· web viewword count: 3262 /3000 words . numbers of figures and tables: 3 figures and 2 tables....
TRANSCRIPT
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
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
)