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: 2 figures, 3 tables, 1 supplementary table

1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

Word count: 3378/3000

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

prevention.

Conferences: A part of this manuscript was 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).

2

1

2

3

4

5

6

7

Synopsis (35343/35)

Primary laser photocoagulation monotherapy for discrete retinoblastoma (particularly ≤3 disc-

diameters) spared two-thirds of patients and/or eyesa significant proportion of patients/eyes from

chemotherapy (systemic, intra-arterial and periocular) and/or plaque radiotherapy without ocular

complications, tumour progression, extraocular spread or systemic metastasis.

3

1

2

3

4

5

6

Abstract (24795049/250)

Background/Aim: Laser photocoagulation is less invasive than chemotherapy (systemic, intra-

arterial or periocular) and/or brachytherapy. We studied the safety and efficacy of laser as as

treatment modalitiesprimary monotherapy for discrete retinoblastoma with well-defined borders

and attached retina. We studied the its safety and efficacy of primary laseras primary

photocoagulation in managing discrete endophytic retinoblastoma with well-defined borders and

attached retina.

Methods: A single-institution retrospective non-comparative review (2004-2018) of discrete

retinoblastoma children tumors managed with primary laser (February 2004-December 2018

monotherapy).used were( 532 or or 810 nm wavelength, duration 0.5-11.0 second duration and

and power was titrated until tumor achieved desired tumor whitening). Treatment Efficacy

success was defined evaluated by tumourtumor initial remission and final long-term stability by

non-invasive therapy (laser/cryotherapy)laser alone without invasive therapy. Invasive therapies

included avoiding non-laser therapies. Safety was evaluated by frequency of laser-related

complications and non-uncontrollable tumor progression.chemotherapy (systemic, intra-arterial

or periocular) and/or , plaque radiotherapy and/or pars-plana vitrectomy.

Results: Eligible were 1127 tumours in 557 eyes of 446 patients. Laser alonemonotherapy

(median 2 sessions) achieved initial stability remission in 95/112 (85%)7 tumours. Initial

encircling only while 5/117 required additional cryotherapy. Encircling laser with encircling

techniquephotocoagulation was associated with tumour progression (910/113, oOne tumour had

vitreous seeding) compared to direct or combined photocoagulation techniques (0/947 and 0/7

tumourstumors respectively, P < = 0.001). Direct laser had no vitreous seeding, haemorrhage, or

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

injury to vital structures. Tumour recurrences developed in 524/112 (46%)3 tumours , but repeat

laser monotherapy achieved long-term stability, except 56 tumor recurrencess that which

required invasive therapyy to achieve final stability. A single laser session achieved final

stability for 16/112 (14%)7 tumours. ROC analysis identified threshold largest basal diameter of

3 disc-diameters (DD) for successful non-invasive therapylaser monotherapy, . With non-

invasive therapylaser alone, where 92100/106 (87%)11 of tumourstumors ≤ 3 DD and 0/6 >3 DD

achieved initial finallong-term stability with laser monotherapy (P < 0.001). No eyes had tumour

progression or extraocular disease. Overall, 35/55 (64%) eyes and 24/44 (55%) patients achieved

finallong-term stability with laser monotherapy. No eyes werewas enucleated for uncontrollable

tumor progression.y.

29/46 patients (93/117 tumours) avoided invasive therapies. Invasive therapies achieved final

stability to 21/117 tumours while a stable eye (4 tumours) was enucleated to avoid frequent

follow-up per parent choice.

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

primary laser photocoagulationlaser monotherapy, avoiding sparing a significant proportion of

patients/eyes from more chemotherapy or other invasive therapies. in 96/111 tumours.

5

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

Introduction

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

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

detachment (RD) or tumour seeding), or indiscrete tumours with ill-defined boundaries due to

extensive tumour, serous RD or tumour seeding.3 Eyes with discrete tumours are classified as

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

TNMH staging. Largest Basal Diameter (LBD) of Three 3mm (≈2 disc-diameters [DD]) Largest

Basal Diameter (LBD) is the cut-off size between Groups A and /B and cT1a/cT1b. Group C/cT2

eyes may also have discrete tumours.

Small discrete tumours are now frequently detected by prenatal or postnatal screening for

high risk familial retinoblastoma.5,6 Optical coherence tomography (OCT) now improves

detection and assessment of small retinoblastoma.7,8 Primary chemotherapy (systemic, periocular

and intraarterial) versus primary focal therapy using cryotherapy, laser therapy and plaque

radiotherapy have been reported as treatment options.9-14 However, there are no definitive

guidelines regarding treatment of discrete retinoblastoma tumours other than its the initial

classification stage (IIRC A, B or C).

At our institute, laser photocoagulation is often considered and utilizeused as monotherapy

for discrete retinoblastoma tumourstumors as primary management. In the current work, we

evaluated the safety and effectiveness of this approach. We identify predictive factors for

ultimate outcomes and recommend draft guidelines for consideration.

6

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

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 tumourstumors were: i) 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. DDiscrete tumoursExcluded were discrete tumors that

primarily treated withreceived other primary treatment modalities as primary treatment, or were

treated with cryotherapy at any orpoint, associated with non-discrete tumours, or or poorly

visualized, were excluded.

Data collection

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

tumour location, LBD in DD at diagnosis (tumour height was not consistently recorded so was

not included in size assessment), initial laser technique (encircling/direct/combined), number of

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

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

outcome) and follow-up duration.

7

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

Laser techniques definitions

Discrete retinoblastoma tumours were primarily treated by laser therapy if <3 mm (IIRC A,

B, TNMH cT1a), non-central and when primary systemic chemotherapy is not required for larger

tumour(s) in the other eye.15 Primary laser photocoagulation (technique, see technique below)

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

document tumour response. If any tumour regression occurred, the laser treatments would

continued in multiple sessions 3 weeks apart during routine EUAs until complete regression was

documented by a flat scar, either clinically or by OCT. If the tumour showed no response or

tumour progression, the treatment would shifted to chemotherapy (systemic, intra-arterial,

periocular or intravitreal) depending on tumour size, location and occurrence of vitreous seeds.

Stability (i.e. flat scar) was defined as (i) initial stability with absence of tumour activity at two

consecutive follow-ups after last treatment and (ii) final stability with absence of recurrence > 12

months post-treatment follow-up.

With clinical or OCT-guidance, various laser techniques3 were utilizeused: (i) encircling

photocoagulation, (tumour surrounded by 2 or 3 rows of confluent laser photocoagulation just

outside the tumour margin; 532 nm laser was preferred over 810 nm laser to attain precise

localization and treatment effect); (ii) direct photocoagulation, (direct whole tumour surface

treated, higher tumours with 810 nm); (iii) combination of encircling and direct

photocoagulation. Encircling Photocoagulation was intended for larger peripheral tumours (

3DD) as initial laser technique to interrupt the tumour vascular supply to achieve initial size

reduction for later direct tumour photocoagulation. Other tumours (< 3DD) were precisely

photocoagulated to preserve vital areas (fovea/optic disc). A combination of these approaches

was utilizeused in for larger tumours.3,16

8

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

Laser3 was delivered through indirect ophthalmoscopy utilizing using either 20 or 22

Diopter condensing lenses. Generally, the lowest power that can produce tumour whitening were

was utilizedused. Laser power was titrated by direct application over tumours until the desired

whitening reaction was seen. However, when peripheral, titration of power sometimes was

performed sometimes over an adjacent normal retinal area as threat to vision was negligible.

Laser duration ranged from 0.5-1 second according to tumour height. When theWith 810 nm

laser when was utilized, photocoagulation rather than thermotherapy parameters was were

utilizeappliedd (i.e. small spot, short 0.7-1.5 second pulses rather than long period application).17

Outcome aAssessment

Laser plans, techniques, responses and outcomes were described. Factors (tumour or

treatment-related) that might contribute to outcome were studiedconsidered. Tumour-related

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

photocoagulation technique and OCT utility. We defined Initial Remission as absence of tumour

activity at two consecutive follow-up visits after last treatment. Long-term stability was defined

as absence of recurrence >12 months post-treatment follow-up.

The primary outcomes were treatment safety and efficacy. Treatment safety was assessed

by frequency of laser related complications and non-uncontrollable tumor progression.

Treatment efficacysuccess was assessedscored when there was by achieving long-term stability

without chemotherapy or other invasive procedures. We define invasive therapy as use of

chemotherapy (systemic, intraarterial, periocular) or plaque radiotherapy. Non-Uncontrollable

tumor progression refers to progression despite invasive therapies, necessitating enucleation or

external beam radiation.

9

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

Treatment success was defined as achieving final stability without chemotherapy or other

invasive procedures. Subsequent treatment required was assessedAs secondary outcomes, we

also assessed by frequency of recurrence after initial stability remission and recurrence burden

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

invasive),ve); iii) treatment duration (≤ or > 2 months), and iiiv) final outcome (control or

enucleation/extraocular spread). Subclinical (invisible) recurrence refers to OCT detected tumour

activity (small hyperreflective homogenous rounded/oval slightly elevated tumour mass) in an

apparently clinically apparent stable scar. Non-invasive therapies included focal 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 tumour 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 tumour into groups by calculating likelihood ratios for LBD values with the highest

ratio selected as threshold. Univariate and multivariate logistic regression analysis was

performed to assess variable associations with tumour recurrence. Reported P-values are two-

sided and <0.05 indicated significance. Analysis was performed using SPSS Version 25 (IBM

Corp, Armonk, New York).

10

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

Results

Sample demographics

A total of 1127 tumours in 557 eyes of 446 children (22 females, Supplementary table 1)

who received primary photocoagulation were reviewed. The median age at diagnosis was 5.8

months (range: 0.1-11198.6 months). All children had a constitutional RB1 pathogenic allele

(H1)1,18 and 17 (37 %, 72 tumours; 28 eyes) had retinoblastoma family history. At first diagnosis,

658 (58%) tumours were present while 479 (42%) tumours developed later. All children

eventually developed bilateral retinoblastoma. Table 1 summarizes the sample characteristics

including staging (IIRC4 and cTNMH), tumour LBD and location.

Tumour response to initial photocoagulation and subsequent management (Figure 1)

After one laser session, 35 tumours (24 eyes) showed complete initial regression remission

designated as initial absence of tumor activity stability onafter 2 follow-ups; 6872 tumours (389

eyes) showed variable degrees of regression while 910 tumours (89 eyes) showed progression.

Four Two eyes had tumours that progressed (34) and tumours that regressed (45) after initial

laser. The initial laser technique was direct (947, 843%), encircling (113, 101%), or combined

encircling and direct photocoagulation (7, 6%).

Tumours that showed initial stability remission after one laser treatment had a median size

of 0.3 DD (range: 0.1-3.0 DD), ; 23 tumours in 13 Group A eyes and 12 tumours in 11 Group B

eyes. Furthermore,Treatment for 34/35 (97%) tumours were treated withconsisted of direct

tumour photocoagulation and for 1/35 (3%), with combined encircling and direct tumour

photocoagulation. All tumours received continued observation.

11

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

Of 6872 tumours that showed partial regression, 368 were in 201 Group A eyes, 302 in 17

Group B eyes and 2 in 1 Group C eyes. The initial laser techniques were direct (603), encircling

(23) or combined photocoagulation (6). The treatment of 1 tumour (1 eye) was switched to

systemic chemotherapy due to minimal regression in an 8- DD tumour after initial laser (young

age too young at presentation for primary IVC). Additional laser sessions at 3-4 weeks interval

were continued for 6771 tumourstumors and,, four of which in 4 eyes had adjuvant cryotherapy

and 5761/67 (85%)71 achieved initial stabilityremission. The median number of laser sessions

was 2 (range, 21-10 sessions) for tumours in Group A/B eyes and 4.5 (range, 4-5 sessions) for

tumours in Group C eyes. The technique for subsequent laser sessions was exclusively direct

photocoagulation for 70/71 tumors and 1/71 tumor received one additional encircling laser

before being switched to systemic chemotherapy. A total of tTen tumours (7 eyes) did not show

the desired regression and eventually required chemotherapy (3 IVC, 6 periocular chemotherapy

[POC] and 1 both) to achieve initial stabilityremission.

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

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

the median tumour size was 2.5 DD (range: 0.6-5 DD). The subsequent treatment was continued

direct laser photocoagulation 4 tumours (3 eyes), adjuvant cryotherapy 1 tumour (1 eye), POC 1

tumour (1 eye), plaque radiotherapy 1 tumour (1 eye), and systemic chemotherapy 3 tumours (3

eyes). Eventually, 34 tumours (23 eyes) were achieved initial remission controlled with laser ±

cryotherapylaser monotherapy while 6 tumours (6 eyes) required invasive therapies.

Among tumours treated with encircling photocoagulation, 910/113 (8277%) progressed after

initial laser compared to 0/947 (0%) tumours treated with direct tumour photocoagulation (P <

0.001) and 0/7 (0%) treated with combined technique (P = 0.001). Of 1127 tumours, 17 tumours

12

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

(14 eyes) eventually required invasive therapy to achieve initial stabilityremission. One eye had

vitreous seeding after encircling photocoagulation controlled with two intravitreal chemotherapy

injections. Direct tumour laser produced no vitreous seeding, incidents of haemorrhage,

misplaced laser or injury to vital structures.

Initial Stabilityremission

Overall, 95100 tumours from 413 eyes achieved initial stability remission with only non-

invasivelaser therapy monotherapyincluding 25/27 (93%) Group A, 17/29 (57%) Group B and

1/1 (100%) Group C eyes. Laser photocoagulation solely, controlled 95 tumours in 39/57 (68%)

eyes. Seventeen tumours in 14 eyes required invasive therapiesy (7 systemic chemotherapy, 8

POC, 1 both, and 1 brachytherapy) including 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 ofto

achieveing initial stability remission or long-term stability with or without invasive therapy;

where, 95100/10611 (90%) of tumours ≤ ≤3 DD achieved initial stability remission with non-

invasive therapylaser alone monotherapy compared to 0/6 (0%) tumours > 3 DD (P < 0.001).

Furthermore, 65/11 (5545%) central tumours received invasive therapy comparelaser

monotherapy to achieve initial remission compare to 273/305 (909%) equatorial/pre-equatorial

tumours (P = 0.01105) and 629/71 (8713%) post-equatorial tumours (P = 0.007). Finally,

invasive therapy was requiredlaser monotherapy was used for 47/113 (3654%) of tumours

treated with initial encircling technique, compared to 8410/947 (8910%) treated with direct

tumour photocoagulation (P < 0.001) and 70/7 (100%) treated with combined encircling and

photocoagulation (P = 0.00176). Table 3 compares the clinical characteristics and outcome of

tumours initially treated with direct tumour versus encircling photocoagulation technique.

13

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

Recurrence and Final long-term sStability

All Ttumours were followed for a median of 721 months (range, 13-172 months) from date

of last treatment. One eye (4 tumours) was enucleated despite no evidence of tumour activity to

reduce follow-up frequency by family preference due to (long range travel difficulties); three 3/4

of the 4 tumours had achieved initial stability remission with laser photocoagulation only

monotherapy and one was treated with additional POC. This eye showed extinguished ERG and

no vision19 and was enucleated 9 months from last active treatment. Histopathology confirmed

no residual active tumour.

Overall, of 95100 tumours that achieved initial stability remission with non-invasive

therapylaser monotherapy, 4850 (510%) tumours in 279 eyes developed a degree of tumour

recurrence: 346/4850 were diagnosed clinically and 14/4850 were diagnosed sub-clinically by

OCT. Median time from last treatment to recurrence was 4 months (range, 1-25 months). A

median of 2 laser sessions (range, 10-7) were used to treat 456 (942%) tumours in 245 eyes.

Invasive therapy was required to control 34 tumours in 34 eyes (1 brachytherapy, and 23 POC).

Of 35 tumours that achieved initial stability remission with one laser session, 16 (46%) from 11

eyes achieved full long-term stability with no additional treatment.; 10 eyes/patients with 15

tumours were completely treated after one laser session, and 1 stable tumour was in an eye that

required additional treatment for a different tumour. Tumour recurrence developed in 19 (54%),

and 1/19 received invasive therapy. Overall 93/117 tumours achieved full stability using non-

invasive therapy only with median follow-up of 73 months (range, 13-168 months).

Of 17 tumours that achieved initial stability remission with invasive therapy, 4 (24%)

tumours developed recurrence 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

14

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

therapy (1 IVC and 1 POC). A median of 4 laser sessions (range, 2-9) were used to treat these

recurrent tumours.

Need for invasive therapy for tumour recurrence was less if treated with initial non-invasive

therapy alone (8% v 50%; P = 0.010). Aside from 4 tumours (1 eye) enucleated for social reason,

all other 113 tumours were successfully salvaged.

Overview

Overall, 92/112 (82%) tumours from 43 eyes achieved long-term stability usingby laser

monotherapy with median follow-up of 73 months (range, 13-168 months). Moreover, 92/106

(87%) of tumors ≤3DD and 0/6 >3DD achieved long-term stability with laser monotherapy

(P<0.001). Need for invasive therapy for tumour recurrence was less if laser monotherapy was

used to achieved initial remission (6% v 50%; P = 0.004). Aside from 4 tumours (1 eye)

enucleated for a social reason, all other eyes with 108 tumours were successfully salvaged. When

we overviewOver the entire treatment course, Throughout the entire treatment, 249/446 (5563%)

patients avoided invasive therapy and avoided invasive therapywere to achieved full long-term

stability with laser monotherapy. In turn, 359/557 (648%) eyes (76 tumours) achieved full

long-term stability with non-invasive therapylaser only monotherapy including 213/257

(845%) Group A, 135/29 (4552%) Group B and 1/1 (100%) Group C eyes. One eye was

enucleated not because of tumour activity.

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

remission and OCT-guidedance treatment, none were significantdid not significantly predict or

for tumour recurrence nor recurrence needing invasive therapy. Visual acuity of 20/20 was

recorded for 446 eyes with 97102 non-central tumours. Of 10 eyes with 11 central, (visually-

15

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

threatening) tumours, the final scar size in relation to the initial tumour size was unchanged for 8

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

systemic chemotherapy). More cCentral tumours treated with non-invasive therapylaser

monotherapy werewas more likely showed stable scar size compared tothan those treated with

invasive therapy (60% v 060%; P = 0.026).

Discussion

Discrete retinoblastoma usually presents in the context of heritable retinoblastoma,5 either

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

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

may be considered thought of 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,5 intensive OCT-guided screening20 and laser

photocoagulation of invisible retinoblastoma.7

Initial management decisions forof a discrete tumour depends on tumour size (LBD and

height), location, proximity to the fovea and optic nerve, and the retinoblastoma stageing for

both each eyes (IIRC/TNMH), the. At SickKids,15 primary treatment decisive decision parameter

is retinoblastoma staging considering both eyes.15 If either eye will requires systemic

chemotherapy (both eyes staged as Group B with central tumours, or one eye staged IIRC Group

C, cT2a or higher with clinical signs predictive of low histopathologic risks21,22),. laser therapy

would beis deferred until completion of chemotherapy (to avoid cutting off the blood supply to

tumor) completion and would beis considered as consolidation rather than primary therapy.

16

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

If one eye requires primary enucleation (advanced IIRC D/E, cT2b/T3), primary IAC14 or

initially uninvolved, the other eye is considered for primary laser photocoagulation when discrete

retinoblastoma is classified as IIRC A. If classified as IIRC B eyes, the tumour location and size

are important considerations. Small ( 3mm) central but foveal sparing and larger peripheral (3-

8 DD) tumours would be given a trial primary laser. Eyes with IIRC C staging can be only

considered for trial primary laser if harboring a discrete tumour with few localized vitreous

seeds.

In certain circumstances, very young age at presentation (< 3 months) favored adopting a

trial primary laser. Young age of presentation 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 utilizeused because of immature

infantile liver and kidney and higher incidence of complications.5 Soliman et al.23 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.24 reported more

abortive IAC procedures with infants 10kg.

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

systemic complications of systemic chemotherapy (mainly chemotherapy-induced ototoxicity23

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

complications.25,26 It is consistent with the principle of nonmaleficence to use the least invasive

means to achieve tumor control without compromising oncologic outcomes. 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

over half of patients avoided were spared from both chemotherapy or brachytherapy systemic

17

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

chemotherapy and IAC to achieve tumour control. None of our patients developed tumour

growth to the extent of eye loss or extraocular disease. The only eye enucleated in our cohort was

because of social factors.27

Generally, laser for tumours is either photocoagulation or thermotherapy. In

photocoagulation (532 and 810 nm), high power, small-spot size for short duration causes

tumour tissue coagulation and eventual necrosis. In Thermotherapy (810 and 1064 nm), low

power, large-spot size and long duration laser energy affects the retinal pigment epithelium with

resultant hyperthermia. Resultant thermal energy in thermotherapy is considered less than

photocoagulation but achieves deeper penetration making it preferable for larger and bigger

tumours than photocoagulation.3

Abramson et al.12 utilizeused primary Transpupillary thermotherapy ThermoTherapy (TTT)

in 91 tumours in 22 eyes and reported success in 84/91 tumour without invasive therapies

(systemic chemotherapy, pPlaque radiotherapy or POC) with best results if tumour is <1.5 DD.

The main limitation was the utility of salvage treatments for other tumours in the same or other

eye of some patients rendering controversial the interpretation attribution of success to only the

TTT controversial. Scar migration is a well-known side effect of TTT after chemoreduction.28 In

our cohort, we utilizeused only photocoagulation because of smaller spot size and better precise

localization. Primary photocoagulation solely controlled 8493% of IIRC Group A eyes and

4557% 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 photocoagulation,29 never occurred in our cohort.

Only one progressive tumour seeded after encircling photocoagulation, which. However, it was

18

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

successfully managed by intravitreal chemotherapy. It is worth mentioning that Current

intravitreal chemotherapy technique30,31 and its effective results has changed the perspective

towards vitreous seeding. Furthermore, There were no cases instances of hemorrhage, misplaced

laser or iatrogenic burns of vital structures. Initial sole eEncircling laser photocoagulation proved

unsuccessful solely to prevent avoid initial tumour progression. None of the tumours treated with

direct photocoagulation or combined technique had progression of the initial tumour progression.

This data discourages its use of encircling laser as the initial laser technique in chemotherapy-

naïve discrete tumours.

Hamel et al17 studied laser therapy (combined primary and post chemotherapy) in 46 eyes of

35 retinoblastoma patients but primary and consolidation laser therapy were not compared.

Tumour size was evaluated by height (using B-scan) rather than LBD. Complications as

including cataract, iris burn, and vitreous traction were related to increased sessions of

laser/cryotherapy for one tumour. This can may be attributed to tumour recurrences diagnosed

based onby clinical assessment, without the advantage of OCT. In our present cohort, tumour

recurrence occurred in 5147% of tumourstumors, . They were all detected during routine follow

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

scars detected subclinical residual/recurrent tumour growth and guided further laser

photocoagulation.7,16

Early management of subclinical recurrence reduced the treatment burden to focal non-

invasive therapies with minimal treatment scar expansion. OCT-detected tumour recurrences are

anticipated to require less treatment duration and burden than clinically-detected recurrence.7

Generally, OCT was reported to improve assessment of small/invisible discrete tumours32 and

19

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

guide tumour management20 to by diagnosinge, localized small tumours and monitoring

sufficiency of laser treatment sufficiency.

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

primary chemoreduction was and laser techniques were not randomized for IIRC group B eyes.

Technical aspects of laser parameters (power, duration, spot size and number of applications)

were not evaluated and are were specific to the laser on the day of use and were omitted from

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

the earlier study period. Cryotherapy was used for 5 tumours which might have affected

outcomes. However, cryotherapy is a non-invasive modality to be considered earlier in

peripheral discrete tumours to avoid iris burns when mild controllable progression or poor

dilatation is a concern.

Based on the current data, we propose a flowchart (Figure 2) to facilitate treatment decisions

for discrete retinoblastoma considering four consecutive parameters: other eye status, tumour

location, tumour size (cut-off points 0.3 and 3 DD) and OCT availability to guide treatment and

follow-up. However, this strategy is for experienced ophthalmologists in Ocular Oncology

centers. Inability for strict follow-up due to logistic or socioeconomic concerns need to be

regarded as a contraindication for this strategy.

In conclusion, primary laser photocoagulation proved to bewas a safe effective non-invasive

treatment alternative in for IIRC Group A and some Group B eyes with 6355% of patients

avoiding systemic invasive therapies and no patients encounteringed tumour spread or

progression beyond preventing ocular salvage.

20

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

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.

Contributors: Conceptualization: SS,BG; Methodology: SS,ZF; Validation: SS,ZF; Data

Curation: SS,ZF; Writing – Original Draft Preparation: SS, ZF, BG; Writing – Review &

Editing: SS, ZF, BG; Image construction: SS, ZF, BG. Supervision: SS, BG.

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. Soliman SE, Dimaras H, Khetan V, et al. Prenatal versus Postnatal Screening for Familial

Retinoblastoma. Ophthalmology. 2016;123(12):2610-2617.6. Imhof SM, Moll AC, Schouten-van Meeteren AY. Stage of presentation and visual outcome of

patients screened for familial retinoblastoma: nationwide registration in the Netherlands. Br J Ophthalmol. 2006;90(7):875-878.

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. 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.

10. Friedman DL, Krailo M, Villaluna D, et al. Systemic neoadjuvant chemotherapy for Group B intraocular retinoblastoma (ARET0331): A report from the Children's Oncology Group. Pediatr Blood Cancer. 2017;64(7).

11. 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.

12. Abramson DH, Schefler AC. Transpupillary thermotherapy as initial treatment for small intraocular retinoblastoma: technique and predictors of success. Ophthalmology. 2004;111(5):984-991.

13. Abouzeid H, Moeckli R, Gaillard MC, et al. (106)Ruthenium brachytherapy for retinoblastoma. International Journal Of Radiation Oncology, Biology, Physics. 2008;71(3):821-828.

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

21

1

2

3

4

5

6

7

89

1011121314151617181920212223242526272829303132333435363738

15. National Retinoblastoma Strategy Canadian Guidelines for Care / Stratégie thérapeutique du rétinoblastome guide clinique canadien. Can J Ophthalmol. 2009;44(Supp 2):S1-88.

16. 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.

17. Hamel P, Heon E, Gallie BL, Budning AS. Focal therapy in the management of retinoblastoma: when to start and when to stop. J AAPOS. 2000;4(6):334-337.

18. 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.

19. 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.

20. Soliman SE, VandenHoven C, MacKeen LD, Heon E, Gallie BL. Optical Coherence Tomography-Guided Decisions in Retinoblastoma Management. Ophthalmology. 2017;124(6):859-872.

21. Kletke SN, Feng ZX, Hazrati LN, Gallie BL, Soliman SE. Clinical Predictors at Diagnosis of Low-Risk Histopathology in Unilateral Advanced Retinoblastoma. Ophthalmology. 2019;126(9):1306-1314.

22. Seddeek AM, Shaarawy AS, El-Shakankiri NM, El-Sabaa BM, Soliman SE. Clinicopathologic evaluation of primary vs secondary enucleated unilateral group D retinoblastoma eyes. J Egypt Ophthalmol Soc. 2020;113(2):6.

23. Soliman SE, D'Silva CN, Dimaras H, Dzneladze I, Chan H, Gallie BL. Clinical and genetic associations for carboplatin-related ototoxicity in children treated for retinoblastoma: A retrospective noncomparative single-institute experience. Pediatr Blood Cancer. 2018;65(5):e26931.

24. Sweid A, Hammoud B, Weinberg JH, et al. Intra-Arterial Chemotherapy for Retinoblastoma in Infants </=10 kg: 74 Treated Eyes with 222 IAC Sessions. AJNR Am J Neuroradiol. 2020;41(7):1286-1292.

25. 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.

26. 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.

27. Soliman SE, Dimaras H, Souka AA, Ashry MH, Gallie BL. Socioeconomic and psychological impact of treatment for unilateral intraocular retinoblastoma. Journal Francais D Ophtalmologie. 2015;38(6):550-558.

28. Lee TC, Lee SW, Dinkin MJ, Ober MD, Beaverson KL, Abramson DH. Chorioretinal scar growth after 810-nanometer laser treatment for retinoblastoma. Ophthalmology. 2004;111(5):992-996.

29. Gombos DS, Cauchi PA, Hungerford JL, Addison P, Coen PG, Kingston JE. Vitreous relapse following primary chemotherapy for retinoblastoma: is adjuvant diode laser a risk factor? Br J Ophthalmol. 2006;90(9):1168-1172.

30. 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.

31. 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.

22

123456789

101112131415161718192021222324252627282930313233343536373839404142434445464748

32. 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.

23

123

4

5

Tables Legends

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

Tumours (n=117).

Sample Characteristic N %

Children (n=44)

Age 0-1 year 35 801-2 years 4 9>2 years 5 11

Median (range) 5.3 (0.1-118.6)Family history

 17 39

Eyes (n=55)

IIRC A 25 45B 29 53C 1 2

Tumors (n=112)

Site Central 11 10Equatorial/pre-equatorial 30 27

Post-equatorial 71 63LDB at

diagnosis and first

laser (DD)

≤1 DD 86 771< DD ≤3 20 183< DD ≤5 4 3

5< DD ≤10 2 2>10 DD 0 0

Median (range) 0.5 (0.1-9)IIRC: International Intraocular Retinoblastoma Classification; LBD:

Largest Bbasal Ddiameter; DD: Disc-Ddiameter.

24

1

2

3

4

5

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

session.

Eye #

Tumour #

Laser Technique

IIRC

Size at Dx

(DD)

Tumour

Location

Subsequent

Treatment Rec Rec Rx

10 4 Encircling B 5.0 post-eq IVC No-

28 15 Encircling B 3.5 post-eqPlaque

radiotherapy

No-

85 39 Encircling B 0.6 central laser No-

88 41 Encircling B 3.0 post-eq laser No-

107 51 Encircling B 2.0 post-eq IVC No-

108 52 Encircling B 4.0 eq POC No-

110 54 Encircling A 1.0 eq cryotherapy No-

112 56 Encircling B 2.5 post-eq IVC No-

89 41 Encircling B 2.0 post-eq laser Yes Laser

92 43 Encircling B 2.5 post-eq laser Yes POC

IIRC: International Intraocular retinoblastoma classification; DD: disc-diameter; Dx: Diagnosis; Rx: treatment; Rec: Recurrence; eq: equatorial; IVC: Intravenous chemotherapy; POC: Periocular chemotherapy.

Eye #

Tumor #

Laser Technique IIRC

Tumor Size at Dx

(DD)Tumor

LocationSubsequent Treatment Rec.

Rec. Rx

25

1

2

10 4 Encircling B 5.0 post-eq. IVC No-

28 15 Encircling B 3.5 post-eq. Plaque radiotherapy No

-

85 39 Encircling B 0.6 central laser No-

88 41 Encircling B 3.0 post-eq. laser No-

107 51 Encircling B 2.0 post-eq. IVC No-

108 52 Encircling B 4.0 eq. POC No-

112 56 Encircling B 2.5 post-eq. IVC No-

89 41 Encircling B 2.0 post-eq. laser YesLaser

92 43 Encircling B 2.5 post-eq. laser YesPOC

IIRC: International Intraocular retinoblastoma classification; DD: disc-diameter; Dx: Diagnosis; Rx: treatment; Rec.: Recurrence; eq.: equatorial; IVC: Intravenous chemotherapy; POC: Periocular chemotherapy.

26

1

2

Table 3. Clinical characteristics and outcome of tumours treated with initial direct versus

encircling photocoagulation techniques

Parameter Direct Technique (n=94)

Encircling Technique (n=11) P-value

Median size at diagnosis (range) 0.4 (0.1-8.0) 2.5 (0.6-9.0) P < 0.001*

Central location 9 (10%) 2 (18%) P = 0.378

Progression in size after initial laser 0 (0%) 9 (82%) P < 0.001*

Median number of laser sessions (range) 2 (1-10) 4 (2-8) P < 0.001*

Required invasive therapy 10 (11%) 7 (64%) P < 0.001*

Recurrence after initial stabilityremission 46 (49%) 3 (27%) P = 0.173

* indicates statistical significance (P < 0.05).

27

1

2

3

Figure Legends

Figure 1: Consort flowchart following all tumours from primary photocoagulation monotherapy

to final long-term stability.

Figure 2: Schematic chart summarizing parameters to be considered in treatment

recommendations considering primary laser monotherapy of discrete retinoblastoma tumours.

The parameters are arranged in four consecutive steps: other eye status, tumor location (zone),

tumor size, and OCT availability for precise treatment and follow-up. Tumor locations to be

considered are color-coded (red, yellow, blue and green) in relation to optic nerve head (ONH)

and fovea (X).

Supplementary table Legend

Raw data regarding different study parameters.

28

1

2

3

4

5

6

7

8

9

10

11