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, FRCPSC; 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

Early Delivery of Children at Risk for RetinoblastomaExpectant 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: 3000 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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Précis: 35/35

Expectant Management of Familial retinoblastomaExpectant management of familial retinoblastoma

(p(Prenatal RB1 RB1-mutation detection and /planned early-term delivery)) achieved resulted in more

infantmore often nos born without tumors at birth, whose tumors could be detected earlier tumor

detection, y and treated when tiny witlh less invasive therapies and better visual outcome, compared to

conventional postnatal screening..

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Abstract (350346/350 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 1 consisted of spontaneously delivered infants who were

conventionally screened within the first week after birth or had postnatal RB1 testing. Expectant Cohort 2

consisted of infants that were expectantly managed (identified by amniocentesis to carry the relative’s

known RB1 mutant allele who and had planned scheduled for early term early delivery (at 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 classificationstage, 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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RESULTS Vision-threatening tumors were present at birth in 50% (4/8) of Conventional Cohort 1

infants, and 25% (3/12) of Cohort 2 infants.. All iInfants in both Cohorts eventually developed tumors in

both eyes. At first treatment, first eye tumor diagnosis, 12% (1/8) of Cohort 1 had both 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 For expectantWhen a parents with a history ofhad

retinoblastoma, eExpectant management with prenatal molecular diagnosis with late preterm/near-term

delivery increaseds the likelihood of infants born 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.

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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

(cConventional 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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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, In Toronto, we

recommend deliveryExpectant management is also utilized when the family presents early during

pregnancy where the RB1 mutation is tested in the fetus via amniocentesis and; if verified to carry the

mutation with approximately 100% risk to develop tumors; Labor is induced at early full term (37 weeks

of gestation)12 and the retinawith full retinal is examinationed on day 1. Further management is then the

same schedule as in conventional screening and treatment. We hypothesized that retinoblastoma tumors

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

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

management andvs conventional screening postnatal managmentmanagement for of children with familial

retinoblastoma. We show that children with expectant management children had earlier detection and

treatment of small tumors, lower treatment morbidity, and better tumor control and visual outcome, than

compared to children born spontaneously without prior to precise genetic diagnosis.

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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

each eye; treatments used; International Intraocular Retinoblastoma Classification (IIRC)13 of each eye

(IIRC); 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. RB1 The gestational age at birth for

each child was calculated (39 weeks was considered full term). Eyes with vVision threatening tumors

were defined as IIRC 13 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

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enucleation or external beam irradiation or extraocular disease. 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 if as overall visual acuity worse or equal than 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.

Results

Patient Demographics

Twenty-one children with familial retinoblastoma were reviewed (101 males, 10 females) and 20

were eligible for this study. as One child presented 3 months after delivery and was excluded

(Supplementary Table 1, Figure 1). 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

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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 familesfamilies had low penetrance RB1

mutations (whole gene deletion, #189; weak splice site mutations, #145, 178, 201; and a missense

mutation,15,16 #5) (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 13/2330 (4353%) eyes, but 0/5 infants with low penetrance mutations

had tumors at birth (Table 21a, b, p=0.02 for eyes, P=0.1 for children; Fisher’s exact test).

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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) (Figure 2a). At first tumor

per eye, eyes of children with null mutations (mean 83, median 39 days) was were significantly earlier

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

(P=0.04*, Chi Square test)(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). (Table 1b, Figure 1). At birth, 38%

of eyes (6/16) in Cohort 1 had a visually threatening tumor (IIRC13 Group B or worse) compared to 17%

of eyes (4/22) of in Cohort 2 of eyes.

Tumors emerged detected at a younger agebirth tended to be in the macular and peri-macular region

(IIRC13 Group B), and tumors detected later were smaller and not threatening vision, as previously

described (Figures 1-2) 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 IIRC13 B eyes (all with tumors

threatening optic nerve and fovea, and 6 with at least 1 tumor >3 mm size) was 9 days, tending younger

than the 92 days for 24 IIRC13 A eyes (tumors are < 3 mm and away from optic nerve and fovea).

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{Murphree, 2005 #12287;Murphree, 2005 #12287;Murphree, 2005 #12287} 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 Bilateral 1 had IIRC13 Group A/A or A/0

eyes, were present At initial diagnosis in 2/8 (25%) children in Cohort 1 compared to 8/12 (67%) in

Cohort 2 (P=0.02, Fisher exact test) (Figure 1, Table 1b2a). At first diagnosis, tumors were not

threatening vision (IIRC13 Group A) in 78/16 (50%) Cohort 1 eyes, compared to 17/24 (71%) Cohort 2

eyes (Table 1a2b).

The Conventional screening group showed larger and more posterior tumors than the expectant

management group shown in figure 2. Before 37 weeks gestation, 7.5% (3/40) of eyes showed tumors and

in all tumors were within the macular area. At 42 weeks gestation (2 weeks after full term birth), 37.5%

(15/40) of eyes showed tumors and in 80% (12/15 eyes) tumors were within macular area.

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,

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carboplatin, etoposide and cyclosporine (Toronto protocol){Chan, 2005 #21688} {Chan, 2005 #11933}

{Chan, 2005 #21688} (4), stereotactic radiation (2), and enucleation of one eye (4) (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 external beam irradiation, EBRT) was possible in 24/8 (2550%) of Cohort 1 and 7/12

(58%) of Cohort 2 (Table 12b).

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 1b2).

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

(Mantel-Cox test) (Figure 22b). 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 12a). Visual

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

of eyes in Cohort 2 (P=0.01, Fisher exact test) (Table 1a2b). Final visual acuity better than 0.5 (20/40)

Seventy one percentwas achieved in 50% (9/18) of eyes in Cohort 1 compared to 71% (17/24) of Cohort

2 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.

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

88% (21/24) of Cohort 2 (P=0.0214*, Fisher exact test) (Table 1a2b, Figure 1). A trend to negative

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

outcome observed for earlier deliveries births (supplementary Figure 34).

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Discussion

This is the first report on outcomes of eExpectant 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. This Our data illustrates suggests that for infants

with high risk of developing retinoblastoma (prenatally confirmed 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,5 637% 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 2a1b).

It is practical to identify 976% of the germline mutations in bilaterally affected probands and to

identify the ~15% of unilateral probands who carry a germline gene mutation.3,10,22 When the proband's

unique mutation is identifiedknown, 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.

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

relatives until age 7 years, often with general anesthesia when under less that 3 years underold.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 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}{Abramson, 1998 #22158;Gombos, 2012

#12243;Abramson, 1994 #6759;Abramson, 1992 #12266;Abramson, 1992 #1457} In our study, the risk

of a vision-threatening tumor dropped from 38% to 1717% by expectant management (Table 12).

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 minimal visual damage. Child #89 (Cohort 1) had a tumor at 36

weeks gestation large enough for detection by obstetrical ultrasound, which showed developed drug-

resistancet tumor following reduced-dose chemotherapy as a newborn,14 ultimately requiring enucleation

at the age of 14 years. 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

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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%).

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

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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 changecorrelated 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 One could argue thatHowever, 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, save 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 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,

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Retinoblastoma

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

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

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

Despite this, Conventional screening will still have the main role in dDeveloping countries with limited

resources and in developed countries with in the absence of highly sensitive genetic testing

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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 mutation 0 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

26

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*Treatment    Focal 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 value Tumor(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.

28