Br J Ophthalmol: first published as 10.1136/bjophthalmol-2019-313985 on 23 May 2019. Downloaded from http://bjo.bmj.

com/ on June 1, 2020 at NHS Wales Swansea Bay University Health

Clinical science

Episcleral brachytherapy for retinoblastoma

Jose J Echegaray,1 Yahya A Al-­Zahrani,2 Arun Singh  ‍ ‍1

1
Department of Ophthalmic Abstract chemoreduction and may provide several advan-
Oncology, Cleveland Clinic Background/Aims  To report visual outcomes, survival tages over other alternatives. An advantage of
Foundation, Cole Eye Institute,
Cleveland, Ohio, USA outcomes and complications following episcleral EB over other types of radiation such as external
2
Retina and Vitreous Service, brachytherapy (EB) for retinoblastoma. beam radiation therapy (EBRT) is the low risk of
King Khaled Eye Specialist Methods  Retrospective review of retinoblastoma cases secondary cancer development due to the ability of
Hospital, Riyadh, Saudi Arabia treated with EB in a single institution. Survival outcomes current plaque designs to shield extraocular tissues
were analysed using the Kaplan-­Meier method. from radiation exposure. In addition, EB is widely
Correspondence to Results  Eleven tumours of 11 eyes were treated with available and accessible as a cost-­effective treatment
Dr Arun Singh, Department of
Ophthalmic Oncology, Cleveland either iodine-125 or ruthenium-106 EB with a mean
modality in most academic centres in the USA.
Clinic Foundation, Cole Eye apical dose of 44 Gy. The tumours were classified as In the present study, we reviewed our centre’s
Institute, Cleveland, OH 44195, group B in 5 (46%), C in 3 (27%) or D in 3 (27%) eyes, experience with EB for retinoblastoma prior to the
USA; s​ ingha@​ccf.​org respectively. Mean follow-­up time was 75.4 months. adoption of local chemotherapy such as IAC and
EB served as primary treatment in 3 eyes (27%) and intravitreal treatment. In addition to reviewing
Received 26 January 2019
Revised 1 May 2019 secondary treatment in 8 eyes (73%). Final visual patient demographics, visual outcomes, survival
Accepted 2 May 2019 acuity was better than 20/200 in 70% of cases. Globe outcomes and radiation-­related complications, we
Published Online First preservation was achieved in 9 (82%) eyes. Local revisit the indications of EB for retinoblastoma in
23 May 2019 recurrence occurred in 18% of cases at a mean onset the context of local chemotherapy.
of 17.4 months after EB. Two group D tumours that
recurred after secondary EB underwent enucleation. Methods
Mean onset of radiation retinopathy was 17.4 months We performed a retrospective review of all cases

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following EB. No metastatic or fatal events were of retinoblastoma treated with EB between
recorded. Kaplan-­Meier analysis showed recurrence-­freeDecember 2005 and December 2012 at the Cleve-
survival and ocular survival of 80% and overall survivalland Clinic Cole Eye Institute. The observed
of 100% at 5 years after EB. patient demographics and tumour character-
Conclusion  EB is an effective primary or secondary istics include gender, age at plaque treatment,
treatment modality for selected retinoblastoma eyes tumour laterality, tumour genetic status, family
(groups B and C). Advanced group D tumours may history, tumour dimensions, tumour classification
represent a risk factor for local recurrence. Visually according to the International Classification of
significant complications such as radiation retinopathy Retinoblastoma and tumour location. Treatment
should be anticipated. characteristics included type of radioisotope used
(I-125 or Ru-106), radiation dosimetry parame-
ters and length of treatment. If overlying vitreous
seeds were present, the brachytherapy regimen
Introduction was designed to include all vitreous seeds within
The introduction of local chemotherapy via the the field of treatment with an adequate dose.
intra-­
arterial (IAC) and intravitreal routes for EB was considered as primary treatment when
the treatment of retinoblastoma transformed the it was used as the initial treatment modality. It
management algorithms of the most common was considered as secondary treatment when the
primary intraocular malignant tumour in child- patient had a history of preceding therapy. The
hood.1 2 Specifically, the era of local chemotherapy latter included chemoreduction (CRD), external
for retinoblastoma has introduced new treatment beam radiation therapy (EBRT), transpupil-
strategies for more advanced cases that were tradi- lary thermotherapy (TTT), laser photocoagula-
tionally managed with enucleation. tion, cryotherapy or subtenon carboplatin. The
The use of episcleral brachytherapy (EB) implant chemoreduction regimen included a combination
to treat intraocular tumours was introduced by of systemic vincristine, carboplatin and etoposide,
Moore in 1930.3 The episcleral plaque design for given in six cycles via the intravenous route.
retinoblastoma was popularised by Stallard.4 But Primary outcome measures included initial
it was the Collaborative Ocular Melanoma Study visual acuity (VA), final VA, local recurrence,
supporting iodine-125 (I-125) EB as a globe-­ enucleation, distant metastasis and deaths. Local
© Author(s) (or their
employer(s)) 2020. No preserving alternative to enucleation for uveal mela- recurrence was defined as new tumour activity
commercial re-­use. See rights noma which further standardised the use of plaque visible on indirect ophthalmoscopy occurring after
and permissions. Published radiation in ophthalmic oncology.5 Presently, I-125 completion of the primary treatment modality.
by BMJ. is the most popular isotope used in the USA, while New tumour activity includes tumour regrowth in
To cite: Echegaray JJ, Al-­ ruthenium-106 (Ru-106) is preferred in Europe. an area of previously regressed tumour and any
Zahrani YA, Singh A. In the context of retinoblastoma, EB remains new vitreous seeds or subretinal lesions. Secondary
Br J Ophthalmol a valuable tool to treat focal tumours primarily outcome measures included tumour regression
2020;104:208–213. or to achieve secondary focal consolidation after type and radiation-­related complications. Tumour
208 Echegaray JJ, et al. Br J Ophthalmol 2020;104:208–213. doi:10.1136/bjophthalmol-2019-313985
 Br J Ophthalmol: first published as 10.1136/bjophthalmol-2019-313985 on 23 May 2019. Downloaded from http://bjo.bmj.com/ on June 1, 2020 at NHS Wales Swansea Bay University Health
Clinical science
regression type was classified according to its clinical appear- enucleation as the event. The OS was estimated using death as
ance as type 1 (cottage cheese), type 2 (fish flesh), type 3 the event.
(combination between types 1 and 2) and type 4 (residual
scar). Radiation-­related complications included development Results
of cataract, non-­proliferative retinopathy (defined as the pres- Demographic data
ence of retinal telangiectasia, oedema, exudation, cotton wool Between December 2005 and December 2012, eleven tumours
spots and retinal haemorrhage without neovascularisation of of 11 eyes were treated with EB. The mean age at the time of
the disc or elsewhere), proliferative retinopathy (defined as the treatment was 9 months (range 1–21 months) and the mean
presence of retinal neovascularisation with or without vitreous follow-­up time was 75.4 months (range 1–123 months). The
haemorrhage), optic neuropathy (defined as acute swelling of gender distribution included seven female and four male patients,
the optic disc with or without surrounding retinal nerve fibre respectively. Five patients (45.5%) had positive family history of
layer infarcts, haemorrhage and oedema), neovascularisation retinoblastoma. Germline RB1 mutation was present in 91% of
of the iris or neovascular glaucoma. Clinical findings were patients, all of which had bilateral disease (table 1).
documented using RetCam images (Clarity Medical System,
Pleasanton, CA) with or without fluorescein angiography and Tumour classification
ultrasonography. Tumours were classified according to the International Classi-
We presented categorical variables using percentages, while fication of Retinoblastoma (ICRB). Five tumours (45.5%) were
continuous variables were shown using median and range. We classified as group B, three tumours as group C (27.3%) and
three tumours as group D (27.3%). The mean tumour size was
estimated recurrence-­free survival (RFS), ocular survival (OcS)
10 mm (range 6–16 mm) in basal diameter and 3.8 mm (range
and overall survival (OS) using the Kaplan-­ Meier method.
1–8 mm) in height. The tumours were located at a mean of 7 mm
To estimate RFS, we used local recurrence as the event. RFS
from the fovea and 8.5 mm from the optic disc margin (table 1).
time was calculated from the time of treatment with EB to the
time of diagnosis of local recurrence. We estimated OcS using
Radiation treatment parameters
EB implants were used as primary treatment in three tumours
(27.3%) and as secondary treatment in eight tumours (72.7%).

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Table 1  Patient demographics and tumour characteristics For cases with preceding treatment modalities, cryotherapy had
been used in 87.5% of cases, TTT in 87.5%, CRD in 75% and
Total patients 11
Gender
 Male 4 (36.4%)
 Female 7 (63.6%) Table 2  Episcleral brachytherapy parameters and outcome
Patient age (months) measures
 Mean 9 Radioisotope
 Range 21 January  Iodine-125 10 (91%)
Laterality  Ruthenium-106 1 (9%)
 Bilateral 10 (91%) Mean plaque size (mm) 14 mm (10–18 mm)
 Unilateral 1 (9%) Mean length of treatment (hours) 55 hours (range 33–78 hours)
Genetic forms Radiation dosimetry
 Sporadic 1 (9%)  Tumour apex 44 Gy (range 40–45 Gy)
 Germline 10 (91%)  Tumour base 100 Gy (range 72–144 Gy)
Family history  Optic disc 21 Gy (range 1–46 Gy)
 Positive 5 (45.5%)  Fovea 45 Gy (range 6–124 Gy)
 Negative 6 (54.5%)  Lens 4 Gy (range 0–15 Gy)
 Mean length of follow-­up 75.4 months Primary treatment 3 (27.3%)
Final visual acuity Secondary treatment 8 (72.7 %)
 >20/40 30% Preceding therapy
 20/40–20/200 40%  Cryotherapy 7 (87.5%)
 <20/200 30%  TTT 7 (87.5%)
ICRB  CRD 6 (75%)
 Group A 0  Subtenon carboplatin 3 (37.5%)
 Group B 5 (45.5%)  Laser photocoagulation 0
 Group C 3 (27.3%) Tumour regression
 Group D 3 (27.3%)  Type 1 1 (11%)
 Group E 0  Type 2 0
Tumour size  Type 3 3 (33%)
 Largest basal diameter 10 mm (range 6–16 mm)  Type 4 5 (56%)
 Height 3.8 mm (range 1–8 mm) Local recurrence 2 (18%)
Tumour location Enucleation 2 (18%)
 Distance to optic disc 8.5 mm (range 4.5–13 mm) Metastasis 0
 Distance to fovea 7 mm (range 1–18 mm) Deaths 0
ICRB, International Classification of Retinoblastoma. CRD, chemoreduction; TTT, transpupillary thermotherapy.

Echegaray JJ, et al. Br J Ophthalmol 2020;104:208–213. doi:10.1136/bjophthalmol-2019-313985 209

 Br J Ophthalmol: first published as 10.1136/bjophthalmol-2019-313985 on 23 May 2019. Downloaded from http://bjo.bmj.com/ on June 1, 2020 at NHS Wales Swansea Bay University Health
Clinical science

Figure 1  (A) Fundus photo of a group C retinoblastoma at

presentation, and type 3 regression following episcleral brachytherapy
as primary therapy. (B) 7.5 years later, she continues to have 20/20

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vision.

subtenon carboplatin in 37.5%. I-125 was used in 10 cases (91%)

while Ru-106 was used in one case. The mean dose was 44 Gy
(range 40–45 Gy) to the tumour apex, 100.8 Gy (range 72–144
Gy) to the tumour base, 45.7 Gy (range 5.5–124.6 Gy) to the
fovea and 21 Gy (range 1–46 Gy) to the optic disc. The mean
length of treatment was 55 hours (range 33–78 hours) (table 2).

Local tumour control

Local recurrence occurred in two cases (18%). Both cases that
had local recurrence after EB were classified as group D tumours
in which implant was used as secondary treatment after a combi-
nation of intravenous chemotherapy, cryotherapy, transpupillary
thermotherapy and subtenon carboplatin. Both were definitively
managed with enucleation. No local recurrences were detected
in eyes with group B or C tumours, or those treated primarily
Figure 2  (A) Kaplan-­Meier curve showing recurrence-­free survival
with EB. Enucleation was performed in two cases (18%), both
of 80% at 5 years. Number at risk at 1 year decreases to 8; decreases
of which were classified as group D eyes, as noted previously.
to 7 at 5 years; further decreases to 2 at 8 years after episcleral
Specifically, there were no enucleations for eyes classified
brachytherapy. (B) Kaplan-­Meier curve showing ocular survival of 80%
as group B or C. Tumour regression was classified by clinical
at 5 years. Number at risk at 1 year decreases to 8; decreases to 7 at 5
appearance as type 1 in one case (11%), type 3 in three cases
years; further decreases to 2 at 8 years after episcleral brachytherapy.
(33%) and type 4 in five cases (56%) (figure 1).
(C) Kaplan-­Meier curve showing overall survival of 100% at 8 years.
Number at risk at 1 year is 10; decreases to 8 at 5 years; further
Ocular survival decreases to 2 at 8 years after episcleral brachytherapy.
Kaplan-­Meier survival analysis estimated RFS to be 80% at 5
years after EB. OcS was also estimated to be 80% at 5 years.
The estimated number at risk for both recurrence and enucle-
ation was 7 at year 5, and decreasing to 2 at year 8 after EB. optic neuropathy, scleral necrosis or neovascular glaucoma was
Survival outcome estimates are depicted as Kaplan-­Meier curve observed in our series. Radiation-­ related complications are
(figure 2). summarised in table 3.

Complications Visual outcome

Radiation-­
related complications included non-­ proliferative Out of the five cases that developed radiation retinopathy, four
retinopathy in two eyes (18%), proliferative retinopathy in cases had a final Snellen VA ranging from 20/20 to 20/30, while
three eyes (27%) and cataract in one eye (9%) (figure 3). No one case had final VA of light perception.
210 Echegaray JJ, et al. Br J Ophthalmol 2020;104:208–213. doi:10.1136/bjophthalmol-2019-313985
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Clinical science
cryotherapy or local recurrences after CRD alone. This is espe-
cially relevant for focal consolidation of larger tumours (>3 mm
in height) after CRD, due to the lack of efficacy of laser, TTT or
cryotherapy for larger lesions. Additionally, EB can serve as an
alternative to TTT for focal consolidation after CRD to address
partially calcified tumours due to their amelanotic nature. Partic-
ularly, tumours with associated subretinal fluid and/or localised
seeding may represent a relative contraindication for the use of
laser or TTT in these cases, and may in turn be susceptible to
brachytherapy. EB also has an advantage over EBRT of limited
radiation exposure to orbital and facial structures. Consequently,
EBRT induced orbital bone deformity and second malignant
tumours are not observed following EB.12–15 Moreover, EBRT
also provides lower 5 years’ control rates (range 31%–64%),
when compared with EB (range 79%–94%).6 16 Overall, the
risks for tumour recurrence following EB include the presence of
tumour seeds in the vitreous and subretinal space, large tumour
size, prior failure of EBRT, lower dose of radiation (<35 Gy)
and increasing patient age.
Our case series details our clinical outcomes with EB prior
to the adoption of local chemotherapy. Our overall local recur-
Figure 3  Fundus photo of group C retinoblastoma (A) that was rence was 18% with a mean radiation dose of 44 Gy to the
treated with standard six cycles of intravenous chemotherapy tumour apex. No local recurrences were observed when Epis-
(Vincristine, Etoposide, Carboplatin (VEC protocol). The tumour showed cleral brachytherapy was applied as primary modality. EB may
dramatic regression (B). The tumour was then consolidated with be effective as primary treatment of an isolated group B tumour.
episcleral brachytherapy (iodine-125, apical dose 45 Gy). The tumour It may also be considered for selected group C tumours with
became increasingly calcified with onset of fine retinal haemorrhages localised seeds. For the latter cases, the radiation dosimetry

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over the tumour surface (C). Fluorescein angiogram revealed areas of planning should include the localised seeds as part of the target
retinal non-­perfusion with fine retinal neovascularisation (D). volume. An advantage that primary EB treatment provides for
the above described specific cases is the potential for avoiding
Overall survival complications of systemic chemotherapy such as fatigue, nausea,
There were no recorded metastases or deaths in our study. vomiting, and thrombocytopenia17 and potential ocular compli-
cations of IAC.18 For selected cases of unilateral, non-­heritable
Discussion group B and C retinoblastoma, EB may therefore offer an effec-
The role of EB in the management of retinoblastoma can be tive chemotherapy-­sparing treatment. This is especially relevant
examined from the perspective of a primary treatment modality for institutions that do not have the capacity to offer IAC. Our
for focal lesions, or as secondary treatment in the context of results are comparable with previously published reports. Shields
systemic intravenous chemotherapy or local IAC or intravitreal and colleagues reported a tumour control rate of 88% and 79%
routes. Since the 1990s, systemic intravenous chemotherapy at 1 year and 5 years, respectively, with an average dose of 40
has provided an effective treatment strategy for bilateral reti- Gy.12 Schueler and colleagues reported a 94% control rate after
noblastoma and advanced unilateral cases (groups B–D).6–8 The 5 years using ruthenium plaques with a high radiation dose
concept of chemoreduction via the intravenous route is defined (>100 Gy).19
as the induction of tumour shrinkage with primary intravenous Our data are consistent with previously reported studies in
chemotherapy, followed by subsequent consolidation treatment which EB had been used as salvage therapy after CRD or EBRT
with focal therapies (laser, cryotherapy, TTT, EB or EBRT). This with 95% efficacy when excluding cases with subretinal or
is evident by an estimated recurrence rate after CRD alone to be vitreous seeding.6 However, other studies have reported overall
as high as 51%. When combined with focal therapy the recur- success rates of 50%–60% when brachytherapy is used as salvage
rence rate drops to 18%.6 9 10 Specifically, for the treatment of therapy after CRD or EBRT. In our series, all recurrences were
advanced group D cases of retinoblastoma systemic intravenous treated with enucleation, as they were all advanced group D
chemotherapy with or without focal consolidation has been esti- eyes. Therefore, patients with group D tumours may have a
mated to have a successful treatment rate of 9%–57% without higher risk for local tumour recurrence after EB and the need for
the need for EBRT or enucleation.11 closer follow-­up of these patients must be recognised.
EB has served as focal consolidation therapy for cases that EB in the setting of retinoblastoma can also lead to ocular
do not respond to previous laser photocoagulation, TTT, comorbidities such as radiation retinopathy, cataract, optic
neuropathy and neovascular glaucoma. In a previous case series,
Shields et al reported retinopathy in 27% of eyes, papillop-
Table 3  Radiation-r­ elated complications athy in 26%, cataract in 31% and glaucoma in 11% of treated
Mean onset after treatment
eyes.12 Schueler et al reported a high incidence of intraocular
Type of complication Patients, n (%) (months) haemorrhage of 29.1% in their series of patients treated with
Ru-106 plaques, with almost half of these patients developing
Cataract 1 (9.1) 32
vitreous haemorrhage.19 Abouzeid et al reported only one
Radiation retinopathy 5 (45.5) 17.4
case of radiation retinopathy in their series, which features an
Non-­proliferative 2 (18.2) 22
average dose of 50 Gy to the tumour apex using Ru-106.20 In
Proliferative 3 (27.3) 14.3
our study, we report a rate of non-­proliferative retinopathy of
Echegaray JJ, et al. Br J Ophthalmol 2020;104:208–213. doi:10.1136/bjophthalmol-2019-313985 211
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Clinical science
18%, proliferative retinopathy of 27% and cataract develop- of 40–45 Gy. Their study also assessed ocular toxicity from EB
ment in 9%. Among those treated with primary EBI, only one radiation exposure showing either no change or improvement in
developed radiation retinopathy. The clinician should therefore the post-­EB electroretinography responses when compared with
have a low threshold for suspecting the development of radia- pre-­EB responses.27 Their data further support the use of EB as a
tion retinopathy in these patients, especially those with previous safe combination therapy with IAC.
systemic chemotherapy. It has also been recognised that eyes that
have previously received EBRT are at higher risk for these ocular
complications, and the total dose to critical structures such as the Conclusion
optic nerve should be carefully monitored. Even in the present era of local chemotherapy, EB may provide
In general, for patients with proliferative radiation retinop- local control in selected cases of primary and recurrent retino-
athy, panretinal photocoagulation is the definitive treatment blastoma tumours. This is especially relevant for those tumours
with or without adjuvant intravitreal anti-­vascular endothelial posteriorly located that may not be amenable to laser or cryo-
growth factor agents. Regarding non-­proliferative radiation reti- therapy as well as with the presence of subretinal fluid and amel-
nopathy, the treatment is individualised (observation, intravit- anotic calcified tumours. However, while the adoption of IAC
real anti-­vascular endothelial growth factor agents, steroids) for continues to expand, the indications for the use of EB as a safe
each patient with detailed discussion with the parents weighing and effective primary treatment modality for focal tumours as
long-­term visual prognosis versus burden of treatment. Although well as its secondary use after systemic CRD remain pertinent
5 out of 11 total cases developed radiation retinopathy, final VA and applicable due to the general accessibility of both EB and
was excellent (20/20 to 20/30) in four cases, while only one case systemic intravenous chemotherapy for the treatment of retino-
had VA <20/200. Although this represents a limited subset of blastoma worldwide, especially for bilateral cases. After treat-
patients, our data suggest that development of radiation retinop- ment, patients must be monitored closely for the development
athy after EB for extrafoveal retinoblastoma may not be visually of any postbrachytherapy recurrences within the first 6 months,
significant in the majority of patients. as well as for any radiation-­related complications.
None of cases in our series developed visually significant
Contributors  JJE, YAAZ and AS collected and analysed the data. JJE and AS wrote
cataract requiring surgery. Nevertheless, cataract surgery can be and revised the manuscript, constructed tables and figures, and critically revised the
safely performed in eyes that have been previously treated for work and references. All authors take responsibility for this study.
retinoblastoma with demonstrated stability of the tumour over

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Funding  The authors have not declared a specific grant for this research from any
the 6–12 months.21 funding agency in the public, commercial or not-­for-­profit sectors.
In the modern era of local chemotherapy, EB continues to Competing interests  None declared.
have an important role in the management of retinoblastoma.
Patient consent for publication  Not required.
IAC is generally used for advanced cases (groups C–E), with an
effective profile for tumour regression. In a recent retrospective Provenance and peer review  Not commissioned; externally peer reviewed.
study of 10 years of experience with IAC, Francis et al reported Data availability statement  All data relevant to the study are included in the
a local recurrence rate of approximately 25%, mostly occurring article.
within 1 year of treatment.22 Their study presented new defini- ORCID iD
tions for outcome measures in retinoblastoma treatment (RFS, Arun Singh http://​orcid.​org/​0000-​0001-​9411-​0320
OcS, OS) and proposed a specific definition for local recur-
rence in retinoblastoma treatment, which we have adopted in
our current study. Their study also suggested that intravitreous References
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