Retrospective evaluation of outcome of laser photocoagulation for 217of discrete

retinoblastoma progression or recurrence intumors Sameh 217 laser treated tumor scars

Sameh E. Soliman, MD,1,2 * Zhao Xun Feng3, Brenda L. Gallie, MD, FRCSC.1,4-6

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

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

Ontario, Canada.

5Departments of Molecular Genetics and Medical Biophysics, Faculty of Medicine, University of

Toronto, Toronto, Ontario, Canada.

6 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

Financial Support: None

Conflicts of interest: None

Running Head: Retinoblastoma recurrenceDiscrete retinoblastoma photocoagulation

Number of Figures and Tables: 3 2 figures, 21 table

Word count: 3398/3000

Keywords: Retinoblastoma, laser, photocoagulation, recurrence, OCT, treatment, burden.

Abstract (362/350)

Objective: To evaluate discrete retinoblastoma response and outcome to primary and secondary

(post-chemoreduction) laser photocoagulation. Discrete retinoblastoma refers to endophytic

tumors with definitive borders and attached retina in GroupGroup A/B/C eyes (International

Intraocular Retinoblastoma Classification).

Design: Retrospective, non-comparative single-institutional interventional case series

Participants: Seventy-one retinoblastoma children with 217 discrete tumors in 88 eyes treated

with laser (February 2004-December 2018) with at least 1-year follow-up.

Methods: Data collected included age, family history, eye staging, pre-laser chemotherapy,

tumor largest basal diameter (LBD) in DD (at diagnosis and initial laser), number of laser

treatments by photocoagulation, OCT utilization, tumor recurrence and follow-up duration.

Initial treatment decision, tumor response and treatment outcome were described. Receiver-

operating characteristic analysis was used to determine the threshold LBD to predict outcome.

Multivariate analysis to study predictive tumor and/or treatment related factors for tumor

recurrence was performed using binary logistic regression analysis.

Main outcome measure: Treatment success evaluated primarily by laser frequency of to

achieveing complete tumor regression (CR) and frequency of tumor recurrence after CR, and

secondarily by the severity of tumor recurrence burden.

Results: All children had heritable retinoblastoma with median age of 5.4 months at diagnosis.

Primary versus secondary photocoagulation was performed for 117 and 100 tumors (93 after

systemic and 7 after periocular chemotherapy) respectively. Post-chemoreduction, tThe

median percentage LBD regressions were 0% (LBD ≤3DD), 30% (3-10DD) and 40%

(>10DD). Tumors ≤3DD treated with primary laser were significantly less likely to require

additional chemotherapy than >3DD. A median of 3 laser treatments (range: 0-15) achieved CR

in 212/217 tumors (2 eyes enucleated/5 tumors). Clinical versus OCT-guided photocoagulation

was utilized in 147/217 and 70/217 tumors respectively and both were comparable to achieve

CR. Recurrence occurred in 91/212 tumors (58 clinical, 33 subclinical). Multivariate analysis

showed OCT-guided treatment as the sole significant predictive factor for decreased recurrence

(P=0.010). Eleven clinical tumor recurrences required systemic/invasive therapy and 2 eyes (4

tumors) required enucleation. At 54 months median follow-up, 208 tumors (84 eyes) showed

CR with >1 year stability.

Conclusion: Laser photocoagulation is an effective non-invasive treatment for discrete

retinoblastoma ≤3DD as systemic chemotherapy showed minimal/no size reduction. CR is

achieved by either clinical or OCT-guided laser treatment. However, OCT guidance achieved

significantly fewer recurrences were predictive by OCT guidance.

Introduction

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

either discrete retinal tumor(s); where (tumor boundaries are well-defined with no or minimal

surrounding serous retinal detachment or tumor seeding),; or indiscrete tumor with ill-defined

boundaries due to extensive tumor, serous retinal detachment or tumor seeding.3 Eyes with

discrete tumors are commonly classified as GroupGroup A/B with the International Intraocular

Retinoblastoma Classification (IIRC)4 or cT1a/cT1b by the TNMH5 classification. The 3Three

mm (≈2 disc-diameters [DD]) largest tumor diameter (LBD) tumor is the diameter cut-off

separates eyes withupper limit for IIRC4 GroupGroup A/ and B and TNMH5 cT1a/ and cT1b.

Occasionally, eyes with IIRC4 groupGroup C/cT2 can also have discrete tumors.

Classically, the primary decision for treating focal laser therapy for discrete retinoblastoma

tumors is limited to tumors < 3 mm any dimension, and depend on size where tumors >3 mm

(IIRC4 B) are usually treatedrecommended for primary with chemoreduction (systemic or intra-

arterial chemotherapy) followed by consolidation focal therapy. The proximity of the tumor to

the fovea or the optic nerve favors a similar treatment approach. Small (< 3 mm) non-central

tumors (IIRC4 A) can be treated with primary laser therapy unless a larger tumor in either eye

required chemoreduction postponing laser treatment for all other tumors.6 The Proximity of the

<3 mm tumor to the fovea or the optic nerve (IIRC B and TNMH cT1b) is favorsalso

recommended for primary chemotherapy. a similar treatment approach.

Optical coherence tomography (OCT) has improved visualization and assessment of small

and even invisible tumors and recurrences.7,8 The concept of OCT-guided laser therapy evolved

to achieve precision outcomes levels.9,10 UnfortunatelyHowever, the current literature on laser

therapy for retinoblastoma is limited with by no definitive guidelines for indications and

techniques of laser.3 Moreover, the role of laser is sometimes not unmentioned or overlooked

when presentingin reports of results of newer treatment modalities as intra-arterial (IAC)11-14 or

peri-ocular (POC) chemotherapy (POC).15,16

In the current work, we retrospectively reviewed all eyes with discrete tumors that received

laser therapy at the Hospital for Sick Children (SickKids) our institute in the last 15 years in trial

to evaluate outcomes and potentially setsuggest guidelines for managing discrete tumors.

Methods

Study design

The study was approved by the Hospital for Sick Children (SickKids) Research Ethics

Board in Toronto, Canada and follows guidelines of the Declaration of Helsinki. This study is a

single-institution retrospective interventional case series.

Eligibility

Records of children with retinoblastoma managed at SickKids between (February 2004 to

and December 2018) were reviewed. Eligible discrete tumors included: i1) tumors arisen fromin

never- previously- detached retina in eyes staged as IIRC groupGroups A/B/C, or ii2) treated

with laser either primarily or following chemotherapy (systemic, intra-arterial or periocular),

with and iii3) minimal 12 months follow-up. Any discrete tumors treated with primary

cryotherapy/brachytherapy or poorly visualized were excluded not to confound evaluation of

effectiveness of laser therapy effectiveness.

Data collection

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

laser treatment (POC, IAC or systemic chemotherapy), tumor location and largest basal diameter

(LBD) in DD at diagnosis (tumor height was not included in size assessment, as it was not

consistently recorded), and initial laser treatment, technique and number of laser treatments,

OCT utilization during treatment and follow-up, treatment duration (time from diagnosis to last

laser therapy), tumor recurrence (timing, type, treatment details and final outcome) and length of

follow-up duration. Tumor height was not included in size assessment, as it was not consistently

recorded.

Assessment

Initial treatment decision, tumor response and treatment outcome were described. Different

Factors (tumor or treatment related) that might have contributed to outcome were studied. Tumor

related factors included LBD in DD, tumor height, location and type of tumor regression, while

treatment related factors includinged laser application technique, and role of , OCT and

chemotherapy utility. Treatment success was primarily evaluated scored by i) frequency of

achieving complete tumor regression (CR) and ii) frequency of tumor recurrence after CR. and

Secondarily, treatment success was qualified by the severity of burden of tumor recurrence

burden (either mild or severe) burden respectively includingconsidering i1) recurrence type

(subclinical/invisible or clinical), ii2) intensity of treatment scale required (focal or

systemic/invasive), iii)3) treatment duration (≤ or > 2 months or more), and iv4) treatment final

outcome (control or enucleation/spread).

Statistical analysis

Data Collected were summarized using frequency/percentage for categorical variables and

median/range for continuous variables. Baseline tumors’ 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 was used to define thresholds to

categorize tumor into groupGroups based on LBD. Likelihood ratios were calculated for all LBD

values with the highest selected as threshold. Univariate and multivariate logistic analysis was

performed to assess variable associations with tumor recurrence using binary logistic regression

analysis. All P-values reported are two sided and < 0.05 indicated significance. All analysis was

performed using SPSS Version 25 (IBM Corrop, Armonk, New York).

Results

Sample demographics

A total of 217 tumors from in 88 eyes of 71 children were enrolled for analysis (See consort

diagram, Figure 1). The median age at diagnosis was 5.4 months (range: 0.1-106 months). . All

children had positive a constitutional RB1 mutation pathogenic allele (H1)1,5 and 19 (27 %) (84

tumors; 32 eyes) had retinoblastoma family history. At first diagnosis, 166 (77%) tumors were

present while 51 (24%) tumors developed later. Table 1 summarizes the sample demographics

characteristics including eyes staging by IIRC4 and cTNMH5, tumor LBD and location. Forty-

seven tumors (34 eyes) were central and visually threatening (median LBD median = 5, DD;

range 0.1-15 DD). Non-central tumors included 122 post-equatorial tumors (43 eyes) (LBD

median LBD = 1, DD; range 0.1-11 DD) and 48 equatorial/pre-equatorial tumors (11 eyes)

(LBD median LBD = 0.5 DD;, range 0.1-10 DD).

Initial treatment decision (Figure 1)

Primary laser photocoagulation was decided for 117 tumors (54%) in 48 eyes/ of 37

patients: , among which 11 (9%) tumors were central, 71 (61%) were post-equatorial, and 35

(29.9%) were equatorial/pre-equatorial; with median LBD median LBD of 1, 0.5 and 0.3 DD

respectively.

Primary chemoreduction followed by consolidation laser photocoagulation was decided for

100 tumors (46%) in 40 eyes/ of 34 patients:, among which 36 (36%) tumors were central, 51

(51%) were post-equatorial, and 13 (13%) were equatorial/pre-equatorial, with median LBD of

9.5, 3 and 2 DD respectively. Primary systemic chemotherapy and POC by (topotecan) was used

to treat 93 and 7 tumors respectively. Ten of the eyes (with 28 tumors) had systemic

chemotherapy because of the other eye required chemotherapy for higher IIRC4 stage diseaseing.

Figure 1 flow-chartconsort diagram follows the studied tumors from initial decision to final

outcome.

Tumor response to initial chemotherapyreduction

Following primary systemic chemotherapy (median 4 cycles; range 1-6), 74/93 tumors

regressed, 14/93 had no change and 5/93 increased in LBD; the overall, median LBD change was

1 DD regression. Central tumors significantly regressed more definitively than non-central

tumors (LBD change, 4 vs 0.5 DD; P < 0.001). The median percentage LBD regressions were

0% for tumor with LBD ≤ 3 DD at diagnosis, 30% for 3DD ≤ LBD < 10 DD and 40% for LBD >

10 DD. There is a moderate significant positive correlation betweenThe tumor LBD at diagnosis

correlated with percentage LBD regression post- chemotherapy and tumor LBD at diagnosis (r =

0.486, P < 0.001, Figure 2)

ROC analysis (Supplementary table 1) identified LBD of 3 DD as the appropriate threshold

for analysis of tumor regression post-systemic chemotherapy, where 26/44 tumors ≤ 3 DD and

48/49 of tumors > 3 DD at diagnosis regressed in size. Post-chemotherapy, tumors ≤ 3 DD were

more likely to be associated with no LBD change/increase than tumors > 3 DD (41% vs 2%; P <

0.001). The likelihood of post-chemotherapy regression was insignificant not different between

central and peripheral tumors ≤ 3 DD (71% vs 57%; p=0.47).

Tumor regression pattern after sytemic chemotherapy was calcific (5, 7%), fish-flesh (45,

61%), mixed predominantly fish-flesh (24, 32%). The median LBD of tumor at diagnosis that

showed calcific regression was significantly larger than tumors that showed fish-flesh or

predominantly fish-flesh regression (10 vs 4.5 DD; P = 0.023). Two of 5 tumors with calcific

regression showed no residual tumor to photocoagulate.

Of 7 tumors that received primary POC, one tumor regressed, one had no LBD change and 5

tumors progressed; the median LBD change was 2 DD increase in size. Four tumors (3 patients,

4 eyes) required additional systemic chemotherapy.

Tumor response to initial laser photocoagulation session

The initial laser techniques for 215 tumors were total tumor photocoagulation (166, 77%),

selective tumor photocoagulation (21, 10%), encircling photocoagulation only (20, 9%) and both

encircling and total tumor photocoagulation (8, 4%). The tumor responses from the first laser

session tumor responses were complete regression (CR) in 42 tumors, partial regression in 155

tumors, progression in 16 tumors, no response one tumor showed no response, and one tumor

developed a transient concealing hemorrhage.

Laser technique for 42 tumors showing CR following a single laser session, was mainly total

tumor photocoagulation (40, 95%) with,of which 33 (79%) tumors having had primary laser

photocoagulation. The median LBD at laser was 0.3 DD (range: 0.1-4 DD) with 41/42 (98%)

tumors had LBD ≤ 3 DD and non-central location. Laser technique for 17 tumors with

progression/no response was mainly encircling photocoagulation (12, 70%) followed by

selective photocoagulation (4, 24%) with 16 tumors having primary laser photocoagulation. The

median LBD at laser was 3.5 DD (range: 0.6-16 DD) with 9/17 (53%) tumors had LBD > 3DD.

Initial progression/no response was likely to be associated with encircling than total

photocoagulation technique (60% vs 0.1%; P < 0.001)

Subsequent laser therapy

The median laser treatments and treatment duration to achieve CR were 3 sessions (range, 0-

15) and 3.2 months (range: 0-18) respectively, significantly shorter for primary photocoagulation

than primary systemic chemotherapy (1 vs 5 months; P < 0.001). There was a moderate positive

correlation between the tumor LBD at initial laser and the total number of laser sessions (r =

0.573, P < 0.001, Figure 2).

Subsequent chemotherapy

Initial total tumor photocoagulation often achieved complete remission without additional

chemotherapy compared to encircling photocoagulation (99% vs 70%; P < 0.001). For tumors

that received combined encircling and total tumor photocoagulation as initial technique, 7/8

(87.5%) tumors showed initial regression, 1/8 (12.5%) developed concealing hemorrhage

(resolved in 3 months) and all (100%) achieved CR without additional chemotherapy.

Of 117 tumors decided for primary laser photocoagulation, 18 tumors (48 eyes, 37 patients)

received additional chemotherapy: 8 tumors (3 patients, 3 eyes) received systemic chemotherapy,

9 tumors received POC and one tumor required both. Tumors ≤ 3 DD treated with primary laser

were significantly less likely to require additional chemotherapy than tumors > 3 DD (2% vs

67%, P < 0.001). Overall, 118 tumors (52 eyes, 44 patients) received invasive/systemic treatment

(POC or systemic chemotherapy) to achieve CR while 99 tumors (36 eyes, 27 patients) patients

received only laser therapy.

OCT versus Clinical laser guidance

OCT-guided and clinical-guided Laser was utilized in 70/217 and 147/217 tumors

respectively. Tumors treated with OCT guidance were more likely to regress following initial

laser than clinical guidance (97% vs 89%; P = 0.045). OCT-guided managed tumors received an

extra cycle of laser therapy compared to clinical guidance (median, 3.vs 2 cycles; P = 0.001).

OCT and clinical guidance were comparable to achieve CR after primary laser therapy (48% vs

44%; P = 0.586). The duration to achieve complete remission was insignificantly longer in OCT

than clinical guidance (median, 3.8 vs 3.3 months; P = 0.071).

Tumor recurrence and its burden

Of 217 tumors, 216 tumors achieved CR while one eye (1 progressive central tumor) was

enucleated following initial POC decision due to family preference to avoid systemic

chemotherapy.17 Another eye (4 tumors) with extinguished ERG and no vision (primary POC for

the main tumor) was enucleated within 6 months to reduce frequency of follow up.

Histopathology showed no residual active tumor.

Overall, 212 tumors from 86 eyes of 69 patients were followed and 91 (43%) tumors from

33 eyes of 25 patients showed recurrence; among which, 58 were clinically diagnosed and 33

(36%) were subclinical recurrences (OCT-diagnosed). The median time from last treatment to

recurrence was 3 months (range, 1-25 months). Median time from last treatment to subclinical or

clinical recurrence was not significantly different between OCT or clinical treated tumors (P =

0.11, 0.38 respectively).

In univariate analysis, tumor recurrence was significantly lower for a) tumors treated with

OCT versus clinical guidance (30% vs 49%; P = 0.009), b) tumors > 3 DD than ≤ 3 DD at

diagnosis (28% vs 49%; P = 0.006) and at initial laser therapy (27% vs 47%; P = 0.013) and c)

tumors treated ≥ 3 laser sessions than tumors treated with 1 or 2 laser sessions (35% vs 51%; P =

0.02). Tumor recurrence was not significantly different between a) central and non-central

tumors (33% vs 46%; P = 0.110) and b) tumors treated with primary chemotherapy and primary

laser (37% vs 48%; P = 0.126). (Table 2)

In multivariate analysis, after adjusting for tumor size at diagnosis and initial laser, tumor

location, chemotherapy usage, and number of laser sessions, OCT guided treatment was only

significantly associated with decreased recurrence (P = 0.010; Table 2).

All subclinical (33, 100%) and 47 (81%) clinical tumor recurrences were treated with focal

therapy only, while eleven clinical tumor recurrences required systemic/invasive therapy in the

form of systemic chemotherapy (3), IAC (1), POC (5), brachytherapy (1) and pars plana

vitrectomy for rhegmatogenous retinal detachment (1). However, 2 eyes (4 tumors, 3 recurrent

and one stable) were eventually enucleated due to aggressive recurrence.

The median treatment duration for recurrences was significantly longer for clinical than

subclinical recurrence (3 months vs 0 month; P = 0.002). The duration of treatment was shorter

for OCT diagnosed recurrence than clinically diagnosed recurrence (0 vs 2 month; P = 0.047).

OCT and clinical diagnosis were comparably likely to be treated with focal treatment only (92%

vs 86%; P = 0.46).

At final follow up (median: 56.3 months), 208 tumors from 84 eyes in 67 patients were

stable. All 71 children are alive and well. The size of final scar increased relative to initial tumor

in 26/208 (13%) tumors that was observed less in OCT-treated than clinically treated tumors but

with no significant difference (6% vs 16%; P = 0.056).

Discussion

Multiple treatment modalities have been introduced following the systemic chemotherapy

era to improve ocular salvage in advanced retinoblastoma namely intraocular chemotherapy

(intravitreal18,19 or intracameral20), intra-arterial chemotherapy21 and tumor endo-resection via

pars-plana vitrectomy in specific situations.22 However, earlier discrete tumors did not show the

same plethora of newer modalities for management and focal therapy using laser or cryotherapy

still represents the mainstay of management with limited role of chemotherapy.

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

affected child is the family proband or with positive family history.1 Positive family history was

found in 27% of children with discrete retinoblastoma in our institute. Establishing treatment

guidelines for discrete retinoblastoma can be recognized as 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,23 intensive OCT-

guided screening9 and laser photocoagulation of subclinical retinoblastoma.7

The 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/TNM). In our institute,6 if a tumor in either eye is large or either eye is IIRC B or

higher, systemic chemotherapy (4-6 cycles) is administered followed by focal consolidation.

Primary laser photocoagulation is utilized in screened familial cases that are discovered as IIRC

A in both eyes either concomitantly or sequentially or in asymmetric retinoblastoma presentation

where one eye is an IIRC A and the other eye is enucleated for advanced IIRC E or D. Periocular

topotecan15 was utilized as a bridge therapy in young children for systemic chemotherapy but

discontinued since 2015 due to technical difficulties and poor results.

The current retrospective evaluation showed that < 3DD (≈5 mm) tumors had minimal/no

regression with systemic chemotherapy regardless of location. This might be related to minimal

vascular supply at that size. Moreover, primary laser photocoagulation for < 3DD tumours was

significantly sufficient with less likelihood for requiring additional treatments. This would highly

influence our current practice. First, any discrete tumor <3DD would be primarily treated with

laser photocoagulation even if chemoreduction is planned for other tumors. Second, if all tumors

in one eye would be treated with primary photocoagulation, the chemoreduction choice can be

shifted towards IAC instead of systemic chemotherapy. Finally, as staging mainly aims to guide

decisions, maybe changing the cut-off point of IIRC A and B or TNM cT1a and cT1b to 5 mm

instead of 3 mm would be valuable.

Shields et al24,25 reported that discrete tumors (defined as tumor with no seeds or subretinal

fluid) show 100% success to chemoreduction and was comparable to groupGroup I by the Reese-

Ellsworth classification system26 that used 4 DD as the cut-off point. Unfortunately, minimal

analysis to chemoreduction response or consolidation therapy details was provided. The only

relevant data shows that 44% of discrete tumors (IIRC A/B; 50/113 eyes) shows a flat chorio-

retinal scar regression pattern while 36% (41/113 eyes) showed mixed calcific and fish-flesh

regression after chemoreduction and focal therapy without analysing separate effects of either.27

Kim et al28 addressed the necessity of chemoreduction in IIRC groupGroup B eyes and the

timing of laser photocoagulation conundrum. They found that 3 cycles of systemic chemotherapy

lead to a 13% decrease in mean LBD for mean LBD of 6 mm (≈3.5DD) and any additional

chemotherapy cycles were associated with increased LBD. They did not correlate individual

tumor size changes in their report and did not study effect of chemotherapy on tumors in IIRC A

eyes (<3 mm). Our data show that tumors with <5mm (≈3 DD) LBD showed minimal or no

regression after chemotherapy and a positive correlation exists between initial size and

percentage reduction after chemotherapy. Chemoreduction using IAC is reported to improve

outcomes in IIRC A-C eyes than systemic chemotherapy.12,29,30 However, minimal analyzable

data are presented to identify the individual IIRC groupGroup response to IAC rather than

compiling less advanced groupGroups A-C together in stating outcomes.

Malipatna et al.15 described our technique for POC using topotecan in a fibrin sealant and

presented its promising preliminary results that showed effectiveness in minimal tumor burden

situations. In 2015, due to technical difficulties, complications31,32 and poor long-term results,

and this technique were discontinued. Our data supported this decision as approximately half of

the cases initially treated with this technique were eventually enucleated. The concept of

periocular chemotherapy is still valid and currently we are investigating a new sustained-release

topotecan within an episcleral implant (chemoplaque)33 that showed promising results in discrete

tumor recurrences.

The introduction of OCT34 helped better assessment of small discrete and even invisible

tumors and facilitated the introduction of OCT-guided tumor management9 concept where the

OCT scans can diagnose, localize and monitor laser treatment sufficiency for small tumors.

Moreover, OCT-guided follow-up of treatment scars can detect subclinical residual or recurrent

tumor growth and guide its laser photocoagulation in a similar way.7,10 Early diagnosis of

subclinical recurrence and treatment reduce the burden of treatment to focal non-invasive

therapies with minimal treatment scar expansion.

Potential tumor and treatment related parameters that might reduce recurrences were

explored. Univariate analysis suggested that tumors > 3DD, treated with ≥ 3 laser sessions and/or

with OCT guidance to be significantly associated with reduction in tumor recurrence. These

parameters are highly interdependent as tumor size and number of laser treatments showed

positive correlation. Furthermore, OCT guided treatment required extra treatment sessions.

However, OCT-guided laser photocoagulation was recognized as the sole significant parameter

in multivariate analysis.

The current analysis pointed that OCT-guided treatment significantly increased likelihood of

tumor regression following initial laser therapy as OCT detected any skipped untreated area and

verified complete tumor photocoagulation.10 Despite requiring a median of a single extra laser

session than clinically treated tumors, OCT-treated tumors showed less tumor recurrences. This

is attributed to the OCT ability to detect subclinical residual tumor and verify its complete

treatment, preventing its regrowth into a clinical recurrence. Moreover, OCT detected tumor

recurrences required less treatment duration and burden than clinically detected recurrence as

smaller tumor requires less treatment.7 Finally, OCT guided treatment showed observed minimal

final scar size expansion because of precise localization of the tumor edge and laser application.

These results further empowers the OCT utility and necessity in managing retinoblastoma.

Familial cases are the primary beneficiary from OCT as it screens, diagnose and guide treatment

of tumors at the invisible level.7

This study is limited by its retrospective nature with its known potential flaws. Technical

aspects of laser therapy including other non-photocoagulation techniques as thermotherapy and

trans-scleral laser were not evaluated; as well as laser parameters settings including power,

duration, spot size and number of applications. As this work is within a single institute with

uniform laser parameter settings and technical experience, these technical aspects was justifiably

omitted from analysis. However, the sample size is potentially adequate to draw valid

conclusions regarding photocoagulation.

In conclusion, laser photocoagulation is an effective non-invasive treatment for discrete

tumors (IIRC GroupGroup A/B/C) retinoblastoma ≤ 3 DD as systemic chemotherapy showed

minimal/no size reduction. Complete regression is comparable achieved by clinical or OCT-

guided laser treatment. However, fewer recurrences and lower subsequent treatment burden was

achieved by OCT.

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. Dimaras H, Corson TW, Cobrinik D, et al. Retinoblastoma. Nat Rev Dis Primers. 2015;1:15021.3. Soliman S, Kletke S, Roelofs K, VandenHoven C, McKeen L, Gallie B. Precision laser therapy for

retinoblastoma. Expert review of ophthalmology. 2018;13(3):149-159.4. Murphree AL. Intraocular retinoblastoma: the case for a new group classification.

Ophthalmology clinics of North America. 2005;18:41-53.5. 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; 2017:819-831.6. National Retinoblastoma Strategy Canadian Guidelines for Care / Stratégie thérapeutique du

rétinoblastome guide clinique canadien. Can J Ophthalmol. 2009;44(Supp 2):S1-88.7. Soliman SE, VandenHoven C, MacKeen LD, Gallie BL. Secondary Prevention of Retinoblastoma

Revisited: Laser Photocoagulation of Invisible New Retinoblastoma. Ophthalmology. 2019.8. Park K, Sioufi K, Shields CL. Clinically Invisible Retinoblastoma Recurrence in an Infant. Retinal

cases & brief reports. 2019;13(2):108-110.9. Soliman SE, VandenHoven C, MacKeen LD, Heon E, Gallie BL. Optical Coherence Tomography-

Guided Decisions in Retinoblastoma Management. Ophthalmology. 2017;124(6):859-872.10. Soliman SE, VandenHoven C, Mackeen LD, Gallie BL. Vision and visual potential for perifoveal

retinoblastoma after optical coherence tomographic-guided sequential laser photocoagulation. Br J Ophthalmol. 2019;103(6):753-760.

11. Francis JH, Levin AM, Zabor EC, Gobin YP, Abramson DH. Ten-year experience with ophthalmic artery chemosurgery: Ocular and recurrence-free survival. PLoS One. 2018;13(5):e0197081.

12. Abramson DH, Marr BP, Brodie SE, Dunkel I, Palioura S, Gobin YP. Ophthalmic artery chemosurgery for less advanced intraocular retinoblastoma: five year review. PLoS ONE. 2012;7(4):e34120.

13. Yousef YA, Soliman SE, Astudillo PP, et al. Intra-arterial Chemotherapy for Retinoblastoma: A Systematic Review. JAMA ophthalmology. 2016;134(6):584-591.

14. Shields CL, Manjandavida FP, Lally SE, et al. Intra-arterial chemotherapy for retinoblastoma in 70 eyes: outcomes based on the international classification of retinoblastoma. Ophthalmology. 2014;121(7):1453-1460.

15. Mallipatna AC, Dimaras H, Chan HS, Heon E, Gallie BL. Periocular topotecan for intraocular retinoblastoma. Arch Ophthalmol. 2011;129(6):738-745.

16. Shields CL, Fulco EM, Arias JD, et al. Retinoblastoma frontiers with intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Eye (Lond). 2012.

17. Soliman SE, Ulster A, MacDonald H, et al. Psychosocial determinants for treatment decisions in familial retinoblastoma. Ophthalmic Genet. 2017;38(4):392-394.

18. 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.

19. 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.

20. Munier FL, Gaillard MC, Decembrini S, Bongiovanni M, Beck-Popovic M. Intracameral Chemotherapy (Melphalan) for Aqueous Seeding in Retinoblastoma: Bicameral Injection Technique and Related Toxicity in a Pilot Case Study. Ocul Oncol Pathol. 2017;3(2):149-155.

21. 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.

22. Zhao J, Li Q, Wu S, et al. Pars Plana Vitrectomy and Endoresection of Refractory Intraocular Retinoblastoma. Ophthalmology. 2018;125(2):320-322.

23. Soliman SE, Dimaras H, Khetan V, et al. Prenatal versus Postnatal Screening for Familial Retinoblastoma. Ophthalmology. 2016;123(12):2610-2617.

24. Shields CL, Mashayekhi A, Demirci H, Meadows AT, Shields JA. Practical approach to management of retinoblastoma. Arch Ophthalmol. 2004;122(5):729-735.

25. Shields CL, Mashayekhi A, Au AK, et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology. 2006;113(12):2276-2280.

26. Ellsworth RM. The practical management of retinoblastoma. Trans Am Ophthalmol Soc. 1969;67:462-534.

27. Shields CL, Palamar M, Sharma P, et al. Retinoblastoma regression patterns following chemoreduction and adjuvant therapy in 557 tumors. Arch Ophthalmol. 2009;127(3):282-290.

28. Kim JW, Aziz HA, McGovern K, et al. Treatment Outcomes of Focal Laser Consolidation during Chemoreduction for Group B Retinoblastoma. Ophthalmol Retina. 2017;1(5):361-368.

29. Munier FL, Beck-Popovic M, Chantada GL, et al. Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. "Alive, with good vision and no comorbidity". Prog Retin Eye Res. 2019:100764.

30. Manjandavida FP, Stathopoulos C, Zhang J, Honavar SG, Shields CL. Intra-arterial chemotherapy in retinoblastoma - A paradigm change. Indian Journal Of Ophthalmology. 2019;67(6):740-754.

31. Milne M, Soliman SE. Prosthetic Fabrication in Identical Triplets with Bilateral Retinoblastoma and a Single Enucleated Globe Using a Myoconjuntival Enucleation Procedure. Journal of Ophthalmic Prosthetics. 2015;20(1):5-11.

32. Astudillo PP, Durairaj P, Chan HS, Heon E, Gallie BL. Hypersensitivity to sub-Tenon's topotecan in fibrin adhesive in patients with retinoblastoma. J AAPOS. 2015;19(1):86-87.

33. Gallie B, Soliman S, Shaikh F, et al. DEPICT HEALTH Supports Clinical Trial of Sustained-release Episcleral Topotecan for Retinoblastoma. Invest Ophtalmol Vis Sci. 2019;60(9):2322.

34. 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.

Tables

Table 1: Demographics Characteristics of the studied sample.

Table 2: Multivariate analysis using Binary logistic regression analysis of factors associated

with tumor recurrence

Figure Legends

Figure 1: A Flow chart following the studied sample tumor numbers from initial treatment

decision through subsequent management until remission until final outcome either

stability or recurrence demonstrating utilized treatments at each step. Lost tumors are

highlighted in red boxes (boxes carrying same symbol */# denote same euncleated eye).

Figure 2: Scatterplots of A) Largest basal diameter of tumor at initial diagnosis and the

percentage size regression following primary systemic chemotherapy B) Largest basal

diameter of tumor at initial laser session and the number of laser sessions to induce

complete remission