Zhao et al. • Resection of Refractory Retinoblastoma

Pars Plana Vitrectomy and Endoresection of Refractory

Intraocular Retinoblastoma

Authors: Junyang Zhao, MD,1* Qiyan Li, MD,2* Songyi Wu, MD,3 Liwen Jin, MD,3 Xiaoli Ma, MD,4 Mei

Jin, MD,4 Yizhuo Wang, MD,5 Brenda Gallie, MD,6,7

1Department of Ophthalmology, Beijing Children’s Hospital, Capital Medical University,

China.

2Department of Ophthalmology, Beijing Tongren Hospital, Capital Medical University,

China.

3Department of Ophthalmology, Quanzhou Children’s Hospital, China.

4Hematology and Oncology Centre, Beijing Children’s Hospital, Capital Medical

University, China.

5Department of Paediatrics, Beijing Tongren Hospital, Capital Medical University, China.

6Departments of Ophthalmology & Vision Science, Hospital for Sick Children and

University of Toronto, Toronto, Canada.

7Techna Institute, University Health Network, Toronto, Canada.

*Junyang Zhao, Qiyan Li contributed equally to this paper.

Financial Support: NoneWord count: 2963

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Abstract

335/350 words

Purpose: To measure survival, metastases, eye salvage and visual acuity following

surgical removal of active retinoblastoma in only remaining eyes that had failed focal

therapy following systemic (IVC) and/or intra-arterial chemotherapy (IAC) in children

affected by bilateral retinoblastoma.

Design: Retrospective, observational study.

Participants: Twenty-one children treated for refractory intraocular retinoblastoma

using pars plana vitrectomy (PPV) and resection between February 1 and June 30,

2013, whose last remaining eyes had failed 3 or more cycles of IVC and/or IAC and

focal therapies (laser, cryo), who had no metastatic disease, and for whom enucleation

of the only remaining eye was under consideration.

Methods: A laser barrier surrounded solid tumors to stabilize the retina before PPV.

Tumor and seeds were removed by PPV with 5 µg/ml melphalan in irrigation fluid.

Silicon oil replaced vitreous volume when required to stabilize the retina and was

removed after 3-6 months. Melphalan 1 µg in 0.2 ml was injected sub-conjunctival at

PPV entry points 2-4 times subsequently. Intravitreal melphalan (20 µg in 0.05 ml) was

injected monthly up to 4 times if active vitreous seeds had been removed. After PPV,

EUA was done every 1-2 months for year 1, 3-4 months year 2, 6 months year 3, and 8

months years 4 and 5.

Main Outcome Measures: Overall survival, metastases, eye salvage, final visual

acuity.

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Results: Median follow-up time from diagnosis was 4.3 years, range 2.8 to 9.8

years, and from PPV was 3.2 (range 1.6 to 3.4) years. One patient was lost to follow-up

with recurrent intraocular tumor; no patient had metastases or died. After PPV, 2 eyes

were enucleated because of intraocular tumor recurrence and 18 eyes were saved.

Useful vision (20/25 to 20/200) was recorded in 15 (79%) of the assessable salvaged

eyes; 3 patients had counting fingers vision; and 1 patient had light perception.

Conclusions: Tumor resection by PPV with melphalan surgical irrigation and post

operative subconjunctival administration contributed to a high rate of tumor control and

useful vision for selected eyes with refractory retinoblastoma, without extraocular

spread.

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Introduction

Retinoblastoma in china

In China 1000 to 1500 children are newly diagnosed with retinoblastoma each year.1 Before

2006, most children with retinoblastoma in China were treated by enucleation, since they

presented with advanced disease resulting in 30 to 50% survival2. A retrospective review of

previously untreated intraocular retinoblastoma (2006 to 2009) in China included 595 eyes in

470 patients.3 The vast majority of eyes presented with advanced intraocular tumor (International

Intraocular Retinoblastoma Classification, IIRC4) Group D (171/595 eyes, 29%) or E (330/595

eyes, 55%).

In 2006 a modern approach to retinoblastoma was instituted in China, including

chemotherapy and focal therapy to salvage eyes. Careful studies showed that neoadjuvant

chemotherapy given to Group E eyes in hope of eye salvage, resulted in a significant increase in

mortality if enucleation of the eye was delayed more than 3 months from diagnosis or after more

than 3 chemotherapy cycles.5 Delay in removing dangerous Group E eyes allowed time for the

disease to spread and become incurable.

Chemotherapy and intra-arterial chemotherapy combined with repeated focal therapy (laser

and cryotherapy) have each resulted in approximately 50% salvage of eyes with Group D

retinoblastoma, without loss of life.6,7 The development of intravitreal chemotherapy (IVitC) is a

significant advance in the treatment of the most intractable feature of recurrent retinoblastoma,

vitreous seeds.8-10 However, with 1200 to 1500 newly diagnosed children each year in China,

there are inadequate medical and family resources to support compliance with the intensive

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number of EUAs, focal therapy treatments, and careful surveillance over several years required

to broadly achieve eye salvage.

Intraocular surgery in eyes with retinoblastoma

Intraocular surgery to improve vision compromised by complications (cataract, vitreous

hemorrhage, etc.), after years of apparent tumor inactivity, is reported with successes and

failures.11-22 The largest series18 shows retention of 29/45 (64%) eyes, with useful vision in 16/45

(36%). However, adverse events of tumor recurrence (14/45, 31%) and metastasis (3/45, 7%)

showed that great caution is warranted prior to intraocular surgery. When vitrectomy is

performed without suspicion of the diagnosis of retinoblastoma, results are generally poor.23-31

For example, Shen reported that 3/3 children died of metastatic disease after misdiagnosis led to

vitrectomy (two) and evisceration (one).31

Kaneko reviewed the challenges in treating primary and recurrent vitreous seeding, and

suggested, in the face of 50% failure to save eyes with vitreous seeds, the novel approach of

“..vitreous surgery combined with infusion of anticancer drugs for eradication of vitreous seeds

and maintenance of visual function”.32 An animal study showed that surgical perfusion of 5

µg/ml melphalan during vitrectomy was not toxic.33 Intravitreal infusion of melphalan during

vitrectomy to treat refractory vitreous seeding was proposed.

The first report of a planned intraocular surgical approach to retinoblastoma was for a heavily

treated (systemic chemotherapy and focal therapy, intra-arterial chemotherapy, and intravitreal

melphalan) eye with recurrent retinoblastoma.34 Pars plana vitrectomy (PPV), lensectomy and

tumor resection, and endolaser to residual tumor was performed with intraoperative melphalan (5

µg/ml) infusion. The eye was enucleated for tumor recurrence 4 months later, showing active

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tumor on pathological examination, but no features suggested risk of extraocular extension. At

12 months follow-up, there was no local recurrence or systemic metastasis.

Ji et al35 described the first clinically successful PPV for a single enlarging vitreous seed in a

IIRC4 Group B eye treated with systemic chemotherapy, cryotherapy, and laser. After 16 months

of treatments, a single vitreous seed was discovered, which increased over 6 months. PPV of the

seed(s) was performed. There was no melphalan infusion in this child’s surgical treatment. The

child retained good vision and had no active tumor at 26 months follow-up.

We now report results of planned pars plana vitrectomy (PPV) and endoresection of active

retinoblastoma refractory to standard treatments (systemic chemotherapy, intra-arterial

chemotherapy, focal therapy including brachytherapy, and intravitreal melphalan). The only

alternative for these eyes was enucleation.

Methods

Study Design

The children were diagnosed with retinoblastoma and treated initially in multiple institutions,

then referred to Quanzhou Children’s Hospital for PPV because active retinoblastoma was

unresponsive to standard therapies. Institutional Ethics Review Board Approval was obtained for

this study from Beijing Children’s Hospital and Quanzhou Children’s Hospital.

This is a retrospective review of children who had PPV for active retinoblastoma managed by

Dr. Junyang Zhao and the Retinoblastoma Team at Quanzhou Children’s Hospital between

February 1 and June 30, 2013, in order to have adequate followup. Inclusion criteria were

bilateral retinoblastoma with one eye removed or phthisic; recurrent active tumor in the

remaining only eye despite multiple treatments of systemic chemotherapy and focal treatments

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(laser, cryotherapy, brachytherapy and/or intra-artery chemotherapy) so enucleation was the only

alternative; and no tumor was seen near the optic nerve head or suggested on neuroimaging prior

to PPV treatment. Children with pre-existing metastasis were excluded from this review.

Demographic data included date of birth, date and age at presentation, gender, and family

history. Extent of retinoblastoma at diagnosis was staged for each eye using the 8th edition of the

AJCC Cancer Staging Manual combining prognosis for eye outcome and the IIRC4 (cT1a and

cT1b equal IIRC Groups A, B; cT2a and cT2b encompass Groups C, D; and cT3 approximates

Group E) with overall cancer stage TNMH (T, tumor; N, node; M, metastasis; H, heritability).36

Details and dates of each treatment before and after PPV were recorded and entered into the

DePICTRB online demo database37 for graphic display (Figure 1). Few specific details of prior

treatments were available on some children who were referred for PPV only when removal of the

last eye was the only remaining option. Generally, systemic chemotherapy consisted of 3-4

weekly cycles of carboplatin (26-28 mg/kg) and vincristine (0.5-1 mg/kg) on day 1 and etoposide

(5-10 mg/kg) or teniposide on day 2. Generally, for intra-arterial chemotherapy, 5-7.5 mg

melphalan with/without 20-30 mg carboplatin was given.

Pre-PPV and last follow-up wide-field retinal images were collected when available. Dates of

diagnosis of metastases and/or death were recorded. Date of last follow-up to December 2016

was recorded.

Surgical approach to PPV

The retinoblastoma expert and the retinal surgeon planned pre-operatively what tumor should be

removed and what calcified tumor and scars could be left untouched. If active tumor was present

in addition to vitreous seeds, laser (532 nm or 810 nm) was performed on two or more sessions

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prior to PPV, to surround the solid tumor with a 1-2 mm wide scar barrier, in order to reduce risk

of retina detachment during PPV.

PPV was performed with a 23G or 25G cutter probe with non-valved cannula (Alcon

Constellation) with 3 port sites. Irrigation fluid contained 5 µg/ml melphalan throughout the

procedure. To decrease risk of tumor cell escape, movement of the vitrectomy cutter in and out

the eye was minimized. Soft active tumors were dissected first by a cutting head, and then

calcified tumor was sonically fragmented and removed. Small intra-retinal seeds were

photocoagulated, and endolaser was performed to reinforce the previous laser barrier before

resection of solid tumor. If necessary to reach all anterior tumor, the lens was removed and tumor

aspirated from the anterior chamber. Silicon oil was injected, if needed, after the tumor was

removed and retina reattached. The 3 incision points were closed with 6-0 absorbable sutures and

0.2 ml melphalan (5 µg, 25 µg/ml) was injected subconjunctival at the three surgical entry

points.

Post-PPV care

After PPV, pupil dilation, anti-inflammatory and antibiotic topical medications were used.

Sub-conjunctival (0.2 ml, 5 µg melphalan) injections at surgical entry points were administrated

monthly up to 4 times. If vitreous seeds were extensive (10 patients), intra-vitreal injection (0.05

ml) of melphalan (20 µg, 400 µg/ml) was given 1 to 4 times one month apart. No adjuvant

systemic chemotherapy was given, but post-PPV chemotherapy was given to four children for

other reasons, described in results. From 6-12 months after PPV, EUA was done every month.

Silicon oil was removed after 3-4 months when the retina was stably reattached. For the second 6

months after PPV, EUA was performed every 2 months; for year 2, every 3-4 months; for year 3,

every 6 months; for years 4 and 5, every 8 months.

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Results

Patient outcomes are summarized in the Consort diagram, Figure 1. Details of each patient are

represented in DePICTRB diagrams (Figure 2) and wide-angle retinal images of eyes before PPV

and at last follow-up (Figure 3).

Twenty-one patients were included who were treated with PPV for their only remaining eye

from February 1 to June 30, 2013. Initial diagnosis of retinoblastoma ranged from August 2006

to November 2012. Follow-up from diagnosis was median 5.1 (range 2.8 to 10.7) years. Follow-

up after PPV was median 3.2 (range 1.6 (#21, lost to follow-up) to 4.2 years). Four patients had a

family history of retinoblastoma: three (#4, 14, 21) had an affected parent and one (#5) had an

affected sibling. The prior enucleated eyes were staged at diagnosis as (8th edition

TNMH36/IIRC4) cT2b/D (5), cT2b/E (1), cT3a/E (1), cT3b/E (1), cT3c/E (8), cT3d/E (2),

unknown/E (1), and unknown/unknown (2) (Figure 2, Supplementary tab le); the three

“unknown” eyes were diagnosed elsewhere, and details for staging could not be retrospectively

accessed. The pathology stages for the enucleated eyes were pT1 (4), pT2a (6), pT2b (1), pT3b

(2), but for 8 eyes enucleated elsewhere, pathological staging was not obtainable. The remaining

eyes treated with PPV as last resort of 21 children were initially staged cT1b/B (1), cT2a/C (2),

cT2b/C (1), cT2a/D (3), and cT2b/D (14).

Treatments prior to PPV

Prior to PPV, all children received systemic chemotherapy with carboplatin, etoposide/teniposide

and vincristine, with addition of cyclophosphamide for two patients (#5, 14), for a median 6.5

(range 2 to 15) cycles. Prior to PPV, 4 eyes had retinal detachment (#3, 15, 16, 17; final

respective visual acuities 20/200, CF, LP, 20/100); 3 eyes (#11, 17, 21) had 1-4 IVitC with

melphalan; and 1 eye (#5) received brachytherapy and cataract extraction. Three children (#1,

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11, 20) had 1 to 4 intra-arterial chemotherapy treatments prior to PPV. However, the prior

treatment data has limited accuracy because details of early treatments are unavailable for some

patients.

Treatments after PPV

Five patients required no more treatment for retinoblastoma after the PPV (Figure 2A). After

PPV, two patients (#4, 13) each received one cycle of systemic chemotherapy because under

resected retinal tumor Bruch’s membrane was surgically noted to be disrupted, revealing choroid

and suggesting choroidal invasion may have been present.. Two patients (#6, 7) received

chemotherapy because the enucleated (non-study) eye showed pT3b high-risk pathology (Figure

2B). One patient had surgery for retinal detachment (#17) and two had cataract surgery (#15, 19).

Ten patients who were considered to have a high burden of vitreous seeds at PPV received

adjuvant IVitC with melphalan (1-4 times) (Figure 2C). One patient (#18) received IVitC to treat

post-PPV vitreous seeds, but still required enucleation. Four patients (#12, 13, 16, 17) had IVitC

while silicon oil was in the eye; although the distribution of IVitC with silicon may have resulted

in a high melphalan dose to retina, no toxicity was observed.

The retinoblastoma was not controlled by one PPV in 4 patients, who all recurred with

anterior tumor, difficult to see behind the iris (Figure 2D). For 2 patients the recurrent disease

was treated by enucleation, and no tumor was observed in the needle tracts on pathological

examination (#18, pT1; #19, pT1). Two patients received one (#20) or two (#21) additional

PPVs for recurrent tumor; patient #20 needed no further therapy after the second PPV and

achieved 20/100 vision; patient #21 declined enucleation for further recurrence after 3 PPV, and

is lost to follow-up (see below).

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Outcomes

Twenty of 21 children were alive and well at last follow-up from PPV median 3.3 (range 2.3

to 4.2) years. No child developed extraocular disease or metastasis, but #21 is lost to follow-up

with active intraocular disease. PPV with resection of tumor with melphalan irrigation resulted in

salvage of 18/20 adequately followed eyes containing retinoblastoma that had failed all the

previous treatments, leaving enucleation as the only remaining conventional option. Available

wide-field retinal images of all 21 eyes before PPV and at last follow-up are shown in Figure 3.

The patient (#21) who is lost to follow-up had two subsequent PPVs for recurrent disease that

failed to control the retinoblastoma. This child had a parent with retinoblastoma, but was

diagnosed with right eye stage cT3b/E, left eye stage cT2b/D at age 27 months. Treatments with

9 cycles of systemic chemotherapy, enucleation of the right eye, three intravitreal injections with

melphalan and three PPV for anterior recurrent tumor at the ora serrate failed to control the

cancer (Figure 2D). Enucleation was again proposed, but refused, and the child is lost to follow-

up with active intraocular disease, so is presumed to have died.

At last follow-up, visual acuity (Figures 1, 2) was functional in 14/18 (78%) of the assessable

salvaged eyes (11 eyes were better than 20/80, 2 were 20/100 and 1 was 20/200). Vision in 3

eyes was counting fingers and in 1 eye, light perception.

No retinal toxicity from melphalan surgical irrigation was observed.

Discussion

Organ salvage cancer therapy is common for most cancers, but the vastly different survival rates

for intraocular and extraocular retinoblastoma1 have correctly dissuaded ophthalmologists from

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exploring “lumpectomy” for retinoblastoma. Inadvertent penetration of an eye with active

retinoblastoma is well known to be dangerous, especially when unrecognized.23-31

In China 2016 to 2009, 55% of children presented with advanced intraocular IIRC Group E

retinoblastoma (enucleation recommended) and 33% Group C/D disease (considered safe to

attempt salvage).3 First approaches to the cT2/C, D eyes now include systemic chemotherapy

and/or focal intra-arterial chemotherapy, followed by focal therapy (laser, cryotherapy and

IVitC). However, often recurrence leads to extensive ongoing repeated treatments, focused on

saving the eye. Parents who have invested much effort and hope in the eye may resist taking it

out when the child would be safer with it removed. The lost to follow-up rate for retinoblastoma

in China 2006-8 was 40% 5 years after diagnosis, and estimated currently to approximate 20%

(Zhao, unpublished data). The lost to follow-up rate in the present study is 1/21 (5%). Patient

#21 is lost to follow-up with active retinoblastoma tumor in the eye that received PPV, and may

have died because enucleation was refused. No child who received PPV for active

retinoblastoma in our study was shown to have dissemination of cancer cells outside the eye at

3.3 years follow-up after PPV.

It has been shown that the careful approach developed by Munier et al.8,9 for direct injection

of melphalan into the vitreous (IVitC) can be performed without extraocular spread of tumor.38

Because in China there are many children with recurrent disease after all standard therapies, a

direct and definitive therapy to save last eyes in children was needed.

We report on 21 children who had already lost their worse affected eyes. Their remaining

eyes eligible for PPV were stage cT2/ C, D with a clear view of the optic nerve and

neuroimaging at diagnosis that indicated no optic nerve involvement. They all had received

systemic chemotherapy to protect the whole child from disseminated disease that might have

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been pre-existing but undetectable at the time of diagnosis. The PPV treatment team for each

child included the retinoblastoma expert who indicated the intended target tumor and the expert

retinal surgeons who performed the PPV. Endolaser surrounding the tumor prior to resection was

performed to avoid retinal detachment and the retina was stabilized with silicon oil when

indicated for risk of detachment. To reduce risk of active retinoblastoma cells escaping, the

surgical irrigation fluid contained melphalan, at the concentration demonstrated in animal studies

to be not toxic to retina.33 A series of subconjunctival injections of melphalan at the surgical port

sites was performed, to further protect against dissemination outside the eye.

For 18 of 21 (86%) children, PPV/resection was the major contributor to saving their last eye

(Figure 1). After PPV, 5 children received no other therapy (Figure 1A); two children received

adjuvant systemic chemotherapy for high risk features in their other enucleated eye (Figure 1B);

10 children had adjuvant IVitC (Figure 2C); and second PPV controlled recurrent disease in the

eye of patient #20 with a good visual outcome, but PPV failed to achieve control of

retinoblastoma in 3 children (Figure 1D).

Anterior recurrent disease was treated by enucleation of the last eye of patients #18, 19. The

four eyes with significant recurrences (#18, 19, 20, 21) all had anterior disease at time of PPV

(Figure 3). Disease anterior to the ora serrata carries increased risk of failure to control the

retinoblastoma, recognized many years ago,39 since these tumors are not well visualized and not

treatable by focal laser or cryotherapy. Advanced anterior disease prior to PPV was controlled in

other children in this study, for example, patient #4 (Figure 3). Ultrasound biomicroscopy is

useful to monitor for anterior tumor, but was not available for the children in our study.

Although no child in this study is known to have died, we count patient #21 as potentially

dead (Figures 1, 2, 3). When the anterior disease recurred a third time after the first PPV the

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parents rejected enucleation and the child was lost to follow-up. The loss to follow-up and

potential death of this child might have been averted if the parents had experienced repeated

counselling that the primary purpose of treatment is to save the child’s life, and is more

important than saving the eye and vision.

This study adds PPV to the array of focal therapy tools to salvage eyes with useful vision. For

the first time, definitive cure was achieved for 18/21 eyes and children by a direct surgical

approach to intraocular retinoblastoma refractory to many prior treatments. This approach

requires careful collaboration of the circle of care of each child, including retinoblastoma and

surgical retinal specialists, pediatric oncologists and the parents.

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Figure Legends

Figure 1. Consort diagram showing 21 eligible patients treated with PPV after many other

therapies failed to control retinoblastoma tumor. No deaths were recorded but one failed PPV

patient is lost to follow-up. Twenty eyes were assessable: 2 eyes were enucleated for recurrence;

18 eyes (90%) were saved, 5/18 with no further treatment, 10/18 with follow-up IVitC, and 1/18

after a second PPV. Two children had CEV after PPV because the other enucleated eye had

pathological features indicating high risk for metastasis. Useful vision was achieved for 14/18

(78%) children. CEV, systemic chemotherapy with carboplatin, etoposide, vincristine; IVitC,

intravitreal melphalan.

Figure 2. A, All eyes of patients #1-5 were saved with no subsequent cancer treatment after

PPV. B, Patients #6, 7 were treated with CEV systemic chemo after PPV because of high-risk

pathology in the other eye after enucleation; all eyes were saved. C, Ten patients were treated

with CEV systemic chemo before PPV and IVitC (20 µg melphalan) after PPV; all eyes were

saved. D, Four patients were considered to have failed the primary PPV: patients #18 and 19 had

enucleation of the PPV eye; #20 had a second PPV procedure and the eye was saved with 20/50

vision; and #21 had two subsequent PPV for recurrent disease with 20/100 vision at last follow-

up with active disease, but then was lost to follow-up and is considered potentially dead.

Figure 3. Wide angle retinal images of the 21 eyes (A) prior to vitrectomy and resection of

active vitreous seeds and/or the tumor source of vitreous seeds, and (B) at last followup.

Graphical Abstract

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