference, andor 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.
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 possibleto optimize visual potential (supplemental Figure 1). OCT identified and
documented the foveaola 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 tthen treated
according to tumor height avoiding the adjacent perifoveal retina. If the tumor showed cavities, the non-
cavitary parts of the tumor were sequentially photocoagulated the until the cavity collapsed.
In Subsequent sessions, OCT determined residual tumor height to determine type of laser to use.
Furthermore, OCT identified areas of subclinical residual or recurrent tumor that were localized via OCT
software calipers. Post-laser OCT ensured accuracy of total laser treatment to the tumor (Figure 1).12
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Eligibility
Eyes 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
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)
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Sameh Soliman, 05/22/18,
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”).
foveolaral thickness (normal versus atrophic), (3) mean foveaola-tumor distance (uninvolved perifoveal
retina between foveaola and nearest tumor/scar) , the measurements were performed using the OCT
software by two independent reviewers (authors SS and CV) and the mean was used), (4) preservation of
the photoreceptor inner segment-outer segment (IS-OS) junction preservation, and (5) secondary macular
changes (cysts, atrophy, retinoschisis, traction or detachment).
Outcomes
Enhanced 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.
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Results
Demographic 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 with cavitary changes) and 8 eyes of 8 children had foveolaral tumor (4/8 with
fish-flesh regression, 2/8 with 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).
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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
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
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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. Green box e) OCT
guided management of invisible residual tumor. OCT scan (pre-laser) detected residual tumor (arrows)
within the treatment scar that is differentiated from gliosis (XXX) by being hyper-reflective, dome shaped
and homogenous. OCT caliper (dashed red line) helps localization of the tumor for indirect laser delivery.
After initial photocoagulation (laser 1), OCT shows incomplete laser treatment to the tumor clearly
demarcated in the center (*1) by difference in reflectivity of the tumor. After laser reapplication within the
same session (laser 2), OCT can show complete laser treatment (*2) with uniformity of internal tumor
reflectivity.
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
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 Legends
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) without 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.
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Gallie Brenda, 06/10/18,
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…….They didn’t say anything about this in the initial submission
*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
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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)
