Pediatric Cataract Surgery Following Treatment for

Retinoblastoma: a Case Series and Systematic Review

Stephanie N. Kletke, MD, FRCSC1,2, Ashwin Mallipatna, MBBS1,2, Kamiar Mireskandari,

MBChB, FRCSEd, FRCOphth, PhD1,2, Brenda L. Gallie, MD, FRCSC1,2, Asim Ali, MD,

FRCSC1,2

Authors’ Affiliations1 Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Canada. 2 Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada.

Corresponding Author:Asim Ali, MD, FRCSC, Ophthalmologist-in-Chief, Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, 555 University Avenue, Toronto, Canada, M5G 1X8. Phone: 416-813-6806, Fax: 416-813-5159, Email: asim.ali@sickkids.ca

Meeting Presentations: American Association for Pediatric Ophthalmology and Strabismus

Annual Meeting (poster; April 9, 2021) and the University of Toronto Ophthalmology Research

Day (poster; April 27, 2021)

Financial Support: None

Conflicts of Interest: Dr. Ali is a consultant for Santen. The other authors have no conflicts of

interest to disclose.

Running Head: Cataract surgery following treatment for retinoblastoma

Keywords: retinoblastoma; cataract; cataract surgery

Acknowledgements: The authors would like to thank Ms. Elena Springall, Liaison and

Education Librarian, Gerstein Science Information Centre, University of Toronto, for her

assistance with the systematic review search methodology.

1

1

2

3

4

5

6

789

101112131415161718

19

20

21

22

23

24

25

26

27

28

Abstract

TOPIC: To determine the visual and refractive outcomes, and ocular and systemic

complications of cataract surgery in eyes treated for retinoblastoma.

CLINICAL RELEVANCE: Retinoblastoma globe salvage therapies induce secondary cataract,

limiting visual development and tumor evaluation.

METHODS: Retrospective consecutive case series of children <18 years with retinoblastoma

who underwent surgery for secondary cataract between 2000 and 2020. A systematic review was

performed of Medline (OVID), Embase, Web of Science and Cochrane databases from inception

to August 2020, including any peer-reviewed English-language publications that reported at least

1 outcome of cataract surgery in children treated for retinoblastoma.

RESULTS: Fifteen eyes of 15 children were included. Mean age at retinoblastoma diagnosis

was 12 months (median, 14; IQR, 4-19). Cataract developed at mean age 39 months (median, 31;

IQR, 20-52), secondary to multiple treatments (n=7), pars-plana vitrectomy (n=3), external-beam

radiotherapy (n=2), laser (n=2), and retinal detachment (n=1). Mean quiescent interval before

surgery was 44 months (median, 28; IQR, 15-64). Primary intraocular lens implantation was

performed in 93%, posterior capsulotomy in 40% and anterior vitrectomy in 33%. Intraoperative

findings included posterior synechiae, anterior capsule fibrosis, posterior capsule plaque, and

zonulopathy. Postoperatively, 100% had improved fundus visibility and 73% (11/15) improved

vision. At final follow-up, visual acuity was 1.0 logMAR or better in 6 eyes (40%). Mean

absolute predictive refractive error was 1.4 ± 1.3 D. Complications included visual axis

opacification (11/15), capsular phimosis (5/15), zonulopathy (4/15), and lens decentration/tilt

(2/14). One child had intraocular recurrence (7%) treated by PPV/tumor endoresection. No child

2

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

developed extraocular extension or metastasis at mean 76 months (median, 78; IQR, 29 – 128)

follow-up.

For the Systematic review, identified a total of 852 studies were identified, 18 meeting inclusion

criteria. Across all studies (n=220 children), intraocular recurrence occurred in 7%, globe

salvage was achieved in 91%, and extraocular extension and metastasis were reported in <1%.

CONCLUSIONS: Modern retinoblastoma therapies, including intravitreal chemotherapy and

vitrectomy, cause secondary cataract. Following cataract surgery, intraocular recurrence risk is

low and extraocular spread is rare. While surgery improves tumor visualization, visual prognosis

may be limited by several factors. Challenges include biometry limitations and higher incidence

of zonulopathy.

3

52

53

54

55

56

57

58

59

60

61

62

63

Globe salvage therapies for retinoblastoma may induce secondary cataract. Historically,

external beam radiotherapy (EBRT) led to cataract development in up to 88% of eyes.1-5

Although cataract may be less likely with lens-sparing techniques, the incidence remains

clinically significant.6 Given the increased second primary cancer risk following EBRT,7 the

management of retinoblastoma shifted to systemic chemoreduction and focal consolidation in the

1990s,8 and more recently to other modalities of chemotherapy delivery. Cataract has been

reported following intra-arterial chemotherapy (IAC),9, 10 related to medication toxicity or

theoretically to cumulative radiation exposure after multiple doses.11, 12 Cataract is also a reported

complication of intracameral chemotherapy13 and intravitreal chemotherapy (IVitC),14-16 resulting

from chemotoxicity or direct trauma. Plaque brachytherapy also induces cataract in 10 to 31% of

eyes.17-19 Cataract may preclude adequate tumor evaluation and limit the child’s visual

development.

Previous reports of cataract surgery in eyes treated for retinoblastoma focused on

outcomes of radiation-induced cataract.20-24 The current literature is limited to small case reports

and series, with no consensus on a safe interval of tumor quiescence before cataract surgery or

optimal surgical approach. Furthermore, the safety of limbal versus pars plana incisions, primary

posterior capsulotomy, anterior vitrectomy, and primary intraocular lens implantation are

debated and unique intraoperative considerations have not been reported.

We sought to determine the visual and refractive outcomes, and ocular and systemic

complications of cataract surgery in eyes previously treated for retinoblastoma.

Methods

Study Design

4

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

We conducted a retrospective, noncomparative, single-institutional, consecutive case

series in accordance with the guidelines of the Declaration of Helsinki. Institutional research

ethics board approval was obtained.

The systematic review, registered in the International Prospective Register of Systematic

Reviews database (CRD42020207372), was performed in accordance with The Cochrane

Handbook for Systematic Reviews of Interventions.25 Reporting followed the Preferred

Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.26

Eligibility Criteria

Children 18 years of age or younger who were diagnosed with cataract secondary to

treatments for retinoblastoma and managed surgically at the Hospital for Sick Children, Toronto,

Canada, between January 2000 and August 2020, were evaluated. Children with less than 6-

month follow-up post-cataract surgery were excluded.

Peer-reviewed, English-language publications describing at least one outcome of cataract

surgery in children treated for retinoblastoma were eligible for the systematic review. Both

prospective and retrospective studies were eligible. There were no date restrictions. Conference

abstracts, reviews and editorials, basic science and animal studies, and articles unavailable for

full-text review were excluded.

Search Methods and Study Selection

Medline (Ovid), Embase, Web of Science, Cochrane, TRIP and ClinicalTrials.gov were

comprehensively searched from inception to August 13, 2020 (complete search strategy available

in Supplemental Table 1). The search strategy was optimized by a the reference librarian (ES)

5

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

with author input. Reference lists of original studies and review articles were manually searched

for additional studies. Following removal of duplicate studies, titles and abstracts were screened

for eligibility and full texts of all potentially eligible studies were reviewed by two independent

reviewers (SNK, AM). Discrepancies were resolved by an independent third reviewer (AA).

Covidence was used to manage the identified studies.27

Data Collection and Risk of Bias Assessment

Case Series

Medical records were reviewed for demographic and clinical features (age at RB

diagnosis, sex, RB laterality, clinical features at diagnosis, staging by the International

Intraocular Retinoblastoma Classification (IIRC),28 retrospective staging by the 8th Edition

American Joint Committee on Cancer (AJCC),29 heritability, family history, RB treatments prior

to cataract surgery (including intravenous (IVC), intra-arterial (IAC), periocular, intravitreal

(IVitC) and intracameral chemotherapy, investigational sustained-release topotecan episcleral

chemoplaque,30 external-beam radiotherapy (EBRT), plaque brachytherapy, pars plana

vitrectomy (PPV), focal laser and cryotherapy), age at cataract diagnosis, cataract laterality,

morphology and suspected etiology, preoperative visual acuity), intervention details (indication

for cataract surgery, age at cataract surgery, interval between last RB treatment and cataract

surgery, tumor status at cataract surgery, biometry, intraocular lens (IOL) power calculations,

target refraction, surgical technique, intraoperative findings and complications, vitreous

cytology), and outcomes following cataract surgery (postoperative complications, visual acuity,

postoperative spherical equivalent refraction (SER) within 6 months, follow-up, secondary

treatments, intraocular tumor recurrence, extraocular extension, and metastasis). Absolute

6

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

predictive refractive error was calculated by the absolute difference between predicted (target)

and observed post-operative spherical equivalent refraction in diopters (D).

Systematic Review

When available, the same data was extracted from eligible studies using a standardized

form. Study characteristics (author, publication year, center/location, journal, study design, years

of study, inclusion and exclusion criteria, number of eyes and children) were also extracted. Data

extraction was performed by a single reviewer (SNK), with complete agreement on partial

review (10%) by an independent reviewer (AM). Risk of bias was assessed at the study level by

the Joanna Briggs Institute (JBI) Critical Appraisal Checklists for case reports and series.31, 32

Data Synthesis and Analysis

The visual and refractive outcomes, intraoperative findings, and the ocular and systemic

complications of cataract surgery were evaluated. Summary outcome measures included

intraocular tumor recurrence, globe salvage, extraocular extension, and metastasis.

Results were summarized using frequency and percentage for categorical variables and

mean, median, range, and interquartile range (IQR) for continuous variables. Summary measures

were presented qualitatively and as proportions, when possible, and included data from this case

series. Proportions were calculated per child for systemic outcomes and per eye for ocular

outcomes. Studies that did not report an outcome were not included in the calculation of that

proportion. Lack of comparative studies precluded a meta-analysis for outcome measures.

Microsoft Excel Version 16.50 (Microsoft Corporation, Redmond, WA, USA) was used for

descriptive statistics.

7

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

Results

Case Series

Demographic and Clinical Features

Fifteen eyes of 15 children met the inclusion criteria (Table 1). One child was excluded

due to insufficient follow-up. Retinoblastoma was diagnosed at mean age 12 months (median,

14; range, 0 – 30; IQR, 4 – 19) and was bilateral in most children (93%). Staging of the study

eye was most commonly Group D/cT2 (67%). Thirteen eyes (87%) had macular involvement. At

presentation, retinal detachment (RD) touched the posterior lens in 1 eye, but no eye had primary

cataract. Cataract was diagnosed at mean age 39 months (median, 31; range, 6 – 92; IQR, 20 –

52), at mean interval 27 months (median, 18; range, 2 – 70; IQR, 10 – 52) following RB

diagnosis.

Globe salvage treatments received prior to cataract surgery are summarized in Table 1.

The primary cataract etiology was multifactorial in 7 eyes (47%), PPV in 3 (20%), EBRT in 2

(13%), laser in 2 (13%) and RD in 1 eye (7%). The indication for pars plana vitrectomy (mean,

1.3 vitrectomies; range, 1 – 2) was RD repair (4/8), tumor endoresection (1/8), vitreous

hemorrhage (1/8), silicone oil removal (1/8), and vitreous seeds (1/8), performed elsewhere.

Details of Cataract Surgery

The indication for cataract surgery was improved fundus visualization in all children.

Some visual improvement was anticipated, depending on the macular status. Cataract surgery

was performed at mean age 79 months (median, 64; range, 35 – 199; IQR, 45 – 97), at mean

interval 66 months (median, 56; range, 8 – 178; IQR, 29 – 79) following RB diagnosis. In all

8

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

cases, tumors were inactive at cataract surgery, following a mean quiescent interval of 44 months

from last RB treatment (median, 28; range, 1 week – 148 months; IQR: 15 – 64). Most children

(73%) were monocular at the time of surgery. The details of cataract surgery are included in

Table 2.

Pre-operative biometry was challenging due to macular tumor location and presence of

silicone oil in some eyes. Adjustments attempted to compensate for eccentric fixation, when

possible. IOL power was estimated based on axial length of the uninvolved eye in the child with

unilateral RB. Cataract extraction was performed in all eyes by limbal approach; a primary IOL

(CEIOL) was inserted in 14 eyes (93%) and one eye was left aphakic. In 2 eyes, CEIOL was

combined with posterior segment surgery (both limbal and pars plana approach). The first

combined case involved PPV for removal of vitreous fibrosis and tractional bands, in an eye with

known tractional RD, retrolental membrane and vitreous opacification. The second combined

case included silicone oil removal, following previous PPV for tumor endoresection. One

previously irradiated eye had concurrent CEIOL and symblepharolysis, by limbal and scleral

tunnel incision. Primary IOL was inserted in the bag in 12 eyes, in the sulcus with optic capture

in 1 eye, and in the bag with posterior optic capture in 1 eye. Primary posterior capsulotomy

(PPC) was performed in 6 eyes and anterior vitrectomy (AV) in 5 eyes. Vitreous samples were

sent for cytologic analysis in 7 cases (including both combined cases), anterior lens capsule in 4

cases, and aqueous samples in 2 cases; all were negative for malignant cells.

Intraoperative findings included posterior synechiae (n=4 eyes), keratopathy (n=4),

anterior capsule fibrosis (n=3), iris atrophy (n=3), zonulopathy (n=2), vitreous fibrosis/traction

(n=2), peripheral anterior synechiae (n=2), subconjunctival fibrosis (n=2), pupillary membrane

(n=1), posterior capsule plaque (n=1), and retrolental membrane (n=1). Posterior synechiolysis

9

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

was performed using a viscoelastic cannula, and if unsuccessful, synechiae were left intact to

prevent capsular tear. Focal anterior capsule fibrosis was avoided during formation of the

continuous curvilinear capsulorhexis, and intraocular scissors were used when more extensive

fibrosis limited rhexis formation. There were no significant intraoperative complications.

Zonulopathy was identified intraoperatively in 2 eyes. The first eye had superior zonular

and iris defects with inferior lens subluxation, post multiple IVitC and focal laser. Punctures in

the anterior capsule adjacent to posterior synechiae suggested a traumatic etiology. A capsular

tension ring and 1-piece IOL were inserted in the bag, without PPC/AV. In the second eye (post

multiple treatments, including IVitC, intracameral chemotherapy, plaque brachytherapy, and

PPV for RD), migration of trypan blue into the anterior vitreous suggested areas of zonular

weakness. PPC/AV were performed but an IOL was not inserted.

Outcomes following Cataract Surgery

All eyes had improved fundus view and 73% (11/15) had improved vision. The

preoperative and postoperative best corrected visual acuities (BCVA) are listed in Table 3.

Preoperative BCVA was 1.0 logMAR or better in 3 eyes (20%). Best recorded postoperative

BCVA was 1.0 logMAR or better in 9 eyes (60%), which was improved in 11 eyes. Final BCVA

was 1.0 logMAR or better in 6 eyes (40%), improved from preoperatively in 9 eyes. Factors

limiting final BCVA included macular tumor/scar (n=13), chronic or previous RD (n=9),

keratopathy (n=5), optic neuropathy (n=4), macular edema (n=2), chronic uveitis (n=1), and

amblyopia (n=1). Mean absolute predictive refractive error (n=6) was 1.4 ± 1.3 D.

Table 4 summarizes the ocular and systemic complications following cataract surgery.

Globe salvage was achieved in 93%. Visual axis opacification (VAO) was most common and

10

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

required a secondary lens procedure in 73% (8/11) at mean age 106 months (median, 116; range,

52 – 145; IQR, 66 – 143), including membranectomy (n=3), PPV with posterior capsulotomy

(n=3), and Nd:YAG capsulotomy (n=2). Post-operatively, zonulopathy was noted in 4 eyes. The

first eye with intraoperative zonulopathy developed anterior hyaloid opacification, capsular

phimosis, traction on the IOL/bag complex from vitreous adjacent to treated tumors, and

posterior IOL tilt, and required membranectomy for VAO. The second eye with intraoperative

zonulopathy developed significant capsular phimosis and zonular stretch, requiring surgical

excision of the collapsed aphakic capsular bag. Pathology showed subcapsular fibroblast

proliferation. In addition, the eye managed with combined CEIOL/PPC/AV and PPV for vitreous

traction developed an exuberant fibrinoid reaction, and the IOL was pulled posteriorly by

adherent retina, encased in fibrosis. Despite secondary PPV for progressive tractional RD, this

eye became phthisical and was enucleated. Pathology showed no active RB. Globe salvage was

achieved in 93%.

Intraocular RB recurrence in the posterior segment developed 2 months post-operatively

in an eye treated extensively prior to CEIOL/PPC/AV. Cataract surgery was performed 1 month

after the last RB treatment. Complete remission was achieved following PPV/tumor

endoresection, with no further recurrence 13 months postoperatively. There were no cases of

extraocular extension or metastases at mean follow-up of 76 months (median, 78; range, 13 –

154; IQR, 29 – 128) after cataract surgery.

Systematic Review

Study Selection

11

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

Figure 1 shows the PRISMA flow diagram of the study selection process. From 1362

abstracts identified from the search strategy, 852 were screened by title and abstract after de-

duplication, and 53 full texts were reviewed. Of these, 18 studies met criteria for inclusion.1, 20-24,

33-44

Study Characteristics

Table 5 shows the characteristics of included publications, which reported on 239 eyes of

220 children. Fifteen studies were retrospective case series,1, 20-24, 33, 34, 36, 37, 39-42, 44 and 3 were

retrospective case reports.35, 38, 43 Two studies were published before 2000,20, 33 9 from 2000 to

2010,21, 22, 24, 34-39 and 7 in 2011 or later.1, 23, 40-44 Most studies focused on surgical management of

radiation-induced cataracts.1, 20-24, 33, 35-42 The average interval of RB remission before cataract

surgery was 21 - 123 months.1, 20, 22, 23, 33-35, 38, 39, 41-44 Post-operative follow-up ranged from 17 - 103

months.20-24, 33, 35, 37, 38, 40-44 Two studies also reported other intraocular surgeries, of which only

cataract surgery cases were included.34, 39 For summary outcomes, the Brooks et al.20 paper was

excluded, due to overlap of 11 patients also published by Honavar et al.34

Risk of Bias within studies

Assessment of risk of bias for all studies is summarized in Supplemental Table 2. All

studies were sufficient for inclusion.

Synthesis of Results

12

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

Table 6 includes the outcomes for which summary proportions were possible, including

the number of studies reporting each outcome, number of events, and percentage of eyes or

children experiencing the outcome.

Intra-operative Findings

Few studies reported ocular findings during cataract surgery. Anterior capsule fibrosis

was reported in a case report of 1 eye.35 Including our series, posterior capsule plaque was

reported in 16 of 63 eyes (25%).22, 35, 40, 44

Visual and Refractive Outcomes

Preoperative visual acuity was reported by 10 studies.1, 21, 22, 24, 33, 38, 40-42, 44 All studies

described postoperative visual outcomes. Honavar et al. reported a final BCVA better than 1.0

logMAR in 44%.34 Miller et al. reported mean final BCVA 0.3 logMAR (range, 0.0 – 1.3),

depending on macular status.21 Other studies similarly reported a wide range of postoperative

acuity (0.0 logMAR – hand motions).1, 22-24, 39-42, 44 Kaliki et al. noted improvement in 16 (55%)

and no improvement in 13 (45%) of 29 eyes.44 Factors contributing to poor visual outcomes

included macular involvement,1, 20-23, 33, 34, 37, 40, 44 radiation complications (keratopathy, retinopathy,

and optic neuropathy),20, 22, 24, 34, 36, 37, 41, 44 amblyopia,20, 22, 37, 43, 44 RD,20, 34, 44 and secondary

glaucoma.41

Few studies reported refractive outcomes after cataract surgery.21, 33, 35 Portellos et al.

reported postoperative refraction within 1 D of predicted in 91% of #??? eyes.33 Two studies

reported myopic progression over follow-up.33, 35

13

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

Ocular Complications

Postoperative complications included VAO,1, 22-24, 34, 35, 38, 40, 41, 44 fibrin/membranes,33, 40, 44

macular edema,21, 23, 41 RD,34, 39, 41, 43 vitreous hemorrhage,24, 34, 41 uveitis,1, 21 IOL decentration/tilt,23

and glaucoma.23, 41 Complications reported by a single study included capsular or hyaloidal

fibrosis (3 of 12 eyes),22 endophthalmitis (1 of 34 eyes),34 phthisis bulbi (1 of 19 eyes),24

hyphema (1 of 29 eyes),44 and corneal decompensation (1 of 34 eyes).34 Across all studies,1, 21-24,

33-36, 38-44 intraocular recurrence occurred in 7% of eyes. Honavar et al.34 reported intraocular

recurrence in 7 of 34 eyes, with no correlation to surgical approach. Recurrence was more likely

following a shorter quiescent interval (6 months compared to 26 months for all intraocular cases

combined).34 Moshfeghi et al.39 reported intraocular recurrence in 1 eye (25%);. cataract surgery

was performed 12 months after last retinoblastoma treatment, but no surgical details were

provided. Recurrence was noted in 3 of 21 eyes by Osman et al.23 The first case was 12 months

post-lens aspiration without PPC, the second was 11 months post-extracapsular cataract

surgery/PPC, and the third was 7 months post-clear corneal surgery without PPC. The intervals

of tumor quiescence was were 37, 3 and 5 months, respectively. Kaliki et al.44 reported

recurrence in 2 of 29 eyes at mean 8-months postoperatively. Globe salvage was achieved in

91% (165/182, n=15).1, 21-24, 33-35, 38-40, 42-44

Systemic Complications

Across all studies, extraocular extension was reported in <1%.21-24, 33, 35, 39, 40, 42-44 Kaliki et

al. described a case of extraocular tumor extension following clear corneal lens aspiration and

PPC/AV, after a presumed quiescent interval of 11 months.44 Cytology showed atypical cells and

enucleation was recommended, but the child was lost to follow-up and developed extrascleral

14

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

extension 11 months later.44 Brooks et al. reported a case of extraocular extension from a

sclerotomy site 9 months after PPV for persistent VH, which developed following pars plana

lensectomy and AV performed 9 months after the last EBRT.20 This case was not included in the

summary proportion due to unclear overlap of children across studies. Honavar et al. reported

metastasis in one child 30 months after extracapsular cataract extraction with PPC and scleral

buckle, which followed a 3-month quiescent interval.34 The eye was enucleated for recurrence 1

year later, and the child died from metastasis despite adjuvant chemotherapy.34 Overall,

metastasis was reported in <1%.21-24, 34, 35, 39, 40, 42-44

Discussion

Our series highlights the outcomes of cataract surgery following modern retinoblastoma

treatments. EBRT contributed to cataract formation in 27% of eyes, mostly within the first

decade, while intra-arterial, intravitreal and intracameral chemotherapy were important etiologies

in the second decade. Cataract was also secondary to vitrectomy in 40% of eyes, mostly within

the second decade, highlighting the changing etiology of cataract over time.

There are important preoperative considerations in pediatric eyes previously treated for

retinoblastoma. In addition to the known challenges in obtaining accurate biometry and IOL

calculation in young children, macular tumors, silicone oil in vitrectomized eyes, concurrent

keratopathy, and contralateral eye involvement in bilateral retinoblastoma offer additional

limitations. However, absolute predictive refractive error was acceptable in a small number of

eyes in our series. We suggest IOL power calculations consider age-based normative data,

measurement of the uninvolved eye in unilateral retinoblastoma, or the preferred retinal locus in

monocular children.

15

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

Intraoperative considerations include posterior synechiae, anterior capsule fibrosis, and

zonulopathy. Presence of vitreous traction, retrolental membranes and tractional RD warrant a

combined approach with a pediatric vitreoretinal surgeon. A high incidence of zonulopathy was

noted in our series. Possible etiologies include trauma from prior IVitC or PPV, posterior

vitreous traction on the IOL-bag complex related to prior treatments and postoperative fibrinous

capsular phimosis. A capsular tension ring may be considered, though an IOL should not be

inserted if capsular support is inadequate.

The systematic review summarized the available published literature on pediatric cataract

surgery in eyes treated for retinoblastoma. Across all studies, intraocular RB recurred in 7% of

eyes, 91% of eyes were salvaged, and extraocular extension and metastases were rare. Overall,

this review suggests that cataract surgery is safe, though the risks and benefits for the child

should be considered in collaboration between the ocular oncologist, pediatric anterior segment

surgeon, and the actively engaged and informed family.

Several surgical approaches have been published, but subgroup analysis by surgical

technique is limited by the low incidence of postoperative ocular and systemic complications.

Some recommend avoidance of PPC/AV,1, 20, 24, 34 given the potential barrier to anterior spread of

tumor cells, while others support its safety.21, 23, 33 We and others42, 44 recommend PPC/AV when

posterior opacity limits vision or fundus visualization, guided by the recommendation of the

ocular oncologist. When PPC/AV are performed, cytology of a vitreous specimen is

imperative.21, 23, 40, 44 This review also suggests that primary IOL insertion is safe and may aid

visual rehabilitation.

The optimal interval between retinoblastoma regression and cataract surgery is not

clearly established. Portellos et al. recommend a minimum quiescent interval of 16 months.33

16

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

Similarly, Payne et al. recommend at least 17 months of tumor inactivity before cataract

surgery.22 Osman et al. and Bayraktar et al. recommend at least 9 months,1, 23 while Kaliki et al.

and Honavar et al. suggest at least 6 months of inactivity is sufficient.34, 44 Reports of tumor

recurrence after cataract surgery following a quiescent interval of over 3 years23 suggest that the

decision to proceed with surgery should by tailored to the child and consider prior therapies,

tumor burden, monocular status, potential for visual improvement, and inadequacy of fundus

view for disease monitoring. Frequent postoperative follow-up is essential to monitor for tumor

recurrence.

Our study has several strengths. We report cataract surgery outcomes following modern

retinoblastoma therapies and identify important surgical considerations and complications. This

systematic review included many children and allowed for summary proportions of outcomes.

However, there are important limitations to consider. We did not determine the incidence of

cataract among all children receiving modern retinoblastoma therapies. The systematic review

included only retrospective case reports and series, with heterogenous inclusion criteria, study

periods, cataract etiology and surgical techniques. Summary proportions were limited by variable

reporting of outcomes and lack of comparative studies prevented meta-analysis.

Modern retinoblastoma therapies, including intravitreal chemotherapy and vitrectomy,

cause secondary cataract. Following cataract surgery, intraocular tumor recurrence risk is low

and extraocular spread is rare. While surgery improves tumor visualization, macular tumors, RD,

optic neuropathy, and keratopathy limit visual prognosis. Surgical challenges include biometry

limitations and higher incidence of zonulopathy. Surgical planning requires collaboration

between the retinoblastoma specialist and pediatric anterior segment surgeon to optimize

outcomes.

17

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

References

1. Bayraktar S, Tuncer S, Ozgun C, Peksayar G, Kebudi R. Surgical Outcomes in Radiation-induced Cataracts After External-beam Radiotherapy in Retinoblastoma. Turk J Ophthalmol. Jun 2018;48(3):127-131. doi:10.4274/tjo.700192. Mouw KW, Sethi RV, Yeap BY, et al. Proton radiation therapy for the treatment of retinoblastoma. International Journal Of Radiation Oncology, Biology, Physics. Nov 15 2014;90(4):863-9. doi:10.1016/j.ijrobp.2014.07.0313. Pradhan DG, Sandridge AL, Mullaney P, et al. Radiation therapy for retinoblastoma: a retrospective review of 120 patients. International Journal Of Radiation Oncology, Biology, Physics. Aug 1 1997;39(1):3-13. doi:10.1016/s0360-3016(97)00156-94. Egbert PR, Donaldson SS, Moazed K, Rosenthal AR. Visual results and ocular complications following radiotherapy for retinoblastoma. Arch Ophthalmol. Oct 1978;96(10):1826-30. doi:10.1001/archopht.1978.039100603380085. Fontanesi J, Pratt CB, Kun LE, Hustu HO, Coffey D, Meyer D. Treatment outcome and dose-response relationship in infants younger than 1 year treated for retinoblastoma with primary irradiation. Med Pediatr Oncol. May 1996;26(5):297-304. doi:10.1002/(SICI)1096-911X(199605)26:5<297::AID-MPO1>3.0.CO;2-D6. Nguyen SM, Sison J, Jones M, et al. Lens Dose-Response Prediction Modeling and Cataract Incidence in Patients With Retinoblastoma After Lens-Sparing or Whole-Eye Radiation Therapy. International Journal Of Radiation Oncology, Biology, Physics. Apr 1 2019;103(5):1143-1150. doi:10.1016/j.ijrobp.2018.12.0047. Temming P, Arendt M, Viehmann A, et al. Incidence of second cancers after radiotherapy and systemic chemotherapy in heritable retinoblastoma survivors: A report from the German reference center. Pediatr Blood Cancer. Jan 2017;64(1):71-80. doi:10.1002/pbc.261938. Gallie BL, Budning A, DeBoer G, et al. Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol. Nov 1996;114(11):1321-8. 9. Suesskind D, Schrader M, Foerster MH, Ernemann U, Aisenbrey S. Cataract formation: a possible complication of intra-arterial chemotherapy for retinoblastoma. Eur J Ophthalmol. May-Jun 2014;24(3):449-53. doi:10.5301/ejo.500039310. Chen Q, Zhang B, Dong Y, et al. Intra-arterial chemotherapy as primary or secondary treatment for infants diagnosed with advanced retinoblastoma before 3 months of age. BMC Cancer. Jul 15 2019;19(1):693. doi:10.1186/s12885-019-5844-511. Obesso A, Alejo L, Huerga C, et al. Eye lens radiation exposure in paediatric interventional treatment of retinoblastoma. Sci Rep. Dec 27 2019;9(1):20113. doi:10.1038/s41598-019-56623-412. Vijayakrishnan R, Shields CL, Ramasubramanian A, Emrich J, Rosenwasser R, Shields JA. Irradiation toxic effects during intra-arterial chemotherapy for retinoblastoma: should we be concerned? Research Support, Non-U.S. Gov't. Arch Ophthalmol. Nov 2010;128(11):1427-31. doi:10.1001/archophthalmol.2010.258

18

383

384

385386387388389390391392393394395396397398399400401402403404405406407408409410411412413414415416417418419420421422423

13. Munier FL, Gaillard MC, Decembrini S, Bongiovanni M, Beck-Popovic M. Intracameral Chemotherapy (Melphalan) for Aqueous Seeding in Retinoblastoma: Bicameral Injection Technique and Related Toxicity in a Pilot Case Study. Ocul Oncol Pathol. Jul 2017;3(2):149-155. doi:10.1159/00045361714. Ghassemi F, Shields CL. Intravitreal melphalan for refractory or recurrent vitreous seeding from retinoblastoma. Arch Ophthalmol. Oct 2012;130(10):1268-71. doi:10.1001/archophthalmol.2012.198315. Smith SJ, Smith BD, Mohney BG. Ocular side effects following intravitreal injection therapy for retinoblastoma: a systematic review. Br J Ophthalmol. Mar 2014;98(3):292-7. doi:10.1136/bjophthalmol-2013-30388516. Francis JH, Marr BP, Brodie SE, Abramson DH. Anterior Ocular Toxicity of Intravitreous Melphalan for Retinoblastoma. JAMA ophthalmology. Dec 2015;133(12):1459-63. doi:10.1001/jamaophthalmol.2015.311917. Abouzeid H, Moeckli R, Gaillard MC, et al. (106)Ruthenium brachytherapy for retinoblastoma. International Journal Of Radiation Oncology, Biology, Physics. Jul 1 2008;71(3):821-8. doi:10.1016/j.ijrobp.2007.11.00418. Shields CL, Shields JA, Cater J, Othmane I, Singh AD, Micaily B. Plaque radiotherapy for retinoblastoma: long-term tumor control and treatment complications in 208 tumors. Ophthalmology. Nov 2001;108(11):2116-21. 19. Soliman SE, Bansal A, De Nicola ML, et al. Applications of iodine-125 plaque radiotherapy for residual or recurrent retinoblastoma. Can J Ophthalmol. Jan 23 2021;doi:10.1016/j.jcjo.2020.12.01620. Brooks HL, Jr., Meyer D, Shields JA, Balas AG, Nelson LB, Fontanesi J. Removal of radiation-induced cataracts in patients treated for retinoblastoma. Arch Ophthalmol. Dec 1990;108(12):1701-8. 21. Miller DM, Murray TG, Cicciarelli NL, Capo H, Markoe AM. Pars plana lensectomy and intraocular lens implantation in pediatric radiation-induced cataracts in retinoblastoma. Ophthalmology. Sep 2005;112(9):1620-4. doi:10.1016/j.ophtha.2005.04.01722. Payne JF, Hutchinson AK, Hubbard GB, 3rd, Lambert SR. Outcomes of cataract surgery following radiation treatment for retinoblastoma. J AAPOS. Oct 2009;13(5):454-458 e3. doi:10.1016/j.jaapos.2009.06.00223. Osman IM, Abouzeid H, Balmer A, et al. Modern cataract surgery for radiation-induced cataracts in retinoblastoma. Br J Ophthalmol. Feb 2011;95(2):227-30. doi:10.1136/bjo.2009.17340124. Hoehn ME, Irshad F, Kerr NC, Wilson MW. Outcomes after cataract extraction in young children with radiation-induced cataracts and retinoblastoma. J AAPOS. Apr 16 2010;doi:S1091-8531(10)00078-9 [pii]10.1016/j.jaapos.2010.01.01225. Higgins J, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions. Cochrane; 2019. Updated July 2019. www.training.cochrane.org/handbook26. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. Jul 21 2009;6(7):e1000097. doi:10.1371/journal.pmed.1000097

19

424425426427428429430431432433434435436437438439440441442443444445446447448449450451452453454455456457458459460461462463464465466

27. Covidence systematic review software. Veritas Health Innovation. 2020. www.covidence.org28. Linn Murphree A. Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin North Am. Mar 2005;18(1):41-53, viii. doi:10.1016/j.ohc.2004.11.00329. AJCC cancer staging manual. 8 ed. Springer International Publishing; 2017:pages cm.30. Gallie B, Shaikh F, Morgenstern D, Mallipatna A. Phase I Sustained-Release Topotecan Episcleral Plaque (Chemoplaque) for Retinoblastoma. https://clinicaltrials.gov/ct2/show/NCT0442887931. Munn Z, Barker TH, Moola S, et al. Methodological quality of case series studies: an introduction to the JBI critical appraisal tool. JBI Evid Synth. Sep 23 2019;doi:10.11124/JBISRIR-D-19-0009932. Moola S, Munn Z, Tufanaru C, et al. Chapter 7: Systematic reviews of etiology and risk. JBI. Accessed August 2020, https://synthesismanual.jbi.global33. Portellos M, Buckley EG. Cataract surgery and intraocular lens implantation in patients with retinoblastoma. Arch Ophthalmol. Apr 1998;116(4):449-52. 34. Honavar SG, Shields CL, Shields JA, Demirci H, Naduvilath TJ. Intraocular surgery after treatment of retinoblastoma. Arch Ophthalmol. Nov 2001;119(11):1613-21. 35. Bhattacharjee H, Bhattacharjee K, Chakraborty D, Talukdar M, Das D. Cataract surgery and intraocular lens implantation in a retinoblastoma case treated by external-beam radiation therapy. J Cataract Refract Surg. Sep 2003;29(9):1837-41. 36. Shanmugam MP, Rao SK, Khetan V, Kumar PJ. Cataract surgery and intraocular lens implantation in retinoblastoma. J Cataract Refract Surg. Sep 2004;30(9):1825-6. doi:10.1016/j.jcrs.2004.06.07637. Sinha R, Titiyal JS, Sharma N, Vajpayee RB. Management of radiotherapy-induced cataracts in eyes with retinoblastoma. J Cataract Refract Surg. May 2004;30(5):1145-6. doi:10.1016/j.jcrs.2004.03.02038. Correa ZM, Marcon IM, Augsburger JJ. Phacoemulsification surgery and foldable intraocular lens implantation in a child with regressed retinoblastoma. Eur J Ophthalmol. Nov-Dec 2005;15(6):821-2. 39. Moshfeghi DM, Wilson MW, Grizzard S, Haik BG. Intraocular surgery after treatment of germline retinoblastoma. Arch Ophthalmol. Jul 2005;123(7):1008-12. doi:10.1001/archopht.123.7.100840. Tartarella MB, Britez-Colombi GF, Motono M, Chojniak MM, Fortes Filho JB, Belfort R, Jr. Phacoemulsification and foldable acrylic IOL implantation in children with treated retinoblastoma. Arq Bras Oftalmol. Oct 2012;75(5):348-51. doi:10.1590/s0004-2749201200050001141. Velasquez-Aguilar M, Matiz-Moreno H, Amato-Almanza M, Chen-Lopez CY, Marquez-Garcia G, Ramirez-Ortiz MA. Outcomes and complications after phacoemulsification in retinoblastoma patients with cataract after radiation treatment. Arch Soc Esp Oftalmol. Apr 2017;92(4):160-165. Facoemulsificacion en pacientes con retinoblastoma y catarata por radioterapia: resultados y complicaciones. doi:10.1016/j.oftal.2016.11.01142. Kim HM, Lee BJ, Kim JH, Yu YS. Outcomes of Cataract Surgery Following Treatment for Retinoblastoma. Korean J Ophthalmol. Feb 2017;31(1):52-57. doi:10.3341/kjo.2017.31.1.52

20

467468469470471472473474475476477478479480481482483484485486487488489490491492493494495496497498499500501502503504505506507508509

43. Stathopoulos C, Sergenti J, Gaillard MC, Munier FL, Daruich A. Pars plana vitrectomy under melphalan irrigation for recurrent retinal detachment in eyes treated for retinoblastoma: a case report. BMC ophthalmology [electronic resource]. Jan 28 2020;20(1):34. doi:10.1186/s12886-020-1315-744. Kaliki S, Maniar A, Kekunnaya R. Cataract surgery in treated retinoblastoma eyes: A study of 29 eyes. Eur J Ophthalmol. Jun 25 2020:1120672120938575. doi:10.1177/1120672120938575

Figure Legends

Figure 1. PRISMA diagram demonstrating the flow of studies through the selection process.

21

510511512513514515516517

518

519