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Impact of early delivery of children with familial retinoblastoma after
prenatal RB1 mutation identification
Sameh E. Soliman, MD; Helen Dimaras, PhD; Vikas Khetan, MD, BS; Jane A. Gardiner,
MD,FRCSC;, 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, 555 University Avenue, Toronto, ON M5G 1X8,
Canada, or at [email protected]
Authors’ Affiliations:
Departments of Ophthalmology & Vision Sciences, (Soliman, Dimaras, Khetan, Gardiner, Héon
, Gallie) and Division of Hematology/Oncology, Pediatrics (Chan), The 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), Faculty of Medicine, and the
Division of Clinical Public Health, Dalla Lana School of Public Health (Dimaras), University of
Toronto, Toronto, Ontario, Canada Department of Ophthalmology and Vision Science,
University of British Columbia, Vancouver, British Columbia, 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
Early Delivery of Children at Risk for Retinoblastoma
Key Words: prenatal retinoblastoma, retinoblastoma gene mutation, RB1, molecular testing,
late pre-term delivery, near-term delivery, amniocentesis
2
Early Delivery of Children at Risk for Retinoblastoma
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.
3
Early Delivery of Children at Risk for Retinoblastoma
Abstract (341/350 words)
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 late
preterm or early term delivery (36 or 37-38 weeks gestation, respectively). 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.
4
Early Delivery of Children at Risk for Retinoblastoma
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.
Infants in both Cohorts eventually developed tumors in both eyes. Useful vision (better
than 0.1, legal blindness) was achieved for 78% (7/9) of Cohort 1 compared to 100%
(12/12) of Cohort 2 (p<0.02). At first eye tumor diagnosis, 11% (1/9) of Cohort 1 had
both eyes Group A (smallest and least vision-threatening tumors) compared to 67%
(8/12) of Cohort 2 (p<0.01). Eye salvageTreatment success (defined as avoidance of
enucleation and external beam irradiation) was achieved in 33% (3/9) patientss, or 6/18
eyes? But manuscript says per eye calculations are /17?) of Cohort 1 compared to
9792% (x11/12) patients or y/24?) of Cohort 2 (p<0.002). There were no complications
related to preterm delivery.
CONCLUSIONS AND RELEVANCE For expectant parents with a history of
retinoblastoma, prenatal molecular diagnosis with late preterm/near-term delivery
increases the likelihood of infants 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.
5
Early Delivery of Children at Risk for Retinoblastoma
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
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
6
Early Delivery of Children at Risk for Retinoblastoma
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
hypothesized that retinoblastoma tumors would be smaller and easier to treat, the earlier they are
diagnosed.
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
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 active 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
7
Early Delivery of Children at Risk for Retinoblastoma
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 overall visual acuity worse than 0.1.
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
8
Early Delivery of Children at Risk for Retinoblastoma
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 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).
At first tumor per child and per eye, children with null mutations (mean 59, median 20 days) tended
to be younger than those with low penetrance mutations (mean 107, median 119 days) (Figure 2a).
Classification of Eyes at Birth
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
9
Early Delivery of Children at Risk for Retinoblastoma
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 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 IIRC18 A eyes (tumors are < 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 (Cohort 1 patient) and presented at age of 3
months (child #8).
Treatment Course
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
10
Early Delivery of Children at Risk for Retinoblastoma
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
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% (4/9) of Cohort 1 and 92% (11/12) of Cohort 2 patients (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 histopathologic features24-26 in
the enucleated eye and is still under active systemic treatment. All children are presently alive.
Children were legally blind (visual acuity less than 0.1 (20/200) using both eyes) in 22% (2/9) 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% (9/18) of eyes in Cohort 1 and 92% (22/24) 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.
Combined tTreatment 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
11
Early Delivery of Children at Risk for Retinoblastoma
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 elective early term or late preterm delivery of infants with
prenatal molecular confirmation of familial retinoblastoma. 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 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).
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.3,10,27 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 (not shown) 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
12
Early Delivery of Children at Risk for Retinoblastoma
identification of the children, who are not at risk and require no clinical intervention, costs significantly
less than clinical screening for tumors.19,28
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.5,29-32 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 perimacular 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,33 or administer a single agent carboplatin
chemotherapy.29 However, reduced doses carry risk of selecting for multidrug resistance in the tumor
cells, making later recurrences difficult to treat.34-36 Periocular topotecan for treatment of small-volume
retinoblastoma37 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;. Oand 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
13
Early Delivery of Children at Risk for Retinoblastoma
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.7,38 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%).39,40 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.
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.41 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).
14
Early Delivery of Children at Risk for Retinoblastoma
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.42 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,43 and
in the other, 2 of 5 tested fetuses of a mosaic proband were born without the parental mutation.44
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.
Acknowledgements
We acknowledge Ivana Ristevski for construction of some of the figures.
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,
15
Early Delivery of Children at Risk for Retinoblastoma
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
16
Early Delivery of Children at Risk for Retinoblastoma
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20
Early Delivery of Children at Risk for Retinoblastoma
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 mutation0 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
21
Early Delivery of Children at Risk for Retinoblastoma
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 valueTumor(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%
22
Early Delivery of Children at Risk for Retinoblastoma
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.
23
Early Delivery of Children at Risk for Retinoblastoma
Figure 2: a, Comparison of birth age at diagnosis of first tumor in each eye, for
children with low penetrance versus 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).
24
Early Delivery of Children at Risk for Retinoblastoma
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 = 0.0313248065403924
Gestational age (weeks)
Visu
al A
cuity
(dec
imal
)
25