Impact of early delivery of children with familial retinoblastoma after prenatal RB1

mutation identification

Sameh E. Soliman, MD; Helen Dimaras, PhD; Vikas Khetan, MB, BS; J. A. Gardiner, ??; Helen S. L. Chan,

MB, BS, FRCSC; Elise Héon, MD, FRCSC; Brenda L. Gallie, MD, FRCSC

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

Hospital for Sick Children, 525 University Avenue, 8th floor, Toronto, ON M5G 2L3, Canada, or at

brenda@gallie.ca

Authors’ Affiliations:

Departments of Ophthalmology & Vision Sciences, (Soliman, Dimaras, Héon , Gallie) and Division of

Hematology/Oncology, Pediatrics (Chan), Hospital for Sick Children, Toronto, Canada; Division of Visual

Sciences, Toronto Western Research Institute, Toronto, Canada (Héon , Gallie); Ophthalmology

Department, Faculty of Medicine, Alexandria University, Egypt (Soliman); Sankara Nethralya Hospital,

Chennai, India (Khetan); Departments of Pediatrics (Chan), Molecular Genetics (Gallie), Medical

Biophysics (Gallie) and Ophthalmology & Vision Sciences (Dimaras, Héon, Gallie), and the Division of

Clinical Public Health (Dimaras) University of Toronto, Toronto, Ontario, Canada. …….(Gardiner).

Financial Support: None

Conflict of Interest: No conflicting relationship exists for any author

Running head: Early delivery of familial retinoblastoma

Word count: 3262 /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

Early delivery of children at risk for retinoblastoma 2

At A Glance:

All the children of a parent who had retinoblastoma are at risk to also

develop retinoblastoma. However, if the unique RB1 mutation of that parent

is molecularly defined, their children can be determined prenatal to be at

near 100% versus 0% risk to develop retinoblastoma. We compared children with familial retinoblastoma delivered spontaneously

without prenatal RB1 testing, to those with prenatal RB1 mutation

identification and planned early delivery. All children eventually developed

tumors in both eyes. Planned early term delivery resulted in more infants born with no tumors,

whose tumors could be detected early and treated when very small with less

invasive therapies. This resulted in better visual outcomes for the children

identified prenatal to be at risk. Early term delivery resulted in no perinatal complications. Prenatal RB1 mutation detection is a good anticipatory planning tool for the

family and child.

Early delivery of children at risk for retinoblastoma 3

Abstract (341/350)

IMPORTANCE: Familial retinoblastoma can be predicted by prenatal RB1 mutation

detection. Early delivery following prenatal detection for treatment of smaller

tumors may achieve better outcomes with minimal therapy.

OBJECTIVE: To compare overall outcomes and intensity of treatment for children with familial

retinoblastoma diagnosed postnatally or by obstetrical ultrasound, and those diagnosed by

prenatal RB1 mutation identification and delivered preterm.

DESIGN: A retrospective, observational study.

SETTING: This study was conducted at The Hospital for Sick Children (SickKids), a

retinoblastoma referral center in Toronto, Canada.

PARTICIPANTS: All children who were born between 1 June 1996 and 1 June 2014 with familial

retinoblastoma, cared for at SickKids.

EXPOSURE(S): Cohort 1 consisted of infants who were spontaneously delivered and had

postnatal RB1 testing. Cohort 2 consisted of infants who were identified by amniocentesis to

carry the relative’s known RB1 mutant allele and had planned early term or late preterm

delivery (36-37 weeks gestation). All children received treatment for eye tumors.

MAIN OUTCOME MEASURES: Primary study outcome measurements were gestational age, age

at first tumor, eye classification, treatments given, visual outcome, number of anesthetics,

pregnancy or delivery complications and estimated treatment burden.

Early delivery of children at risk for retinoblastoma 4

RESULTS: Of Cohort 1 (n=9) infants, 67% (6/9) already had vision-threatening tumors at birth.

Of Cohort 2 (n=12) infants, 25% (3/12) had vision-threatening tumors at birth. Both Cohorts

eventually developed tumors in both eyes. Useful vision (better than 0.1, legal blindness) was

achieved for 78% of Cohort 1 compared to 100% of Cohort 2 (p<0.02). At first eye tumor

diagnosis, 11% of Cohort 1 had both eyes Group A (smallest and least vision-threatening

tumors) compared to 67% of Cohort 2 (p<0.01). Eye salvage (defined as avoidance of

enucleation and external beam irradiation) was achieved in 33% of Cohort 1 compared to 97%

of Cohort 2 (p<0.002). There were no complications related to preterm delivery.

CONCLUSIONS AND RELEVANCE: Prenatal molecular diagnosis with late preterm/near-term

delivery resulted in more eyes with no detectable retinoblastoma tumors at birth, and better

vision outcomes with less invasive therapy. Prenatal molecular diagnosis facilitates anticipatory

planning for both child and family.

Early delivery of children at risk for retinoblastoma 5

INTRODUCTION

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 already have retinoblastoma

tumor(s) at birth, often in the posterior pole of the eye where they threaten

vision.4-8 Because focal laser treatment near the optic nerve and macula may

compromise vision, treatment of these small tumors can be 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, 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

Early delivery of children at risk for retinoblastoma 6

Full term birth is defined as live birth after 37 weeks gestation.12 Preterm

birth is defined as live birth occurring before completion of 37 weeks. The

American College of Obstetrics and Gynecology has suggested the

description of ‘early term’ be ascribed to infants born after completion of 37

but before 39 weeks gestation.12,13 The main concern with preterm or early

term delivery is the potential effect on neurological and cognitive

development and later school performance measured in children with a wide

range of indications for early delivery.14-16 For otherwise normal children with

high risk of cancer and visual dysfunction from large macular tumors,

blindness17 may exceed such risks of early delivery. We present the first report of outcomes of late preterm/early term delivery

for children demonstrated prenatal to carry the RB1 mutant allele of a

parent. We show that such children had earlier detection and treatment of

small tumors, lower treatment morbidity, and better tumor control and visual

outcome, than children born spontaneously without precise genetic

diagnosis.

Methods

Study Design

Early delivery of children at risk for retinoblastoma 7

Research ethics board approval was obtained from The Hospital for Sick

Children (SickKids). Data collected for children 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; age and location of

first tumor(s) in each eye; treatments used; International Intraocular

Retinoblastoma Classification18 of each eye (IIRC); Tumor Node Metastasis

(TNM) staging for eyes and child;11 treatment duration; date of last follow-up;

and visual outcome at last follow-up. RB1 mutation testing was performed by

Impact Genetics (formerly Retinoblastoma Solutions), as previously

described.19

The gestational age at birth for each child was calculated (39 weeks was

considered full term). Vision threatening tumors were defined as IIRC18 Group

B or worse, which includes tumor size and proximity to optic nerve or

macula. Treatments were summarized as focal therapies (laser therapy,

cryotherapy and periocular subtenon’s injection of chemotherapy) or

systemic therapies (systemic chemotherapy or stereotactic external beam

irradiation). Active treatment duration (time from diagnosis to last

treatment) and number of examinations under anesthesia (EUAs) were

counted. Treatment success was defined as avoidance of enucleation or

external beam irradiation or extraocular disease. Acceptable visual outcome

was defined as visual acuity better than 0.1 decimal (20/200). Legal

blindness is defined as visual acuity worse than 0.1.

Early delivery of children at risk for retinoblastoma 8

Data analysis

Basic descriptive statistics were used for comparisons between patients

diagnosed postnatal (Cohort 1) and those provided 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.

Results

Patient Demographics

Twenty-one children with familial retinoblastoma were reviewed (11 males,

10 females) and eligible for this study (Supplementary Table 1, Figure 1).

Diagnosis for Cohort 1 (9 children, 43%) was by observation of tumor or

postnatal testing for the parental RB1 mutation. Six were born full term and

3 were delivered late preterm because of pregnancy-induced hypertension

(child #7), fetal ultrasound evidence of retinoblastoma20 (child #9) or

spontaneous delivery (child #8). The 12 children (57%) in Cohort 2 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

Early delivery of children at risk for retinoblastoma 9

All study subjects were offspring of retinoblastoma probands. Nineteen

probands were bilaterally and 2 were unilaterally (mother #8, father #19)

affected. The familial RB1 mutations were previously detected except for the

unilaterally affected parent of #8. This unilaterally affected parent had not

been tested, because she believed that since she had unilateral

retinoblastoma, her children were not at risk for retinoblastoma. Cohort 1

children were (#1-9) 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 16 families. Five had low penetrance RB1

mutations (whole gene deletion, #19; weak splice site mutations, #15, 18,

21; and a missense mutation,19,21 #5) (Supplementary Table 1). No proband

in this study was mosaic for the RB1 mutation. All study subjects were

eventually bilaterally affected. At birth, 9/16 (56%) infants with null RB1

mutations had tumors, affecting 14/31 (45%) eyes, but 0/5 infants with low

penetrance mutations had tumors at birth (Table 1a, b, P=0.02 for eyes,

P=0.04 for children; Fisher’s exact test). (The Group A eye of Child #8 was

excluded from per eye calculations as the child was first examined at 3

months of age with Group A/D tumors, so first detectable tumor in the Group

A eye is unknown. We presume the Group D eye had tumor at birth, Table 1).The age at first tumor per child was insignificantly younger for those with null

mutations (mean 59, median 20 days), than those with low penetrance

mutations (mean 107, median 119 days) (Figure 2a).

Classification of Eyes at Birth

Early delivery of children at risk for retinoblastoma 10

Of Cohort 1 eyes, 53% (9/17) had tumor at birth, compared to 21% (5/24) of

Cohort 2 eyes (P=0.05*, Chi Square test), excluding the IIRC18 Group A eye of

child #8, as above (Table 1a). We assumed that child #8 had tumor at birth

since he had Group D IIRC18 in the right eye at 3 months of age. Of Cohort 1

children, 66% (6/9) and 25% (3/12) of Cohort 2 had tumor in at least one eye

at birth (Table 1b, Figure 1). At birth, 39% of eyes (7/18) in Cohort 1 had a

visually threatening tumor (IIRC18 Group B or worse) compared to 17% of

eyes (4/22) in Cohort 2.Tumors emerged at a younger age in the macular and peri-macular region

(IIRC18 Group B), as previously described.22 The median age of diagnosis of

15 IIRC18 B eyes (all threatening optic nerve and fovea, 6 also >3 mm size)

was 9 days, tending younger than the 92 days for 24 IIRC18 A eyes (< 3mm

and away from optic nerve and fovea).18 The gestational age showed the

same tendency (7 and 60 days respectively).Bilateral IIRC18 Group A eyes were present at initial diagnosis in 2/9 (22%)

children in Cohort 1 compared to 8/12 (67%) in Cohort 2 (P=0.01, Fisher

exact test) (Table 2a). At first diagnosis, tumors were not threatening vision

(IIRC18 Group A) in 8/17 (47%) Cohort 1 eyes, compared to 17/24 (71%)

Cohort 2 eyes (Table 2b). One eye was an IIRC18 D eye and presented at age

of 3 months (child #8).

Treatment Course

Early delivery of children at risk for retinoblastoma 11

All infants were frequently examined from birth onwards (except child #8

who presented at age 3 months) 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)23{Chan, 2005 #21688} (4), stereotactic radiation (2), and

enucleation of one eye (5) (Supplementary Table 1, Figure 1). Cohort 2

patients were treated with focal therapy (all); chemotherapy (5), enucleation

of one eye and stereotactic radiation (1) (Figure 1). Treatment by focal

therapy alone (avoidance of systemic chemotherapy or EBRT) was possible

in 4/9 (44%) of Cohort 1 and 7/12 (58%) of Cohort 2 (Table 2b). The median active treatment duration was 458 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 25 (range 18-81) and for Cohort 2 was 29 (range 20-

41). .

Outcomes

Early delivery of children at risk for retinoblastoma 12

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 44% of Cohort 1 and 92% of Cohort 2 (P=0.05, Fisher

exact test) (Table 2). Kaplan Meier ocular survival for Cohort 1 was 62%

compared to 92% for Cohort 2 (P=0.02, Log-rank (Mantel-Cox) test) (Figure

2b). One child (#6) (11%) in Cohort 1 showed high-risk histo-pathologic

features in the enucleated eye and still under active treatment. All children

are presently alive.Children were legally blind (visual acuity less than 0.1 (20/200) using both

eyes) in 22% of Cohort 1 and 0% of Cohort 2 (P=0.02, Fisher exact test)

(Table 2a). Visual outcomes were better than 0.1 for 50% of eyes in Cohort 1

and 92% of eyes in Cohort 2 (P=0.02, Fisher exact test) (Table 2b). Seventy

one percent of eyes (17/24) of Cohort 2 had final visual acuity better than

0.5 (20/40) compared to 50% (9/18) of eyes in Cohort 1.

Early delivery of children at risk for retinoblastoma 13

Treatment success (avoidance of enucleation and/or stereotactic radiation)

and good vision per eye was documented 50% (9/18) of Cohort 1 and 88%

(21/24) of Cohort 2 (P=0.014*, Fisher exact test) (Table 2b, Figure 1). A

negative correlation trend was found between gestational age and final

visual outcome (r=-0.03) with better visual outcome observed for earlier

deliveries (Figure 3).

Discussion

This is the first report on the outcome of early delivery of children for

retinoblastoma. We show that prenatal molecular diagnosis of familial

retinoblastoma and elective late preterm/early term delivery allowed

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

outcomes and less intensive medical interventions in very young children.

This data illustrates that for infants with high risk of developing

retinoblastoma (RB1+/- or family history) 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 67% 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 2a).

Early delivery of children at risk for retinoblastoma 14

It is practical to identify 96% of the germline mutations in bilaterally affected

probands and to identify the >15% of unilateral probands who carry a

germline gene mutation.3,10,24 When the proband's unique mutation is

identified, molecular testing of family members can determine who else

carries the mutation and is at risk to develop retinoblastoma. We report 12

infants identified in utero by molecular testing to carry the mutant RB1 allele

of a parent. The 50% of tested infants who do not inherit their family’s

mutation require no surveillance. Without molecular information, repeated retinal examination is

recommended for all first degree relatives until age 7 years, the first 3 years

under general anesthesia.11 Such repeated clinical screening may impose

psychological and financial burden on the children and families. Early

molecular RB1 identification of the children, who are not at risk and require

no clinical intervention, costs significantly less than clinical screening for

tumors.19,25

Early delivery of children at risk for retinoblastoma 15

The earliest tumors commonly involve the macular or paramacular region,

threatening loss of central vision, while tumors that develop later are usually

peripheral, where they have less visual impact.5,26-29 In our study, the risk of a

vision-threatening tumor dropped from 39% to 17% by prenatal mutation

detection and planned early delivery (Table 2). Macular and paramacular

tumors are difficult to manage by laser therapy or application of a

radioactive plaque, since these threaten the optic nerve and central vision.

Systemic chemotherapy effectively shrinks tumors such that focal therapy

can be applied with minimal visual damage. Child #9 (Cohort 1) had a tumor

at 36 weeks gestation large enough for detection by obstetrical ultrasound,

which showed drug-resistant tumor following reduced-dose chemotherapy as

a newborn,20 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,30 or

administer a single agent carboplatin chemotherapy.26 However, reduced

doses carry risk of selecting for multidrug resistance in the tumor cells,

making later recurrences difficult to treat.31-33 Periocular topotecan for

treatment of small-volume retinoblastoma34 may increase the effectiveness

of focal therapy without facilitating resistance.

Early delivery of children at risk for retinoblastoma 16

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. 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%).Early screening of at-risk infants with positive family history as soon as

possible after birth is the internationally accepted convention for

retinoblastoma.7,35 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%).36,37 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 appeared to

change patient outcomes.

Early delivery of children at risk for retinoblastoma 17

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

neurological and cognitive development and later school performance.14-16

One could argue that 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,17 though this has not 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, save

for the tumor growing in their eye. Early term delivery requires an interactive

team of neonatologist, ophthalmologist and oncologist to reach the best

timing for better outcome.38 We show that safe late preterm/early term

delivery resulted in lower tumor burden at birth (Cohort 2) that was

significantly easier to treat than in Cohort 1 (Figure 3, Table 2). Safe late preterm and early term delivery resulted in more

infants 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).

Early delivery of children at risk for retinoblastoma 18

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 wish to terminate an affected pregnancy.39 There have been two prior

reports indicating pre-natal molecular testing for retinoblastoma; in one, the

fetus sibling of a proband was found not to carry the sibling’s mutation,40 and

in the other, 2 of 5 tested fetuses of a mosaic proband were born without the

parental mutation.41 This is the first report that elective safe late preterm/early term delivery of

prenatally diagnosed infants with familial retinoblastoma results in improved

outcomes. 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 infants that

are prenatally molecularly diagnosed with retinoblastoma, as a potential

stem cell source in later anti-cancer therapy. We conclude that the infants

with familial retinoblastoma who are likely to develop vision-threatening

macular tumors, have an improved chance of good visual outcome with

decreased treatment associated morbidity with prenatal molecular diagnosis

and safe, late-preterm delivery.

Early delivery of children at risk for retinoblastoma 19

Acknowledgements

Author contributions:

SS and BG had full access to all the data in the study and take responsibility for the integrity of the data

and the accuracy of the data analysis.

Study concept and design: Soliman, Gallie,

Acquisition, analysis, or interpretation of data: Soliman, Dimaras, Khetan, , Gardiner, Gallie

Drafting of the manuscript: Soliman, Dimaras, Khetan, Gallie

Critical revision of the manuscript for important intellectual content: Dimaras, Gallie, Chan, Héon

Statistical analysis: Soliman, Dimaras, Gallie

Study supervision: Chan, Héon, Gallie

Early delivery of children at risk for retinoblastoma 20

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Early delivery of children at risk for retinoblastoma 25

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

Eyes 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 % YES

Null RB1 mutation 14 17 31 45% 9 7 16 56%

Low penetrance

RB1 mutation 0 10 10 0% 0 5 5 0%

Total 41 21

Fisher's exact test p=0.02* p=0.04*

Cohort 1 9 8 17 53% 6 3 9 67%

Cohort 2 5 19 24 21% 3 9 12 25%

Total 41 21

Fisher's exact test p=0.05* p=0.09

Early delivery of children at risk for retinoblastoma 26

Table 2: Outcome parameters and their level of significance

Table 2a: Outcome parameters per child        

Cohort 1(n=9) Cohort 2 (n=12)

No % No % P value

Tumor(s) at birth 6 67% 3 25% 0.087IIRC AA at first tumor 2 22% 8 67% 0.009*Treatment  Focal therapy only 3 33% 7 58%

0.39Systemic chemotherapy 6 67% 5 42%

Treatment success 3 33% 11 92%   0.002*Ocular salvage 4 44% 11 92% 0.046*Visual Outcome

Acceptable vision (better than 0.1) 7 78% 12 100%0.017*

Legal Blind 2 22% 0 0% 

Table 2b: Outcome parameters per eye

Cohort 1(n=18)

Cohort 2(n=24)   

No % No % P value Tumor(s) at birth 10 56% 5 21% 0.027*Good visual prognosis (A) at first tumor 8 44% 17 71% 0.1Treatment success 11 61% 22 92% 0.025*Ocular salvage 13 72% 23 96% 0.07Visual Outcome

Acceptable vision (better than 0.1) 9 50% 21 88%0.014*

Poor Vision 9 50% 3 13%

Early delivery of children at risk for retinoblastoma 27

Figure 1: Schematic representation of each child in Cohort 1 (postnatal RB1

detection) and Cohort 2 (prenatal RB1 detection) from delivery until time of first

tumor, IIRC at first tumor per eye, treatment burden (focal, systemic chemotherapy,

or radiation treatment). Number of EUAs, visual acuity at last follow up and follow

up duration.

Early delivery of children at risk for retinoblastoma 28

Figure 2: a, Comparison of birth age at diagnosis of first tumor in each eye, for

children with low penetrance versuss null RB1 mutations. b, Kaplan Myer curves

showing significantly worse proportion avoiding failure (defined as enucleation or

external beam radiation) for Cohort 1 vs. Cohort 2 (P=0.02*, Log-rank (Mantel-Cox)

test (X2=5.7).

Early delivery of children at risk for retinoblastoma 29

Figure 3: Relationship between visual acuity per eye at last follow up (decimal) and

gestational age at delivery in weeks showing a negative correlation.

26 28 30 32 34 36 38 400

0.5

1

1.5

2

f(x) = − 0.0284788135593221 x + 1.66274293785311R² = 0.0313248065403926

Gestational age (weeks)

Visu

al A

cuity

(dec

imal

)