Primary Laser Therapy as monotherapy for discrete retinoblastoma

Sameh E. Soliman,1-3 * Zhao Xun Feng, 4, Brenda L. Gallie.1,5-7

Authors’ affiliations

1 Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto,

Canada.

2 Department of Ophthalmology and Vision Sciences, Ocular Oncology Unit, Princess Margaret

Hospital, Toronto, Canada.

3Department of Ophthalmology, Faculty of Medicine, University of Alexandria, Alexandria,

Egypt.

4 Faculty of Medicine, University of Ottawa, Ottawa, Canada.

5Department of Ophthalmology & Vision Sciences, Faculty of Medicine, University of Toronto,

Toronto, Ontario, Canada.

6Departments of Molecular Genetics and Medical Biophysics, Faculty of Medicine, University of

Toronto, Toronto, Ontario, Canada.

7 Division of Visual Sciences, Toronto Western Research Institute, Toronto, Ontario, Canada.

*Corresponding author: Sameh E. Soliman, 8 Hillcrest Ave., Toronto, ON, M2N6Y6.

samehelsayedsoliman@yahoo.com

Running Head: Primary laser in retinoblastoma

Number of Figures and Tables: 1 figure, 2 tables

Word count: 2992/3000

Keywords: Retinoblastoma, laser, photocoagulation, recurrence, OCT, burden, secondary

prevention.

Conferences: A part of this manuscript is accepted for presentationwas presented virtually in the

World Ophthalmology Congress 2020 (WOC 2020, Cape Town, South Africa) and was accepted

in the annual meeting of the Association for Research in Vision and Ophthalmology 2020

(ARVO 2020, Baltimore, USA).

At a glance (25/35)

Laser photocoagulation as primary monotherapy safely and effectively controlled 96/111 discrete

retinoblastomas ≤ 3 disc-diameters, avoiding localized, regional or systemic chemotherapy and

associated complications.

Abstract (24824854/250)

Background/Aaim: Discrete retinoblastomas are endophytic tumors with well-defined borders

and attached retina diagnosed early in disease progression. We studied the safety and efficacy of

primary laser photocoagulation in managing discrete endophytic retinoblastoma with well-

defined borders and attached retina.

Methods: A single-institution retrospective non-comparative record review of retinoblastoma

children managed with primary laser for discrete retinoblastoma (February 2004-December

2018). Treatment success was defined by frequency ofby tumor tumor achieving initial complete

regression (CR)stability and final stability final stability by non-invasive therapy

(lLaser/cryotherapy). Invasive therapies included without the use of chemotherapy (systemic or

periocular), or other invasive procedureplaque radiotherapy and/or pars-plana vitrectomy).

Results: Eligible were 117 tumors in 57 eyes of 46 patients. Non-invasive therapyLaser

(laser/cryotherapy) (median 2 sessions) alone was successful to achieved initial CRinitial

stability initial stability in 10095/117 tumors while 5/117 required additional cryotherapy. One

laser session with was sufficient to achieve initial stability for 353515/117 tumors and final

stability for 16/117 tumors.

Additional Iinvasive therapy was required for requiring only one laser session while 17/117

tumors to achieve initial stability, and for 21/117 tumors to achieve long-term stability. OneA

single laser session achieved initial stability initial stability for 35/117 tumors and final stability

final stability for 16/117 tumors. required (7 additional systemic chemotherapy, 8 (7), periocular

chemotherapy, (8),1 both, and 1 (1 ) or plaque radiotherapy (1). After initial stabilityA stable

eye (, 4 stable tumors) in 1 eye werewas enucleated due to parental choice to avoid frequent

follow-up per parent choice. Tumor rRecurrences developed in 54/113 tumors, 6 of which

required invasive therapy (1 systemic chemotherapy, 3 periocular chemotherapy, 1 plaque

radiotherapy, 1 pars plana vitrectomy). Overall, 93/117 tumors achieved final stability with non-

invasive therapy alone. ROC analysis identified threshold largest basal diameter of 3 disc-

diameters (DD) as thresholdfor successful non-invasive therapy.:; Wwith non-invasive therapy

alone, 100/111 of tumors ≤ 3 DD and 0/6 >3 DD achieved CR initial stability initial stability

with non-invasive therapy alone compared to 0/6 of tumors > 3 DD (P < 0.001). Despite

HoweverDespitemore fFewer tTumors recurrednces occurred less with tumorswhen treated with

invasive (4/17) than non-invasive therapy alone recurred in (4/17 v 50/100) (:recurred than those

treated with invasive therapy ( of tumors treated with non-invasive therapy alone and 4/17) of

tumors treated with invasive therapy (PP = 0.043), but fewer of the recurrences required

subsequent ); However, the proportion of recurrence requiring invasive therapy therapy was less

for those treated with non-invasive therapy alone (4/50 v 2/4 ; P = 0.010). No eyes were lost due

tohad tumor progression or extraocular disease. Overall, 29/46 patients (93/113 tumors) avoided

chemotherapy or other invasive proceduretherapies.

Conclusions: Discrete retinoblastoma ≤ 3 DD can be effectively and safely managed with

primary laser photocoagulation, avoiding chemotherapy or other invasive procedure therapies in

96/11111 casestumors., 29/46 patients.

Introduction

Retinoblastoma, the most common pediatric intraocular malignancy,1,2 presents with either

discrete retinal tumor(s) (well-defined boundaries with no/minimal surrounding serous retinal

detachment (RD) or tumor seeding), or indiscrete tumors with ill-defined boundaries due to

extensive tumor, serous RD or tumor seeding.3 Eyes with discrete tumors are classified as Group

A/B by International Intraocular Retinoblastoma Classification (IIRC)4 or cT1a/cT1b by TNMH5

staging. Three mm (≈2 disc-diameters [DD]) Largest Tumor Basal Diameter (LBD) is the cut-off

size between Groups A/B and cT1a/cT1b. Occasionally, Eyes with Group C/cT2 eyes may also

have discrete tumors., but were not included in this study.

Small discrete tumors are now more frequently detected owing to by prenatal or postnatal

screening for high risk familial retinoblastoma either prenatal or postnatal.6,7 Furthermore,

Optical coherence tomography (OCT) now improvesd visualization detection and assessment of

small retinoblastoma.8,9 Primary chemotherapy (systemic, periocular and intraarterial) versus

primary focal therapy using cryotherapy, laser therapy and plaque radiotherapy were

randomlyhave been reported as treatment options.10-15 However, there are no definitive guidelines

regarding treatment of discrete retinoblastoma tumors does not exist.

At our institute, discrete retinoblastoma tumors are primarily treated by laser therapy if <3

mm (IIRC A, B, TNMH cT1a),. non-central and primary absent systemic chemotherapy is not

required for larger tumor(s) in other eye requiring systemic chemotherapy.16 Otherwise, primary

chemotherapy followed by focal consolidation is recommended.16 Furthermore,

Photocoagulation is preferred over thermotherapy due to smaller spot size for supporting precise

localization and treatment effect. Photocoagulation can be encirclinging the tumor to is intended

to cut its vascular supply to achieve initial size reduction for later direct tumor photocoagulation.,

Other tumors were directly photocoagulated to whole tumor, selective avoiding vital areas

(fovea/optic disc) or treated with combinations of these approaches.3,17

In the current work, We now evaluate laser photocoagulation for discrete tumors as a

primary management modality regarding safety and effectiveness. together with trialWe

identifying predictive factors for ultimate outcomes and recommending draft potential guidelines

for consideration.

Methods

Study design

The study was approved by SickKids Research Ethics Board and follows the Declaration of

Helsinki. This study is a single-institution retrospective non-comparative interventional case

series.

Eligibility

Records of children with retinoblastoma managed at SickKids (February 2004-December

2018) were reviewed. Eligible discrete tumors includedwere: i) tumors in never-previously-

detached retina in eyes staged IIRC Groups A/B/C, ii) treated with primary laser

photocoagulation, and iii) had minimal 12 months follow-up. Discrete tumors primarilyy treated

otherwisewith other modalities, or associated with non-discrete tumors, or poorly visualized,

were excluded not to confound evaluating laser effectiveness.

Data collection

Data collected included age at diagnosis, family history, eye staging (IIRC/cTNMH), pre-

laser treatment (POC, IAC or systemic chemotherapy)t, tumor location, and LBD in DD at

diagnosis (tumor height was not consistently recorded so was not to be included in size

assessment), and initial laser technique (encircling/direct/selective/combined), and number of

laser treatments, OCT utilization (treatment and follow-up), treatment duration (time from

diagnosis to last laser therapy), tumor recurrence (timing, type, treatment details and final

outcome) and follow-up duration.

Laser techniques definitions

Discrete tumor management Primary laser photocoagulation for discrete tumor management

consisted of primary laser photocoagulation utilization of a photocoagulation (technique, (see

below) followed by assessment after 2-3 weeks during examination under anesthesia (EUA) to

document tumor response. If any degree of tumor regression occurred, the laser treatment would

continue in multiple sessions 3 weeks apart during routine EUAs until complete regression (CR)

was documented by total a flat scar either clinically or byor by n OCT. If the tumor showed no

response or tumor progression, the treatment plan would eventually shift to chemotherapy either

(systemic, periocular, intravitreal or intra-arterial chemotherapy) dependingent on tumor size,

location and occurrence of vitreous seeds. Initial stability Initial stability (IS) was defined as

absence of tumor activity at two consecutive follow-ups since last treatment session and final

stability was defined as absence of recurrence with a minimum ofgreater than 12 months post-

treatment follow-up.

With clinical or OCT-guidance, vVarious laser techniques3 were utilized:3 including (i)

encircling photocoagulation,: where the tumor is surrounded by 2 or 3 rows of confluent laser

photocoagulation burns just outside the tumor margin (532 nm laser is preferred over 810 nm

laser for smaller spot size) to interrupt the tumor vascular supply;, (ii) direct photocoagulation,

whole tumor photocoagulation: where the wholedirect tumor surface is paintedtreated, by direct

tumor photocoagulation (higher tumors require with longer wavelength; i.e. 810 nm);, (iii)

selective tumor photocoagulation,: where tumor is directly painted photocoagulated avoiding

selected tumor areas in proximity to vital structures (fovea or optic nerve) either clinically or

OCT-guided;. (iv) combination of these ed techniques can be utilized. The direction of painting

from tumor margin to center or vice versa varied among treating physicians.

Assessment

Laser decisionplans, techniques, responses and outcomes were described. Factors (tumor or

treatment-related) that might contribute to outcome were studied. Tumor-related factors included

location, LBD and initial regressionresponse. Treatment-related factors included

photocoagulation technique , chemotherapy and OCT utility. Treatment success was defined as

primarily by frequency of achieving complete tumor regression (CR)initial stability and final

stabilityinitial and final stabilities avoiding without chemotherapy and or other invasive

procedures. Subsequent tTreatment stability required was assessed by frequency ofby frequency

of later tumor recurrence after initial stabilityinitial stability CR and recurrence burden

considering recurrence ( i) type (subclinical/invisible or clinical), (ii) subsequent treatment

intensity required (focal or systemic/invasive);, iii) treatment duration (≤ or > 2 months), and iv)

final outcome (control or enucleation/extraocular spread).. Subclinical (invisible) recurrence

refers to an OCT detected tumor activity in an apparently clinically apparent stable tumor scar.

Focal (Non-invasive) therapies included non-surgical focal treatments namely laser and

cryotherapy. All other treatments were considered invasive.

Statistical analysis

Data were summarized using frequency/percentage and median/range for categorical and

continuous variables respectively. Baseline tumor characteristics were compared using Pearson’s

chi-square and Mann-Whitney U tests for categorical and continuous variables respectively.

Correlation between variables was determined using Pearson Correlation-Coefficient. Receiver-

Operating Characteristic (ROC) analysis defined LBD thresholds to categorize tumor into groups

by calculating lLikelihood ratios for LBD values with the highest ratio selected as threshold.

Univariate and multivariate logistic regression analysis was performed to assess variable

associations with tumor recurrence. All Reported P-values reported are two-sided and <0.05

indicated significance. Analysis was performed using SPSS Version 25 (IBM Corp, Armonk,

New York).

Results

Sample demographics

A total of 117 tumors in 57 eyes of 46 children who received primary photocoagulation were

enrolled (Figure 1). The median age at diagnosis was 5.8 months (range: 0.1-118.6 months). All

children had a constitutional RB1 pathogenic allele (H1)1,5 and 17 (37 %, 72 tumors; 28 eyes) had

retinoblastoma family history. At first diagnosis, 68 (58%) tumors were present while 49 (42%)

tumors developed later. Table 1 summarizes the sample characteristics including staging (IIRC4

and cTNMH5), tumor LBD and location.

Tumor response to initial tumor photocoagulation and subsequent management (Figure 1)

After one laser session, 35 tumors (24 eyes) showed apparent complete regressionCRinitial

stabilityinitial stability; 72 tumors (39 eyes) showed variable degrees of regression while 10

tumors (9 eyes) showed progression. Four eyes had both tumors that progressed (4) and tumors

that regressed (5) after initial laser. The initial laser photocoagulation technique was whole

directtumor painting (97, 83%), encircling (13, 11%), or combined encircling and whole direct

tumor paintingphotocoagulation (7, 6%).

Tumors that showed apparent CRinitial stabilityinitial stability after a single laser treatment

had a median size of 0.3 DD (range 0.1-3.0 DD); 23 tumors in were from 13 Group A eyes and

12 tumors were fromin 11 Group B eyes. Furthermore, 34/35 (97%) tumors were treated with

wholedirect tumor photocoagulation and 1/35 (3%) with combined encircling and wholedirect

tumor photocoagulation painting. Ten eyes (15 tumors) from 10 patients were completely treated

after a single laser session. All tumors showing initial apparent CRstabilityIS received continued

observation.

For Of 72 tumors that showed partial regression, 38 tumors were from in 21 Group A eyes,

32 from in 17 Group B eyes and 2 from in 1 Group C eyes. The initial laser techniques were

whole direct tumor photocoagulation (63), encircling (3) and or combined photocoagulation

technique (6). The treatment plan of 1 tumor (1 eye) was switched to systemic chemotherapy due

to minimal regression in an 8 DD tumor after initial laser session. Subsequently, Additional laser

sessions at 3-4 weeks interval were continued for 71 tumors, four of which in 4 eyes had

adjuvant cryotherapy and 61/71 achieved initial stabilityinitial stabilityCR. The median number

of laser sessions was 2 (range, 1-10 sessions) for tumors in Group A/B eyes and 4.5 (range, 4-5

sessions) for tumors in Group C eyes. Ten tumors (7 eyes) did not show desired regression and

eventually required chemotherapy (3 IVC, 6 periocular chemotherapy [POC] POC and 1 both) to

achieve CRinitial stabilityinitial stability.

Ten tumors that progressed in size (Table 2) after initial laser were from in 8 Group B eyes

and 1 Group A eye. All progressed tumors initially had received encircling photocoagulation; the

median tumor size was 2.5 DD (range: 0.6-5 DD). The subsequent treatment decision was

continued laser for 4 tumors (3 eyes), adjuvant cryotherapy for 1 tumor (1 eye), POC for 1 tumor

(1 eye), plaque radiotherapy for 1 tumor (1 eye), and systemic chemotherapy for 3 tumors (3

eyes). Eventually, four 4 tumors (3 eyes) were controlled with laser ± cryotherapy while six 6

tumors in (6 eyes) required invasive therapies.

Among tumors treated with encircling techniquephotocoagulation, 10/13 (77%) progressed

in size after initial laser session compared to 0/97 (0%) tumors treated with whole direct tumor

paintingphotocoagulation (P < 0.001) and 0/7 (0%) treated with combined technique (P =

0.001). Of 117 tumors, 17 17 21 tumors (14 eyes) eventually required invasive therapy to

achieve initial stabilityinitial stabilityCR. One eye had vitreous seeding after encircling

photocoagulation controlled with two intravitreal chemotherapy injections. Direct tumor laser

produced no vitreous seeding, was encountered from direct tumor laser in any session. There

were no incidents of haemorrhage, misplaced laser or injury to vital structures.

Treatment SuccessInitial Stability

Overall, 100 tumors from 47 43 eyes achieved CR initial stabilityinitial stability with non-

invasive therapy including 25/27 (93%) Group A, 17/29 (57%) Group B and 1/1 (100%) Group

C eyes (laser and cryotherapy only). Laser photocoagulation solely, controlled 95 tumors from in

44 39/57 (68%) eyes. In turnNon-invasive therapy achieved CRinitial stability in, 43/57 (75%)

eyes containing 91 tumors, achieved CR for all its 91 tumors with non-invasive therapy

including 25/27 (93%) Group A, 17/29 (57%) Group B and 1/1 (100%) Group C eyes. Seventeen

tumors in 14 eyes required invasive therapy : (7 systemic chemotherapy, 8 POC, 1 both, and 1

brachytherapy) . In terms of eyes, tThe CRinitial laser was achieved by Furthermore, laser

therapy alone in 39/57 (68%) eyes with containing all its 79 tumors were treated with laser

therapy only, while and by laser and adjuvant cryotherapy in 4/57 (7%) eyes containing (12

tumors) were treated with laser and adjuvant cryotherapy. Seventeen tumors from in 14 eyes

required primary invasive therapy:, 7 had systemic chemotherapy, 8 had POC, 1 had both, POC

and systemic chemotherapy and 1 had brachytherapy. The 14 eyes that received invasive therapy

wereincluding 2/27 (7%) Group A and 12/29 (60%) Group B eyes.

ROC analysis identified LBD of 3 DD as the appropriate threshold for analysis of achieving

CR initial stabilityinitial stability with or without invasive therapy where, 100/111 (90%) of

tumors ≤ 3 DD achieved CR initial stabilityinitial stability with non-invasive therapy alone

compared to 0/6 (0%) tumors > 3 DD (P < 0.001). Furthermore, 5/11 (45%) central tumors

received invasive therapy compare to 3/35 (9%) equatorial/pre-equatorial tumors (P = 0.005) and

9/71 (13%) post-equatorial tumors (P = 0.007). Finally, invasive therapy was required for 7/13

(54%) of tumors treated with initial encircling technique, received invasive therapy compared to

10/97 (10%) treated with wholedirect tumor painting photocoagulation (P < 0.001) and 0/7 (0%)

treated with combined encircling and photocoagulation painting (P = 0.016).

Treatment stabilityRecurrence and Final Stability

All tumors were followed up for a median of 71 months (range, 13-172 months) sincefrom

date of last treatment. One eye (4 tumors) was enucleated despite no evidence of tumor activity

apparent CR to reduce follow-up frequency as perby family preference (out of provincelong

range travel difficulties);. tThree of the four4 tumors had achieved initial complete

regressionCRinitial stability ISinitial stability with non-invasivelaser therapy photocoagulation

alone only and one tumor was treated with periocular chemotherapyPOC. This eye showed

extinguished ERG and no vision18 and was enucleated 9 months from last active treatment.

Histopathology confirmed no residual active tumor.

Overall, of 100 tumors that achieved initial complete regressionstability ISinitial with non-

invasive therapy, 50 (50%) in 29 eyes tumors developed a degree of tumor tumor recurrence:;

36/50 were diagnosed clinically among which 36 tumors were diagnosed clinically whileand

14/50 tumors were diagnosed sub-clinically with by OCT in a subclinical phase. The Median

time from last treatment to recurrence was 4 months (range, 1-25 months). A median of 2 laser

sessions (range, 0-7) were used to treat recurrent 46 (92%) recurrent tumors for in 46 (92%)

tumors (25 eyes). Invasive therapy was required to control 4 tumors from in 4 eyes (1

brachytherapy, 1 PPV and 2 POC). OverallOverall, 97/100 tumors that achieved initial stability

with non-invasive therapy were successfully salvaged with median follow-up of 72 months

(range, 13-168 months). Of 35 tumors that achieved initial primary complete regressionCRinitial

stabilityISinitial stability with one laser session, 16 (46%) achieved final stabilityFSfull stability

with no additional treatment, 19 (54%) developed tumor recurrence,; among which 1/19 one of

which received invasive therapy. Ten eyes (15 tumors) fromof 10 patients were completely

treated after a single laser session.; one .. Overall 93/117 tumors achieved final stability FSfull

stability using non-invasive therapy only with median follow-up of 73 months (range, 13-168

months).

Of 17 tumors that achieved initial complete regressionCRinitial stability ISinitial stability

with invasive therapy, 4 (24%) tumors developed recurrence all diagnosed clinically. The median

time from last treatment to recurrence was 2.4 months (range, 1.9-3.0 months). Of 4 recurrences,

2 (12%) required invasive therapy (1 IVC and 1 POC). A median of 4 laser sessions (range, 2-9)

were used to treat these recurrent tumors. Overall, 13/14 eyes (14/17 tumors) were completely

salvaged within median follow-up was 68 months (range, 15-172 months).

Although the recurrence rate was higher for tumors that achieved initial complete

regressionstability IS with non-invasive therapy alone compare than those that received invasive

therapy (50% v 24%; P = 0.043), recurrences requiring invasive therapy was less common for

tumors treated with non-invasive therapy alone (8% v 50%; P = 0.010). Aside from 4 tumors (1

eye) enucleated for social reason, all other 113 tumors were successfully salvaged. with median

follow-up 73 months (range, 13-172 months).

Overview

Throughout the entire treatment, 29/46 (63%) patients avoided invasive therapy to achieve

final resolutionstabilityFSfull stability. In turn, 39/57 (68%) eyes (76 tumors) achieved final

resolution stability FSfull stability with non-invasive therapy only including 23/27 (85%) Group

A, 15/29 (52%) Group B and 1/1 (100%) Group C eyes. One eye was enucleated not because of

tumor activity.

After adjusting for tumor size, location, invasive therapy to achieve initial remission and

OCT-guidance treatment, none were significant predictor for tumor recurrence nor recurrence

needing invasive therapy. One eye was enucleated not because of tumor activity. Visually 46

eyes with 102 non-central tumors had within normal 20/20 vision. Of 10 eyes with 11 central

visually threatening tumors, the final scar size in relation to the initial tumor size was unchanged

for 8 tumors and increased for 3 tumors, all of which received invasive therapy (2 POC, 1 POC

and systemic chemotherapy). Central tumor treated with non-invasive therapy was significantly

more likely to have unchanged scar size compare to tumors treated with invasive therapy (0% v

60%; P = 0.026).

Discussion

Discrete retinoblastoma usually presents in the context of heritable retinoblastoma,6 either

the affected child is proband or has a positive family history (37% of children with discrete

retinoblastoma at SickKids). Establishing treatment guidelines for discrete retinoblastoma can be

considered a secondary prevention tool for familial retinoblastoma, which is currently an

evolving concept with multiple published recommended practices as prenatal molecular

screening, early-term delivery,6 intensive OCT-guided screening19 and laser photocoagulation of

invisible retinoblastoma.8

Initial management decisions for a discrete tumor depend on tumor size (LBD and height),

location, proximity to the fovea and optic nerve, and the retinoblastoma staging for both eyes

(IIRC/TNMH). At SickKids,16 primary laser photocoagulation is utilized whenin screened

familial cases that are discovered as retinoblastoma is diagnosed IIRC A/B, or cT1/T2a in both

eyes (concomitantly or sequentially) or or in asymmetric retinoblastoma where one eye is IIRC

A/B, or cT1/T2a and the other eye is enucleated for advanced IIRC D/E, or cT2b/T3.16 If a

tumor in either eye is large or either eye is IIRC B, or cT2b or higher, systemic chemotherapy

(4-6 cycles) or IAC15 is administered followed by focal consolidation, . Periocular topotecan20

was utilized as a bridge therapy in young children for systemic chemotherapy but was

discontinued in 2015 since it had only partial activity. There is evolving evidence about the

effectiveness and utility of IAC15 and was introduced at SickKids since 2016 for selected

unilateral and more advanced eye in asymmetric bilateral retinoblastomas ifwhen the eye harbors

clinical signs predictive of low histopathologic risks.20,21

The rationale of primary laser photocoagulation is to achieve tumor control while avoiding

systemic complications of systemic chemotherapy (mainly chemotherapy-induced ototoxicity22

and increased susceptibility to infections) and local complications of IAC mainly vascular

complications.23,24 This is well known concept in medicine where you start with non-invasive

modalities as long as it does not put patient at increased risk of mortality or morbidity. In our

cohort, around two-thirds of patients avoided both systemic chemotherapy and IAC to achieve

tumor control. None of our patients developed tumor growth to the extent of eye loss or

extraocular disease. The only enucleated eye enucleated in our cohort was for because of social

factors.25

Young age of presentation (<6 months) is common in discrete retinoblastoma and even

earlier in the familial subgroup.1 Classical treatment options are sometimes limited as proper

regimen and dosage of systemic chemotherapy cannot be utilized because of immature infantile

liver and kidney and higher incidence of complications.6 Soliman et al.22 reported 4.5 months of

age as the cut-off point of higher incidence of carboplatin related ototoxicity. Furthermore, IAC

utility before the age of 6 months is controversial. Sweid et al.26 reported more abortive IAC

procedures with infants 10kg.

Abramson et al.13 utilized primary Transpupillary thermotherapy (TTT) in 91 tumors in 22

eyes and reported success in 84/91 tumor without invasive therapies (systemic chemotherapy,

Plaque radiotherapy or POC) with best results if tumor is < 1.5 DD. The main limitation was the

utility of salvage treatments for other tumors in the same or other eye of some patients rendering

the interpretation of success to only the TTT controversial. Scar migration is a well-known side

effect of TTT after chemoreduction.27 In our cohort, we utilized only photocoagulation because

of smaller spot size and better localization. Primary photocoagulation solely controlled 93% of

IIRC Group A eyes and 57% of selected IIRC group B eyes. Scar migration was only associated

with systemic chemotherapy.

Primary laser photocoagulation proved safe during treatment. Iatrogenic vitreous seeding as

an anticipated complication of direct laser photocoagulation28 never occurred in our cohort. Only

one progressive tumor seeded after encircling photocoagulation. However, it was successfully

managed by intravitreal chemotherapy. It is worth mentioning that current intravitreal

chemotherapy technique29,30 and its effective results has changed the perspective towards vitreous

seeding. Furthermore, there were no cases of hemorrhage, misplaced laser or iatrogenic burns of

vital structures. Encircling laser photocoagulation alone proved unsuccessful alone to prevent

initial tumor progression for tumors > 3 DD.

In our cohort, tumor recurrence occurred in 5047% of tumors. They were all detected during

routine follow up and none was discovered at a stage beyond salvage. OCT-guided follow-up of

treatment scars detected subclinical residual/recurrent tumor growth and guided further laser

photocoagulation.8,17 Early management of subclinical recurrence reduced the treatment burden

to focal non-invasive therapies with minimal treatment scar expansion. OCT-detected tumor

recurrences are anticipated to require less treatment duration and burden than clinically-detected

recurrence.8 Generally, OCT was reported to improve assessment of small/invisible discrete

tumors31 and guide tumor management19 to diagnose, localize small tumors and monitor laser

treatment sufficiency.

This study is limited by its retrospective nature. The decision of primary laser versus

primary chemoreduction was not randomized for IIRC group B eyes. Technical aspects of laser

parameters settings (power, duration, spot size and number of applications) were not studied, and

are specific to each laser machine on the day of use. As this work is within a single institution

with uniform lasers and technical experience, these technical aspects were omitted from analysis.

The role of OCT-guided treatment was not fully addressed due to limited availability in the

earlier study period.

In cConclusion, primary laser photocoagulation proved to be a safe effective non-invasive

treatment alternative in IIRC Group A and some group B eyes with 63% of patients avoiding

systemic therapies and no patients encountered tumor spread or progress beyond ocular salvage.

Acknowledgement/Disclosure

This research did not receive any specific grant from funding agencies in the public,

commercial, or not-for-profit sectors. No financial disclosures exist for any of the authors.

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Figure Legends

Figure 1: Consort flowchart following all tumors from primary photocoagulation monotherapy to

final stability.

Table Legends

Table 1: Sample Characteristics regarding included children (n=46), Eyes (n=57) and tumors

(n=117).

Table 2: Characteristics and response of tumors that progressed in size following initial laser

session.