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. samehelsayedsoliman@yahoo.com

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. patrickowatts@hotmail.comVisual 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.

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