Tylectomy for Intraocular Retinoblastoma: Five-Year Outcomes

Junyang Zhao, MD1,2*; Zhao Xun Feng3*; Qiyan Li, MD4*; Songyi Wu, MD5; Liwen Jin,

MD5; and Brenda L. Gallie, MD, FRCSC6-9

AFFILIATIONS

1Department of Ophthalmology, Liuzhou Maternity and Child Healthcare Hospital,

Guangxi, China

2Pediatric Oncology Center, Beijing Children’s Hospital, Beijing, China

3Faculty of Medicine, University of Ottawa, Ottawa, Canada

4Department of Ophthalmology, Beijing Tongren Hospital, Beijing, China

5Quanzhou Aier Eye Hospital, Quanzhou, China

6Department of Ophthalmology, Hospital for Sick Children, Toronto, Canada

7Krembil Research Institute, Toronto, Canada

8Techna Institute, Toronto, Canada

9Departments Ophthalmology, Medical Biophysics, Molecular Genetics, University of

Toronto, Canada

* Co-first authors: Junyang Zhao, Zhao Xun Feng and Qiyan Li

Senior author: Junyang Zhao

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CORRESPONDING AUTHOR

Brenda L. Gallie, MD, Department of Ophthalmology and Vision Science, Hospital for

Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G1X8; email:

brenda@gallie.ca; telephone: 14162949729

PRIOR PRESENTATION

The data was presented in part in a paper at the 2019 International Society of Ocular

Oncology meeting in Marina del Rey, Los Angeles and Poster presentation at AACR

Special Conference on Advances in Pediatric Cancer Research, Montreal, Quebec,

Canada, September 19, 2019.

CONFLICT OF INTEREST

No conflicting relationship exists for any author

RUNNING HEAD

Safety and Efficacy of Vitrectomy Tylectomy for Retinoblastoma

NUMBER OF FIGURES AND TABLES

2 tables, 3 figures, 3 online only tables and 1 online only figure

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Key Points: 78/? words

Question: What are the safety and efficacy of intraocular tumor excision (tylectomy) for

retinoblastoma?

Findings: Retrospective cohort study of 225 children with intraocular retinoblastoma

treated after completion of standard chemotherapy with tylectomy for retinoblastoma

showedhad 95% 5-year Overall Survival of 95% and 96% 5-year Cause-Sspecific

Survival of 96%. The 5-year eye salvage rate was 81%; and 45% of eyes avoided

complete blindness.

Meaning: Tylectomy in carefully selected Patients with tylectomy included in eye

salvage therapy can offerexperienced similar survival similar to primary enucleation,

with lifelong benefits of vision and eye retention.aining the eye and vision.

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Abstract 400 words

Importance: Intraocular surgery has been taboo in the management of retinoblastoma

due toin concern of for extraocular spread. We showed Intraocular excision (tylectomy)

of retinoblastoma (tylectomy) can contributed to care in well-selectedof patients with

retinoblastoma with survival rates similar to those published for other treatments.

Objective: We studied survival, eye salvage and visual acuity of a large cohort of

retinoblastoma children/eyes treated with secondary tylectomy following after systemic

chemotherapy.

Design: Retrospective cohort study. Children treated with tylectomy between in 2013 to

and 2014 with 5-years follow-up.

Setting: Three Chinese tertiary referral centers.

Participants: Consecutive children with retinoblastoma treated with secondary

tylectomy following after primary standard of care chemotherapy. Children with Clinical

or radiologic evidence of extraocular disease were was an absolute contraindication to

tylectomy.

Exposures: Consolidation Tylectomy was defined as intraocular excision of non-

calcified or partially calcified tumor within two<2 months of finalafter completion of

chemotherapy session. Salvage Tylectomy was defined as resection of active recurrent

tumor >2 months after completion of final chemotherapy session. Data reviewed

included age, sex, clinical IIRC Group at diagnosis, time from diagnosis and from end of

chemotherapy to tylectomy, pre-op and post-op chemotherapy, extent of retina excised,

enucleation, and length of follow-up.

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Main Outcome Measures: The primary outcomes were Overall Survival (OS) and

Cause-Specific Survival (CSS, survival relative to metastasis from the tylectomy eye).

Secondary outcomes were recurrence-free survival, eye salvage and visual acuity.

Results: A total of 245 eyes from 225 patients had Consolidation Tylectomy (151,

61.6%) or Salvage Tylectomy (94, 38.4%). Median age at diagnosis was 18.3 months

(range, 1.0–99.8 months). At The 5-year follow-up, Overall Survival rateOS was 94.5%

(95% CI: 91.5%–97.6%) and . The 5-year Cause-specific Survival (CSS) was 96.3%

(95% CI: 93.8%–98.9%). Children who hadWith Consolidation or Salvage Tylectomy 5-

year CSS was similar (96.3% vs 96.3%, P = .988) had similar survival to those with

Salvage Tylectomy (5-year CSS 96.3% vs 96.3%, P = .988)and. Children who received

adjuvant systemic chemotherapy following tylectomy had 5-year CSS similar to those

treated without adjuvant chemotherapy (100% vs 94.8%, P = .102). The 5-year eye

salvage rate following tylectomy was 80.6% (95% CI: 75.4%–85.8%), similar for

Consolidation Tylectomy and Salvage Tylectomy (78.6% vs 83.9%, P = .274). Children

treated with or without adjuvant systemic chemotherapy following tylectomy had similar

5-year CSS (100% vs 94.8%, P = .102). The 37.6% of eyes that required a total

retinectomy for globe salvage had, as expected, no light perception following tylectomy.

Vision was better than 20/200 (not blind) in 19.0% of all eyes, and better than light

perception in 60.2% of eyes with partial or no retinal resectionOf eyes with partial or no

retinal resection, 60.2% avoided complete blindness (better than no light perception)

and 19.0% avoided legal blindness (better than 20/200 vision).

Conclusions: Tylectomy secondary tofollowing standard chemotherapy alloweds for

preservation of eye and vision in appropriately selected retinoblastoma patients.

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Survival after tylectomy was similar to published reports of other treatment modalities

for retinoblastoma.

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INTRODUCTION:

The high mortality of extraocular retinoblastoma compared to primary enucleation led to

the dogma that intraocular procedures hashave no role in an eyes with retinoblastoma.1

This waswas successfully challenged with the emergence of intravitreal

chemotherapy.by planned intravitreal pars plana injections through pars plana

demonstratinge effectivenesssuccess in treating vitreous seeds with low risk (<1%) of

extraocular tumor spread.2 Considering the efficacy of intravitreal melphalan3,4 and

recenttechnical advances in small gauge vitrectomy system,5 we now incorporated

tylectomyretinoblastoma resection as a useful part of the in multimodal retinoblastoma

management.6

Tylectomy is defined as the surgical removal of a tumor or cyst. The term, now obsolete,

was used synonymously with lumpectomy to refer to a limited resection of breast as

oppose to total mastectomy. There has been a shift in Modern cancer practice has

embraced toward organ conserving surgery such as breast cancer lumpectomy,7 penile

cancer glansectomy,8,9 kidney cancer partial nephrectomy8,9 and testis cancer partial

orchiectomy.10 While lumpectomy officially refers only to breast cancer, the little-known

word “tylectomy” refers to We now revive the term, tylectomy, to refer to surgical

excision removal of a tumor (tulos, Greek for lump). of We propose the word tylectomy

to describe organ conserving, surgical resection retinoblastomaretinoblastoma as an

organ conserving surgery of the eye that offers both cosmetic and functional

advantages in comparison to enucleation.

The high mortality of extraocular retinoblastoma compared to primary enucleation led to

the dogma that intraocular procedure has no role in an eye with retinoblastoma.7 This

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was successfully challenged with the emergence of intravitreal chemotherapy. Planned

intravitreal injections through pars plana demonstrate effectiveness in treating vitreous

seeds with low risk (<1%) of extraocular tumor spread.8 Considering the efficacy of

intravitreal melphalan9,10 and recent advances in small gauge vitrectomy system,11 we

now incorporated tylectomy as a useful part of the multimodal retinoblastoma

management.12

Despite trial attempted eye salvage with combinations of chemotherapy (systemic

chemotherapy,11 intra-arterial chemotherapy (IAC)12 and intravitreal3,13{Francis, 2017

#20106;Munier, 2012 #8588}) refractory disease and tumor recurrence remain common.

Intraocular complications such as cataract, retinal detachment, vitreous hemorrhage,

and vitreous seeding further hinder eye salvage by precluding visualization of active

tumor and focal therapy (laser, cryotherapy, brachytherapy).14,15 In comparison to

chemotherapy, tylectomy physically excisesfor intraocular tumorretinoblastoma, could

remove tumor offering promising potential to circumvent chemotherapy resistance while

simultaneously treating ocular complications.

Our prior tylectomy case series showed promise in treating resection of refractory

retinoblastoma6 but concerns of iatrogenic tumor spread remained, given small sample

size. Indeed, Intraocular surgery in eyes with unsuspected retinoblastoma are has been

associated with metastatic disease,16,17 but metastasis was not identified in case reports

of planned tumor excision.6,18-22 We propose that planned tylectomy with intention to

cure may be safer than intraocular surgery with coincidental discovery of

retinoblastoma. The primary objective of the current study is was to evaluate Overall

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Survival (OS) and Cause-Specific Survival (CSS, survival relative to metastasis from the

tylectomy eye). Secondary outcomes were eye salvage rate and visual acuity.

METHODS:

Date collection and Ethics

This is a retrospective cohort study of patients with intraocular retinoblastoma was

treated with by tylectomy at three Chinese treatment centers between February 1, 2013

and December 13, 2014. Date of last follow-up was June 16, 2019. Retrospective

review of medical records without research consent of medical records was approved

by the Ethics Boards of Liuzhou Maternity and Child Healthcare Hospital, Beijing

Tongren Hospital, and Quanzhou Aier Eye Hospital in accordance with the Declaration

of Helsinki.

Clinical information collected included age at diagnosis, sex, disease laterality,

International Intraocular Retinoblastoma Classification (IIRC)23 clinical Group, pTNM 8th

edition histopathologic staging,24 type and regimen of chemotherapy, causes of death,

and dates of diagnosis, chemotherapy, tylectomy, recurrence, enucleation, last follow-

up and death. We considered patients lost to follow-up when parents could not be

contacted ≥2 years after last follow-up.

Treatment

Standard treatments preceding before tylectomy was considered are illustrated outlined

in Fig 1. All 245 eyes were treated with primary chemotherapy (systemic or intra-

arterial) with follow-up every 1-2 months during active treatment. Children with no active

tumor after treatment were followed every month for the first 4 months, every 2 months

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for the next 8 months and then longer intervals. The most common primary

chemotherapy, and adjuvant chemotherapy after tylectomy (when selected by parents),

was systemic (intravenous carboplatin 560 mg/m2 Day 1, etoposide 150 mg/m2 Days 1

and 2 or teniposide 230 mg/m2 Day 2, and vincristine 1.5 mg/m2 Day 2 on a 28-day

cycle).

Indications for tylectomy were consolidation after chemotherapy or salvage of eyes that

developed tumor recurrence. Consolidation Tylectomy was defined as resection of

noncalcified or partially calcified retinoblastoma within <2 months of after last

chemotherapy session. Salvage Tylectomy Salvage tumorectomy was defined as

resection of recurrent active tumor delivered >2 months of last chemotherapy session.

For Consolidation Tylectomy, Confirmation of Tumor activity was not confirmed in the

Consolidation Tylectomy cohort, due to lack of extended observation precluded by lack

of extended observation of tumor stability prior to surgerytylectomy. Tylectomy was

offered at the clinician’s’ discretion, considering factors including lack of significant

regression, progression or new tumor activity (new subretinal, epiretinal or vitreous

seeds) while on chemotherapy, opacities obscuring tumor visualization, parent

preference and refusal of enucleation (Fig 1).

In 2013-2014 IAC was available in only two Chinese centers. If parents chose primary

intra-arterial chemotherapyIAC, prompt referrals were made; few parents pursued

IACchose this therapy because of long travel distance and high treatment cost. Tumor

that manifest as only vitreous seeds without evident active retinal tumor was treated

with intravitreal chemotherapy. Simultaneous presentation presence of vitreous seeds

and active retinal tumor may bewas considered for tylectomy.

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Indications and Contraindications

All patients were screened for extraocular disease at diagnosis or prior to tylectomy by

computed tomography (CT) or magnetic resonance imaging (MRI). Absolute

contraindications to tylectomy were evidence of optic nerve invasion and extrascleral

invasion. Relative contraindications were obscured optic disc, foveal invasion or

extensive retinal invasion requiring complete retinectomy. The decision to proceed with

tylectomy was individualized for each patient was on the basedis of on clinical

presentation features and parents’ choice. For Group E eyes (advanced intraocular

retinoblastoma) enucleation was presented to parents as the safest treatment option.

Procedure

Under general anesthesia, a dilated fundus exam was performed with scleral

depression. Tumor-free sclerotomies sites were identified. In eyes with poor fundus

visualization due to vitreous opacities, ultrasound biomicroscopy or B-scan

ultrasonography were used to survey sclerotomy sites. To reduce risk of retinal

detachment, laser scars were placed around tumors prior and during surgery.

Standard three-port 23- or 25-gauge non-valved trocar/cannulas were inserted

transconjunctivally at pre-selected sites. Melphalan (5 μg/ml) in balanced salt solution

(dose nontoxic to retina in animal studies25) was infused continuously throughout the

surgery and irrigated onto ocular surface every 3-5 minutes. Using a vitrector, vitreous

seeds were aspirated, and soft tumors were endoresected and aspirated. Any visible

tumor that extended into choroid was resected down to bare sclera via vitrector, after

endodiathermy to occlude choroidal vasculature surrounding the tumor. Lensectomy

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was performed for cataract, and in cases whereif anterior segment tumor seedsing was

were aspirated or invaded ciliary body was resected. Residual calcified tumors were

disrupted by fragmatome through 20-gauge sclerotomies, and either aspirated or

removed from the sclerotomy sites using forceps.

Silicone oil was placed after tylectomy to stabilize residual retina whenever retinal

detachment was threatened, as in a partial retinectomy >3 mm or anterior resection.

After tylectomy, the scleral surface was exposed with peritomy and washed with 5 μg/ml

melphalan irrigation fluid. Tenon’s capsule and conjunctiva were sutured. At end of

surgery, 0.2 ml melphalan (5 μg, 25 μg/ml) was injected subconjunctival at the port

sites.

Statistical Analysis

Sex, age at diagnosis, follow-up, IIRC Group, time from diagnosis to tylectomy,

chemotherapy cycles, indication for tylectomy, degree of retinectomy, and enucleation

after tylectomy were summarized using frequency/percentage for categorical variables

and median/range for continuous variables. Continuous variables were compared

between groups via Mann-Whitney U test. Kaplan-Meier method was used to estimate

Cause-Specific Survival (CSS), Overall Survival (OS), Recurrence Free Eye Salvage

and Eye Salvage rates. CSS included Children who died with metastasis, with or

without radiological evidence of tumor spread from the tylectomy eye, were included in

CSS. Children with MRI evidence of tumor spread onlyexclusively from the non-

tylectomy eye or who died without metastasis, or with MRI evidence of tumor spread

only from the non-tylectomy eye, were not included in the CSS. Log-rank test was

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performed to compare OS, CSS and eye salvage between groups. When a child

received tylectomy for both eyes, for survival analysis, we excluded the eye with the

better IIRC Group in survival analysis if the child received tylectomy for both eyes; if

both tylectomy eyes had the same Group, the right eye was excluded. Children were

censored at last follow-up. All P-values reported are two sided; P < 0.05 indicated

significance. All analysis was performed using SPSS Version 25 (IBM Corp, New York).

RESULTS

Patient and Eye Characteristics and Prior Treatments

A total of 245 eyes (from 225 patients) had Consolidation Tylectomy (151, 61.6%) or

Salvage Tylectomy (94, 38.4%) (Fig 2 and Table 1, online only). Median age at

diagnosis was 18.3 months (range, 1.0–99.8 months). The IIRC Group At diagnosis

IIRC was Group B (13), Group C (21), Group D (172), Group E (38) and one unknown.

All 225 patients had primary chemotherapy; 206 (84.1%) had received only systemic

chemotherapy pre-tylectomy (median 3, range 1–15 cycles), 11 (4.5%) received only

IAC pre-tylectomy (median 2, range 1–3 cycles) and 28 (11.4%) received both

(medians, systemic chemotherapy 3 cycles, IAC 2 cycles). In addition to systemic

chemotherapy and/or IAC, prior to tylectomy 16 (6.5%) eyes received intravitreal

chemotherapy, 2 (0.8%) external beam radiation and 1 (0.4%) I125 plaque radiotherapy.

Median time from diagnosis to tylectomy was 4.3 months (range 0.3–78.2 months),

longer for Salvage Tylectomy than Consolidation Tylectomy (medians 11.2 2.8 v 2.8

11.2 months; P < .001). Median follow-ups were 67.8 months (range 1.0–150.2 months)

after diagnosis and 63.6 months, (range 0.6–76.6 months) after tylectomy. Lost to

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follow-up were 8 children with 9 eyes (follow-up after tylectomy median 6.6 months,

range 1.1–28.0).

The Degree of retina resected depended on the extent of tumor invasion: 6 (2.4%) eyes

had only tumor resection with no retinectomy, 147 (60.0%) had partial retinectomy and

92 (37.6%) had complete retinectomy by parental choice to avoid enucleation.

Simultaneous lensectomy was performed for 51 (20.8%) eyes. On fundus examination,

151 (61.6%) eyes had obscured optic disc, 44 (17.9%) eyes had vitreous hemorrhage,

67 (27.3%) eyes had vitreous or epiretinal seeding, 62 (25.3%) eyes had exudative or

rhegmatogenous retinal detachment, and 8 (3.2%) eyes had cataract. Silicone oil

taHmponade was used in 89 (36.3%) eyes. Following tylectomy, 58 (23.7%) eyes

received adjuvant systemic chemotherapy (median 1 cycle, range 1–5).

Survival

The 5-year CSS was 96.3% (95% CI: 93.8%–98.9%) (8/225 children died of disease

from the eye that had tylectomy). The 5-year Overall SurvivalOS rate was 94.5% (95%

CI: 91.5%–97.6%) (overall 12/225 children died) (Fig 3). For only Group D/E eyes, the

CSS and 5-year OS Overall Survival rates were 95.8% and 94.8% respectively. If we

assume all 8 (8/225 (4%) lost-to-follow-up patients have died, the 5-year CSS and

Overall Survival were 92.8% and 88.9% respectively.

Patients who had Consolidation and Salvage Tylectomy had Similar Consolidation and

Salvage Tylectomy 5-year Overall Survival OS (95.6% v 92.7; P = 0.361) and 5-year

CSS (96.3 v 96.3%; P = 0.988) were recorded. For Patients who hadtreated with

adjuvant systemic chemotherapy, had 5-year CSS was 100% (95% CI: 96.6–100%),

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not different from those who received without no adjuvant chemotherapy (94.8%, 95%

CI: 91.4%–98.2%, P = .102).

Characteristics of Patients Who Died

Death of 4/12 patients was unrelated to the eye that had tylectomy:; 3 had extraocular

tumor extension evident on head MRI from the non-tylectomy eye but not the tylectomy

eye and 1 child died from infection (Table 2, online only). Of 8 deaths related to

tylectomy eye, 4 had posterior tumor extension into the orbit, with no tumor clinically

observed at the sclerotomy sites; 1 had optic nerve invasion; and the extension site was

unknown for 3 children (Study IDs #49, 144, 208). All children who developed

metastasis have died.

All 8 children who died with metastasis attributable to the tylectomy eye had received

pre-tylectomy systemic chemotherapy (median 5.5 cycles; range 2–9); none had

received adjuvant IAC or systemic chemotherapy.

Tumor Recurrence Following Tylectomy

Following tylectomy, the 5-year recurrence-free eye salvage was 69.7% (95% CI:

63.7%–75.7%) (Fig 4), not significantly different between those with Consolidation and

Salvage Tylectomy (69.6 v 70.1%; P = 0.858). Seventy-two eyes had tumor recurrence,

median 6.6 months (range 0.8–52.8) after tylectomy. The Locations of recurrence were

anterior chamber (13), posterior chamber (3), peripheral posterior segment (23),

posterior pole (27), vitreous (3), both posterior pole and vitreous (2), and both anterior

chamber and posterior pole (1). Details of the 72 eyes with tumor recurrence after PPV

tylectomy are presented in Table 3, online only.

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Eye Salvage

Overall 5-year eye salvage rate following tylectomy was 80.6% (95% CI: 75.4%–

85.8%), including eyes having treated with additional salvage therapies. Patients who

had Consolidation and Salvage Tylectomy had similar eye salvage rates (5-year eye

salvage rate, 78.6% v 83.9%; P = .274). Patients with IIRC B/C eyes had significantly

higher eye salvage rate than those with IIRC D/E eyes (5-year eye salvage rates

respectively 100% v 78.0%; P = .005).

Of 245 eyes, ocular complications (some of these complications coincided with tumor

recurrence). following tylectomy included cataract (75, 30.6%), band keratopathy (42,

17.1%), vitreous hemorrhage (41, 16.7%), retinal detachment (6, 2.4%) and phthisis

bulbi (4, 1.6%). Some of these complications coincided with tumor recurrence.

Vision

Complete retinectomy at choice of parents to avoid enucleation was performed on 92

eyes, all which (as expected) had no light perception (NLP); 14/92 (15.2%) were

subsequently enucleated. Tylectomy with partial or no retinectomy was performed for

153 eyes with 31/153 (20.3%) subsequently enucleated. Snellen visual acuity was

undetermined for 28/153 eyes (18.3%) mostly due to young age. Of 94 eyes

successfully salvaged with partial or no retinectomy and documented visual acuity,

visual acuities at last follow-up were 20/20–20/60 (23, 24.5%); 20/80–20/160 (6, 6.4%);

20/200–20/400 (9, 9.6%); finger counting, hand motion or light perception vision (42,

44.7%); and NLP (14, 14.9%). If we count enucleated eyes as NLP, 23.2% of eyes

intended for vision salvage avoided legal blindness (visual acuity better than 20/200),

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14.1% for Group D/E eyes. Overall, 55.9% of eyes are NLP because of complete

retinectomy or poor vision following partial retinectomy or enucleation.

DISCUSSION

Tylectomy is a component of an organ salvage therapy in order aims to maximize the

cosmetic and functional outcomes of eyes with retinoblastoma without compromising

survival. Currently, three Chinese centers routinely perform tylectomy as part of the

multimodal treatment of retinoblastoma. The main concern of tylectomy is increased

mortality from iatrogenic tumor spread. Our study evaluated survival, eye salvage and

vision of 225 children (245 eyes) treated with tylectomy with 5-year follow-up. The

concern that tylectomy would increase mortality from iatrogenic tumor spread was not

observed.

Retinoblastoma resection was considered a viable option because of two major

advances in retinoblastoma care. With recognition ofSince intravitreal melphalan as is

an effective agent to treat retinoblastoma,3,4 during surgery a non-toxic concentration of

melphalan was continuously infused into the eye and periodically irrigated onto the

ocular surface. Submersion of tumor cells even in sterile distilled water is has been

suggested to render retinoblastoma cells nonviable. Second, small gauge non-valved

cannula was considered to reduce risk of subconjunctival and scleral wall seeding by

directing intraocular content to the outer conjunctival surface where melphalan irrigation

is applied.

For the 225 consecutive patients treated with tylectomy, we observed 5-year CSS of

96.3% and 5-year Overall SurvivalOS of 94.5%,. These are similar to survival rates

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reported for other treatment modalities including primary enucleation (Table 4).26-29 It is

evident that there are social factors beyond treatment modality that affect

retinoblastoma survival including national income level, delay to diagnosis, social stigma

against enucleation and treatment abandonment.30,31 Enucleation is commonly regarded

as the safest treatment for intraocular retinoblastoma, so. For comparison, we

retrospectively reviewed all 920 consecutive Chinese patients treated with primary

enucleation by J.Z from 2006 to 2015, the observing 5-year Overall Survival was 92.6%

(unpublished; raw data included in Table 5, online only). Enucleation is commonly

regarded as the safest treatment for intraocular retinoblastoma. The comparable

survival to enucleation supports tylectomy as a reasonable contribution to the treatment

of retinoblastoma.

We observed that The anterior segment is was a common area for tumor recurrence

following tylectomy, possibly related to limited access during vitrectomy to tumors

seeded on iris, ciliary body and zonules. Despite complete retinectomy and resection of

diseased choroid during tylectomy, invisible choroidal seedings may persist and recur.

Furthermore, as with IAC,32 tylectomy is localized only to the eye and lacks any

systemic chemoprotection. For these reasons, since 2017 we have recommended 2

cycles of adjuvant systemic chemotherapy following tylectomy. In the present study,

CSS of patients who received adjuvant systemic chemotherapy was 100%, but not

statistically different from those who received no adjuvant chemotherapy, 95%.

Hope for eye salvage and visual outcome can influence parents’ choice between

enucleation and trial eye salvage. Most tylectomy was performed with the intent of

vision salvage, but some parents refused enucleation despite no possibility of vision due

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to extensive disease. We did not recommend tylectomy for such eyes, but nevertheless

respected parents’ decision to preserve a non-seeing eye, in order to avoid treatment

abandonment.

In low- and middle income settings like China, it is not uncommon for children to be lost-

to-follow-up for a variety of reasons including unwillingness to enucleate, financial

constraints, long distance from treatment center and perception that disease was

cured.33 Instead of risking loss of patients with active tumor inside their eyes, most

parents were receptive to tylectomy prior to cessation of follow-up. While death is the

uniform outcome of untreated retinoblastoma, lost children who had tylectomy may

survive despite cessation of follow-up.

We compiled results from recent published series reporting eye salvage rate and

Snellen visual acuity following systemic chemotherapy or IAC, compared to our current

study (Table 5).11,34,35 An exact comparison of our results with other studies is not

possible due to selection bias and non-uniform clinical classification.

The strengths of this study are the large sample size and uniform protocols performed

by a single highly specialized multidisciplinary team, led by the vitreoretinal surgeon and

retinoblastoma specialist. A limitation of this study is the lack of histopathology on

material aspirated during tylectomy. Furthermore, histopathologic evaluation of

sclerotomy sites was not performed because the standard histopathology sections did

not contain the sclerotomy sites. For all of these children, the safest approach is primary

enucleation. However, when parents chose eye and/or vision salvage over enucleation,

tylectomy may be considered in patients who showed poor response to chemotherapy

or when treatment abandonment is a risk. Absolute contraindications were CT/MRI

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evidence of optic nerve invasion and extrascleral extension. Tylectomy of

retinoblastoma without careful selection of sclerotomy sites, continual melphalan

infusion, dedicated retinoblastoma expertise and appropriate consent from the family

has potential to be dangerous.

In 1989, Fisher et al showed that lumpectomy with adjuvant irradiation for Stage I and II

breast cancer yield non-inferior survival compared to mastectomy.7 Similar to the

lumpectomy in breast cancer, we now showed tylectomy in well-selected patients

(radiography excluding extraocular tumor) had similar survival to those treated with

enucleation, with lifelong benefits of retaining the eye, vision and maximizing quality of

life for many children.

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REFERENCES

1. Dimaras H, Corson TW, Cobrinik D, et al. Retinoblastoma. Nat Rev Dis Primers 2015; 1: 15021.2. Smith SJ, Smith BD. Evaluating the risk of extraocular tumour spread following intravitreal injection therapy for retinoblastoma: a systematic review. Br J Ophthalmol 2013; 97(10): 1231-6.3. Francis JH, Abramson DH, Ji X, et al. Risk of Extraocular Extension in Eyes With Retinoblastoma Receiving Intravitreous Chemotherapy. JAMA ophthalmology 2017; 135(12): 1426-9.4. Francis JH, Brodie SE, Marr B, Zabor EC, Mondesire-Crump I, Abramson DH. Efficacy and Toxicity of Intravitreous Chemotherapy for Retinoblastoma: Four-Year Experience. Ophthalmology 2017; 124(4): 488-95.5. Mohamed S, Claes C, Tsang CW. Review of Small Gauge Vitrectomy: Progress and Innovations. J Ophthalmol 2017: 6285869.6. Zhao J, Li Q, Wu S, et al. Pars Plana Vitrectomy and Endoresection of Refractory Intraocular Retinoblastoma. Ophthalmology 2018; 125(2): 320-2.7. Fisher B, Redmond C, Poisson R, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989; 320(13): 822-8.8. Tan HJ, Norton EC, Ye Z, Hafez KS, Gore JL, Miller DC. Long-term survival following partial vs radical nephrectomy among older patients with early-stage kidney cancer. JAMA 2012; 307(15): 1629-35.9. Roos FC, Steffens S, Junker K, et al. Survival advantage of partial over radical nephrectomy in patients presenting with localized renal cell carcinoma. BMC Cancer 2014; 14: 372.10. Bazzi WM, Raheem OA, Stroup SP, Kane CJ, Derweesh IH, Downs TM. Partial orchiectomy and testis intratubular germ cell neoplasia: World literature review. Urol Ann 2011; 3(3): 115-8.11. Berry JL, Jubran R, Kim JW, et al. Long-term outcomes of Group D eyes in bilateral retinoblastoma patients treated with chemoreduction and low-dose IMRT salvage. Pediatr Blood Cancer 2013; 60(4): 688-93.12. Munier FL, Mosimann P, Puccinelli F, et al. First-line intra-arterial versus intravenous chemotherapy in unilateral sporadic group D retinoblastoma: evidence of better visual outcomes, ocular survival and shorter time to success with intra-arterial delivery from retrospective review of 20 years of treatment. Br J Ophthalmol 2016.13. 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): 1078-83.14. Tawansy KA, Samuel MA, Shammas M, Murphree AL. Vitreoretinal complications of retinoblastoma treatment. Retina 2006; 26(7 Suppl): S47-52.15. Francis JH, Marr BP, Abramson DH. Classification of Vitreous Seeds in Retinoblastoma: Correlations with Patient, Tumor, and Treatment Characteristics. Ophthalmology 2016; 123(7): 1601-5.16. Shields CL, Honavar S, Shields JA, Demirci H, Meadows AT. Vitrectomy in eyes with unsuspected retinoblastoma. Ophthalmology 2000; 107(12): 2250-5.17. Kaliki S, Taneja S, Palkonda VAR. INADVERTENT INTRAOCULAR SURGERY IN CHILDREN WITH UNSUSPECTED RETINOBLASTOMA: A Study of 14 Cases. Retina 2019; 39(9): 1794-801.18. Seregard S, Kock E, af Trampe E. Intravitreal chemotherapy for recurrent retinoblastoma in an only eye. Br J Ophthalmol 1995; 79(2): 194-5.19. Ohshima K, Kaneko T, Takagi S, Kaneko A, Yokouchi Y, Takeuchi S. Clinicopathological investigation of a retinoblastoma eye enucleated after vitreous surgery with melphalan perfusion. Japanese Journal Of Ophthalmology 2009; 53(2): 186-8.

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LEGENDS

FIG 1. Standard care for IIRC Group retinoblastoma leading to eligibility for tylectomy.

IVC, intravenous chemotherapy; IAC, intra-arterial chemotherapy

FIG 2 (Online only). Consort diagram.

*We elected to perform endoresection on retinoma for one child because he lived in a

remote rural community with no access to ophthalmology service for serial monitoring of

tumor progression.

FIG 3. Kaplan-Meier curves of patient survival following tylectomy. (A) Cause-specific

survival, (B) Overall survival.

CSS, cause-specific survival; OS, overall survival

FIG 4. Kaplan-Meier curves of eye salvage following tylectomy. (A) Recurrence free

eye salvage (B) Eye salvage rate

RF, recurrence free

Table 1 (Online Only). Clinical characteristics of patients and eyes

Table 2 (Online Only). Clinical characteristic of patients who died

Table 3 (Online Only). Treatments and outcomes of tumor recurrence after PPV

Table 4. Recent published series reporting survival rate following specific treatment

modalities

Table 5. Recent published series reporting snellen visual acuity in eyes with

retinoblastoma.

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