Expectant management versus conventional screening in infants with

familial retinoblastoma

Sameh E. Soliman1,2, MD; Helen Dimaras1,3,4, PhD; Vikas Khetan1,5, MD, BS; Jane A.

Gardiner1,6, MD, FRCSC; Helen S. L. Chan7,8, MB, BS, FRCPC; Elise Héon1,3,9, MD, FRCSC;

Brenda L. Gallie1,3,9,10, MD, FRCSC

Corresponding Author: Dr. Brenda Gallie at the Department of Ophthalmology and Vision

Sciences, the Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8,

Canada, or at brenda@gallie.ca

Authors’ Affiliations:

1Departments of Ophthalmology & Vision Sciences, The Hospital for Sick Children, Toronto,

Canada

2Ophthalmology Department, Faculty of Medicine, Alexandria University, Egypt.

3Department of Ophthalmology & Vision Sciences, Faculty of Medicine, University of Toronto,

Toronto, Ontario, Canada.

4Division of Clinical Public Health, Dalla Lana School of Public Health, University of Toronto,

Toronto, Ontario, Canada.

5Sankara Nethralya Hospital, Chennai, India.

6Department of Ophthalmology and Vision Science, University of British Columbia, Vancouver,

British Columbia, Canada

7Division of Hematology/Oncology, Pediatrics The Hospital for Sick Children, Toronto, Canada

8Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

9Division of Visual Sciences, Toronto Western Research Institute, Toronto, Ontario, Canada.

10Departments of Molecular Genetics and Medical Biophysics, Faculty of Medicine,

University of Toronto, Toronto, Ontario, Canada.

Financial Support: None

Expectant Management in Familial Retinoblastoma

Conflict of Interest: No financial conflicting relationship exists for any author. BLG is an unpaid

medical director for Impact Genetics Inc.

Running head: Expectant management in familial retinoblastoma

Word count: 2886 /3000 words

Numbers of figures and tables: 3 figures and 2 tables

Key Words: prenatal retinoblastoma, retinoblastoma gene mutation, RB1, molecular testing,

late pre-term delivery, near-term delivery, amniocentesis

Meeting Presentation: Association for Research in Vision and Ophthalmology, Seattle,

Washington, USA, 2016

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Expectant Management in Familial Retinoblastoma

Précis: 35/35

Expectant management of familial retinoblastoma (prenatal RB1 mutation detection and planned early-

term delivery) achieved more often no tumors at birth, earlier tumor detection, less invasive therapies and

better visual outcome, compared to conventional postnatal screening.

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Expectant Management in Familial Retinoblastoma

Abstract (350/350 words)

OBJECTIVE To compare overall outcomes for children with familial retinoblastoma conventionally

screened postnatal, to those expectantly managed with prenatal RB1 mutation identification and delivered

early term.

DESIGN A retrospective, observational study.

PARTICIPANTS Twenty children with familial retinoblastoma born between June 1996 and June 2014,

examined within first week after birth and cared for at The Hospital for Sick Children (SickKids)

Toronto, Canada.

METHODS Conventional Cohort consisted of spontaneously delivered infants who were conventionally

screened within the first week after birth or had postnatal RB1 testing. Expectant Cohort consisted of

infants that were expectantly managed (identified by amniocentesis to carry the relative’s known RB1

mutant allele and scheduled for early term delivery (36-38 weeks gestation). All children received

treatment for eye tumors.

MAIN OUTCOME MEASURES Main outcome measures were gestational age at birth, age at first

tumor each eye, eye stage, treatments given, ocular salvage, treatment success (defined as avoidance of

enucleation and external beam irradiation), visual outcome, number of anesthetics, pregnancy or delivery

complications and estimated treatment burden.

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Expectant Management in Familial Retinoblastoma

RESULTS Vision-threatening tumors were present at birth in 50% (4/8) of Conventional Cohort infants,

and 25% (3/12) of Cohort 2 infants. All infants eventually developed tumors in both eyes. At first

treatment, 12% (1/8) of Cohort 1 had eyes Group AA or A0 (smallest and least vision-threatening tumors)

compared to 67% (8/12) of Cohort 2 (p=0.02). Treatment success was achieved in 38% (3/8) patients of

Cohort 1 compared to 92% (11/12) patients of Cohort 2 (p<0.002). Acceptable vision (better than 0.2)

was achieved for 50% (8/16) of Cohort 1 eyes compared to 88% (21/24) of Cohort 2 eyes (p=0.014).

Useful vision (better than 0.1, legal blindness) was achieved for 88% (8/9) of Cohort 1 children compared

to 100% (12/12) of Cohort 2 children. There were no complications related to early-term delivery.

CONCLUSIONS AND RELEVANCE When a parent had retinoblastoma, expectant management with

prenatal molecular diagnosis with late preterm/near-term delivery increased the likelihood of infants born

with no detectable tumors, and better vision outcomes with less invasive therapy. Prenatal molecular

diagnosis facilitates anticipatory planning for both child and family.

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Expectant Management in Familial Retinoblastoma

Retinoblastoma, the most common primary ocular malignancy in children, is commonly initiated

when both alleles of the RB1 tumor suppressor gene are inactivated in a precursor retinal cell, followed by

progressive mutations in other specific genes.1,2 Both alleles may be lost only in the retinal cell from

which one tumor arises (non-heritable retinoblastoma), or a germline mutation (50% of children)

predisposes to development of multiple retinal tumors during childhood and other cancers later in life.

Ten percent of patients inherit a family-specific mutation from a parent.1,3

Children with an RB1 germline mutation may have retinoblastoma tumor(s) at birth, often in the

posterior pole of the eye where they threaten vision.4-8 Focal laser treatments near the optic nerve and

macula may compromise vision, making treatment of these small tumors difficult. Most of these children

are bilaterally affected, with either simultaneous or sequential detection of tumors.4,7 Later developing

tumors tend to be located peripherally.7,9 Low penetrance (10% of families)3 and mosaic10 mutations result

in fewer tumors and more frequent unilateral phenotype.10 The timing of first tumors after birth has not

yet been studied.

It is recommended that infants with a family history of retinoblastoma be examined for tumor

detection and management as soon as possible after birth and repeatedly for the first few years of life

(conventional screening), including under anesthesia.11 Early diagnosis when tumors are small and

treatable with less invasive therapies is thought to optimize salvage of the eye and vision.6,7,11 We have

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Expectant Management in Familial Retinoblastoma

managed familial retinoblastoma by screening the fetus for the RB1 mutation of the proband parent. If the

child carries the RB1 mutation and has a near 100% risk to develop bilateral tumors, we recommend

delivery at early full term (37 weeks of gestation)12 with full retinal examination on day 1. Further

management is conventional screening and treatment. We hypothesized that retinoblastoma tumors are

smaller and easier to treat, the earlier they are diagnosed.

We present a retrospective comparative review of expectant prenatal genetic diagnosis vs

conventional postnatal managment of children with familial retinoblastoma. We show that children with

expectant management had earlier detection and treatment of small tumors, lower treatment morbidity,

and better tumor control and visual outcome, compared to children born spontaneously prior to genetic

diagnosis.

Methods

Study Design

Research ethics board approval was obtained from The Hospital for Sick Children (SickKids). Data

collected for children with familial retinoblastoma born between 1 June 1996 and 1 June 2014 included:

relation to proband; laterality of retinoblastoma in proband; sex; gestational age at birth; pregnancy,

prenatal abdominal ultrasound (if done); delivery or perinatal complications; type of genetic sample tested

and result; penetrance of RB1 mutation; timing of first examination; age and location of first tumor(s) in

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Expectant Management in Familial Retinoblastoma

each eye; treatments used; International Intraocular Retinoblastoma Classification (IIRC) of each eye;

Tumor Node Metastasis (TNM) staging for eyes and child;{, 2009 #10292} active treatment duration;

date of last follow-up; and visual outcome at last follow-up. The gestational age at birth for each child

was calculated (39 weeks was considered full term). Eyes with vision threatening tumors were defined as

IIRC t treatment) and number of examinations under anesthesia (EUAs) were counted. Treatment success

was defined as avoidance of enucleation or external beam irradiation. Acceptable visual outcome was

defined as visual acuity better than 0.2 decimal (20/100) in an eye. Useful vision is defined as overall

visual acuity better than 0.1 in the better eye and legal blindness as overall visual acuity worse or equal to

0.1 in the best eye.

Data analysis

Basic descriptive statistics were used for comparisons between patients seen postnatal (in first week)

and conventionally screened (Cohort 1) and those provided expectant management defined as prenatal

testing and planned late preterm or early term delivery (Cohort 2). These included Student T-Test, Chi

Square Test, Fisher Exact Test, Mann Whitney Test and Mood’s Median Test. Correlations and Kaplan-

Meyer Survival Graphs were plotted using Microsoft Excel 2007 and Prism 6 for Mac.

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Expectant Management in Familial Retinoblastoma

Results

Patient Demographics

Twenty children with familial retinoblastoma were reviewed (10 males, 10 females) and 20 were

eligible for this study. Diagnosis for Cohort 1 (Conventional Management) (8 children, 40%) was by

observation of tumor or postnatal testing for the parental RB1 mutation. Six were born full term and 2

were delivered late preterm because of pregnancy-induced hypertension (child #7), or fetal ultrasound

evidence of retinoblastoma14 (child #8). The 12 children (60%) in Cohort 2 (Expectant Management) were

prenatally diagnosed to carry their family’s RB1 mutation: 3 were spontaneously premature (children #10,

13, 15; 28-37 weeks gestation) and 9 were referred to a high-risk pregnancy unit for elective late

preterm/early term delivery (36-38 weeks gestation).

Molecular diagnosis

All study subjects were offspring of retinoblastoma probands. Nineteen probands were bilaterally

and 1 was unilaterally (father #19) affected. The familial RB1 mutations were previously detected. Cohort

1 children were (#1-8) tested postnatal for their family’s RB1 mutation by blood; Cohort 2 children (#10-

21) were tested prenatal by amniocentesis at 16-33 weeks gestation.

Null RB1 mutations were present in 15 families. Five familes had low penetrance RB1 mutations

(whole gene deletion, #18; weak splice site mutations, #14, 17, 20; and a missense mutation,15,16 #5)

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Expectant Management in Familial Retinoblastoma

(Supplementary Table 1). No proband in this study was mosaic for the RB1 mutation. All study subjects

were eventually bilaterally affected. At birth, 8/15 (53%) infants with null RB1 mutations had tumors,

affecting 13/23 (53%) eyes, but 0/5 infants with low penetrance mutations had tumors at birth (Table 2,

p=0.02 for eyes, P=0.1 for children; Fisher’s exact test).

At first tumor per child, children with null mutations tended to be younger (mean 59, median 20

days) than those with low penetrance mutations (mean 107, median 114 days). At first tumor per eye,

children with null mutations (mean 83, median 39 days) were significantly younger than those with low

penetrance mutations (mean 134, median 119 days) (p=0.03, Median Mood test) (Figure 2).

Classification of Eyes at Birth

Of Cohort 1 eyes, 50% (8/16) had tumor at birth, compared to 21% (5/24) of Cohort 2 eyes (Table

1a, Figure 1). Of Cohort 1 children, 63% (5/8) and 25% (3/12) of Cohort 2 had tumor in at least one eye

at birth (Table 1b, Figure 1). At birth, 38% of eyes (6/16) in Cohort 1 had a visually threatening tumor

(IIRC Group B or worse) compared to 17% (4/22) of Cohort 2 of eyes.

Tumors detected at birth tended to be in the peri-macular region (IIRC Group B), and tumors

detected later were smaller and not threatening vision, as previously described (Figure 1 and maybe a new

figure of location of tumors).{Balmer, 1995 #8632;King, 2015 #24993} The median age of diagnosis of

first tumor of 15 IIRC B eyes (threatening optic nerve and fovea, and 6 with at least 1 tumor >3 mm) was

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Expectant Management in Familial Retinoblastoma

9 days, tending younger than the 92 days for 24 IIRC A eyes (tumors < 3 mm and away from optic nerve

and fovea). The gestational age at first tumor diagnosis for these eyes showed the same tendency (7 and

60 days respectively).

At initial tumor diagnosis, 2/8 (25%) children in Cohort 1 had IIRC Group A/A or A/0 eyes,

compared to 8/12 (67%) in Cohort 2 (P=0.02, Fisher exact test) (Figure 1, Table 1b). At first diagnosis,

tumors were not threatening vision (IIRC Group A) in 7/16 (50%) Cohort 1 eyes, compared to 17/24

(71%) Cohort 2 eyes (Table 1a).

Treatment Course

All infants were frequently examined from birth onwards as per the National Retinoblastoma

Strategy Guidelines for Care.11 If there were no tumors at birth, each child was examined awake every

week for 1 month, every 2 weeks for 2 months. After 3 months of age, the children had EUA every 2-4

weeks. If there was tumor at birth, the children had EUAs every 2-4 weeks until control of tumors was

achieved. Cohort 1 patients were treated with focal therapy (all), chemotherapy using vincristine,

carboplatin, etoposide and cyclosporine (Toronto protocol){Chan, 2005 #21688} {Chan, 2005

#21688}T) was possible in 2/8 (25%) of Cohort 1 and 7/12 (58%) of Cohort 2 (Table 1b).

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Expectant Management in Familial Retinoblastoma

The median active treatment duration was 523 days (0-2101 days) in Cohort 1, compared to 447

days (0-971 days) in Cohort 2. The median number of EUAs in Cohort 1 was 29 (range 18-81) and for

Cohort 2 was 29 (range 20-41).

Outcomes

There were no adverse events associated with spontaneous preterm or induced late preterm or early

term birth. There were no pregnancy, delivery or perinatal complications reported for any of the infants.

Follow up (mean, median) was 8, 5.6 years; Cohort 1, 8.4, 5.6 years; and Cohort 2, 7.6, 5.8 years

(Supplementary Table 1). At the last follow up, the mean age of Cohort 1 was 10 years (median 10, range

3-19) and the mean age of Cohort 2 was 9 years (median 9, range 3-16).

Neither enucleation nor external beam irradiation were required (defined as treatment success) in

33% (3/8) of Cohort 1 and 92% (11/12) of Cohort 2 patients (P=0.02, Fisher exact test) (Table 1b).

Kaplan Meier ocular survival for Cohort 1 was 62% compared to 92% for Cohort 2 (P=0.03, Log-rank

(Mantel-Cox test) (Figure 2). One child (#6) (11%) in Cohort 1 showed high-risk histopathologic

features19-21 in the enucleated eye and received adjuvant treatment. All children are presently alive without

metastases.

Children were legally blind in 12% (1/8) of Cohort 1 and 0% of Cohort 2 (Table 1a). Visual

outcomes considered acceptable were better than 0.2 for 50% (8/16) of eyes in Cohort 1 and 88% (21/24)

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Expectant Management in Familial Retinoblastoma

of eyes in Cohort 2 (P=0.01, Fisher exact test) (Table 1a). Final visual acuity better than 0.5 (20/40) was

achieved in 50% (9/18) of eyes in Cohort 1 compared to 71% (17/24) of Cohort 2 eyes.

Combined treatment success and good vision per eye was documented 50% (8/16) of Cohort 1 and

88% (21/24) of Cohort 2 (P=0.02*, Fisher exact test) (Table 1a, Figure 1). A trend to negative correlation

was found between gestational age and final visual outcome (r=-0.03) with better visual outcome

observed for earlier births (supplementary Figure 3).

Discussion

This is the first report on outcomes of expectant management of familial retinoblastoma (elective

early term or late preterm delivery of infants with prenatal molecular confirmation). This approach

allowed treatment of tumors as they emerged, resulting in better ocular and visual outcomes and less

intensive medical interventions in very young children. Our data suggests that for infants with high risk of

developing retinoblastoma (prenatally confirmed RB1+/-), the risk of vision and eye loss despite intensive

therapies after spontaneous delivery outweighs the risks associated with induced late preterm delivery

(Figure 1). Consistent with previous reports,5 63% of children with a germline gene mutation already had

tumors at full term birth, compared to 25% when the germline mutation was detected prenatally with

planned late preterm or early term delivery (Table 1b).

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Expectant Management in Familial Retinoblastoma

It is practical to identify 97% of the germline mutations in bilaterally affected probands and ~15% of

unilateral probands who carry a germline gene mutation.3,10,22 When the proband's unique mutation is

known, molecular testing of family members can determine who else carries the mutation and is at risk to

develop retinoblastoma and other cancers. We report 12 infants identified in utero by molecular testing to

carry the mutant RB1 allele of a parent. The tested infants who do not inherit their family’s mutation (not

shown) require no surveillance.

Without molecular information, repeated retinal examination is recommended for all first degree

relatives until age 7 years, often with general anesthesia when less that 3 years old.11 Such repeated

clinical screening may impose psychological and financial burden on the children and families. Early

molecular RB1 identification of the children not at risk who require no clinical intervention, costs

significantly less than clinical screening for tumors.16,23

The earliest tumors commonly involve the macular or perimacular region, threatening loss of central

vision, while tumors that develop later are usually peripheral, where they have less visual impact.

{Abramson, 1992 #22157;King, 2015 #24993} In our study, the risk of a vision-threatening tumor

dropped from 38% to 17% by expectant management (Table 1). Macular and perimacular tumors are

difficult to manage by laser therapy or radioactive plaque, since these threaten the optic nerve and central

vision. Systemic chemotherapy effectively shrinks tumors such that focal therapy can be applied with

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Expectant Management in Familial Retinoblastoma

minimal visual damage. Child #8 (Cohort 1) had a tumor at 36 weeks gestation large enough for detection

by obstetrical ultrasound, which developed drug-resistance following reduced-dose chemotherapy as a

newborn,14 ultimately requiring enucleation. Systemic chemotherapy in neonates is difficult due to the

unknowns of immature liver and kidney function to metabolize the drugs, increasing the potential of

severe adverse effects. The conventional recommendation is to either reduce chemotherapy dosages by

50%, particularly for infants in the first three months of life,28 or administer a single agent carboplatin

chemotherapy.24 However, reduced doses carry risk of selecting for multidrug resistance in the tumor

cells, making later recurrences difficult to treat.29-31 Periocular topotecan for treatment of small-volume

retinoblastoma32 may increase the effectiveness of focal therapy without facilitating resistance.

Imhof et al7 screened 135 children at risk of familial retinoblastoma starting 1-2 weeks after birth

without molecular diagnosis and identified 17 retinoblastoma cases (13% of screened children at risk). Of

these, 70% had retinoblastoma in at least one eye at first examination and 41% of eyes had vision

threatening macular tumors; 41% of patients (7/17) had eye salvage failure (defined by radiation or

enucleation) and one case metastasized; and of eyes, 74% (27/34) had good visual acuity (defined by

vision >20/100). Our Cohort 1 children were also diagnosed postnatal but with additional molecular

confirmation of disease risk. In comparison, Cohort 2 showed fewer vision threatening tumors (17%),

fewer treatment failures (8%) and better visual outcome (88%).

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Expectant Management in Familial Retinoblastoma

Early screening of at-risk infants with positive family history as soon as possible after birth is the

internationally accepted convention for retinoblastoma.7,33 In our series, amniocentesis (to collect sample

for genetic testing) was performed in the second half of pregnancy, where risks of miscarriage are low

(0.1-1.4%).34,35 We show that for those confirmed to carry their family’s RB1 mutation, planned late

preterm/early term delivery (36-38 weeks gestation) resulted in smaller tumors with less macular

involvement and better visual outcome. We did not observe a difference in treatment burden between our

two Cohorts, likely because treatment course did not differ; however, early delivery and thus earlier

treatment correlated with better overall patient outcomes.

A concern with late preterm or early term delivery is its reported effect on neurological and

cognitive development and later school performance.36-38 However, the visual dysfunction from a large

macular tumor common in retinoblastoma patients is equally concerning, as it can cause similar

neurocognitive defects due to blindness,39 though this has not been studied in a comparative manner.

Moreover, the results from studies reporting on preterm and early term babies may also be difficult to

generalize, as they tend to include many children with complex reasons for early delivery. In contrast,

retinoblastoma children are otherwise healthy normal babies, except for the tumor growing in their eye(s).

Early term delivery requires an interactive team of neonatologist, ophthalmologist and oncologist to reach

the best timing for better outcome.40. Safe late preterm and early term delivery resulted in more infants

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Expectant Management in Familial Retinoblastoma

born tumor-free, facilitating frequent surveillance to detect tumors as they emerged, enabling focal

therapy of small tumors with minimal damage to vision (Figures 1, 3).

Counseling on reproductive risks is important for families affected by retinoblastoma including

unilateral probands. In developed countries, where current therapies result in extremely low mortality,

most retinoblastoma patients will survive to have children. Prenatal diagnosis also enables pre-

implantation genetics (to ensure an unaffected child) and informs parents who may wish to terminate an

affected pregnancy.41 There have been two prior reports indicating prenatal molecular testing for

retinoblastoma; in one, the fetus sibling of a proband was found not to carry the sibling’s mutation,{Lau,

2008 #14499} and in the other, 2 of 5 tested fetuses of a mosaic proband were born without the parental

mutation.43

It is our experience that retinoblastoma survivors and their relatives with full understanding of the

underlying risks are often interested in early diagnosis to optimize options for therapy in affected babies

rather than termination of pregnancy. We also surmise that since germline mutations predispose to future,

second cancers in affected individuals, perhaps it is worth investigating the role of cord blood banking for

infants that are prenatally molecularly diagnosed with retinoblastoma, as a potential stem cell source in

later anti-cancer therapy, including for their later independent cancers. We conclude that the infants with

familial retinoblastoma, who are likely to develop vision-threatening macular tumors, have an improved

17

Expectant Management in Familial Retinoblastoma

chance of good visual outcome with decreased treatment associated morbidity with expectant

management rather than conventional postnatal screening of at risk children with positive family history.

Conventional screening will still have the main role in developing countries with limited resources and in

developed countries in the absence of highly sensitive genetic testing

Acknowledgements

We acknowledge Ivana Ristevski for construction of some of the figures.

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Early Delivery of Children at Risk for RetinoblastomaExpectant Management in Familial Retinoblastoma

Table 1: Occurrence of tumors at birth. (*, Significant difference.)

Table 1a Table 1bEyes with tumors at birth Children with tumors at birth

(excluding IIRC A eye of child #8

first examined at age 3 months)

(child #8 included)

YES NO total%

YES YES NO total % YESNull RB1 mutation 13 17 30 43% 8 7 15 53%

Low penetrance

RB1 mutation0 10 10 0% 0 5 5 0%

Total 40 20

Fisher's exact test

p=0.016*

p=0.1

Cohort 1 8 8 16 50% 5 3 8 63%Cohort 2 5 19 24 21% 3 9 12 25%Total 40 20

Fisher's exact test p=0.09

p=0.16

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Early Delivery of Children at Risk for RetinoblastomaExpectant Management in Familial Retinoblastoma

*significant difference

23

Early Delivery of Children at Risk for RetinoblastomaExpectant Management in Familial Retinoblastoma

Table 2: Outcome parameters and their level of significanceTable 2a: Outcome parameters per child

Cohort 1(n=8) Cohort 2 (n=12)

No % No % P value

Tumor(s) at birth 5 63% 3 25% 0.167IIRC AA at first tumor 1 13% 8 67% 0.02*TreatmentFocal therapy only 2 25% 7 58%

0.196Systemic chemotherapy 6 75% 5 42%

Treatment Success§ 3 38% 11 92% 0.018*Ocular salvage 4 50% 11 92% 0.1

Visual Outcome 0%Useful vision¥ 7 88% 12 100%

1Legal Blind¶ 1 13% 0 0%

Table 2b: Outcome parameters per eye

Cohort 1(n=16) Cohort 2(n=24)

No % No % P valueTumor(s) at birth 9 56% 5 21% 0.04*Good visual prognosis (A) at first tumor

7 44% 17 71% 0.109

Ocular salvage 12 75% 23 96% 0.13

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Early Delivery of Children at Risk for RetinoblastomaExpectant Management in Familial Retinoblastoma

Treatment Success§ 10 63% 22 92% 0.042*Visual Outcome

Acceptable vision∑ 8 50% 21 88%0.014*

Poor Vision 8 50% 3 13%Combined Treatment Success & Acceptable vision

8 50% 21 88% 0.014*

* significant result; § Avoided enucleation or external beam radiation; ¥ vision > 0.1 in better seeing

eye;¶ vision ≤ 0.1 in better seeing eye; ∑ vision > 0.2 in an eye.

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